UNSC Marine Expeditionary Reconnaissance

This fanfiction article, UNSC Marine Expeditionary Reconnaissance, was written by RelentlessRecusant. Please do not edit this fiction without the writer's permission.

Myrmidon Program ("SPARTAN Detachment IV")
Unit information
Type	Advanced Special Operations Forces
Government	United Nations Space Command
Branch	UNSC Special Operations Command UNSC Office of Naval Intelligence
Part of	UNSC Naval Special Warfare Command UNSC Progressive Warfare Command UNSC Directorate of Strategic Intelligence UNSC Department of Covert Operations UNSC Department of Biological Warfare
Role	Advanced special operations Direct action Counterterrorism Counterproliferation Counterinsurgency Special reconnaissance Foreign internal defense Civil-military operations Unconventional warfare
Alternate names	SPARTAN Detachment IV Task Force Myrmidon UNSC Special Combatant Component
Nickname	"M-boys"
Organization
Garrison	Asphodel Meadows (2578-2590) Midgard (2590—2594) Dashan (2600-2604)
Subordinate Units	1st Commando Battalion Myrmidon Squadron ALPHA ("A") Myrmidon Squadron BRAVO ("B") Myrmidon Squadron CHARLIE ("C") Myrmidon Squadron DELTA ("D") 2nd Commando Battalion
Personnel information
Commander	Admiral Kawika Son (2578-2596) Vice Admiral Carter (2597-2606)
Historical information
Active	Insurrection on Dashan Beyond Veil's Azure Crisis Dashan Crisis
Engagements	Midgard Campaign (2590—2594) Beyond Veil's Azure Campaign (2594-2596) Dashan Campaign (2600—2604) Galactic War (2604—2606) Battle of Sanctuary (2606)
Current Status	Active (Galactic Era)

[Source]

"It’s a new world. New SPARTANs for a changing time."

―Admiral Kawika Son, Commander-in-Chief, UNSC Naval Special Warfare Command

UNSC Marine Expeditionary Reconnaissance was a special operations capability developed by the Marine Special Operations Command and the Office of Naval Intelligence. Formulated by Beah Schore and Kawika Son, it was initiated in 2560 and certified as Special Operations Capable in 2570. Known more colloquially as the "Myrmidons", in homage to the preceding SPARTANs, Marine Expeditionary Reconnaissance forces provided deep reconnaissance, direct action, and counterterrorism capabilities to the Marine Corps at the Echelon Above Fleet Marine Force level.

Generally acknowledged as the futuristic successors of the highly-successful SPARTAN-IIs, the SPARTAN-IIIs (the UNSC Naval Special Commando Unit), and the High Priority Assassination Program, the Myrmidons were enhanced by bioinformatically-guided eugenics, highly advanced chemical augmentations, embryonic augmentations, and next-generation weaponry. Heavy usage of a modern understanding of bioinformatics and human genetics, chemical biology, and developmental biology imbued the Myrmidons with the cutting edge of human fitness, with substantially enhanced physical and mental capabilities that exceeded those of their predecessors. In this manner, the UNSC Special Operations Command sought to develop futuristic Special Forces that would enable humanity's survival in an evolving, demanding, and ever more hostile galaxy.

Overview

Master Chief Petty Officer Kimberly Ivy Blackburn—the product of eugenics and chemical biology—was the proof of principle that inspired the Myrmidon Program.

The unofficial unit insignia adopted by the Myrmidons.

"It’s all changed. No more mass deployments, no more accelerating training and augmentation protocols. We took two decades to step back, to rethink everything. The UNSC is in good waters now. There is no more war. We took two decades, redrew the thinking board. The new SPARTANs—the Myrmidons—are different. A single company of soldiers, counterterrorism and defense only. The best of the best. Combinatorial chemical biology, chemical genetics, and specific chemical embryonic teratogenesis and postnatal enhancement. All chemical augmentations, no biological augmentations."

―Rear Admiral Kawika Son addressing SPARTAN-G006 and SPARTAN-G294 in 2578

The Myrmidon Detachment was a cooperative initiative jointly sponsored by the UNSC Office of Naval Intelligence and the UNSC Special Operations Command. Its precedent was Kimberly Ivy Blackburn, the product of a Naval Intelligence special access program that conclusively demonstrated that bioinformatics, eugenics, chemical biology, and developmental biology were potent tools to change physical and mental attributes of human beings: through small molecules and selection of certain genetic attributes, it was possible to successively reduce genetic susceptibility to disease, and to potently increase favorable attributes in humans — intelligence, strength, endurance, and other properties. This initially-controversial paradigm, known as "human synthesis", later became very lucrative to the UNSC Special Operations Command during its search to devise a supersoldier program to succeed that of the SPARTANs.

Circa 2578, Rear Admiral Kawika Son of the Naval Special Warfare Command and Beah Schore of the Harvard Stem Cell Institute would re-examine the usage of eugenics and chemical augmenters to enhance human physical and mental fitness once again: their resultant protocols, extremely time-consuming and intensive, were suitable only to augment an extremely small number of individuals — however, the resultant individuals were projected to have remarkable physical and mental capabilities. Their ideas were put into practice in 2580, when the first generation of second-epoch child soldiers, the Myrmidons, would be borne. The Myrmidons were the second conceptual succession of the SPARTAN paradigm, the epitome of mankind's technologies and strategic doctrines in the Post-War Era. However, because the conceptual advances and core values of the fourth-generation Myrmidons were so striking different from the preceding three SPARTAN programs, instead of merely being labeled "SPARTAN-IVs", the Office of Naval Intelligence would name these fourth-generation soldiers as "Myrmidons", in honor of the Myrmidons of Greek mythology, another Greek warfighting tribe similar to the Spartans in ancient times.

The Myrmidon initiative drew from nearly one century of SPARTAN warfare (the SPARTAN-Is had their genesis in 2491) and lessons learned from all three previous SPARTAN battalions. The Myrmidons, their creation the product of seven hundred years of research into chemistry and human biology — coupled with next-generation weapons and armor, as well as novel tactical doctrines — would take the place of the SPARTANs of old as the au courant and most formidable special forces of the UNSC.

The eugenics, bioinformatics, developmental biology, and chemical biology necessary to impart the exceptional physical and mental fitness of the Myrmidons was undertaken by the UNSC Department of Biological Warfare of the Office of Naval Intelligence. Subsequently, when they emerged from their training and were certified as combat-ready, they were placed under the jurisdiction of the UNSC Department of Covert Operations of the Directorate of Strategic Intelligence, which was the ONI division responsible for Naval Intelligence's classified special activities units, and the UNSC Progressive Warfare Command, which was the SOCOM division for the Special Operations Command's special-missions units.

The Myrmidon Program as a whole was under the jurisdiction of the UNSC Naval Special Warfare Command, which was subordinated underneath the UNSC Navy, the UNSC Special Operations Command, and the UNSC Office of Naval Intelligence.

Casus genesis

The Myrmidons were created in order to combat the newest threats to the UNSC—not massive wars but rather, terrorists and guerillas who threatened the prosperity of human citizens.

Myrmidons storm a fortified enemy position by fast-roping from overhead helicopters.

A Myrmidon sharpshooter wields a suppressed sidearm at close quarters.

"All of my life I have despised the UNSC for its readiness to use child soldiers and its tacit disregard for human life, and now I had the opportunity to influence its next generation of killers, to paint them in my own colors."

―Lieutenant Commander Simon-G294, commenting on the irony of his involvement as a Myrmidon instructor

The causation of the formation of the Myrmidons, their casus genesis, lay simply in the state of galactic affairs.

At the time of the nucleation and formation of the Myrmidons, it was the late 2570s — in the nearly three decades that had passed since 2552 and the closure of the Human-Covenant War, the state of the UNSC and mankind had substantially changed after the Great War. Although the UNSC's military forces would continue to resume their force projection during the Vector Era, galactic affairs and the balance of galactic power were no longer dependent on massive militaries or threatening fleets.

"Terrorists. Insurrectionists."

―Chief Petty Officer August Plummer's first thoughts of the UNSC colony world Hekate, in 2570

By the 2570s, the truce between the UNSC and the reformed Covenant was strong, and the two galactic superpowers were bound together by cords of fealty, with strong political and commercial collaboration between the two massive governments. The threat to the UNSC was no longer posed by the Covenant; it was now internal, with domestic threats at home consisting of organized rebel movements, religious fanatics, and savage criminals and murders within the UNSC's very colony worlds.

In the 20^th century, it had been shown that massive landborne armies were incapable of combating terrorism, and it was shown again in the 27^th that the stentorian and supermassive UNSC Army and UNSC Marine Corps were incapably equipped to wage mankind's campaign against terrorism. The skills, technology, and tactics necessary to wage a global war such as the Human-Covenant War were far different than the specialized skills, technology, and stratagems to defeat the UNSC's infestation of terrorism on its very own colonies, such as Hekate.
In response, the UNSC Special Operations Command became mankind's foremost champion in stamping out terrorism — the training and usage of specially-trained and specially-armed Special Forces who operated in small numbers to specifically prosecute and cauterize terrorist, pirate, and criminal threats with minimal collateral damage. The Myrmidon Program initiated and visualized by Kawika Son and Beah Schore in the midst of these turbulent times for humanity were intended to achieve the same goals: instead of waging galactic wars like their SPARTAN predecessors, small numbers of extremely-augmented and well-trained Myrmidons would be raised to defend humanity from the insidious threat of terrorism and bloody revolt. The extremely intensive resources, training, and time required to breed, augment, train, and equip the Myrmidons made it prohibitive to generate large numbers of them: and the Special Operations Command and the Office of Naval Intelligence only required a small number of commandoes to prosecute terrorists. Therefore, the Myrmidons and the initiatives of the Special Forces and Naval Intelligence went hand-in-hand.

Ancillary to this paradigm, the first generation of the Myrmidon Program, under Kawika Son's and Beah Schore's leadership, would only consist of one hundred Myrmidon child soldiers ("1 Commando"), who were born in 2580. Ironically, it was only when the UNSC wanted to wage a galactic war (a supposedly "short and victorious" war to overthrow the Covenant for once and for all), that the Myrmidon Program in 2594, under Carter, would make the second class of Myrmidons nine hundred children strong, generating nine hundred remarkable commandoes ("2 Commando") for the UNSC's intended conquest of the galaxy, which was the initially-victorious Galactic War of the Galactic Era.

Organization

File:Myrmidons on Dashan2.jpg

Myrmidons of 1^st Commando Battalion, Special Operations Task Force Myrmidon were on deployment with Joint Task Force 11 of Combined Joint Special Operations Task Force Dashan from between 2600-2604. Dashan would be the first ever deployment since the Beyond Veil's Azure Crisis (2594-2596) on which the Myrmidons would sustain casualties.

The Myrmidon Program, as a collaboration between five departments (Biological Warfare, Strategic Intelligence, Covert Operations, Progressive Warfare Command, and Naval Special Warfare Command) across three uniformed services (UNSC Navy, UNSC Special Operations Command, and the UNSC Office of Naval Intelligence), had a highly atypical and amorphous command structure and internal organization.

Asset Development Program (2580—2590)

The initiative, as previously stated, was founded by Kawika Son and Beah Schore — however, Schore, a civilian chemical biologist at the Harvard Stem Cell Institute, would largely only have a theoretical influence over the Myrmidons.

Rear Admiral Son would largely take responsibility for the Myrmidons after their formation, and became accountable and responsible for them: in this regard, he would become the senior commander of the Myrmidon Detachment. In the ten years between their birth (2580) and their initial deployment (2590), the Myrmidons would largely be known as the "Asset Development Program", a special access program of the UNSC Department of Biological Warfare (colloquially known as the "Myrmidon Program"). The moniker "Asset Development Program" was adopted, as the Myrmidons were not yet an operational military unit; the Myrmidon Program, besides the one hundred initial Myrmidon children, would be supplemented by the Training Detachment, who would foster and train the child soldiers during their first formative ten years, and the unit would be supported by divisions of the Department of Biological Warfare, which would continue their postnatal regimen of chemical augmentations and ensure that their physical and mental fitness was been enhanced as anticipated.

Special Operations Task Force Myrmidon (2590—2606)

Two Myrmidons of the 1^st Commando Battalion converse briefly while on deployment at Bifröst—fully replete in RACE combat exoskeletons but with raised visors.

In 2590, the first class of Myrmidons, one hundred strong, would graduate from their training program and would begin active field deployment as part of Special Operations Task Force Myrmidon (TF Myrmidon), which was their formal designation within the UNSC Special Operations Command. Because one of the major design philosophies of the Myrmidons was counterterrorism (the usage of a small number of highly-trained elite light infantry for highly-intensive counterterror and counterinsurgency operations), the Myrmidons as of 2590 maintained only one company of infantry, numbering approximately one hundred strong. While this was an extremely small number of operators for any conventional special forces group, it was in accordance with the UNSC's need for a covert and specialized counterterrorism task force.

Special Operations Task Force Myrmidon would have three elements: the Myrmidon warriors themselves (known as the "Mobility Detachment" or as "1 Commando"), and two other divisions: the Myrmidons would be directed by a Command Detachment and would receive support by a dedicated Support Detachment.

Task Force Myrmidon was also amalgamated into larger command structures upon certain circumstances: during the Midgard Campaign (2590-2904), a Myrmidon detachment would become attached to Task Force 51, an elite UNSC counterterrorism division. Later, during the Dashan Campaign (2600-2604), the first-generation Myrmidons would also become attached to Joint Task Force 11/Combined Joint Special Operations Task Force Dashan, a newly-activated UNSC counterterrorism unit.

The second-generation Myrmidons of the 2^nd Commando Battalion, upon their graduation, would later be attached to Joint Task Force Anaconda of the Directorate of Strategic Intelligence during the Galactic War: the invasion of the Covenant.

Command Detachment, Special Operations Task Force Myrmidon

Vice Admiral Carter, Director of Strategic Intelligence and Commander of Joint Task Force Anaconda, would assume command of Special Operations Task Force Myrmidon in 2600.

"In this unit, it appears that there's a concept amongst the brass that when an officer comes up with an idea for a mission, they deserve as much credit as the operators who actually do the fighting."

―Master Chief Petty Officer Karen-M013, after an extended deployment on Bifröst

"While having one’s teammates turn on someone is bad, if the officers noticed you fucked up, the results are notably worse."

―Petty Officer 2^nd Class Redmond-M094, during training exercises

The Command Detachment, otherwise known as the "Headquarters & Headquarter Company" (HHC) of Special Operations Task Force Myrmidon was accountable for the training, oversight, direction, and operation of the entire Myrmidon unit as a whole, including its command, mobility, and support elements. The command staff of the Myrmidons were largely comprised of officers from the UNSC Naval Special Warfare Command, the UNSC Office of Naval Intelligence, and the UNSC Department of Biological Warfare. The staff of the Command Detachment, as with most military staffs, encompassed a handful of imperative functions: Personnel (N-1), Operations (N-3), Plans (N-5), Information Operations (N-7), Finance (N-8), and Civil Affairs (N-9). The remaining key functions were entrusted to the Support Detachment.

The importance of the Myrmidons and their assignments ensured that the ONI Department of Counterintelligence would have heavy counter-intelligence and counter-espionage activities around the Myrmidon command staff to ensure operational security.

The commander of the Myrmidon Command Detachment was the senior commander of the entire Myrmidon Program—this would be the title of "Senior Commander, Special Operations Task Force Myrmidon", and would be a flag officer-rating command.

The first commander of the Myrmidon Detachment was Rear Admiral Kawika Son, an officer of the UNSC Naval Special Warfare Command and a flag officer of the UNSC Navy, and he would assume command in 2578. By the time that Son retired from the UNSC Defense Force in 2600, several years after the closure of the devastating Beyond Veil's Azure crisis, he would hold the rank of Admiral and would serve as the Commander-in-Chief of the UNSC Naval Special Warfare Command.

He would be succeeded by Vice Admiral Carter, Director of Strategic Intelligence of the UNSC Office of Naval Intelligence, in 2600. Carter would become triply-hatted as the Commander of the Directorate of Strategic Intelligence, Commander of Joint Task Force Anaconda, and as the Senior Commander of Special Operations Task Force Myrmidon.

During the commissioning of Special Operations Task Force Myrmidons, many officers and soldiers of the Special Operations Command would be recruited to populate the Command Detachment—in 2590, Kawika would achieve the rank of Vice Admiral. The executive officer would be Rear Admiral Evelyn Lake, formerly of the Directorate of Fleet Intelligence. The chiefs of operations would be Rear Admiral Chandler Danial and Rear Admiral Randall Hayes, both flag officers of the UNSC Naval Special Warfare Command. The deputy chief of operations would be Commander Cassidy-G044, and the assistant chief of operations would be Senior Chief Petty Officer "Apollo" 2994. Master Chief Petty Officer Whitney-G179 would serve as the noncommissioned officer-in-charge of Task Force Myrmidon.

Beah Schore and Kimberly Ivy Blackburn, both at the Harvard Stem Cell Institute, would consult for the command staff of the Myrmidons.

Mobility Detachment, Special Operations Task Force Myrmidon

"Enemy presence substantial—send Myrmidons."

―Captain Raphael-M064 requesting reinforcements from Admiral Douglas A. Davidson, shortly before his death in the Battle of Hotel California

The actual cohort of Myrmidon child soldiers would be known as the "Mobility Detachment" within Task Force Myrmidon. The first batch of Myrmidons, numbering one hundred strong, would graduate in 2590 and would be deployed as the 1^st Commando Battalion. The second batch of Myrmidons, numbering nine hundred strong, would graduate in 2604 and would form the 2^nd Commando Battalion. The Myrmidon child soldiers were the heart of Task Force Myrmidon—they were responsible for prosecuting the unit's special warfare missions in the field.

The disparate sizes of the "1 Commando" and the "2 Commando" would dictate that they have different command structures and organizations.

1^st Commando Battalion (2590—2606)

The Order of Battle for the first-generation Myrmidon Mobility Detachment, 1^st Commando Battalion.

"What else is there to do?"

―Petty Officer 2^nd Class Redmond-M094 unsuccessfully attempting to comprehend life outside the military after a discussion with Kimberly Ivy Blackburn

The first-generation Mobility Detachment (1 Commando) would be commanded by a Navy Captain (CAPT, O-6), the company commander, and would have a Master Chief Petty Officer (MCPO, E-9) who would serve as the unit's noncommissioned officer-in-charge (NCOIC). Upon the initial embarkment of the Mobility Detachment in 2590, Captain Raphael-M064 would serve as the Unit Commander, and Master Chief Petty Officer Karen-M013 would serve as the Noncommissioned Officer-in-Charge. After Raphael-M064 was killed in the Battle of Hotel California on Dashan in 2604, Commander Caroline-M063 would assume command over the unit.

The hundred-odd company was divided into four operational squadrons (A—D): Myrmidon Squadron ALPHA ("A"), Myrmidon Squadron BRAVO ("B"), Myrmidon Squadron CHARLIE ("C"), and Myrmidon Squadron DELTA ("D"). Each squadron was comprised of between twenty to thirty operators. The operational squadron was the fundamental deployment unit of the Myrmidons; typically, Myrmidons units were deployed to their respective sector of operations in the squadron-size formation, which each sector covering several hundred square light-years of UNSC territory.

Each operational squadron was under the core leadership of a Navy Commander (CMDR, O-5) and the squadron's senior enlisted, a Chief Petty Officer (CPO, E-7). The O-5 would serve as the squadron's commanding officer (CO) and the E-7 would serve as the squadron chief. Additional leadership was provided by two more officers: a squadron executive officer (XO), typically a Navy Lieutenant (LT, O-3), and a squadron operations officer, typically a Lieutenant, Jr. Grade (LTJG, O-2). The remaining fifteen to twenty-five operators were all enlisted, special warfare specialists that were either a Petty Officer Third Class (PO3, E-4), a Petty Officer Second Class (PO4, E-5), or a Petty Officer First Class (PO1, E-6), although there were a few exceptions.

Each squadron was intended to be a core operating unit of the Myrmidons—the several dozen members of each squadron would represent diverse special warfare skills, highly capable of prosecuting counterterrorism and counterinsurgency within their respective Sectors, which typically included a handful of UNSC colony worlds. In the eventuality of open warfare, such as the Beyond Veil's Azure Crisis, each squadron was properly outfitted to independently carry out direct action and special reconnaissance missions across an entire global theater of operations.

All four Myrmidon squadrons were "direct action" capable, that is, that they fulfilled elite counterterrorism and counterinsurgency roles within the UNSC Special Operations Command, practicing even advanced special operations such as in extremis hostage rescue. However, all squadrons carried a secondary certification to further augment the infantry company as a whole. Myrmidon Squadron ALPHA ("A") and Myrmidon Squadron BRAVO ("B") were specially certified for airborne assault, Myrmidon Squadron CHARLIE ("C") was specially certified for dedicated reconnaissance roles, and Myrmidon Squadron DELTA ("D") was specially certified for covert action.

Beneath the squadron-level formation, their hierarchical organization was not formally defined; instead, sub-squadron units were formed to meet specific mission requirements. While the majority of missions required either individual Myrmidons solo or a Myrmidon fire team (two-three operators), larger missions employed Myrmidon squads (four-six operators) or whole Myrmidon troops (eight-twelve operators). However, according to the official Table of Organization & Equipment (TO&E) of the Myrmidon detachment, Myrmidons were assigned to assault teams that consisted of either three or four operators—the number of operators needed for a close-gun assault for one room in a hostage situation.

A single counterterrorism or counterinsurgency operation, no matter on what scale, almost never could employ an entire squadron in the field — however, should open warfare arise that would require the firepower and manpower of an entire twenty- or thirty-man Myrmidon Squadron, regular squadron-integration exercises were continually scheduled so that the entire squadron or even the entire company could operate as a single cohesive unit.

2^nd Commando Battalion (2604—2606)

Second-generation Myrmidons of the 2^nd Commando Battalion perform a breaching maneuver, engaging soldiers of the Galactic Resistance.

The second-generation Myrmidons, borne in 2594, would graduate in 2604, immediately after the disastrous Battle of Hotel California of the Dashan Campaign. Nine hundred operators strong, the "2 Commando" was finally a "battalion" in the true sense of the word, unlike the vastly-undermanned 1 Commando.

The 2^nd Commando Battalion, commonly known as the Myrmidon Special Operations Battalion or as the UNSC Special Combatant Component amongst the UNSC Office of Naval Intelligence, was commanded by a full Navy Captain (CAPT, O-6), with a Command Master Chief Petty Officer (CMDCM, E-9) serving as the senior unit advisor.

The novel battalion would be comprised, in its entirety, of nine full maneuver companies, each approximately one hundred strong and named based on a modified variation of the NATO Phonetic Alphabet based on where the four first Myrmidon squadrons had left off (with "D" Squadron, Delta). Each company was led by a Navy Commander (CMDR, O-5) and its noncommissioned officer-in-charge would be a Master Chief Petty Officer (MCPO, E-9). The nine maneuver companies (E—M) were named as follows: ECHO Company ("E"), FOXTROT Company ("F"), GHOST Company ("G"), HOTEL Company ("H"), INDIGO Company ("I"), JOKER Company ("J"), KILO Company ("K"), LEOPARD Company ("L"), and MAKO Company ("M").

Each maneuver company would be comprised of three rifle platoons, each approximately thirty- to forty-operators strong. Each platoon would be commanded by a Lieutenant Commander (LCDR, O-4) and would have a platoon chief, a Senior Chief Petty Officer (SCPO, E-8).

Each rifle platoon would be comprised of three or four operational squadrons ("squads"), each led by a full Navy Lieutenant (LT, O-3) as a commanding officer, a Lieutenant Junior Grade (LTJG, O-2) as an assistant commander, and a Chief Petty Officer (CPO, E-7) as a squad chief. Each squadron, typically composed of approximately ten Myrmidons, would be divided into three fire teams: one four-man team led by the Lieutenant, one three-man team led by the Lieutenant Junior Grade, and one three-man team led by the Chief Petty Officer.

The Table of Organization & Equipment (TO&E) for the 2^nd Commando Battalion appeared to be far "stricter" than that of the 1 Commando, with extremely rigidly-set companies, platoons, squadrons, and fire-teams of designated numbers. This largely reflected the purpose of the 2 Commando—unlike their first-generation comrades, the second generation had been bred by the Directorate of Strategic Intelligence for a singular purpose: to act as shock troops for the UNSC's impeding surprise invasion of the Covenant, known as the Galactic War. Therefore, their Order of Battle depicted the ordered and regimented units in which the second-generation Myrmidons would stalwartly march into battle against the Covenant.

Support Detachment, Special Operations Task Force Myrmidon

The Order of Battle (OB) for the Myrmidon Support Detachment.

The Myrmidon Support Detachment was an integral component of the Myrmidon Detachment, typically commanded by a Marine Corps Colonel (COL, O-6).

The Myrmidon operators were extensively supported on all levels; the individual level, the team level, the squadron level, and the company level. The unit, with its high operations tempo (OPTEMPO), invariably required extensive auxiliary support to continue sustained operations. The Support Detachment was comprised of a Special Operations Air Wing, a Logistical Detachment, an Intelligence Detachment, a Training Detachment, a Communications Detachment, and a Medical Detachment.

The Special Operations Air Wing (SOAW) was responsible for operating attack and transport aviation assets in support of the Myrmidons, and was comprised of elite pilots, technicians, and ground crews from the UNSC Army's Reconnaissance Aviation Expeditionary Force (RAVEN) and also elite UNSC Navy squadrons. The Air Wing was directed by a Navy Captain (CAPT, O-6) from the naval starfighter community.

The Logistical Detachment was responsible for the continued resupply and rearmament of the Myrmidons, and was integral to the sustained deployment of the Myrmidons across the myriad battlefields of the Milky Way Galaxy; it was commanded by a Marine Corps Lieutenant Colonel (LTCOL, O-5).

The Myrmidon unit operated its own independent Intelligence Detachment; on most operations, the Myrmidons received extensive intelligence support. The Myrmidon Intelligence Detachment was strongly affiliated with the UNSC Office of Naval Intelligence, with high-confidence ONI intelligence supporting most Myrmidon field actions. The intelligence section was led by an ONI Commander (CMDR, O-5).

The Myrmidon Training Detachment, based on Asphodel Meadows, was commanded by a Navy Commander (CMDR, O-5). Lieutenant Commander Simon-G294 would serve as the Executive Officer of the Training Detachment during the training of the Myrmidons on Asphodel Meadows in the 2580s.

The Myrmidon Communications Detachment, responsible for long-range cohesive integration of the Myrmidons on a galactic scale as well as fielding short-range planetary and regional communications for Myrmidon field units, was commanded by a Marine Corps Major (MAJ, O-4).

The Myrmidons also operated their own independent clinical unit, the Medical Detachment, which was affiliated with the UNSC Medical Corps and was directed by a Navy Lieutenant Commander (LCDR, O-4).

Chemical Augmentations

Introduction to Chemical Biology

The conceptual paradigm for the Myrmidon chemical augmentation initiative, (1) high throughput screening (drug discovery), (2) development of bioactive compounds, and (3) embryonic, physiological, and psychological augmentation.

A pie chart depicting the biological pathways enriched for perturbation by the entire augmentative small molecule collection. Several pathways, such as Wnt (10), MAPK/ERK (4), and Dopamine (4), are notably enriched.

A pie chart depicting the target organ systems of the entire augmentative small molecule collection. Several systems, such as embryonic stem cell (18) and nervous system (16), are notably enriched for perturbation.

"We took twenty years to step back, rethink everything. To change all the augmentations from biological to small-molecule chemical compounds, with augmentations specifically tailored to each child. The entire Myrmidon objectives, core fundamentals, all different. It’s a new world. New SPARTANs for a changing time."

―Rear Admiral Kawika Son, 2578

Novel chemical augmentations were one of the foremost goals of the Myrmidon philosophy. Championed by the chemical biologist Beah Schore, the augmentation program of the Myrmidons sought to be the first-ever entirely-chemical augmentation program, with exclusively small-molecule chemical compounds used to augment both the physical and mental attributes of the Myrmidons.

• Exclusive chemical augmentation: The Myrmidon augmentation program was the first military augmentation program ever to exclusively use small-molecule chemical compounds ("drugs") in the augmentation procedure. While the preceding SPARTAN generations were augmented through a combination of techniques such as high-risk surgeries as well as recombinant proteins, these "biological" effectors were highly discouraged. Surgeries were highly risky, intensive, required special medical talent, and their safety and effects varied substantially from subject to subject, with the benefits and risks varying with the surgeon, the surgical conditions, and the state of the patient. Furthermore, open surgeries were notoriously risky. Other biological augmentations, such as the mutagenic psychoactive proteins employed with the SPARTAN-IIIs of Gamma Company, were similarly disadvantageous because of the in vivo bioavailability of the proteins as well as substantial batch-to-batch variations in the recombinant proteins during manufacturing.

Small molecule augmentations (a "purely chemical" approach) were more advantageous for a number of reasons:

• Small molecules are widely bioavailable, showing strong distribution and circulation into target tissues
• Small molecules provide potent control over specific biological targets
• Small molecules provide rapid temporal control over biological systems
• Small molecules show dose-controllable control over biological systems
• Small molecules may provide favorable phenotypes by modulation of a specific target or by modulation of multiple targets
• Small molecules are technically easy to produce, are cheap, and show no batch-to-batch variation
• The combinatorial effects of multiple small molecules exerting differential effects over biological systems ("combination chemical genetics") is mathematically simplistic to model and to mathematically understand the effects of drug augmentation

Therefore, the purely chemical augmentation of the Myrmidons provided substantial advantages over "biological" methods of augmentation such as surgeries, recombinant proteins, or viral genetic-delivery vectors.

• Embryonic augmentation: Previous SPARTAN biological augmentations were restricted in their utility because the augmentations were performed only in adult stages of life. However, Kimberly Ivy Blackburn was a precedent that showed that biochemical modification during embryonic development within the womb could result in augmentations with a dramatically expanded potency; augmentations that modified embryonic development resulted in far more profound changes in physiological and psychological function. However, an exceptional understanding of human developmental biology, based on previous studies of mammalian and invertebrate developmental biology, revealed core signaling pathways that controlled differentiation and tissue specification during development — coupled with chemical biology methods to chemically perturb these select signaling pathways, this allowed for small molecule modification of development to enhance select tissues during development. This allowed for augmentation of the child soldiers even before they were born. Embryonic augumentation had a number of select advantages:

• Embryonic augmentation allows for extensive augmentation even before birth
• Because tissues are still plastic and growing during embryogenesis, embryonic augmentation allows for extensive modification of even the basic shape and function of the human body, whereas adult-only augmentation is restricted in its ability to change body physiology and anatomy
• Embryonic augmentation is painless because of the lack of conscious nociception during development

• Anatomical Augmentation: While many previous SPARTAN programs and their augmentations sought to control the function ("physiology") of bodily tissues, the Myrmidon Program furthermore sought to modify the actual structure ("anatomy") of the human body and thus control its function. This anatomical modification was primarily achieved through chemical control of embryogenesis; directed self-renewal of pluripotent and multipotent stem cells, combined with directed differentiation, led to vastly increased sizes of various tissues, such as the limb, heart, pancreas, etc...
• Physiological Augmentation: Furthermore, the Myrmidon Program sought to modify the adult function of tissues. Compounds were employed to increase physical strength, physical endurance, learning, memory, cognition, and other attributes of the nervous system, musculoskeletal system, and other systems. Even de novo properties, such as organ and limb regeneration, were imparted during this phase of adult augmentation.
• Psychological Augmentation: Both mind and body are integral to warfighting. Therefore, the Myrmidon Program sought to modify the adult mind and psychology as well as anatomy and physiology. Enhanced cognition was a primary target of the Myrmidon Program, with over a dozen compounds imparting increases in learning, memory, attention, reaction time, and executive function. Furthermore, during combat, further psychological modification was performed, with drugs reducing pain and inducing animalistic behavior. The Myrmidon Program believed that combinatorial modification of both bodily physiology and mental psychology would lead to exponential increases in combat potential.

Finally, no less than sixty-two small molecules were chosen to augment the Myrmidon child soldiers throughout all stages of life. These were specific perturbers of human biology at the embryonic, postnatal, and adult stages of life, including both chemical agonists and antagonists to provide quantificable and dose-responsive control over human physiology and psychology with defined desired phenotypic effects and defined off-target side effects. All compounds were real-world compounds originally characterized in the 20^th or 21^th century.

Bioinformatics and chemical informatics were employed to analyze the composition of the small molecule collection and their annotated biological targets and activities to study the biological perturbers. Through target-pathway clustering, it was found that several key pathways were notably enriched for perturbation (see above).

Notably, eighteen percent of all compounds modulated the Wnt signaling pathway, a key signaling pathway in stem cell biology, differentiation, development, and adult homeostasis and regeneration. The second-most enriched pathways were the dopamine pathway and the MAPK/ERK pathway, both targeted by approximately seven percent of the total collection. The dopamine pathway is a monoamine neurotransmitter pathway that plays key roles in cognition, mood, personality, memory, and stem cell biology. The mitogen-activated protein kinase / extracellular signal-regulated kinase (MAPK/ERK) pathway is a key mitogenic pathway integral in both stem cell biology and body growth.

Chemical clustering by target organ system revealed that a full one-third of the collection targeted stem cell systems, mostly embryonic stem cells, demonstrating the actual utility of using small molecules to modulate stem cells for desirable embryonic and adult phenotypes. The second-most enriched target system was the central nervous system and the peripheral nervous system, with nearly thirty percent of the collection modulating nervous activity to generate useful phenotypes such as enhanced cognition and modified psychology and perception.

Summary of Chemical Augmentations

"Remember trainees, alcohol is bad, but consuming performance enhancing drugs without knowing the side effects is perfectly logical."

―Lieutenant Commander SPARTAN-G294 to his trainees

Follows a summary of the general phenotypic effects of the sixty-two drugs and their twenty general major effects used to augment the Myrmidons during various phases of their lives. For details, users should consult the detailed list of compounds that are below.

1. Increased body size
   1. Body size was increased by direct or indirect encouragement of human embryonic stem self-renewal prior to gastrulation (A-83-01, Dorsomorphin, SU5402, PD184352, CHIR99021, Reversine, Y-27632, Pluripotin, Theanine, Flurbiprofen, and Stauprimide)
   2. Body size was increased during adult life through overactivation of the mitogen-activated protein kinase signaling pathway (ZM 336372)
2. Artificially induced puberty during early childhood: Allowed for exponential muscular and skeletal growth during chronologically-prepubescent ages
   1. Puberty was indirectly induced through androgen activation (LGD2226)
   2. Puberty was directly induced through insulin-like growth factor and insulin signaling (Demethylasterriquinone B1), causing substantial increase in skeletal muscle mass and increased density and length of long bones
   3. Increased muscle and bone were generated during embryogenesis by chemical specification of embryonic stem cell differentiation to the mesoderm (BIO-Acetoxime)
3. Increased brain size: May be linked to increased intelligence and sensory perception
   1. Brain size was indirectly increased by chemical specification of embryonic stem cell differentiation to the neuroectoderm (Selegiline and SB-431542)
   2. Brain size was directly increased by chemical encouragement of neural stem cell differentiation to neurons (L-AP4)
4. Increased heart size: Allows for enhanced distribution of oxygenated blood to peripheral tissues and increased athletic capability during extreme stress
   1. Heart size was directly increased by increased specification and proliferation of cardiovascular progenitors during development (SB-216763)
5. Increased hematopoietic cell number: Increased blood supply (increased oxygen), decreased clottting time, and increased immunity to acquired infections
   1. Hematopoietic cell number was directly increased by increased embryonic specification of hematopoietic stem cells and their adult proliferation (LY 171883, SNAP, and 16,16-dimethyl-Prostaglandin E2)
6. Increased pancreas size: Increased capacity for glucose-sensitive insulin secretion and therefore better metabolism and allowance for mobilization of energy stores during times of extreme stress
   1. Pancreas size was indirectly increased by chemical specification of embryonic stem cell differentiation to the definitive endoderm (Cymarin, IDE1, and IDE2)
   2. Pancreas size was directly increased by increased embryonic specification of pancreatic progenitors from the definitive endoderm ((—)-Indolactam V)
   3. Embryonic generation of pancreatic endocrine β-cells were increased at the expense of other pancreatic fates during pancreatic differentiation (All-trans retinoic acid and Trichostatin A)
7. Increased perception: Allows for sharper eyesight, hearing, sense of touch, taste, and smell
   1. Perception was embryonically enhanced by enhanced development of the somatosensory cortex during neurogenesis (Tianeptine)
8. Increased lung size: Allows for better oxygenation of blood and enhances athletic capability
   1. Lung size was indirectly increased by chemical specification of embryonic stem cell differentiation to the definitive endoderm (Cymarin, IDE1, and IDE2)
   2. Lung size was directly increased by chemical augmentation of signaling pathways that direct lung development (PK115-584 and Compound E)
9. Increased leg and arm size
   1. Leg and arm size was directly increased by repression of BMP signaling that represses limb development during embryogenesis (LDN-193189)
10. Physical endurance
    1. Physical endurance was directly increased by reprogramming of myocytes to endurance-sustaining Type II muscle fibers through the AMPK, PPAR, and sirtuin signaling pathways (A-769662, GW01516, SRT1720, and Resveratrol)
11. Increased muscle mass
    1. Muscle mass was directly increased by muscle recruitment of hematopoietic stem cells for muscular regeneration (NP549) and through direct reprogramming of brown adipocytes to myocytes (T0070907)
12. Increased learning and memory
    1. Learning and memory were increased by increased neurogenesis from adult neural stem cell populations ((S)-(-)-Sulpiride, Compound 9, QS11, Neuropathiazol, and TWS119)
    2. Learning and memory were increased by increased long-term potentiation through L-type Ca⁺² channel signaling (FPL 64176)
    3. Learning and memory were increased by increased cholinergic signaling ((S)-(-)-Cotinine)
    4. Learning and memory were increased by indirectly increased dopaminergic signaling through blockade of the dopamine transporter (O-1783)
13. Increased color vision
    1. Color vision and increased visual resolution were directly imparted by sustenance of cone photoreceptor cells during adult life (A-443654)
    2. Vision was indirectly increased by enhanced growth and regeneration of the optic nerve (BPIQ-II)
14. Ability to regenerate limbs and organs
    1. The evolutionarily-lost capability to regenerate organs and limbs was re-imparted through adult re-activation of the canonical Wnt/β-catenin pathway (SB-415286)
15. Increased blood vessels: allows for increased perfusion of tissues with oxygenated blood and increased athletic performance
    1. Blood vessel angiogenesis was directly stimulated by Hedgehog signaling (Hh-Ag1.5)
    2. Blood vessel formation during embryonic life was increased by mitogen-activated protein kinase signaling (ZM 336372)
16. Brain and heart function even during extremely acute injury
    1. Action potentials in neural and cardiac tissues even after acute systemic trauma were maintained by global activation of voltage-gated Na⁺ channels (Batrachotoxin)
17. Increased heartrate and breathing rate
    1. Heart rate, breathing rate, and blood pressure were increased by adrenergic signaling (Dobutamine)
18. Aggressive and violent behavior
    1. Aggressive and violent behavior were artificially induced by blockade of serotoninergic signaling (SB-224289)
    2. Animalistic behavior and decreased higher cognitive function were produced by dopaminergic blockade (Haloperidol)
19. Decreased pain perception
    1. Pain perception was dramatically decreased by withdrawal of trophic support for nociceptive nerves (GW 441756)
    2. Pain perception was indirectly abrogated through irreversible changes in opioid signaling (Fentanyl isothiocyanate)
    3. Pain perception was decreased through sensory alterations produced by cannabinoid signaling (JZL184 and (R)-(+)-WIN 55212)
20. Increased lifespan
    1. Lifespan was increased through neural simulation of caloric restriction (Mianserin)
    2. Lifespan was increased through re-activation of telomerase activity (Cycloastragenol)
    3. Lifespan was increased through abrogation of reactive oxygen species that induce DNA damage and senescence (EUK-134)
    4. Lifespan was increased through activation of the sirtuin pathway and inhibition of insulin-like growth factor-mediated metabolism (Resveratrol and SRT1720)

Manipulation of the human embryo

Chemical augmentation of Myrmidons began at the embryonic stage, with in utero catherization of pregnant women to perfuse developing human embryos with small-molecule compounds to elicit specific effects on human developmental biology.

Phase I: Expansion of pluripotent stem cells

Capture of authentic ground state pluripotency from the human inner cell mass (ICM). Ten chemical compounds promote embryonic stem cell self-renewal and block apoptosis and differentiation (see below) to expand the human pluripotent progenitor cell pool.

Firstly, compounds were employed to inhibit the maturation of the human pluripotent inner cell mass (ICM) to the epiblast, maintaining the "ground state" pluripotency of authentic pluripotent cells in the human inner cell mass. This blockade of embryonic maturation allowed for the continual self-renewal and expansion of human embryonic stem (hES) cells, enlarging the pluripotent progenitor pool and allowing for increased numbers of differentiated cells to be formed in embryonic and adult life, increasing mean body size and organ mass.

In order to employ chemical probes to blockade pluripotent stem cell differentiation and maturation, Beah Schore composed a collection of compounds known to either enhance embryonic stem cell self-renewal or to specifically block the differentiation of embryonic stem cells to certain lineages.

Finally, ten small-molecule compounds were chosen for final employment.

An Activin receptor and Nodal receptor inhibitor, A-83-01 ("A8"), was employed to block stem cell differentiation to the definitive endoderm. A bone morphogenetic protein receptor (BMPR) inhibitor, Dorsomorphin ("DM"), was employed to block stem cell differentiation to the mesodermal lineage. A fibroblast growth factor receptor (FGFR) inhibitor, SU5402 ("S5") and an extracellular signal-regulated kinase (ERK) inhibitor, PD184352 ("P1"), were employed to block stem cell differentiation to both the neuroectodermal and mesodermal lineages. Cells that managed to escape the chemical blockade and begin differentiation were rapidly de-differentiated by a mitogen-activated protein kinase (MAPK) and a nonmuscle myosin II heavy chain inhibitor, Reversine ("RV").

Overexpression of Nanog, a key member of the pluripotent transcriptome, has been shown to render stem cells refractory to differentiation, whereas deficiency of Nanog (Nanog^-/-) has been shown to render pluripotent cells towards differentiation to multiple lineages, including the primitive endoderm. Because β-catenin and canonical Wnt signaling has been shown to increase Nanog expression, a glycogen synthase kinase 3 (GSK3) inhibitor, CHIR99021 ("C9"), was employed to inhibit the global differentiation of pluripotent stem cells.

A p160-Rho-associated coiled-coil kinase (ROCK) inhibitor, Y-27632 ("Y2"), was employed to inhibit the apoptosis of pluripotent stem cells and to enhance their survival.

Finally, three final compounds were chosen to specifically induce the self-renewal of stem cells. These included a Ras GTPase-activating protein (RasGAP) and an extracellular signal-regulated kinase (ERK) inhibitor, Pluripotin ("SC"), and two natural products with uncharacterized biological targets, Theanine ("TN") and Flurbiprofen ("FP").

Thus, in conclusion, combinatorially, these ten compounds potently blocked the maturation of the inner cell mass (ICM) and the loss of pluripotency by blockade of differentiation, enhancement of stem cell survival, and enhancement of stem cell self-renewal.

Chemical expansion of the pluripotent inner cell mass
Chemical Name	Abbreviation	Phenotypic Effect	Biological Target	Mechanism
A-83-01	"A8"	Inhibition of differentiation	TGFβ/Activin Receptors	Repression of endodermal differentiation
Dorsomorphin	"DM"	Inhibition of differentiation	TGFβ/BMP Receptors	Repression of mesodermal differentation
SU5402	"S5"	Inhibition of differentiation	FGFR1	Repression of endodermal and mesodermal differentiation
PD184352	"P1"	Inhibition of differentiation	MAPK/ERK	Repression of endodermal and mesodermal differentiation
CHIR99021	"C9"	Inhibition of differentiation	GSK3	Activation of Wnt signaling and Nanog expression
Reversine	"RV"	Reversal of differentiation	Polypharmacological	De-differentiation of differentiated cells
Y-27632	"Y7"	Inhibition of apoptosis	ROCK	Suppression of chemically-induced apoptosis
Pluripotin	"SC"	Promotion of self-renewal	RasGAP and MAPK/ERK	Long-term renewal of embryonic stem cells
Theanine	"TN"	Promotion of self-renewal	Unknown	Short-term renewal of embryonic stem cells
Flurbiprofen	"FP"	Promotion of self-renewal	COX-2	Short-term renewal of embryonic stem cells

Inhibitors of stem cell differentiation

The chemical structure of A-83-01, a TGFβ/Activin receptor inhibitor.

• A-83-01: Chemical inhibitor of TGFβ/Activin receptors, specifically the activin receptor (ALK4), the TGF-β receptor (ALK5), and the nodal receptor (ALK7)

Chemical Name: 3-(6-Methylpyridin-2-yl)-1-phenylthiocarbamoyl-4-quinolin-4-ylpyrazole

Biological Target: ACVR1B (ALK4), TGFβRI (ALK5), ACVR1C (ALK7)

Biological Activity: Blockade of embryonic stem (ES) cell differentiation to the definitive endoderm, maintaining the pluripotency of human pluripotent stem cells and expanding the pluripotent progenitor pool

Biological Annotation: Activin and Nodal signals of the TGFβ family are responsible for the differentiation of pluripotent stem cells to the definitive endoderm. Suppression of TGFβ signals leads to blockade of endodermal differentiation.

The chemical structure of Dorsomorphin, a TGFβ/BMP receptor inhibitor.

• Dorsomorphin: Chemical inhibitor of TGFβ/BMP receptors, specifically ActRIA (ALK2), BMPRIA (ALK3), and BMPR1B (ALK6)

Chemical Name: 6-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine

Biological Target: ActRIA (ALK2), BMPRIA (ALK3), and BMPR1B (ALK6)

Biological Activity: Blockade of embryonic stem (ES) differentiation to the mesoderm, maintaining the pluripotency of human pluripotent stem cells and expanding the pluripotent progenitor pool

Biological Annotation: Dorsomorphin is a specific inhibitor of ALK2, ALK3, and ALK6, serving to block transmission of BMP signals, specifically BMP-2, BMP-4, BMP6, and BMP-7 and subsequent phosphorylation of SMADs. The requirement of BMP signals in gastrulation for mesodermal specification means that suppression of BMP signaling in the pluripotent inner cell mass leads to repression of the mesodermal lineage.

The chemical structure of SU5402, an FGFR1 inhibitor.

• SU5402: Chemical inhibitor of fibroblast growth factor receptor 1 (FGFR1)

Chemical Name: 3-[(3-(2-carboxyethyl)-4-methylpyrrol-2-yl)methylene]-2-indolinone

Biological Target: FGFR1 (Fibroblast Growth Factor Receptor 1)

Biological Activity: Blockade of embryonic stem cell (ES) differentiation to the endoderm and mesoderm, maintaining the pluripotency of human pluripotent stem cells and expanding the pluripotent progenitor pool

Biological Annotation: Fgfr1 and Fgf4 are extensively implicated in stem cell biology and developmental biology. FGF4, an FGFR1 ligand, activates the ERK pathway in embryonic stem cells and inhibits their self-renewal, instead inducing differentiation to the mesodermal and endodermal lineages. Blockade of FGFR1 by SU5402 leads to repression of differentiation-inducing FGF signaling and reduces the competence of embryonic stem cells to differentiate, instead promoting self-renewal.

Structural Mechanism: Competitively binds to the ATP-binding site on FGFR1 protein, inhibiting kinase activity by competing with ATP. Interacts with FGFR1 trough three separate intermolecular interactions with the kinase domain in a hydrophobic haven, and demonstrates even electron distribution.

The chemical structure of PD184352, a MAPK/ERK inhibitor.

• PD184352: Chemical inhibitor of the MAPK/ERK pathway

Chemical Name: 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one)

Biological Target: Mitogen-activated protein kinase kinase (MKK1)

Biological Activity: Blockade of embryonic stem cell (ES) differentiation to the endoderm and mesoderm, maintaining the pluripotency of human pluripotent stem cells and expanding the pluripotent progenitor pool

Biological Annotation: ERK is phosphorylated upon FGF4 signaling, triggering lineage commitment of embryonic stem cells, and phospho-ERK is indeed required for endodermal or mesodermal differentiation of embryonic stem cells. Inhibition of the MAPK/ERK pathway with PD184352 leads to repression of the autoinductive FGF4 signal, encouraging pluripotency and embryonic stem cell self-renewal.

The chemical structure of CHIR99021, a GSK3 inhibitor.

• CHIR99021: Chemical inhibitor of GSK3β, activator of canonical Wnt signaling and Nanog expression

Chemical Name: 6-(2-(4-(2,4-dichlorophenyl)-5-(4-methyl-1H-imidazol-2-yl)pyrimidin-2-ylamino)ethylamino)nicotinonitrile

Biological Target: Glycogen synthase kinase 3 (GSK3α/β), IC₅₀ = 6.7 nM

Biological Activity: Globally blocks pluripotent stem cell differentiation to all lineages, leading to the maintenance of pluripotency of human pluripotent stem cells and expanding the pluripotent progenitor pool

Biological Annotation: GSK3β is a biological inhibitor of Wnt signaling, and Wnt signaling is implicated in stem cell self-renewal, controlling the embryonic stem cell transcriptome and cell cycle. The role of Wnt signaling in stem cell self-renewal is believed to be through activation of Nanog transcription, and Nanog is a core member of the pluripotency transcriptome, actively suppressing differentiation and safeguarding against loss of pluripotency. GSK3 inhibition and Wnt signaling has been shown to blockade stem cell differentiation and lead to embryonic stem cell self-renewal.

The chemical structure of reversine, a promiscuous chemical inhibitor.

• Reversine: Polypharmacological inhibitor of multiple kinases and receptors

Chemical Name: 2-(4-morpholinoanilino)-N6-cyclohexyladenine

Biological Target: Aurora kinase A, Aurora kinase B, Adenosine receptor A₃, MEK1, and Myosin II Heavy Chain

Biological Activity: De-differentiates differentiating cells, leading to reprogramming of differentiated cells to authentic pluripotent stem cells and maintenance of the pluripotent progenitor pool through indirect inhibition of differentiation

Biological Annotation: Reversine has been shown to de-differentiate myoblasts to a putative multipotent mesenchymal stem cell (MSC)-like intermediate, relaxing lineage specificity and leading to ectopic expression of mesodermal and neuroectodermal transcripts.

Inhibitors of stem cell apoptosis

The chemical structure of Y-27632, a ROCK inhibitor.

• Y-27632: Chemical inhibitor of p160-Rho-associated coiled-coil kinase (ROCK)

Chemical Name: (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide

Biological Target: p160-Rho-associated coiled-coil kinase (ROCK)

Biological Activity: Blocks apoptosis of cells of the pluripotent inner cell mass, leading to increased numbers of pluripotent progenitors

Biological Annotation: ROCK family kinases are responsible for cell cycle regulation and control of apoptosis. Blockade of ROCK signaling through Y-27632 has been shown to improve the survival of dissociated human embryonic stem cells, putatively through the inhibition of chemically-induced apoptosis. Y-27632 is believed to play a similar role in enhancement of the survival of pluripotent human inner cell mass.

Enhancers of stem cell self-renewal

The chemical structure of pluripotin, a dual RasGAP and ERK inhibitor.

• Pluripotin: Polypharmacological inhibitor of both RasGAP and ERK1/2

Chemical Name: N-(3-(7-(1,3-dimethyl-1H-pyrazol-5-ylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide

Biological Target: Ras GTPase-activating protein (RasGAP) and extracellular signal-regulated kinase (ERK)

Biological Activity: Sustains self-renewal of embryonic stem cells, leading to increased numbers of pluripotent progenitors

Biological Annotation: Murine embryonic stem cells spontaneously differentiate, and require both leukemia inhibitory factor (LIF) and murine embryonic fibroblast (MEF) feeder layers to sustain self-renewal. Pluripotin replaces the dual requirement for LIF and feeders, and stem cells cultured in the presence of pluripotin maintain their pluripotency and can be expanded indefinitely in culture in chemically-defined conditions.

The chemical structure of theanine, a natural product.

• Theanine: Natural product derived from Camellia sinensis and Boletus badius

Chemical Name: 2-amino-4-(ethylcarbamoyl)butyric acid

Biological Target: Uncharacterized

Biological Activity: Sustains self-renewal of the human pluripotent inner cell mass, leading to increased numbers of pluripotent progenitors

Biological Annotation: Theanine was identified through a high-throughput screen to maintain short-term pluripotency of human embryonic stem (hES) cells in the absence of FGF2. As theanine has been shown to increase central nervous system (CNS) concentrations of γ-aminobutryic acid (GABA), its role in embryonic stem cell proliferation is contradictory, as it has been shown that autocrine or paracrine GABAergic signnaling in stem cell cultures leads to repression of embryonic stem cell proliferation.

The chemical structure of flurbiprofen, a selective COX-2 inhibitor.

• Flurbiprofen: Chemical inhibitor of cyclooxygenase 2 (COX-2)

Chemical Name: 2-(3-fluoro-4-phenyl-phenyl)propanoic acid

Biological Target: Cyclooxygenase 2 (COX-2)

Biological Activity: Sustains self-renewal of the human pluripotent inner cell mass, leading to increased numbers of pluripotent progenitors

Biological Annotation: Flurbiprofen was identified through a high-throughput screen to maintain short-term pluripotency of human embryonic stem (hES) cells in the absence of FGF2. Although its precise molecular mechanism is unknown, fluribprofen's activity as an anti-inflammatory agent is mediated through inhibition of protein and leukocyte migration, inhibition of prostaglandin synthesis, stabilization of the cell membrane, and activation of mitochondrial ATPase.

Phase II: Chemically-directed differentiation to germ layers

During the first days of embryogenesis, embryonic development was arrested by the ten chemical compounds employed in "Phase I" of the augmentation, producing a vastly-expanded pool of pluripotent progenitors in the human inner cell mass (ICM), increasing the number of embryonic stem cells ready to undergo development, expanding the number of differentiated cells to be possibly developed in development. However, specification of the three primary germ layers (definitive endoderm, mesoderm, and neuroectoderm) was necessary.

Therefore, in the succeeding days, seven small molecules were employed to efficiently differentiate the expanded pluripotent progenitor pool, transitioning them sequentially from the inner cell mass to the patterning epiblast and the primitive streak (mesendoderm), and later, to the three major germ lineages.

Because during the first phase, pluripotent stem cells were potently stimulated to proliferate and self-renew, it was necessary to de-orbit them from their pluripotency program and instead to transition them to a state amenable to differentiation. This was achieved by employing stauprimide ("SP"), an indirect inhibitor of c-myc, therefore decreasing stem cell proliferation and making them receptive to differentiation cues.

Next, either the mesendoderm or the neuroectoderm was established by a simple fate switch; the presence or absence of TGFβ signaling.

Two putative histone deacetylase (HDAC) inhibitors, IDE1 ("I1") and IDE2 ("I2"), were used to indirectly mimic TGFβ/Activin signaling, specifying a mesendodermal fate in a subset of cells, along with the GSK3 inhibitor BIO-Acetoxime ("BA") to stimulate the Wnt pathway, formatively creating the mesendoderm. Cymarin ("CY"), a cardiac glycoside known to induce SOX17 expression in embryonic stem cells, was used ancillarily to specify the definitive endoderm.

The TGFβ/Activin receptor inhibitor SB431542 ("S1") was employed to inhibit Activin signaling in a subset of cells, diverting them from endodermal differentiation and instead specifying the neuroectoderm in the absence of defining signals. This was further confirmed by selegiline ("SE"), a selective MAOA inhibitor previously shown to encourage the development of the neuroectoderm.

Chemical specification of germ lineages
Chemical Name	Abbreviation	Phenotypic Effect	Biological Target	Mechanism
Stauprimide	"SP"	Priming of stem cells for differentiation	NME2	Repression of stem cell proliferation
BIO-Acetoxime	"BA"	Differentiation to mesendoderm	GSK3	Activation of Wnt signaling
Cymarin	"CY"	Differentiation to definitive endoderm	Na+/K+ pump	Molecular mechanisms unknown
IDE1	"I1"	Differentiation to definitive endoderm	Unknown	Activation of SMAD2 phosphorylation
IDE2	"I2"	Differentiation to definitive endoderm	Unknown	Activation of SMAD2 phosphorylation
Selegiline	"SG"	Differentiation to neuroectoderm	MAOA	Molecular mechanisms unknown
SB431542	"S4"	Differentiation to neuroectoderm	TGFβ/Activin receptors	Blockade of endodermal TGFβ signaling

Dysregulation of pluripotent stem cell self-renewal

The chemical structure of stauprimide, an NME2 inhibitor.

• Stauprimide: Chemical inhibitor of NME2 and downregulator of c-myc

Biological Target: NME2 (Nonmetastatic cells, protein expressed in-2)

Biological Activity: Primes pluripotent stem cells for differentiation, enhancing differentiation of the pluripotent inner cell mass to all lineages and increasing the number of differentiated cells produced

Biological Annotation: C-myc is a core component of the pluripotency transcriptome, regulating cell proliferation and chromosomal accessibility through chromatin remodeling. Stauprimide was characterized as an NME2 inhibitor, thereby downregulating c-myc expression, thus, stauprimide was found to globally enhance the differentiation efficiency of human (hES) and murine (mES) embryonic stem cells to all lineages, including endodermal, mesodermal, and neuroectodermal, suggesting that it exits pluripotent stem cells from pluripotency and self-renewal and forces them into an activated state that is receptive and sensitized for pan-lineage differentiation.

Chemical differentiation to the mesendoderm

The chemical structure of BIO-Acetoxime, a GSK3 inhibitor.

• BIO-Acetoxime: Chemical inhibitor of glycogen synthase kinase 3 (GSK3)

Chemical Name: (2′Z,3′E)-6-Bromoindirubin-3′-acetoxime

Biological Target: Glycogen synthase kinase 3 (GSK3)

Biological Activity: Differentiates the embryo to the mesendoderm (primitive streak), defining formation of the definitive endoderm and the mesoderm

Biological Annotation: BIO-acetoxime is a GSK3 inhibitor, and therefore is an activator of Wnt signaling. Wnt signaling in the developing embryo sequentially specifies the mesendoderm and later, the mesoderm.

The chemical structure of cymarin, an inhibitor of the Na⁺/K⁺ pump.

• Cymarin: Chemical inhibitor of the Na⁺/K⁺ pump

Chemical Name: (3S,5S,8R,10S,13R,14S,17R)-5,14-dihydroxy-3-((2R,4S,5S,6R)-5-hydroxy-4-methoxy-6-methyltetrahydro-2H-pyran-2-yloxy)-13-methyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthrene-10-carbaldehyde

Biological Target: Na⁺/K⁺ pump

Biological Activity: Differentiates the embryo to the definitive endoderm

Biological Annotation: Molecular mechanism of action unknown

The chemical structure of IDE1, a putative histone deacetylase inhibitor.

• IDE1: Putative chemical inhibitor of histone deacetylases (HDAC)

Chemical Name: 2-[(6-carboxyl-hexanoyl)-hydrazonomethyl]-benzoic acid

Biological Target: Chemically-biased to inhibit histone deacetylases (HDAC)

Biological Activity: Differentiates the embryo to the definitive endoderm

Biological Annotation: Differentiates human embryonic stem (hES) and murine embryonic stem (mES) cells to the definitive endoderm with comparable efficiency as Activin A, and indirectly activates TGFβ/Activin signaling.

The chemical structure of IDE2, a putative histone deacetylase inhibitor.

• IDE2: Putative chemical inhibitor of histone deacetylases (HDAC)

Chemical Name: 7-(2-cyclopentylidenehydrazino)-7-oxohepatanoic acid

Biological Target: Chemically-biased to inhibit histone deacetylases (HDAC)

Biological Activity: Differentiates the embryo to the definitive endoderm

Biological Annotation: Differentiates human embryonic stem (hES) and murine embryonic stem (mES) cells to the definitive endoderm with comparable efficiency as Activin A, and indirectly activates TGFβ/Activin signaling.

Chemical differentiation to the neuroectoderm

The chemical structure of selegiline, a monoamine oxidase B (MAOB) inhibitor.

• Selegiline: Chemical inhibitor of monoamine oxidase B (MAOB)

Chemical Name: (R)-N-methyl-N-(1-phenylpropan-2-yl)prop-2-yn-1-amine

Biological Target: Monoamine oxidase B (MAOB)

Biological Activity: Differentiates the embryo to the neuroectoderm

Biological Annotation: Molecular mechanisms unknown

The chemical structure of SB431542, a TGFβ/Activin receptor inhibitor.

• SB431542: Chemical inhibitor of TGFβ/Activin receptors, specifically the activin receptor (ALK4), the TGF-β receptor (ALK5), and the nodal receptor (ALK7)

Chemical Name: 4-(5-Benzol[1,3]dioxol-5-yl-4-pyrldin-2-yl-1H-imidazol-2-yl)-benzamide

Biological Target: ACVR1B (ALK4), TGFβRI (ALK5), ACVR1C (ALK7)

Biological Activity: Differentates the embryo to the neuroectoderm

Biological Annotation: In development, a variety of signals of the TGFβ/Activin, TGFβ/BMP, FGF, and Wnt familes act during gastrulation to specify the mesoderm and endoderm. However, an absence of these signals leads instead to the specification of the neuroectoderm — indeed, the neuroectodermal domain is expanded by ectopic blockade of BMP or TGFβ. Suppression of TGFβ/Activin signaling by SB431542 represses endodermal differentiation cues and aides in differentiation to the neuroectoderm.

Phase III: Chemically-directed multipotent stem cell specification

During the prior phases of the embryonic Myrmidon augmentation, the pluripotent inner cell was first expanded, then directed to differentiate into the three major germ lineages. Subsequently, during "Phase III" of the augmentation, multipotent stem cells would be specified from these germ lineages, leading to substantially enhanced numbers of the differentiated cells generated from those multipotent stem cells.

From the definitive endoderm, multipotent pancreatic progenitors were specified by activation of protein kinase C (PKC) signaling. Treatment with a PKC agonist, (—)-Indolactam V ("IV"), would substantially increase the number of pancreatic progenitors specified.

From the mesoderm, both cardiovascular stem cells and haematopoietic stem cells would be specifically induced, contributing to increased heart mass and increased haematopoietic cells, respectively.

Cardiovascular progenitors in development are both pre-specified and self-renewed by Wnt/β-catenin signaling, therefore the GSK3 inhibitor SB-216763 ("S2") was employed to activate Wnt signaling and to substantially increase the number of multipotent cardiovascular stem cells generated.

Haematopoietic stem cells are embryonically specified and renewed by the combined cyclooxgenase (COX)—prostaglandin pathway, and therefore, a leukotriene D₄ receptor antagonist, LY 171883 ("L1"), was employed to significantly increase the number of developmental haematopoietic stem cells.

Chemical specification and renewal of multipotent stem cells
Chemical Name	Abbreviation	Phenotypic Effect	Biological Target	Mechanism
SB-216763	"S2"	Substantially increased heart size	GSK3	Increased specification and renewal of cardiovascular progenitors
LY 171883	"L1"	Increased haematopoietic cell number	LD4 receptor	Increased specification and renewal of haematopoietic stem cells
(—)-Indolactam V	"IV"	Increased pancreas size	PKC	Increased specification or renewal of pancreatic progenitors

Cardiovascular stem cell specification

The chemical structure of SB-216763, a GSK3 inhibitor.

• SB-216763: Chemical inhibitor of glycogen synthase kinase (GSK3)

Chemical Name: 3-(2,4-Dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyr role-2,5-dione

Biological Target: Glycogen synthase 3 (GSK3), IC₅₀ = 34.3 nM

Biological Activity: Leads to greatly increased numbers of embryonic cardiovascular progenitors (MICPs), leading to highly increased numbers of cardiac muscle, smooth muscle, and endothelial vasculature

Biological Annotation: Specification and self-renewal of cardiovascular progenitors are controlled by the Wnt/β-catenin signaling pathway, and inhibition of GSK3 by SB-216763 leads to Wnt pathway activation and subsequent increase in pre-specification and self-renewal of human cardiovascular progenitors.

Haematopoietic stem cell specification

The chemical structure of LY 171883, a leukotriene D₄ receptor antagonist.

• LY 171883: Chemical inhibitor of the leukotriene D₄ receptor

Chemical Name: 1-[2-Hydroxy-3-propyl-4-[4-(1H-tetrazol-5-yl)butoxy]phenyl]ethanone

Biological Target: Leukotriene D₄ receptor

Biological Activity: Leads to greatly increased numbers of haematopoietic stem cells during development

Biological Annotation: The linked cyclooxygenase (COX) and prostaglandin pathways have been shown to be both necessary and integral in the developmental specification and self-renewal of embryonic haematopoietic stem cells. Modulation of prostaglandin signaling by LY 171883 leads to a marked increase in the number of haematopoietic stem cells.

Pancreatic progenitor specification

The chemical structure of (—)-Indolactam V, a protein kinase C (PKC) agonist.

• (—)-Indolactam V: Chemical agonist of protein kinase C (PKC)

Biological Target: Protein kinase C (PKC)

Biological Activity: Substantially increases the number of multipotent pancreatic progenitors and the number of downstream endocrine β-cells produced

Biological Annotation: PKC signaling appears to necessary for either the induction or expansion of pancreatic progenitors, and PKC inhibitors severely depress the numbers of pancreatic progenitors. Conversely, PKC activation by (—)-Indolactam V causes a substantial increase in the number of human pancreatic progenitors. (—)-Indolactam V directly specifies the multipotent embryonic pancreatic domain from the definitive endoderm at the expense of hepatic specification, and does not increase the efficiency of initial allocation to the definitive endoderm.

Phase IV: Chemically-directed terminal differentiation

Chemical specification of differentiated embryonic tissues
Chemical Name	Abbreviation	Phenotypic Effect	Biological Target	Mechanism
Tianeptine	"TN"	Increased vision and tactile perception	SERT	Enhanced maturation of visual and somatosensory cortices
L-AP4	"LA"	Increased brain mass and neuronal mass	mGluR4	Increased differentiation to neurons
All-trans retinoic acid	"RA"	Increased pancreas size and β-cell mass	RAR	Increased pancreatic and β-cell specification
Trichostatin A	"TA"	Increased pancreas size and β-cell mass	HDAC	Increased pancreatic and β-cell specification
PK115-584	"P1"	Increased lung size	Tcf4/β-catenin	Distal lung expansion
Compound E	"CE"	Increased lung size	γ-secretase	Enhancement of aveolar differentiation
LDN-193189	"L1"	Increased arm and leg size	TGFβ/BMP receptors	Augmentation of FGF-SHH signaling

Differentiation to neurons

The chemical structure of tianeptine, a serotonin transporter activator.

• Tianeptine: Chemical activator of the serotonin transporter

Chemical Name: 7-(3-Chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-ylamino)heptanoic acid S,S-dioxide

Biological Target: Serotonin transporter (SERT)

Biological Activity: Enhances visual and tactile sensation

Biological Annotation: Genetic deletion of MAOA leads to substantially elevated serotonin levels and disorganization of the visual and somatosensory cortices, leading to severe visual and somatosensory impairment. Tianeptine has the reverse effect, reducing serotonin levels by activating the serotonin transporter, leading to enhanced development of the visual and somatosensory cortices and enhanced sensation.

The chemical structure of L-AP4, an agonist of group III metabolic glutamate receptors.

• L-AP4: Chemical agonist of group III metabotropic glutamate receptors (mGluR)

Chemical Name: L-(+)-2-Amino-4-phosphonobutyric acid

Biological Target: Group III metabotropic glutamate receptors (mGluRs)

Biological Activity: Increases the neurons developed during development

Biological Annotation: Activation of group III metabotropic glutamate receptors potently differentiates neural stem cells to neurons, and improves neuronal survival. Specifically, this effect appears to be mediated through mGluR4 — mGluR4 activity inhibits the proliferation of neurospheres and induces neurogenic commitment.

Differentiation to the pancreas

The structure of all-trans retinoic acid, an endogenous ligand for retinoic acid receptors (RARs).

• All-trans retinoic acid: Chemical activator and endogenous ligand for the retinoic acid receptors (RARs)

Chemical Name: (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraenoic acid

Biological Target: RARα ("Retinoic acid receptor alpha"), RARβ ("Retinoic acid receptor beta"), and RARγ ("Retinoic acid receptor gamma")

Biological Activity: Creates an enlarged pancreas with especially high numbers of endocrine β-cells

Biological Annotation: Retinoid signaling plays an integral role in pancreatic development. Retinoid signaling is integral for development of the dorsal endoderm and for the formation of the pancreas, and it has been shown that not only does retinoic acid signaling specify the pancreas, but that retinoic acid expands pancreatic endocrine progenitors and greatly increases the number of differentiated pancreatic endocrine cell types formed, also acting to directly specify insulin-secreting β-cells.

The chemical structure of trichostatin A, a histone deacetylase inhibitor.

• Trichostatin A: Chemical inhibitor of Class I and Class II histone deacetylases (HDACs)

Chemical Name: R-(E,E)]-7-[4-(Dimethylamino)phenyl]-N-hydroxy-4,6-dimethyl-7-oxo-2,4-heptadienamide

Biological Target: Class I and Class II histone deacetylases (HDACs)

Biological Activity: Creates especially high numbers of pancreatic endocrine cells, especially insulin-secreting β-cells

Biological Annotation: Histone deacetylases are downregulated during pancreatic development, suggesting that their repression is permissive to pancreatic differentiation. Histone deacetylase inhibition leads to promotion of pro-endocrine progenitors at the expense of endocrine differentiation, and trichostatin A has been shown to especially enhance the formation of insulin-secreting β-cells and somatostatin-secreting δ-cells.

Differentiation to the lungs

The chemical structure of PK115-584, a Tcf4/β-catenin inhibitor.

• PK115-584: Chemical inhibitor of the Tcf4/β-catenin interaction

Chemical Name: 1-[3,10-dihydroxy-12-[2-(4-hydroxyphenoxy)carbonyloxypropyl]-2,6,7, 11-tetramethoxy-4,9-dioxoperylen-1-yl]propan-2-yl benzoate

Biological Target: Tcf4/β-catenin, protein kinase C (PKC), and myosin light chain kinase (MLCK)

Biological Activity: Increased lung size

Biological Annotation: Wnt5a^-/- mice demonstrate increased embryonic lung epithelium and mesenchyme proliferation, resulting in expansion of the distal lung and increased lung size. This phenotype was mimicked by PK115-584, which is a promiscuous inhibitor of the Wnt signaling pathway that acts by inhibiting the Tcf4/β-catenin interaction.

The chemical structure of Compound E, a γ-secretase inhibitor.

• Compound E: Chemical inhibitor of the γ-secretase complex

Chemical Name: (S)-2-(2-(3,5-difluorophenyl)acetamido)-N-((S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)propanamide

Biological Target: Presenilin-1 (PS1)

Biological Activity: Increased aveolar size and volume

Biological Annotation: Notch signaling is influential in lung development, arresting distal lung progenitors before they can commit to an aveolar differentiation program, serving to inhibit aveolar development and differentiation. Conversely, Notch inhibition by Compound E acted instead to increase commitment to aveolar differentiation, increasing aveolar size and volume.

Differentiation to the limb mesenchyme

The chemical structure of LDN-193189, an inhibitor of TGFβ/BMP receptors.

• LDN-193189: Chemical inhibitor of TGFβ/BMP receptors, specifically ActRIA (ALK2), BMPRIA (ALK3), and BMPR1B (ALK6)

Chemical Name: 4-(6-(4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)quinoline

Biological Target: ActRIA (ALK2), BMPRIA (ALK3), and BMPR1B (ALK6)

Biological Activity: Increases the size of leg and arms

Biological Annotation: During embryogenesis, limb specification and growth is controlled by a highly complex auto-regulatory loop comprised of the genes Grem1, Fgf4, Fgf8, and Shh. Gremlin (Cktsf1b1, Grem1) is an endogenous BMP antagonist that is necessary for proper limb development. Unopposed BMP signaling leads to repression of expression of FGF signals, and blockade of BMP transmission specifically by Gremlin is required for proper induction of Fgf4 and Fgf8 and proper subsequent limb formation by a Fgf-Shh cascade. In the developing mesenchyme, BMP is potently co-repressed by LDN-193189, a synthetic inhibitor of BMP receptors, leading to an expanded domain of BMP-negative cells and expansion of the developing limbs, leading to enlarged legs and arms.

Augmentation of the adult human

Chemical augumentation of the adult human
Chemical Name	Abbreviation	Phenotypic Effect	Biological Target	Mechanism
A-769662	"A7"	↑ Physical endurance and strength	AMPK	Metabolism enhancement and muscle fiber reprogramming
GW501516	"G5"	↑ Physical endurance and strength	PPARδ	Mitochondrial modification and muscle fiber reprogramming
Resveratrol	"RT"	↑ Lifespan and ↑ Physical endurance and strength	AMPK & Sirtuin 1	Metabolism enhancement and muscle fiber reprogramming
SRT1720	"S1"	↑ Physical endurance and strength	Sirtuin 1	Metabolism enhancement and muscle fiber reprogramming
NP549	"N5"	Increases muscle mass	GSK3	Muscle recruitment of hematopoietic stem cells
T0070907	"T0"	Converts brown fat to muscle	PPARγ	Reprogramming of brown adipocytes to skeletal myocytes
FPL 64176	"F6"	↑ Learning and memory	L-type Ca+2 channels	Enhanced long-term potentiation (LTP), synaptic plasticity
(S)-(-)-Sulpiride	"SP"	↑ Memory storage capacity, ↑ Learning & memory	D2/D3 receptors	Increased adult neurogenesis
Compound 9	"C9"	↑ Memory storage capacity, ↑ Learning & memory	NMDA receptor	Increased adult neurogenesis
QS11	"Q1"	↑ Memory storage capacity, ↑ Learning & memory	ARFGAP1	Increased adult neurogenesis
Neuropathiazol	"NP"	↑ Memory formation	Unknown	Increased adult hippocampal neurogenesis
TWS119	"T1"	↑ Memory storage capacity, ↑ Learning & memory	GSK3β	Increased adult neurogenesis
(S)-(-)-Cotinine	"CT"	↑ Memory and ↑ Attention	α3β2/α6β2 nAChRs	Increased cholinergic forebrain transmission
O-1783	"O1"	↑ Decision making, ↑ Reaction time, ↑ Attention	Dopamine transporter	Increased dopaminergic transmission
Hh-Ag1.5	"H5"	Forms new large blood vessels	Smoothened	Induction of angiogenic signals
SNAP	"SA"	↑ Blood flow and forms new blood vessels	Nitric oxide donor	Vasodilation and hematopoietic stem cell mobilization
Prostaglandin E2	"E2"	↑ Red blood cells, ↑ Clotting ability, ↑ Immunity	DP1/DP2 receptors	Increased hematopoietic stem cell proliferation
A-443654	"A4"	↑ Color vision and ↑ Visual resolution	Akt/PKB	Increased growth and survival of cone photoreceptors
BPIQ-II	"B2"	↑ Vision	EGFR	Promotion of optic nerve growth and regeneration
SB-415286	"S4"	Enables limb and organ regeneration	GSK3	Activation of Wnt-FGF signaling
LGD2226	"L1"	Artificially induces puberty in very young children	AR	Indirect activation of IGF-I synthesis (puberty)
Demethylasterriquinone B1	"B1"	↑ Muscle mass, ↑ Bone growth	INSR, IGF1R	Activation of mTOR and protein synthesis
G-1	"G1"	↑ Body size, ↑ Body mass, ↑ Organ mass	GPR30	Increased postnatal growth, EGFR transactivation
ZM 336372	"Z3"	↑ Body size and ↑ Blood vessel formation	Raf1	Increased postnatal growth, apoptosis suppression

Musculoskeletal

The chemical structure of A-769662, an AMPK activator.

• A-769662: Chemical activator of 5' adenosine monophosphate-activated protein kinase (AMPK)

Chemical Name: 4-hydroxy-3-(2'-hydroxybiphenyl-4-yl)-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile

Biological Target: 5' adenosine monophosphate-activated protein kinase (AMPK)

Biological Activity: Induces 44% increase in physical endurance and 23% increase in exercise capacity in untrained subjects

Biological Annotation: AMPK is activated by exercise, and is integral in maintenance of the muscle transcriptome and for oxidative metabolism. On a phenotypic scale, AMPK's molecular mechanisms lead to its integral role in exercise endurance. As a master transcriptional regulator, AMPK regulates transcription of metabolism-associated genes in muscle — pharmacological activation of AMPK leads to induction of a novel transcriptional program in muscle that imparts enhanced oxidative metabolism and endurance in muscle. Pharmacological activation of AMPK by A-769662 results in a substantial increase in physical endurance and physical capacity even without exercise.

The chemical structure of GW501516, a PPARδ activator.

• GW501516: Chemical activator of peroxisome proliferator-activated receptor δ (PPARδ)

Chemical Name: 2-(2-methyl-4-((4-methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)methylthio)phenoxy)acetic acid

Biological Target: Peroxisome proliferator-activated receptor δ (PPARδ)

Biological Activity: Increases exercise endurance by 68% and exercise capacity by 70% in combination with exercise

Biological Annotation: PPARδ is a master transcriptional regulator of skeletal muscle metabolism, and its induction substantially improves exercise endurance. PPARδ appears to increase endurance through three distinct mechanisms: muscular metabolism, mitochondrial biogenesis, and muscle fiber reprogramming. PPARδ expression induces the expression of genes associated with oxidative metabolism and fatty acid uptake, increasing energy uptake and utilization of muscle fibers, and it also induces mitochondrial biogenesis, augumenting this effect by increasing capacity for cellular metabolism. Furthermore, PPARδ interestingly reprograms muscle fibers to type I "slow-twitch" fibers, increasing the muscular capacity for endurance. Therefore, pharmacological activation of PPARδ by GW501516 leads to substantial changes in muscle that combinatorially lead to significant improvements in physical endurance and capacity.

The chemical structure of resveratrol, an activator of both sirtuin and 5' adenosine monophosphate-activated protein kinase (AMPK).

• Resveratrol: Chemical activator of Sirtuin 1 (SIRT1) and 5' adenosine monophosphate-activated protein kinase (AMPK)

Chemical Name: 3,5,4'-trihydroxytrans-stilbene

Biological Target: Sirtuin 1 (SIRT1)

Biological Activity: Doubles physical endurance during exercise and increases average lifespan by 70%

Biological Annotation: Both targets of resveratrol, AMPK and sirtuin, play integral, albeit distinct, roles in general metabolism as well as skeletal muscle physiology. AMPK's roles in skeletal muscle physiology are multifacted — it induces the production of new mitochondria and also enhances fatty acid oxidation (oxidative metabolism). In contrast, sirtuin appears to instead enhance mitochondrial activity not by sheer content, but rather transcriptional effects that modify mitochondrial metabolism and also reprogramming of muscle fiber type to slow-twitch and longer-endurance fibers. Taken together, pharmacological activation of both AMPK and sirtuin by resveratrol potently enhances muscle physiology, leading to increased endurance and strength by modulation of both muscular metabolism and mitochondrial function. Furthermore, sirtuin is tightly linked to lifespan — through modulation of bodywide metabolism and adipose tissue consumption, resveratrol increases mean lifespan.

The chemical structure of SRT1720, an activator of Sirtuin 1.

• SRT1720: Chemical activator of Sirtuin 1 (SIRT1)

Biological Target: Sirtuin 1 (SIRT1)

Biological Activity: Increases physical strength and doubles physical endurance during exercise

Biological Annotation: Sirtuin is a critical modulator of bodily metabolism, lifespan, and skeletal muscle physiology. Its roles in lifespan appear to be linked to the fact that sirtuin enhances energy expenditure in metabolic tissues, precipitously decreasing white fat mass, that it stabilizes genomic DNA, and that it improves cell survival and protects against apoptosis. Sirtuin also is a key regulator of muscle physiology — it enhances endurance by reprogramming Type II "fast-twitch" muscle fibers to Type I "slow-twitch" muscle fibers, and augments mitochondrial activity by enhancing glucose metabolism. Pharmacological activation of SIRT1 by SRT1720 therefore leads to substantial improvements in muscular endurance as well as extension of lifespan.

The chemical structure of NP549, an inhibitor of glycogen synthase kinase 3 (GSK3).

• NP549: Chemical inhibitor of glycogen synthase kinase 3 (GSK3)

Biological Target: Glycogen synthase kinase 3 (GSK3), IC₅₀ ≤ 0.04 nM

Biological Activity: Increases muscle mass

Biological Annotation: During muscle regeneration, Wnt signaling controls the myogenic specification of CD45⁺/Sca1⁺ stem cells and is integral for muscle regeneration, with Wnt blockade severely impairing myogenesis during muscular regeneration. Ectopic Wnt signaling strongly promotes the myogenic dedication of these stem cells. Therefore, potent activation of Wnt signaling by GSK3 inhibition by the ruthenium inhibitor NP549 leads to dramatic muscular specification of CD45⁺/Sca1⁺ stem cells and increased myogenesis and muscle mass.

The chemical structure of T0070907, a peroxisome proliferator-activated receptor γ (PPARγ) inhibitor.

• T0070907: Chemical inhibitor of peroxisome proliferator-activated receptor γ (PPARγ)

Chemical Name: 2-Chloro-5-nitro-N-4-pyridinylbenzamide

Biological Target: Peroxisome proliferator-activated receptor γ (PPARγ), IC₅₀ = 1 nM

Biological Activity: Converts brown fat into skeletal muscle

Biological Annotation: PRDM16 ("PRD1-BF1-RIZ1 homologous domain containing 16") is a transcriptional regulator that controls a bidirectional fate switch between skeletal muscle and brown adipocytes. PRDM16 reprograms skeletal myocytes to a brown adipogenic lineage; conversely, loss of PRDM16 from brown adipocytes leads to their reprogramming into skeletal myocytes, with adoption of a muscle transcriptiome within days. One of PRDM16's indirect targets is PPARγ; PPARγ facilitates adipogenic reprogramming. Therefore, blockade of the PRDM16-PPARγ pathway by the PPARγ antagonist T0070907 leads to direct conversion of brown fat to skeletal muscle, reducing fat mass and increasing muscle mass.

Learning, Memory, and Cognition

The chemical structure of FPL 64176, an agonist of voltage-gated L-type Ca⁺² channels.

• FPL 64176: Chemical agonist of voltage-gated L-type Ca⁺² channels (LTCCs)

Chemical Name: 2,5-Dimethyl-4-[2-(phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylic acid methyl ester

Biological Target: L-type Ca⁺² channels (Ca_v1.1, Ca_v1.2, Ca_v1.3, and Ca_v1.4)

Biological Activity: Enhances learning and memory

Biological Annotation: Calcium influx through L-type Ca⁺² channels activates calmodulin and a cascade of kinase and transcriptional changes that ultimately lead to synaptic plasticity and long-term potentiation (LTP) as well as putative neural stem cell proliferation. Supporting this, inhibition of L-type Ca⁺² channels leads to impairments in spatial memory. Conversely, activation of L-type Ca⁺² channels by FPL 64176 potently induces long-term potentiation and enhances learning and memory.

The chemical structure of (S)-(-)-Sulpiride, a dopamine D₂ and D₃ antagonist.

• (S)-(-)-Sulpiride: Non-selective chemical antagonist of the dopamine D₂ and D₃ receptors

Chemical Name: (S)-(-)-N-[(1-ethylpyrrolidin-2-yl)methyl]-2-methoxy-5-sulfamoylbenzamide

Biological Target: Dopamine D₁ receptor (K_i = 45 μM), Dopamine D₂ receptor (K_i = 15 nM), Dopamine D₃ receptor (K_i = 13 nM), Dopamine D₄ receptor (K_i = 1 μM), Dopamine D₅ receptor (K_i = 77 μM)

Biological Activity: Increased memory storage capacity and enhanced learning and memory

Biological Annotation: Dopamine signaling, including through the D₁, D₂, and D₃ receptors, inhibits the proliferation of neural stem cells. Blockade of dopamine signaling by (S)-(-)-Sulpiride, conversely, enhances the proliferation of neural stem cells and rescues them from apoptosis, enhancing neurogenesis. Neurogenesis has been implicated to expand memory storage capacity as well as learning and memory.

The chemical structure of Compound 9, a putative agonist of NMDA receptors.

• Compound 9: Tentative chemical agonist of N-methyl-D-aspartate (NMDA) metabotropic glutamate receptors (NMDARs)

Chemical Name: N-Cyclopropyl-5-(thiophen-2-yl)isoxazole-3-carboxamide

Biological Target: N-methyl-D-aspartic acid (NMDA) receptor (tentative)

Biological Activity: Increased memory storage capacity and enhanced learning and memory

Biological Annotation: Excitatory transmission potently induces neurogenesis and neural stem cell differentiation, tentatively linking excitatory activity and a requirement for new neurons for memory storage capacity. This sensing of excitatory transmission is primarily mediated through Ca⁺²-mediated signaling through L-type Ca⁺² channels (LTCCs) and NMDA receptors (NMDARs). Compound 9 is a small-molecule mimetic of local excitatory transmission, potently activating Ca⁺² influx through NMDA receptors and leading to rapid genome acetylation and neuronal commitment in neural stem cells, potently inducing neurogenesis in vivo. Neurogenesis has been implicated to expand memory storage capacity as well as learning and memory.

The chemical structure of QS11, an GTPase activating protein of ADP-ribosylation factor 1 (ARFGAP1) inhibitor.

• QS11: Chemical inhibitor of GTPase-activating protein of ADP-ribosylation factor 1 (ARFGAP1)

Chemical Name: (S)-2-(9-(biphenyl-4-ylmethyl)-2-(2,3-dihydro-1H-inden-5-yloxy)-9H-purin-6-ylamino)-3-phenylpropan-1-ol

Biological Target: GTPase activating protein of ADP-ribosylation factor 1 (ARFGAP1)

Biological Activity: Increased memory storage capacity and enhanced learning and memory

Biological Annotation: QS11, an ARFGAP1 inhibitor, is a synergist of Wnt signaling — it does directly activate Wnt signaling, but instead synergizes to enhance Wnt signaling in Wnt-active tissues, such as the neurogenic hippocampus. Wnt signaling enhances adult hippocampal neurogenesis, and ectopic Wnt signaling enhances neurogenesis. Therefore, QS11 controls neural stem cell activity and also learning and memory.

The chemical structure of neuropathiazol, an inducer of hippocampal neurogenesis.

• Neuropathiazol: Chemical activator of hippocampal neurogenesis

Chemical Name: ethyl 4-[methyl-(2-phenyl-1,3-thiazol-4-yl)amino]benzoate

Biological Target: Unknown

Biological Activity: Increases both memory formation and consolidation

Biological Annotation: Neuropathiazol induces the differentiation of adult hippocampal neural progenitor cells (HCN) into neurons at the expense of astrocytes, stimulating hippocampal neurogenesis. The adult parahippocampal–hippocampal network is integral in memory, in both formation and consolidation of memories.

The chemical structure of TWS119, a glycogen synthase 3β (GSK3β) inhibitor.

• TWS119: Chemical inhibitor of glycogen synthase kinase 3β (GSK3β)

Biological Target: Glycogen synthase kinase 3β (GSK3β), IC₅₀ = 30 nM

Biological Activity: Increased memory storage capacity and enhanced learning and memory

Biological Annotation: Wnt signaling plays integral roles in stem cell biology during both development and adult life. Surprisingly, TWS119 directs the neuronal differentiation of pluripotent embryonic carcinoma (EC) and embryonic stem (ES) cells, despite the inhibitory role of Wnt signaling in neural differentiation during gastrulation. Promotion of neurogenesis by TWS119 leads to enhancements in both learning and memory.

The chemical structure of (S)-(-)-Cotinine, a nicotinic acetylcholine receptor (nAChR) agonist.

• (S)-(-)-Cotinine: Chemical agonist of α3β2 and α6β2 nicotinic acetylcholine receptors (nAChRs)

Chemical Name: (S)-1-Methyl-5-(3-pyridinyl)-2-pyrrolidinone

Biological Target: α3β2/α6β2 nicotinic acetylcholine receptors (nAChRs)

Biological Activity: Enhances working and reference memory, increases attention, and increases neuronal survival

Biological Annotation: The cholinergic system is strongly involved in cognition, and activation of cholinergic signaling has been shown to reverse cognitive deficits. Activation of the cholinergic system has been shown to enhance working and reference memory and attention, even in cognitively-impaired subjects, and to improve neuronal survival. (S)-(-)-Cotinine is a nicotine metabolite in humans and is an agonist of specific striatal nicotinic acetylcholine receptors, potentiating cognitive-enhancing effects.

The chemical structure of O-1783, a dopamine active transporter (DAT) inhibitor.

• O-1783: Chemical inhibitor of the dopamine active transporter (DAT) inhibitor

Biological Target: Dopamine active transporter (DAT), IC₅₀ = 17 nM

Biological Activity: Enhances decision making, reaction time, planning, memory, attention, and wakefulness

Biological Annotation: Cognitive enhancers of the 20^th century, such as methylphenidate ("Ritalin") and modafinil, were potent inhibitors of the dopamine active transporter (DAT), potentiating strong cognitive-enhancing effects, whose effects appear in part to be mediated by the catecholaminergic system. Potentiation of dopaminergic transmission leads to highly beneficial effects in executive function, enhancing decision making, reaction time, memory, and wakefulness. These results are recapitulated by a synthetic oxacyclic derivative of methylphenidate, O-1783, which is as equally potent as its precedessor.

Cardiovascular and Circulatory

The chemical structure of Hh-Ag1.5, a Smoothened (Smo) receptor agonist.

• Hh-Ag1.5: Chemical agonist of the Smoothened (Smo) receptor

Chemical Name: 3-chloro-4,7-difluoro-N-(4-methoxy-3-(pyridin-4-yl)benzyl)-N-(4-(methylamino)cyclohexyl)benzo[b]thiophene-2-carboxamide

Biological Target: Smoothened (Smo)

Biological Activity: Potently induces formation of new blood vessels

Biological Annotation: The Hedgehog (Hh) signaling pathway is a morphogen that controls neovascularization in adult tissues. Ectopic Hedgehog stimulation nearly triples capillary density and induces the growth of new large-diameter blood vessels to increase oxygen perfusion of target tissues. This adult neovascularization was recapitulated with Hh-Ag1.5, a potent agonist of Hedgehog signaling.

The chemical structure of SNAP, a nitric oxide donor.

• SNAP: Chemical donor of nitric oxide (NO)

Chemical Name: (S)-Nitroso-N-acetylpenicillamine

Biological Target: Nitric oxide donor, functional mimetic of endogenous nitric oxide synthase (NOS)

Biological Activity: Increases blood flow and induces formation of new blood vessels

Biological Annotation: Nitric oxide (NO) is a short-range signaling molecule that plays important roles in the hematopoietic and circulatory systems during both adult life and development. In the adult, it induces vasodilation, increasing blood flow, and also induces neovascularization of ischemic tissues. SNAP, a functional agonist of nitric oxide signaling by acting as a stable nitric oxide donor, enhances both blood flow and blood vessel growth through the nitric oxide pathway.

The chemical structure of 16,16-dimethyl Prostaglandin E2, an endogenous DP₁ and DP₂ receptor agonist.

• 16,16-dimethyl Prostaglandin E2: Eicosanoid DP₁ and DP₂ receptor agonist

Biological Target: Eicosanoid DP₁ receptor (PTGDR, "Prostaglandin D2 Receptor") and eicosanoid DP₂ receptor (GPR44, "G protein-coupled receptor 44")

Biological Activity: Increases oxygen carrying capacity, blood clotting, and immunity

Biological Annotation: The cyclooxygenase (COX)-prostaglandin pathway is a central modulator of hematopoietic stem cell formation and proliferation, potently inducing self-renewal of haematopoietic stem cells in the adult. Prostaglandin regulation of haematopoietic stem cells converges on the Wnt/β-catenin pathway. Induction of haematopoietic stem cell proliferation leads to increased formation of haematopoietic lineage cells, increasing oxygen carrying capacity (erythrocytes), clotting (platelets), non-specific immunity (granulocytes, monocytes / macrophages, natural-killer cells), and specific immunity (B lymphocytes and T lymphocytes).

Eyesight and Vision

The chemical structure of A-443654, an Akt activator.

• A-443654: Paradoxical chemical activator of Akt/PKB

Chemical Name: (S)-1-(5-(3-Methyl-1H-indazol-5-yl)pyridin-3-yloxy)-3-(1H-indol-3-yl)propan-2-amine

Biological Target: Akt/PKB (Protein Kinase B)

Biological Activity: Improves color vision and high-resolution vision

Biological Annotation: Retinitis pigmentosa, an incurable disease of blindness, is caused by a progressive loss of cone photoreceptors because of a loss of survival and growth signals through the mammalian target of rapamycin (mTOR) pathway. Conversely, stimulation of Akt, an upstream modulator of mTOR, by a paradoxical chemical activator of Akt, A-443654, leads to growth of cone photoreceptors and improvements in color vision and high-acuity vision.

The chemical structure of BPIQ-II, an EGFR inhibitor.

• BPIQ-II: Chemical inhibitor of the epidermal growth factor receptor (EGFR)

Chemical Name: 8-[(3-Bromophenyl)amino]-1H-imidazo[4,5-g]-quinazoline

Biological Target: Epidermal growth factor receptor (EGFR)

Biological Activity: Enhances growth of the optic nerve during adulthood

Biological Annotation: EGFR mediates the inhibitory effects of myelin (Nogo-66) and chondroitin sulfate proteoglycans (oligodendrocyte myelin glycoprotein) on axonal regeneration. Pharmacological or genetic inhibition of EGFR promotes neurite outgrowth from a number of cell types, and increases axonal regeneration after damage of the optic nerve, and blockade of EGFR by BPIQ-II leads to increased optic nerve growth and vision.

Regeneration of Organs and Limbs

The chemical structure of SB-415286, a GSK3 inhibitor.

• SB-415286: Chemical inhibitor of glycogen synthase kinase (GSK3)

Chemical Name: 3-(3-chloro-4-hydroxyphenylamino)-4-(2-nitrophenyl)-1H-pyrrole-2,5-dione

Biological Target: Glycogen synthase 3 (GSK3), IC₅₀ = 77.5 nM

Biological Activity: Enables regeneration of limbs and organs

Biological Annotation: Lower vertebrates are capable of extensive tissue regeneration even after substantial damage, and this process involves genes in the FGF family (Fgf2, Fgf10, and Fgf20) and the Wnt family (Wnt8 and Wnt10). Importantly, FGF2 is capable of even regenerating chicken limb buds, which do not naturally regenerate. Wnt signaling is a highly-conserved master regulator of regeneration, controlling limb regeneration (through regulation of FGF signaling) as well as controlling regeneration of the liver and the hematopoietic system. Therefore, ectopic activation of Wnt signaling by pharmacological inhibition of GSK3 by SB-415286 leads to regeneration of both limbs and organs in advanced vertebrates such as humans.

Body Size and Organ Size

The chemical structure of LGD2226, an androgen receptor agonist.

• LGD2226: Chemical agonist of the androgen receptor

Biological Target: Androgen receptor (K_i = 1 nM)

Biological Activity: Artificially initiates puberty, leading to increased muscle mass, bone growth, and sexual progression

Biological Annotation: In males, puberty is initiated by testosterone, which binds to androgen receptors. Abnormally high levels of testosterone young children lead the precocious initiation of puberty, even earlier than the age of five. LGD2226 is a synthetic quinoinone derivative that is an agonist for the androgen receptor, mimicking the activities of testosterone and causing skeletal muscle growth, bone growth, sexual maturation, and "growth spurts" because of linear bone growth and increases in bone density.

The chemical structure of Demethylasterriquinone B, an insulin receptor and insulin-like growth factor receptor agonist.

• Demethylasterriquinone B1: Chemical agonist of the insulin receptor and the insulin-like growth factor receptor

Biological Target: Insulin receptor (INSR; EC₅₀ = 3-6 μM) and the insulin-like growth factor receptor (IGF1R; 100 μM)

Biological Activity: Increases muscle growth, bone growth, and metabolism

Biological Annotation: Demethylasterriquinone B1 (also known as L-783,281) activates both the insulin receptor and the insulin-like growth factor receptor, which are two structurally-similar and cross-talking pathways that are responsible for the growth of skeletal muscle, the growth of bone, and body growth during the induction of puberty. Genetic ablation of INSR or IGF1R leads to dwarfism, with retarded muscle and bone growth, as well as mental retardation and other deleterious effects. Concordantly, insulin and insulin-like growth factor (IGF) are known to be anabolic hormones that promote growth and puberty. Therefore, activation of the insulin receptor and the insulin-like growth factor receptor with Demethylasterriquinone B1 mimic puberty and adult growth and increase muscle and bone mass.

The chemical structure of G-1, a GPR30 agonist.

• G-1: Selective chemical agonist of G Protein-Coupled Receptor 30 (GPR30)

Biological Target: G Protein-Coupled Receptor 30 (GPR30)

Biological Activity: Increases body size and organ mass

Biological Annotation: GPR30 is an alternative receptor for estrogen, and plays substantial roles in adult growth. While estrogen reduces mean body size and height, genetic ablation of GPR30 leads to decreased body size and organ mass, indicating that GPR30 is essential for growth and weight; GPR30's transactivation of the epidermal growth factor receptor (EGFR) pathway may also participate in its growth-enhancing effects. Therefore, selective activation of GPR30 with G-1 leads to increased body size, weight, and organ mass.

The chemical structure of ZM 336372, a Raf1 activator.

• ZM 336372: Paradoxical chemical activator of Raf1

Chemical Name: N-[5-(3-dimethylaminobenzamido)-2-methyIphenyl]-4-hydroxybenzamide

Biological Target: Raf1 (V-raf-1 murine leukemia viral oncogene homolog 1, c-Raf)

Biological Activity: Increases body size and increased blood vessel formation

Biological Annotation: Raf1 is a Ras GTPase-controlled kinase that is the upstream regulator of the classical mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway, a key signaling pathway that controls cell growth and survival. Raf1^-/- mice are growth-impaired and have extensive defects in their vasculature; correspondingly, the major function of Raf1 is believed to be inhibition of apoptosis. Therefore, pharmacological activation of Raf1 by ZM 336372 leads to both increased body size and increased vascularization.

Augmentation during acute combat

Chemical augumentation during acute combat
Chemical Name	Abbreviation	Phenotypic Effect	Biological Target	Mechanism
Batrachotoxin	"BX"	Maintains brain function and heartbeat even near death	Nav channels	Reactivation of action potentials
Dobutamine	"DB"	↑ Heartbeat, ↑ Breathing, ↑ Blood pressure	α/β-adrenoreceptors	Non-selective adrenergic signaling
SB-224289	"S2"	↑ Aggression, ↑ Violent behavior	5-HT1B receptor	Blockade of modulatory serotonin signaling
(R)-(+)-WIN 55212	"W5"	↓ Pain and alters perception	CB1/CB2 receptors	Enhanced cannabinoid signaling
JZL184	"J1"	↓ Pain and alters perception	MAGL	Increased 2-arachidonoylglycerol signaling
Haloperidol	"HP"	↑ Animalistic behaviors and ↓ Complex cognitive functions	D2-like receptors	Neuroleptic activity through dopaminergic blockade
GW 441756	"G4"	↓ Pain	TrkA	Selective ablation of nociceptive neurons

Combat Physiology

The chemical structure of batrachotoxin, a voltage-gated Na⁺ channel agonist.

• Batrachotoxin: Chemical agonist of voltage-gated Na⁺ channels

Chemical Name: (1S)-1-[(5aR,7aR,9R,11aS,11bS,12R,13aR)-1,2,3,4,7a,8,9,1 0,11,11a,12,13-Dodecahydro-9,12-dihydroxy-2-11a-dimethyl -7H-9,11b-epoxy-13a,5a-propenophenanthro[2,1-f][1,4]oxaz epin-14-yl]ethyl 2,4-dimethyl-1H-pyrrole-3-carboxylate

Biological Target: Voltage-gated Na⁺ channels (e.g. Na_v1.8)

Biological Activity: Maintains brain function, heart beat, breathing, and muscle contraction even during death-inducing situations

Biological Annotation: Voltage-gated Na⁺ (Na_v) channels are ubiquitously distributed and play pleiotropic roles in the body. They are essential for initiation and conduction of all neuronal action potentials and cardiac action potentials, and therefore Na_v channels are a prerequisite for life — without Na_v channels, it would be possible to maintain brain function, heart function, lung function, or any form of muscular function. Na⁺ is the principal excitatory ion of the central nervous system (CNS) and peripheral nervous system (PNS), and also is in part responsible for the pacemaker potential that is the master regulator of heartbeat. During death, ATP-dependent cellular processes begin to break down, leading to the loss of Na⁺/K⁺ exchanger activity, loss of separate ionic concentrations across the membrane, and loss of effective electrical conduction. Batrachotoxin artificially "jump-starts" neural activity by ectopic influx of Na⁺ ions into the cell, regardless of membrane potential, therefore recapitulating action potentials, and ectopically inducing action potentials broadly across the central and peripheral nervous systems as well as the heart. The loss of electrical activity in the brain, spinal cord, and heart found during death begins to be reversed, with ectopic action potentials recapitulating normal physiological activity. While this presents with broad sensory hallucinations and artificial seizure-like motor activities, this allows for effective partial brain function, heart function, and lung function even during cardiac arrest and other life-threatening situations.

The chemical structure of dobutamine, a non-selective α/β-adrenoreceptor agonist.

• Dobutamine: Non-selective chemical agonist of the α₁, β₁, and β₂ adrenoreceptors

Chemical Name: 4-[2-[[3-(4-Hydroxyphenyl)-1-methylpropyl]aminoethyl-1,2-benzenediol

Biological Activity: Increases heart rate, breathing, and blood pressure

Biological Annotation: The endogenous adrenergic receptor agonist epinephrine induces the "flight-or-fight" response through non-selective activation of α-adrenoreceptors and β-adrenoreceptors. Combinatorially, this dual activation leads to a number of highly rapid and potent physiological changes, including increased heart contraction strength, increased heart rate, bronchodilation, and vasoconstriction of peripheral blood vessels. The sympathomimetic dobutamine mimics these effects, inducing physiological priming that enhances combat capabilities, and also reverses cardiac arrest.

Combat Psychology

The chemical structure of SB-224289, a selective 5-HT_1B receptor inhibitor.

• SB-224289: Chemical inhibitor of the serotonin 5-HT_1B receptor

Chemical Name: 1'-Methyl-5-[[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-y l)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydrospiro[furo[2 ,3-f]indole-3,4'-piperidine

Biological Target: 5-HT_1B receptor

Biological Activity: Induces aggression, rage, and hyperactivity

Biological Annotation: The 5-HT_1B receptor is necessary for control of aggressive behavior. Genetic deletion of the 5-HT_1B receptor in mice (5-HT_1B^-/-) leads to increased aggression and violent behavior, while conversely, agonists of the 5-HT_1B receptor lead to reduced aggressive behavior. Therefore, pharmacological inhibition of the 5-HT_1B receptor by SB-224289 leads to increased aggression, rage, and hyperactivity in humans.

The chemical structure of (R)-(+)-WIN 55212, a CB₁ and CB₂ receptor agonist.

• (R)-(+)-WIN 55212: CB₁ and CB₂ cannabinoid receptor agonist

Chemical Name: (R)-(+)-[2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone

Biological Activity: Reduces pain and alters perception

Biological Target: Cannabinoid CB₁ and CB₂ receptor agonist (K_i = 62.3 ± 31 nM, CB₁ and K_i = 3.30 ± 0.40 nM, CB₂)

Biological Annotation: The pain-killing and recreational properties of the drug marijuana (Δ⁹-tetrahydrocannabinol) have been known since antiquity. Its effects are mediated through the endocannabinoid system, a G-protein-coupled-receptor (GPCR) signaling system that is ubiquitous throughout the body. Although the endocannabinoid system is closely linked to pain perception, mechanistic studies have revealed both positive and negative roles of endocannabinoid signaling in nociception; however, indirect agonists are potent analgesics in humans. Therefore, ectopic stimulation of the CB₁ and CB₂ receptors by (R)-(+)-WIN 55212 leads to reduction in pain and subjective modifications in perception.

The chemical structure of JZL184, a MAGL inhibitor.

• JZL184: Chemical inhibitor of monoacylglycerol lipase (MAGL)

Chemical Name: 4-Nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate

Biological Target: Monoacylglycerol lipase (MAGL), IC₁₀₀ ≈ 0.25 μM

Biological Activity: Reduces pain and alters perception

Biological Annotation: Anandamide and 2-arachidonoylglycerol are two endogenous agonists of cannabinoid receptors. Although modification of endocannabinoid signaling is possible through synthetic compounds, it is also possible to enhance endocannabinoid signaling by modulating levels of endogenous endocannabinoids. 2-arachidonoylglycerol is inactivated by monoacylglycerol lipase (MAGL), thereby terminating its transmission. Pharmacological blockade of monoacylglycerol lipase by JZL184 produces a phenotype indicative of increased endocannabinoid transmission, including analgesia.

The chemical structure of haloperidol, a dopamine D₂-like receptor inhibitor.

• Haloperidol: Chemical inhibitor of dopamine D₂-like receptors

Chemical Name: 4-[4-(4-Chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone

Biological Target: Dopamine D₁ receptor (K_i = 80 nM), Dopamine D₂ receptor (K_i = 0.1 μM), Dopamine D₃ receptor (K_i = 1.2 nM), Dopamine D₄ receptor (K_i = 7 nM), Dopamine D₅ receptor (K_i = 2.3 nM)

Biological Activity: Induces animalistic behavior and represses higher cognitive functions

Biological Annotation: Dopaminergic signaling is central in cognition and behavior. Pharmacological modulators of dopamine receptors potently modulate behavior, cognition, sleep, seizure activity, and a plethora of other neurological phenomena. Haloperidol, a modestly-selective inhibitor of dopamine D₂-like receptors, induces neuroleptic effects in humans, suppressing complex behaviors while preserving animalistic behaviors and primal reflexes. Induction of animalistic behavior in combat substantially enhances combat capabilities.

The chemical structure of GW 441756, a TrkA inhibitor.

• GW 441756: Chemical inhibitor of the neurotrophin TrkA receptor

Chemical Name: 1,3-Dihydro-3-[(1-methyl-1H-indol-3-yl)methylene]-2H-pyrrolo[3,2-b]pyridin-2-one

Biological Target: TrkA ("Neurotrophic tyrosine kinase, receptor, type 1"), IC₅₀ = 2 nM

Biological Activity: Confers almost complete protection against pain

Biological Annotation: TrkA is a high-affinity receptor for nerve growth factor (NGF), a key neurotrophin that plays critical roles during development and adult life. Mutations in both TrkA and NGFβ in humans confer congenital insensitivity to pain. During neurological development, NGF/TrkA signaling is responsible for promoting the survival of sensory neurons in the dorsal root ganglion (DRG) responsible for nociception; ablation of NGF/TrkA signaling by GW 441756, a synthetic aza-oxindole inhibitor of TrkA, leads to gradual death of nociceptive neurons, thus rendering almost complete protection against pain and a selective and complete absence for the small-diameter and unmyelinated fibers responsible for nociception.

Second-Generation Chemical Augmentations: Modulation of Lifespan and Pain

Main article: Methuselah Program

During the Galactic Era, the second iteration of the Myrmidon Program would heavily rely on the core chemical augmentations of the first generation — the significant upscaling of the number of child subjects, nearly by an order of magnitude, would restrict intensive research and pharmacogenetics to produce further optimizations of the first chemical protocol largely devised by Beah Schore and Kawika Son. However, notably, the UNSC Department of Biological Warfare's collaboration with Acumen Science Laboratories, the Methuselah Program, would mature, generating a list of four chemical compounds that extended lifespan in adult humans.

Two of these compounds, resveratrol and SRT1720, allosteric sirtuin activators, were already serendipitously included in the augmentation protocol, albeit for phenotypic effects beside lifespan extension. However, Methuselah's findings would uncover three more small molecules, mianserin (a serotonin transporter inhibitor), EUK-134 (a superoxide dismutase/catalase mimetic), which had both been previously shown to extend lifespan in C. elegans., and cycloastragenol (a telomerase activator) —these three molecules were applied combinatorially to extend lifespan, through simulated caloric restriction, abrogation of oxidative stress, and increased telomerase activity, respectively.

Furthermore, a fourth, unrelated compound — fentanyl isothiocyanate (FIT), a highly-potent and irreversible δ-opioid receptor agonist that is a modified, alkylating isothiocyanoto analog of fentanyl, was employed to further increase analgesia during combat, rendering the second-generation Myrmidons nearly impervious to pain during combat.

The chemical structure of mianserin, a promiscuous inhibitor of serotonin receptors, adrenergic receptors, the H₁ histamine receptor, and the norepinephrine receptor.

• Mianserin: Promiscuous chemical antagonist of various receptors and transporters, notably including the 5-HT₂ receptor
  • Biological Targets: Histamine H₁ receptor, 5-HT_1D receptor, 5-HT_2A receptor, 5-HT_2B receptor, 5-HT_2C receptor, 5-HT₃ receptor, 5-HT₆, 5-HT₇, α1 adrenergic receptor, α2 adrenergic receptor, and norepinephrine transporter
  • Biological Activity: Increases lifespan
  • Biological Annotation: Mianserin, a dibenzazepine tetracycle, is a promiscuous antagonist of serotonin receptors, adrenergic receptors, the H₁ histamine receptor, and the norepinephrine receptor, and is employed in human patients as an antidepressant. Pharmacological studies have indicated that serotonin signaling is implicated in C. elegans lifespan — inhibition of serotonin signaling through the 5-HT₁ or 5-HT₂ receptors (cyproheptadine, methiothepin, mianserin, mirtazepine) increases lifespan, whereas potentiation of serotonin signaling through selective blockade of serotonin transporters (fluoxetine, sertraline, paroxetine) leads to significant decreases in lifespan. In C. elegans, mianserin appears to inhibit homologs of both serotonin and norepinephrine receptors, and its mechanism of action appears to be through the same pathway as dietary restriction, as dietarily-restricted animals did not respond to mianserin. The role of serotonin signaling inhibition in lifespan extension is believed to be based on the role of serotonin as a "food presenting" signal — blocking serotonin is believed to simulate a state of perpetual hunger, therefore generating a neural simacrulum of hunger and leading to lifespan extension.

The chemical structure of EUK 134, a mimetic of superoxide dismutase / catalase.

• EUK-134: Chemical mimetic of superoxide dismutase / catalase (SOD)
  • Biological Target: 2O₂^- (superoxide radical)
  • Biological Activity: Increases lifespan
  • 'Biological Annotation: Oxidative stress reduces lifespan by inducing DNA damage, therefore impairing the ability of cells to proliferate. Cells defend against oxidative stress by employing proteins known as superoxide dismutases (SOD), which convert the unstable superoxide radical (2O₂^-) into peroxide (H₂O₂), which is subsequently degraded into harmless H₂O and O₂. Subsequently, chemical facsimile of SOD, through the small molecule EUK-134, limits oxidative damage and DNA damage and therefore increases lifespan.

The chemical structure of cycloastragenol, a chemical activator of telomerase.

• Cycloastragenol (TAT-2): Chemical activator of telomerase
  • Biological Target: Telomerase (hTERT)
  • Biological Activity: Increases lifespan
  • Biological Annotation: Telomerase is an unusual reverse transcriptase that is necessary to maintain the integrity of chromosomes during DNA replication Its essential DNA-repairing activity is necessary to repair the genomes of mitotically-active cells, and in fact, telomerase activity induces the proliferation of stem cells and is required to safeguard the genomic integrity of stem cells and to preserve their function Aging is accompanied with DNA damage that limits the function of stem cells, which causes the phenotypic decline typically seen during aging. Contrarily, suppression of DNA damage through induction of telomerase increases lifespan. Cycloastragenol, a Chinese natural product otherwise known as TAT-2, is a chemical activator of telomerase in human cells, thereby extending lifespan.

The chemical structure of fentanyl isothiocyanate, an irreversible agonist of the δ opioid receptor.

• Fentanyl isothiocyanate: Irreversible chemical agonist of the δ opioid receptor
  • Biological Activity: Severely reduces pain during combat
  • Biological Annotation: The δ opioid receptor is a G-protein-coupled receptor (GPCR) that is expressed in the nervous system; its activation leads to the inhibition of GABAergic transmission that represses descending anti-nociceptive circuits , thereby relieving inhibition of pain-relieving neural circuitry. Endogenous opioids are believed to the body's resident mechanism to relieve pain and to produce euphoria. Fentanyl isothiocyanate is an isothiocyanato-analog of fentanyl, a synthetic agonist of the δ opioid receptor, and acts by alkylating the receptor, therefore irreversibly activating it. Therefore, application of fentanyl isothiocyanate potently induces analgesia and euphoria, repressing pain imparted in combat.

Equipment

Reactive Accelerative Combat Exoskeleton (RACE)

A Myrmidon, suited in the Reactive Accelerative Combat Exoskeleton (RACE) armor, on arboreal operations.

The RACE powered armor would further augment the extraordinary agility of the Myrmidons, imparting them with supernatural strength, speed, and endurance.

The Mark 4 RACE exoskeleton of the Galactic Era was sinister in appearance, jet-black armor with glowing crimson lights.

The Reactive Accelerative Combat Exoskeleton (RACE) was one of the novel warfighting technologies of the late 26^th century specifically designed to further the combat prowess of the Myrmidons. The RACE exoskeleton was the futuristic iteration of the antediluvian MJOLNIR armor of the SPARTAN-II Program, and was a novel powered armor that would serve as the default multirole armor of the Myrmidons, serving several key features, including:

• Protection against small-arms fire and light explosives
• Defensive measures against nuclear-biological-chemical (NBC) warfare
• Electronically connecting all Myrmidons and their commanders in the local theater
• Integrated short-range, long-range, and tight-beam communicators
• Supplementary augmentation of physical strength and agility through hydraulics
• Intravenous catheters allowing for automatic dispensation of small-molecule drugs
• Automatic measuring and recording of biological statistics (heartbeat, blood pressure, breathing, electroencephalogram, body temperature, electrocardiogram, etc...)
• Internal temperature maintenance and insulation against extreme environments
• Integrated electronic heads up display (HUD) and short-range motion detector
• Self-contained respiration and atmospheric supply (80% N₂, 20% O₂, trace gases) allowing for deep-space operations and operations in hostile atmospheres

Iterations of the RACE powered armor included integrated power cells that allowed for near-indefinite operation of the powered armor in the field; the in-house power was used primarily to power the armor and power the hydraulics to extensively enhance the strength, agility, and endurance of the Myrmidons through electronically-coupled physical force as well as to power the onboard electronic systems, such as the communications equipment and integrated HUD.

Because of the variegated atmospheric and physical conditions of the worlds that the Myrmidons were employed, the RACE powered armor was specifically designed for multi-environment operation, with internal temperature and atmospheric homeostasis to maintain body temperature and internal atmospheric composition to allow for operation in nearly any hostile environment, even deep space and also ice worlds such as Dashan.

In contrast to the MJOLNIR armor, the RACE exoskeleton, with novel advances in UNSC engineering, was far more light-weight, flexible, and adaptable, and therefore was a skintight suit — however, there was no collateral compromise to protection; several layers of multilayer titanium would impart far greater protection than could be afforded with the aging MJOLNIR armor, and the RACE exoskeleton would withstand small-arms fire and light explosives and also incorporated countermeasures against nuclear-biological-chemical (NBC) warfare.

The Mark 0 RACE was the prototypic iteration of the RACE exoskeleton and was a design that UNSC Special Operations Command was testing in the 2560s to see if it could conceptually be utilized as a standardized powered armor system to be used to augment all UNSC special forces units. A primitive version of the fully-developed RACE system of the 2580s, the Mark 0 iteration was a crude theoretical antecedent, little more than a self-contained environmental suit with light defensive capabilities, essentially a cut-down version of the MJOLNIR armor intended for widespread distribution. In contrast, the Mark 1 RACE represented the next theoretical progression in the exoskeleton series, with expanded onboard communications capabilities and an extensive onboard power supply that drove a high-powered, yet bulky and clumsy, hydraulics system to enhance the user's strength and speed. Although UNSCSOCOM would seriously consider the Mark 1 model for widespread UNSC special forces usage, the proposal would stagnate for a number of practical and logistical reasons.

Kawika Son and the Myrmidon planning staff would uncover the Mark 1 iteration's plans during the conceptualization of the Myrmidon Program, and Rear Admiral Son would insist that his Myrmidons be equipped with some form of self-contained powered armor to enhance their physical capabilities as well as to provide electronic integration throughout the unit. During the late 2570s and the early 2580s, the Mark 2 RACE would be designed as per Son's specifications, and the modern-day RACE exoskeleton would begin to its formation under Son and his team; the development of a light-weight and skin-tight suit utilizing advanced material sciences to reduce weight and increase flexibility. Select Myrmidons trainees and elite UNSC special forces personnel would tentatively try the Mark 2 RACE in a limited capacity, but despite the small sample size, the results and comments were highly favorable, encouraging the Myrmidons to further develop the RACE powered armor concept. The Myrmidons would undergo familiarization training with the RACE progression during their training with the early Mark 2 RACE concept.

Finally, by the end of their training in the late 2580s, Son's team in collaboration with the UNSC Office of Naval Intelligence and the UNSC Special Operations Command would develop the Mark 3 RACE (A), the Beyond Veil's Azure-era Myrmidon combat armor, optimized for assault and counterterrorism. The Mark 3 RACE (A) would become the default Myrmidon armor as they were deployed in 2590 to the reaches of the Milky Way galaxy on full active deployment.

However, Son and his colleagues in the UNSC Naval Special Warfare Command, after experiencing costly lessons with Task Force 51 and the Midgard Campaign, would insist on further and more specialized variations with the RACE powered armor. As a result, the Mark 3 RACE (E), a specialized electronic warfare (EW) variant, would be developed, as well as the Mark 3 RACE (S), a highly prototypic and specialized powered armor that sacrificed substantial power and strength for limited active camouflage capabilities, with reactive photocell technology providing enhanced electronic stealth, modeled after the Semi-Powered Infilitration (SPI) Armor of the SPARTAN-IIIs. However, neither the "E" or "S" variants would see any kind of widespread deployment.

By the dawn of the 27^th century and the Galactic Era, the surviving Myrmidons would don the Mark 4 RACE, incorporating bloody lessons learned in Myrmidon warfare during the Beyond Veil's Azure Crisis.

The color scheme of the early RACE exoskeletons was variegated; tan camouflage was given for desert operations, olive camouflage was given for arboreal or jungle operations, white camouflage was given for arctic or tundra operations, and grey digital camouflage was given for urban operations. However, as Myrmidon casualties mounted during 2594 and the Beyond Veil's Azure Crisis, many Myrmidons would begin to customize their armors as badges of pride and individualism. Officers, such as Captain Raphael-M064 and Commander Ashley-M014 would adopt red colors. Senior enlisted personnel, such as Master Chief Petty Officer Karen-M013 and Chief Petty Officer Eve-M005, would adopt blue colors. Many of the junior enlisted Myrmidons would adopt green colors, although proficient specialists would adopt other color schemes — sharpshooters such as Lieutenant Blake-M079 would adopt black colors while other specialist classes would often adopt alternative colors.

However, during the Galactic Era, Captain Raphael-M064, the Myrmidon field commander, would insist that the Mark 4 RACE would have a standardized color scheme; all the Myrmidons of the Galactic Era would wear jet-black Mark 4 RACE exoskeletons with glowing crimson articulation lights with the appearance of arterial blood, giving them a decidedly sinister look.

Weaponry

A12 Close-Quarters Battle Carbine

An image of an A12 Special Operations-Capable Carbine in use with Myrmidon Delta Squadron, sporting a digital jungle camouflage finish.

A technical blueprint of a MA12-SOC/CQB Carbine (Special Operations Capable/Close Quarters Battle).

Main article: MA12 carbine

"Evenly balanced and light."

―Lieutenant Commander Simon-G294

The MA12 Special Operations Capable / Close Quarters Battle (SOC/CQB) Carbine, 5.56mm, often referred to colloquially as the "A12 Carbine", was a highly modular and modificable short-range carbine that served as the default armament for many of the Myrmidons.

Although technically it was a member of the "MA" series of firearms, such as the MA5B assault rifle and the MA5C assault rifle of the Human-Covenant War, it was vastly different from its ancestral predecessors. Whereas the MA5 series was an inaccurate rugged weapon distributed to rank-and-file UNSC Marines, the MA12-SOC/CQB was instead a surgical scalpel, the versatile weapon of choice for advanced UNSC special forces operators.

The A12 featured an extended forty-round 5.56mm clip, light ammunition suitable for infantry engagements. Its design was highly rugged, designed to operate in hostile environments such as the desert environments of Midgard as well as extreme temperatures, such as the ice world of Dashan. It had a collapsible glazed fiberglass stock, instead of the burnished metal of the BR55 battle rifle, making the A12 highly lightweight and with a slender profile, making it easy to maneuver and carry in intense close-quarters environments, where speed and maneuverability were key over firepower.

Furthermore, the A12 carbine had a full-bore heavy barrel that allowed for increased accuracy and stabilized prolonged automatic firing. The muzzle was shortened, allowing for easy close-quarters usage and decreasing weight, and was also threaded, being compatible with a number of flash suppressors and sound suppressors for covert-operations wet work.

The underside receiver sported a magazine release and a "S/1/F" trigger group; primarily the semiautomatic setting was used, conserving ammunition and enhancing accuracy. Coupled with the inherent accuracy of the Myrmidons, it was anticipated that semiautomatic fire would allow for "one-shot, one-kill" usage of the carbine in the hands of the talented Myrmidons. Failing that, the "F" setting (full automatic) was also employed against heavier targets or in more target-rich environments and also to maximize fire volume.

The upper receiver was an open mount that received a number of scopes and sights, typically a red aiming reference ("red dot sight") for close-quarters combat, although rarely, telescopic sights were employed for engagements over longer-ranges. The sight was modificable with a night-vision filter for nighttime fighting as well as an infrared filter for more specialized applications. Furthermore, a "gun camera" was also attachable to allow for real-time image intelligence (IMINT) in highly specialized Office of Naval Intelligence missions to identify high-priority targets.

M7SF Submachine Gun

The M7SF Submachine Gun (Mark 7 Caseless / Special Forces).

The M7SF Submachine Gun (Special Forces), Caseless 5x23mm was the 2580 era iteration of the M7/Caseless Submachine Gun employed during the Human-Covenant War. Whereas its predecessor, the M7/Caseless, was an inaccurate weapon with a high rate of fire (unaffectionately called the "bullet hose") typically issued for self-defense to officers, vehicular crews, and pilots, three decades of work by the UNSC Special Operations Command would transform the M7/Caseless into the highly-capable precise killing implement known as the M7SF to the Myrmidons.

The M7SF was designed specifically for close-quarters combat applications, where the submachine gun's light weight, smaller size, and maneuverability made it more preferable than the A12 carbine or other assault weapons. However, the special forces concern with the M7/Caseless was its inaccuracy; while the M7/Caseless was small and light, its shot grouping was unacceptable for sensitive Myrmidon operations, such as hostage rescue. Therefore, the M7SF featured a longer and heavier full-bore barrel, therefore increasing dispersion of the kinetic energy of the projectile along its length and increasing accuracy at the cost of slightly increased weight. This was compensated for the M7SF's new plastics, which decreased weight compared to the traditional fiberglass stock.

The M7SF had a threaded barrel that typically accommodated a flash/sound suppressor; this severely abrogated the muzzle flash and sound of each shot, therefore making the position of the shooter far more difficult to discern in camouflaged environments. Furthermore, the suppressor was conducive to many of the covert operations undertaken by the Myrmidons, where it was imperative to confirm mission confidentiality, and also where individuals needed to be discriminately eliminated without alerting nearby individuals.

The upper receiver was typically reciprocated to a red aiming reference (red dot sight) or a close combat optic (reflex scope) to increase accuracy. Thermal imaging and night vision (light-amplifying) filters were also available for warfighting in dark and/or cold environments.

While the M7SF was equipped with the traditional "S/1/F" (safed, semiautonomatic, or fully automatic) trigger group, to preserve accuracy, Myrmidons typically employed the semiautomatic setting in urban combat situations; Myrmidons were trained as conventional counterterrorist teams to kill with a single shot to the head, with a second shot ("double tap") to ensure that the target was permanently downed.

AS DAM Anti-Materiél Sniper Rifle

The AS DAM Anti-Materiél Sniper Rifle (Directed Anti-Materiél).

Main article: AS DAM

The AS DAM Anti-Materiél Sniper Rifle is a special-application anti-materiél and anti-vehicular sniper rifle designed by the HRV Armament Company and Acumen Science Laboratories. The first weapon of its kind, the sniper employs extremely-dense kinetic penetrators made of iridium, the second most-dense element known to mankind. The extraordinary density of the kinetic penetrator rounds imparts the AS DAM penetration power that far surpasses the SRS99D S2 AM Sniper RIfle of the Human-Covenant War era. The unique iridium ammunition of the AS DAM allows it to be effectively employed against stationary materiél (i.e. fuel tanks, missile launchers, installations, etc...) as well as stationary vehicles, from vans, armored personnel carriers, and even tanks. The extreme density of the iridium round, coupled with the extremely high muzzle velocity from the AS DAM, allows the rifle to defeat the armor or plasma shields of almost any stationary armored target found on the battlefields of the Galactic Era.

The AS DAM was introduced to the Myrmidons to give trained snipers a potential anti-vehicular and anti-materiél role. However, typically, the minimal operating team for one of these sniper rifles requires at least a sniper and a spotter, who also provides security. Naval Special Warfare teams typically employ a third team member that is dedicated to provide security for the sniper team. The sniper rifle allows Myrmidons to abrogate enemy personnel, materiél, or vehicles from extreme ranges with high accuracy. The usage of one of these rifles against personnel is extraordinary overkill: the sheer kinetic power of the projectile, which can defeat tanks, is extraordinarily devastating against infantry. Furthermore, the application of the rifle can be tuned: engine blocks or wheels can be targeted to selectively disable vehicles.

The rifle was also employed as a psychological warfare weapon against insurgents: the selective and unerring culling of enemy vehicular and personnel detachments with the sniper rifle was often psychologically terrifying, combined with the massive shockwave and report with every shot.

The AS DAM, capable of penetrating many types of armors and barriers, also has obtained a unique role in a counter-sniper position.

History

The renowned Beah Schore, Director of the Harvard Stem Cell Institute at Cambridge, Massachusetts (Earth), would serve as an integral advisor for the Myrmidon Program, directing its exemplary conceptual bounds in chemical biology.

Nucleation

Artemis-2995: "Everyone in the [High-Priority Assassination Program] is being reassigned to this training initiative. UNSCSOCOM is pulling off all the tier-one units for this."

Apollo-2994: "This have to do with this Blackburn girl?"

Artemis-2995: "[No]. UNSCSOCOM is raising the second epoch of SPARTANs."

— Artemis-2995 recruiting Apollo-2994, Operation: RALLY VIOLET^[src]

The Myrmidon Program would formally have its genesis in 2578. Conceptualized by Dr. Beah Schore of the Harvard Stem Cell Institute and Rear Admiral Kawika Son of the UNSC Naval Special Warfare Command, it would be authorized in early 2578 by the UNSC Office of Naval Intelligence, given the highest priority to train and operate the next iteration of SPARTAN child soldiers, the fourth generation of the SPARTAN Program.

Almost immediately, Admiral Son would begin the nucleation of a core cadre of individuals to train the Myrmidons. While Schore's team would begin investigation of the chemical biology necessary to augment the future warriors, Son would authorize Operation: MARSHAL YELLOW on Hekate and Operation: RALLY VIOLET on Bifröst, gathering ex-SPARTANs such as Simon-G294, Cassandra-G006, Apollo ("Agent 2994"), and Artemis ("Agent 2995") to serve as program advisors and dedicated drill instructors (DIs) to teach the future Myrmidons where their predecessors, the SPARTANs, had gone astray.

In the end, the senior members of the Training Detachment would be comprised almost exclusively of SPARTAN-IIIs, employing the prior generation of SPARTANs to train and lead the generation of the future. Commander Esther-G071 and Lieutenant Commander Simon-G294 would serve as the commanding officer and the executive officer, respectively, of the training element. These choices were chosen based on their past infamy; Esther-G071 was galactically-renowned for her famous last stand on Carinae-312 against the Sangheili that allowed the UNSC to avert total galactic destruction during the Memory Crisis, while Simon-G294 was a former UNSC traitor, and was brought in specifically by Admiral Son to provide an ethical and moral element to the training of the Myrmidons, ensuring that they would practice ethical warfare and constrain themselves to moral boundaries to prevent them from forming atrocities. Commander Daniels-G288 (Vulcan Team), Lieutenant Commander Joshua-G024 (Xiphos Team), and Lieutenant Commander Clara-G235 were also assistant executive officers for the training element. Lieutenant Colin-G092 and Lieutenant Amy-G094, both of Xiphos Team, would be assistant officers-in-charge as well, completing the SPARTAN-III leadership of the Training Detachment.

The remainder of the trainers would be hands-on drill instructors, instructing the children Myrmidons in the methodical rigor of special warfare. These would be largely comprised of UNSC special warfare operators, drawn from organizations such as Naval Special Warfare and Marine Force Reconnaissance, and supplemented with a smaller number of SPARTAN-IIIs.

The Special Warfare School was considered by many of the trainees to be the most devastatingly rigorous component of their training; it was designed to train them in special operations in the advanced battlespace, such as in extremis hostage rescue and assassination, and it was extremely physically and psychologically demanding. It would be governed by Senior Chief Whitney-G179 and Senior Chief Jennifer-G272; the former was chosen because of her exemplary actions during the Memory Crisis, and the fact that she was one of four UNSC personnel that had ever set foot aboard a Forerunner Dreadnought and lived to tell the tale. The Naval Intelligence Office of Special Investigations ensured that the children Myrmidons would have maximum knowledge of past UNSC/Forerunner encounters and would be trained in first-contact protocols, in the contingency that the Myrmidons would come across Forerunner technology during the course of their operations.

The Scout-Sniper School was directed by Lieutenant Maria-G173, Senior Chief Konrad-G319, Chief Angelina-G152, and Chief Christie-G205; all four of them SPARTAN-III designated sharpshooters. The Scout-Sniper School was arranged like a conventional sniper training course for the UNSC Special Forces, with maneuvering, special reconnaissance, and marksmanship components. Maneuvering was strongly emphasized in the program; how to smuggle oneself across a secured area under enemy guard to reach a position to take the killing shot.

Lieutenant Colin-G092 and Chief Petty Officer Kruger-G107 would be instructors in Demolitions, the application of modern field demolitions equipment to generate an "explosive solution" to battlefield problems, Lieutenant Daniel-G204 would be a trainer in field intelligence, whereas Chief Petty Officer Jack-G208 would train the Myrmidons in Special Reconnaissance. Meanwhile, the Combat Medicine School was administered by Lieutenant Cassandra-G006 and Chief Petty Officer Rachael-G025, both of them famous medical specialists amongst SPARTAN-III Gamma Company; their course in combat medicine included both practical and theoretical components, teaching the Myrmidons both of the theory of human physiology and combat trauma, and then practically how to stabilize wounded fellow Myrmidons in the field, and to secure them until they were exfiltrated to more properly-equipped UNSC medical facilities.

Lastly, Lieutenant Commander Clara-G235 would be a drill instructor in the Vehicular School, cross-training the Myrmidons on a variety of combat and non-combat vehicles, as the SPARTAN-IIs of lore had been trained—this would allow the Myrmidons to operate personnel carriers, tanks, and even VTOLs if their mission required it.

Birth and Embryonic Augmentation

The infamous Simon-G294 would be pardoned of his past crimes against the UNSC and would assume the position of Executive Officer (XO) of the Myrmidon Training Detachment.

A member of the Delta Squadron practising firearms. I caught sight of this soldier, performing surprisingly beyond normal human performances. He reminded me of the legendary SPARTAN-IIs. 2594. A picture of a Myrmidon on field maneuvers, taken by acclaimed photographer Kam Nadiah.

"They’re too different. They’re better, but [... unnatural]."

―Artemis-2995, regarding the Myrmidons' augmented capabilities

The birth of the Myrmidons was founded on their precedent, Kimberly Ivy Blackburn; artificial selection of optimal gamete donors and recipients to ensure that the progeny borne would be of unparalleled caliber on a genetic scale. One hundred sperm donors were chosen from decorated members of the UNSC special warfare community and conscientiously-accepting chosen women were artificially inseminated to produce artificial genetic crosses between the most exceptional that mankind had to offer.

Selection of gamete donors was carried out intensively, with extensive bioinformatics and high-throughput genetic sequencing employed to ensure that only the most exceptional humans were selected to be the parents of the future Myrmidons. Gamete donors were selected from a pool of decorated UNSC special warfare veterans of appropriate age, and these primary donors were intensively screened for physical, mental, and genetic fitness by the Myrmidon Program staff. Highly-fit individuals, secondary donors, were further screened with bioinformatics; genetic sequencing was employed to sequence single nucleotide polymorphisms (SNPs) and restriction fragment length polymorphisms (RFLP) to identify individual polymorphisms linked to disease susceptibility and also referenced against polymorphism sequence records obtained from the SPARTAN-Is, SPARTAN-IIs, SPARTAN-IIIs, and Kimberly Ivy Blackburn. Additionally, selection was performed to isolate only individuals that had the rs314276 single-nucleotide polymorphism in LIN28B, a genetic polymorphism shown to induce puberty at an early onset.

From the secondary pool, tertiary donors were finally selected based on bioinformatic analysis to confirm that they had few to none polymorphisms associated with disease susceptibility and that they had moderate to high homology to the polymorphism arrays of prior SPARTANs. What remained were two hundred-odd highly-fit UNSC special warfare veterans of both sexes; genetic crosses were made utilizing algorithms to calculate fitness post-breeding. These willing donors were matched, and sperm collection and artificial insemination of female hosts was performed.

Several days after artificial insemination and zygote formation, the first phase of chemical augmentation began — while the future Myrmidons were still in the uterus.

Embryonic stem cells are the founder cells of the entire body, capable of giving rise of every tissue in the adult body. However, in the human embryo, only several dozen of these embryonic stem cells are made, and these subsequently differentiate into all tissues, therefore limiting the amount and sizes of tissues that are produced in the embryo and the adult. Therefore, small molecule compounds were used to repress their differentiation, encouraging them to proliferate until large numbers of pluripotent stem cells were generated that could generate larger bodies.

Prior to implantation, sterile catheters were surgically integrated into the host uteruses, and a cocktail of small molecule compounds were perfused to inhibit the differentiation of the pluripotent inner cell mass (ICM) and to retain pluripotency, expanding the human pluripotent progenitor pool to increase the number of differentiated cells formed in postnatal and adult life. These compounds included inhibitors of differentiation (A-83-01, Dorsomorphin, SU5402, PD184352, Reversine, and CHIR99021), enhancers of embryonic stem cell self-renewal (Pluripotin, Theanine, and Flurbiprofen), and an inhibitor of stem cell apoptosis (Y-27632).

After sufficient expansion of the pluripotent inner cell mass, chemical blockade of differentiation was relieved, and the differentiating embryos underwent the second phase of embryonic augmentation; the embryos now underwent long-term latent chemical perfusion with a compound cocktail that chemically directed the embryonic specification or amplification of multipotent stem cell pools to increase downstream differentiated cell formation. Embryonic stem cells were relieved of self-renewal by cell cycle slowing (Stauriprimide), and were subsequently differentiated to the endoderm (IDE1, IDE2, and Cymarin), mesoderm (BIO-Acetoxime), and the neuroectoderm (Selegiline, SB431542).

However, in embryonic development, the embryonic tissues are directly formed from embryonic progenitor cells; these cells give rise to the various tissues of the embryo, which subsequently develop into the tissues of the adult. Therefore, the size of the embryo's tissues are limited by the numbers of their respective progenitor cells. To increase the size of the embryo, specific embryonic progenitor populations were chemically renewed; chemical activation of Wnt/β-catenin (SB-216763) was used to expand cardiovascular progenitors that would give rise to the heart, leukotriene inhibition (LY 171883) was used to specify and amplify haematopoietic stem cells in the bone marrow, and protein kinase C inhibition ((—)-Indolactam V), was employed to specify pancreatic progenitor cells. This led to increases in the size of the heart and pancreas, as well as increases in the number of haematopoietic cells available in the embryo and the adult.

Finally, specific embryonic tissues were specified directly through small molecules to directly increase the size of certain tissues. The maturation of the visual and somatosensory cortices in the brain was promoted in order to ensure finer sensory acuity in the adult Myrmidons through dopaminergic repression (Tianeptine). Brain size was increased by encouragement of neural stem cell differentiation to neurons (L-AP4). Retinoid signaling (All-trans retinoic acid) and histone deacetylase inhibition (Trichostatin A) were used to increase pancreas size and increase the numbers of pancreatic endocrine β-cells, enhancing the metabolism of the future Myrmidons. The size of the lung was increased, as well as its capacity of air, increasing the athletic competency of the Myrmidons, through Wnt and Notch regulation (PK115-584, Compound E). Furthermore, the size of the arms and legs of the children were increased by chemical inhibition of BMP signaling (LDN-193189), resulting in increased BMP-negative limb mesenchyme that was suitable for limb development.

The combination of the daring chemical augmentations; treatment of the children with drugs even while they were still embryos in the wombs of their mothers, would produce fearsome progeny whose characteristics were far superior than any other children — they were far larger than other human children, as a resultant of expanded numbers of transient pluripotent stem cells, and would have larger limbs, lungs, brains, hearts, and pancreata. These would make them more physically adept and more potent fighters than their predecessors in the SPARTAN-II and SPARTAN-III Programs, who were born as typical human children and instead acquired their potent capabilities after birth.

By the closure of 2578, all the Myrmidon progeny were successfully borne.

Galactic War

Battle of 34 Cygni M (Operation: MASTER STROKE)

The disastrous Battle of 34 Cygni M showed more than anything else that the Myrmidons were not invulnerable.

"34 Cygni [...] I'd say it's on the low side of the threat index."

―Lieutenant Commander Blackwell, UNSC Amorous Delay

Shortly after the fall of the core of the Covenant Empire, the Directorate of Fleet Intelligence embarked on a series of military reconnaissance missions to perform reconnaissance of the Covenant "Borderlands" to detect if any Covenant fleets had fled into the periphery of Covenant space. The UNSC Amorous Delay, an Oracle-class prowler, was dispatched to perform reconnaissance of the 34 Cygni System, a Bl1a+ hypergiant system 6,269 light-years from Earth as a part of this reconnaissance directive.

Although 34 Cygni was classified as a "low-threat" planetary system by Naval Intelligence, surprisingly, the Amorous Delay would detect an extremely high-power neutrino source on the thirteenth planet of the system, 34 Cygni M, a planet previously believed to be inhabited. Analysis of the Amorous Delay's reconnaissance data at the UNSC Directorate of Naval Intelligence Operations on Asphodel Meadows would cause considerable consternation amongst ONI staff: the only manmade sources capable of generating neutrinos were either nuclear reactors, or even more ominously, antimatter. The UNSC Department of Strategic Intelligence would begin to strongly believe that 34 Cygni M was likely harboring an antimatter bomb — magnetically-confined antimatter with a considerable damage potential.

The possibility that the renegade Covenant fleets, or else the Galactic Resistance, had antimatter explosives, significantly alarmed the Special Operations Command. Vice Admiral Carter, Commander-in-Chief of Joint Task Force Anaconda, announced his intention to dispatch a JTF Anaconda detachment to reconnoiter 34 Cygni M, and to neutralize the neutrino source. Eventually, discussions between the Fleet Office and the Naval Special Warfare Command would lead to the assignment of a fully-armed Mjöllnir-class destroyer, the UNSC Lexington, to 34 Cygni.

The finalized operation, known as Operation: MASTER STROKE by the UNSC, was for the Lexington to make a stealth entry into the 34 Cygni System, and to dispatch D774 Cormorant stealth dropships into 34 Cygni M's atmosphere, with an entire forty-man second-generation Myrmidon platoon onboard, "Joker One", led by Lieutenant Commander Lawrence-M517. The Myrmidons would infiltrate the planetary surface, reconnoitering and investigating the neutrino source. Afterwards, the Myrmidons would act as forward fire observers, calling down orbital gunfire from the Lexington to neutralize the presumed Covenant or Rebel threat.

The "operation", however, was an elaborate orchestration by Kawika Son of the Galactic Resistance to discriminately slaughter UNSC special forces; using the "neutrino source" as a lure, the rebels intended to trap the UNSC commando contingent that would be eventually dispatched to 34 Cygni M to investigate the radiation emissions. Furthermore, 34 Cygni's remote location, over six thousand light-years from Earth, would make JTF Anaconda unable to reinforce its forces once they came under rebel assault. Additionally, 34 Cygni itself, a massive hypergiant, would flood the system with radiation, rendering any distress calls impossible. The strategic location of the 34 Cygni System would deprive the UNSC of the endless array of naval support that always ensured victory on the ground: in this manner, the rebels intended to achieve a victory.

The Lexington's clandestine entrance into the system was detected by Simon-G294 in the Jian, a rebel stealth ship, hidden in the asteroid ring of the planetary system, thereby alerting the rebels that the UNSC had fallen for the risk-laden gambit.

The airborne insertion of the Myrmidons with the Cormorant dropships was initially successful: although the rebels knew that the Lexington was hiding behind the fourteenth planet of the system, the stealth characteristics of the D774 Cormorants ensured that the Myrmidons would be inserted in a clandestine fashion. Once the forty-man Myrmidon platoon had rallied, JOKER 14, a ten-man reconnaissance squad led by Lieutenant Alexander-M407 and Chief Petty Officer Bethany-M964, was dispatched down the river of a canyon in order to perform close reconnaissance of the neutrino source, which was still emitting at the terminus of the river.

As JOKER 14 made progress down the river, closing on their objective, the Myrmidons would finally be spotted by Redmond-M094, a former Myrmidon-turned-Rebel sniper. Led by Redmond, several rebels in camouflaged position along the canyon walls would begin coordinated sniper fire on the Myrmidon scouts down far below, using AS DAM anti-vehicular sniper rifles to defeat the substantial defenses of the Myrmidons' Mark IV RACE combat exoskeletons. Lieutenant Alexander-M407 would be the first killed, at the hands of Redmond-M094 — the first Myrmidon to perish in the Galactic War. Shortly therefore, JOKER 14, caught under heavy sniper fire and pinned down in the canyon's river, would be slaughtered. A three-man team led by Chief Petty Officer Bethany-M964 would attempt to escape, retreating and gaining elevation, eventually engaging Redmond in combat: however, they would be massacred in close quarters by the arrival of Artemis-2995 and Kimberly Ivy Blackburn.

The remaining contingent of Platoon Joker-One, still at a forward rendezvous point many kilometers upstream, were unaware of the deaths of their comrades because of heavy radio jamming by the rebels.

Several hours later, the rebels amassed several hundred infantry, assaulting the stationary position that Joker-One was holding upstream in the evening. However, the Myrmidons, even though only thirty strong, were far superior to the majority of the rebel contingent, mostly comprised of Unggoy, Kig-Yar, Sangheili, and unaugmented human fighters. With night vision devices, the Myrmidons drove off the rebel assault with few fatalities, slaughtering many of the rebels that had attempted to storm their positions. It was then that Lieutenant Commander Lawrence-M517 surmised that JOKER 14 had been lost in action during their reconnaissance mission, and in force, the remaining three Myrmidon squadrons pushed forward on the river, closing on the neutrino source. The Lieutenant Commander decided not to call in orbital gunfire at this point, in order to preserve the presumed secrecy of the presence of the UNSC destroyer in the outer rim of the system.

On the surface, the rebels were largely powerless to halt the Myrmidon advance down the river; however, rebel sniping missions would continue throughout the night, incurring several fatalities and a handful of casualties amongst the Myrmidon platoon, although Myrmidon counter-sniper missions were successful in also causing the deaths of several rebel snipers.

Marching throughout the night, by daybreak, Joker-One had achieved a tactical position at the mouth of the river, where the river led into a massive sinkhole: the source of a rebel camp, with a massive central fortress housing the neutrino emissions. Meanwhile, the rebels had substantially reinforced their defenses, with a substantial number of both Covenant and human fighters, supported by the Arbiter himself and a cadre of Sangheili Honor Guards, as well as Wraith-class and Locust-class assault vehicles. Small Myrmidon detachments were tasked on special reconnaissance missions, detailing the strengths of the rebel defenses around their camp, and noting rebel sniper positions and heavy weapon emplacements, and preparing laser rangefinders to call in orbital gunfire.

Lieutenant Commander Lawrence-M517: "This is Joker One-Six to Lexington Fire Control. Requesting fire mission at grid 98516 by 015399, altitude oh-five-seventeen on Objective Pendulum. Be advised, enemy infantry and mechanized formations are present in substantial force at the objective."

Captain Lawrence Cleft: "Negative, negative! We are under heavy sierra-romeo assault, repeat—heavy enemy orbital activity—all forward compartments have been compromised—"

Lieutenant Commander Lawrence-M517: "Sierra-romeo?"

Lieutenant Alice-M860: "Seraphs, sir. Covenant interceptors."

— Joker-One's request for orbital gunfire from the UNSC Lexington^[src]

The Myrmidons signaled for orbital support from the Lexington above, but their call was intercepted by rebel electronic warfare, led by Perseus-2042. Shortly thereafter, a Covenant Assault Carrier, a former element of the Sanghelios Defense Fleet and allied with the rebels, jumped in-system, engaging the Lexington with overwhelming fighter wings. Within minutes, the destroyer, far outmatched by the gargantuan carrier, would be decimated, unable to call for reinforcements to UNSC Fleet Command. The loss of the destroyer, with all hands and support craft, would leave Joker-One stranded on 34 Cygni M, far below.

Knowing that they were far outnumbered, unable to retreat from 34 Cygni, and would be unable to communicate with Special Operations Command thousands of light-years away, Lieutenant Commander Lawrence-M517 committed his platoon to a suicide mission: they would storm the rebel camp, securing the antimatter bombs, and then detonating them, forever destroying the planet of 34 Cygni M and all the rebels on it in a matter-antimatter annihilation reaction.

Even despite the overwhelming number of rebel troops, tanks, and emplacements guarding the camp, the Myrmidons fought admirably. Led in a massive frontal assault by their platoon commander, the surviving twenty-five-odd Myrmidons surged into the camp at weakly-defended gaps in their defenses. Myrmidon sharpshooters on the perimeter managed to disable many rebel and Covenant vehicles with iridium penetrators, depriving the enemy of a vital advantage while the majority of their contingent stormed the camp, assaulting quickly and lightly. The rebel forces, caught unaware, were unable to resist the terrible wrath of the Myrmidons: armored in their exoskeletons and armed with top-of-the-line UNSC weaponry, the Myrmidons broke through many of the rebel defenses with few fatalities, finally storming the central command center that was the source of the neutrinos. Covenant spacecraft from orbit were largely unable to stop the Myrmidon assault as the Myrmidons quickly dashed and bypassed many of the bases's defensive contingents.

With over twenty Myrmidons surviving, but many wounded, Lieutenant Commander Lawrence-M517 secured the rebel command post, with hundreds of dead rebels scattered throughout the camp. Only one squadron leader, Lieutenant Francis-M133, was killed in the assault on the command center, with many more Covenant and human rebel command staff slaughtered by the fierce close-quarters combat with the Myrmidons.

Lieutenant Commander Lawrence-M517: "Eight-Five! Where is that fucking bomb? Blow them to hell!"

Senior Chief Petty Officer Carole-M385: "Sir! Begging the Commander's pardon, sir — the neutrino source is not an antimatter bomb, sir. It's an unshielded Slipspace drive."

Lieutenant Commander Lawrence-M517: "Then—then our deaths will be for nothing—?"

— Lieutenant Commander Lawrence-M517 and Senior Chief Petty Officer Carole-M385, shortly before their deaths^[src]

While the enraged camp full of rebels prepared to retake their command post, the Myrmidons prepared to defend their captured fortress in the center of the camp while Senior Chief Petty Officer Carole-M385 attempted to arm the supposed antimatter bombs in the depths of the command post. It was to the astonishment of the Myrmidons that the neutrino source was in fact merely an unshielded Slipspace drive from a cargo freighter — the device, violating matter-energy causality, had been a copious source of neutrinos: an inexpensive lure to bring the Myrmidons to this desolate world and kill them.

Moments later, a massive rebel attack, led principally by Esther-G071 and Kimberly Ivy Blackburn, would strike the Myrmidon-held fortress.

The children, stunned by the revelation that they had been drawn across six thousand light-years and had lost the majority of their platoon attacking a simple Slipspace drive, were demoralized, fatally. Many could not believe that dozens of their friends had been killed simply to reach an unshielded Slipspace reactor — the rebel counterattack, led by former SPARTAN-IIIs, brutally slaughtered many of the shocked Myrmidons. Many of the Myrmidons were deprived of the will to fight, and were horribly massacred by the enraged rebel stock troops.

Seconds before his death, a lost and vacant Lieutenant Commander Lawrence-M517 would transfer command of the platoon to Lieutenant Jasmine-M644, one of his squad leaders. Shortly thereafter, the Lieutenant Commander would engage Kimberly Ivy Blackburn in one-on-one combat, the latter dismembering him, and then slaying him before the horrified eyes of his platoon subordinates. Lawrence would die, his mind and resolve lost: he had spent his entire childhood training for war, only to have his entire detachment die in a simple trap.

Soon, many of the platoon's still-surviving leaders, such as Senior Chief Petty Officer Carole-M385 and Lieutenant Alice-M860, would fall as well, their position overrun by hundreds of feral rebels.

Lieutenant Jasmine-M644 and a few others would escape the devastated command center, heavily wounded, sprinting away to the periphery of the camp, where the Myrmidon sharpshooters that had taken out the Covenant Wraiths and Locusts awaited. Entrusted with command of the devastated Joker-One platoon, Lieutenant Jasmine-M644 and six other atrociously-wounded Myrmidons would flee into the river, where a handful of them would killed by relentless plasma bombardment from strafing Seraph interceptors, the children vaporized in superheated plasma charges.

After mere minutes of the airborne assault, only Lieutenant Jasmine-M644 would remain — endeavoring to hold off until the UNSC would send scouts into the system to investigate the fates of Joker-One, Lieutenant Jasmine would hold out for nearly a week in the wilderness, evading the rebels and frustrating their best efforts to find her. It was only after six and a half days of terrified fleeing that Jasmine would collapse into sleep, physically exhausted and emotionally devastated. In her sleep, she would be found by David Wellesley, who killed the sleeping girl.

The atrocious Battle of 34 Cygni M would mark the death of an entire Myrmidon platoon, Joker-One: the largest loss of Myrmidon life ever in a single engagement. The Myrmidons' invulnerability was finally dethroned, with many ONI officers shocked at how easily their finest warriors had been trapped and slaughtered.

The slaughter intoned that the Myrmidons were like any other infantry unit: vulnerable to sniper fire, easily able to be encircled and trapped, and most all: that they were able to be killed.

Trainee Roster

1^st Generation (2580—2607)

A Myrmidon in light tactical armor for close-quarters counterterrorism operations.

• M005-Eve: Squadron Chief, Delta Squadron
• M008-Eleanor
• M013-Karen: Detachment Senior Enlisted, Special Combatant Component
• M014-Brandon: Commanding Officer, Bravo Squadron
• M021-Florian: Commanding Officer, Delta Squadron
• M028-Alyssa: Designated Sharpshooter, Delta Squadron
• M047-Bjorn: Operations Officer, Delta Squadron
• M049-Ezekiel: Squadron Chief, Charlie Squadron
• M050-Alexis: Designated Sharpshooter, Charlie Squadron
• M055-Gordon: Designated Sharpshooter, Delta Squadron
• M063-Caroline: Commanding Officer, Alpha Squadron
• M064-Raphael: Commanding Officer, Special Combatant Component
• M079-Blake: Executive Officer, Charlie Squadron
• M085-Everest: Commanding Officer, Charlie Squadron
• M094-Redmond: Designated Sharpshooter, Delta Squadron
• M097-Daphne: Delta Squadron

Order of Battle

Task Force Myrmidon (2590—2604)

The formalized order of battle (OB) of the Myrmidon Program.

Current as of the Beyond Veil's Azure Crisis (2594)

• Myrmidon Headquarters Company (HHC)
  • Commanding Officer: Vice Admiral Kawika Son, Commander-in-Chief, UNSC Naval Special Warfare Command (VADM, O-9)
  • Noncommissioned Officer in Charge: Master Chief Petty Officer Whitney-G179 (MCPO, E-9)
  • Executive Officer: Rear Admiral Evelyn Lake (RADM, O-8)
  • Chief of Operations: Rear Admiral Chandler Danial (RADM, O-8)
  • Chief of Operations: Rear Admiral Randall Hayes (RADM, O-8)
  • Chief of Intelligence: Rear Admiral Peter Thoreau (RADM, O-8)
  • Deputy Chief of Operations: Commander Cassidy-G044 (CMDR, O-5)
  • Assistant Chief of Operations: File:Senior Chief Petty Officer Insignia.png Senior Chief Petty Officer Apollo-2994 (SCPO, E-8)
  • Senior Commissioned Advisor: Rear Admiral Beah Schore (Ret.)
  • Senior Enlisted Advisor: Master Chief Petty Officer Kimberly Ivy Blackburn (Ret.)

Captain Raphael-M064 was Commanding Officer, Myrmidon Mobility Detachment, serving as the field commander of the Myrmidons.

• Myrmidon Mobility Detachment
  • Commanding Officer: Captain Raphael-M064 (CAPT, O-6)
  • Detachment Senior Enlisted: Master Chief Petty Officer Karen-M013 (MCPO, E-9)
• Myrmidon Squadron ALPHA (Direct Action / Assault)
  • Commanding Officer: Commander Caroline-M063 (CMDR, O-5)
  • Squadron Senior Enlisted: CPO (Chief Petty Officer, E-7)
  • Alpha Squadron XO: LT (Lieutenant, O-3)
  • Squadron Operations Officer: LTJG (Lieutenant Jr. Grade, O-2)
• Myrmidon Squadron BRAVO (Direct Action / Assault)
  • Commanding Officer: Commander Brandon-M014 (CMDR, O-5)
    • Squadron Senior Enlisted: CPO (Chief Petty Officer, E-7)
    • Bravo Squadron XO: LT (Lieutenant, O-3)
    • Squadron Operations Officer: LTJG (Lieutenant Jr. Grade, O-2)
• Myrmidon Squadron CHARLIE (Direct Action / Reconnaissance)
  • Commanding Officer: Commander Everest-M085 (CMDR, O-5)
  • Squadron Chief: Chief Petty Officer Ezekiel-M049 (CPO, E-7)
  • Executive Officer: Lieutenant Blake-M079 (LT, O-3)
  • Operations Officer: (LTJG, O-2)
  • Myrmidon Team CHARLIE-ONE ("Specter Team") (Close-range assault)
    • Commander Everest-M085
    • Chief Petty Officer Ezekiel-M049
  • Myrmidon Team CHARLIE-FOUR ("Phantom Team") (Sniper / Reconnaissance)
    • Lieutenant Blake-M079
    • Chief Petty Officer Alexis-M050
• Myrmidon Squadron DELTA (Direct Action / Covert Action)
  • Commanding Officer: Commander Florian-M021 (CMDR, O-5)
  • Squadron Chief: Chief Petty Officer Eve-M005 (CPO, E-7)
  • Executive Officer: LT (Lieutenant, O-3)
  • Operations Officer: Lieutenant Jr. Grade Bjorn-M047 (LTJG, O-2)
  • Myrmidon Team DELTA-ONE ("Valkyrie Team") (Close-range assault)
    • Commander Florian-M021 (CMDR, O-5)
    • Chief Petty Officer Eve-M005 (CPO, E-7)
    • Lieutenant Jr. Grade Bjorn-M047 (LTJG, O-2)
    • Petty Officer 2^nd Class Daphne-M097 (PO2, E-5)
  • Myrmidon Team DELTA-SEVEN ("Loki Team") (Sniper / Reconnaissance)
    • Petty Officer 1^st Class Alyssa-M028 (PO1, E-6)
    • Petty Officer 2^nd Class Gordon-M055 (PO2, E-5)

Numerous SPARTAN-IIIs, such as Senior Chief Petty Officer Whitney-G179 (pictured) would be recruited to both train and support the Myrmidons during their training.

• Myrmidon Support Detachment
  • Commanding Officer: Captain Artemis-2995 (CAPT, O-6)
  • Commander, Aviation Wing
  • Commander, Logistical Detachment
  • Commander, Intelligence Detachment
  • Myrmidon Training Detachment
    • Commanding Officer, Training Detachment: Commander Esther-G071 (CMDR, O-5)
    • Executive Officer, Training Detachment: Lieutenant Commander Simon-G294 (LCDR, O-4)

• • • Executive Officer, Training Detachment: Commander Daniels-G288 (CMDR, O-5)
    • Executive Officer, Training Detachment: Lieutenant Commander Joshua-G024 (LCDR, O-4)
    • Executive Officer, Training Detachment: Lieutenant Commander Clara-G235 (LCDR, O-4)

• • • Assistant Officer-in-Charge, Training Detachment: Lieutenant Colin-G092 (LT, O-3)
    • Assistant Officer-in-Charge, Training Detachment: Lieutenant Amy-G094 (LT, O-3)
    • Special Warfare School, Primary Trainer: File:Senior Chief Petty Officer Insignia.png Senior Chief Petty Officer Whitney-G179 (SCPO, E-8)
    • Special Warfare School, Primary Trainer: File:Senior Chief Petty Officer Insignia.png Senior Chief Petty Officer Jennifer-G272 (SCPO, E-8)
    • Sniper School, Primary Trainer: Lieutenant Jr. Grade Maria-G173 (LTJG, O-2)
    • Sniper School, Primary Trainer: File:Senior Chief Petty Officer Insignia.png Senior Chief Petty Officer Konrad-G319 (SCPO, E-8)
    • Sniper School, Primary Trainer: Chief Petty Officer Angelina-G152 (CPO, E-7)
    • Sniper School, Primary Trainer: Chief Petty Officer Christie-G205 (CPO, E-7)
    • Demolitions School, Primary Trainer: Lieutenant Colin-G092 (LT, O-3)
    • Demolitions School, Primary Trainer: Chief Petty Officer Kruger-G107 (CPO, E-7)
    • Field Intelligence School, Primary Trainer: Lieutenant Daniel-G204 (LT, O-3)
    • Field Reconnaissance School, Primary Trainer: Chief Petty Officer Jack-G208 (CPO, E-7)
    • Combat Medicine School, Primary Trainer: Lieutenant Cassandra-G006 (LT, O-3)
    • Combat Medicine School, Primary Trainer: Chief Petty Officer Rachael-G025 (CPO, E-7)
    • Vehicular School, Primary Trainer: Lieutenant Commander Clara-G235 (LCDR, O-4)
  • Commander, Communications Detachment
  • Myrmidon Medical Detachment
    • Executive Officer, Medical Detachment: Lieutenant Cassandra-G006 (LT, O-3)

Myrmidon Special Operations Battalion (2995)

The introduction of the second-generation Myrmidon force in 2995 at the dawn of the Galactic War would lead to the formation of the Myrmidon Special Operations Battalion, UNSC Naval Special Warfare Command. This second iteration would encompass a full battalion that numbered approximately nine hundred strong, bringing the entire strength of the Myrmidon Program to just under a thousand Myrmidon operators.

The novel battalion would be comprised, in its entirety, of nine full maneuver companies, each approximately one hundred strong and named based on a modified variation of the NATO Phonetic Alphabet based on where the four first Myrmidon squadrons had left off. Each company was led by a Commander (O-5) and a Master Chief Petty Officer (E-9), and would be comprised of three rifle platoons, each approximately thirty strong. Each platoon would be led by a Lieutenant Commander (O-4) and a Senior Chief Petty Officer (E-8), and would be comprised of three or four operational squadrons, each led by a Lieutenant (O-3) and a Chief Petty Officer (E-7).

The entire battalion would be administrated by its commanding officer, a Captain (O-6), and its senior enlisted advisor, a Command Master Chief Petty Officer (E-9).

The maneuver companies were named as follows:

1. Myrmidon Company ECHO
2. Myrmidon Company FOX
3. Myrmidon Company GHOST
4. Myrmidon Company HOTEL
5. Myrmidon Company INDIGO
6. Myrmidon Company JOKER
7. Myrmidon Company KILO
8. Myrmidon Company LIMA
9. Myrmidon Company MAKO

On the Myrmidon tactical intranet, standard UNSC voice procedure was used, with each Company assigned a unique callsign (i.e. "Joker"). Subsequently, the company commander would be referred to as "Joker Six" and the company chief was referred to as "Joker Five", with the assistant commanding officer referred to as "Joker Four". The subordinate platoons were designated as "Joker One", "Joker Two", and "Joker Three". Individual squadrons were referred to be adding a second digit onto the platoon's identifying number, for example: JOKER 32 or JOKER 14.

Joker Company, First Platoon

• Lieutenant Commander Lawrence-M517, Commanding Officer of First Platoon (Joker)
• Senior Chief Petty Officer Carole-M385, Platoon Chief
• Lieutenant Alice-M860, Section Leader of Squad One (Rifles)
• Lieutenant Francis-M133, Section Leader of Squad Two (Rifles)
• Lieutenant Jasmine-M644, Section Leader of Squad Three (Rifles)
• Lieutenant Alexander-M407, Section Leader of Squad Four (Recon)
• Chief Petty Officer Bethany-M964, Section Chief of Squad Four

Behind the Scenes

• The Myrmidons are named after the Myrmidons of Greek mythology, another Greek warfighting tribe similar to the Spartans in ancient times.

• As of September 2009, it has taken the author one hundred and forty-nine (149) separate publications from research journals (which are all referenced below) to accrue the fifty-eight (58) drugs that are described as chemical augmenters for the Myrmidons. Each one of the fifty-eight drugs is referenced extensively by articles in basic research, transitional research, and/or clinical research.

Acknowledgements

The author (RelentlessRecusant) thanks his mentors and colleagues at the Harvard Stem Cell Institute, the UMDNJ-Robert Wood Johnson Medical School, the UMDNJ University Hospital, and Rutgers University for mentoring him over the years to allow him to accrue his knowledge of chemical biology, stem cell biology, developmental biology, and human physiology that was needed to write this article.

The author also thanks Actene for allowing him to use characters from Team Jian and the High-Priority Assassination Program in this article, as well as ODST Joshie, who allowed him to use characters from Team Xiphos in this article.

References

Literary References

• Halo: Beckon Forth Sunrise (2578)
• Halo: Children of War (2580-2590)
• Halo: Beyond Veil's Azure (2590-2596)
• Halo: Galactic Era (2600-2604)