|This article, Acumen Science Laboratories, was written by -AR- and RelentlessRecusant. Please do not edit this fiction without the writers' permission.|
- "Humanus rememdium per progressio"
- ―Company slogan (Human cures through progress)
- "Human life [is] the most precious commodity in this galaxy."
- ―Beah Schore, Chief Scientific Officer
Acumen Science Laboratories (ASL) is a major interplanetary conglomerate that is a leader in UNSC healthcare, specializing in pharmacology and drug discovery, chemical biology, and providing high-quality reagents for biological research. Originally modestly founded by Dr. Benjamin Greaves of Dana Farber Cancer Center of Boston, Massachusetts, the corporation would be originally headquartered at London, Earth in 2342.
Later, Acumen Science's preliminary and continual successes in the development of life-saving pharmacological agents and paradigm shifts in the developing field of regenerative medicine would allow Acumen Science to merge with other life sciences corporations, and Acumen would reach monopoly proportions, spreading across dozens of UNSC colony worlds, later re-headquartering upon the Spirit of Progress, a massive space staation in orbit over Earth that drew significant media attention. Acumen Science continually is asked to collaborate with other pharmacology corporations, and is contracted by the UNSC Defense Force and the UNSC Office of Naval Intelligence.
Acumen Science is best known for Acuplanin, the first pharmacological treatment for Type 1 Diabetes, VyThera, the first safe vaccine for HIV-1, CerebroLive, the first effacious treatment for multiple sclerosis, and Influcure, the first cure for the avian influenza.
Acumen Science Laboratories is managed by a Chief Executive Officer (CEO) that oversees Acumen Science's directions at the highest levels; advising the CEO are other highly-titled executives, such as the Chief Scientific Officer (CSO), which directs the company's scientific and research directions, the Chief Financial Officer (CFO), and the Chief Marketing Officer (CFO). All executives are held liable to a Board of Directors.
Acumen Science Laboratories's most outstanding strength is its highly advanced, developed, and efficient pharmacology program, which is dedicated to drug discovery, compound development, clinical trials, and delivering accessible cures to the common man or woman. Acumen Science's pharmacology division is highly regimented in order to facilitate a highly-streamlined system of drug discovery and development, and there are four major research & development (R&D) programs which manage Acumen Science's gross pharmacological initiatives.
The Molecular and Cellular Biology Program (MCB) is the tier-one program of Acumen Sciences, the basic research and life sciences division responsible for the dissection of developmental, physiological, pathophysiological, and regenerative molecular and cellular mechanisms in the developing and adult human. Through an academic research direction, the MCB Program is responsible for the dissection of highly complex biological processes and the identification of plausible molecular effectors for drug discovery; the MCB Program is paramount to all of Acumen Science's researches.
The MCB Program sets the framework for rationally-designed drug discovery to ameliorate pathology in model systems; drug development is then placed in the responsibility of the Chemical Biology Program, which practices screen development, assay development, high-throughput screening (HTS), high-content analysis (HCS), database informatics, hit identification, in silico optimization, and structure-activity relationship (SAR) studies to generate lead compounds that effect a key biological pathway of interest through chemical small-molecule modulation. The generation of lead compounds marks the hand-off from the "drug discovery" group to the "drug development group"; the Clinical Medicine Program. Preliminary toxicology studies are performed to grant UNSC Medical Corps approval for first-in-human (FIH) three-phase clinical trials of lead compounds in humans, and extensive effaciousness, toxicology, and pharmaepidemiology is performed by the Clinical Medicine Program to finally drive small-molecule lead to bioavailable life-saving drug.
Acumen Science's successes are founded on this simple three-step system; Molecular & Cellular Biology → Chemical Biology → Clinical Medicine. These programs identify the three paradigms of Acumen Science's rationally-designed approach to drug discovery, with basic sciences to identify small-molecule targets, the development and optimization of hit compounds, and finally lead maturation and drug development.
A fourth program, the Stem Cell and Regenerative Medicine Program (SCRM), is an orphan program founded by Dr. Beah Schore, current Chief Scientific Officer and former Harvard University and Howard Hughes Medical Institute investigator. Drawing assets from the consolidated MCB Program, the Stem Cell & Regenerative Medicine Program is actively providing a framework for second-generation cures through stem cell biology and regenerative medicine and the diversification of Acumen's portfolio.
- Department of Bioinformatics
- Department of Chemical Biology
- Department of Comparative Biology
- Department of Developmental Biology
- Department of Heuristic Biology
- Department of Medicinal Chemistry
- Department of Metabolism
- Department of Neurobiology
- Department of Pathology
- Department of Pharmacology
- Department of Signal Transduction
- Department of Stem Cell Biology / Center for Regenerative Medicine
- Department of Systems Biology
- Department of Toxicology
Acumen Science is a galactic leader in human healthcare, and has a substantial investment in many prominent basic, translational, and clinical fields in biology and chemical biology. Acumen routinely employs advanced high-throughput screening (HTS) and high-content analysis (HCA) in large drug discovery programs to identify chemical entities that modulate a molecular pathway of interest, and then employs intensive counterscreening, structure-activity relation (SAR) studies, toxicology studies, and other assays to develop lead compounds for drug development. After first-in-human (FIH) assays and clinical trials, Acumen Science collaborates with the UNSC Medical Corps to file patents for its drugs.
The drug discovery process that Acumen Science employs is outlined below.
Pharmacology and High-Throughput Screening
Acumen Science's namesake is pharmacology—the research and design of pharmacological compounds to prevent or ameliorate human disease. It is through Acumen that pharmacology has reached a new grand scale and has made several significant paradigm shifts, and through its sheer size, Acumen has been able to generate a colossal pharmacology initiative.
Pharmacobiology is a highly complex and diversified field that includes pharmacological chemistry, pharmacognosy, chemical biology, pharmacokinetics, pharmacodynamics, pharmacogenetics, and pharmacotherapy, vaguely outlining crucial steps in the development process from small molecule hit to disease-curing drug.
Generation of small-molecule libraries
Acumen Science has a significant investment in the generation of chemical small-molecule libraries; high-content libraries containing thousands or millions of unique and chemically-defined small-molecule chemicals for biological screening. For standardization purposes, the billions of Acumen's libraries are typically solubilized in dimethyl sulfoxide (DMSO) solvent to control for solvent-induced toxicity, and chemical compounds are concentrated a concentration of 10 μM to allow for dilution to effective concentrations. However, long-chain fatty acid libraries are non-polar, and are instead solubilized in complex solutions of lipids and carrier proteins. Biological libraries are solvated differentially, depending on the classification of their contents. Chemical libraries are typically retained for up to two years at a holding temperature of -20 °C, while biological libraries are typically retained for two weeks at the same temperature.
High-throughput screening necessitates advanced and efficient combinatorial chemistry to rapidly synthesize diverse chemical libraries to actuate screening. Much lessons have been learned from the early chemical initiatives of the 21st and 20th centuries, where the early drug discovery programs focused on the generation of massive libraries but didn't focus on the separation of mixed products; the screening of libraries where each well represented multiple entities added multi-compound effects to screening, including false positives, combinatorial toxicity, and false negatives. Thus, hits relied on the resolution of compound mixtures, and this was largely unsuccessful.
Acumen's intensive chemical sciences investigations are consolidated into the Department of Medicinal Chemistry, which is responsible for the generation of small-molecule chemical libraries; the Department of Medicinal Chemistry invests significantly with the Department of Chemistry and Chemical Biology at Harvard University, the Department of Chemistry at the Massachusetts Institute of Technology (MIT), the Department of Chemistry at the University of Virginia, and the Department of Natural Products at the Hebrew University of Jerusalem, four Earth-based research universities in the former United States of America (USA) and Israel which have been leaders in chemical biology.
where small-molecule compounds are rapidly synthesized from combinatorial synthesis of known bioactive organic precursors or, to a much lesser extent, are found from pharmacognosy and exploration of biodiverse animal and plant life. Acumen Science maintains a pharmacognosy edge, and has been known to "seed" distant colonies, such as Beryl, in order to screen for bioactive and novel small-molecules in the indigenous flora and fauna. These small-molecule libraries are typically organic or are organometals, necessitating a thorough knowledge of organic chemistry and physical chemistry to synthesize.
Screening of small-molecule libraries are targeted to a specific molecular target, or untargeted, only looking for phenotype, as in the case of Acuplanin. Acumen Science has and is renowned for its high-content, high-throughput chemical biology facilities, how Acumen made its trademark appearance even on Earth, and Acumen has invested countless trillions of credits in the design and construction of vast screening facilities in order to serve as its powerhouse. This gives it a gross lead in the design of pharmacologicals against any possible competitor. Such screening facilities are configured to screen billions or trillions of 96-well or 384-well plates within a single day, and with incredible resolution and high-content automated assay systems. This allows for the reliable generation of "lead compounds" that show greatest desired bioactivity, and are subsequently optimized through cheminformatics approaches — quantitative structure-activity relationship (QSAR), in silico artificial modeling, virtual high-throughput screening, bioactivity profiling and specificity, etc... Untargeted screens that generate lead compounds are biologically profiled through mass spectrometry, chemical genetics and complementation.
Optimized lead compounds that show the most specific bioactivity profile after several months of optimization and secondary screening are then chosen for drug design, where medicinal chemistry is used to enhance the "drug"-ness of a compound; to ensure its easy administration to a patient, its distribution within the patient's body, its pharmacodynamics, and its pharmacokinetics and metabolism and eventual secretion. Acumen Science typically places high priority into ensurance that a lead compound can be further optimized to fit the Lipinski's Rule of Five; that it has the desirable aqueous and lipid solubility necessary to be orally administered (in a pill or tablet), absorbed in the gastrointestinal (GI) tract, is soluble in the aqueous blood, and is capable of diffusing through the lipid cellular membrane to act on its intracellular targets.
Chemical to Drug
New chemical entities (NCE) must undergo extensive animal and human trials under the oversight of the UNSC Medical Corps before a drug is marketable and legally prescribable and usable in humans. Potential drug candidates first undergo experimentation in animal models, where they are evaluated for in vivo pharmacokinetics and also for pharmacodynamics and toxicity, specifically cardiotoxicity, hepatotoxicity, neurotoxicity, and renotoxicity, the four major causes of death with drugs. Successful kinetic and toxic profiling will lead to Stage I clinical trials, where NCEs are carefully administered to human patients—the first time the drug is given to humans. Secondary toxicities, such as reproductive toxicity and immunotoxicity, are studied at this stage. The lack of undesirable side effects in the healthy human adult will lead to the controlled and limited testing of drugs in their intended patients in successively advanced clinical trials. At the end, clinical data is compiled by the UNSC Medical Corps. Acumen Science's carefulness and thoroughness in pre-clinical chemical biology and modeling typically ensure that a very high percentage of its drug-hopefuls eventually are confirmed as drugs usable in humans.
At this time, contraindications are established for Acumen's prospective drugs, and chemical engineering is performed to ensure large-scale manufacture of Acumen's drugs and their conversion into a clinically-usable form, such as a tablet or a stabilized solution for intravenous or intramuscular perfusion.
Small-Molecule Modulation of Hedgehog Signaling
The Hedgehog (Hh) signaling pathway is a highly complex and conserved molecular signaling pathway that controls embryonic development and adult tissue homeostasis. During embryonic development, Hh signaling is a potent morphogen, and local Hh concentrations establish defined signaling gradients that pattern the embryo, such as ventralization of neural tissues. Hedgehog still remains a potent biological signal in the adult, where it has been shown to control adult stem cell niches.
While hedgehog (Hh) was originally identified as one signaling factor in Drosophila, three highly-conserved paralogs exist in the mammal; these include sonic hedgehog (Shh), desert hedgehog (Dhh), and Indian hedgehog (Ihh), each with defined and unique biological activity and are differentially expressed.
Hedgehog is an exemplary model of a traditional signal transduction pathway. It is principally governed by the Patched (Ptch) receptor, which in the absence of hedgehog ligand, binds and represses the Smoothened (Smo) G-protein-coupled receptor (GPCR). Presence of hedgehog factor leads to the binding of Patched receptor and relieves its inhibition of Smoothened. In the mammal, this requires Smoothened activity at non-motile cilia, which leads to the activation of Gli family zinc-finger transcription factors, which serve as transcription activators (Gli1 and Gli2) and repressor (Gli3) that mediate hedgehog-mediated transcription.
Small Molecule Regulation
In the 1960s, the alkaloid natural product KAAD-Cyclopamine was found to induce cyclopia in newborns; human children were being born with one eye, not two. This extraordinary birth defect has since spurred extensive investigation of cyclopamine's devastating molecular mechanisms, and the 20th and 21th centuries have seen a significant realization and characterization of the hedgehog (Hh) signaling pathway, especially when cyclopamine's effects were found to be mediated by Smoothened, a critical component of hedgehog signaling.
Cyclopamine's substantative mutagenic effects have spurred extensive investigation into the molecular pathways of hedgehog (Hh) signaling, and since then, because of a detailed understanding in the molecular transduction of hedgehog signals in the 21st century, it has been possible to design high-throughput screening assays to selectively inhibit or activate hedgehog signaling at specific molecular levels.
The first and most obvious level at which to perturb hedgehog signaling is at its most superficial level; the sonic hedgehog (Shh) signaling ligand. In 2009, a team led by Stanton at the Broad Institute of Harvard and MIT and the Howard Hughes Medical Institute identified as 12-membered macrocycle, robotnikinin (IUPAC name: (E)-N-(4-chlorobenzyl)-2-(5,12-dioxo-2-phenyl-1-oxa-4-azacyclododec-8-en-6-yl)acetamide), IC50 = 5 μM in inhibiting Gli1-luciferase transcription in a model of human skin against N-palmitoylated recombinant Shh N-terminus fragment.
The most extensive regulation of hedgehog signaling by small molecules has occurred at the level of the Smoothened (Smo) receptor. The alkaloid teratogen cyclopamine, and its synthetic chemically-optimized derivative, KAAD-cyclopamine, have been shown to inhibit hedgehog signaling at the level of Smo by directly binding to its heptahelical bundle. Cyclopamine has been described to have IC50 = 300 nM, but Taipale and colleagues at the Johns Hopkins University School of Medicine and the Howard Hughes Medical Institute in 2000 reported the cyclopamine synthetic derivative KAAD-cyclopamine ("3-Keto-N-(aminoethyl-aminocaproyl-dihydrocinnamoyl)cyclopamine"), which is over tenfold more potent and has an IC50 = 20 nM for inhibitory activity.
Small Molecule Regulation of Wnt Signaling
Small Molecule Regulation of Bone Morphogenetic Protein Signaling
Small Molecule Regulation of Glucokinase Activity
Small Molecule Regulation of Drug Addiction
Small Molecule Regulation of Central Nervous Regeneration
Small Molecule Regulation of Notch Signaling
Small Molecule Regulation of Muscular Reprogramming
Small Molecule Regulation of Neurological Disorders
Non-Canonical Drug Programs
Some of the marketed organic and inorganic pharmacologicals that have made Acumen famous are listed below—
- Influcure: Influenzavirus A and high-pathogenicity avian influenza (H5N1) pharmacological cure; viral PB2 RNA polymerase specific inhibitor, designed on research performed by Harvard Stem Cell Institute (HSCI). Represented a paradigm shift for the generation of a viral polymerase inhibitor that was not a nucleotide analog for rather a specific inhibitor to the polymerase structure.
- CerebroLive (Silver hexapotassium aurophosphate): Prophylactic treatment and also cure for multiple sclerosis (MS) and Guillain-Barré syndrome; artificial superconductor of fully- or partially-myelinated fibers, preventing disease progression if used in early stages.
- OsteoStrong (Strontium carbide): Treatment and cure for osteoporosis and osteopenia, used in more elderly individuals to enhance end-life lifestyle.
- VyThera: First effacious and safe inactivated vaccine for HIV-1, succeeded in almost immediately curbing the spread of the UNSC's HIV pandemic, as well as having some therapeutic benefit in currently-infected individuals. Peptide and small-molecule analog complex designed for most rapid temporal kinetics in antibody generation and immune plasma cell proliferation and response.
- Acuplanin: First cure for Type 1 Diabetes. Polypharmacological with complex biological activity with known kinase and transcription factor affinity. Represented a paradigm shift for the generation of a novel transcription factor inhibitor.
Stem Cell and Regenerative Biology
Regenerative Medicine and Xenobiology
Acumen is a one of the strongest galactic proponents of "regenerative medicine", an evolving clinical paradigm where clinical therapy involves the regeneration of diseased or damaged tissue in contrast to the past paradigm of using pharmacological agents that inhibit pathogenic or pathological activity, even despite Acumen's titanic investment in pharmacologicals. Acumen's associations with the UNSC Office of Naval Intelligence have given it unrestricted access to Covenant corpses captured on the battlefield, most notably the Lekgolo (Hunter) species, whose regenerative capacity and intercellular communicatory mechanisms are unrivaled by any other galactic species, with perhaps the exception of the Flood. Investigating Lekgolo biology and their compartmentalization and diversification of a single multi-function template cell has given Acumen investigators a peerless edge in regenerative biology, allowing Acumen Science to begin thinking on how to use Covenant xenobiology to understand human and animal regeneration by dissecting its cellular and molecular mechanisms, and how to use Lekgolo regeneration perhaps as a future clinical augment to current limited human regenerative capacity.
Under PATRIOT, Acumen also has access to the human Flood combat form corpses of SUBTANK, collected by UNSC forces on the Ark; Acumen has been rumored to be at the forefront in regenerative biology because of its dissection and understanding of Flood biology. Already, Commander Lauryn Alden's group has dissected several novel genes believed to control non-focal telomeric activity as well as cell cycle control mechanisms that may facilitate certain aspects of the Flood's paramount regenerative capacity.
Stem Cell Biology
Acumen also takes a more conventional approach to regenerative biology, and following in the footsteps of the Harvard Stem Cell Institute and the Harvard University Department of Stem Cell & Regenerative Biology from the 21st century, maintains an extremely active interest in stem cell biology in humans and other mammalian model organisms. Acumen seeks an integrative molecular biology, cellular biology, systems biology, computational biology, and chemical biology approach to understand several crucial aspects of stem cell biology; the self-renewal of stem cells, the directed differentiation of stem cells and their fate mapping, the recapitulation of in vivo embryonic development through the differentiation of pluripotent stem cells, and the highly specific control of stem cell biology through chemical biology and small-molecule compounds. Acumen's most likely clinical avenues for stem cell biology are cell therapy, the usage of stem cell-derived terminally-differentiated cells or undifferentiated progenitor / stem cells to alleviate human disease or injury, or else the augmentation of resident stem cells within the patient through pharmacological manipulation. Much of their research into stem cell biology came to a head when they were tasked by a Alliance of United Races to lead the development of Elixia.
Beginnings: Strategic Partnerships and Acquisitions
Acumen was first conceived by Dr. Benjamin Greaves, M.D., a prestigious thoracic surgeon medically trained at Stanford Medical School, Earth who would later complete a research fellowship at the Dana-Farber Cancer Institute, Boston, Massachusetts, a Harvard Medical School-affiliated clinical and research cancer center. Difficulties in private practice would drive Greaves to seek guidance and advice from mentors at Stanford and Harvard, who would urge him to take a step in an unexpected and life-changing direction—to start a corporation.
Greaves would tentatively push forward with a new corporation based in medical research, which he would name Acumen Science Laboratories, which he would incorporate and headquarter at London, Earth. Almost immediately, the emerging Acumen would be fostered by Greaves's academic and familial connections, and his mentors and colleagues at Harvard and Stanford would arrange for Acumen to partnered with some of the most influential modern academic research laboratories at prestigious academic institutions such as Harvard University, Harvard Stem Cell Institute (HSCI), the Massachusetts Institute of Technology (MIT), Stanford University, the California Institute of Technology (CalTech), and Cornell University. Greaves would use his reputation to attract large initial investor support, and would funnel this money into the design of extremely high-content high-throughput chemical biology screening facilities. Greaves would offer his high-screening facilities as research facilities with his partnered academic institutions, such as HSCI and MIT, and under an agreement, whatever research was gleaned from HSCI's and MIT's research would become trademarked under Acumen and could be used to make therapeutic treatments.
This became tremendously successful, and augmented with Acumen's chemical biology expertise, HSCI, MIT, and Greaves's other academic partners would make novel, ground-breaking paradigm shifts in basic biological research that would initially draw Acumen into the spotlight for providing the resources for this novel research. Later, a discovery at Harvard elucidating the genomics of the avian influenza ("bird flu") and the proteomics of its viral particulates would lead to the development of the polymerase inhibitor Influcure, a targeted inhibitor of influenzavirus-specific PB2 RNA polymerase. Acumen's development of Influcure led to the impossibility of an avian flu pandemic ever breaking out, making Acumen initially quite prestigious in biomedical research. With excessive investment support, Greaves was able to draw the world's brightest minds into Acumen, and would design strategic partnerships with leading academic institutions such as Harvard and MIT to ensure Acumen's lead in biological research.
Later, Greaves would also expand into manufacturing beyond pharmacologicals, and Acumen swelled in size by acquiring several smaller products and beginning to manufacture products beyond drugs, including myriad medical appliances, vehicles, and tools in addition to pharmacologicals. Soon, on Earth, Acumen was seen as a supercorporation, holding a monopoly on many military and civilian markets. However, Greaves was careful to ensure extremely reasonable prices and also gave freely to charity, and few concerns were raised about Acumen's monopoly over the economy.
With the Insurrectionists swelling on the Outer Rim, the UNSC Defense Force became actively engaged in counterinsurgency and counterterrorism operations. However, UNSC Marine forces became increasingly ineffectual at successfully quelling the threat, and rebel forces were easily capable of blending back into civilian populations before the Marines could retaliate, and often, the rebels had a decentralized command structure that made it extraordinarily difficult to root out resistance on a single planet without intensive years of continual warfare and searching for rebel encampments.
Black Dealings: ONI and WMDs
The UNSC Office of Naval Intelligence and the UNSC Special Operations Command would contract corporations for intelligent, strategic solutions to counter the elusive and entrenched rebel forces. Acumen would see an opportunity, and began building on its manufacturing base, expanding from civilian appliances and tools into military matters. Cooperating with academic collaborators from MIT and Princeton University, Acumen swiftly made progress, and proposed the predecessor to the BLOODHOUND missile — a highly-accurate laser-guided missile that could hit targets in urban environments with the precision of a millimeter and could have a controllable blast radius. Acumen was soon awarded the contract, and UNSC special forces began routinely employing the BLOODHOUND as a highly-specific, low-collateral casualty way to "burn out" rebel forces in civilian urban environments. Acumen would develop a special relationship with the UNSC Office of Naval Intelligence — ONI recognized the usage of partnering with a firm so large it transferred trillions of credits a day, and found a generous soul in Acumen, where ONI could obtain funding from Acumen's limitless financial accounts to fund illegitimate ONI black operations. Acumen turned a blind eye to this, and ONI would use Acumen monies to fund programs such as Dr. Catherine Halsey's SPARTAN-II program. ONI would develop a close rapport and a symbiotic relationship with Acumen, with both organizations becoming highly dependent and grateful to each other for their own mutual benefit. Section Three, ONI's black-ops division, would literally explode in size and capabilities because of the limitless black operations it could run from Acumen funding, and this earned ONI's legendary mythology of fielding uncountable numbers of special and black operations.
Acumen also participated in legitimate fronts of the UNSC counterinsurgency effort, and ONI ensured that Acumen would receive most contracts for the manufacture of weapons, ammunition, and vehicles. Weapons and ammunition manufacture became a primary concern of Acumen's swelling manufacturing divisions, but Acumen would also cooperate with the Department of Biological Warfare to create biological and chemical weapons of mass destruction (WMD) against rebel forces.
The Covenant's destructive war against mankind came as both a blessing and a curse for the corporation. Acumen earned a monopoly over the UNSC military market, supplying weapons, vehicles, ammunition, and equipment for Marine forces fighting on the front line, and even amongst battlefront Marines, Acumen equipment would earn respect and trust for being reliable even in the haze of fighting or in extreme environments.
Acumen Science also would launch headfirst into xenobiology, and with Covenant corpses procured by ONI, Acumen would research the molecular, cellular, and physiological biology of Covenant species, and would design biological and chemical WMDs that time and time again would impede Covenant advances to allow for Marine forces to escape with their lives. Acumen would also gleam extraordinary and novel insights into biology from Covenant xenobiology, and from the regenerative biology of the Lekgolo (Hunters), Acumen would begin a regenerative biology initiative to understand the mechanism behind alien regeneration and to augument human medicine and regeneration.
However, Acumen would lose countless amounts of money as its research facilities on many UNSC colonies were glassed, and even as Acumen would begin to recentralize and attempt to move many R&D projects to Earth and Reach, the two most fortified UNSC colonies, Reach would be incinerated in 2552, and the Prophet of Regret's attack on Earth, the First Battle of Earth, would lead to the destruction of the company's new HQ, the orbital station Spirit of Progress, in orbit over Earth. During the Brute occupation of Earth and the Second Battle of Earth, when humanity was at its most desperate moment, Acumen Science would provide all its stockpiles of military weaponry and vehicles on Earth to the UNSC Defense Force at no cost, giving the UNSC resistance movement under Admiral Hood and Commander Keyes the crucial edge it needed to survive until Truth's extraction.
With the end of the War, Acumen would be famously hailed by the UNSC Defense Force for its generosity on Earth, which had saved humanity, as well as for its continual support of the UNSC war effort. ONI would also offer covert acknowledgement for Acumen's biochemical WMDs.
Post-War: Prosperity and Advancements
Near the end of 2552, after the Battle of the Ark and the triumphant conclusion of the War, the Spirit of Progress would finish its completion in Earth orbit, and this was seen by the Earth media as a true example of the human spirit — how progress would continue, even in the aftermath of a xenocidal and devastating war.
In 2561, Acumen would be galvanized by its policy of recruiting the best academic minds when it acquired galactically-renowned Harvard principal investigator Beah Schore, who became the Chief Scientific Officer of Acumen, directing all of its research directions, and also the Chair of the Department of Experimental Biology. Under Schore, Acumen would take novel and fast-paced directions, bringing itself even more into the public spotlight as Schore would develop VyThera, the first safe HIV-1 vaccine, and one that would stem the UNSC HIV pandemic, and also Acuplanin, the first cure for Type 1 Diabetes. Acumen would become renowned in the academic, clinical, civilian, and military communities as the galactic leader in biological and pharmacological research.
Flood Xenobiology: PATRIOT (2553 — 2571)
During the engagement in the Ark Theater of Operations, ONI officer Wakes would have the intiative to initialize Operation: SUBTANK, an effort to recover as many corpses possible of human combat forms before the UNSC / Sangheili withdrawal from the theater. SUBTANK would gather seventy-three Flood corpses, and ONI Director of Special Intelligence Gibson and Beah Schore would approach each other to renew the Acumen / ONI partnership in biological research, although this time, with a far darker undertone.
Beah's interests and Acumen's interests into the Flood were because of its extraordinary regeneration; the Flood genus had an unparalleled and extraordinary biology in terms of regeneration, intelligent plasticity, and directed in vivo evolution, and Schore was eager to exploit the Flood's regenerative biology — even more substantial than the Legkolos' own stunning regeneration. Acumen and ONI would partner in the morally-dubious Project: PATRIOT to begin to unravel the Flood xenobiology; Acumen, to develop regenerative cures, ONI, to develop biological weapons and augumentations for soldiers, from ONI's corpses from SUBTANK.
Molecular Mechanisms for Flood Infection
In January 2553, Acumen would extract a unified and verified combinatorial Flood genome from pooled nanogram extractions from all of the corpses, generating the unified LIBRARY, a complete and continuous genome of the Flood with over 1.8 billion unique sequences, utilizing low-pH phenol DNA extraction and single-copy, high-fidelity genomic PCR under Project: ORPHAN. Under the umbrella of the massive Project: SNOWFLAKE, Acumen would use high-throughput cloning to clone all billions of unique Flood sequences into lentiviral vectors and generate a library of lentiviral DNA clones of each sequence. Human, primate, murine, Sangheili, and Jiralhanae cultured cell lines were transduced with DNA clones, identifying which sequences were protein-encoding genes or else protein productless.
However, the overxpression studies would yield two hundred fifty seven sequences — BRANDY — which would induce a novel phenotype in the cultured cell lines. Lentiviral high-copy overexpression of any of the BRANDY sequences would lead to sequential dedifferentiation and re-differentiation of the cells, a phenomenon termed "Brandy reprogramming". The dedifferentiation involved epithelialization to a planar, monolayer morphology and a loss of original cell fate and phenotype, and this was partially mediated by EMT mechanisms (FGF8/FGFR1; epithelial-to-mesenchymal transition). This was followed by responses unique to each cell line, and cells would have drastic morphological and genetic differentiation events to novel cell types unique to the original transduced cell. Under microarray analysis, BRANDY reprogramming led to the expression of novel DNA sequences not found in any genetic library except for the Flood genome. BRANDY reprogramming led to the expression of BRANDY sequences, indicating a positive feed-forward mechanism in reprogramming, and also expression of a novel subset of Flood genes, codenamed "SWIFT".
Later, it was found that co-expression of all the BRANDY factors in a single lentiviral cocktail greatly increased the temporal kinetics of Brandy reprogramming, and this was suggested as a mechanism for Flood infection — Brandy reprogramming occurred on the scale of seconds to minutes while other forms of reprogramming, such as conventional iPS or SCNT, took days to months. Ectoptic overexpression of BRANDY genes was thus postulated by Beah Schore as a mechanism for Flood infection form parasitization into combat forms. This was confirmed when it was shown that miRNA knockout of BRANDY factors had no effect on BRANDY reprogramming, indicating that this parasitization was extremely robust and capable of defeating endogenous defenses. Three of the BRANDY factors (B3); Mirage, Phantom, and Edge, were found to considerably accelerate temporal kinetics of pooled BRANDY reprogramming, suggesting an integral role of these genes in Flood infection form parasitization.
Furthermore, BRANDY reprogramming resulted in a novel reprogramming phenomenon in cultured cell lines that led to the generation of a novel, plastic neuronal phenotype demonstrating activity-dependent plasticity and spontaneous synaptic reorganization and signaling, with statistically-complex cellular structures forming that were reminiscent of in vivo central nervous system circuitry, as assayed by Fura-2-AM live Ca+2 imaging and electrophysiological techniques.
Under Project: NIMBUS, the Department of Experimental Biology would further elucidate the mechanisms of Flood infection, eventually finding that the three B3 factors encoded transcription factors that when hybridized to the Flood genome, formed a structurally-complex and unique structural complexes as revealed by NMR and X-ray crystallography, and it was found that co-transduction of the B3 transcription factors and the pooled BRANDY sequences improved temporal kinetics and reprogramming efficiency (>100,000-fold increase in efficiency), suggesting another tier to Flood infection form activity. The highest-order B3 transcriptional complex was shown to have highest DNA affinity for sixteen of the BRANDY genes, known as GAMBLE, which had various kinase, phosphatase, polymerase, or ionophore activities. Sequential co-transduction of the B3 proteins and the GAMBLE genes, followed by transduction with all the BRANDY genes, was shown to have exceedingly high temporal kinetics and efficiency in reprogramming.
The Flood: A Controlled Weapon of Mass Destruction
- "...Insufficient funding and personnel to sustain these inconclusive, resource-intensive, and unethical projects..."
- ―Admiral Gibson's public disclaimer statement
The UNSC Office of Naval Intelligence would further research into the mechanism of Flood infection, but found that instead of achieving full reprogramming, that a classified combination solely of the B3 transcription factors and the GAMBLE genes resulted in de-differentiation but not reprogramming in cultured cell lines. This project, known as CUMULUS, would have its experimental data destroyed by Executive Order 99036 issued by Director of Special Intelligence Gibson. Later, under Project: RAINFALL, ONI would study the stabilization of the purified proteins and deoxyribonucleotide polymers to sustain thermal, radiological, and kinetic effects as well as to achieve maximal in vitro transcription and translation. ONI would develop BLUE SHIFT after extensive presence at the Chi Ceti IV Munitions Testing Range and at the Asphodel Meadows Naval Special Warfare Center. After the conclusion of RAINFALL, ONI would decommission large parts of the Chi Ceti IV testing facility and would completely close the Asphodel Meadows NAVSPECWAR installation. Gibson would later disown all ONI involvement with CUMULUS and RAINFALL, discontinuing both projects. BLUE SHIFT would later be classified under the highest security ratings.
"Human synthesis": Artificial Human Design
- Main article: FORECAST
Acumen would later conduct in silico modeling and a high-throughput, high-content combinatorial screen and for small molecule compounds that could functionally replicate certain protein products of the B3 and LIBRARY genes, and would eventually devise SCARLET, a classified mixture of small molecules whose synergistic, combinatorial activity induced particular Flood-like phenotypic characteristics in vitro in cultured cell lines.
The Department of Biological Warfare, Section Three, would later request SCARLET from Acumen Science, under the terms of Acumen's and ONI's PATRIOT contract. Schore would reluctantly hand over SCARLET to Biological Warfare, fearing that ONI would test SCARLET as a biological weapon against animals. Acumen Science could not have underestimated ONI's cruelty and tenacity; Commodore Cooke, the chief of FORECAST, would conduct an in utero screen of pregnant women with SCARLET, artificially hormone-priming and artificially impregnating four thousand women, and then exposing them to billionfold concentrations of SCARLET—a potent teratogen and mutation, shown by Acumen to induce horrible birth defects in animal fetuses at nanomolar concentrations.
Cooke would give his four thousand pregnant women and their developing human fetuses molar concentrations of SCARLET, hoping to generate disastrous birth defects in the fetuses and to analyze the results, hoping to find a birth defect that was beneficial, knowingly slaughtering eight thousand women and unborn children by mutating them into Flood-like abominations, hoping to find a single mutated fetus that would have a beneficial Flood-like mutation that ONI could use in a future supersoldier program.
Using billionfold concentrations of SCARLET, the effects were immediate and satanic. Within six hours of exposure, women would be growing hands from their chins and sprouting intestines within their mouths, and the fetuses would have hair growing from their eyes and double heads blossoming. With twenty-four hours, most of the women were dead, as were the fetuses within their womb, and by thirty-six hours, the program would be terminated by Admiral Montgomery, who would be horrified by Cooke's machinations and how the rogue ONI flag officer had wiped away four thousand pregnant mothers and four thousand fetuses without a thought. By the end of two days, only one of the mothers, Alexandria Clarissa Blackburn, would cling to life, struggling to survive as the SCARLET agent reprogrammed her body, attempting to transfigure her into a partial Flood form.
When Beah Schore heard about how ONI had abused SCARLET to destroy human lives, he would launch into an insurmountable rage, thundering into Asphodel Meadows Naval Special Warfare Center and fierily confronting Cooke, who had blithely used Acumen's SCARLET in his "in utero diversification screen". Cooke, already chastised by Admirals Gibson and Montgomery, would be close to losing his command as Schore denounced ONI and its horrible usage of Flood technologies; something that Acumen had investigated in order to save human life, not to mutate human fetuses.
Schore, Montgomery, and dozens of Acumen and ONI physicians would endeavor to save Alexandria's life, and Schore would put Acumen's full molecular biology capacities at Alex's disposals, undergoing high-content histological genetic and kinomic modelling to understand SCARLET's Flood reprogramming pathological process and attempting to use Acumen's arsenal of small-molecule kinase inhibitors to slow the Flood xenomorphic reprogramming of Alex and her unborn fetus while Montgomery and his physicians would maintain Alex's threadbare life by dozens of pharmacologicals, until Alex's life was more chemical than biological. Schore's and Montgomery's efforts would finally culminate in Alexandria's survival—and surprisingly, her child. Alex would reach term and give birth to Kimberly Ivy Blackburn, who as a developing embryo, had undergone irreversible teratogenesis and reprogramming by SCARLET. While Alex was saved by BLUEBERRY, an Acumen-developed small-molecule chemical inhibitor cocktail that was the specific counteragent to SCARLET, it was too late for Kimberly; she would be born with unchangeable Flood-related growth defects as a result of SCARLET.
Kimberly Ivy Blackburn, renamed "Talon" by ONI, would be taken by Section Three from her mother, and CPO Talon would be trained as a child soldier. At the age of two, Kimberly would undergo extensive biochemical and surgical augmentations, including with Acumen product silver hexapotassium aurophosphate (CerebroLive), and many of the small-molecule compound signaling protein analogs used in her augmentations were the result of high-throughput screens and artificial modeling done previously at Acumen for non-military applications. At the age of four, Kimberly would begin her formal military training, but the in utero growth defects that Cooke had done were unmistakable; while upon sight she appeared quite normal, she had extensive psychological and neurological issues, and from birth was psychotic, schizophrenic, and sociopathic, and she also had extensive cellular pathologies, most notable rhabdosarcoma; the unrestrained growth of her musculature. It was at the age of ten that Beah Schore would see her again, although Schore would always care for and look after the child that had been born mutated as a result of misapplied Acumen science.
After recuperating from its heavy losses during the Ares System Incident, the Acumen Science Paramilitary reached its peak in membership during the Necros Wars' beginnings. The corporation contributed heavily to the UNSC's war effort, loaning money, and increasing its production of wartime weaponry, ammunition, and vehicles, as well as developing new armor systems and technology for troops. Currently, Acumen Science Laboratories is collaborating with several leading technological corporations in a joint effort to find a solution to the threat of the Necros. Along with this, prior war it developed Elixia.
The research organization sports many facilities dotted across Earth, most notably those in Albany, Seoul, London, Berlin, Moscow, and, the main center of the company's work, the orbital station in orbit just below Earth's Super MAC Defense Grid. Acumen Science maintains research facilities on other planets as well however, the most important of which were those on Harvest and Coral before their glassings by the Covenant during the Human-Covenant War. Acumen Biomedical is also said to invest in subterranean high-containment biological research laboratories such as MAGI SIX.
Acumen Science Laboratories makes use of approximately 150 refitted military Frigates and Cruisers for its paramilitary, although the organization as a whole has close to 4,000 freighters in service for transport of its goods. More private vessels however, have also been used for the transport of corporate executives and for discreet meetings by the Board of Directors.
Through its consolidation of numerous smaller companies, Acumen Science has become heavily sectioned, being the parent company of multiple others, as well as possessing numerous branches and divisions.
Acumen Science Laboratories is divided into two primary organizations, both of which are responsible for different areas of research and manufacture.
Acumen Biomedical Solutions
Acumen Biomedical Solutions, colloquially known as "Acumen Biomedical", is the biological and clinical division of Acumen Science. Acumen Biomedical is a forefront in biological research, including fundamental basic research, translational research, and clinical research, especially the development of novel pharmacological agents to treat human disease. Acumen Biomedical is also involved in the manufacture of high-quality medical equipment, including specialized field surgery drones currently being tested by the UNSC Marine Corps.
An evolving trend for Acumen Biomedical's future research is regenerative medicine, and to this end, Biomedical also investigates xenobiology in an effort to understand regenerative molecular and physiological mechanisms in regenerative alien species. Departments within Acumen Biomedical include the Department of Experimental Biology, the Institute for Theoretical Biotechnology, and the Acumen Science Extraterrestrial Research Division.
Acumen Biomedical was bolstered by the recruitment of Harvard investigator Beah Schore to Acumen. Schore, the Chief Scientific Office for Acumen, was responsible for vaulting and energizing Acumen Biomedical, including the development of its trademark cures for HIV-1 and Type 1 Diabetes. Schore would also be heavily involved with Acumen Biomedical's interest in regenerative medicine to cure an evolving mankind.
Acumen Technologies is the branch of Acumen Science responsible for most of the company's income, manufacturing and designing automobiles, aircraft, tools, electronics, appliances, and even firearms and ammunition in contracts with the UNSC. Departments and Divisions within Acumen Technologies include Acumen Automotive, Acumen Aeronautics, the Acumen Technologies Weapons Development Division, the Department of Theoretical Technology, and the Department of General Technological Development.
Projects and Products
Acumen Science, after acquiring transplanetary and monopoly status, has diversified into a significant number of fields in which to market its various products. It is heavily invested in pharmacologicals, including Acuplanin and Influcure, as well as related biological research into non-pharmacological cell-based regenerative medicine, biol-chem WMD (biological & chemical weapons of mass destruction), and xenobiology. It also has a proliferous number of other products, and sports the "AS" line of specialized rifle weapons systems in active usage by the UNSC Office of Naval Intelligence, including the AS DAM, the AS SOCK, and the AS SOLAR, made in conjunction with HRV Armament Company. Acumen also invests in civilian appliances, technologies, and vehicles, including futuristic computational systems appropriately priced for the civilian market.
Acumen Science Laboratories, due to the nature of the work within its facilities, maintains a large and well-kept security force. Each facility possesses a security detachment ranging anywhere from 200-300 personnel, depending on size, and job applicants for Acumen security-positions are required to take physical tests akin to those conducted by Law Enforcement.
Acumen Science's Security force is primarily divided into two groups; the Acumen Facility Security, and Acumen Emergency Response Unit, AFS and AERU respectively. The AFS is employed simply for general guard duties, while the AERU is equipped to handle any larger-scale threat until paramilitary forces may be deployed. Weaponry ranges from civilian to military-issue, and although the Acumen's security does not readily utilize military vehicles, armored cars and civilian model cars are employed.
A.F.S., Acumen Facility Security
While Acumen Science does possess substantial security forces for the maintenance and well-keeping of their research facilities, it is also possible, due to the company's carefully stroked relations with the UNSCDF, for UNSC Troops to be called upon with relative speed for assistance in the protection of their research centres, in the event that Facility Security prove to be insufficient.
AFS members are offered physical protection on par with UNSC Law Enforcement, standard-issue being woven-alloy combat vests, helmets equipped with ear-piece radios, pistol holsters, and arm and shin guards.
Weaponry is generally issued according to station, with guards on upper levels of Acumen facilities being issued "worse" weaponry than those on the more discreet, lower levels. Upper level security guards are commonly issued stun batons and relatively low-calibre civilian issue sidearms, while those in lower floors may possess weaponry such as military-grade sidearms, shotguns, or occasionally civilian-issue rifles.
AFS Security Guards mostly employ specially designed security vans and armoured cars, both commonly painted white with "Facility Security" in blue lettering. Security Vans are more commonly used for simple transport, while Armoured Cars are used for transport of special materials and/or the transport of valuable goods.
A.E.R.U., Acumen Emergency Response Unit
With equipment on par with Law Enforcement Tactical Assault and Response teams, members of Acumen Emergency Response Units are issued steel-framed combat boots, near military-grade combat armour, AC4 Helmet Mounted Displays, ear-piece radios, and combat knives. Night vision or otherwise normal goggles, and balaclavas are commonly worn as well.
Emergency Response Units are issued military-grade weaponry, with the M7S Sub-Machine Gun, M90 Shotgun, and M6J Carbine forming the staple of their armoury. Weapons are typically required to have laser sightd equipped, while other attachments are optional for a degree of weapon customization.
The second author of this article, RelentlessRecusant, wishes to thank several influential mentors, colleagues, and friends at the Harvard Stem Cell Institute whose mentorship and advice have helped considerably in particular aspects of this article.
- ↑ Geysen et. al (2003). Combinatorial Compound Libraries for Drug Discovery: An Ongoing Challenge. Nature Reviews Drug Discovery (2): 222-230.
- ↑ Wichterle et. al (2002). Directed Differentiation of Embryonic Stem Cells into Motor Neurons. Cell (110), 385–397.
- ↑ Machold et. al (2003). Sonic Hedgehog Is Required for Progenitor Cell Maintenance in Telencephalic Stem Cell Niches. Neuron (39), 937–950.
- ↑ Hebrok et. al (2000). Regulation of pancreas development by hedgehog signaling. Development (127), 4905-4913.
- ↑ Rubin and de Sauvage (2006). Targeting the Hedgehog pathway in cancer. Nature Reviews Drug Discovery (5): 1026-1033.
- ↑ Borzillo and Lippa (2005). The Hedgehog Signaling Pathway as a Target for Anticancer Drug Discovery. Current Topics in Medicinal Chemistry (5), 147-157.
- ↑ 7.0 7.1 Chen et. al (2002). Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes & Development (16): 2743–2748.
- ↑ Stanton et. al (2009). A small molecule that binds Hedgehog and blocks its signaling in human cells. Nature Chemical Biology (5), 154-156
|Acumen Science Laboratories|
|Departments||Department of Bioinformatics · Department of Chemical Biology · Department of Chemical Engineering · Department of Comparative Biology · Department of Developmental Biology · Department of Heuristic Biology · Department of Medicinal Chemistry · Department of Metabolism · Department of Natural Products · Department of Neurobiology · Department of Pathology · Department of Pharmacology · Department of Signal Transduction · Department of Stem Cell Biology/Center for Regenerative Medicine · Department of Systems Biology · Department of Toxicology|
|Departments||Chemical Biology Program · Clinical Medicine Program · Molecular and Cellular Biology Program · Stem Cell and Regenerative Medicine Program|
|Small Molecules||(R)-(+)-WIN 55212 · 2C-E · A-769662 · A-83-01 · GW501516 · JZL184 · O-1783 · PK115-584 · Selegiline · WF-23|
|Employees||Beah Schore · Benjamin Greaves · Fabien Rook · Lauryn Alden|
|Source · Edit|
|Chemical Biology: Small-Molecule Control of Biological Systems (RelentlessRecusant)|
|Receptor Tyrosine Kinases||A-83-01 (TGFβ/Activin) · BPIQ-II (EGFR) · Dorsomorphin/LDN-193189 (TGFβ/BMP) · SU5402 (FGFR)|
|Signaling Kinases||A-769662 (AMPK) · BMS-354825 (BCR-ABL, Src)· BIO-Acetoxime (GSK3) · CHIR99021 (GSK3) · GO 6976 (PKC) · IMD-0354 (IκBa) · PD184352 (MAPK) · SB203580 (MAPK) · Y-27632 (ROCK)|
|G Protein-Coupled Receptor||(R)-(+)-WIN 55212 (CB1/CB2) · ±-Sulpride (D2) · A 841720 (mGluR1) · BP-554 (5-HT1A) · Hh-Ag1.5 (Smo) · Cyclopamine/KAAD-Cyclopamine (Smo) · SANT1 (Smo) · SB-277011 (D3)|
|Ion Channels||BAY K8644 (Cav1.2) · Bicuculline (GABAAR) · Cymarin (Na+/H+) · G-strophanthin (Na+/H+) · L-AP4 (Na+/H+) · Oxcarbazepine (Na+) · Resiniferatoxin (TRPV1) · Sarmentogenin (Na+/H+) · Theanine (AMPAR, NMDAR)|
|Transporters||O-1783 (DAT) · WF-23 (DAT, SERT)|
|Nuclear Receptor||All-trans retinoic acid (RAR/RXR) · GW501516 (PPARδ) · RU-486 (Nr3c1, Nr3c3)|
|Protein Phosphatases||Endothall (PP2A)|
|Polypharmacological||Phosphoserine (mGluR4) · PK115-584 (Tcf4/β-catenin, PKC) · Pluripotin · Reversine|
|Other||2C-E (DAT) · 4-methoxyphenyl-HTI-286 (α/β-tubulin) · Compound E/DAPT (presenilin-1) · D-cysteine · D-phenylalanine · Flurbiprofen (COX) · JZL184 (MAGL) · QS11 (RAFGAP1) · RO-28-1675 (glucokinase) · Robotnikinin (Shh) · Selegiline (MAOB)|
|Libraries||Kinase Inhibitor Library|
|Small molecule-mediated manipulation of the adult human induces selective and reversible control of physiological and psychological phenotype (Rubin et. al, 2590. Nature Medicine)|
|Source · Edit|
|Companies active during the Necros War|
Misriah Armoury | Oracle | Trinity Arms | Weapon Systems Technology | UAE Systems | Masver-Tor | United North American Defence Systems | AMG Transport Dynamics | Allied Aerospace Development Company | Reyes-McLees Shipyards | Rolls-Royce Aerospace Engines | SHVT Shipyards | Katakes-Robinson Company | Combined Arms Mining Company | General Mining Corporation | Lockheed Martin | Kosyetze Agriculture | Ariake-Kassa Fabrication | Acumen Science Laboratories | Nintendo-Microsoft Electronics | Wal-Mart Target Corporation | Angel Arm