The Biology of Evil Part 1

A bizarre incident occurred in the later months of 2009. Three Resident Evil fans with a passion for SCIENCE endeavored to explain the scientific background of the series, to codify the Biology of Evil, in unprecedented depth. Their investigations found a home at Project Umbrella, an unparalleled repository for Resident Evil information and a vibrant community of fans. The case was apparently closed after three voluminous reports, covering the entirety of the Umbrella Corporation’s crimes against nature.

But the Evil Committee’s experiments were far from finished…

Intro to the Re-Animated Edition

It all began back in 2009, with a discussion about the anatomical details of Lickers, and whether they were truly covered in exposed muscle or whether they had a layer of protective fascia that could protect the muscle beneath even in the absence of skin. That discussion sparked a friendship and a suggestion of a collaborative effort: with their combined scientific acumen and their encyclopedic knowledge of Resident Evil, could they produce a thorough scientific accounting of the viruses and monsters of the series? It seemed impossible. Resident Evil has all the trappings of science fiction – secret laboratories, genetic experiments, an infectious disease harnessed as a biological weapon – but it operated on Rule of Cool as much as it did on anything resembling SCIENCE. A spider the size of a Buick, human-shaped plants walking around like Gumby as designed by David Cronenberg, a monstrous malformation of angry flesh that grows at impossible speed…these did not seem like things that anyone could explain rationally, let alone a handful of undergrads.

But we did it. Three reports, about 150 pages in total, encompassed everything from Resident Evil 0 to Code: Veronica, and a few other games besides. Anything that had anything to do with Umbrella or the T-Virus, at least up to the time of publication, was covered. It was more than any of us had originally thought possible. Project Umbrella, which had originally brought us all together, was happy to host these documents. People even seemed to like them.

Time went on. We struggled to make sense of Resident Evil 4, which switched the focus to parasites, continued the trend of increasingly bizarre mutations, and generally made our work harder. Even as we plugged away at it, the Resident Evil series continued. Each new entry gave us more and more to explain, even as these fantastical monsters were increasingly inexplicable by even the roughest interpretation of real-world SCIENCE. We had less and less time to burn, with two of us in grad school, and meatspace imposing its own responsibilities on all of us. And, it pains me to say, Project Umbrella’s code was falling apart as though the self-destruct sequence had been activated with five minutes until detonation. The Biology of Evil Project went dormant.

Times are different now. Two of us on the Evil Committee have Ph.Ds. SCIENCE itself has marched on. Resident Evil 2 and 3 have new remakes with updated enemies and lore. And just recently, representatives from Project Umbrella (our old partner, you know) have asked for permission to re-upload our old reports. The site has clawed its way up through the soft earth of the grave and it’s looking better than ever. They have a plethora of translated material that completely turns around some of our old ideas, and gives us new ones. And so, the hour is ripe to pick up our scalpels, dust off our lab coats, and get back into the thick of things.

You have once again entered the world of scientific horror. Good luck…

A series of essays on the science behind Resident Evil

By Doktor Wunderbar (the scientist formerly known as Hieronymus), The Doctor, and T-A.L.O.S.

For Project Umbrella

The authors claim full ownership and rights to this document. This document may be displayed at www.projectumbrella.net; this document may be reproduced elsewhere only with explicit permission from the authors. Project Umbrella is an unofficial fan site, and is in no way affiliated with Capcom or Resident Evil.

“Real world virology and Resident Evil are not friends.”

--El Bastardo

For a series of games about viruses and medical experiments, Resident Evil is pretty light on actual scientific information. It’s a good thing, too, because whenever Capcom tries to get technical, with precious few exceptions, it becomes obvious that they wouldn’t know real SCIENCE if it staggered up to them and bit out their throats.

Let’s clarify something straight up. Most of what we see in the games is flat-out impossible. Biology can’t overcome basic physical principles like conservation of matter, and the rates of growth we frequently see require some serious suspension of disbelief. We can’t tell you how to make a real T-Virus, as much as some of us would like to recklessly make that information publicly accessible. But as men of SCIENCE, we feel it is our duty and our privilege to dig through the evidence— – the files, the dialogue, the gameplay itself— - to approach the games from a scientific perspective and to work out how these viruses and monsters would work if they could work at all.

This is what Capcom apparently thinks a virus looks like. It’s actually a molecule called uroporphyrin, which is found in small concentrations in urine. Source: Wesker’s Report

The following report is a revision of work previously published, updated to cover the Remakes and new information that has become available since this work was originally written. This first installment covers Progenitor Virus and the T-Virus, but we have more Reports to update, and we haven’t given up the dream of covering the entire Resident Evil series. We’ve relied on speculation more than we would like, but we’ve always tried to fit out theories to the evidence, and we’ve relied on real scientific information as much as possible. Handy scientific definitions have been provided in footnotes, and literature citations are available at the end. It should be noted that this report does assume a certain familiarity with the games, but most of the in-game files and assorted game-related information can be accessed through Project Umbrella or the wiki, which has been improved substantially since this Report was initially written.

It should go without saying that for most of this document, we’ll be approaching the series canon from a Watsonian [1] perspective, or an in-universe perspective. That’s the whole point of these documents and arguably of fiction in general – to suspend disbelief and put yourself in a world where these events are happening. From time to time however, we have found a Doylist [2] or out-of-universe perspective to be useful – not only to describe the sources from which we’re getting information, but also to help us interpret canon using older ideas from which the canon was derived.

definitions

[1] Watsonian - an in-universe perspective on a work of fiction, named for the idea of fictional character Dr. John Watson describing his equally fictional friend Sherlock Holmes as though both were quite real.

[2] Doylist - an out-of-universe perspective on a work of fiction, named for the idea of author Sir Arthur Conan Doyle describing Sherlock Holmes as a fictional creation.

Progenitor

We began our efforts with the one virus from which all others in the series are derived – the Progenitor Virus. Its existence was first hinted at in Code: Veronica, far from an early entry in the series; but since then, Progenitor has come to rival even the T-Virus in the Resident Evil mythos.

Code Veronica (and an EX file in the N64 version of Resident Evil 2) tell us little about the virus itself; only that it was discovered by Spencer, Ashford, and Marcus at some point, and the T-Virus was derived from it.

We learn more in Resident Evil 0. The B.O.W. Report is particularly helpful. The file tells us that Progenitor has related, but distinct, effects on different animals; lower organisms typically exhibit extreme growth and changes in aggression, while mammals seem to exhibit muscle growth and aggression, but little change in actual size.

The closest we have to an image of purified, concentrated Progenitor Virus is this image of Wesker's experimental virus. Source: Umbrella Chronicles

In Resident Evil 5, everything finally becomes clear. Not only do we find out that Wesker’s powers are due to a variant of Progenitor, we also learn a bit about the early history of the virus. Resident Evil 5, more than any other game, is key to understanding Progenitor.

What information we have about Progenitor – and indeed, most viruses in Resident Evil – falls into two broad categories: origins and symptoms. Since an understanding of the symptoms can, in this case, better help us to understand the biology of the virus, that’s where we’ll start.

We know from Resident Evil 0 that Progenitor has different effects based on the species which is infected, and we know from Resident Evil 5 that the virus also has different effects based on the individual infected. We’ll start by discussing symptoms in humans, and then try to extrapolate what we know to the other organisms.

Retrovirus

Let’s start with some basic virology. There are many kinds of viruses, and they do a lot of different things, but one of our favorite kinds is Group VI, the retroviruses. Retroviruses are unique for two reasons: first, they are able to “reverse-transcribe” their genetic material, which they store as RNA, into DNA inside of a host cell. Second, they can integrate this DNA into the DNA of a host cell, becoming a permanent part of that cell, instead of leaving their genetic material floating around in the cytoplasm. That characteristic makes retroviruses useful tools for gene therapy and transgenics, both of which involve the introduction of foreign DNA to cells to permanently change them.

Even Capcom’s microscopy is maddeningly ambiguous. The top images may depict either electron micrographs of the T-Virus (real retrovirus shown below left), or light microscopy of blood cells from an infected subject (real-life cells can be seen bottom right), or possibly both. If they are retroviruses, they’re at least the right shape. Sources: Degeneration and Resident Evil 2

These characteristics, particularly integration, make the retrovirus classification a very good candidate for the group to which Progenitor belongs. Numerous files throughout the Resident Evil series also seem to support the theory: Wesker’s Report II describes the “Founder Virus” (Progenitor) as an RNA virus able to modify genes; the Resident Evil 5 file Brandon’s Journal No. 1 claims James Marcus hypothesized a virus which could alter DNA; File No. 1, History of Resident Evil, claims Progenitor can “reconstitute” a living organism’s DNA.

Wesker’s Report II also astutely notes that RNA viruses are prone to mutation, which could explain a lot of the physiological transformations we see in organisms like G-Types and Umbrella’s “ultimate weapon,” T-ALOS. Retroviruses, it turns out, are especially prone to mutation due to the low fidelity of the reverse transcriptase [1] complex.

We have come to the conclusion that Progenitor is indeed a retrovirus, for those reasons and more. At first, however, we were not convinced. All viruses are able to insert their genetic material in a host cell, essentially altering that cell’s genetic content, even if the cell’s chromosomal content is not altered by integration. It may have been possible for another virus to insert genetic material which might cause unusual effects, without this material ever entering the nucleus and becoming part of the subject’s genetic code. Furthermore, we have learned that there are no currently known plant retroviruses.

definitions

[1] Reverse transcriptase (RT) - Also referred to as an RNA-dependent DNA polymerase, this enzyme transcribes RNA into DNA thus preparing the viral genome for integration into the host’s DNA. Unlike conventional DNA polymerases, however, reverse transcriptase lacks a proofreading mechanism during transcription; this leads to an accumulation of genomic errors, hence why RNA viruses using RT tend to mutate so rapidly.

This is HIV 1, an enveloped retrovirus. The envelope makes cell entry slightly easier.

We investigated a number of viruses, including rhabdoviruses and toposviruses, both of which can infect both plants and insects. Rhabdoviruses include the rabies virus, which has obvious similarities to the behavioral effects of the T-Virus (and indeed, a sharp eye will catch a clinical case report on a pediatric rabies case in the epilogue of Resident Evil Outbreak). Ultimately, however, we returned to retroviruses. While there are no plant retroviruses currently known to exist, there is some evidence in the form of retrotransposons and other retroelements which point to such retroviruses existing in plants in fairly recent biological history [i],[ii],[iii]. More importantly, the B.O.W. Report in Resident Evil 0 describes effects of the Progenitor Virus being passed from one generation to another. Although vertical transmission has been documented for a variety of viruses, the somatic benefits of Progenitor infection (as opposed to the negative effects, like dying) would be more readily heritable if the virus integrated its genetic material into the host genome, as a retrovirus would.

And we now have access to an interview with Kenichi Iwao, the writer for the very first Resident Evil, who says that he was inspired by the idea of gene transfer using retroviral vectors [iv].

Wesker doesn’t look like he is experiencing a lot of tissue damage as a result of Progenitor infection. Therefore, Progenitor probably replicates by exocytosis [1]. In exocytosis, mature virus particles are enveloped in vesicles which merge with the cell membrane, expelling the virus into the intercellular space without damaging the cell membrane. This mechanism leaves host cells alive, rather than destroying them as in the classic lytic cycle [2]. Another form of exocytosis, budding, would involve the virus taking a piece of the cell’s membrane with it, giving Progenitor a viral envelope [3]. Budding is common in retroviruses which produce latent infections. However, if the virus replicates too rapidly, budding can deplete the cell membrane, killing the host cell.

definitions

[1] Exocytosis - Also referred to as budding, this process involves the non-destructive discharge of virions from a cell, effectively reducing it to a continuous viral factory. Many enveloped viruses causing persistent host infection (e.g. HIV, HSV-1) preferentially exit in this fashion. Exocytosis can also involve vesicular transport outside the cell, preserving the cell membrane.

[2] Lytic cycle - The most well-known method of viral egress whereby progeny virions burst en masse and destroy the host cell.

[3] Viral envelope - A lipid membrane coating a virus, typically aiding attachment and penetration of host cells.

[i] Zaki EA. Plant retroviruses: structure, evolution and future applications. African Journal of Biotechnology. 2003 June; 2(6): 136-139.

[ii] Miguel C, Simoes M, Oliveira MM, Rocheta M. Envelope -Like Retrotransposons in the Plant Kingdom: Evidence of Their Presence in Gymnosperms (Pinus pinaster). Journal of Molecular Evolution. 2008 November; 67(5): 517-525.

[iii] Hafez EE, Abdel Ghany AA, Paterson AH, Zaki EA. Sequence heterogeneity of the envelope-like domain in cultivated allotetraploid Gossypium species and their diploid progenitors. Journal of Applied Genetics. 2009; 50(1): 17-23

[iv] Crimson-Head.com, Exclusive interview with Kenichi Iwao.

Evolution and the Ndipaya

Progenitor is one of the rare viruses which can infect both plants and animals – and more importantly, it’s one of the few that can infect both plants and humans. Some plant viruses do have limited pathogenicity in humans; one paper revealed that the pepper mild mottle virus can cause an immune response, but its effect seems limited to the gut [i]. The cowpea mosaic virus can enter human cells, but cannot replicate within them [ii].

We have read the deep lore of Resident Evil, and a possible explanation suggests itself. And when we say deep, we mean it – let’s back up about four billion years to the origin of life on Earth. The most prominent hypothesis for life’s beginning is the RNA World hypothesis [iii]. RNA, the stuff retroviruses use, is simpler than DNA and has the added benefit that it can perform enzymatic activity, meaning it can facilitate biologically useful chemical reactions. (DNA doesn’t have enzymatic activity, but it has the benefit of being more stable, and having two complementary strands gives it a convenient backup in the event of damage.) There is a body of research showing that RNA can even copy itself without needing DNA[iv]. This would have been a world without cells at all, only replicating molecules taking advantage of nearby energy sources – pure biochemistry in the stygian laboratory of Hadean Earth.

And it’s here, the deep lore tells us, where Progenitor emerged in a world neither truly alive nor truly dead. That’s right – it’s not just the Progenitor of the T-Virus, it’s the Progenitor of all life. The novelization for Umbrella Chronicles [v], like the game itself, has elements of…dubious canonicity, but it adds some interesting material. One such nugget is a passage, taking place in the 1960s after the recovery of Progenitor, in which James Marcus repeats the famous Miller-Urey abiogenesis experiment of 1953. He makes one modification – the addition of Progenitor to the initial mix. Miller and Urey observed the formation of a number of organic molecules, some of which are important biological precursors[vi]; however, James Marcus observed the formation of primitive, membrane-bound cells capable of replication. To illustrate the magnitude of this difference, imagine Miller and Urey building a spark plug and James Marcus building a Ford Model T.

definitions

[i] Colson P, Richet H, Desnues C, Balique F, Moal V, Grob JJ, Berbis P, Lecoq H, Harlé JR, Berland Y, Raoult D. Pepper mild mottle virus, a plant virus associated with specific immune responses, Fever, abdominal pains, and pruritus in humans. PLoS One. 2010 Apr 6;5(4):e10041.

[ii] Koudelka KJ, Destito G, Plummer EM, Trauger SA, Siuzdak G, Manchester M. Endothelial targeting of cowpea mosaic virus (CPMV) via surface vimentin. PLoS Pathog. 2009 May;5(5):e1000417. Epub 2009 May 1.

[iii] Neveu M, Kim HJ, Benner SA. The "strong" RNA world hypothesis: fifty years old. Astrobiology. 2013 Apr;13(4):391-403. doi: 10.1089/ast.2012.0868. Epub 2013 Apr 3. PMID: 23551238.

[iv] Johnston WK, Unrau PJ, Lawrence MS, Glasner ME, Bartel DP. RNA-catalyzed RNA polymerization: accurate and general RNA-templated primer extension. Science. 2001 May 18;292(5520):1319-25. doi: 10.1126/science.1060786. PMID: 11358999.

[v] Crimson-Head.com, Umbrella Chronicles Novels A&B. https://www.crimson-head.com/translations/biohazard-umbrella-chronicles

[vi] MILLER SL. A production of amino acids under possible primitive earth conditions. Science. 1953 May 15;117(3046):528-9. doi: 10.1126/science.117.3046.528. PMID: 13056598.

Okay, we hear you collectively saying. This novelization, never officially translated into English, makes this claim. This is the same novelization that features Wesker telepathically ordering Nemesis to do what it was programmed to do anyway and engaging in a psychic battle with Sergei Vladimir. And of course its retelling of Resident Evil 3 alone should be enough to issue a restraining order preventing it from approaching within 500 yards of canon. But it’s not the only source suggesting an RNA World origin for Progenitor. Kenichi Iwao was the lead writer for the original Resident Evil4. He makes the cryptic claim that a “Theory of Evolution through Viruses” was introduced by a Japanese researcher. This theory intrigued him enough to influence his scenario for Resident Evil, but he claims it was later discredited. We haven’t been able to find the specific Japanese source he mentioned, but the idea of evolution through viruses is recurrent through biology and it certainly hasn’t been discredited [i],[ii],[iii],[iv]. Viral fossils called endogenous retroviruses, or ERVs, are common in the genetic code of almost every living thing. These are the genetic remains of viruses that long ago infected organisms and combined their genomes with that of their host, and their genetic code has been passed down ever since just like any other set of genes [v]. Sometimes endogenous viruses (not always retroviruses) make important contributions to evolution [vi].

These particles are human endogenous retroviruses. Our DNA codes for them, but they normally don’t get produced. Some scientists induced these to develop. Source: Löwer et al 1995

definitions

[i] Van Blerkom LM. Role of viruses in human evolution. Am J Phys Anthropol. 2003;Suppl 37(Suppl ):14-46. doi: 10.1002/ajpa.10384. PMID: 14666532; PMCID: PMC7159740.

[ii] Irwin, N.A.T., Pittis, A.A., Richards, T.A. et al. Systematic evaluation of horizontal gene transfer between eukaryotes and viruses. Nat Microbiol 7, 327–336 (2022). https://doi.org/10.1038/s41564-021-01026-3

[iii] Patrick Forterre, David Prangishvili, The major role of viruses in cellular evolution: facts and hypotheses, Current Opinion in Virology, Volume 3, Issue 5, 2013, Pages 558-565, ISSN 1879-6257, https://doi.org/10.1016/j.coviro.2013.06.013. (https://www.sciencedirect.com/science/article/pii/S1879625713001077)

[iv] Koonin EV, Dolja VV. Virus world as an evolutionary network of viruses and capsidless selfish elements. Microbiol Mol Biol Rev. 2014 Jun;78(2):278-303. doi: 10.1128/MMBR.00049-13. PMID: 24847023; PMCID: PMC4054253.

[v] Löwer R, Löwer J, Kurth R. The viruses in all of us: Characteristics and biological significance of human endogenous retrovirus sequences. Proc. Natl. Acad. Sci. USA. 1996; 93:5177-5184.

[vi] Enard D, Cai L, Gwennap C, Petrov DA. Viruses are a dominant driver of protein adaptation in mammals. Elife. 2016 May 17;5:e12469. doi: 10.7554/eLife.12469. PMID: 27187613; PMCID: PMC4869911.

Getting back to Progenitor’s evolution, Progenitor can infect plants and animals because it existed before plants and animals diverged – long before. And eventually, in most places on Earth, it either died out, mutated to something completely different, or merged into host genomes and stayed there as an inactive, endogenous retrovirus. Progenitor remained in a recognizable form in only one place on earth, in only a single host – a species of the Asteraceae or daisy family, growing in a small pool of light at the bottom of a cave in western Africa.

Let’s address the elephant in the room before we go on: the overwhelming scientific consensus is that humans evolved in Africa [i],[ii],[iii]. Most of the evidence comes from the south and east portions of the continent, but some research suggests that populations of archaic humans from all over the continent may have contributed to modern Homo sapiens [iv],[v],[vi]. And as some of our earlier sources have pointed out, viruses have contributed to human evolution. So it wouldn’t be impossible for Progenitor to have played a role not only in the origin of life on Earth, but also much more recently in the evolution of humanity – either by infecting humans near its final reservoir in west Africa, or by infecting humans in east or south Africa before its range contracted to that single cave. There’s no evidence for or against this hypothesis, but it was one of the ideas that intrigued us most about putting Progenitor in the continent that served as humanity’s cradle.

The reverence given these flowers may have led to Progenitor’s adaptation to human hosts. Source: Resident Evil 5

But let’s move on to material that is better supported by series canon. At some point, probably contemporaneous with the late Neolithic or Chalcolithic, or possibly the early Bronze Age, some human group found this last reservoir of Progenitor and did what humans do when we see something novel. They tried to eat it. In Resident Evil 5, File No. 7 on the Ndipaya tribe indicates that most people who ingested this flower died, but a select few survived and some of them gained extraordinary abilities. These individuals became rulers of the Ndipaya tribe, and the tribe itself built an extraordinary underground city surrounding the last habitat of these flowers. Because of the power within the flowers and the evocative environment of a sunlit cavern, they called the flowers “Stairway to the Sun” and the last habitat in which they grew became known as the Sun Garden. Much, much later, a European named Henry Travis would come along and record them in his own records under the name Sonnentreppe. Hundreds of years after that, a man named Henry Travis would come among the Ndipaya, recording their rituals, myths, and legends. Hundreds of years from then, a man named Ozwell Spencer would read of the tribe and their sacred flower, and start getting ideas – and delusions of grandeur.

We do want to point out at this stage that in the original version of this document, we did not have access to the information about the possible RNA World origin of Progenitor. We proposed an alternate explanation in which the predecessors of the Ndipaya tribe were themselves infected with a retrovirus that acquired certain human genes through horizontal transfer. These genes, we proposed, would have influenced some of the traits that make Progenitor distinctive – for instance, its capacity to grant immense power to those who survive infection. They would have buried their dead in the Sun Garden out of some religious association between the sun and divinity, and the human virus would have recombined with a plant virus already present in Sonnentreppe. However, we know that the Ndipaya maintained burial chambers well above the Sun Garden, in the upper ruins of the city, and there were separate crypts in the monarch’s chambers on the far end of the city. We also note that there are no known plant retroviruses with which a human retrovirus might trade genetic material. So while this new explanation does require us to propose that a holdover from the RNA World persisted for 3.8 billion years in a nearly unchanged state, it does simplify the narrative in other ways. For instance, a second reservoir of Progenitor, now extinct or lost from history, might explain the existence of the “Irish Giant” described in Biohazard the Stage [vii], an ostensibly canon stage play set in the Resident Evil universe. It has Chris, Piers, and Rebecca. There’s a subtitled version on YouTube. Go check it out. We’ll be here when you get back.

definitions

[i] University Of Cambridge. "New Research Confirms 'Out Of Africa' Theory Of Human Evolution." ScienceDaily. ScienceDaily, 10 May 2007. <www.sciencedaily.com/releases/2007/05/070509161829.html.

[ii] Liu H, Prugnolle F, Manica A, Balloux F. A geographically explicit genetic model of worldwide human-settlement history. Am J Hum Genet. 2006 Aug;79(2):230-7. doi: 10.1086/505436. Epub 2006 May 30. PMID: 16826514; PMCID: PMC1559480.

[iii] Stringer C (June 2003). "Human evolution: Out of Ethiopia". Nature. 423 (6941): 692–3, 695. Bibcode:2003Natur.423..692S

[iv] Scerri, E. M. L.; Chikhi, L.; Thomas, M. G.: Beyond multiregional and simple out-of-Africa models of human evolution, Nature Ecology & Evolution 3, pp. 1370 - 1372 (2019)

[v] Pan-Africanism vs. single-origin of Homo sapiens: Putting the debate in the light of evolutionary biology, Andra Meneganzin,Telmo Pievani,Giorgio Manzi, Volume 31, Issue 4, July/August 2022, Pages 199-212, First published: 18 July 2022 https://doi.org/10.1002/evan.21955

[vi] Gibbons A. Experts question study claiming to pinpoint birthplace of all humans. Nature 2019. https://www.science.org/content/article/experts-question-study-claiming-pinpoint-birthplace-all-humans

[vii] https://youtu.be/TtuDN0Pwvxk

Infection

As we described, Progenitor can infect species ranging from plants to insects to humans. Infection of plants is not a problem, since a virus typically enters the cytoplasm of the plant’s cells directly, through open wounds that breach individual cells. Often, but not always, these wounds are caused by invertebrates feeding on the plant. Sometimes plants can be infected through pollen, and this was one of our initial hypotheses for transmission of Progenitor between individual Sonnentreppe plants. However the virus gets in, once it’s inside a plant cell, it can spread from cell to cell via plasmodesmata [1], pores that connect the cytoplasm of each plant cell to its neighbors.

Animal cells don’t have plasmodesmata. In order to infect animal cells, a virus must first attach to receptor proteins [2] on the cell’s surface. In order to create the drastic changes we see in most Progenitor hosts, the virus would have to infect nearly every cell in the host’s body.

These facts give us three requirements for the host cell receptor to which Progenitor must attach: It must be located on the cell surface; it must be present in nearly every animal species; and it must be present in nearly every cell in the body. We therefore believe Progenitor responds to a phospholipid, perhaps phosphatidylserine.

Every cell in nature has a plasma membrane, also known as a cell membrane – a thin skin of phospholipids that separates the goo inside from everything outside. There are a number of types of these phospholipids – phosphatidylcholine is one of the most common types – but, compared to the nigh-infinite array of surface proteins produced by different cells and organisms, the number of phospholipid types is relatively manageable. Every cell in the human body – and every cell in everything else, ever – uses more or less the same phospholipids, albeit in different proportions. That means that a virus that targets phospholipids could infect an enormous variety of animals, and could infect every tissue in a given animal – two very important characteristics of Progenitor and the T-Virus.

There is a real-world virus, the vesicular stomatitis virus, that has a similarly wide range of cells that it can infect (it cannot replicate in all of these cell types, but we’re not worrying about that). For a while, scientists believed that vesicular stomatitis virus bound to phosphatidylserine on host cells – while we now know that the whole story is a little more complicated, it appears that phosphatidylserine may still play an important role [i], [ii]. It’s within the realm of possibility that Progenitor and the T-Virus could achieve cell entry in a similar way.

definitions

[1] Plasmodesmata – Pores between plant cells, allowing free movement of cytoplasmic material between cells. These pores play a role in a variety of biological functions including trafficking and signaling.

[2] Receptor proteins - A molecular structure present upon a cell’s plasma membrane to which a virus must attach in order to be integrated into the cytoplasm.

[i] Hrefna Kristin Johannsdottir, Roberta Mancini, Jurgen Kartenbeck, Lea Amato, and Ari Helenius Host Cell Factors and Functions Involved in Vesicular Stomatitis Virus Entry. J Virol. 2009 January; 83(1): 440–453.

[ii] David A. Coil and A. Dusty Miller. Phosphatidylserine Is Not the Cell Surface Receptor for Vesicular Stomatitis Virus. J Virol. 2004 October; 78(20): 10920–10926.

Death

After working on the Progenitor Virus, we tried to dissect the mechanisms behind the T-Virus and its effects. Our conclusions will be more fully outlined later, but we know that, basically, the difference between the T-Virus and Progenitor is that, while both viruses kill people, the T-Virus keeps the bodies walking. (That’s not entirely accurate; we don’t think of T-Virus victims as being actually “dead” in the medical sense, but it will work for now.) Therefore, Progenitor probably kills people the same way the T-Virus does – and we believe the T-Virus kills people through a combination of extreme genetic reassortment, i.e. lethal mutation (as described in the guidebook BIO HAZARD Director's Cut Official Perfect Guide - Inside of BIO HAZARD) [i] or through a cytokine storm induced by a viral superantigen [1], or through some combination of the two. We’ll discuss these possibilities in turn.

Let’s start with the genetic reassortment. As stated above, this phenomenon can be described in a simpler way as extreme mutation. Mutation is a natural part of a retrovirus’s toolkit, as retroviruses naturally have the ability to integrate themselves into the host genome. As one might expect, randomly inserting a full viral genome into the host genetic code can disrupt what’s already there, the same way that copying and pasting text from elsewhere can completely disrupt a paragraph. Endogenous retroviruses, mentioned above, are retroviruses that have integrated into a host genome and lost the ability to replicate, basically becoming part of the host. They share some characteristics with retrotransposons, native elements of the host DNA that have the peculiar ability to move from one place to another in the host genome. They can also make copies of themselves, and even to pick up parts of the host genome as they do, increasing their ability to disrupt or change the genome. These functions give them the ability to influence their own expression and the expression of other genes [ii]. It’s speculated that retroviruses may have evolved from retrotransposons, and it’s not inconceivable that a retrovirus like Progenitor or T might retain this ability.

Most of the time, transposon activity and endogenous retroviruses present no problem for the host. After all, our genomes are full of both of them [iii]. But there is some evidence that somatic mutations are a contributor to cellular aging [iv], [v]. Somatic mutations are those that occur during an organism’s lifespan, in the cells of its body that don’t directly contribute to reproduction. That is, any mutation that doesn’t ultimately get carried into a sperm or egg cell is a somatic mutation. These can take the form of the retrotransposon code itself entering the genome at random points, or it can be actual physical damage to DNA incurred as those retrotransposons move in and out of chromosomes. As with any other mutation, the great majority of these are harmless, and a tiny few are beneficial, but some may be detrimental in some way – by, for instance, causing cancer [vi]. Enough harmful mutations will lead to cell death, to cell cycle arrest, or to loss of function.

We also considered the possibility that pathology and death are caused by a viral superantigen. Although superantigens are typically associated with bacteria, they have been associated with viruses as well, including retroviruses27. This superantigen would cause systemic inflammation and subsequent necrosis of the skin and the outer layers of connective tissue, leading to septicemia and shock, not to mention fluid loss and exposure to all kinds of nasty secondary infections. Our rationale for this mechanism will have to wait until we discuss the T-Virus itself.

We might note that, to our knowledge, this lethal effect applies only to humans. The B.O.W. Report in Resident Evil 0 indicates no such problems with lethality in animal hosts, suggesting that the hypothesized superantigen is highly species-specific.

Assuming for now that our superantigen hypothesis is correct, we might assume that those individuals like Albert Wesker, who can survive infection, do so through two methods that are independent but not mutually exclusive. Resistant individuals might survive the excessive somatic mutation we propose by having more robust DNA repair mechanisms. Such mechanisms would not prevent the formation of dangerous mutations from the random insertion and movement of retrotransposons, but they would prevent the secondary DNA damage that happens as those snippets of genetic code physically enter and leave the genome. Effective DNA repair might therefore reduce the buildup of genetic damage leading to death.

A second mechanism might be that resistant individuals may overcome the effects of a superantigen by modulating their immune response. If these hosts possess more-effective regulatory T-cells, then they can shut down the sort of immune overreaction caused by a superantigen. This ability would also make them more likely to survive numerous real-world diseases, including the dreaded smallpox. Alternately, it’s possible that high levels of testosterone are down-regulating certain parts of the immune system, preventing over-response to the superantigen; a recent study found that chimps with high testosterone levels generally carry more parasitic infections [vii]. High testosterone levels also correlate with “alpha-male” behavior, and so would correlate with being king of a civilization of warrior-architects or being a sunglasses-wearing megalomaniac.

definitions

[1] Superantigen (SAg) - A group of antigens capable of initiating a large, non-specific immune response in a host. This detrimental influx overwhelms the body and can have fatal consequences if left unchecked.

[i] BIO HAZARD Director's Cut Official Perfect Guide - Inside of BIO HAZARD. https://www.projectumbrella.net/bio-hazard-directors-cut-official-perfect-guide--inside-of-bio-hazard.html

[ii] Nelson PN, Hooley P, Roden D, Davari Ejtehadi H, Rylance P, Warren P, Martin J, Murray PG; Molecular Immunology Research Group. Human endogenous retroviruses: transposable elements with potential? Clin Exp Immunol. 2004 Oct;138(1):1-9. doi: 10.1111/j.1365-2249.2004.02592.x. PMID: 15373898; PMCID: PMC1809191.

[iii] Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W, Funke R, Gage D, Harris K, Heaford A, Howland J, Kann L, Lehoczky J, LeVine R, McEwan P, McKernan K, Meldrim J, Mesirov JP, Miranda C, Morris W, Naylor J, Raymond C, Rosetti M, Santos R, Sheridan A, Sougnez C, Stange-Thomann Y, Stojanovic N, Subramanian A, Wyman D, Rogers J, Sulston J, Ainscough R, Beck S, Bentley D, Burton J, Clee C, Carter N, Coulson A, Deadman R, Deloukas P, Dunham A, Dunham I, Durbin R, French L, Grafham D, Gregory S, Hubbard T, Humphray S, Hunt A, Jones M, Lloyd C, McMurray A, Matthews L, Mercer S, Milne S, Mullikin JC, Mungall A, Plumb R, Ross M, Shownkeen R, Sims S, Waterston RH, Wilson RK, Hillier LW, McPherson JD, Marra MA, Mardis ER, Fulton LA, Chinwalla AT, Pepin KH, Gish WR, Chissoe SL, Wendl MC, Delehaunty KD, Miner TL, Delehaunty A, Kramer JB, Cook LL, Fulton RS, Johnson DL, Minx PJ, Clifton SW, Hawkins T, Branscomb E, Predki P, Richardson P, Wenning S, Slezak T, Doggett N, Cheng JF, Olsen A, Lucas S, Elkin C, Uberbacher E, Frazier M, Gibbs RA, Muzny DM, Scherer SE, Bouck JB, Sodergren EJ, Worley KC, Rives CM, Gorrell JH, Metzker ML, Naylor SL, Kucherlapati RS, Nelson DL, Weinstock GM, Sakaki Y, Fujiyama A, Hattori M, Yada T, Toyoda A, Itoh T, Kawagoe C, Watanabe H, Totoki Y, Taylor T, Weissenbach J, Heilig R, Saurin W, Artiguenave F, Brottier P, Bruls T, Pelletier E, Robert C, Wincker P, Smith DR, Doucette-Stamm L, Rubenfield M, Weinstock K, Lee HM, Dubois J, Rosenthal A, Platzer M, Nyakatura G, Taudien S, Rump A, Yang H, Yu J, Wang J, Huang G, Gu J, Hood L, Rowen L, Madan A, Qin S, Davis RW, Federspiel NA, Abola AP, Proctor MJ, Myers RM, Schmutz J, Dickson M, Grimwood J, Cox DR, Olson MV, Kaul R, Raymond C, Shimizu N, Kawasaki K, Minoshima S, Evans GA, Athanasiou M, Schultz R, Roe BA, Chen F, Pan H, Ramser J, Lehrach H, Reinhardt R, McCombie WR, de la Bastide M, Dedhia N, Blöcker H, Hornischer K, Nordsiek G, Agarwala R, Aravind L, Bailey JA, Bateman A, Batzoglou S, Birney E, Bork P, Brown DG, Burge CB, Cerutti L, Chen HC, Church D, Clamp M, Copley RR, Doerks T, Eddy SR, Eichler EE, Furey TS, Galagan J, Gilbert JG, Harmon C, Hayashizaki Y, Haussler D, Hermjakob H, Hokamp K, Jang W, Johnson LS, Jones TA, Kasif S, Kaspryzk A, Kennedy S, Kent WJ, Kitts P, Koonin EV, Korf I, Kulp D, Lancet D, Lowe TM, McLysaght A, Mikkelsen T, Moran JV, Mulder N, Pollara VJ, Ponting CP, Schuler G, Schultz J, Slater G, Smit AF, Stupka E, Szustakowki J, Thierry-Mieg D, Thierry-Mieg J, Wagner L, Wallis J, Wheeler R, Williams A, Wolf YI, Wolfe KH, Yang SP, Yeh RF, Collins F, Guyer MS, Peterson J, Felsenfeld A, Wetterstrand KA, Patrinos A, Morgan MJ, de Jong P, Catanese JJ, Osoegawa K, Shizuya H, Choi S, Chen YJ, Szustakowki J; International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome. Nature. 2001 Feb 15;409(6822):860-921. doi: 10.1038/35057062. Erratum in: Nature 2001 Aug 2;412(6846):565. Erratum in: Nature 2001 Jun 7;411(6838):720. Szustakowki, J [corrected to Szustakowski, J]. PMID: 11237011.

[iv] Cagan, A., Baez-Ortega, A., Brzozowska, N. et al. Somatic mutation rates scale with lifespan across mammals. Nature 604, 517–524 (2022). https://doi.org/10.1038/s41586-022-04618-z

[v] Vijg J, Dong X. Pathogenic Mechanisms of Somatic Mutation and Genome Mosaicism in Aging. Cell. 2020 Jul 9;182(1):12-23. doi: 10.1016/j.cell.2020.06.024. PMID: 32649873; PMCID: PMC7354350.

[vi] Miles B, Tadi P. Genetics, Somatic Mutation. 2022 Apr 21. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 32491819.

[vii] Muehlenbein MP, Watts DP. The costs of dominance: testosterone, cortisol and intestinal parasites in wild male chimpanzees. Biopsychosoc Med. 2010 Dec 9;4(1):21. Epub ahead of printIn humans, Progenitor infection can have one of two results. We know from Resident Evil 5’s Report on Project W and from File No. 7 on the Ndipaya tribe that most people who are infected with Progenitor, whether by ingesting Sonnentreppe or by direct injection, simply die. (We’re aware that Wesker’s virus was simply called “an experimental virus” in File No. 12 on Albert Wesker; however, we believe it was derived from Progenitor, so we’re going to try to learn what we can from its effects.) We are never told just how these people die, but we can make some guesses.

Amazing super powers

Progenitor is far more interesting when it keeps people alive. We know from multiple encounters with Albert Wesker that whatever virus he was administered gave him super-strength, speed, agility, and healing powers. It’s hard to know if the virus caused these effects because it is based on Progenitor, or because it is an experimental variant of it. However, Chief Researcher Brandon’s Journal No. 1 also suggests the flower “Stairway to the Sun” gives people who ingest it “incredible abilities.” File No. 7 on the Ndipaya tribe indicates some youths consumed the flower in order to fight off Umbrella agents violating their ruins. These files lead us to believe that Wesker owes his powers to Progenitor.

Super strength

We can only speculate on the source of these abilities, but at the base of everything is metabolism. Wesker needs energy to run faster, punch harder, dodge bullets, and heal from small explosions and steel beams to the face. We think Progenitor up-regulates a number of hormones, particularly thyroid hormones and hypothalamic trophic hormones, and probably a lot of intermediate metabolic enzymes as well. Which ones? We dunno, all of them. To be honest, there are quite a few, and the interactions between them are quite complex. In order to increase growth and basal metabolism without causing serious pathological consequences, they would all probably need to be tweaked somewhat. Fatty acid catabolism to provide energy would keep subjects fit and healthy. Metabolic up-regulation would also help to promote rapid healing. Progenitor may also aid healing by maintaining populations of stem cells in the body. Yet, despite this complexity, a large amount of this metabolic modification may occur through a single master chemical, as we will discuss in the section on P30.

This pipe thought it was a match for the Progenitor Virus. It was wrong. Source: Code: Veronica X

Wesker suffered a severe burn in 1998. By 2003, his face shows no traces of scarring. Sources: Code: Veronica X and Umbrella Chronicles

Perhaps Progenitor simply reactivates silent genes from deep biological history; the same genes that allow reptiles to produce functional tissue instead of scar tissue in response to injury. Evolutionary developmental biology and junk DNA [1] suggest many such ancient genes might still be intact (or mostly intact) in our genetic code, despite not having been used in millions of years. Additionally, if some enzyme, perhaps produced by Progenitor itself and not merely up-regulated by it, were to degrade extracellular tissue, this enzyme might reduce the amount of granulation tissue [2] in scars, allowing them to be replaced by healthy tissues.

definitions

[1] Junk DNA - Alternatively described as non-coding DNA, the majority of the human genome contains genetic sequences for which no function has yet been elucidated. “Junk” DNA includes repetitive elements as well as the remnants of ancient genes and viruses.

[2] Granulation tissue - A fibrous connective tissue comprised of a myriad of different cell types (e.g. inflammatory cells, new blood vessels) which fills a wound during the healing process; eventually, this tissue is replaced by new skin. A pronounced lesion of granulation tissue is colloquially known as proud flesh.

Progenitor may silence a gene called P21, either through up-regulation of specific repressors, or through short interfering RNA. Organisms in which P21 is inactivated are able to heal from wounds without scarring; their cells can more easily revert to a pluripotent stem-cell state [i].

definitions

[i] Bedelbaeva K, Snyder A, Gourevitch D, Clark L, Zhang XM, Leferovich J, Cheverud JM, Lieberman P, Heber-Katz E. Lack of p21 expression links cell cycle control and appendage regeneration in mice. PNAS USA. 2010 Mar 30;107(13):5845-50.

Thanks to the Progenitor Virus, Wesker has great muscle tone, but it clearly has not helped him bulk up as much as some other S.T.A.R.S. members. Source: Resident Evil 5

On to the matter of super-strength. At the end of Resident Evil 5, Wesker removed his shirt for the first time in the series (outside of some rather…misguided fanfiction lurking about the internet [i]). We, being men of SCIENCE, noted calmly and dispassionately that Wesker is ripped – but despite his enviable muscle tone, he doesn’t look much bulkier than when he was a member of S.T.A.R.S. So, while it’s easy to say that Progenitor simply increases expression of certain growth factors, we think that Progenitor also codes for a mutant variant of the myosin [1] light-chain protein, one that’s slightly stronger than what normal humans produce. This stronger light-chain myosin would allow for a stronger power stroke during muscular contraction and would probably give Wesker’s muscles greater tensile strength while contracted. This mutant gene may have a slightly stronger promoter [2] than the original, causing it to be expressed preferentially. It may also be that Progenitor expresses the ACTN3 gene, which is correlated with human athletic performance [ii]. This gene is inactive in a large portion of the human population, and Progenitor may augment it with an active variant, or may induce double expression of this gene in populations that already possess it.

As long as Progenitor is modifying Wesker’s muscle tissue, it might stimulate his body to gradually increase the percentage of Type IIb [3] skeletal muscle (that is, fast-twitch muscle), helping him to move faster. This alteration actually occurs in some forms of real-world exercise and physical conditioning, and happens to be responsible for the awesomeness of the late Bruce Lee.

Wesker’s reflexes could further improve if Progenitor increases the number of ion gates in the nodes of Ranvier, which are regularly-spaced, unmyelinated locations on the axons of neurons. The nodes of Ranvier and the ion channels located there are critical in passing along action potentials. An increase in these ion channels might allow membrane depolarization to occur more quickly, thereby helping his nerves to conduct signal faster, but we’re just speculating there.

Finally, it is possible, though admittedly unlikely, that Progenitor expresses a form of cytosolic phosphoenolpyruvate carboxykinase (GTP), or PEPCK-C. Since PEPCK-C increases a variety of metabolic functions, including adipose tissue proliferation, this variant would have to be expressed solely in muscle tissue; the gene may have a promoter sequence similar to that of skeletal muscle actin, or possibly myosin. Chimeric (recombinant) genes like these are easy to build in a laboratory, but a recombination event of particularly low probability would be required to produce one in nature. Progenitor’s function as a retrovirus may assist in this regard by acting as a transposon [4] in the host genome. A recombinant gene like the one described has been found to imbue mice with excellent physical endurance and longevity [iii].

definitions

[1] Myosin - A class of motor proteins most abundant in the thick filaments of muscle fibers. Alongside actin, it is responsible for the contraction and relaxation of the muscle.

[2] Promoter - A specific nucleotide sequence in DNA that binds RNA polymerase and indicates where to begin transcribing a certain gene.

[3] Type IIb skeletal muscle - Fast-twitch muscle fibers relying on anaerobic metabolism to create energy in rapid, powerful bursts of speed. As a result of possessing the highest rate of contraction, this muscle tissue type also undergoes fatigue quicker.

[4] Transposon - A segment of DNA that is capable of inserting copies of itself into other DNA sites within the same cell.

[i] Just kidding. We want nothing to do with this.

[ii] Yang N, MacArthur DG, Gulbin JP, Hahn AG, Beggs AH, Easteal S, North K. ACTN3 genotype is associated with human elite athletic performance. American Journal of Human Genetics. 2003 Sep; 73(3):627-31.

[iii] Hakimi P, Yang J, Casadesus G, Massillon D, Tolentino-Silva F, Nye CK, et al. Overexpression of the cytosolic form of phosphoevolpyruvate carboxykinase (GTP) in skeletal muscle repatterns energy metabolism in the mouse. Journal of Biological Chemistry 2007; 282(45): 32844-32855.

Senses

The B.O.W. Report suggests that mammals infected with Progenitor develop improved hearing. The Lickers created by the T-Virus are also frequently described as having excellent hearing. This improvement might come about as a result of the same healing factors described above, which may promote the growth of new hair cells [1] in the cochlea of the inner ear. Additionally, Progenitor may silence a gene called GJB2 and replace it with a mutant variant, as we discussed with myosin above. GJB2 codes for a protein called Cx26, a growth factor which has been found to affect hearing as well as skin growth and healing [i].

definitions

[1] Hair cells - Sensory receptors with hair-like processes located in the cochlea and responsible for converting sound vibrations into electrical signals for the brain via their oscillation patterns.

[i] Mutation In Deafness Gene Can Help Heal Wounds And Prevent Infection. Science Daily. 2006 May 8. http://www.sciencedaily.com/releases/2006/05/060508085304.htm

The B.O.W. Report also describes a slight decrease in visual acuity, and it’s also worth noting that in Resident Evil 5, Wesker had a hard time dodging rockets in the dark during the battle on the flight deck. The reason for this ocular degeneration is not clear, but originally we had postulated that the large-scale hormonal up-regulation caused by the Progenitor Virus led to an increase in the secretion of aqueous and vitreous humors – the substances that fill one’s eyeballs. Increased secretion of these materials would lead to increased intraocular pressure, which would in turn alter the shape of the lens and retina – leading to blurred vision.

That was one possibility, but we’ve since stumbled upon another. It could be that the Progenitor Virus up-regulates expression of a gene called sonic hedgehog (and yes, it was named after the swift blue critter) [i], [ii], [iii]. The hedgehog signaling pathway, of which sonic hedgehog is a part, is a regulatory system involved in embryo development, but it also plays a role in maintaining stem cell populations in the adult body. Stem cells are useful in healing injuries and producing new tissue, making hedgehog genes useful for Progenitor to up-regulate.

We still can’t explain the eyes. Source: Code: Veronica X

definitions

[i] Bhardwaj G, Murdoch B, Wu D, Baker DP, Williams KP, Chadwick K, Ling LE, Karanu FN and Bhatia M. Sonic hedgehog induces the proliferation of primitive human haematopoetic cells via BMP regulation. Nat Immunol 2001; 2 (2): 172–180.

[ii] Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, Jackson KW, Suri P and Wicha MS. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res 2006; 66 (12):6063–6071.

[iii] Ahn S and Joyner AL. In vivo analysis of quiescent adult neural stem cells responding to Sonic hedgehog. Nature 2005; 437 (7060): 894–897.

Telomeres (red) are protective, repeating DNA segments that get shorter with each cell division. When they disappear, the chromosome becomes susceptible to irreversible damage.

Unfortunately, sonic hedgehog also inhibits another gene, PAX6. This gene is also involved in embryological development, and it has particular importance in the development of the eyes. Like hedgehog, it is also expressed in adults; PAX6 has been found to have a role in maintaining populations of progenitor keratocytes in the cornea of the eye, which synthesize corneal proteins necessary for vision [i]. Inhibiting PAX6 would cause many of these cells to become fibroblastic, preventing the synthesis of these necessary proteins and potentially reducing visual acuity.

We really have no idea why the Progenitor Virus seems to give people slitted pupils or why it changes the color of the iris. It could be a result of recombination in reptilian hosts before humans ever stumbled upon Sonnentreppe and the Progenitor Virus…but that’s just a guess for now.

definitions

[i] Funderburgh ML, Du Y, Mann MM, SundarRaj N, Funderburgh JL. PAX6 expression identifies progenitor cells for corneal keratocytes. FASEB J 2005; 19(10):1371-3.

Longevity

We know from File No. 7 that Ndipaya kings, who were basically chosen for kingship based on their ability to survive Progenitor infection, were known for extreme longevity (at least one king lived hundreds of years).

Telomere function is an active area in longevity research, and not coincidentally, it also comes up in Resident Evil [i]. The enzyme telomerase is described in the Lost in Nightmares scenario of Resident Evil 5, in the file Spencer’s Memoirs 4. Our chromosomes have bits on the end called telomeres. These telomeres are degraded a little bit every time our cells divide, and when they’re degraded too much, our cells begin to fail and we get symptoms like liver spots and death. Telomerase is an enzyme which is supposed to repair telomeres, and we have a little of it – just enough to reduce the rate of degradation, but not enough to prevent it altogether. Apparently individuals infected with Progenitor make a lot more telomerase, inhibiting telomere degradation and natural cell aging in that regard.

Our cells have natural mechanisms to fight tumor formation, but obviously, these mechanisms are not perfect. It is likely that Progenitor plays a role in reducing somatic mutation and fighting cancer; it could accomplish this by up-regulating DNA repair mechanisms, suppressing oncogenes [1], and up-regulating oncolytic [2] processes. Some Progenitor protein products may also have natural antioxidant capabilities. Antioxidants reduce the amount of reactive oxygen species (radicals [3]) in the body; these radicals can damage DNA and cause cell death or tumor formation. By reducing their presence, Progenitor might eliminate one cause of aging.

Based on current research, we also suspect Progenitor causes short-RNA interference [4] of genes like Daf-2 or Daf-16 [ii], [iii]. This gene codes for an insulin-like protein involved in the mechanisms which make germ-line cells [5] (the cells which eventually become sperm and eggs) hardier and more resistant to aging than normal cells.

We do also need to point out a passage of interest in the novelization of Umbrella Chronicles, which we previously mentioned above9. As we mentioned before, in this novelization, James Marcus conducted an early experiment that introduced the Progenitor Virus as an additional component to the Miller-Urey experimental setup. But he also added some dead bacteria – Escherichia coli, which he had previously killed with 0.1 parts per million of chlorine. Under these conditions, Progenitor resurrected the bacteria to full activity. Or maybe the Progenitor E. coli [6] resurrection experiment and the Progenitor Miller-Urey experiment were separate, with E. coli being killed prior to the first experiment and Progenitor being killed prior to the second, using exactly the same method. The translation isn’t totally clear. Either way, in this novelization, the Progenitor virus somehow restored dead cells to activity under certain conditions. This phenomenon would have obvious implications for the creation of zombies by the T-Virus, and it would also have implications for the ability of Progenitor to extend the lifespan and improve healing after injury.

definitions

[1] Oncogene - A gene capable of transforming normal cells into cancer cells under certain conditions, as in mutation or overexpression.

[2] Oncolytic - Pertaining to the destruction of tumor cells.

[3] Radical - An atom bearing unpaired electrons, inducing it to participate in chemical reactions to fill their valence shell, and making it highly reactive as a result. In the body, oxygen represents the most common radical found.

[4] Short-RNA interference - A functional process by which short interfering RNA (siRNA) interferes with expression of a particular gene.

[5] Germ-line cells - The progenitors of gamete cells, germ-line cells can reproduce indefinitely before maturing into ova or spermatozoa.

[6] Escherichia coli - Otherwise known as E. coli, this is an extremely common bacterium that can be found in the lower digestive tract of any human. Because it is so common and mostly harmless, it is commonly used in genetic research.

[i] Harley CB, Liu W, Blasco M, Vera E, Andrews WH, Briggs LA, Raffaele JM. Researchers Discover Telomerase-Activating Compound, Hope to Eventually Reverse Aging. Rejuvenation Research. 2010. 00:1-12.

[ii] Recruitment Of Reproductive Features Into Other Cell Types May Underlie Extended Lifespan In Animals. Science Daily. 2009 June 8. http://www.sciencedaily.com/releases/2009/06/090607153254.htm

[iii] Amrit FRG, Boehnisch CML, May RC. Phenotypic Covariance of Longevity, Immunity and Stress Resistance in the Caenorhabditis Nematodes. PLoS One 2010; 5(4):e9978.

As we previously said, the novelization contains a lot of material that simply isn’t canon and a lot more that we can and will choose to ignore. But for fun, let’s briefly consider how Progenitor might resurrect a dead cell. One of the most basic characteristics of a virus is that it needs living cells to infect, so activity in a dead cell seems counterintuitive from the start. But recall that Progenitor may be a holdover from the RNA World (and in this novelization, it likely is). That means that Progenitor’s RNA genome probably has some enzymatic activity of its own. It may well be able to catalyze the synthesis of phospholipids and the repair of lipid membranes, among other basic cellular functions to restore and maintain homeostasis. That’s a tall order for any real virus, but simple enough in the world of Resident Evil, where a virus can turn a person into a ferocious, ambulatory tumor the size of a bus in the span of a few hours. When Marcus applied heat and an electrical discharge, he would have supplied the most important factor that a virus cannot – energy to fuel anabolic metabolism.

However, canonically, even the T-Virus can’t truly resurrect the dead, and it literally makes zombies, which in two games have literally crawled out of graves. This novel is describing Progenitor, which does not make zombies at all (probably). So we can probably just ignore all of this.

Aggression

The images on the left show normal amounts of MAO-A activity. The brain on the right shows reduced activity, and it just so happens that the person who owns this brain is a jerk. Source: Alia-Klein et al 2008

The B.O.W. Report in Resident Evil 0 indicates that insects and mammals infected with Progenitor become more aggressive, and amphibians develop a greater appetite (which may be the only way amphibians can actually show aggression, as far as we know). It stands to reason that Albert Wesker and the Ndipaya kings also exhibit greater aggression, although increased aggression might be hard to detect in a megalomaniac and a warrior-king.

This increased aggression may be due to lower levels of monoamine oxidase A [1]; decreased MAO-A levels have been associated with violent behavior in humans [i], [ii]. For this reason, the gene for MAO-A has been referred to as the “warrior gene” [iii]. Monoamine oxidase reduces levels of amino acid-based neurotransmitters like serotonin; artificially high levels of serotonin have been shown to turn lobsters into the lobster equivalent of assholes [iv].

Progenitor may interfere with the function of the MAO-A gene through the introduction of siRNA to reduce its expression, or by producing an antagonist, a substance that specifically interferes with MAO-A activity. The result would be increased serotonin expression and increased aggression.

definitions

[1] Monoamine oxidase A (MAO-A) - A structurally distinct form of the monoamine oxidase enzyme encoded by the MAOA gene. The enzyme itself catalyzes the oxidative deamination of primary amines to form aldehydes and hydrogen peroxide; typical substrates include neurotransmitters such as serotonin, norepinephrine, epinephrine, and dopamine

[i] Alia-Klein N, Goldstein RZ, Kriplani A, Logan J, Tomasi D, Williams B, Telang F, Shumay E, Biegon A, Craig IW, Henn F, Wang GJ, Volkow ND, Fowler JS. Brain Monoamine Oxidase A Activity Predicts Trait
Aggression. Journal of Neuroscience. 2008 May 7; 28(19): 5099-5104.

[ii] Beaver KM, DeLisi M, Vaughn MG, Barnes JC. Monoamine oxidase A genotype is associated with gang membership and weapon use. Comprehensive Psychiatry. 2009; accessed through www.sciencedirect.com.

[iii] Warrior Gene' Linked To Gang Membership, Weapon Use. Science Daily. 2009 September 13. http://www.sciencedaily.com/releases/2009/06/090605123237.htm

[iv] Kravitz EA. Hormonal control of behavior: amines and the biasing of behavioral output in lobsters. Science. 1988; 241(4874): 1775-81.

Fertility

The Progenitor Virus enhances your performance, but makes you sterile. Go figure.

Over the generations, there would probably be a lot of evolutionary pressure for the Ndipaya to evolve toward a tribe-wide acceptance of the Progenitor Virus. So why haven’t they?
The obvious hypothesis is that, in addition to superpowers, Progenitor also causes infertility, which we like to think of as its own kind of superpower. There is a problem with this hypothesis, however; the B.O.W. Report from Resident Evil 0 informs us that monkeys infected with the virus actually become more fertile. Or at least, it says so in the official English translation; the original Japanese text makes no mention of increased fertility. But we know from Resident Evil 5 that Lickers infected with Progenitor (which would be a superinfection, given that they already carry the T-Virus in their genomes) become fertile.

The Progenitor Virus enhances your performance, but makes you sterile. Go figure.

But actually, it all makes sense in a weird sort of way. We’ve already suggested that Progenitor boosts the metabolism and causes the host to produce a lot of hormones. These factors, especially the hormones, might result in increased ovulation [1] in females – that is, greater fertility. The increased metabolism, however, also means a higher core body temperature – not a problem for females and their ova, but a big problem for sperm production in males (hence our extremely vulnerable testicles). Without skin, Lickers would lose body heat a lot faster, but the Ndipaya selfishly chose to keep their skin. If most Ndipaya monarchs were male (and the history of civilizations worldwide suggests they would be), they would be childless. It would therefore become necessary to find a successor some other way – and a tendency to eat poisonous plants is the mark of a good leader.

There is another possible explanation which derives from the superantigen hypothesis presented above. People with relatively weak cell-mediated immunity would be more likely to survive a Progenitor infection, as the virus’s superantigen would have a hard time driving their immune systems into a self-destructive cytokine storm. However, cell-mediated immunity and humoral immunity (the part of the immune system involving antibodies) are often inversely correlated. It turns out that sheep with a strong humoral immunity live longer but are less fertile, as their immune systems attack their own sperm or ova [i]. Likewise, a “genetically superior” Ndipaya king with a strong humoral immunity would be resistant to many common infections and would survive Progenitor infection due to weak cellular immunity, but might have trouble siring a child even without the added effects of the Progenitor virus.

definitions

[1] Ovulation - The discharge of a mature ovum from an ovarian follicle into the uterus.

[i] Graham AL, Hayward AD, Watt KA, Pilkington JG, Pemberton JM, Nussey DH. Fitness correlates of heritable variation in antibody responsiveness in a wild mammal. Science. 2010 Oct 29;330(6004):662-5.

Giant animals

The good news is that everything we’ve discussed regarding Progenitor in Wesker and the Ndipaya (except perhaps the fatality rate) also applies when we discuss other mammals, at least according to the B.O.W. Report in Resident Evil 0. The bad news is that the effects are totally different in insects.

We’ve suggested before that Progenitor causes increased hormonal expression in hosts. In arthropods, one of the hormones affected could be something called prothoracicotropic hormone [1]. The more of this hormone an arthropod produces, the more often it molts. The more the organism molts, the larger it can grow. So, that’s probably a good place to start. We have also claimed that the Progenitor virus stimulates production of other growth hormones as well.

We see several mutant arthropods in Resident Evil 0: the Stinger, the Centurion, and the Plague Crawlers. Unfortunately, none of these are products of the Progenitor Virus – the Resident Evil Archives indicate that all were produced by exposure to the T-Virus. Therefore, we don’t know how large insects get when infected with the Progenitor Virus. We do see some insects grow to unusual but believable sizes as a result of T-Virus infection, such as the wasps in Resident Evil and its remake, and the cockroaches in Resident Evil 2. Given the well-known limits on the size of real insects, that’s probably a good benchmark for insects infected with the Progenitor Virus.

According to the Resident Evil Archives, Lurkers are actually products of the T-Virus, not the Progenitor Virus, as the B.O.W. Report in Resident Evil 0 would suggest. Their extreme growth will be discussed in the essay on the T-Virus.

definitions

[1] Prothoracicotropic hormone (PTTH) - An insect hormone that effects release of molting hormone from prothoracic glands thus stimulating the molting process.

There are some animals we never see directly, but which appear on some carvings in the Ndipaya ruins. We can assume that they are products of the Progenitor Virus; however, they seem to have been affected to a far greater degree than most other Progenitor subjects. Their digitigrade legs suggest they were never human, but the spikes on their backs do not suggest any normal animal of that size which has lived in the past few million years.

We have speculated that these creatures might be beasts of war, created by the Ndipaya by feeding the Progenitor-infected flower Sonnentreppe to some large mammals. That alone would not create the mutations we see, but a breeding program would lead to strange and interesting genetic recombination events as parts of the Progenitor Virus’s genome are randomly shuffled in the process of meiosis[1] and then combined in a new organism. Superinfection might be another factor; superinfection would involve the same cells being infected more than once, as very large quantities of virus are introduced to the animal, perhaps by force-feeding it lots of Sonnentreppe.

Judging by the carvings, this did not go well for the Ndipaya.

When you breed animals specifically to kill, don’t be surprised when they’re good at it. Source: Resident Evil 5

definitions

[1] Meiosis - The process of cell division by which sperm and eggs are formed.

Sonnentreppe and viral replication

We’ve discussed the effects of Progenitor in animals. We want to discuss how it reproduces in plants. This is kind of a mystery, since Brandon Bailey’s Journal No. 1 in Resident Evil 5 tells us Progenitor simply couldn’t be found in plants grown outside of the Sun Garden in the Ndipaya ruins.

Bailey’s failure to isolate Progenitor may result from a basic characteristic of latent viral infections [1]: the viral genome may be in the host’s cells, but the virus is quiescent – that is, no new virus is being produced. HIV is known for this kind of sneakiness. It looks like Bailey suspected this, because he and his team tried to grow Sonnentreppe in different soils and light exposures, and he tried variations of every condition he could think of in an attempt to get the virus to express.

There are a couple of explanations here. One is that Progenitor is not capable of vertical transmission in plants – that is, infected plants produce seeds that are not infected. This phenomenon could happen if the virus does not integrate into the plant genome and is not expressed in reproductive tissues. Perhaps, for instance, it is transferred from plant to plant by nematodes in the soil, or by the insects that we see buzzing around it in Resident Evil 5. However, the technique of growing plants from cuttings has been known for thousands of years [i], and this technique would handily solve that problem.

The other option is that every Sonnentreppe plant is presumably infected already, and indeed, the infection may be transmitted in the seeds or pollen to each new generation of plant, either because the virus is directly encoded into the genome as an endogenous retrovirus, or because these tissues are infected. However, the virus remains latent in the plant’s own DNA unless certain conditions are met. The exact conditions required for Progenitor expression in Sonnentreppe are unknown, but may result from a single gene, such as a transcriptional cofactor, expressed under the conditions of the Sun Garden and nowhere else.

The situation may be quite different when Progenitor infects humans. This virus is obviously able to replicate in plants; however, human tissue may be susceptible to infection but not permissive of replication – that is to say, the virus can get into a human cell and change its DNA, but can’t make new viruses in a human cell to go off and infect anything else. Or perhaps it replicates at a very low level, sufficient to induce widespread infection of host cells, without producing enough virus to be harvested.

We base this hypothesis on a couple of factors. First, if Progenitor could replicate efficiently in human tissues, Umbrella wouldn’t have needed the laboratory by the Sun Garden after they obtained the virus for the first time. They could get as much Progenitor as they wanted just by growing their virus in human subjects and sucking out the precious, virus-laden fluids. Instead, they expanded the laboratory and kept it running in secret for decades.

definitions

[1] Latent viral infection - A stage in the replication cycle of certain viruses wherein production of new virions has halted; since the viral genome is a lingering part of the host, however, the virus can reactivate at any given time, usually in response to environmental factors.

[i] Historia Plantarum, Theophrastus, https://archive.org/details/enquiryintoplant01theouoft/page/130/mode/2up

The properties of the G-Virus also suggest that it may not be able to replicate efficiently, or at all, in human cells – in order to create a new G-Type, it has to transfer its own cells into a new host rather than merely transmitting infectious fluid like blood or saliva. We wondered why the G-Virus might be engineered to be replication-incompetent, and the simplest answer was that it wasn’t engineered that way – the trait was a holdover from the Progenitor Virus from which it was derived. (We’ll go into more detail about this in the third Report.)

The kinds of effects produced by Progenitor infection in humans require a major shift in the body’s homeostasis. Such an effect could be produced by infection of every cell in the body, although if the virus is incapable of replication this would require an extraordinarily large inoculum (something we’ve calculated to be just about barely within the realm of possibility, given the volume of material we see Wesker inject into himself). Another possibility holds that only a small proportion of the body’s cells are infected, but the hormones and growth factors produced by these cells are enough to alter the body’s homeostasis. This ties in to a possible explanation for Wesker’s plot serum in Resident Evil 5, which we will describe later.

The effects of plasmolysis according to Capcom and reality. Source: Resident Evil remake

The Trevor Family

A few things remain to be discussed – namely, the variants and derivatives of the Progenitor Virus.

In the remake of Resident Evil, one file, the Family Picture and Notes, describes two early Progenitor experiments in which the women of the Trevor family are administered two experimental variants – Type A and Type B. The file goes on to describe – using the real, but completely non-applicable term “plasmolyzing [1]” – how only Progenitor Type B results in “viral fusion” (though it should be noted that in the original Japanese text, the file refers to “tissue fragmentation” and “failure to colonize” rather than “plasmolysis”). If Progenitor has a viral envelope, it would indeed be capable of “virus fusion,” as described in the file; in virology, fusion describes the initial stage of infection in which its envelope merges with the cell membrane, inserting the naked virus into the cell. More importantly, as a retrovirus, after this “viral fusion” it would be capable of integration into the host genome, and in fact this trait is one of the reasons it was so important to Ozwell Spencer. But why would only one of the two variants be capable of fusion, and why didn’t it kill Lisa Trevor?

The first possibility is the simplest, but relies on chance to the extent that it feels like a cop-out. It may simply be that Lisa Trevor possessed the genetic qualities necessary to survive Progenitor infection, and her mother Jessica did not. It is entirely possible for Lisa to have this trait, even if her mother and father do not. Thanks to the intricacies of inheritance, some traits, such as eye color, rely not just on a single gene, but on interplay between several. Another good example is hair; an individual might inherit genes for blond hair or for red hair from its parents, but if it also has a dominant gene or two recessive for baldness, hair color becomes irrelevant. The phenomenon is called epistasis [2]. The trait allowing some individuals to survive Progenitor infection may be an example of this kind of inheritance. However, this explanation ignores the fact that two different versions of Progenitor were being described.

We might also speculate that, in researching Progenitor, Umbrella decided to modify the central characteristics of the Progenitor Virus – either its ability to act as a retrotransposon or its superantigen activity, both of which we have described above. Ozwell Spencer’s goal, of course, would be a virus with some lethality to select for genetically optimal humans, but less than total lethality, because you can’t build a master race if you kill absolutely everyone.

The phrases “failure to colonize” and “viral fusion” both suggest a failure of Progenitor Type A to enter host cells. In the language of SCIENCE, “fusion” means the ability of the viral membrane to fuse with a host cell membrane, so a failure here means the virus simply cannot infect host cells. We could throw Capcom a bone here and propose an alternate interpretation, in which the virus successfully enters the cell, but fails as a retrovirus to successfully integrate into the host genome. Let’s hold on to that interpretation for later. In either case, it seems to provoke an immune response or at least necrosis of infected cells, causing “tissue fragmentation.”

In contrast, the Type B strain was injected into Lisa Trevor. The Japanese translation of the Family Picture and Notes indicates that this strain exhibited successful colonization and some “remodeling of the host vessel”, despite some observed “tissue fragmentation during cell activation.” Given that Jessica Trevor was disposed of, and Lisa Trevor was retained for further study, it seems likely that this Type B strain was the basis of further research.

definitions

[1] Plasmolysis - the process in which the plasma membrane of a plant cell detaches from the cell wall due to reduced cytoplasmic volume.

[2] Epistasis - a phenomenon in which the effect of a gene is dependent upon the presence or absence of other genes.

The Wesker Prototype Virus and PG67A/W

We have assumed throughout this essay that the virus with which Albert Wesker injected himself is the same as, or is very similar to, the Progenitor Virus. We make this assumption because Progenitor is known from several files to cause physiological changes in humans, and these changes are hinted to physically improve those who survive infection. We also know that Spencer saw the Progenitor Virus as the key to Project W (or the Wesker Plan; Resident Evil 5 isn’t really consistent on a title). So while File No. 12 on Albert Wesker calls the virus “experimental,” we’re pretty sure it’s still quite similar to Progenitor.

However, the virus is also described in Umbrella Chronicles. In the Virus Memo, William Birkin claims that the virus is from the “mutation stocks” (or that it is a “variant strain,” going by the Project Umbrella translation) and that it is “designed to conquer death.” When animals are injected with the virus prior to severe injury, they supposedly have a 90% rate of full recovery, and a 70% chance of improved cardiovascular and muscular performance. These statistics contradict not only what we know about the Progenitor Virus (which kills most individuals who are infected), but also what we know about the virus given to the Wesker Children (most of whom died).

The information from these games may be compatible if we assume that the virus is a “variant strain” from the “mutation stocks” of the original Progenitor virus. As we’ve pointed out, B.O.W. Report file from Resident Evil 0 series does not specify any particular lethality in animals, but the Resident Evil 5 file on the Ndipaya tribe specifies extreme lethality in humans – possibly as a result of superantigen activity. We can assume, then, that Ozwell Spencer provided William Birkin with a sample of Progenitor Virus “from the mutation stocks” of the original Progenitor Virus, but did not tell Birkin anything about it. Birkin ran some tests, injected small amounts of the virus into rats, and found that most of them survived and showed extreme physical improvement. This kind of work could be done over a long weekend, or perhaps an evening, and could be done by a single person, perhaps allowing Birkin to avoid the scrutiny of Monitor. Birkin would have relayed these statistics to Wesker and gave him a sample of the virus.

Birkin noted that the virus was not tested in humans. What he didn’t know is that this experimental virus, like the Progenitor Virus itself, may be harmless to rats, but the viruses are usually lethal to humans, possibly due to the specificity of the superantigen lethality factor. Hence, everything in the Virus Memo is technically correct, but its information is incomplete.
It is important to note that Birkin specifies that the virus has the greatest effect when the subject is infected about five minutes prior to severe physical trauma. This could indicate that hormones released as a result of stress and injury dramatically up-regulate the expression of Progenitor genes, or at least help to kick-start the body into expressing them for the first time. Progenitor may therefore share a promoter with certain vertebrate stress-activated genes such as those in the SAPK pathway [i]. This doesn’t come up much in the games with regard to Progenitor, but we will see it again when we describe the T-Virus.

The game that keeps on giving, Resident Evil 5 also introduces another complication to the Wesker Prototype Virus – its effects are temporary without a “special serum.” A major plot element was that Albert Wesker had to periodically inject himself with a serum designated PG67A/W. Jill Valentine explained that the serum helped to keep the virus in Wesker’s body in a delicate balance. Too little serum and Wesker might lose his powers; too much, and the serum could act as a poison.

The syringes containing the serum (and their cases) were printed with the Tricell logo and what looked like a label from a template. The serum is probably produced at a Tricell facility, more than likely either the Uroboros research facility in Africa, or the smaller facility on the freighter. In spite of this, we believe that the serum was not actually developed by Tricell, but brought to them by Wesker, for reasons that will be explained.

definitions

[i] Tibbles LA, Woodgett JR. The stress-activated protein kinase pathways. Cellular and Molecular Life Sciences. 1999; 55:10.

What does PG67A/W mean? It may be that PG67 is the real name of the Wesker Prototype Virus, although we have no proof for this assertion. Making that assumption, we’re pretty sure PG stands for Progenitor; 67 stands for either the year the Wesker Virus was created or the start of Project W; and W stands for Wesker. The A could stand for anything, depending on what the serum actually does.

In fact, 1967 is not an unreasonable time for this virus to have been created. The Resident Evil remake’s file “A Family Photo and Notes” tells us that in 1967, Umbrella infected Jessica Trevor with Progenitor Type A, and infected Lisa Trevor with Progenitor Type B – two “variant strains,” possibly from “mutation stocks,” to call back Umbrella Chronicles’ Virus Memo. The official translation of the Family Photo file states that Type B exhibited “fusion” and “plasmolysis,” and that Type A did not. The Project Umbrella translation changes the language a bit, describing Type B as showing successful “establishment” while Type A failed to establish itself, but it also states that both viruses induced “cell activation.”

An official Tricell label, complete with warning not to administer to children under the age of two. Source: Resident Evil 5

As we’ve stated, “plasmolysis” is nonsense, but the rest of the file is useful. We’ve described Progenitor as a retrovirus, and it turns out that retroviruses can do some interesting things – one of them, HIV, can manufacture proteins needed for its own survival inside a cell even before it invades the cell’s own DNA. If Progenitor does the same thing, then Type A could produce the sort of superpower-inducing proteins and enzymes that make the virus special even before the virus takes permanent hold in the cell. If the virus fails to integrate into the host DNA, it would eventually be cleared from the cell and the supply of super-sauce would stop. A simple mutation in the proteins required to import into the nucleus could accomplish this phenotype.

So, putting it all together, PG67A/W is the Wesker Virus, which is Progenitor Type A – a variant strain of Progenitor created in 1967. It may have been somewhat altered by either Spencer (as part of the Wesker Program) or by Wesker (because he’s insane), hence the “/W” suffix. Type A can infect cells and cause “cell activation,” which allowed it to save Wesker’s life after he took a Tyrant in the gut. However, Type A doesn’t “establish itself,” so the presence of the virus and the powers it provides are both temporary. He would have had trace amounts of the virus left in that syringe he used on himself, and he had training as a virologist, so it’s not impossible that he found a way to make more for himself. Progenitor proper has been described as being difficult to grow outside of Sonnentreppe, but perhaps the technology to do so had been developed in the 30 years hence. Perhaps wesker only made small quantities at first – enough to power him up for, say, an expedition to steal T-Veronica, or a trip to see old friends like Sergei Vladimir or Ozwell Spencer – until he found the African facility. Or perhaps Wesker had obtained samples of Sonnentreppe by late 1998 and had used them to culture the virus, as was apparently happening on the freighter in Resident Evil 5. Either way, what was once a temporary power boost and a cure for acute cases of death has now become a permanent power trip and a gateway drug to megalomania. We’ve already described how Progenitor itself is highly immunogenic, so a very high dose might cause pathologic inflammation even in a normally tolerant subject like Wesker.

We should point out a couple of alternative hypotheses, some of which were preferred in the earliest versions of this Report. The “A” in PG67A/W could refer to “Activator” or “Antibody.” In the first case, the Wesker Virus might integrate reliably into the host (Albert Wesker’s) genome, but after a while, the useful genes that promote super powers might be suppressed. This is not unusual in transgenic organisms; sometimes when new genes are introduced, if they are not necessary for survival and if they exert an excessive metabolic cost, the body finds a way to shut them down through epigenetics. Activators are proteins that bind to the regulatory regions of genes to promote expression of those genes. If PG67A/W introduced exogenous activators into Wesker’s cells, either as the proteins themselves or as mRNA encoding activators for Progenitor genes, he could re-activate the enhancements we have described above on a regular basis. However, we cannot say for certain that over-expression of these activators would have a toxic effect.

The other option adheres closely to the language used in the game, which describes PG67A/W as a “serum.” Historically, serums – or to be technically correct, antiserums – have been extracted from animals immunized against certain pathogens, as a way to introduce antibodies against a disease to people suffering from that disease. Before the age of antibiotics, this was the only way to protect people against certain infections like diphtheria; even now, it is the primary treatment against snakebites. If Wesker’s prototype virus was “unstable” because it would gradually begin to replicate out of control, regular infusions of antiserum might keep the level of free virus down, reducing both superantigen activity and the threat of excessive recombination from superinfection.

One more note about the Wesker Virus. In the file Wesker’s Notes on Differing Mutations in Umbrella Chronicles, Wesker considers the way Sergei Vladimir mutated after injecting himself with “the virus” and speculates that the effects of this virus may be tied to the host’s state of mind. We have no way of knowing what virus Sergei infected himself with (although we have some theories which we will get to in a later installment), but Wesker wonders what implications there might be for himself if the virus actually does reflect the host’s mental state.

There are cases in which a host’s mental state can affect certain physiological conditions such as inflammation or the general state of one’s health. The placebo effect is a great example; recent studies have suggested these effects may be as much biological as psychological [i]. However, Wesker himself admits he has no evidence for his theory, and given the enormous difference between his mutation and Sergei’s, we think his theory is a bit daft. Wesker bases his claim on intuition, but his intuition didn’t save him from getting dumped into a volcano. So there.

definitions

[i] Jarcho JM, Mayer EA, London ED. Neuroimaging Placebo Effects: New Tools Generate New
Questions. Clinical Pharmacology & Therapeutics. 2009; 86(4): 352–354

P30

Resident Evil 5 also introduces us to one more derivative of Progenitor: P30.

P30 is an “ancillary chemical” discovered by Wesker during his research on the Progenitor Virus; he used the substance to control Jill Valentine. It has two effects: it imbues the subject with almost superhuman speed, strength, and agility; and it renders the subject highly susceptible to suggestion. The only drawback is that the host’s body rapidly metabolizes the chemical, so its effects last only a short time unless it is administered continuously.

That first collection of traits – the speed, strength, and agility – will sound awfully familiar after the above discussion of the effects of the Progenitor Virus. This similarity, along with P30’s nature as a product of Progenitor research, suggests a couple of possible explanations.

Our first hypothesis was that P30 is a modified version of a chemical or protein synthesized by the Progenitor Virus in a host. This chemical may be one of several master substances which alter the hormonal balance in the host, increasing metabolism. Like some known trophic hormones, this substance could affect the production of a wide variety of other hormones, up-regulating some and down-regulating others.

P30 must be injected directly into the chest because of its extremely short half-life in the body. Source: Resident Evil 5

However, Progenitor is known to cause aggression, while P30 blots out free will. We are not neurochemists, but it’s possible that aggression, reason, and decision-making depend on similar chemical signals. We submit that the master chemical from which P30 is derived may also be the trigger for increased aggression in Progenitor hosts. If P30 were modified to increase aggression, these modifications might have unintended consequences, and may actually reduce an individual’s ability to use reason or to make decisions for himself or herself.
P30’s remarkably short half-life may be due to the action of a plasma-borne peptidase, suggesting P30 has a natural human analogue to which such a peptidase might be specific. P30 might not even be a particular compound, but rather an mRNA sequence with an appropriate lipid-based delivery vehicle to get it into cells derived from the Progenitor genome. Once inside target cells, P30 would induce these traits transiently until the mRNA degrades.

The second option we explored is that P30 is biologically unrelated to Progenitor, but was discovered as part of an attempt to understand Progenitor’s effects. Such research might have taken into account the various traits that Wesker and the Ndipaya kings were known to have. The researchers would have worked backwards, so to speak, looking for common receptors and chemical pathways that would have to be involved. And perhaps they would have stumbled on an agonist [1] for these receptors and pathways that produced similar effects. As it happens, there is a real-life drug that can at least approach these characteristics.

Phencyclidine is better known to most people as PCP. It is known to induce violent behavior in users [i], [ii], although claims of such violence tend to be exaggerated [iii]. However, it is a stimulant, a class of drugs that increase physical performance, and there are reports that users are less perceptive to pain [iv]. PCP is also a dissociative drug capable of inducing a state of depersonalization in users, a fact that has a couple of important implications. First, depersonalization can further reduce perception of pain and knowledge of the body’s limits.

Most of us have more muscle strength than we realize; our brains prevent us from using it because doing so would damage the muscle. This limitation seems to be lifted by certain psychological states like extreme panic and apparently some states of intoxication. But dissociation and depersonalization also reduce free will. A person’s own motives become foggy and malleable. That characteristic, combined with the addictive nature of PCP, make it easier for a person with control over the dosage of the drug to dictate the behavior of the subject.
Are we saying that P30 is PCP? No. But it may be a compound with a similar pharmacological effect, biologically unrelated to Progenitor but discovered as part of research into the physiological effects of the virus.

definitions

[1] Agonist - a substance that initiates or enhances a response when it interacts with a receptor.

[i] Giannini AJ (1998). "Chapter 35: Phencyclidine". In Tarter RE, Ammerman R, Ott PJ (eds.). Handbook of Substance Abuse: Neurobehavioral Pharmacology. New York: Plenum Publishing Corporation. pp. 579–587. ISBN 978-1-4757-2913-9.

[ii] Bey T, Patel A (February 2007). "Phencyclidine intoxication and adverse effects: a clinical and pharmacological review of an illicit drug". The California Journal of Emergency Medicine. 8 (1): 9–14. PMC 2859735. PMID 20440387

[iii] Inciardi JA (1992). The War on Drugs II. Mayfield Publishing Company. ISBN 978-1-55934-016-8.

[iv] Luisada PV (August 1978). Petersen RC, Stillman RC (eds.). "The phencyclidine psychosis: phenomenology and treatment" (PDF). NIDA Research Monograph. National Institute on Drug Abuse (21): 241–53. PMID 101872

T-Virus

Progenitor may be the mother of all Resident Evil viruses, but in terms of lives lost, B.O.W. research conducted, and overall presence in the games, the Tyrant Virus reigns supreme.

We are first introduced to the T-Virus in the original Resident Evil, where we learn that it makes zombies and monsters. As interesting as that is, we don’t learn much else until much later, when Wesker’s Report II and Resident Evil 0 are released. There, we finally learn a little more about the origins of the T-Virus – which we will discuss later.

The T-Virus seems to have three categories of effects: most humans and other mammals which are infected become zombies; most other organisms mutate unpredictably into things big and scary; and when used under controlled, laboratory settings, the T-Virus can apparently be used to design monsters. So far, we have tried to understand the first two effects of the virus, and we have some ideas about the third; those ideas will have to wait for the next installment of this Report.

Resident Evil 0 explains that the T-Virus was created as a result of James Marcus splicing leech DNA into the Progenitor Virus. Where possible, we will try to explain what traits we think are a result of Progenitor, and what traits were introduced with the leech DNA.

We will discuss T-Veronica later, in its own essay. The NE-T Virus will be dealt with when we get to Nemesis and other B.O.W.s.

Prior to full zombification, T-Virus symptoms include fever and tachycardia. These symptoms are consistent with superantigenic toxic shock and elevated metabolism. Source: Degeneration

Development

Like many things in Resident Evil, the origins of the T-Virus have been revised and retconned over time. Let’s spend a little time looking at the origins of the T-Virus from a Doylist perspective, as there is some lore that was later retconned that may yet inform how we interpret the canon. With that groundwork laid, we can address the canonical origin of the T-Virus from a Watsonian perspective, as we prefer to do.

The Clay Virus

In the very beginning, with the release of the first game, a little guide was released in Japan with the concise and not-at-all cumbersome title BIO HAZARD Director's Cut Official Perfect Guide: Inside of BIO HAZARD [i]. Inside of BIO HAZARD as we’ll call it for short gives a lot of background information about the world of Resident Evil as it stood in 1996, and in particular it outlines Kenichi Iwao’s ideas for the nature and origin of the Tyrant Virus.

Inside of BIO HAZARD already contains some elements that would survive various retcons to become the Progenitor Virus. In this early canon, the precursor of the T-Virus was something called the Clay Virus, and a prototype of this virus was discovered during an experiment using a primitive arthropod. That detail suggests two possibilities. The first possibility is that an ancient endogenous virus was discovered in a primitive arthropod, in an intact or nearly intact state, and it was refined into functional strains of Clay and T-Virus. The second possibility is that the Clay Virus prototype was always somewhat artificial – that perhaps genetic engineering experiments were conducted on this primitive arthropod using retroviral vectors, and the incidental introduction of ancient genes into the retroviral genome produced something unexpected and kind of neat. We can already see here some of the lore that will be codified in Resident Evil 0 and Resident Evil 5, albeit in different forms – a virus was discovered in an ancient lifeform, and/or genes from an ancient invertebrate perfected this virus.

The Clay Virus is described as having a few interesting properties in general. It spreads through “internal secretory systems” which might charitably be interpreted as the lymphatic system and circulatory system, ultimately reaching virtually every tissue. From there, it induces an increase in growth hormone, leading to a slight increase in size (and the astute observer will recognize that zombies in the first game are in fact pretty damn tall). If affects the brain, increasing aggression but suppressing pain and fear. The ε or Epsilon strain, the strain responsible for both zombies and the Tyrant, also causes necrosis of the cerebral neocortex, eliminating the capabilities for memory and language. Finally, it slows down metabolism, reducing the need for food and oxygen (and, to a limited extent, a working circulatory system), but inducing necrosis in some parts of the body, like the neocortex as we just mentioned.

Infected cells also undergo “mutated evolution” on an individual basis, which we believe is consistent with our description in the sections on Progenitor describing retrotransposon activity. It also “fundamentally functions as an intermediary of genetic combination between different species that would normally be unstable,” making it easier to perform sophisticated transgenics. That capability is consistent with what we described about retroviruses introducing foreign DNA and facilitating gene therapy and transgenics. Basically, the Clay viral genome does not merely enter the cell, it can bring in foreign DNA with it (under the right circumstances) and it can shuffle around DNA inside the cell until a stable configuration is reached. Indeed, the ε strain is described as having the ability to “instantly evolve” any creature it infects – however, infected creatures often failed to survive the rapid and dramatic biological changes. This characteristic lends credence to our proposed cause of death from Progenitor infection – extreme mutation.

Incidentally, it would make our lives a lot easier if there was anything, anything in the real world that could stabilize recombinant DNA from wildly different sources as the Clay Virus is supposed to do. Sometimes it’s easy to slot in a single gene, like GFP. But to reshuffle entire developmental expression programs? It would be like giving half of your engineering team blueprints for a submarine and the other half blueprints for a space shuttle and hoping the resulting kluge can launch from undersea to orbit.

But that’s what the Clay Virus does. According to Inside of BIO HAZARD, the Clay Virus prototype strain was both discovered in and responsible for creating the Web Spinners and Black Tiger, the giant spiders seen in the game. It seems counterintuitive for the virus to create the monster in which it was discovered, but our second interpretation – laboratory manipulation inadvertently creating the Clay Virus prototype – seems to make sense here. The α or alpha strain, which may be the same as the prototype strain, was later use to create the FI-03 Neptune, the zombie sharks. A refinement of the initial strain, βI or Beta I, was used to infect dogs to create the MA-39 Cerberus. This strain was tweaked just a little and the βII or Beta II strain was used to create the MA-121 Hunter. Finally, the near-perfect ε or Epsilon strain was used to create Yawn, Plant 42, and the ultimate lifeform – the T-002 Tyrant. By extension, it’s also responsible for zombies (via accidental airborne release), wasps (which fed on Plant 42’s pollen), and crows and adders (which fed on all of the infected meat escaping from the mansion).

definitions

[i] BIO HAZARD Director's Cut Official Perfect Guide: Inside of BIO HAZARD. https://www.projectumbrella.net/bio-hazard-directors-cut-official-perfect-guide--inside-of-bio-hazard.html

The Mother Virus/Progenitor Virus

Code: Veronica was the first game to address an “original virus” within the game itself rather than in supplementary materials. The file Alexander’s Memo describes the discovery of a “mother virus” in Africa, which seems to rule out its discovery during experiments involving Web Spinners – unless those experiments took place in Africa. A separate file, the Queen Ant Report, describes a different virus being isolated from a queen ant by Alexia Ashford to serve in combination with the mother virus (or Progenitor Virus) as the basis for T-Veronica. So it seems that the idea of a virus derived from an ancient arthropod from Kenichi Iwao’s scenario was split off to serve a different purpose here.

And finally, that brings us to Resident Evil 0 and Resident Evil 5, which together give a canonical origin for both Progenitor and the T-Virus. As described above, Progenitor is derived from an ancient flower, no longer an arthropod but still in Africa. The file Marcus’s Diary 1 in RE0 indicates that DNA from the humble leech – not an arthropod, but at least an invertebrate – was used to transform Progenitor into the T-Virus that we all know and love.

So what does leech DNA do that transforms Progenitor into T? We can gain some insights by examining the difference between the two viruses, and by examining what Marcus, Spencer, and Ashford were trying to do with Progenitor to begin with. A few things stick out.

We know from the file From Chief Researcher Brandon’s Journal No. 1 and No. 2 that Progenitor just could not be produced outside of the Sun Garden in Africa. So we can posit that the first goal was simply to create variant of Progenitor that could be mass-produced.

We can also glean Spencer’s motives from a few files, such as Spencer’s Memoirs in the RE5 DLC Lost in Nightmares, Stuart’s Memo in Revelations 2, and Spencer’s Letter in Resident Evil Village that Spencer’s goal was to transform humanity in his own image. To do this, he needed to reduce the lethality of Progenitor, which killed most of the people who became infected. We also know from Wesker’s Report II that William Birkin was considering (apparently independently of James Marcus) that it would be pretty neat if a virus didn’t just kill you but kept you walking to infect other people. We have additional support from the Family Picture and Notes in Resident Evil (2002) that when two variants of Progenitor were tested on Jessica and Lisa Trevor, Jessica was disposed of because the virus failed to successfully colonize her and Lisa was kept for further study because the virus did colonize her (the wording “colonize” comes from the Japanese version). So, the long-term goal was to reduce the lethality of the virus.

How could leech DNA achieve these goals? The first one is obvious. We mentioned before that endogenous retroviruses exist in humans and other organisms. It seems likely that leeches have their own endogenous retroviruses, although our search for examples suggests that the people who have looked for them appear to be grossly outnumbered by the people studying human endogenous retroviruses who have the name Leech. If Progenitor is a holdover from the RNA World, it’s also possible that an endogenous retrovirus in leeches is a fragment of an ancient Progenitor strain, possessing genes missing from the African Sonnentreppe strain that facilitate replication without relying on specific flowers grown in a specific place. Alternately, regulatory elements such as promoters from the leech genome itself may have had a particular compatibility with the Progenitor genome, and may have been used to Frankenstein a working virus together.

The second goal, improving survival or at least preventing somatic death, is a little more tricky. We could handwave it and say that the leech ERV also has greater compatibility with metazoan genetics and a lower tendency to introduce lethal mutations. However, we saw above in Inside of BIO HAZARD that one of the effects of the Clay Virus is to reduce metabolism. The Clay Virus concept appears to have been consigned to the scrap heap, and even if it’s considered canon, we would not know if its metabolism-reducing activity was there from the beginning or whether it was specific to the zombie-creating ε strain. But reducing metabolism would certainly slow down cellular damage from a variety of sources. We go into more detail about metabolism in a dedicated section below.

Zombies!

This is what you’re here for. More than Tyrants, more than B.O.W.s or any mutants, the T-Virus is known to fans for creating something very much like the cannibalistic walking corpses first brought into popular consciousness by George Romero. T-Virus zombies are not actually dead in the sense that Romero’s zombies were, but there is no doubt that they were inspired by his Living Dead series. But how do they work?

Necrosis

The first thing someone will notice about a person infected with the T-Virus – before the moaning, the shambling, the hunger for human flesh – is the decay. T-Virus zombies look like they are rotting. This decomposition could come about in one of several ways.

The simplest explanation is that the virus replicates uncontrollably, lysing host cells and destroying tissues. This explanation is fairly solid, and should not be overlooked, but T-Virus infection can cause decomposition and brain damage in minutes rather than the hours a normal virus would need at minimum. We would like to see an explanation that works more rapidly. Furthermore, we assumed earlier that Progenitor does not reproduce by lysis, so in theory, neither should the T-Virus.

A second explanation involves the superantigen we’ve been invoking throughout the Progenitor section. In fact, rapid zombification is the reason we introduced the superantigen theory in the first place.

A superantigen is a protein built to kick the host’s immune system into overdrive with the function of causing harm. While it might seem counterintuitive for a virus to actively overstimulate the host’s immune system, this phenomenon is common, and such overstimulation actually helps the virus evade immune detection.

Note the desiccated, peeling flesh of the scalp, the forehead, and the sphenoid area behind the eyes. Source: Resident Evil Remake

When stimulated by a normal antigen, a form of white blood cells called cytotoxic T-cells (which have nothing to do with the T-Virus) produce cytokines [1], perforins [2], and other substances designed to kill target cells, like those infected with a virus. When the immune system is overstimulated, a cytokine storm can result. In a cytokine storm, so much of these cytotoxic chemicals are released that the body’s tissues begin to die – a condition called necrosis. It is only a matter of time before this dead tissue begins to rot, and it can look nasty enough long before that.

There is no plausible way that leech DNA could be involved in either of these mechanisms. We suspect that this superantigen must have come from Progenitor.

definitions

[1] Cytokines - A generic term referring to signaling proteins released by immune cells in generating a response to a pathogen. Cytokines therefore control the strength and duration of an immune response thus they serve as immunomodulators in this capacity.

[2] Perforins - A cell-destroying protein which acts by forming pores in the plasma membrane of a cell, facilitating its eventual lysis.

A third explanation holds that the body of an infected individual begins to actively consume its own proteins as a source of energy. We believe that the leech DNA which was incorporated into Progenitor to create T may contribute certain metabolic enzymes and hormones which would accelerate this process; we will elaborate further on this topic shortly. Degradation of host proteins helps to explain a zombie’s rotted appearance, but it fails to explain the extremely rapid onset of behavioral changes – changes we believe are better explained by the superantigen hypothesis.

A fourth hypothesis refers back to Kenichi Iwao’s Clay Virus, which reduces metabolism in its hosts. If metabolism is reduced enough, tissue will die. If certain tissues (the more primitive brain structures, for instance) are prioritized and less-essential tissues (such as skin) are given lower priority, guess which tissues die first. This phenomenon may hold true for zombies and in that capacity may contribute to later stages of infection, but if it has any contribution at all, it is eventually reversed if the host survives long enough. We will explain more in later sections.

These zombies lack the bloated abdomen which occurs in most corpses due to decomposition of the internal organs. They also lack any evidence of decomposition beneath the skin and superficial musculature. Source: Resident Evil 2

We believe that necrosis and decomposition is (mostly) limited to the skin. Obviously, zombies need most of the brain (but obviously not all of it), nervous system, and muscles intact to move and seek prey. We do have some theories as to how these tissues survive when everything around them is dead, and we will get to those theories shortly. We also know that zombies can remain active for several months (the T-Virus spread through the Arklay Mansion on May 11, 1998, and zombies were still shambling through its halls on July 24). Finally, we know that, depending on the stimulus and T-Virus strain zombies become either Crimson Heads, Pale Heads, or Lickers, and all of these appear very metabolically active (contradicting Iwao’s idea of reduced metabolism), despite the ruptured capillaries [1] and loss of skin.

We therefore believe that many vital organs (such as the heart, lungs, pancreas, and assorted glands) and major blood vessels in the body’s core must remain alive, even if they are damaged by septic shock [2] and function at lower levels than before. They are probably reactivated in full during late-stage transformations such as V-ACT, Lickers, and Pale Heads (for reasons we’ll get to later). In this light, we suspect that the T-Virus (and probably Progenitor) preferentially targets the skin and tissues of the outer integument [3] for replication. Any superantigen produced probably remains largely concentrated in those tissues. Some virus, of course, must make its way into the core tissues in order to cause the transformations which will be discussed later.

definitions

[1] Capillaries - The body’s smallest blood vessels which not only connect arterioles and venules but also serve as semipermeable membranes for the interchange of various substances between blood and tissues.

[2] Septic shock - An occurrence induced by severe infection where the body’s vascular system is overwhelmed as a result of the pathogen’s specific virulent factors, such as an endotoxin or superantigen. The systemic nature of this condition taxes the body to fatal levels.

[3] Integument - The organ system covering the body which consists of the skin, including its various layers, and its associated appendages.

The Living Dead

A simplified diagram of metabolic pathways. We did not want to go into this much detail.

We have already explained why the T-Virus causes rotting, and we’ve speculated that Progenitor uses the same mechanism to kill people. This rotting would shut down blood circulation, cutting off the supply of oxygen and nutrients to important tissues like the brain. Why, then, don’t T-Virus victims stay dead?

This is where the leech DNA starts to come in. Metabolism in animals can be said to occur in three stages; glycolysis [1], the Krebs cycle [2], and the electron transport chain [3]. The electron transport chain, and the ATP synthases [4] which are driven by it, produce the most usable energy by far of any of the three stages. The electron transport chain is also the only stage in the process which requires oxygen. Glycolysis and the Krebs cycle are both anaerobic [5] processes; human cells cannot survive on these processes alone, but both do provide
some usable energy. Glycolysis causes increased acidity which is usually counteracted by the electron transport chain.

Animals have another anaerobic metabolic pathway – fermentation. Fermentation allows muscles to keep functioning even when oxygen reserves have been exhausted, generating lactate as a byproduct.

A simplified diagram of metabolic pathways. We did not want to go into this much detail.

definitions

[1] Glycolysis - The splitting of glucose into pyruvate through a series of ten reactions. This metabolic pathway is known to occur in all living cells, underscoring its universal importance in the biochemical reactions of both aerobic and anaerobic organisms .

[2] Krebs cycle - More commonly known as the citric acid cycle, this eight-step metabolic pathway completes the conversion of glucose into carbon dioxide. This effectively transforms molecules of carbohydrates, proteins, and fats from foods into energy usable by the cell.

[3] Electron transport chain - A linked set of enzymes that perform mediating biochemical reactions which, when coupled with the process of oxidative phosphorylation, is capable of forming Adenosine Triphosphate (ATP). ATP is more or less considered a “unit of currency” in energy transfers occurring within the cellular environment and is indispensable for metabolic reactions.

[4] ATP synthase - A transmembrane enzyme that acts on the energy created by the electron transport chain to synthesize Adenosine Triphosphate (ATP) from Adenosine Diphosphate (ADP) and an inorganic Phosphate.

[5] Anaerobic - Referring to an organism, environment, or cellular process that exists in the absence of molecular oxygen.

Both of these processes are present in every animal, including humans and leeches. We propose that James Marcus took from the leech genome the genes which code for the enzymes in these processes, as well as genes for hormones which up-regulate these processes, and expressed them in the T-Virus. Marcus would have had to place them among the early-activating genes of the virus, allowing expression of these genes to begin almost immediately, even before the virus integrates into the host genome. When expressed in the host, these enzymes and hormones would allow the cells to continue to produce energy even as circulation shuts down and cells start running out of oxygen. The result would be something discussed in Wesker’s Report II – a virus that keeps its host alive long enough for the virus to spread to others.

These cells might continue to obtain nutrients from the lysate [1] of the dead cells and tissues surrounding them. This material would be mostly protein, and it turns out that leeches use degradation of protein as an energy source even in the absence of oxygen [i]. This would, incidentally, speed up their decomposition and increase the need for them to consume animal tissue. If the T-Virus also contains genes for various amino acid deaminase [2] enzymes, then the infected cells could produce ammonia as they break down the proteins of dead cells for energy. The ammonia would help to reduce the acidity produced by increased glycolysis.

If each cell continues to obtain nutrients from its surroundings, and continues to function in the absence of oxygen, then the importance of the heart, lungs, and circulatory system are drastically reduced. Not only can the zombie function with these organs operating at a reduced level, the zombie can keep going even if these organs are severely damaged. A human grievously injured by zombies can rise up as one himself, and a zombie can continue to seek prey after taking half a dozen bullets in the chest, as we see throughout the Resident Evil series.

Intro to the Re-Animated Edition

Contents

Progenitor

Retrovirus

Evolution and the Ndipaya

Infection

Death

Amazing super powers

Super strength

Senses

Longevity

Aggression

Fertility

Giant animals

Sonnentreppe and viral replication

The Trevor Family

The Wesker Prototype Virus and PG67A/W

P30

T-Virus

Development

The Clay Virus

The Mother Virus/Progenitor Virus

Zombies!

Necrosis

The Living Dead