Methuselah, Oisín and the Zombie Apocalypse
Part 1 of a series on the mission to defy aging
3317 B.C. The birth year of Methuselah. The grandfather of Noah. A figure in Christianity…Judaism…and Islam. Of everyone mentioned in the Bible, he is said to have lived the longest…dying at the ripe old age of 969.
2001 A.D. The founding of the Methuselah Foundation. A biomedical charity co-founded by David Gobel and Dr. Aubrey de Grey. The Foundation’s mission? To make 90 the new 50 by 2030.
Ambitious? Yes. Ostentatious? Perhaps.
But ask Gobel why he chose that mission, and he will tell you “because it’s falsifiable.”
Of greater importance to him is a commitment to a “return on mission.” In Gobel’s words, the return on mission is “how many lives are saved and how many people are not suffering that otherwise would have suffered.”
For Gobel and the Methuselah Foundation, it’s about focus…with a mindset fueled by urgency and grounded in action…action that focuses on the organic and cultural aspects of aging…in search of the greatest leverage to prevent or reverse the damage associated with aging.
And maintain focus they have. The biomedical charity has helped change the way the world thinks about aging.
The Methuselah Foundation…inception to 2014…
Methuselah Mouse Prize (Mprize)
After only two years in existence, the Methuselah Foundation introduced the world’s first longevity prize — the Mprize. The prize has a two-fold purpose. One purpose is to reward scientific advances. The other is to increase acceptance of efforts to increase human “healthspan” — years of healthy life — and lifespan.
When the Methuselah Foundation came into existence, such efforts were viewed as folly, even immoral by some. And conducting research to prevent or reverse aging was viewed by many as career suicide.
The Mprize has helped change that. Investment in efforts to increase human healthspan and lifespan has gone from very little to well over a billion dollars.
A cash prize for breaking the world record for the oldest-ever mouse was first awarded to a team led by Dr. Andrzej Bartke at Southern Illinois University. Another cash prize for the most successful approach to rejuvenating the health of old mice was first awarded to Dr. Stephen Spindler of the University of California, Riverside. Dr. Z. Dave Sharp of the University of Texas Health Science Center at San Antonio received the first award for extending the lifespan of already aged mice in 2009.
Methuselah Fund (M Fund)
In anticipation of changing attitudes about preventing/reversing aging the Methuselah Foundation also created the M Fund. The M Fund invests donations in startups that advance the Foundation’s mission. “The M Fund is strategically positioned to make audacious bets in the longevity biotech startup world,” says Managing Director, Sergio Ruiz. “We have several partners and a large investor network of mission-oriented individuals who want to see medical breakthroughs move from the academic research setting into the clinic. We know that the best way to accelerate the advent of life-saving and life-improving products and interventions is to incubate mission-driven teams and help them become companies with a focus on improving patients’ lives.” The M Fund invests private and institutional capital in companies that can tackle the following mission-oriented goals:
• get rid of the crud…waste and damaged/destructive cells and structures,
• restore compromised circulation,
• replace degenerated/damaged body parts…from vasculature to organs to bones,
• debug the genetic code…from mutations to faulty replication,
• replenish supplies…with stem cells and immune support, and
• rejuvenate senses and physical competence.
SENS Research Foundation (SENSRF)
The SENSRF was spun out from the Methuselah Foundation in 2009, with ongoing support. The SENSRF is based on a long-term research framework — Strategies for Engineered Negligible Senescence (SENS) — designed by de Grey to develop regenerative therapies that repair seven major classes of cellular and molecular damage associated with aging. SENS-related research programs have been established at Arizona State University, Rice University, and the University of Cambridge.
SENSRF’s Undoing Aging Conference
The Methuselah Foundation sponsored, and later funded, six SENS-focused events at the University of Cambridge from 2003 through 2009. These events became the leading series of conferences dedicated to using regenerative therapies to prevent/reverse aging. The events played a central role in building an international network of researchers and programs. The series continues as the SENSRF’s Undoing Aging Conference.
The 300
Inspired by the 300 Spartans who held the pass at Thermopylae in 480 B.C., Gobel created The 300. The 300 is a group of 300 individuals pledging $25,000 each (7.5M) to help Methuselah Foundation on its mission.
SENS Challenge
The Methuselah Foundation has had its share of detractors. In 2005 MIT Technology Review published a pejorative profile of de Grey and SENS. The profile was accompanied by a column written by Jason Pontin, editor in chief, in which Pontin called de Grey a “troll.” This series of events prompted Gobel to propose a challenge to Pontin, which he accepted. Per the terms of the challenge, MIT and Methuselah each pledged to pay $10,000 to any molecular biologist who could demonstrate that SENS “is so wrong that it is unworthy of learned debate.” Three qualifying submissions were reviewed by a distinguished group of judges — Rodney Brooks, Anita Goel, Vikram Kumar, Nathan Myhrvold, and J. Craig Venter. In a summary written by Pontin, himself, the unanimous view was that no submission met the “criterion of the challenge and disproved SENS.”
Supercentenarian Research Foundation (SRF)
In 2006 Methuselah contributed $100,000 and direction to launch SRF with Dr. L. Stephen Coles and Dr. Elliot Bergman. The focus of SRF is the cause of death in supercentenarians (i.e., people aged at least 110 years). Working with Robert Young, who is a gerontology consultant and researcher known for validating supercentenarians, Coles and Dr. Stanley Primer determined that the cause of death is senile systemic amyloidosis (SSA). As humans age, a transport protein known as transthyretin begins to unravel and stick to the inside of blood vessels. Blood flow is restricted, and heart failure results.
Ending Aging: The Rejuvenation Breakthroughs That Could Reverse Human Aging in Our Lifetime
In 2008 de Grey and Michael Rae published Ending Aging. The book was well-received. With publication of the book, de Grey’s public advocacy (e.g., TEDGlobal in 2005) and the Foundation’s Mprize, researchers, and donors, Methuselah Foundation became the first charity to mobilize the movement to undo aging. The Foundation built and defended the scientific case for approaching age-related damage as an engineering and cultural problem. By changing the conversation, the Foundation helped make longevity research a fundable area.
Organovo
In 2009 the Methuselah Foundation became the first outside investor in Organovo. Organovo designs and creates 3-D human tissues that — for the first time — enable drugs to be tested before administration to a person. In the future, these tissues will be implanted into the body to repair/replace damaged/diseased tissues.
Organovo has introduced the first architecturally correct human liver and kidney assays. These assays have the potential to improve drug development dramatically — by reducing the cost of toxicology testing and eliminating the need for animal testing.
In 2013 the Methuselah Foundation launched a $500,000 partnership with Organovo to place their 3-D printers in research labs as a springboard to create bio-printed tissues for surgical transplantation. The printers are currently in place at Yale School of Medicine (Dr. John Geibel), UCSF School of Medicine (Dr. Edward Hsiao), and Murdoch Children’s Research Institute (Dr. Melissa Little).
Silverstone Solutions
In 2010 the Methuselah Foundation invested in Silverstone Solutions. Founded by David Jacobs and acquired by BiologicTx in 2013, Silverstone Solutions has turned its kidney-pair-matching software, MatchGrid, into a cloud-based service. Hospitals and transplant organizations are using MatchGrid to match living organ donors with patients who have willing but incompatible donors. As a result, more patients can receive a living donor kidney, instead of waiting 5–10 years for a cadaver organ.
New Organ Alliance (NOA)
Conceived by Gobel, the NOA was launched in 2011. A collective initiative of key partnerships and prizes advancing the bioengineering and banking of tissues and organs, the NOA is at the center of coordinating greater efforts to industrialize “new parts for people.” As Gobel sees it, our replacement organs come from cadavers or ill-matched living donors, and most people in need don’t even have a chance of receiving a replacement organ from either source.
New Organ Liver Prize
Methuselah Foundation created the world’s first organ bioengineering prize — the New Organ Liver Prize — in partnership with the Institute of Competition Sciences in 2013. An award of $1M will be given to the first team to create a regenerative/bioengineered solution for keeping a large animal alive for 90 days without innate liver function. Currently, there are 13 active teams working on this objective. The New Organ Liver Prize is strongly endorsed by The Founding Fellows of the Tissue Engineering & Regenerative Medicine International Society (TERMIS).
Gerontology Research Group Grant
In 2013 the Methuselah Foundation awarded a grant to Dr. L. Stephen Coles, co-founder and executive director of the Gerontology Research Group and noted researcher on supercentenarians (i.e., people aged at least 110 years). The grant supported research of new methods of personalized gene sequencing and pre-testing of potential chemotherapy courses in immunodeficient mouse models.
Organ Preservation Alliance (OPA)
In 2014 the Methuselah Foundation sponsored and contributed to the OPA. OPA is a charity working to accelerate organ banking. The OPA organized the first Organ Banking Summit, facilitated events in Washington, DC, and co-created the first Organ and Tissue Preservation Community of Practice with the American Society of Transplantation. The OPA also contributed to new grant programs from the Department of Defense for organ preservation research. Recently, they hosted the Organ Banking Summit at Harvard Medical School and received $2M from the Pineapple Fund.
National Institute on Aging Intervention Testing Program (NIAITP)
An award of $10,000 was given to Dr. Huber Warner in 2014 for founding the NIAITP. The program is a gold-standard assessment of treatments attempting to slow aging in mice.
And, with all of that and more going on, the Methuselah Foundation turned its focus to Oisín Biotechnologies.
Oisín Biotechnologies…no Celtic myth…reality…
In Celtic myth, Oisín was a Gælic warrior-bard who lived in the 7th century. Oisín sought the land of youth, which, at that time, was a magical island off the western coast of Ireland.
Like the Gælic warrior-bard, Oisín Biotechnologies is in pursuit of youth. But rather than searching for an island off the western coast of Ireland, Oisín Biotechnologies is working to reverse the damage caused by the aging process, itself — with the help of the Methuselah Foundation as a founding investor.
Oisín’s aim is to ameliorate degenerative, aging conditions by safely removing senescent cells. For more than a decade prior to Oisín’s founding, the Methuselah Foundation had been promoting this approach under the SENS strategy. Even mainstream research institutions believed that clearing senescent cells was likely to be beneficial. Indeed, in 2016 researchers at the Mayo Clinic reported this approach extended the life of mice by up to 25%. And, while Mayo’s results were impressive, the mice were transgenic. In other words, their methodology wasn’t clinically viable for humans.
Gobel says, “We invested in Oisín because of the promise of their targeted approach to removing senescent cells without causing collateral damage or side effects. We think of this as ‘getting the crud out’ — one of our key themes.” And the Methuselah Foundation provided strategic advice, web marketing, and a grant to find out if Oisín’s platform technology could selectively and effectively destroy prostate cancer cells. The results were so impressive that further development of the platform technology for cancer treatment is being pursued as a spin-off company. Incorporated in late 2017 as Oisín Oncology, the company is now known as OncoSenX. OncoSenX is a joint venture with Entos Pharmaceuticals. Meanwhile, Oisín Biotechnologies continues to work on improving the platform technology for broad, anti-aging applications.
So, I had a chat with Matthew Scholz, co-founder and CEO of Oisín Biotechnologies, to learn more about their platform technology. But, first, a little bit about Scholz.
A “bio-techie” in a class of his own…
Scholz is a serial entrepreneur with a background in computer security and immunology. He started programming at the advanced age of eight years old and went on to study computing and software systems at the University of Washington. When asked why computer security, Scholz is quick to respond, “because I thought it was fun.” Along the way, he established a fleet logistics company — Point B Telematics — that helped manage construction, service, and delivery fleets. And he developed a mobile app that enabled people to get their paper mail on their mobile phones.
So how does someone, who started programming computers as a kid, transition to immunology? By effectively learning biology and immunology on the fly over the course of more than a decade.
What’s interesting about this is the nexus. Scholz managed information technology systems that were frequently attacked by viruses. He learned how to improve nonbiological systems by focusing on their weaknesses. Now Scholz is focusing on biological systems being weakened by aging. He is working to improve biological systems by focusing on a major cause of aging — senescent cells.
Scholz is quick to point out that a persistent thesis for him has been “that the essence of life is information — chemistry is just the substrate.” As Scholz sees it, transitioning from compromised information technology systems to compromised (i.e., aging) biological systems is not a fundamental shift. Rather, he contends, it is “just learning a new operating system / programming language.”
Before Oisín Biotechnologies and OncoSenX, Scholz founded — and became the CEO of — Immusoft. The goal for Immusoft? Not surprisingly, Scholz responds, “an ‘app store’ for the human body.” The biotech company is focused on turning a patient’s B cells — lymphocytes that produce antibodies — into miniature drug factories.
Scholz says, “There are a lot of parallels between computer security and gene therapy. Both are fundamentally predicated on getting the target to execute code to alter its behavior. They use different languages and have different defenses, but the concept is the same. It’s not a coincidence that we refer to certain kinds of computer code as ‘viruses’. In many ways, they are quite analogous to the kind that manipulate the code of life.”
When asked what led him to focus on aging, Scholz responds, “Aging has been on my mind for a long time. Even at Immusoft, my long-term goal for the platform was to recreate the biochemical environment of youth in old age. I reasoned that it would never be possible to take enough drugs to accomplish this but, if you can program the body, you can do anything.”
It wasn’t until a chance meeting at a Health Extension Salon sponsored by Joe Betts-LaCroix in 2012, however, that Oisín Biotechnologies was first conceived. While there, Scholz talked about his plan for Immusoft. Afterwards, Judy Campisi took the stage to present her work at the Buck Institute for Research on Aging and the results of a recent mouse study at the Mayo Clinic. She explained how researchers at Mayo had created transgenic mice in which senescent cells — in particular p16+ senescent cells — could be easily cleared with an otherwise innocuous drug. p16 is a tumor suppressor that arrests cell division.
Scholz thought the results were amazing but didn’t think it was a feasible approach from a clinical perspective. He leaned over to the guy sitting next to him — Gary Hudson — and said, “That’s amazing, but I would do it totally differently.” That comment led to drinks at the bar, where Scholz explained to Hudson his strategy. And that conversation led to a collaboration that would become Oisín Biotechnologies. Because, you see, Hudson not only liked what Scholz had to say, he also knew Gobel. And Gobel and the Methuselah Foundation were eager to fund Scholz’s proof of principle.
Selective Ablation of Senescent Cells…or…
“the Zombie Apocalypse”
Scholz chose selective ablation of senescent cells because he considered senescent cells to be the first kind of damage to cause material harm. Scholz says, “Senescent cells seem to have a very profound impact on loss of function with age.”
Indeed, senescent cells are cells that no longer divide because they have been irreversibly damaged. These cells are typically killed by the immune system or die by a series of biochemical events collectively referred to as “apoptosis” — programmed cell death. Unfortunately, not all of these senescent cells are cleared by these processes, and as we age senescent cells accumulate. The result? Zombie cells — cells that can’t resume normal function and don’t die. The good news, obviously, is that we don’t turn into zombies. The bad news is that zombie cells play a role in age-related diseases — due, in part, to what they secrete. The potent mix of signals generated is referred to as the “senescence-associated secretory phenotype.” Chronic inflammation results, tissues fail to regenerate properly, and more cells become senescent — resulting in more zombie cells.
So, not unlike humans battling zombies in various cult movies, Oisín is leading a charge against zombie cells. How? By selectively killing senescent cells with a targeted DNA approach.
So, why a targeted DNA approach? Scholz replies, “It goes back to my initial thesis — that the essence of life is information. We don’t try to debug computer software by changing the microchips in the computer. So, why should we try to debug life by monkeying around with its chemical substrate?”
Scholz goes on to say, “I don’t think it’s typically thought of in this light, but a damaged cell knows it’s damaged. It has exquisite technology for detecting damage and a highly optimized apparatus for programmed death. So, instead of trying to devise a molecular entity that will somehow identify and only kill the damaged cells, why not just provide it with a computer program — DNA — that says ‘if you’re damaged, kill yourself’.” According to Scholz, this approach affords Boolean logic, which is impractical, if not impossible, for small molecule drugs. He says, “You can quite easily write a genetic program that says ‘if you’re a p16+ myocyte, but not a cardiomyocyte, then die’. This kind of logic gate is virtually impossible to build with chemistry, but it’s pretty simple with information.”
Scholz contends, “The DNA approach also allows us to adapt far faster than traditional drug development would allow for. If tomorrow someone finds a new population of cells to kill or learns of a subset of cells that we must not kill, it takes a week or two to make a new construct. If you need to tweak a small molecule drug to alter its behavior, it could take years, and the unintended consequences of the modification (both in terms of the pharmacology and manufacturing) are far less predictable than a logic gate written in DNA.”
Scholz characterizes Oisín’s targeted DNA platform as distinct from that of pharmaceutical drug development. Scholz says, “The targeting and effect of any given drug is based entirely on its structure. This fundamental attribute can be particularly problematic when the drug is a poison designed to kill cells. The problem with this approach is that sometimes the molecule can interact with things it wasn’t intended to, or it interacts with the correct target but in a cell population or organ where it is not needed or is harmful. Small molecule drugs can also be metabolized, and sometimes the metabolites have their own unintended or harmful effects. Oisín’s approach, on the other hand, takes targeting out of the realm of chemistry and brings it into the realm of information. Oisín’s delivery technology is indiscriminate — a DNA payload is delivered to any cell with which the nanoparticle fuses. But, unlike a drug, the physical entity — the nanoparticle — isn’t what drives the therapeutic effect. The actual effect is mediated by the DNA payload. The DNA encodes logic that determines in which cells it will activate. With this approach, there is no ‘drug’ — just a program written in DNA that tells the target cells to do something. In the case of a senescent cell, the DNA tells the cell to die via apoptosis.”
Scholz characterizes most of the other approaches being developed to kill zombie cells as various small molecule poisons and repurposed chemotherapies. He considers them to be limited by their toxicities. He notes that there are some that are less toxic, but they’re also less effective.
The DNA constructs designed and made by Oisín can recognize and selectively kill senescent cells. More specifically, the DNA constructs contain a suicide gene (e.g., caspase 9, which is inducible or self-activating, and under the control of the p16 promoter (the “on-off” switch for the gene; p53 promoter for cancer treatment)). The construct targets p16+ senescent cells. When the p16 promoter is switched “on,” the construct transiently expresses the caspase 9 gene in the senescent cells, causing them to die.
In mouse longevity studies, Oisín has shown a significant synergistic effect from killing p53+ and p16+ cells. Scholz says, “I expect that, as the field evolves, additional targets will be discovered as well, and the ability to easily incorporate these targets will serve to put more distance between Oisín and the other approaches.”
Oisín has demonstrated that the approach works in cell culture and in aged mice. They are now conducting experiments that will show that the approach improves health and increases lifespan in organisms ranging from mice to primates. And more complex payloads are under development.
Other indications are being spun-out or licensed out, starting with oncology. A lipid nanoparticle (LNP) is used to deliver the DNA construct to cancer cells. Pre-clinical toxicity data in rats and non-human primates show that Oisín’s Fusogenix™ LNP is not toxic at doses up to 10x the expected human therapeutic dose. The LNP is non-immunogenic, even when combined with adjuvant. This is an advantage that Oisín has over competitors, who are struggling with toxicity issues.
Scholz points out that OncoSenX is going into the clinic ahead of Oisín Biotechnologies. Manufacture is already at human scale, and multiple non-human primate toxicology studies have been completed. OncoSenX is now working on their first regulatory submission. Scholz expects the DNA construct that recognizes and kills p53+ cells to be in clinics in 2020.
Other targets are under consideration for future constructs. OncoSenX has already built and performed initial animal studies on more advanced immunotherapeutic versions. The more advanced versions express immune-stimulating molecules in cancer cells before killing them. The goal is to turn the tumor into a vaccine against itself.
With the wind in their sails…
So what’s next for Oisín Biotechnologies? Scholz thinks the platform will be used to deliver human telomerase reverse transcriptase (hTERT) mRNA to extend telomeres. Telomeres are regions of repetitive nucleotide sequences at the ends of chromosomes. Telomeres protect chromosomal ends from deterioration or fusion with other chromosomes. Telomere length shortens with age, rendering the chromosomes vulnerable to deterioration and fusion.
Another application anticipated by Scholz is the use of the platform to deliver factors to rejuvenate stem cells. Oisín has already made a DNA construct to deliver DNA encoding follistatin. They intend to use it to treat age-related sarcopenia — the loss of muscle mass, which results in reduced strength. Topical and companion animal versions are also under development.
With the zombie apocalypse now fast becoming a reality, Oisín Biotechnologies is keeping its sights focused on increasing lifespan and, perhaps more importantly, healthspan. And, in doing so, Oisín will be helping Gobel and his Foundation realize a substantial “return on mission” — perhaps proving that 90 really can be the new 50.
By 2030 though? Time will tell. But the wind is in their sails, the water looks smooth as glass, and a new day — full of youthful promise — is dawning. As for that magical island off the coast of Ireland, Oisín Biotechnologies — with Scholz at the helm — is turning myth into reality.
Karyl Landeau, Ph.D., J.D.
Freelance Writer
To learn more about the Methuselah Foundation, Oisín Biotechnologies, and OncoSenX visit: www.mfoundation.org, www.methuselahfund.com, www.oisinbio.com, and www.oncosenx.com.
Methuselah Foundation
2014–2019 Timeline
-Funded bowhead whale genome sequencing at University of Liverpool
-Co-organized and co-funded events at White House Meeting on Regenerative Medicine and Organ Bioengineering & Banking Roadmap Workshop
-Further developed “Solving the Organ Shortage through Organ Banking and Bioengineering,” beta roadmap report
-Invested as founder of Leucadia Therapeutics and provided grant support and assisted in closing of pre-Series A funding
-Funded large-scale efficacy study by Ichor Therapeutics
-Partnered with NASA to launch Vascular Tissue Challenge at White House Organ Summit
-Organized Vascular Tissue Challenge Roadmapping Workshop in 2016; Expanded in 2018. Funded Litmon for monitoring longevity-related scientific literature
-Launched Methuselah Fund to invest in mission-critical start-ups
-Funded OncoSenX
-Invested as founder and Incubated Volumetric Biotechnologies (leading competitor for NASA Tissue Engineering Prize)
-Invested as founder and incubated in Turn Biotechnologies
-Invested in Viscient Biosciences
