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David Shaywitz
Can you improve your health without obsessing about it?
I’ve been, well, obsessing about this question as I continue to spend more time and mindshare in the world of healthy aging evangelists, enthusiasts, and entrepreneurs, longevity champions keen to guide you, and often test you, towards their conceptions of healthier aging.
(See this piece on the longevity boom, and this on the role of GLP-1RAs.)
There seem to be two general flavors of longevity champions.
First are those who were always athletes, and who have long been interested in improving performance. Examples here include Australian Pete Hull, founder of the rapidly growing fitness chain Fitstop (interesting podcast interview here) and Will Ahmed, founder of Whoop, a wearable company. Hull was a competitive Motocross rider and later a personal trainer before he found his way to entrepreneurship; his gym focuses on “performance-based functional fitness.” Ahmed was a squash phenom at Harvard, and developed Whoop based on an interest in “understanding his body better.” The company’s tagline is “Power your performance with 24/7 data.”
But not all champions were passionate about health and longevity from a young age; some arrive at this epiphany after a personal revelation. Examples here include champions like Nick Norwitz and Dr. Peter Attia. Norwitz writes that his interest in metabolism derived from his struggles with severe inflammatory bowel disease; his successful management of this condition with a ketogenic diet after conventional approaches failed sparked his curiosity about nutrition and metabolism.
Attia, while apparently always athletic, traces his epiphany to a specific date — September 8, 2009, as he describes in Outlive – on which he recognized (spurred, he writes, by a comment from his wife) that he had become “not thin Peter,” and metabolically unhealthy. Consequently, he, also, “quickly became obsessed with understanding nutrition and metabolism.”
Attia’s obsession (which seems unquestionably the correct term here) is readily apparent from his book, as he describes the many components of healthy eating, movement, breathing, and sleeping. Each topic (like movement) ramifies into subtopics (cardiovascular, strength, balance), each with their own subtopics (VO2 max, Zone 2 exercise, lactate threshold, etc). His podcasts can get into even more granular detail, such as this discussion with researcher and Olympic cycling coach Inigo San-Millan about the intricacies of Zone 2.
This approach to longevity – focused on measurement and optimization of multiple parameters in effort to improve “performance” in many individual areas, and ultimately overall, obviously has a familiar ring to it. Ask the CEOs of Fortune 500 companies how they operationally drive improvements, and they’ll likely tell you something similar, explaining how they deconstruct a corporate mission into constituent activities, set relevant goals, measure performance and evaluate progress.
While this approach may help improve the bottom line of established corporations and help good athletes become great, I’m less sure this approach is actually likely to help the people who have the most to gain: those who are not at particularly focused on wellness, for whom the greatest challenge is getting started.
(In a similar way, perhaps, it’s generally unhelpful for a startup to fixate on operational efficiencies while it’s still searching for product-market fit.)
But even for those who are already interested in wellness, the amount of information on offer from longevity gurus is utterly overwhelming.
To pick a (real) example, a longevity champion might discuss the health benefits of saunas on one day, of fermented foods on the next, and of saffron the day after that. The issue isn’t necessarily the quality of the advice (the examples above actually include relevant references from the biomedical literature, although many champions are less rigorous). Rather, the problem is that of all the many things someone could potentially focus on to improve health, in the face of so much incoming information, how is someone supposed to even begin?
This dilemma reminds me very much of the challenge facing already busy physicians who are confronted with continuously expanding lists of mandated topics for each visit; while in theory it might be helpful to address all, in practice, this isn’t feasible – as the late Bill Gardner so thoughtfully discussed a decade ago, and as I discussed in The Bulwark in the context of COVID, here.
Gardner was inspired by the example of the “flood” of mandates facing military officials, leading to “ethical fading,” where corners inevitably are cut, rationalizations are “rampant,” and culture is corroded. To avoid this, as Dr. David Blumenthal advocated, you need to ruthlessly prioritize, and establish core priorities (or metrics) upon which to focus.
Similarly, many who might benefit from the pursuit of selective wellness advice are likely finding themselves overwhelmed and paralyzed by the volume (and lately, velocity) of well-intended advice.
In the future, AI might help us navigate this flood of information and data. As the always-eloquent Nathan Price (a professor at the Buck Institute for Research on Aging, CSO of Thorne, and co-author, with Lee Hood, of the 2023 book, The Age of Scientific Wellness) argues in a fascinating talk at the Buck, AI could provide a mechanism to integrate extensive personal data (include data collected by ever-more powerful wearables, as Subha Madhavan and I recently discussed) with the latest scientific research to deliver personalized health recommendations.
But today, what’s desperately needed is a fundamentally different approach to wellness, an approach that doesn’t seek to enumerate, measure, and optimize the vast number of factors and parameters that might have some effect on your health – where most longevity programs seem focused. Rather, we should emphasize a few critical high-value goals, where success could have the most significant impact on health.
Given both the prevalence of obesity and associated metabolic dysfunction — which seems to impact all the major diseases of aging (the “Four Horseman,” to use Attia’s phrasing) — and the remarkably efficacy of GLP-1RA medicines, this seems like a particularly promising place to start. As I’ve argued, success here is likely to generate an “agentic dividend” which could then be utilized to begin to motivate other health-promoting activities, kicking off a virtuous cycle. Initiating any sort of regular movement seems like a great goal to pursue next.
I’d argue that even beyond the value of motivating the many who don’t yet pursue health very actively, it’s also critical to create opportunities that speak to the many people who are keenly interested in health but are quite reasonably turned off by the narcissistic obsession with performance that seems to characterize longevity champions and enthusiasts.
There needs to be room for people who want to be healthier, but do not want the pursuit of health and obsession with health metrics and health blogs and health podcasts and health influencers to occupy a major portion of their lives — a degree of balance and wisdom of prioritization that in itself seems … rather healthy.
I envision a health enablement program that supports rather than overwhelms, meeting people where they are and illuminating the highest value opportunities for health improvement (like GLP-1RAs, for many, also low impact exercise to start with). Ideally this would be coupled with content that generally is not about health, fitness, or performance.
Instead, the program would focus on:
I see a particular need and opportunity for such an approach among the “Vanguard” 50+ highly agentic generation I described here.
This would be a great place to wrap, but I feel obliged to present a bit of a devil’s advocate response as well – inevitably informed by my own experiences. And what I’ve seen (as I’ve described in part here and here) is that the lifestyle changes that improved health may require are inherently disruptive — which of course is also the point.
For example, to transition durably – even with the help of GLP-1RAs – from a typical western diet to a lower calorie diet (ideally healthier as well) can require a profound shift from habits and customs developed over a lifetime. This is an underappreciated challenge. Moreover, when you are eating deliberately, and avoiding alcohol on most occasions, you’re probably a lot less fun socially, and can be a bit of a wet blanket if everyone is drinking beer and tearing into chips, and you’re drinking water while nibbling on celery.
In addition, as much as I love my exercise routine – which includes cardiovascular (I’m partial to outdoor jogging when it’s nice and Peloton when it’s not), strength, and balance (including twice-weekly pilates) – it’s a significant amount of time, about an hour a day, and I’m typically waking up at 4:30am to get through it before my regular day begins. This also means that when possible, I tend to go to bed fairly early to ensure a solid evening of sleep, another vital health priority.
While these practices may be extremely disciplined, it also means a lot of my life is structured around a significant commitment to diet, exercise, and sleep, which is unlikely to be ideal for many.
My hope is that it’s possible to make progress towards improved health without committing to everything, at least not all at once. Ideally (as I’ve described), progress on the eating front, likely abetted by GLP-1RAs, can create the seeds of success elsewhere.
But I also recognize – having observed this in others and experienced it on my own – how easy it is to fool yourself. We’ve all seen people who devour cake yet comfort themselves by choosing to wash it down with a diet coke, for example, or decide that a walk from the car to the door constitutes meaningful exercise.
While I’d like to say “at least that’s a good start,” I’m not sure it usually is; I suspect there’s a threshold effect, and if you don’t commit to a degree of change that involves activities that are at least somewhat unfamiliar, and probably uncomfortable, it might not be enough.
Bottom line is that while healthy aging may not require the obsession and immersion exemplified by many of its greatest champions, it requires more than good intentions, pro forma effort, or a magic jab alone. The challenge, inevitably, is discovering the right balance, and finding a way to age healthily while ensuring we’re using our precious time for something more meaningful than simply the continued pursuit of more of it.
Kevin Parker is today’s guest on The Long Run.
Kevin Parker, co-founder and CEO, Cartography Biosciences
Kevin is the co-founder and CEO of South San Francisco-based Cartography Biosciences. The company is using multi-omic tools to map out which targets are specifically expressed on cancer cells. The idea is to find new, precise targets that antibody drugs can aim for.
Cartography got started during the pandemic, raised a $57 million Series A round in the summer of 2022, and last year formed a partnership with Gilead Sciences.
Now, please join me and Kevin Parker on The Long Run.
Sam Rodriques, co-founder and CEO, FutureHouse
Monday was my last day as a group leader at The Francis Crick Institute.
I got my job at the Crick in 2020, almost exactly 5 years ago, right as COVID was beginning. I had finished my PhD in 2019, and had always told myself that I would only ever be an academic if I could find a place where I didn’t have to write grants, didn’t have to teach, and wasn’t on a tenure clock.
The Crick is one of a very small number of research institutes that affords its academics such privileges. It is endowed with extraordinary facilities, right in the heart of London. The offer for early-career researchers is almost too good to be true: almost $1 million a year in core support in personnel, reagents, and core facility usage, plus a generous startup equipment budget.
The Crick delivered on its promises, but European science faces some extraordinary headwinds. The general lack of funding has been well-documented. Red tape is far beyond anything that American academics have to deal with. But the biggest challenge of all is cultural. It’s less visible and far more pernicious.
Consider this example. About six months in, I was sitting in a meeting with some other faculty and core facility leaders, arguing that we needed to build out an ambitious screening platform similar to those at the Broad Institute of MIT and Harvard. Heads bobbed up and down. I thought we were getting somewhere.
As people were filing out, one of the group leaders hung around behind.
“Sam, you really have a lot of that American energy.”
I chuckled.
“Don’t worry,” she said, “Stay here for three years, and we’ll beat it out of you.”
It was sardonic humor. I later came to understand what she meant.
Another time, I showed up at the sequencing core facility at 3 pm on Friday with a library of samples ready to load for a batch run. I was eager to come back a day or two later with lots of data to sort through and analyze.
If only things moved that fast. I was told that I could submit a request form that would be processed the week after next (not next week, of course, because the person responsible was on annual leave). Then, when the person was back from leave, they would reach out to schedule a time to discuss my requirements in more detail. I asked if I could simply load the library on a benchtop Illumina Miseq machine that was sitting, idle, in plain view. This request was met with bewilderment.
Forget about it.
Then there was the time health and safety regulators were called to inspect my lab because I had stacked two stackable hybridization ovens without a proper risk assessment on file.
Worst of all, I felt the gnawing sense of falling behind in the global scientific competition, as one promising student or postdoc after another would decline an offer to go to San Francisco or Boston. Usually, that was because they were excited about the work we were doing, and wanted to be where the action was, where there was a critical mass of potential collaborators with complementary skills.
This is only part of the story, though. The UK abounds in excellent researchers. The Crick, in particular, is a remarkable institution. Paul Nurse, the Crick’s visionary leader, has attracted some of the most talented early-career group leaders in the world, like Pontus Skoglund, David Bauer, and many others. Paul has also cultivated a “can-do” attitude among his executive team: whenever I needed something, I knew that Paul or Richard Treisman or Sam Barrell or Steve Gamblin or another executive would back me up.
If the UK wants to maximize its scientific output, it needs to double down on funding for the Crick and its other top-performing institutions.
The UK has also been at the forefront of new experiments in ways to do science. ARIA, the UK’s Advanced Research & Invention Agency, has done a spectacular job in moving fast and supporting contrarian research through its programs and through new structures like Focused Research Organizations (FROs). Pillar VC’s new Encode fellowship (also ARIA-supported) is one of the best ideas I have seen for how to bring AI talent to hard science problems.
Nevertheless, there is only so much you can do against a cultural background that penalizes ambition. The further you got at the Crick away from the top executives, the more you would encounter the traditional European “second place is OK as long as you gave it a good shot,” kind of attitude.
The group leader’s sardonic warning was right: I did not last for three years. I was burning with ambition to seize the moment with AI to answer biological questions. It took me about a year to recognize that the UK would not be a long-term home, and another year and a half to found FutureHouse, in the second half of 2023.
I have lived in San Francisco since then. I haven’t regretted that decision for a minute. I have found talented students and postdocs who want to solve big problems. I have found investors willing to take risks. I have found a supportive community of entrepreneurs. It was the right move to pursue an ambitious research agenda, and pursue entrepreneurial dreams, in America.
At the elite levels, Europe has an extreme brain drain problem. The most ambitious people are mostly in the US, and so the most ambitious people continue to come here.
The US’s position as a talent magnet is not something we can take for granted; I am sure that with the correct combination of policies, we could eventually drive people elsewhere.
But it is also not a position that will be easily lost. There simply is nowhere else in the world that is anywhere near as attractive for talent. As long as the most ambitious and determined people can still find ways to get here, they will.
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David Li, co-founder and CEO, Meliora Therapeutics
We have entered a new era in biotech.
Turmoil at the FDA has introduced new uncertainty. NIH funding cuts and grant delays have led to academic institutions to hold off on job offers to young scientists. The Trump Administration’s reset of trade relations with the world caused a financial market meltdown, and wild rebound.
All of these things are contributing factors making the biotech downturn longer and more intense than almost anybody imagined. The XBI biotech stock index is at its lowest point in three years.
Amidst all the gloom and uncertainty, the National Security Commission on Emerging Biotechnology, a bipartisan committee created by Congress, released a report warning of imminent danger. The US biotech industry could lose its once formidable biotechnology advantage over China, the authors write.
By now, many have commented on China’s rise in biotech (see my initial post in January), and the trend has only continued. After my guest editorial was published, another five out-licensing deals from China were announced during the JP Morgan Healthcare Conference. Large pharma is continuing to invest in China (see AstraZeneca’s newly announced $2.5 billion investment in R&D).
While the report often comes across as hawk-ish as it portrays China as dangerous and nothing but a strategic competitor, my view is that the report falls short of suggesting actions that will meaningfully change the trajectory of the US biotech industry.
Recommendations in the report include:
The report starts with a strong call to action but ends up severely short on details. It misses a number of foundational factors that would make US biotech more competitive.
What should be part of the national strategy?
Currently there is a lack of a credible funding for incremental de-risking of science.
While cost efficiency is certainly important for any startup, the pendulum in today’s market has swung too far in the risk-averse direction. In many instances, startups are expected to have first-in-human data in their first round of funding! As a response, startups are raising more capital than ever to fund all the way through clinical value inflection points if possible.
This is simply incompatible with exploration of novel biology that requires incremental de-risking.
In a more balanced, less bearish financing environment, high-risk / high-reward concepts are first tested in vitro to generate proof of concept. That then unlocks preclinical model experiments, which then unlock financing for bringing a molecule into the clinic.
One large financing round upfront to cover all these steps isn’t a prudent use of capital, and isn’t friendly for founders and management teams.
Suggestion: Address the early-stage funding gap through multiple paths
The currency of our land is clinical data.
It is usually the key value inflection for therapeutic assets, the key piece of evidence that persuades investors to invest. But the cost of gathering the required preclinical evidence, before even entering the clinic, is too high in the US.
The comparatively high cost of preclinical work in the US makes reaching human clinical data for a single program — let alone multiple programs — quite a high bar. Many investors now look to other countries, where it’s possible to gather the data faster, and at a lower cost, before taking the next step.
To be globally competitive, US biotechs must efficiently and expediently reach the clinical value inflection point. This is especially true as Chinese biotechs are now on the order of 5-10x cheaper and likely twice as fast. The data produced is often of a high quality, even when compared directly to US biotechs. US biotechs must confront this reality and act accordingly.
Suggestions: Strive for efficiencies through
This means doubling down on novel biology, mechanisms, and modalities, rather than only focusing on clinic ready assets derived from incrementally novel targets.
Chinese biotechs have long looked to US for true scientific innovation leadership. Many have built businesses on the fast-follower model.
That’s changing. The China biotech ecosystem is learning and evolving – and quickly. Over the last several quarters, novel targets are being funded in the early stages.
Why is this happening? China has 5,000 startups and growing. The biotechs in the China ecosystem are striving for novelty in order to establish differentiation from each other in a cutthroat competition for funding, business development attention, and more. The bleeding edge of Chinese biotech startups are now exploring more and more new targets out of necessity for survival.
However, the US still holds a comparable advantage in deconvoluting novel mechanisms, better understanding pathways for disease, applying novel pharmacology approaches and matching them with the appropriate patient populations. It is precisely in these uncharted grounds of novel biology that the US derives its significant advantage, and where China and others are still lacking.
Suggestion: Sensible funding of basic and translational sciences
The US should continue to fund basic and translational sciences via the NIH, NSF, and other government agencies. While not immediately impacting venture funding and startup creation per se, the structural advantage of being the birthplace of novel biology exploration pays compounding dividends for the US ecosystem over time. Over a long enough time period, this research investment is the ultimate driver for global competitiveness.
It’s clear that we are entering a new era for our industry. Patient demand for good medicines is unrelenting. A patient in need does not care much if the medicine comes from the US biopharma industry, or somewhere else.
The US system must evolve with the times in order to capitalize on its strengths in pioneering true innovation, otherwise risk losing its pole position in global biotech.
The runway to do so is shrinking quickly.
Larry Corey, MD
I grew up in an era of Superman comic books.
Superman captivated the imagination of a generation of kids like me. It told stories of an otherwise ordinary human who could achieve extraordinary feats of speed and strength, leaping tall buildings with a single bound, to defeat the bad guys. Miracles could happen on a foundation of truth and justice, and that this was “the American way.”
Superman, of course, was a work of fiction. Kryptonite isn’t in the periodic table. But the optimistic narrative proved true over the course of my career in science. I have seen numerous medical miracles in my life, many of them starting in a lab.
CAR T cells to fight blood cancers; anti-cholesterol drugs for prevention of heart disease; ways to dissolve clots from strokes; gene therapies for genetic diseases; antisense RNA for treatment of eye and liver disease; and yes, mRNA vaccines for COVID. One of the greatest miracle technologies in the last few years has been the rapid expansion of mRNA vaccines and treatments.
Using mRNA to deliver a therapy to a cell or to produce an antigen to show the immune system what to defend the body against—a bounding leap of scientific advancement—has, largely to our dismay, been accompanied by an anti-science backlash.
Proposals are bubbling up around the country—Montana, Florida, Idaho, and Texas—to ban or restrict use of the technology, including some products already FDA approved. Scientists seeking grants to support their research are being advised to scrub the language “mRNA” from their grant proposals.
These ideas ignore a mountain of evidence supporting mRNA’s potential for medical advances in a wide variety of diseases. These gains were made through the federal government’s enormous investment in basic research. Scientists have been working painstakingly on the mRNA molecule since its discovery in the 1960s.
The journey for mRNA vaccines started in the early 1990s and culminated in the successful COVID-19 vaccines of 2020. Katalin Karikó and Drew Weissman won the Nobel Prize in 2023 for work that paved the way for the mRNA vaccines. Three to four billion doses were administered worldwide and these vaccines are widely acknowledged to have saved over a million lives in our country.
It’s true that viral escape has resulted in the reduction of efficacy against symptomatic disease. But in the elderly population most vulnerable to COVID, mRNA COVID-19 booster vaccines have low side effects and continue to reduce the risk of Emergency Room visits, hospitalization and death. The extension of mRNA technology to other respiratory diseases and viral infections such as cytomegalovirus and herpes simplex viruses are under investigation.
The mRNA technology is uniquely promising for developing new vaccines because of how quickly it can be designed and scaled up. Previous technologies would have taken too much time or money to effectively defend people against a fast-moving infectious disease.
The beauty of RNA is its price, its simplicity, its ability to be duplicated, and its iterative potential.
In my field of HIV vaccines, where we use mRNA in structure-based design, it’s a game changer. One can produce an mRNA vaccine for a Phase I clinical trial, to evaluate safety at a variety of doses, for about $1 million. That modest budget allows us to use rigorous protocols for GMP (Good Manufacturing Practices), and still have a candidate vaccine ready in four to six months, or even as fast as 70 days in a pandemic.
To train the immune system against this notoriously wily virus, we need four separate vaccinations, and we have two or three choices as to what might be the best structure for each vaccine prototype. The ability to quickly design and iterate mRNA gives us the options we need to keep making tweaks to come up with the optimal combination of structures and sequence of shots.
We have also used protein-based vaccines extensively, but making a protein vaccine usually takes three times as long and triple the budget. More than $4 million is needed to produce a small batch for early vaccine trials, and it usually takes 12 to 15 months to manufacture.
About 30 to 40 percent of the time, after all this time and expense on manufacturing runs, we come away empty handed and unable to run the trials. That’s because the protein cannot always be predicted to fold exactly or be well stabilized when manufactured.
Protein-based vaccines, when properly conceived and folded, can have advantages over mRNA for population-based control because they have a long shelf life and only require basic refrigeration. But those advantages only kick in once you know what to make and how you are making it.
We need mRNA for the research enterprise. That does not mean it will always emerge as the technology used in the global rollout of a product like a vaccine. One could use mRNA in discovery to identify the right protein components, then switch to a conventional protein subunit vaccine.
The speed and modularity of mRNA for vaccine research is also useful for research into cancer and autoimmune disease. The long list of potential indications includes malignant melanoma, brain cancer, liver disease, colon cancer, interstitial lung disease; and many genetic diseases. One of the most impressive late-stage developments is mRNA for use in personalized cancer vaccines to prevent the cancer from spreading.
A new generation of startups have emerged to develop second-, third-, and fourth-generation mRNA vaccine products—to make the lipid nanoparticles specific for a target organ; to get rid of the lipid nanoparticle; to decrease the amount of toxicity; to improve the transcription of RNA so there’s greater potency; and just to develop immunotherapies to deliver intracellularly what before now has not been possible. It’s as if the mRNA vaccine allowed the mRNA technology to reach a threshold to expand its use exponentially—a potentially transformative tool in health care worldwide.
Why are we seeing such a strong backlash? From both a health-care perspective and an economic standpoint, it makes no sense. The gap is wide between the scientific publications and what is pushed out on the dark web. There’s a cynicism that says everything in the research sector is wrong. Why has this gone so far? Why can’t we easily explain that mRNA doesn’t alter your DNA? It stays in the cytoplasm and doesn’t get into the nucleus. God designed it so it couldn’t get to your DNA.
How can the business community, which has so much invested in this, not challenge the political tsunami threatening to overwhelm the achievements of science?
Why aren’t they out there telling the science side? Are they working “behind the scenes” out of fear of retribution? What’s the fear?
Shouldn’t the greater fear be that we don’t deliver what we know we can? That people will die or have incredible morbidity by not having access to a discovery that can alter their lives?
Fear remains our greatest foe in this American tale. What’s happened to truth, justice, and the American way?
Looks like we need an mRNA champion with a red cape.
George Eastwood, executive director, Emily Whitehead Foundation
Leading a nonprofit that helps kids and families with terrible diseases requires a certain ability to roll with the punches.
That feeling hit last week when I heard about Peter Marks’ forced resignation as Director of the FDA’s Center for Biologics Evaluation and Research (CBER). Here was a scientific champion of innovative cell and gene therapies at the FDA. He was respected by many in the rare disease community as someone seeking to do what’s best for patients with little or no treatment options. Seeing him unceremoniously pushed out felt like a punch in the gut.
I called Sharon King, a rare disease advocate, valued Emily Whitehead Foundation board member and friend. Her daughter was diagnosed in 2006 with CLN1 Batten Disease, a rare, inherited, and always fatal neurodegenerative disease.
“Ever since my daughter’s diagnosis, I’ve always needed to look for the silver lining,” Sharon told me through tears. “But with Peter leaving, that’s incredibly difficult. He has been a consistent champion for the rare disease community, willing to embrace new ideas to help us find a way forward. His leaving is no small loss for our community.”
That sentiment is widely shared in the rare disease community. In the years of collaborating with Peter and watching him work, I’ve observed three qualities that made his leadership transformative.
First was his unique ability to connect an entire ecosystem.
Peter Marks, former director, Center for Biologics Evaluation and Research, FDA
At numerous meetings, Peter directly engaged with pharma executives, technology innovators and clinicians, always exhibiting the same level of thoughtful attention. He wasn’t concerned with people’s status. He was more concerned with how the person he was speaking with could contribute toward solving the problem.
Last fall, I saw that when he flew to Philadelphia on a Friday night to deliver a compassionate speech at the Emily Whitehead Foundation’s Believe Ball. It was a celebration of 25 patient Warriors and their families. These Warriors, representing various diseases and modalities, were able to be treated because of his work evaluating the risks and benefits of cell and gene therapies. Everyone in the room felt that spirit of hope, and shared purpose that Peter helped enable.
His second key leadership trait was his transparency. When secondary malignancy concerns emerged with CAR-T therapies after several years of being available on the market, the FDA initially issued black boxed warnings across the entire class. This created fear, uncertainty and tension with clinicians and developers. Rather than doubling down on an across-the-board warning that could curb access to patients who might benefit, Peter assured all the relevant audiences – physicians, drug developers, patients, and payers – that the FDA would take a balanced position based on the best available evidence of safety and efficacy for each product.
“We are in the process right now of reevaluating the need for the current labeling on these products. You may see some actions, in some cases, removing warnings, in some cases, adding warnings, changing warnings,” Peter said at the time. This straightforward communication reassured both industry and patient communities.
Finally, his courage in making difficult decisions stood out.
His decision to overrule the FDA advisory committee and approve Sarepta Therapeutics’ Elevidys, a gene therapy for Duchenne Muscular Dystrophy, required courage. It demonstrated his willingness to stand firmly behind innovative treatments that could transform lives. It underscored his willingness to not only consider the totality of data for a new treatment, but also to listen to patient voices about the difference a new medicine can make.
Peter Marks’ legacy at the FDA includes many concrete achievements: numerous biologics license approvals, groundbreaking gene therapies for previously untreatable rare diseases, and innovative programs like START and the Rare Disease Innovation Hub. His commitment to integrating advances in science and technology into the regulatory process enhanced the availability of safe and effective medical products for countless patients.
The FDA now has a leadership gap in this important job. We urge the Administration to act swiftly in appointing a long-term successor who understands the delicate balance between rigorous evaluation and urgent patient needs. This is not just about continuity but about preserving Peter’s patient-centric approach.
When I commiserated with Sharon again after processing this sad news, we tried to find the silver lining.
Perhaps it exists in what Peter leaves behind: a regulatory framework that values patient input, transparency and innovation. Our responsibility now is to ensure his pioneering approach continues, inspiring the next generation of FDA leadership to bring life-saving therapies to those who need them most.
Luke Timmerman, founder & editor, Timmerman Report
The 5th annual Timmerman Traverse for Life Science Cares is fired up and ready for outdoor adventure in 2025.
We’re on a mission to raise $1 million to fight poverty.
This year’s team is preparing for a pair of challenging hikes in the Pacific Northwest, Aug. 18-19. We’ll cover 20 miles of trails, ascend 7,000 vertical feet, and savor some of the most spectacular scenery in North America.
We’ll enjoy fresh air and exercise. We’ll make new friends. Together, we are giving back to our communities.
We are off to a strong start this year with $200,000 already in the bank. Each hiker is required to raise at least $35,000. Many will go above and beyond.
The money we raise will flow through a network of nonprofits in the five cities where Life Science Cares operates – Boston, San Francisco, San Diego, Philadelphia and New York.
These nonprofits are on the ground in each city, tackling a variety of needs. Some cover basic, immediate needs like food and shelter. Others provide long-term pathways out of poverty through education and job training.
Life Science Cares provides a lifeline to these nonprofits. It is the bridge between the biotech community and the broader community. Life Science Cares connects us to each other and to our mission – alleviating suffering from disease.
Please show your support for these men and women working in common cause.
Please subscribe and tell your friends why it’s worthwhile. Quality journalism costs money. When you subscribe to Timmerman Report at $199 per year, you reward quality independent biotech reporting, and encourage more.
Times are tough in biotech, but this is an industry where we learn, adapt, and move forward.
I’m proud to announce that the 2025 Timmerman Traverse for Damon Runyon Cancer Research Foundation has hit its fundraising goal of $700,000 to support high-risk / high-reward cancer research. We stand at $702,555 in closed donations.
Our team of 16 hikers is now packing bags and gearing up to trek to Everest Base Camp at 17,500 feet / 5,364 meters. We will hike in Nepal Apr. 15-25.
This Timmerman Traverse campaign, like all others, required sweat and sacrifice. We had to overcome adversity. It took creativity and relentlessness. We kept working because it’s important to uplift the next generation of outstanding cancer researchers, especially in a moment of so much potential.
We did it together.
Now we will enjoy some quiet time, away from the daily work world. We will come together as a community of men and women united in shared purpose.
We will slow down, unplug. We will stare up in awe at one of the marvelous mountain ranges of the world. We will feel the challenge of hiking uphill, on dirt and rock, breathing thin air. We will sip warm tea in rustic lodges, around a wood burning stove. We will play card games and tell stories. We will shiver when sliding into our sleeping bags at night.
We will form friendships to last a lifetime.
Thanks to our top-tier sponsors – Bristol Myers Squibb; Kite, a Gilead company; and Alnylam Pharmaceuticals.
Thanks also to Cooley, Higgins Group, HLX Life Sciences, KMAK Capital, Latham & Watkins, Lincswitch Therapeutics, Lumanity, Lyfe Capital, NeoGenomics, Nucleate, PH Foundation, PhaseV, Relation Therapeutics, TD Securities and WilmerHale.
Thanks to Aragen, Argot Partners, Bain Capital Life Sciences, BioInvent, British Land, Causaly, DH Life Sciences, Emily Whitehead Foundation, ImmunoPrecise Antibodies, Lonza, Nurix Therapeutics, OrbiMed, Recursion, Saras Capital, Singular Biotech, and TCG Life Sciences.
For a full list of corporate sponsors, click here.
Thanks to this year’s team:
Friends, family, and colleagues can follow our progress on the expedition here.
Finally, thanks for everyone who donated, and everyone who makes it their life mission to alleviate suffering from cancer.
We may come up with a few ideas on the trail to share with you later. — Luke
L to R: Henry Kilgore of the Whitehead Institute, Luke Timmerman, and Will Chen of the University of Washington on Kilimanjaro, Feb. 2024. Henry and Will are Damon Runyon Fellows who participated in the inaugural Timmerman Traverse for Damon Runyon on Kilimanjaro, Feb. 2024. They are a couple of the brilliant young scientists that our donations support.
Enjoy a few more photos from my Everest and Everest Base Camp archives.
Monks in training, Thame Monastery.
The legendary Lakpa Rita Sherpa, 17-time Everest summiter, in front of a Tibetan Buddhist stupa, with Ama Dablam in the background.
Hiking into and above the clouds.
Spinning the prayer wheels, paying respects to the local culture, sending forth good vibrations through the Khumbu Valley.
Luke Timmerman with mountain guide Jangbu Sherpa at Everest Base Camp. 2018.
David Roblin is today’s guest on The Long Run podcast.
David is the CEO of London-based Relation Therapeutics. The company uses multi-omic tools to look for drug targets in human tissue samples. It seeks to find the relationships between perturbed biological states and disease, with the help of machine learning.
Relation emphasizes relationships in another sense as well – the cultural kind among biologists, engineers, physicians and other professionals who need to find ways to meld their disciplines together to improve biopharma R&D success rates.
David Roblin, CEO, Relation Therapeutics
The startup has raised more than $80 million to date from a diverse group of tech and biotech investors. Late last year, it announced a preclinical partnership with GSK in which the pharma giant is supporting Relation’s work to discover novel drugs for fibrosis and osteoarthritis.
David comes to this work after a long career as a physician, then as an R&D executive at large biopharma companies Bayer and Pfizer, and in translational research from The Francis Crick Institute..
I met David and the team in London in late January. I was wearing another hat there, as part of a fundraising event for the Timmerman Traverse for Damon Runyon Cancer Research Foundation. I learned about the London biotech community, and how the many players – academia, hospitals, startups, and large tech and pharma companies – are seeking to work together and put the pieces together to improve the biopharma R&D enterprise. I hope you will learn something too.
Now, please join me and David Roblin on The Long Run.
Sam Blackman, MD, PhD; entrepreneur-in-residence, GV
It’s been a rough week (again) for those of us within the biotech ecosystem. Actually, it’s been a rough month. Hell, let’s just say it’s been a hard year. Or two.
Rather than writing about the negatives – there will be plenty of time for that, I suspect – I’d like to share a delightful little story.
I recently returned from a meeting on pediatric sarcomas held at Cold Spring Harbor Laboratory. I’ve never been before, and it was hard to not be awed by the campus and the sense of legacy you have in the buildings and on the grounds and by the innumerable photographic reminders of the role that CSHL has played, as a physical place, in the history of molecular biology and biotechnology.
Not only was the physical place inspiring, and so were the people at the conference. I felt fortunate to refresh long-standing connections that included Alejandro Sweet-Cordero and Kim Stegmaier. Both were young faculty members in the Pediatric Hematology/Oncology division at Dana-Farber back when I was but a wee fellow.
The combination of photographic history and personal re-connections was a reminder that one of the enduring joys provided by a life in science and medicine are the career-spanning, or sometimes life-spanning, relationships that you can build. It is this joy that will make so many of us flock to Chicago this year (twice!) for AACR and ASCO.
Returning to my home on Orcas Island after the CSHL meeting, I got back to one of the more mundane tasks that I’ve been tackling during my recent “retirement” from Day One Biopharmaceuticals – cleaning out the storage room. Absolute joy and delight came from cleaning out an old filing cabinet.
There was a dusty drawer full of papers and certificates, many dating back to my medical and graduate school years (mid-1990s), and some dating back to my undergraduate years. I found a photocopy of the first journal article I co-authored, a stack of old student and hospital IDs from medical school (which serve only to remind me that I somehow managed to transform hair follicle stem cells into adipose-derived stem cells over the past 30 years), letters of recommendations from former college professors, and other ephemera that reminded me of exactly how long I’ve been a denizen of the medical and scientific ecosystem.
One surprising treasure was a program booklet from the 1998 MD/PhD National Student Conference. That year I was midway through my MD/PhD program at the University of Illinois Chicago and was lucky to have somehow managed to have my abstract selected for this conference, which was held every year, hosted by the University of Colorado Health Sciences Center (the conference is still ongoing and is in its 40th year this year).
The 1998 conference featured lectures by Carol Greider, Michael Welsh, Richard Klausner, Mark Groudine, and Michael Brown. In addition to hearing 5 incredible keynote talks, I remember that a number of us went mountain biking with Carol Greider. Looking back it was quite a reminder that I had the privilege of sharing a few days with a current Nobel Laureate, a future Nobel Laureate, a future NCI director, and multiple National Academy of Medicine members.
Perusing the list of attendees, I realized that for those 3 days in Aspen, not only was I sitting in the same room with then current luminaries, but many of the young scientists at that meeting ended up becoming highly accomplished future colleagues.
It turns out that I was sitting in the same room with Mike Thompson, MD, PhD, FASCO, who I’ve gotten to know through the years (on Twitter and in real life), Shannon Morris, who I would end up working together with in oncology clinical development at GSK, with James LaBelle, who I’d get to know and befriend as fellow fellows in pediatric oncology at Dana-Farber Cancer Institute, David Berman, who I would meet and interview in 2007 when he was at BMS, and who would be the person who inspired me to go into a career in drug development, and, most amazingly, Jeremy Bender, who would in 2020 become my CEO, my dear friend and partner, and with whom I would continue to build Day One Biopharmaceuticals into the success that it has become.
This week, my “retirement” is coming – unsurprisingly – to a premature end, as I am in Cambridge to begin the next chapter of my career as an entrepreneur-in-residence at GV. The time for looking back has concluded, and now it’s time to again look forward. But the past and future remain inextricably linked.
Robert Copeland
Much to my delight, and in keeping with the theme, I learned that Robert Copeland has also recently joined GV as an advisor. He and I are being reunited as colleagues. Many of you will know Bob from his innumerable scientific accomplishments, including the discovery and development of the first approved EZH2 inhibitor tazemetostat. But I have the privilege of also knowing Bob first as my biochemistry professor at the University of Chicago back in 1991 when he co-taught a course with the legendary Herbert Friedmann. And while I don’t remember the specifics from 30-plus years ago, I suspect that my introduction to the lac operon and the fundamental concepts of molecular biology came to me first via Bob Copeland.
Once again, Shakespeare was right: what’s past is prologue (a statement that is, ironically, inscribed on a statue found at the National Archives building in Washington, D.C. and an important reminder for all of us, today).
As Gary Gilliland, an incredible physician-scientist and my former department head at Merck, told me in my last meeting with him before I left to take new job, “Remember, Sam, it’s a long dance.”
Gary was, of course, absolutely correct.
We occupy an incredibly small world, and an even smaller one for those of us lucky to have a career in science and medicine and biopharmaceutical R&D. Our future is, of course, profoundly influenced by those who teach, train, and collaborate with us over the years. But unlike so many other fields, the long, if not epic, arcs of science and medicine all but guarantee that we accumulate a lifetime of colleagues, as well as colleagues for life.
In a world that is so fractured, I feel the need to cling even more tightly to the threads that connect people across space and time, like the ones tucked away in that filing cabinet drawer. Especially the threads that connect the remarkable people in our biotech community — people who have dedicated themselves to the pursuit of truth and the insatiable desire to positively impact human health.
I save them and treasure the threads that connect us much like I treasure those old papers and pictures, knowing that it is the connections that will sustain and hold us together, admixing and sometimes reconnecting us at unexpected points, so we can continue working together towards the greater good.
David Shaywitz
The arrival of generative AI prompted many to worry about the adverse impact on human agency; after all, if the technology can effectively do what we’re doing, where does that leave us?
This concern was the central focus of Reid Hoffman’s “Superagency,” which I reviewed for the WSJ earlier this year – see here. Essentially, Hoffman argues that new technologies can take some time to adjust to, but ultimately they empower us to do more things and greater things.
In the moment, however, that’s not how many experience the technology; in the review, I discuss a 2024 research paper out of MIT exploring the impact of generative AI on material scientists. The technology seemed to make the researchers more productive – and apparently even more creative – but also robbed them of the aspect of their work that provided them the most satisfaction.
As I wrote,
Mr. Hoffman, presumably, would argue that future scientists, accustomed to partnering with AI, will experience an enhanced sense of agency based on all they will be able to accomplish. Whether this forecast ultimately accords with our lived experience is the unanswered question upon which Mr. Hoffman’s cheery thesis depends.
Reid Hoffman
Recently, I’ve been thinking a lot about agency in the context of another remarkably powerful emerging technology – GLP-1 receptor agonists, the wildly popular anti-obesity medicines developed by Lilly and Novo.
According to the most recent CDC data, over 40% of Americans are categorized as suffering from obesity (defined, however imperfectly, as a BMI of 30 or higher); 9.2% of Americans suffered from extreme obesity (BMI 40 or higher). As the CDC points outs, “This means that more than 100 million adults have obesity, and more than 22 million adults have severe obesity.”
These numbers are climbing; twenty years earlier, about 30% of Americans were classified as suffering from obesity, and 4.7% suffered from extreme obesity, according to the CDC.
Prior to the arrival of GLP-1 medicines, durably losing weight in the extraordinarily obesogenic environment that we inhabit was virtually impossible without bariatric surgery. But not for lack of effort; millions of Americans endured cycle after cycle of desperately trying to lose weight, only to fail entirely, or to briefly succeed and then regain the weight rapidly. I can relate (see here, here).
One consequence of this pattern was a sense of futility around lifestyle changes for health. Yes, doctors preached the benefits of “diet and exercise,” and everyone is familiar with this advice. However, the sad reality is that the constant failure of the diet component often resulted in a broader sense of demoralization. What’s the point of sweating on the treadmill for half an hour if you’re just going to undo the apparent benefit by scarfing down some oreos later that day? (To be sure: there are many important intrinsic benefits of exercise, but it could be a difficult argument to make when someone is watching themselves get heavier day after day.)
The demoralization associated with failed (or being failed by) diet/nutrition programs (presumably coupled with the increased difficulty of exercising when you are heavier) thus had a cascading effect, depriving many of the absolutely extraordinary health benefits associated with physical activity, as I’ve discussed here and just this week here.
Enter the GLP-1s. In addition to all the remarkably positive effects they seem to have on their own (including some that appear independent of weight loss, as endocrinologist Daniel Drucker notes in a recent review, here), I suspect that among the greatest health opportunities associated with GLP-1 medicines will be their enhancement of our sense of agency.
According to University of Pennsylvannia professor Martin Seligman (see my discussion here) agency boils down to the belief that “I can make a positive difference in the world.” As I wrote,
Referencing what he describes as an extensive literature, Seligman argues that “people who have high agency are physically healthier,” adding “If you look at people with high agency holding constant the traditional risk factors, they live on average 6-8 years longer,” compared to people with low agency.
He continues, “Optimistic people—people who believe that they can control things far into the future, bounce back. They resist depression. They succeed. They try harder and give up less at school.” They do better in college than their SATs predict, he says, and do better at work. In contrast, “pessimistic people are less productive than their talents predict.”
From a health perspective, he says “about 20 well-done studies” have shown that after accounting for “the usual risk factors,” it turns out that “being in the bottom quartile of pessimism is roughly equivalent to smoking 2-3 packs of cigarettes a day for longevity. “
The point is that according to Seligman, enhanced agency is associated with better health. The massive opportunity I suspect GLP-1s may represent is that by allowing people – finally – to achieve mastery of their diet and appetite, these medicines might profoundly enhance our sense of agency.
Martin Seligman, Zellerbach Family Professor of Psychology, University of Pennsylvania; Founding Director, Positive Psychology Center
In addition to this being intrinsically beneficially to our health as Seligman suggests, it’s easy to imagine that success in the nutrition management will motivate many to embrace other health enhancing behaviors, including in particular exercise, which presumably will generate still more positive feedback and enhance our sense of agency even further.
In short, GLP-1s will generate what I’d call an agentic dividend that can be — and should be — leveraged to drive other healthy behaviors.
A bit optimistic? Only if GLP-1s prove financially inaccessible to most people – unfortunately, a very real possibility.
A skeptic might also argue that GLP-1s are fundamentally a cheat – in helping us lose weight without the suffering, we don’t really acquire the mastery, and perhaps the sense of enhanced agency, that weight loss without medical assistance might provide.
This is an understandable argument (if also somewhat dated with its emphasis on raw willpower). It’s also arguably moot since so few people were durably successful this way. I suspect that without the psychological burden of serial diet/nutrition failures, we will be far more enthusiastic about embracing additional healthy activities.
I am particularly excited by the profound opportunity here to recognize and leverage the agency enhancement that GLP-1s will provide and use it to fuel additional health-positive behaviors, starting with exercise, and building out from that foundation.
David Shaywitz
Dying, with few exceptions, has never been especially popular, and our shared interest in not dying hardly constitutes breaking news. Nevertheless, the aspiration of living longer — and remaining healthier while doing it — appears to be all the rage.
Consider these recent headlines:
There have also been a slew of longevity-focused books over the last several years; Outlive, by Dr. Peter Attia, is perhaps the best known, and has spent over ninety weeks on the New York Times Bestsellers list. Also relevant: Dr. Howard Luks’s Longevity…Simplified: Living A Longer, Healthier Life Shouldn’t Be Complicated.
What’s going on – what accounts for this apparent surge of interest?
To oversimplify, there are two general (and not entirely distinct) lines of work that seem to account for this.
First, there’s the biological study of longevity itself – what accounts for the intrinsic limits of lifespan, and how might this be extended? Much of this biology, as Dockser Marcus describes in the WSJ, originated from studies in the Guarente Lab at MIT, and has been pursued by researchers including David Sinclair (now Professor in the Department of Genetics at Harvard Medical School) and Brian Kennedy (former CEO of Buck Institute for Aging, currently Distinguished Professor in Biochemistry and Physiology at the National University of Singapore).
Leonard Gaurente, Novartis professor of biology, MIT
Similar to many frontier areas, the underlying science of aging has proved particularly challenging. As Dr. Eric Verdin, CEO and president of the Buck Institute for Research on Aging in Novato, California told Dockser Marcus,
“…the more you study something, the more you understand the complexity. There is no magic pill—even though we all would love the idea that there’s going to be something magical that solves all of your problems and prevents you from aging.”
The second area of work involves the factors that cause us to get sick and frail when we age. Attia describes four “chronic diseases of aging,” which he calls “the Four Horsemen”:
Dr. Attia’s framework, shared by others, is that each of these diseases develops very slowly over time, yet we tend to intervene only relatively late in the process.
The “goal should be to act as early as possible,” Dr. Attia argues. “We should be proactive instead of reactive in our approach. Changing that mindset must be the first step in attacking slow death.”
There also appears to be a shared belief that a key factor contributing to all four Horsemen (to various degrees) is metabolic dysfunction – essentially the idea that through excessive and unhealthy eating, and insufficient exercise, we develop insulin resistance, and our bodies enter a generalized pro-inflammatory state.
This contributes not only to cardiovascular disease and type 2 diabetes, but (at least to some extent) to cancer and neurodegeneration as well. Through focusing early on improved diet and more exercise, and monitoring progress closely, the hope is that we might delay, perhaps for many years, the arrival of the Horsemen.
One common attribute of many (but not all) researchers and entrepreneurs focused on either the biology of longevity or the prevention of chronic disease (or both) is a sense that action is required and warranted before definitive proof (in the form of randomized controlled trials, the gold standard of medical science) has been documented.
For example, Dockser Marcus writes,
Dismissing promising results because they aren’t definitive isn’t fair, Guarente said: “It is moving in the direction where there will be stronger and stronger data, maybe not in everything, but in some significant human health areas in the future.”
Similarly, Attia argues (in a section titled “From evidence based to evidence informed”) that while the “purists of evidence-based medicine demand data from RCTs before doing anything (emphasis in original),” the study of longevity isn’t particularly amenable to tradition RCTs because “it would take too long to do the study” and “the interventions are very complex, particularly if they involve exercise, nutrition, and sleep.”
Thus, he says, rather than wait for definitive proof that might never come, he argues we should extrapolate aggressively and thoughtfully from what we know, and recognize we’ll not achieve “absolute certainty,” but rather it’s about managing risk.
He argues we should think about approaching our health like an investment strategy, “seeking the tactics, based on what we know now, to deliver a better-than-average return on our capital, while operating within our own tolerance of risk.”
With this context, we can appreciate the rationale underlying both the consumer longevity companies (generally focused on extensive testing) profiled in depth by Dr. Topol and the supplements promoted by some of the longevity biologists interviewed by Dockser Marcus. Many longevity biologists are also working on developing what they hope will be FDA-approved medicines to combat aging.
We can also start to appreciate some of the critical dynamics associated with the surge in interest in longevity. If you believe traditional medicine is either excessively conservative about assessing risk or insufficiently proactive, or both, and if you are sufficiently well-off to afford the additional testing, then longevity companies are here to serve you.
On the other hand, Dr. Topol observes, “As is the case with the companies attempting to reverse aging, the ones marketing longevity, healthspan and advanced prevention to consumers have not yet provided any evidence for benefit.”
He continues,
That is not to say the concept behind these companies— a much broader collection of data— is wrong. My contention is that it is flawed because it is indiscriminate as to who undergoes testing and what tests (such as total body MRI or multi-cancer early detection) and when they are performed.
As Dr. Topol points out, according to Bayes Theorem, “if the pre-test probability is low, the accuracy of the test is substantially reduced.”
In short, the testing approach utilized by many longevity companies seems likely to generate a plethora of false positives, as well as additional testing, procedures, and anxiety. That’s a key concern for both physicians and payers — that we’ll run all these tests and waste a lot of time and money searching for problems that aren’t really there, and potentially generating new, iatrogenic problems in the process.
(Dr. Zak Kohane and colleagues described the challenge of “incidentalomas” in 2006, here; I’ve recently reviewed a book about Bayes Theorem for the WSJ here; the topic is also covered in another book I recently reviewed for the WSJ – Sir David Spiegelhalter’s The Art of Uncertainty – here.)
While today’s consumer-focused longevity companies focus on testing, the research around longevity science, while complex, as Dr. Verdin noted, remains exciting and promising. The work could ultimately lead to FDA-approved medicines capable of resetting our intrinsic rate of aging and significantly increasing our potential lifespan.
Despite differences in thresholds for various diagnostic tests, there seems to be remarkable alignment around lifestyle interventions that can promote longevity. As Dr. Luks nicely summarizes (recommendations with which Attia and others seem to largely agree), key elements include:
Dr. Howard Luks, author, “Longevity… Simplified”
As longtime TR readers recognize, I’m especially impressed by the impact of exercise, and I’m hardly the only one. As Attia writes, “The data demonstrating the effectiveness of exercise on lifespan are as close to irrefutable as one can find in all human biology.”
The disproportional impact of getting the sedentary to move even a little (as I’ve discussed here) is striking:
I am especially attracted to the idea of a healthspan platform that’s rooted less in arcane laboratory testing, and more in promoting a combination of activity and agency (which I suspect GLP-1RA medicines can help propel), particularly among the motivated tech-savvy highly agentic 50+ generation I’ve referred to as “The Vanguard.”
Longevity is having a moment, driven both by decades of research into the biology of aging and by research suggesting metabolic dysfunction leading to chronic inflammation may contribute to major diseases of aging, exerting a deleterious effect over a very long time. The hope is that earlier intervention (perhaps prompted by a suggestive value on a laboratory test or imaging study) could mitigate the damage. One concern is that if testing is performed without consideration of pre-test probabilities, many false positives will be identified and pursued. On the other hand, GLP-1 medicines provide a profound opportunity, particularly when combined with suitable physical activity, for individuals to significantly enhance their years of healthy life. In addition, with continued research, longevity science may one day deliver FDA-approved medicines capable of significantly increasing intrinsic human lifespan.
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Eddie Pauline, President and CEO, Ohio Life Sciences
The current debate over capping federal research overhead rates misses the forest for the trees.
Federal investments in medical research have built a thriving U.S. biotech sector that employs 2.3 million people. Funding from the National Institutes of Health (NIH) provides the foundation for this success, supporting universities and research institutions that attract top scientists and foster innovation.
Laura Gunter, President, North Carolina Life Sciences Organization
The Trump Administration’s proposed cuts to NIH’s indirect cost reimbursement—dismissed by some as mere “overhead”—threaten to undermine American exceptionalism, ceding our leadership in life sciences, global health and biosecurity to China.
After World War II, the U.S. created the world’s greatest research enterprise, which has driven American innovation for decades.
Rather than centralizing federal research, the U.S. made the decision to conduct research at universities and institutes throughout the country by co-investing in the development of research infrastructure.
Marc Cummings, President and CEO, Life Science Washington
By funding world-class facilities, the U.S. attracted the best scientists to conduct breakthrough research, which, in turn, secured private investment to turn that research into life-saving medicines. Today, life science companies invest $65 for every dollar the NIH contributes to a successful drug. That’s an incredible return on investment.
So, this debate isn’t really about overhead. It’s about maintaining the partnership between the federal government, universities, and medical research institutions that have allowed the United States to be the global leader in science and innovation for decades.
Stephen Rapundalo, President and CEO, Michigan Biosciences Industry Association
These funds keep the lights on, maintain state-of-the-art labs and enable cutting-edge research that powers America’s biotech industry. Reducing them may seem like a well-intended cost-cutting measure, but it’s a dangerous step toward dismantling the very infrastructure that allowed the United States to be the global leader in biotech investment and new drug development.
Meanwhile, China isn’t debating overhead rates. It’s investing aggressively in universities, research parks and industry partnerships. It subsidizes companies conducting research within its borders, making it cheaper to conduct research, clinical trials, and innovate there. The results are staggering: In less than a decade, China has gone from a non-player to licensing nearly one-third of all new molecules acquired by large pharma last year.
Simply put, our economic, health and national security depends on maintaining leadership in developing new treatments, cures and defenses against biothreats. We cannot afford to rely on a foreign competitor—and potential adversary—for the health and safety of the American people.
For generations, our nation’s early investments in research created new industries like biotechnology and precision medicine, transforming lives and driving the U.S. economy. These investments didn’t just benefit coastal research hubs. Universities and research institutions in red, blue and purple states alike depend on NIH funding to fuel local economies, support jobs and drive scientific discovery.
From biotech clusters in North Carolina and Washington to leading research universities in Ohio and Michigan, this funding is critical to maintaining American competitiveness across the country. The argument for capping Facilities & Administrative rates is that institutions can cover the gap in funding through endowments.
The reality is that most institutions, particularly public universities, will need to look to their states, which means increased state taxes, to find the funding — or simply forgo the funding altogether.
This isn’t a distant threat. It’s already hurting U.S. institutions and companies. Research institutions have already started to pause hiring, curb spending and rescind offers to graduate students, risking the loss of the best and brightest talents to other countries that have sought for years to replicate the American innovation engine.
Meanwhile, stock prices of companies supplying research tools plummeted 15-20% after the proposed NIH cuts were announced. The message from the market was clear: Weakening America’s research enterprise has immediate economic consequences.
China understands that. While we debate cuts, it’s doubling down on building facilities, attracting top talent and fostering partnerships with the goal of becoming a global leader in life sciences innovation.
We still have the advantage, but it won’t last without action. Protecting America’s leadership in life sciences isn’t just about national pride—it’s about economic strength, global health and national security.
Think of it this way: Taxpayers could save money by cutting “indirect costs” like fire trucks and fire stations. But no firefighter wants to work without a truck, and no one wants their fire department to arrive on a bicycle. Cutting indirect costs would leave our research system similarly unprepared.
A federal judge has issued a preliminary injunction in the case. Rather than placing a cloud of uncertainty over every research project and forcing our most innovative minds to look abroad for opportunities, we’re calling on the Trump Administration to drop the case regarding NIH overhead cuts and start a meaningful dialogue with industry and research leaders to identify opportunities for efficiency while maintaining our position as the world’s dominant life science powerhouse.
The choice is clear: We can invest to maintain our leadership or watch it slip away to China. America cannot afford to get this wrong.
This editorial was co-authored by the leaders of four state biotech associations:
Joe Horsman, biotech investor, Madrona Venture Group
Before Roche officially announced their new sequencer in a pre-AGBT webinar in February 2025, only true sequencing aficionados had heard of Stratos Genomics or Sequencing by Expansion (SBX).
The SBX chemistry underlying Roche’s new sequencer was developed by Stratos Genomics, which Roche acquired in 2020 and paired with nanopore sensors from Genia Technologies, which Roche acquired way back in 2014.
Stratos Genomics has an unlikely origin story, starting from a skunkworks operation in Seattle-based Stratos Product Development. The now defunct Stratos Product Development worked on a range of technical products, including Microsoft Xbox controllers, Apple laptops, and Nike sunglasses.
In 2007, Stratos Genomics was born in a closet-sized lab based on a napkin sketch outlining the fundamental idea behind SBX: copying DNA into an expandable, surrogate molecule for easy nanopore sequencing. Over the intervening 18 years, a relatively unknown group of scientists and engineers painstakingly developed the chemistry that brought the initial SBX napkin sketch to life.
Stratos Genomics is perhaps one of the most unlikely candidates to develop technology that is now taking on sequencing giant Illumina. The leadership is devoid of ex-Illumina stars and academic luminaries. Group leaders inside Stratos (and now Roche) often lack long academic or industry accolades—or even PhDs—instead spending years working their way up from research associates inside the organization.
There was no mega-round from a brand name Silicon Valley VC to generate buzz. Very little capital went into the company at all. Stratos only raised around $60 million during its entire 15-year history prior to acquisition.
Mark Kokoris, former CEO, Stratos Genomics; VP and head of SBX Technology, Roche Diagnostics Seattle
The CEO, Mark Kokoris, likewise eschews the limelight—you won’t find him at many conferences or sitting on panels. Instead, he is laser-focused on building the next generation of sequencing in a Seattle office building converted into a lab. With this profile, it is not surprising that the sequencing world was taken by surprise when Roche announced an SBX-driven sequencer that seems poised to upend the status quo—they quite literally did not see it coming.
The sequencing world is buzzing about it now. Roche announced at the AGBT conference last month that the SBX technology reduces the time from sample to genome from days to hours—a potentially big leap in R&D productivity. It could also provide useful differentiation in the type of data it throws off as a “midi-read” instrument, positioned between the short-read (Illumina) and long-read (PacBio and Oxford Nanopore Technologies) players.
SBX is a novel approach to nanopore sequencing, giving high accuracy short reads—almost a hybrid between Illumina-like SBS (sequencing by synthesis with short reads of DNA) and Oxford Nanopore which directly detect DNA and can give reads length of over 4 million bases.
With SBX, the DNA sequence is copied into a synthetic, surrogate molecule. A highly modified polymerase copies the DNA sequence, incorporating expandable nucleotides (XNTPs) instead of dNTPs, each of the 4 XNTPs contains a reporter molecule corresponding to its DNA base identity. After the DNA template is copied, the surrogate molecule is cleaved at the alpha phosphate, causing the molecule to expand 50X the length of the native DNA.
This “Xpandomer” is then sequenced through a nanopore. Because of the large sizes of the surrogate molecule only one base is read at a time, and the reporter molecule gives a clear, distinct signal for each base.
This was a heroic undertaking, requiring the combination of world-class chemistry, protein engineering, biochemistry and lots of determination. I saw some of this work firsthand, as I worked at the company from 2018-2022. For example, the polymerase evolution and engineering to specifically incorporate XNTP could barely begin until you had designed, generated and purified all 4 XNTPs! This could easily have been a cost and time prohibitive barrier to even starting.
So how did this dark horse bring this wild sequencing chemistry into the real world? Essentially, through one thing: grit. Long hours (11-hour days were completely normal), meticulous attention to every detail of the sequencing chemistry (Mark Kokoris will talk for days about chemical minutiae at every step of the process), and an unwavering belief that SBX could—and would—happen.
Over almost 20 years, SBX was willed into existence with (sometimes literal) blood, sweat, and tears.
But SBX is the type of scientific breakthrough that every scientist should be rooting for. When you hear about accurately copying DNA into a synthetic polymer 50 times the length of DNA—let alone see the chemical structures in the preprint (below)—every scientific bone in your body yells, “No way that works!” And yet, it works, and works really well, claiming a world record for DNA sequencing speed.
Look at this thing! Yikes
Expandable nucleotide structure. From Fig. 3, BioRxiv preprint. https://www.biorxiv.org/content/10.1101/2025.02.19.639056v2
However, big questions remain. Early access starts in 2025, but full commercialization won’t be until 2026, and there are still no hints on pricing. So, any predictions of disruption must come with an asterisk.
SBX brings two new (and underappreciated) axes to the sequencing discussion: flexibility and speed. These are tailor-made to solve pain points for clinical-facing customers.
With an instrument that offers flexible throughputs, large diagnostic providers no longer need to wait to fill up a sequencing lane—potentially bringing down clinical turnaround-times. SBX also uncouples read length from sequencing time, sequencing run times can be tailored to the amount of data needed. Obtaining 2X150 reads (300bp) on Illumina’s NovaSeq at the most cost-effective, high throughput can take up to 48 hours.
With Roche’s pedigree in diagnostics, Illumina is now being attacked on all sides. Element Biosciences is coming from the bottom up with a flexible sequencer accessible to many academic labs. Ultima Genomics is gunning straight at the mega-core, hyperscaler labs like the Broad Institute with an unquenchable thirst for raw read numbers, at below $100 per genome.
Even future growth markets like China are slipping away, with Illumina recently placed on an import ban list by the Chinese government, in favor of homegrown MGI. Now Roche steps into the fray, poised to take a shot at one of Illumina’s future bright spots, the clinical diagnostics market, with a full sample-to-answer offering and a large sales force capable of competing with Illumina around the world.
Illumina will be forced to respond. The big question is, “does Illumina still have enough scrappy, startup DNA left to fight, or will they retrench to service a dedicated install base?”
Illumina isn’t likely going anywhere. This dominant sequencing giant built the NGS market and ecosystem, embedding sticky workflows and customer relationships. The switching costs are high for these long-term customers. Illumina has a high-quality, well-known commodity, and a generation of scientists has been trained on its instruments. That will be hard to unseat. If you have an iPhone, and all your apps and data have been on it for years, what would it take to switch to an Android phone?
Entrenched as Illumina is, its growth prospects are very much in question. Illumina has been reducing its revenue forecasts as the entire biopharma industry grapples with a stagnant investment environment and now sweeping cuts to the NIH. New competitors in the sequencing field will make a return to growth much more challenging.
Illumina is also looking to break into adjacent fields like spatial biology, but these are far from green fields and incumbents won’t just roll over. Illumina’s new XLEAP sequencing chemistry is a nice, incremental improvement but perhaps a sign of a shift away from the ambitious, step-change innovations that drove the cost of sequencing from millions of dollars per genome to under $100.
For Roche, diagnostics will likely be the primary focus. There will certainly be research- and academic-focused instruments, but Roche’s greatest strength is its ability to offer a fully integrated solution for diagnostics. Roche has a checkered reputation in the academic sequencing world since discontinuing the 454 pyrosequencing platform in 2016. They will likely have to commit real resources to demonstrate SBX’s commitment to researchers. In contrast, Roche boasts a world-class molecular diagnostic sales force and end-to-end clinical solutions, positioning it to become the leader in clinical sequencing.
Roche’s SBX entrant poses an even bigger threat to Thermo Fisher Scientific and its Ion Torrent sequencer. While Ion Torrent doesn’t receive much attention, it has quietly built a strong business serving a largely clinical customer base. Roche poses an existential threat to Ion Torrent.
Among all the hype, what Is Roche’s weak spot? Expect to hear a lot about accuracy and Q scores from rivals as SBX’s launch date approaches. Single-read accuracy has been the Achilles’ heel of every single-molecule sequencing method. While Oxford Nanopore and PacBio have each developed solutions, Roche will face criticism that their raw read accuracy doesn’t measure up especially as PacBio’s Onso (the product of another sequencing acquisition—Omniome) and Element compete for ever-higher Q scores. Q50+, anyone?
Will Roche’s big announcement spur further consolidation? Will large diagnostic players view a sequencer as a must-have, spurring Abbott, Thermo Fisher, Danaher, or Qiagen to buy one of the up-and-coming players? Singular Genomics was recently taken private by Deerfield—perhaps expect their sequencing box to quietly find a diagnostics-focused home.
Alternatively, will Illumina position itself as the “white knight,” the neutral platform for diagnostic companies to standardize on? Upwards of 50% of its revenue is likely clinical-focused, a space it can’t afford to concede to Roche. This is perhaps the most bullish opportunity for the beleaguered sequencing incumbent facing a seemingly never-ending stream of challenges.
Disclosure: the author was previously an employee of both Stratos Genomics and Roche.
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Thanks to everyone who attended the TR10 anniversary party Mar. 13 at Adaptive Biotechnologies.
The toasts and roasts were funny, perceptive and heartfelt. It was a joyous occasion.
Enjoy a few photos. Click to enlarge.
Photos by Robert Wade.
