Biotech Leaders Get It
3
Nov
2026

The AI Moment in Drug Discovery: Daphne Koller on The Long Run

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03 Nov 2026

Daphne Koller is today’s guest on The Long Run.

Daphne is the founder and CEO of South San Francisco-based Insitro. It’s one of what you could call the first-generation companies that uses AI to speed up and improve drug discovery. Insitro was founded in 2018 and has secured $750 million in funding from venture capital firms and through partnerships with big drugmakers that include Bristol Myers Squibb, AstraZeneca, and Gilead Sciences.

Daphne Koller, founder and CEO, Insitro

Insitro has been collecting and curating biological data for years to get to the point where AI can be useful enough to even approach the most important hurdle in R&D – that being human clinical trials.

In this conversation, Daphne offers a reality check on what AI can and can’t do at the moment for the discovery of new medicines. She goes into specific detail about programs that her team is developing for fatty liver disease, ALS, and brown-fat driven markers with implications for cardiometabolic disease.

 

The Long Run is sponsored by AlphaSense

 

Anyone who’s tried to stay current on a fast-moving therapeutic area knows the real problem isn’t finding information — it’s that there’s too much of it, and it changes every week.

AlphaSense just launched SuperAnalyst, an always-on agent that works like a power user inside the platform on your behalf. It draws on AlphaSense’s full life sciences content universe — clinical trial data, peer-reviewed literature, regulatory filings, conference presentations, and expert transcripts with researchers, clinicians, and executives — and it keeps monitoring your space even after you’ve closed your laptop.

It’s designed to act like an extension of your research team. It remembers the programs and competitors you’re tracking, follows your process, and applies it automatically to new data as it comes in. And every output links back to its original source, so when you’re citing a trial result you can see exactly where the number came from.

Take the task you’ve been meaning to get to — tracking a competitor’s trial program or flagging the next regulatory decision before it hits— and hand it to SuperAnalyst.

Start your free trial at alpha-sense.com/TheLongRun.

AND

Quick question: when was the last time a CRO told you what something costs before you signed an NDA, sat through two scoping calls, and waited a week for a Scope of Work? In bioanalysis, pricing gets treated like a closely-guarded secret. Dash Bio thinks that’s backward. It publishes pricing publicly, on its website, and even has a calculator that shows how the price changes if you redesign your study. You can see what your study costs before you talk to a human being. No surprise line items, no “it depends”, no games. Dash was built to be the bioanalysis company that’s actually straightforward to work with: transparent pricing, guaranteed timelines, and data in days, not months.

If you’re tired of pricing that feels like a negotiation every single time, run your bioanalysis with Dash. Visit dash.bio/pricing and see exactly how much your next bioanalysis study will cost.

Now please enjoy this conversation with Daphne Koller on The Long Run.

31
Oct
2026

AI and Tocqueville at Harvard

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31 Oct 2026

David Shaywitz

I found myself this week back on my undergraduate campus, giving a seminar about “AI, Health, and Agency” for, of all things, Harvard’s Program in Constitutional Government, invited by Professor (emeritus) Harvey C. Mansfield, who at 94, remains sharper than most of us are or likely ever were.

He is not only one of the university’s most distinguished scholars, but also, famously, one of its only (openly) conservative faculty members — and also one of the most demanding.

Back when I was an undergraduate (in the Days of Giants), he was known as “Harvey C-Minus Mansfield” because of his tough grading. Even after grade inflation became effectively mandatory, he reportedly would provide students with two scores – their official Harvard grade along with what he thought they actually deserved.

Professor Harvey C. Mansfield and David A. Shaywitz

For years I knew him only by reputation, and was intrigued by his extraordinary scholarship and independent thinking. At some point, I reached out with a question relating to a perspective on history that I had attributed to a Harvard political science professor but couldn’t locate a specific citation. It didn’t ring a bell for him, but he pointed me towards other, far more useful references, including Tocqueville, one of his areas of great expertise. An occasional correspondence ensued, and more recently, the invitation to speak.

As I prepared for the talk, I landed on a question I wanted to ask him, related both to agency and to Tocqueville; it’s his thoughtful response – related not to agency but to AI – that I want to share with readers. 

First, some context.

Tocqueville

“Democracy in America,” write Mansfield and the late Delba Winthrop in their Editors’ Introduction to their definitive translation, “is at once the best book ever written on democracy and the best book ever written on America.”

Tocqueville, accompanied by his friend Gustave de Beaumont, had journeyed from France to America, and together, the two men spent nine months from 1831-1832 visiting as much of the country as they could, eager to see, as Mansfield and Winthrop explain, “what a great republic was like.”

Tocqueville would publish his observations in two volumes: the first, in 1835, was “a sensational success,” Mansfield has written, but the second, in 1840, was “received without much enthusiasm.”

Tocqueville’s “Democracy in America”

Nevertheless, Volume Two includes one of his most memorable essays (Chapter 20) contrasting what he describes as “aristocratic” historians and “democratic” historians, establishing a tension that resonates to this day.

Aristocratic historians, Tocqueville suggests, overindex on the influence of individual people, taking what we might now term a “Great Man” view of history. 

Such historians, he says, “ordinarily make all events depend on the particular wills and humors of certain men.” 

When aristocratic historians “cast their eyes on the theater of the world,” Tocqueville writes, “they perceive first of all a very few principal actors who guide the whole play.”

Focusing in this way, “gives them an exaggerated idea of the influence that a man can exert and naturally disposes them to believe that one must always go back to the particular action of an individual to explain the movements of the crowd.”

Democratic historians, on the other hand, “attribute almost no influence to the individual over the destiny of the species or to citizens over the fate of people,” Tocqueville asserts.

These historians tend to see “the actors much less and the acts much more.”

Tocqueville worries that in adopting this approach, democratic historians “not only deny to a few citizens the power to act on the destiny of the people, they also take away from peoples themselves the ability to modify their own fate, and they subject them either to an inflexible providence or a sort of blind fatality.”

Mansfield suggests that the explanations offered by democratic historians “imply that man is not a master of himself, he is not the master of events, thus not free.”

Democratic historians, Mansfield continues, “seem determined to show that progress is not a goal, achieved consciously, voluntarily by human beings,” and cites the observation by Tocqueville (also in Chapter 20) that “Historians of antiquity instruct on how to command, those of our day teach hardly anything other than how to obey.”

Astutely, Mansfield observes that this formulation, while leveling most citizens, elevates the historians themselves: they “appear great…seeming to dispose of the great causes they describe and complacently looking down on the rest of humanity unaware of the forces driving them forward.”

This air of righteous condescension seems easily recognizable within much of contemporary academia.

Projecting forward

It doesn’t take much imagination to see a remarkably similar tension to that described by Tocqueville expressed today, particularly between approaches (typically from the right) that focus on elevating individual achievement and those (more often from the left) emphasizing the need to reduce disparities.

One example: increasingly divergent views of agency. Martin Seligman’s just-published book, Agency: The Psychological History of Human Progress (expanding on this 2021 publication) argues that agency is the hidden engine of civilizational advancement. Not surprisingly, Silicon Valley, in particular, has latched onto the ideal of agency, spurring critics like Sophie Haigney, who wrote a New York Times op-ed entitled “All the Worst People Seem to Want to be High Agency.”

Many academic leaders who were influenced by Seligman nevertheless are increasingly emphasizing the role of the social environment in enabling agency.

One example: University of Pennsylvania scholar Angela Duckworth’s latest book, “Situated,” focuses on what she calls “situational agency,” emphasizing the contributions of your environment, and the importance of shaping your surroundings.

Another example: in a recent correspondence, a positive psychology expert from Harvard’s School of Public Health asked “How do we ensure the social conditions are in place to enable people to have sufficient agency? It’s not a viable choice for everyone, is it?”

Mansfield, Tocqueville, and AI

While the contrasting views of agency seemed to me an echo of Tocqueville’s two types of historians, when I raised the question at the end of my talk, Mansfield offered in response what struck me as an even more important question: is the impact of AI likely to be more “democratic” in effect or more “aristocratic,” each in the Tocqueville sense.

In other words, will AI affect everyone similarly, potentially helping everyone but resulting in a compression of differences, or will it provide an opportunity for the peaks of human performance and achievement to extend even higher – potentially at the risk of exacerbating disparities?

My initial response was to emphasize both the opportunities to elevate everyone as well as the particular potency of technology when wielded by people who are already domain experts – not least because such experts are better able to guide it, to recognize where it’s falling short, and redirect it skillfully.

Mansfield wasn’t having it.

“Do you really think that if Melville had this technology, he’d write a better version of Moby Dick?” he asked rhetorically.

I didn’t think so either -– but, as Ethan Mollick has repeatedly observed, as recently as his latest blog post, “AI is still quite a bad long-form writer” –- it’s a lagging area of expertise.

In responding to Mansfield, I highlighted that in the hands of expert software developers, AI seemed to make the best ones even more productive and effective, and to enable users to contemplate more ambitious projects than they might have otherwise considered possible.

But hand-waving explanations aside, I think Mansfield’s asking a really important question (and perhaps two): what’s the likely pattern of benefit for AI — widely distributed or spiky –- and (more provocatively, perhaps) what pattern would we prefer to see?

I actually confronted a version of this question when I was tasked a few years ago with developing the AI strategy for a large pharma’s R&D organization.  After an engaging and remarkably encouraging “listening tour” across the organization, I proposed a strategy focused on concentrating future AI resources around a handful of deeply committed individuals and teams who had already taken it upon themselves to pursue particularly promising approaches and had started to make real progress.

This strategy -– essentially, make the peaks higher — was explicitly rejected by both the head of the R&D Digital and Data group and by the company’s head of R&D, who both emphasized their preference for an approach that would “elevate everyone’s AI skills 5%,” rather than supercharge (gratuitously, in their minds) those who already “got it.” 

In my view, the key to organizational adoption was actually demonstrating tangible, palpable success in some domain, which not only would organically motivate others in the organization (people gravitate towards conspicuously useful tools and technologies), but would also separate this from yet another perfunctory corporate innovation initiative.  I lost the argument, but not my conviction in the approach, at least in this scenario.

More AI Questions, More Tocqueville

Back to the seminar: in a highly engaged discussion following the talk, attendees raised a number of thoughtful questions (albeit not related to Tocqueville). Two in particular stood out:

  • An ethics professor who teaches MIT undergraduates shared that her students are very concerned about AI taking jobs, and asked how to counsel them.
  • A student (I assume) pointed to the recent solution of a raft of difficult math proofs by AI, and asked how we think about a world where people (even if in the loop) can’t evaluate the quality or accuracy of what the technology is delivering.

What I took away from these questions (and many others) was a deep appreciation for how dynamic, exciting and unsettled  this moment in AI really is. Everyone seems to sense that big changes are ahead, but just what these changes will be, and how things will eventually settle out is completely unknown –- no matter what tech VCs confidently assert, and what playbooks management consultants inevitably provide.

Tocqueville might have recognized and uniquely understood the feeling. In the final chapter of Democracy in America, he reflects on the dizzying dynamics of an evolving country in the throes of tumultuous change, trying desperately, eagerly, hopefully to determine its identity, and define its future.

“The new society that I sought to depict and that I wish to judge,” Tocqueville writes, “is only being born. Time has not yet fixed its form; the great revolution that created it still endures, and in what is happening in our day it is almost impossible to discern what will pass away with the revolution itself and what will remain after it.”

He continues, “The world that is arising is still half entangled in the debris of the world that is falling, and in the midst of the immense confusion that human affairs presents, no one can say what will remain standing of aged institutions and old mores and what of them will in the end disappear.”

Contemplating all he has observed, Tocqueville writes “I feel full of fears and full of hopes. I see great perils that it is possible to ward off; great evils that one can avoid or restrain, and become more and more firm in the belief that to be honest and prosperous, it is still enough for democratic nations to wish it.”

A contemporary, somewhat optimistic observer, surveying the current state of AI, could hardly have offered a more apt description.

 

 

23
Oct
2026

Creating PROTACs and RIPTACs: Tim Shannon on The Long Run

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23 Oct 2026

Tim Shannon is today’s guest on The Long Run.

Tim is a general partner at Canaan Partners. He was a pulmonary and critical care physician in the early part of his career, before moving over to R&D leadership in industry, and then eventually into venture capital investing.

Tim Shannon, general partner, Canaan Partners

Tim got started as a VC during the Great Financial Crisis. That may not sound good, but it was the beginning of a biotech venture capital boom. During those years, Tim met Craig Crews, a professor of chemistry and pharmacology at Yale University. They got to work together on New Haven, Conn.-based Arvinas, a developer of a new class of small molecule drugs that act as targeted protein degraders, or PROTACs for those who like snappy acronyms.

They followed up that company by working together on Halda Therapeutics. It developed a different type of targeted protein degrader that acts through induced proximity, or a ‘hold and kill’ mechanism. These drugs are called RIPTACs for short. Halda was acquired a little over a year ago by Johnson & Johnson for $3 billion, based on encouraging early results for patients with advanced prostate cancer. Many other scientists are seeking to build on this success.

This conversation touches on an important concept that doesn’t get discussed often enough. Timing is important in biotech. You don’t want to be too early, or too late, when a new technology wave emerges.

The Long Run is sponsored by AlphaSense

So far 2026 has been a year of transition for healthcare and life sciences. Over the first half of this year, the AlphaSense healthcare research team analyzed the individual stories moving the needle across the life sciences ecosystem as part of the Sector Spotlight series. They feature the high-stakes battles for new drug markets (like oral GLP-1s and targeted radioligand therapies), a resurgent biotech IPO market, and more.

Follow the sector’s key debates during 2H26 and beyond, with the latest Sector Spotlights directly in AlphaSense.

AND

Quick question: when was the last time a CRO told you what something costs before you signed an NDA, sat through two scoping calls, and waited a week for a Scope of Work? In bioanalysis, pricing gets treated like a closely-guarded secret. Dash Bio thinks that’s backward. It publishes pricing publicly, on its website, and even has a calculator that shows how the price changes if you redesign your study. You can see what your study costs before you talk to a human being. No surprise line items, no “it depends”, no games. Dash was built to be the bioanalysis company that’s actually straightforward to work with: transparent pricing, guaranteed timelines, and data in days, not months.

If you’re tired of pricing that feels like a negotiation every single time, run your bioanalysis with Dash.

Visit dash.bio/pricing and see exactly how much your next bioanalysis study will cost.

 

Please enjoy this conversation with Tim Shannon on The Long Run.

15
Oct
2026

AAV Gene Therapy: What It Will Take To Get Through the Wilderness

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15 Oct 2026

Richard Wilson, SVP, Primary Focus Lead – Genetic Regulation – Astellas Pharma; Vice Chair, Alliance for Regenerative Medicine

When Luke first asked for my perspective on the state of AAV gene therapy over the summer, he asked me “Will AAV ever deliver on its early promise? Be safe? Be commercially successful?”.

After ruminating for a while, I settled on the Stockdale paradox (as chronicled in Jim Collins’ Good to Great) as the best description of where we stand.

The Stockdale paradox states:

“You must never confuse faith that you will prevail in the end — which you can never afford to lose — with the discipline to confront the most brutal facts of your current reality, whatever they might be.”

This acceptance of the brutal facts, combined with faith of prevailing in the end, was with me heading into this year’s Alliance for Regenerative Medicine Meeting on the Mesa. Meeting there with colleagues helped me distill what has to happen next.

The key takeaway? It’s execution time. Gene therapy developers need to show we can turn this impressive science into a meaningful business. Plain and simple.

The most brutal (perceived) facts

The early days of gene therapy teased the possibility of a steady stream of transformative treatments. Surely, amazing, life-changing therapies would emerge for patients and financial rewards would inevitably flow to those innovators who could simply develop the right copy/paste science. We would hop from gene to gene, swapping genetic payloads into viral vectors and collectively work our way through the whole genomic atlas of rare disease. Talent and capital coalesced around this enticing opportunity.

The reality has not proven nearly so straightforward. Safety concerns and varying degrees of efficacy have sown seeds of doubt. When some safe and effective gene therapies have struggled commercially, and a revolving door of regulators have occasionally moved the goalposts and sent mixed messages about what’s required, you have what can charitably be called a rough patch for the field of cell and gene therapy. Even as the biotech market rebounded in 2026,  gene therapy appears to have lagged.

Why?

For starters, the gene therapy business model operates by different rules. More on that in a minute.

The biotech industry is sustained by a large financial feedback loop. It rewards and incentivizes innovation that brings value to patients and to society. When the system works, discoveries from academic labs become biotech startups backed by venture capital, grants, angel investors and such. Those investors earn returns when strong data enables IPOs, acquisitions, or licensing deals. Society benefits from medical innovations that should save healthcare costs and improve lives over time. (Peter Kolchinsky makes this point well in his excellent book “The Great American Drug Deal.”)

When expected commercial returns are less clear however, the system stalls: large companies hesitate to license or acquire, public investors step back, and early investors lose hope for returns and the appetite to fund new companies.

Gene therapy poses a particular challenge to the biopharma business model that typically depends on recurring revenue streams from regularly re-dosed pills or injections. The opportunity to realize a commercial return for gene therapy occurs just one time per patient for an adeno-associated viral (AAV) vector delivered gene therapy.

This means that payors are being challenged to adapt to a business model which relies on front-loading payment for outcomes that can range from durable life-changing benefits to more incremental, shorter-term improvements in quality of life. And like other medicines, some patients may respond more strongly than others, creating uncertainty around population-level outcomes from studies with a small sample size.

Insurers are being asked to pay million-dollar per patient price tags upfront, uncertain whether the benefits may vary, and also wary that patients may switch insurers every few years. This possibility can allow a another payor to reap the rewards of a patients treatment, without having to pay for it. Insurers confronted with a patient in need of an expensive gene therapy have a perverse incentive to consider delaying, resisting or hoping another healthcare system will front the cost of the life-changing gene therapy.

That’s not the only business challenge for gene therapy developers. Companies who develop new therapies for rare genetic diseases capture near-term revenues by treating the existing patient population. Once those people get their one-time therapy, longer term revenues are mainly driven by the incident patient population – the number of patients who are born and/or are newly-diagnosed each year. The nature of some rare diseases means that pool can become quite small over time.

For larger companies looking for multi-billion dollar products to replace the franchise products losing patent protection,  a single gene therapy addressing a rare disease is unlikely to produce the investment math needed to become another Keytruda. This can temper interest from some of the larger pharma players, limiting the pool of buyers for programs and companies, cooling the market in turn.

The peak of elevated expectations

Early expectations were buoyed by the success of the first gene therapy approved for Spinal Muscular Atrophy (SMA), Novartis’ onasemnogene abeparvovec-xioi (Zolgensma). With the potential to deliver transformative benefit to young children with a crippling and deadly condition, Zolgensma is on track to exceed $1 billion in revenue for a sixth consecutive year.

Investors who hoped to bet on the next Zolgensma have been left wanting. The most oft-cited cautionary examples are gene therapies for Hemophilia A and B that have fallen far short of their pre-launch expectations.

As humans we reach for simple explanations to make sense of a complex world. “Well SMA was the outlier and hemophilia is the norm”. The complicated truth of the matter is that one needs to dig deeper to unearth the success factors behind a commercial launch.

Hemophilia is complicated by strong injectable biologic competitors that serve the needs of many patients. A one-time treatment also challenges the economic incentives at US infusion centers. Patients are often hesitant to switch.

Compare and contrast this situation with Sarepta Therapeutics’ delandistrogene moxeparvovec-rokl (Elevidys) for Duchenne Muscular Dystrophy (DMD). The one-time gene therapy was introduced to the market in 2023. The initial sales trajectory was strong – demonstrating that a combination of a motivated community living with a significant unmet medical need, urgency to treat and support of payors who saw value in intervention came together in spite of concerns about whether Duchenne families would hold off treatment in favor of next-generation offerings.

In 2025 two deaths of wheelchair-bound DMD patients who developed acute liver failure after treatment temporarily halted dosing of the drug and limited the eligible patient population. The product’s withdrawal, new boxed warning, and re-introduction to the US market made headlines. Fewer people noticed a more encouraging development that happened in parallel. Sarepta’s partner outside the US, Roche, reported over $200 million in ex-US sales for the first half of 2026, despite lacking an approved Marketing Authorisation Application (MAA) in the European Union. That reinforces the significant commercial potential that exists beyond the US.

To frame this differently, the modality does not predetermine commercial success or failure, rather it’s the needs of the community and the assessment of value in treatment that determines commercial success. (See the Alliance for Regenerative Medicine’s excellent 2026 ARM State of the Industry deck for more on this point).

So, if we buy into the thesis that new product rollouts in AAV gene therapy CAN be successful, then what other factors need to be in play to turn “can be successful” into “are successful”?

The risk/benefit balance

Fatalities in clinical trials or in the marketplace should never be overlooked or trivialized. For AAV gene therapies, there has long been an intense focus on safety dating back to 1999 and the Jesse Gelsinger tragedy.

By now, an expanding body of evidence suggests  these fatalities have not been completely random, but rather stem from a constellation of factors that are discreet and may well be addressable.

Emerging consensus centers on factors such as total viral vector dose, immune response/immune suppression regimen, patient or disease specific factors such deletions of exons 8 or 9 in DMD, or pre-existing hepatobiliary disease in X-linked Myotubular Myopathy, and potential product quality attributes.

The gene therapy field has been taking important steps to understand how to avoid exposing patients to risks that may exceed benefits and finding ways to create potentially safer and more effective treatments.

Next-generation gene therapies for DMD employing engineered capsids appear to be effectively de-targeting the liver, while delivering strong transduction in skeletal and smooth muscle where you want the gene expressed. Proficiency with localized delivery and increased tissue selectivity to address regions of the CNS, the heart and other organs has reduced the amount of viral vector needed. Scientists can now accurately express just the right amount of the MECP2 protein on a cell-by-cell basis in patients living with Rett Syndrome without over-expression that drives toxicity.

We’re seeing the emergence of a second wave of AAV approaches achieve clinical proof of concept. While it would be premature to we have solved all safety challenges, it’s also inappropriate to write the field off as unsafe .

On the “benefit” side, we are witnessing a steady stream of clinical data. In addition to those conditions cited above, we’re seeing unprecedented effects in diseases as diverse as Limb Girdle Muscular Dystrophies, Dravet Syndrome, OTOF-related hearing loss, X-linked retinitis pigmentosa, Huntington’s disease, Friedreich Ataxia, and many more.

Are all these programs perfect? No. But that’s not the point. The takeaway is that gene therapy is chipping away at previously intractable conditions.

Regulatory uncertainty – becoming more certain?

Much has been written about the changing times at FDA, in the Center for Biologics Evaluation and Research (CBER) and the Office of Therapeutic Products (OTP), that have directly impacted the cell and gene therapy sector. Contrary to the perception that companies are looking for more permissive regulation; consistency and predictability are typically the most important factors most CEOs seek.

Adaptability to the specific requirements of each indication can be critical here as well. Not all conditions are suitable for double-blind placebo or sham-controlled studies; not all diseases have robust natural history data available for use as a comparator.  If a pathway is agreed to by regulators one year and a regulator reverses course the following year, how will any management team invest the resources necessary to complete a development program in support of a new medicine?

Consider the case of Uniqure. The company received notably conflicting advice on potential pathways to approval during a series of leadership changes at FDA resulting in wild swings in their stock price and market perception. The company  has recently aligned on a path to filing a Biologics License Application to market its gene therapy for Huntington’s Disease in the US. The recent appointment of Karim Mikhail as director of CBER along with  gene therapy approvals in Glycogen Storage Disease 1a, Sanfilippo Syndrome type A (MPSIIIA) bode well for the field.

Regulatory uncertainty is not restricted to the United States – differing evidentiary requirements on either side of the Atlantic can further complicate matters. However, encouraging signs are emerging in 2026 as we are seeing the FDA stand by some of its prior commitments and just this week the agency released a new white paper and initiative to create a new framework for rare disease review.

If the FDA follows through and clears some of the new products for sale based on prior guidance, then it’s critical that that companies seize the opportunity to demonstrate the commercial potential of these new medicines. Eventually, that will persuade investors to come back in large numbers. One last factor has been the recent strength of the marketplace for the Priority Review Voucher program, set up to incentivize investment in R&D for rare pediatric diseases. Per the RTW Institute PRV tracker there have been 9 PRV sales in 2026 alone (including the two recent voucher sales by Ultragenyx) all at around the $200 million per voucher mark. Three of these sales have gone to developers of AAV gene therapies, proving an additional much-needed incentive for the rare disease space.

The prognosis

So, having faced the brutal reality, do I have faith that we will prevail in the AAV field? Yes. I do. It may not be exactly in the manner we’ve become accustomed to in other fields and with other modalities, but the preponderance of breakthroughs seen in patients combined with a clearer view of what commercial factors may be needed for the next successful therapy lead me to conclude that we have a strong chance.

7
Oct
2026

Touch, Pain, and the Edge of Neuroscience: Ardem Patapoutian on The Long Run

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07 Oct 2026

Ardem Patapoutian is today’s guest on The Long Run.

Ardem is a professor of neuroscience at Scripps Research in San Diego, and an investigator with Howard Hughes Medical Institute. His lab is focused on ion channels on the surface of cells that sense mechanical force, and how those signals are translated into our sense of touch, pain, and other basic bodily functions.

Ardem Patapoutian, professor, Scripps Research

This curiosity driven work in the peripheral nervous system led Ardem down a path to where he was eventually recognized with the Nobel Prize in 2021. It was for the discovery of PIEZO1 and PIEZO2, a couple of ion channels. Genetic studies established that PIEZO2 is the main mechanical transducer for touch, and proprioception (our sense of where our body is in physical space without having to look) among other things. PIEZO1 is now known to mediate our sense of blood-flow, which impacts blood pressure regulation and the development of blood vessels.

This field of discovery has significant implications for many areas of medicine. Listeners may be aware that another ion channel discovery, for Nav1.8, led Vertex Pharmaceuticals to successfully develop a pain reliever that acts in the peripheral nervous system and avoids addiction pathways in the brain. That line of inquiry into peripheral ion channels is closely related to the kind of basic curiosity-driven research done in labs like Ardem’s at Scripps Research.

Like many great American scientists, Ardem is an immigrant to this country. He grew up in Lebanon and is of Armenian heritage. His life story is inspiring. It offers an example of how America can bring out the best in people, and how we can be a beacon to the world.

The Long Run is sponsored by AlphaSense

So far 2026 has been a year of transition for healthcare and life sciences. Over the first half of this year, the AlphaSense healthcare research team analyzed the individual stories moving the needle across the life sciences ecosystem as part of the Sector Spotlight series. They feature the high-stakes battles for new drug markets (like oral GLP-1s and targeted radioligand therapies), a resurgent biotech IPO market, and more.

Follow the sector’s key debates during 2H26 and beyond, with the latest Sector Spotlights directly in AlphaSense.

 

Quick question: when was the last time a CRO told you what something costs before you signed an NDA, sat through two scoping calls, and waited a week for a Scope of Work? In bioanalysis, pricing gets treated like a closely-guarded secret. Dash Bio thinks that’s backward. It publishes pricing publicly, on its website, and even has a calculator that shows how the price changes if you redesign your study. You can see what your study costs before you talk to a human being. No surprise line items, no “it depends”, no games. Dash was built to be the bioanalysis company that’s actually straightforward to work with: transparent pricing, guaranteed timelines, and data in days, not months.

If you’re tired of pricing that feels like a negotiation every single time, run your bioanalysis with Dash. Visit dash.bio/pricing and see exactly how much your next bioanalysis study will cost.

 

 

Now please enjoy this conversation with Ardem Patapoutian on The Long Run.

23
Sep
2026

Long-Lasting Antibodies for Immune Diseases: Cameron Turtle on The Long Run

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23 Sep 2026

Cameron Turtle is today’s guest on The Long Run.

Cameron Turtle, CEO, Spyre Therapeutics

Cameron is the CEO of Waltham, Mass.-based Spyre Therapeutics. The company is developing antibody drug candidates that are engineered to be longer-lasting than today’s drugs for immune disorders.

This means patients could take fewer injections and the drugs should stay stable in the bloodstream to keep the disease under control longer. Crucially, it opens the door for combinations of antibodies that could raise the bar on efficacy higher than any single drug can do for immune disorders and do it in a relatively straightforward treatment regimen that patients can stick with.

Spyre was spun out in 2023 from an antibody discovery shop called Paragon Therapeutics, which itself was founded by Fairmount Funds, a hedge fund, in 2021. The team created a set of antibody drug candidates against targets that are well-validated by others in clinical trials, and which represents a series of billion-dollar opportunities. Spyre’s portfolio includes antibodies aimed at alpha4 beta7, TL1A, and the p19 subunit of IL-23.

They are being tested as single agents and in combinations to tamp down excessive inflammation in patients with inflammatory bowel disease.

Investors like the company’s prospects. Spyre had $1.1 billion in cash at the time of this recording to fund a wide-ranging clinical development program. Its current market valuation is about $8 billion.

The Long Run is sponsored by AlphaSense.

So far 2026 has been a year of transition for healthcare and life sciences. Over the first half of this year, the AlphaSense healthcare research team analyzed the individual stories moving the needle across the life sciences ecosystem as part of the Sector Spotlight series. They feature the high-stakes battles for new drug markets (like oral GLP-1s and targeted radioligand therapies), a resurgent biotech IPO market, and more.

Follow the sector’s key debates during 2H26 and beyond, with the latest Sector Spotlights directly in AlphaSense.

 

Quick question: when was the last time a CRO told you what something costs before you signed an NDA, sat through two scoping calls, and waited a week for a Scope of Work? In bioanalysis, pricing gets treated like a closely-guarded secret. Dash Bio thinks that’s backward. It publishes pricing publicly, on its website, and even has a calculator that shows how the price changes if you redesign your study. You can see what your study costs before you talk to a human being. No surprise line items, no “it depends”, no games. Dash was built to be the bioanalysis company that’s actually straightforward to work with: transparent pricing, guaranteed timelines, and data in days, not months.

If you’re tired of pricing that feels like a negotiation every single time, run your bioanalysis with Dash. Visit dash.bio/pricing and see exactly how much your next bioanalysis study will cost.

 

Now please enjoy this conversation with Cameron Turtle on The Long Run.

9
Sep
2026

Drugs That Go Where None Could Before: Mathai Mammen on The Long Run

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09 Sep 2026

Mathai Mammen is today’s guest on The Long Run.

Mathai is the CEO of Cambridge, Mass.-based Parabilis Medicines. The company has a platform for making drugs that hit elusive biological targets known as drivers of disease. Parabilis attacks them with alpha-helical peptide drug candidates that can get inside cells and bind with relatively flat and smooth surfaces of proteins. It pursues these targets which conventional small molecules and biologics haven’t been able to hit.

Mathai Mammen, chairman, president and CEO, Parabilis Medicines

The initial application of this technology is for a drug candidate against the beta-catenin and TCF complex. This first-of-its-kind drug candidate, zolucatetide, is being evaluated in clinical trials for desmoid tumors and a couple other rare diseases. Beta-catenin is implicated in an estimated 10 percent of all cancers, which means this drug has broad potential.

Parabilis went public earlier in 2026, raising $770 million for its drug development programs. It’s the largest IPO ever for a venture-backed biotech company. The idea is to begin with zolucatetide, but also expand Parabilis’ R&D portfolio with other alpha-helical peptides to hit historically undruggable targets that are important drivers of disease.

Mathai came to this role after a long career as a scientific entrepreneur at Theravance, followed by top leadership jobs in large pharma at Merck and Johnson & Johnson. He and his family have endured personal tragedy. That’s part of what focuses him on the human dimension of the biotech industry. Success can be defined many ways, but one clear way is by providing patients and their families more years of quality time together. 

The Long Run is sponsored by

 

 

So far 2026 has been a year of transition for healthcare and life sciences. Over the first half of this year, the AlphaSense healthcare research team analyzed the individual stories moving the needle across the life sciences ecosystem as part of the Sector Spotlight series. They feature the high-stakes battles for new drug markets (like oral GLP-1s and targeted radioligand therapies), a resurgent biotech IPO market, and more.

Follow the sector’s key debates during 2H26 and beyond, with the latest Sector Spotlights.

 

Quick question: when was the last time a CRO told you what something costs before you signed an NDA, sat through two scoping calls, and waited a week for a Scope of Work? In bioanalysis, pricing gets treated like a closely-guarded secret. Dash Bio thinks that’s backward. It publishes pricing publicly, on its website, and even has a calculator that shows how the price changes if you redesign your study. You can see what your study costs before you talk to a human being. No surprise line items, no “it depends”, no games. Dash was built to be the bioanalysis company that’s actually straightforward to work with: transparent pricing, guaranteed timelines, and data in days, not months.

If you’re tired of pricing that feels like a negotiation every single time, run your bioanalysis with Dash. Visit dash.bio/pricing and see exactly how much your next bioanalysis study will cost.

 

 

Now please enjoy this conversation with Mathai Mammen on The Long Run.

3
Sep
2026

IYKYK: Leave the Vortex, Take the Influence

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03 Sep 2026

David Shaywitz

It’s not just your kids who aspire to become influencers. Attracting attention –- often through provocative content delivered through social media at high volume –- can seem increasingly like a business imperative, as the a16z co-founders have described (here, here) and, in the case of Andreessen, unhesitatingly embraced.

The Attention Imperative

But they’re not alone; many physicians, researchers, and policy wonks are gamely experimenting with short video content. A top health reporter and print journalist somewhat sheepishly confessed to me that she was “going to try making some short videos this fall — if you can’t beat ‘em….”

I’ve also spoken with prospective writers who want to discuss with me ideas they have for books they’re contemplating. They’ve passed on the remarkable (or perhaps not so remarkable) feedback that they seem to be receiving from agents and editors -– namely that while of course the quality of ideas still matter, publishers (ultimately) also are keenly interested in the size of your audience –- number of followers, what popular podcasts you can get booked on, etc.

You can see the principle of accumulated advantage –- the rich get richer –- playing out before your eyes, and recognize that beyond emotional neediness, there is also real economic value at stake in getting noticed, especially given the centrality of algorithms that select for activating content.

Yet in this age of escalating bombast, I’ve been encouraged by several recent examples of healthcare leaders who have demonstrated through understated personal example that there’s another way.

Curious, Not Reactive

The first is an approach I was reminded of by two distinct examples this week, involving leaders in different organizations in disparate regions of the country. In both cases, a thoughtful piece of original content from the leader had triggered an outsized reply, and the executive was faced with a choice of how to respond.

Rather than follow the contemporary playbook and fight fire with fire, both leaders elected to reply with thoughtful, considered responses, pushing back against points they disagreed in a calm and composed fashion.

The insight for me wasn’t the public response -– probably what many PR firms might advise, or at least (according to a16z) the old-school ones -– but rather the private rationale.

After acknowledging that the provocateur in question was “built for the attention economy,” one leader explained to me, “I usually find that I learn something from him, even when I disagree, and that he’s more often a force for good than the converse,” adding, “Doesn’t mean he’s always right — he’s not.”

The ability to approach (at least some) attention-seekers with genuine curiosity, and a true desire to learn, seem to have allowed both of these leaders to respond thoughtfully rather than reactively, maintaining dignity and credibility in a way that might not win the day’s X exchange, but was clearly recognized and appreciated by those who had observed it.

Not Confusing Heat With Light

The extent to which many of us have been so distracted by the drama of social media that we’re forgetting how distorting it can be was highlighted in a wonderful recent walk-and-talk around the Charles with a phenomenally successful –- and relatively low-profile –- biopharma leader I’ve known for some time.

In our conversation, he was describing his experiences to me in what seems like an unusually eventful and remarkably productive year, marked by financing, transactions, and encouraging regulatory engagement. Along the way, he told me, he received lots of advice and benefited from much of it.

But what really struck him, he said, was how many of the most impactful and powerful people in the biopharma system with whom he interacted were people like himself, with little or no social media presence, but whose credibility on the basis of experience, connections, capital, and insight nevertheless had turned them into –- well -– influencers. They’re not in the headlines, they’re not engaged in the latest X spat, but they contribute disproportionately to the shape and success of the industry. They are the people for whom the phrase IYKYK (if you know, you know) seems to have been invented.

Bottom Line

The bottom line is that you don’t have to descend into the social media maelstrom to exert influence in health and medicine. True, a few seem to have dived in and emerged not just unscathed but elevated, enhancing their careers while maintaining their credibility. Scott Gottlieb and Eric Topol both come to mind here — largely, in my mind, on the enduring strength of their publications and longer essays.

Yet for each Gottlieb and Topol there seem to be so many others desperately seeking attention, with cringy content that is gratuitously provocative, AI-generated, and frequently both.

The good news is there’s another way –- and we can pursue it by prioritizing quality in our work, authenticity in our interactions, and approaching provocateurs with curiosity, a judo move that allows us to extract the insight and sidestep the distraction.

It’s what many of our industry’s most effective leaders have been doing -– quietly -– for years.

25
Aug
2026

A Vaccine for Epstein-Barr Virus: Gary Nabel on The Long Run

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25 Aug 2026

Gary Nabel is today’s guest on The Long Run.

Gary is the CEO of Weston, Mass.-based ModeX Therapeutics. The company has a platform for making multi-specific biologics into vaccines and cancer treatments. ModeX was founded in 2020, building on work that started at Sanofi when Nabel was the chief scientific officer there.

Gary Nabel, co-founder and CEO, ModeX Therapeutics

The initial application of this technology, currently in clinical trials, is for a vaccine against Epstein-Barr Virus. This virus is known to cause infectious mononucleosis, a disease that comes with flu-like symptoms that can last weeks or months. But what has become clearer in recent years is that EBV, which lays dormant in most adults, can be reactivated later in life and cause a lot of other problems. EBV is implicated as a culprit in several types of cancer, multiple sclerosis, and autoimmune diseases.

There is no vaccine against the virus, and the ModeX candidate still has a long way to go. But if ModeX and its partner, Merck. are successful, it could theoretically prevent a lot of debilitating chronic diseases. ModeX is using the same technology toolkit to spur an immune response against cancer and to treat or prevent COVID-19. 

There’s a fascinating story here about how deeper understanding of the biology of EBV infections, and the expanding capabilities in the antibody engineering toolkit, have led us to this point of possibility. Gary’s career, starting as a virologist, then taking senior scientific positions at the NIH and Sanofi, has ended up leading down this very interesting startup path.

The Long Run is sponsored by AlphaSense.

So far 2026 has been a year of transition for healthcare and life sciences. Over the first half of this year, the AlphaSense healthcare research team analyzed the individual stories moving the needle across the life sciences ecosystem as part of the Sector Spotlight series. The eight spotlights can be downloaded here. They featuring the high-stakes battles for new drug markets (like oral GLP-1s and targeted radioligand therapies), a resurgent biotech IPO market, and more.

Follow the sector’s key debates during 2H26 and beyond, with the latest Sector Spotlights directly in AlphaSense.

AND

Quick question: when was the last time a CRO told you what something costs before you signed an NDA, sat through two scoping calls, and waited a week for a Scope of Work? In bioanalysis, pricing gets treated like a closely-guarded secret. Dash Bio thinks that’s backward. It publishes pricing publicly, on its website, and even has a calculator that shows how the price changes if you redesign your study. You can see what your study costs before you talk to a human being. No surprise line items, no “it depends”, no games. Dash was built to be the bioanalysis company that’s actually straightforward to work with: transparent pricing, guaranteed timelines, and data in days, not months.

If you’re tired of pricing that feels like a negotiation every single time, run your bioanalysis with Dash.

Visit dash.bio/pricing and see exactly how much your next bioanalysis study will cost.

 

Now please enjoy this conversation with Gary Nabel on The Long Run.

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