21
Feb
2024

Joy, Gratitude and Next Steps for Timmerman Traverse

Luke Timmerman, founder & editor, Timmerman Report

Reporting this morning from Tanzania.

I’m feeling joyful and grateful.

My latest biotech team wrapped up another $1 million Timmerman Traverse fundraising campaign for the Damon Runyon Cancer Research Foundation. All 20 members of the team reached the summit of Kilimanjaro, the highest peak in Africa at 19,341 feet.

We raised awareness of Damon Runyon’s national network of brilliant, brave and bold young scientists. We raised significant funds to support them. We forged meaningful friendships on the trail.

We cried. We laughed. We sang. We danced. We hugged. We marveled at the night stars. We were in awe of the strength and hospitality of our Tanzanian hosts.

Some people faced challenges on the trail like never before. Many had to dig deep. 

These mountaineering programs have now catalyzed the biotech community to give back $8.9 million since 2017. More than 120 people have accepted the challenge and participated in these experiences around the world. About 10,000 people have given at least once to one of these campaigns. Many people are giving over and over. 

The Timmerman Traverse campaigns are tapping into something deep and meaningful.

The desire to give back to those who are less fortunate.

The desire for physical challenges.

The desire to experience natural beauty.

The desire to form strong, lasting friendships.

Ultimately, it’s about being part of something much bigger than one’s self.

I’m feeling the fire in the belly. I’m hungry to make an even bigger impact. This campaign with Damon Runyon Cancer Research Foundation is the start of a big year. 

This year, I’m challenging myself to step up to a new level, leading not just one, but *two* more biotech community expeditions for worthy causes.

The first is the Timmerman Traverse for Life Science Cares. That team is fully recruited and preparing for a magnificent pair of day hikes in the Pacific Northwest in August.

This team will raise $1 million to fight poverty in the United States. This program is now entering its fourth year and has already raised more than $3 million to fight poverty in the US since 2021. I’m proud of the impact this program has had, and the ripple effect it is having.

This program has already given birth to an initiative that’s creating 1,000 biotech industry internships for young people from underrepresented minority groups around the US. And we’re still in the early days. Watch for an announcement of the Timmerman Traverse for Life Science Cares 2024 team in March.

The second expedition is the Timmerman Traverse for Sickle Forward. This team will go back to Kilimanjaro in September, in conjunction with National Sickle Cell Awareness Month.

This will be another $1 million campaign to raise funds to expand newborn screening of sickle cell disease in Africa. Newborn screening can prompt the kinds of early interventions that save lives. We’re talking about catching sickle cell early, so infants can go on prophylactic antibiotics, anti-malarial medications, or have access to cheap, generic hydroxyurea. These are practical interventions in low-resource settings.

We also have a partner willing to make a $1-for-$1 match to amplify sickle cell research in the United States. That means this campaign has the potential to raise $2 million to fight sickle cell disease and uplift people around the world with this long-neglected malady.

I’m not doing this alone. As the old African proverb says, if you want to go fast, go alone; if you want to go far, go with a group.

This campaign for Sickle Forward is being led by three co-chairs.

  • Luke Timmerman, founder and editor, Timmerman Report; 3-time summiteer of Kilimanjaro and climber of 6 of the 7 summits.

    Ted Love, chairman, BIO

  • Ted Love, chairman of the board, BIO; former CEO of Global Blood Therapeutics, developer of novel treatments for sickle cell disease.
  • Alan Anderson, physician-scientist, medical director of the Comprehensive Lifespan Sickle Cell Disease Program, PRISMA Health in Greenville, South Carolina; Executive Director, Sickle Forward

All three of us will climb Kilimanjaro with the full team in September.

It’s important to add that Eric Murphy will be with us. Eric, the lead guide for Alpine Ascents International on Kilimanjaro, has worked with me on all three campaigns on Kilimanjaro since 2019, plus another trek to Everest Base Camp.

His unparalleled knowledge of the mountains, clear communication, patience, and trusting partnership with local guides and crew are what make these large-scale expeditions possible. He’s a great friend. 

Alan Anderson, physician-scientist; founder, Sickle Forward

My task now is to recruit a few fellow sickle cell disease warriors from the biotech community.

If you — or your company — is willing to step up and make a major contribution to help children in Africa live longer and healthier lives, please see me or Ted or Alan.

I can provide you with an invitation with all the details to get started.

Let’s show the world we can come together and take action against poverty and health disparities.

luke@timmermanreport.com

 

20
Feb
2024

Timmerman Traverse for Damon Runyon, Kilimanjaro 2024 Photo Gallery

The Timmerman Traverse for Damon Runyon Cancer Research Foundation is in the books.

We have raised about $1.1 million for this national network of brilliant, brave and bold young scientists. 

All 20 members of the team made it to the summit of Kilimanjaro, the highest peak in Africa, at 19,341 feet. 

It’s an experience none of us will ever forget. 

We had some rainy days, some sunny days, and truly stellar night skies. We were lucky to have picture-perfect weather on summit day. We marveled at the changing landscape, from the forest zone, to the heather and morland, to the alpine desert at higher elevation. 

Team Roster 

Enjoy the photos

CLICK to ENLARGE

17
Feb
2024

New Medical Podcast (Like Winter and the 2024 Red Sox) Offers Bleak Outlook, While Four Books Instill Hope

David Shaywitz

As Bostonians tentatively emerge from the bleak cold of another New England winter and begin to search for signs of spring, we instinctively turn to the Red Sox. 

Unfortunately, I am informed by my daughters that the team’s prospects appear dismal this season, so we’ll need to look elsewhere for hope.

We might consider instead Boston’s other great preoccupation: biomedical science. 

Here, our prospects are better. I’ll tell you about three recent books, and one forthcoming one, that highlight the promise of medical innovation, and emphasize the urgent need for more rapid progress.

But before we get there, to remind us that we still are in the middle of winter, a few words on a medical podcast that offers a chilly, somewhat grey and gloomy take on medical training and the muted expectations of future clinicians.

“Not Otherwise Specified” podcast, Season 2; Dr. Lisa Rosenbaum, host

Most practicing clinicians I know seem unhappy about both their work and the direction medicine appears to be heading. Common complaints are that medicine has become more bureaucratic, detached, and “corporate” than they hoped and expected when they went through medical school.

Lisa Rosenbaum, MD; host of “Not Otherwise Specified.”

This dissatisfaction is palpable even (perhaps especially) at the trainee level. Many interns and residents have come to regard medicine as a job, rather than as a calling, as was perhaps the case for previous generations.  In fact, some suggest that the idea of medicine as a “calling” represents an insidious corporate ruse, designed to justify the extraction of cheap labor.

In a compelling new season of the New England Journal of Medicine (NEJM) podcast, “Not Otherwise Specified,” Lisa Rosenbaum, a cardiologist and contributor at the NEJM, has tackled this delicate topic with the nuance and empathy that have long characterized her work. You can find the trailer here and follow along.

Through a series of revealing interviews, Rosenbaum explores evolving perspectives on medical training. She discusses the outsized impact of COVID on trainees, who seem to have been pressed into intensive service while many senior physicians and hospital administrators provided nominal oversight from the safety of home – an experience that indelibly scarred and understandably soured many young doctors.

Rosenbaum also explores the difficulty experienced by medical educators as they try to figure out the evolving relationship with trainees, whose expectations for a comfortable and conducive environment can conflict with the intense immersion many educators believe is critical for both learning and successfully transitioning to the real-world practice of medicine.

Educators, according to the podcast, are increasingly wary — if not terrified — of criticism through either social media or satisfaction surveys. Social media has the potential to tarnish the reputation of the institution, while poor marks on satisfaction surveys can interfere with accreditation and cost program administrators their jobs. 

Indeed, medical educators are so concerned about being called out that Rosenbaum was nearly unable to find anyone to speak on the record.  This fear of professional cancellation evocates the difficulties of challenging emerging orthodoxies that writers such as John McWhorter, Yascha Mounk, Jonathan Haidt, Bari Weiss and others have thoughtfully examined.

What emerges from Rosenbaum’s podcast is a sense that many young doctors feel like they aren’t so much being trained as they are being taken advantage of by a cynical system.  Meanwhile, many educators struggle with the concern that trainees are unduly fragile, are not being adequately trained, and seem content with a less visionary (or alternatively: more grounded) view of what it means to be a doctor. 

Put another way, many young doctors view medicine is a job, a way to earn a relatively comfortable living. Like other employees, they seek work/life balance, and satisfaction outside the daily grind of demanding patients, endless documentation, and daily disputes with payors

Whether this represents an advance for healthcare, because doctors appropriately have been brought back down to earth, or a setback, because the transcendent aspect of the mission has been lost, remains to be seen.

(My perspective on work/life balance and finding joy in your work rather than exclusively outside of it, here.)

Chasing My Cure, by David Fajgenbaum

If Rosenbaum’s podcast describes where the average doctor is headed, David Fajgenbaum’s “Chasing My Cure,” published in 2019 (I listened to the audiobook, narrated by the author), reminds us of the promise and possibility of medicine at its most outrageously ambitious.  A high school athlete and then quarterback at Georgetown University, Fajgenbaum was drawn to medicine, specifically oncology, following the death of his mother from brain cancer while he was a sophomore in college.

David Fajgenbaum, MD, associate professor of medicine, University of Pennsylvania

Fajgenbaum started medical school at the University of Pennsylvania, but soon found himself dealing with a collection of rapidly worsening symptoms – fatigue, swollen lymph nodes, and then multi-organ failure – that sent him to the ICU and initiated a long diagnostic odyssey.

Eventually, he was diagnosed with Castleman Disease, a rare, devastating lymphoproliferative disorder that was (and unfortunately remains) poorly understood. It seems to be associated with persistently elevated cytokines, often including IL-6. Fajgenbaum found himself on the brink of death multiple times (he was even administered last rites) as he perilously ricocheted between relapse and remission, from severe illness to tentative recovery.

Fajgenbaum also found a new career purpose. When he realized that no one really understood the disease that was trying persistently to kill him, he resolved to approach it scientifically, and coordinate the required foundational work himself. He organized the Castleman Disease Collaborative Network (CDCN) and attended business school to learn the best way to build innovative organizations. He also established a systematic method to diagnose Castleman Disease, successfully fought for a diagnostic code for the illness, and methodically collected samples from patients with the disease, including himself.

The initial therapies he tried – anti-IL-6 antibodies, intense chemotherapy – didn’t deliver sustained remissions. As he reviewed the data from collected blood samples, including his own, he hypothesized that in his cells, the mTOR signaling pathway might be overactive. That led him to try rapamycin (sirolimus) to see if it might help tamp down his persistently elevated levels of inflammatory cytokines. 

The result was extraordinary. Before starting on the medicine, Fajgenbaum experienced horrific relapses every nine months or so. Since he started on sirolimus, he’s been relapse-free – for 10 years and counting.

Motivated by this experience, Fajgenbaum, now a physician on staff at the University of Pennsylvania, created an organization called Every Cure. It’s an effort to systematize drug repurposing, with the view that existing drugs might be useful for some of the many patients suffering from conditions, especially rare conditions, for which there’s no treatment.

Fajgenbaum’s book also highlights the complexity of research; while anti-IL-6 antibodies help some Castleman patients, they didn’t help him. Meanwhile, sirolimus, a medicine that transformed his life, sadly wasn’t helpful for some other patients with the disease.

Fajgenbaum exemplifies perhaps the ultimate example of the purpose-driven life, drawn to medicine by the explicit intention to avenge his mother’s death. Over time, his motivation expanded to leveraging biomedical science to defeat Castleman disease, and beyond that, to helping other patients find existing medicines that might help them.

For Fajgenbaum, from the beginning, medicine has always been a calling.

To repurpose the words of Senator Ted Kennedy in 1980: “The work goes on, the cause endures, the hope still lives, and the dream shall never die.”

We the Scientists, by Amy Dockser Marcus

Amy Marcus is a brilliant and unusually sensitive reporter at the Wall Street Journal who covers biomedicine from the perspective of patients. Her latest book (published February 2023; I listened to the audiobook) offers a moving account of the efforts by parents of children afflicted with the fatal lysosomal storage disease Niemann-Pick type C (NPC) to catalyze research into their children’s condition.

Amy Dockser Marcus, author, “We the Scientists.”

Marcus poignantly contrasts the desperate urgency of NPC parents with the more deliberate pace of traditional science and focuses on the parents’ efforts to become “citizen-scientists” to accelerate the development of scientific understanding and potential treatments. 

We learn, sadly, that in even the most motivated hands, science and the pursuit of cures can be incredibly frustrating and disappointing, the process stuttering and often divisive.  The challenge of simply willing a cure into being is likely to feel all too familiar to many other patients and advocates, although hopefully, advances in both science and its democratization, as Marcus describes, will lead to the progress that patients urgently require, and families so urgently seek.   

Gene Machine, by Venki Ramakrishnan

With the classic exception of James Watson’s The Double Helix, scientific autobiographies tend to offer a gauzy, somewhat airbrushed account of the author’s personal story and scientific insights, a stylized rendition of the hero’s journey. Jennifer Doudna’s A Crack in Creation, published in 2017, is an example of this archetype.

Venki Ramakrishnan, Nobel Prize-winning structural biologist

In the words of Marcus, who reviewed it for the Wall Street Journal, Doudna (who shared the Nobel Prize in 2020 for her pioneering work on CRISPR) “offers little insight into how the human side of science—fights over credit, the potential for profit, a desire for recognition—may affect the presentation or analysis of data.”

In Gene Machine (2018; again, I listened to the audiobook), Venki Ramakrishnan – who shared the 2009 Nobel Prize for his work on the structure of RNA – affords us at least a glimpse into the human drama as shares the story of his career, emphasizing the many turns of fortune that led to his eventual prize-winning work. 

While not as brazen as Watson (famous for sentences such as “I have never seen Francis Crick in a modest mood”), Ramakrishnan discusses his insecurities about recognition, his irritation with other researchers, his initially reluctant but ultimately impassioned campaign for the Nobel, and his view of prizes in general – particularly the seemingly arbitrary and outdated criteria associated with how they are often awarded. 

His depiction of top researchers as frenemies engaged in intense “coopetition” as they build upon each other’s work while aggressively seeking to be the first to uncover an important insight will ring true to – and potentially trigger – anyone who’s spent time in the lab.

Race for a Remedy by Makhdum Ahmed

I was given the opportunity by Makhdum Ahmed – a physician-scientist and drug developer – to preview his first book, Race for a Remedy, due to be published this summer. Ahmed nicely integrates his own journey from academic physician-scientist to industry researcher with the story of several important emerging technologies he’s had a chance to explore: small molecule oncology drugs, cell therapies, and most recently, bispecific T-cell engagers.

Makhdum Ahmed, physician-scientist-drug developer-author

The last approach, he says, provides an especially promising opportunity to “harness the power of T-cells (and other immune cells) without the need to extract, genetically engineer, and re-infuse a T-cell with the same end result, that is, killing off the enemy, the tumor cells, efficiently.” 

He blends in a dash of medical history and a dollop of his own experiences – enough of each to emphasize both the promise and the limitations of emerging technologies. To his credit, he doesn’t shy away from discussing examples of programs he worked on that didn’t pan out.  While his prose is less ornate than that of authors like Sid Mukherjee (my WSJ review of Song of the Cell here), Ahmed’s description of his experiences are immediately relatable, and we can’t help but root for his future success.

PS

Readers interested in medical history might also enjoy Death to Beauty, an account of the discovery of Botox and its development as a pharmacological therapy – initially for the eye disorder strabismus. My WSJ review here, with additional, biotech-focused discussion and an emphasis on the concept of field discovery at TR, here.

9
Feb
2024

Botox: A Luminous Example of Field Discovery

David Shaywitz

In this weekend’s Wall Street Journal, I review Death To Beauty, a new book by Dr. Eugene Helveston. It’s about the fascinating history of botulinum toxin and the California ophthalmologist, Alan Scott, who drove it into clinical use.

The book review, of course, speaks for itself, but I wanted to highlight for TR readers an aspect of the story that seems especially relevant for biopharma colleagues: the importance of field discovery.

MIT professor Eric von Hippel developed and championed the concept of field discovery as an underappreciated source of innovation. As von Hippel describes it, field discovery emphasizes the role of users, rather than manufacturers, in identifying relevant uses for technology.

He writes,

“Innovation process scholars have assumed that product manufacturers would be the developers of all or most new products. However, empiric research during the past two decades has shown that product users rather than manufacturers are the actual developers of many of the commercially important new products and new product applications in fields studied to date.”

This description is from a 2012 paper he wrote highlighting the role of clinicians in identifying important off-label uses for drugs. In his study, it was clinicians (not pharma companies) who originally identified the majority of off-label uses for medicines.

The importance of field discovery driven by so-called “lead users” as critical drivers of innovation is likely familiar to long-time readers (see here, here, here, here and references therein).  

This framework highlights specifically the value of inquisitive practitioners in drug discovery, and more generally the need for front-line users to pull through and refine new technology in order to more fully capture its value.

Joseph Goldstein, Distinguished Chair in Biomedical Research; UT Southwestern

Since ancient times, of course, the medicinal use of natural products such as aloe and willow bark derived from astute observation. Even in the modern era, many drugs and drug classes, especially in neuroscience, were developed by following up a clinical observation. Legendary physician-scientists Judah Folkman (as I’ve discussed here), Michael Brown, and Joseph Goldstein (see here), have repeatedly emphasized the critical importance of inquisitive clinicians.

The role of astute observation in biopharmaceutical drug development is perhaps most famously exemplified through the story of sildenafil (Viagra), a vasodilator originally developed by Pfizer for the treatment of chest pain. However, an alert study nurse noticing that the young male phase 1 subjects tended to lie on their front to preserve their modesty alerted researchers to an alternative indication (see here, and also this podcast hosted by Luke Timmerman and Meg Tirrell).

The importance of lead users extends far beyond clinicians contributing observations that point to new indications for therapeutics. Innovative front-line workers play a critical role in catalyzing the development of new technologies – principally by coming up with relevant use cases, and adapting or evolving the technology to serve this purpose. 

Technology, as we’ve discussed, often arrives with lots of promises and hype, but often with only a limited sense of exactly what problems it might be able to solve most effectively. It takes someone obsessed with solving a problem in front of them, and willing to try out an emerging technology, for a promising new use case to be revealed and developed.

Botox fits into field discovery paradigm nicely. It was originally developed and FDA-approved for the treatment two somewhat obscure ophthalmological disorders, strabismus and blepharospasm.

Jean Carruthers

However, an eye doctor named Jean Carruthers (who trained with Alan Scott) was an investigator in the original botox clinical trial. She was told by a patient that the injection (for an eye condition) had the unintended effect of improving her skin. 

Carruthers took notice, and together with her husband, a dermatologist, they pursued the development of botulinum for cosmetic indications. Botox is now well-known for its ability to reduce wrinkles, and that feature transformed it into a multi-billion-dollar business.  

Other uses of botulinum were soon discovered as well; in addition to a range of cosmetic uses, the drug is now FDA approved for a range of conditions including limb spasticity, cervical dystonia, excessive sweating, excessive salivation, overactive bladder, and migraine. 

The very breadth of applications evoke Dulcamara’s classic description of his magical elixir in Donizetti’s L’Elisir d’amore.    

Ei corregge ogni difetto,
Ogni vizio di natura,
Ei fornisce di belletto
La più brutta creatura;
Camminar ei fa le rozze,
Schiaccia gobbe, appiana bozze,
Ogni incomodo tumore
Copre sì che più non è …

(“It corrects every defect
All the faults that nature made;
It bestows both beauty and grace
To the ugliest of all creatures
It does cause the lame to walk
And the hunchback it makes straight
All the tumors, all the swellings,
It so covers that they vanish…)

To which the chorus responds,

Qua, dottore, a me, dottore …
Un vasetto … due … tre …

(“Here, dear doctor – for me, Doctor,
Here’s a vial – give me two, three.”)

Botox was initially envisioned as serving a tiny market.  Scott, the California ophthalmologist, originally couldn’t even find a pharma company interested in acquiring the company he founded to manufacture the medicine. He eventually sold it to Allergan for a mere $9 million.  Today, the product now delivers billions in sales for multiple indications, most unanticipated at the time the drug was first approved. Allergan, the company that ran the R&D programs that maximized the value of Botox, was acquired by AbbVie for $63 billion in 2019.

Inspired by this and other examples (particularly in immunology – think Humira) of a single therapeutic proving useful for multiple clinical indications, biopharma companies are increasingly focused on systematically contemplating such additional uses, seeking, in a sense, to industrialize serendipity. 

This may be especially wise since clinicians, more harried than ever, may have less time for the sort of reflection and critical observation that’s historically proved so valuable. 

Inside baseball

Helveston’s account of the history of Botox touches on aspects of drug development that biopharma colleagues might find especially intriguing. For instance, Scott somehow managed to develop the drug, through FDA approval, for only around $4 million (money he raised, in part, by mortgaging his house). 

Also surprising: Scott reportedly had no contact at all with the FDA for nine of the 15 years between 1974, when he first submitted the IND, and 1989, the year the drug he received FDA approval. The original IND application apparently sat on someone’s desk for four years before the agency was nudged to action by a well-placed colleague, yet even after that, there was no contact at all between Scott and the FDA for five years during the 1980s when trials were underway.

Helveston’s account also reveals that a key botulinum researcher in the early nineteenth century, Justinus Kerner, was also a polymath and poet who first developed the art of symmetrical inkblots, called klecksographs; these were subsequently adapted and incorporated by Swiss psychiatrist Herrmann Rorschach in his now-famous projective test. 

We are also reminded by Helveston of Paracelus’s dictum: “What is there that is not poison? All things are poison and nothing is without poison. Solely the dose determines that a thing is not a poison.”  Botulinum, of course, serves as a canonical example.  It is “the most lethal toxin known” to humanity, according to Helveston, yet therapeutic at extremely low doses.  (As an aside, we’re told that at one point the CIA supposedly contemplated assassinating Cuba’s Fidel Castro by lacing his favorite cigars with botulinum, presumably at not such low doses.  This idea was never carried out.)

“Curiosity never waned”

Arguably Helveston’s most enduring and uplifting takeaway concerns not botulinum but Alan Scott. It’s easy to imagine how Scott might have become embittered and disappointed, particularly since the drug he devoted his life to developing didn’t ultimately find much use in the indication Scott cared most about, strabismus, and Scott received minimal compensation for a product that would generate billions in revenue. 

Helveston, to his credit, explores this question, and discovers that by all accounts, Scott was remarkably content. He was truly driven by curiosity, and motivated to unlock the mystery of nature. His purpose, Helveston writes, was to “ask questions and find answers.” 

Even in his late 80s, Scott (who passed away in December 2021, six months shy of his 90th birthday) always enjoyed participating on an ophthalmology listserv where difficult cases were discussed, and where he might offer relevant insights.  He was also excited by a project he was noodling on with a grandson, a NASA astronomer, focused on developing a device to measure eye alignment digitally.  

Through his final months “Alan Scott was in the game and never quit,” Helveston reports.  “His curiosity never waned.” 

In this, Scott evokes the great French geneticist Jacques Monod, whose last words were said to be “Je cherche à comprendre” – “I am trying to understand.”

9
Feb
2024

CRISPR to Protect the Bone Marrow & Attack Cancer: Robert Ang on The Long Run

Today’s guest on The Long Run is Robert Ang.

Robert is the CEO of Cambridge, Mass.-based Vor Bio.

Robert Ang, CEO, Vor Bio

The company is working on what I think you could call an elegant application of CRISPR gene editing for the treatment of acute myeloid leukemia.

The idea here takes some explaining but is pretty simple. Patients with acute myeloid leukemia typically get treated with adult stem cell transplants, otherwise known as bone marrow transplants. Vor seeks to make a single, important change to those transplants.

It uses CRISPR to delete the gene for making the CD33 antigen that appears on the surface of those cells.

That’s important because that marker is found on both blood-forming stem cells that reside in the bone marrow, and on the runaway malignant cancer cells in patients with AML.

The concept, from scientific founder Sid Mukherjee at Columbia University, is essentially, if you can delete CD33 from those critical blood-forming cells in the bone marrow, you can shield them from a powerful cancer drug aimed at the CD33 antigen.

Pfizer’s Mylotarg is the original antibody-drug conjugate that works this way. It has been around 20 years, but its use has been limited because of toxicity.

Vor has shown, in preliminary clinical trial results, that it can successfully delete the CD33 antigen from adult blood-forming stem cells, that these cells can engraft in the bone marrow to reconstitute a patient’s immune system, and that it’s safe. Then, importantly, in a few patients, the company has shown it can deliver the Mylotarg hammer, and that it can do its job, hitting the cancer cells that bear CD33, without damaging the newly transplanted blood-forming stem cells in the bone marrow.

This is a case where CRISPR isn’t the therapy itself for cancer, but it’s an important tool that enables us to reimagine how to better use an existing drug.

Vor isn’t stopping there. It’s developing a CD33-directed CAR-T cell therapy that could be given to these same patients. Nobody has developed such a treatment because, ordinarily, it would have been considered way too toxic to the bone marrow. But it suddenly enters the realm of the possible if you can use CRISPR to shield the bone marrow. 

I wrote about this concept, and Vor’s early clinical trial results, on Timmerman Report in November 2023.

Like many biotech entrepreneurs, Robert has taken a circuitous path. He’s an immigrant, and a physician. When that didn’t feel right for him, he explored the world of healthcare in management consulting and venture capital.

He found something here that he’s passionate about, and it shows in this conversation.

Now, please join me and Robert Ang on The Long Run.

22
Jan
2024

Gene Expression In Therapeutic R&D: Rick Young on The Long Run

Today’s guest on The Long Run is Richard A. Young.

Rick Young, professor, MIT, Whitehead Institute; co-founder, Syros Pharmaceuticals, CAMP4 Therapeutics, Omega Therapeutics, Dewpoint Therapeutics

Rick is a professor of biology at MIT and a core member of the Whitehead Institute dating back to its founding in the 1980s. Rick’s long and prolific research career has been dedicated to studying gene expression. He’s won a number of awards, and is a member of the National Academy of Sciences and the National Academy of Medicine.

In the past decade, Rick’s work has increasingly captured the interest of scientific entrepreneurs seeking to translate these findings into new therapies.

He’s been involved in the formation and guidance of four companies in the Greater Boston area that we discussed today. They are Syros Pharmaceuticals, CAMP4 Therapeutics, Omega Therapeutics, and Dewpoint Therapeutics.

In this discussion, we talked about Rick’s journey in science, and the confluence of factors that make this such a time of possibility in biology and drug discovery. We walked through a brief description of each company and what it’s aiming to accomplish.

And…

I will be in Cambridge, Mass. on Jan. 23 for “Bridging the Gap.” It’s an event organized by Soufiane Aboulhouda, a member of the Timmerman Traverse for Damon Runyon Cancer Research Foundation. I’m moderating a conversation with Phil Sharp of MIT and Vicki Sato of Denali Therapeutics and VIR Biotechnology.

An outstanding lineup of scientists and entrepreneurs make this a can’t-miss event.

Get Tickets Here

Now, please join me and Rick Young on The Long Run.

9
Jan
2024

Investing in Healthy Aging: Jens Eckstein on The Long Run

Jens Eckstein is today’s guest on The Long Run.

Jens Eckstein, investment partner, Hevolution Foundation

He’s an investment partner at Hevolution Foundation. It’s a Saudi Arabia-backed fund that supports basic research in healthy aging and invests in startups with partners to translate that science into interventions that help people live healthier, longer lives.

These efforts are sometimes branded as increasing “healthspan” if not necessarily “lifespan.”

Jens is based in Cambridge, Mass. and has had a long career in biotech and venture capital. In this conversation, we discuss how he first got interested in this field about 20 years ago, how the field has evolved, and where some of the opportunities are to help people live healthier and longer lives.

This isn’t all about coming up with some overhyped magic pill – there are a lot of factors at play in aging and diseases of aging. I think listeners will appreciate Jens’ scientifically grounded approach to separate the signal from the noise.

Now please join me and Jens Eckstein on The Long Run.

 

I’m going to be in Cambridge, Mass. on Jan. 23 for an event that supports the Timmerman Traverse for Damon Runyon Cancer Research Foundation. It’s called “Bridging the Gap.” It’s organized by Soufiane Aboulhouda, a member of my latest team on a mission to raise $1 million for cancer research. An outstanding lineup of scientists and entrepreneurs make this a can’t-miss event. I’m moderating a conversation with Phil Sharp of MIT and Vicki Sato of Denali Therapeutics and VIR Biotechnology.

Get Tickets Here

2
Jan
2024

Rebooting AI in Drug Discovery on the Slope of Enlightenment   

Jason Steiner, Architect & Advisor, AI-Drug Discovery

The past few years have seen a wave of AI investment in drug discovery in both large pharma companies and in venture-backed biotech startups. Expectations are running high. Management teams are betting that even marginal improvements on the ~90% failure rate of clinical trials will be worth the investment.    

While there have been hints of improved R&D metrics in speed and cost, there has not yet been a clinical approval of a drug that may genuinely be considered “AI generated.” Benevolent AI and Atomwise, a couple of well-known AI-driven drug discovery startups, have made large strategic shifts in the aftermath of failures in clinical translation.

As AI tools mature, however, we are working our way through the Gartner hype cycle to the early stages of the Slope of Enlightenment. The future of AI in drug discovery is brighter than ever.  The rise of “AI-first” biotechs, major strategic initiatives from pharma leaders like Genentech, GSK, and Sanofi, an ecosystem of industry providers developing products for the entire R&D pipeline, and a keen focus from regulatory agencies like the FDA are all pointing toward a more productive future.

The path to an approved clinical product is long and we haven’t seen an obvious AI drug discovery success, like a novel molecule invented in whole cloth by AI sailing all the way through the clinical trial process to FDA approval (though some companies may advertise this).

That’s probably a bit further out in the future, but when it happens, the whole world will know. In the near-term future, we might expect to see more substantial progress behind the scenes. There are many steps on the way where AI may be useful, and AI’s role in the fundamental mechanics of the drug discovery and development process are where I expect it to shine.

For those looking outside in, some of the major trends are detailed below:

Knowledge Management is King 

This is not unique to pharma, however, its application across the massive data troves in both the scientific literature and proprietary databases is currently the most significant productivity lever.  Efforts such as the JulesOS agent developed by GSK provide prompt-level access to the vast array of internal data to users without any need to know of such data a priori. 

Similarly, an array of startups such as Elicit are providing products that can search and synthesize the scientific literature base en masse. Some of these capabilities are also being offered by frontier multimodal LLMs.

One such application was demoed by Google in its release of the Gemini model, showing the ability to scan hundreds of thousands of scientific papers, extract desired data, and update graphics and charts for review papers.  

While it is still in early stages, the development of AI systems that can both synthesize, search, and reason across data is on the leading edge of scientific research in the form of “AI Scientists”.  While de novo scientific hypothesis generation and testing is still in its nascency, the combination of generative models such as LLMs and search architectures such as those that powered the Alpha series of models from Deepmind, may enable a more automated form of science. 

A key component of this will be building the physical and experimental systems that can translate AI-generated content into real physical testing and close the hypothesis/data loop.    

Data is Different and Requires New Organization

One of the key shifts in life science research that began with genomics and is now expanding to many other types of biological information is the rise of “hypothesis-free” data generation. 

In more traditional life science research, data has been viewed primarily as a means to answer a specific scientific hypothesis. 

In the context of machine learning, however, data is viewed more from the perspective of the characteristics of its statistical distribution. This is a fundamentally different view on data generation.

As Aviv Regev, Genentech’s head of early R&D, has stated (paraphrasing) – they may make chemical compounds that will never become drugs, but that will be useful for training models that can generate many drugs.

Aviv Regev

A key requirement of effectively implementing this strategy is the “lab in the loop” model that integrates wetlab and computational functions. This type of model is being pursued by an increasing number of AI-first biotech companies but remains relatively rare in traditional pharma where organizational structures often place computational groups as separate functional departments that more frequently default to service providers for the therapeutic and commercial units instead of being fully integrated. 

A more comprehensive integration of wet and dry lab teams can yield greater efficiency for both, for example, by prioritizing better design of experiments for improved productivity. Such active learning has recently been demonstrated, for example, by improving the efficiency of experimental design to search the genetic perturbation space of CRISPR screens using prior knowledge and deep learning models. This closed-loop integration often requires large established companies to overhaul existing workflows and ways of thinking.

AI Applications Supersede Architecture and Scale

Much of the AI industry has consolidated around transformers as the architecture of choice for development because of its inherent scalability on existing computing accelerators. The term “LLM” has often become erroneously synonymous with AI in general. The primary focus of many of the frontier models has been toward massively increasing the size and scale of the data and compute they require to train. 

However, for many applications (both in bio and beyond), this trend is not critical. Model architectures are becoming more computationally efficient and frequently getting better at learning from smaller and more curated data sets. Just in the past year, for example, new architectures for non-attention-based sequence models such as Hyena and Mamba were published that rival and may exceed performance metrics of attention-based models with significantly lower computational overhead. 

Further, the architecture space of models addressing biological questions has been much more varied both in size and diversity than those in the LLM field. Smaller models with more task relevant architectures will continue to drive useful applications in drug discovery. Scale and attention are certainly not all you need to drive R&D productivity. 

Realizing the Promise of AI in Drug Discovery

Platform technologies in the life sciences have ebbed and flowed in favor over the past few years. They hold the promise of dramatically improved long-term productivity often at the cost of high near-term investments. Major platforms like CRISPR, mRNA and AI hold tremendous promise for the future of medicine, and we are in the early days. The success of mRNA during COVID and the recent FDA approval of the first CRISPR cell therapy for sickle cell disease are key examples. 

But the productivity power of a platform is demonstrated most powerfully not in the first success, but the second. 

While both mRNA and CRISPR are specific modalities that have had decades of foundational research underpinning them, AI is a broad-spectrum enabling technology that applies to the industry writ large. It is being aimed to address the fundamental levers of cost, probability of success, and time to develop a product. 

However, if we consider an average development time of 12 years and an average clinical success rate of 10%, the second success proof point is challenging especially if we have not yet seen the first. Even a doubling of the success rate and halving the development time — both tremendous achievements — would yield a net probability of 4% for seeing two clinical successes over more than half a decade, requiring a minimum of 25 pipeline candidates per platform. 

The industry has gone through peak expectation cycles. Companies that have overpromised are in the trough of disillusionment. But the future of AI in drug discovery is just in the early days of the slope of enlightenment. 

It’s an exciting future.

 

Jason Steiner is an architect and advisor specializing in AI for drug discovery. To read more about the intersection of technology and biology — Jason writes at Techbio<>Biotech

He is also a member of the Timmerman Traverse for Damon Runyon Cancer Research Foundation, a biotech industry effort to raise $1 million for young cancer researchers with bold and brave ideas.  

As Jason puts it:

The pace of technological development in the life sciences is tremendous and is often being led by early career scientists pursuing innovative research efforts. Unfortunately, public funding for young scientists has been declining for decades. To ensure that we can keep the pipeline of future scientific developments strong, particularly to address major diseases like cancer, please consider making a donation.

27
Dec
2023

Give to the Next Generation of Scientists

Luke Timmerman, founder & editor, Timmerman Report

This is the time of year when many people sit down and think about the causes they want to support.

I’m asking you to consider donating today to young scientists through the Damon Runyon Cancer Research Foundation.

Why Young Scientists?

Our system for funding science doesn’t do enough to support young people. The average age of a first-time NIH grant recipient was 32 in 1970. That number has now crept up to about 42.

This means too many brilliant scientists in this new generation are being forced to toil on insufficient wages, and without the independence they need to break new ground. People need a chance to get on a sustainable career path in their 30s. 

By supporting outstanding young scientists, we in the biotech community can make a difference. We can breathe oxygen into creative new ideas that otherwise would be cast aside by cautious, incremental funding agencies.

If we don’t do more to support young scientists, many will continue to leave their scientific dreams behind, opting for more lucrative careers so they can get married, have kids, and afford a home.

When this happens, science misses out.

Why Damon Runyon Cancer Research Foundation?

It supports bold and brave young scientists across the US.

Damon Runyon has a keen eye for talent and a terrific track record. In its more than 75-year history, its grant recipients have gone on to win many accolades, including:

  • 13 Nobel Prizes
  • 15 Lasker Awards
  • 7 National Medals of Science
  • 100 elected memberships in the National Academy of Sciences

By betting on promising early-career scientists and giving them the freedom to pursue their own ideas, Damon Runyon is a force multiplier for cancer research and biology.

Decades ago, its scientists were the first to cure a solid tumor with chemotherapy. More recently, its discoveries include the first targeted ALK inhibitor for lung cancer and the first demonstration that CRISPR could edit genes in mammalian cells.

In the mid-2000s, before it was cool, Damon Runyon invested in scientists who were exploring cancer immunotherapy with checkpoint inhibitors and CAR-T cell therapy.

I’m committed. I’m personally leading a team of biotech executives and investors who are raising $1 million for Damon Runyon. At the end of the campaign, we’ll gather together to climb Mt. Kilimanjaro, the highest peak in Africa.

Cancer affects almost everyone at some point in life, either personally or through members of our families.

We are living in a moment of tremendous possibility for cancer research and development.

Our support today will pay dividends for generations. This is our chance.

Please go directly to the Timmerman Traverse for Damon Runyon Cancer Research Foundation’s website to see who’s on the team and how you can make a donation today. 

DONATE HERE

 

Thank you

 

 

 

26
Dec
2023

Bispecific Antibodies for Cancer: Shelley Force Aldred and Nathan Trinklein on The Long Run

Today, I have a dynamic duo of scientific entrepreneurs on the show – Shelley Force Aldred and Nathan Trinklein.

Rondo co-founders Shelley Force Aldred (CEO) and Nathan Trinklein (CSO)

They are the co-founders of San Francisco-based Rondo Therapeutics. The company raised $67 million in a Series A financing announced in March 2022. Shelley is the CEO and Nathan is the chief scientific officer. Rondo is developing bispecific T-cell engaging antibodies against solid tumors.

For those of you who have an active Timmerman Report subscription, see a report on Rondo here.

These two have been working together since graduate school at Stanford University. They are now on their fourth company. Their biggest success together was TeneoBio, a company that developed bispecific antibodies for liquid tumors. Amgen agreed to acquire that one for $900 million upfront in July 2021.

Now, please join me and Shelley Force Aldred and Nathan Trinklein on The Long Run.

 

Bridging the Gap

I’m going to be in Cambridge Mass on Jan. 23 for an event that supports the Timmerman Traverse for Damon Runyon Cancer Research Foundation. It’s called “Bridging the Gap,” and it’s organized by Soufiane Aboulhouda, a member of my latest team on a mission to raise $1 million for cancer research. An outstanding lineup of scientists and entrepreneurs make this a can’t-miss event. I’m moderating a conversation with Phil Sharp of MIT and Vicki Sato of Denali Therapeutics and VIR Biotechnology.

Get Your Tickets Now!

 

21
Dec
2023

The Cultures of Large and Small Pharmas, plus: Can They Overcome The “Productivity Paradox” and Seize the AI Moment?

David Shaywitz

Spurred by several questions I’ve received from students and trainees, today’s year-end column examines some of the ways large biopharma companies are fundamentally different from small biotech companies and startups. 

We’ll also ask whether biopharma can overcome new technology’s dreaded “productivity paradox” and learn, quickly, how to apply AI to accelerate drug development.

Large Pharmas vs Smaller Companies (Including Startups)

Very large pharmas (to borrow from Fitzgerald) are different from the rest of us.  To appreciate these distinctions, it’s helpful to examine how large and small biopharma companies (including startups) approach key challenges facing the industry.

Challenge 1: Most drug candidates don’t turn into approved products, and only a tiny fraction of molecules entering phase I emerge at the other end as FDA approved medicines.
Advantage: Large biopharmas

Arguably, the single most important advantage large biopharmas have is that their size enables them to pursue a portfolio approach and absorb losses that tend to sink smaller companies – it’s that simple. If you are J&J or Roche, with a market cap in the hundreds of billions, you can absorb the inevitable program failures; if you are a startup or small biotech, it’s much more difficult.  (Note: this is also a key reason why drug development is so expensive – the calculations need to factor in and account for not only the cost of rare successful program but also the amalgamated cost of the many, many setbacks.)

Challenge 2: Drug development requires flawless execution across a huge number of disparate steps
Advantage: Large biopharmas

Another key advantage big pharmas have is that they tend to have deep expertise across a range of areas, from chemistry to statistics to clinical development to marketing.  Moreover, their large size (at least in theory) increases the likelihood that big pharma programs get both the attention of vendors (like CROs), and discount pricing (for the same reason a large hospital system can negotiate more effectively with insurers than can solo practitioners).

While many startups are founded on the idea that they’ve identified a key obstacle – for instance, a traditionally “undruggable” target that they’ve figured out how to attack – the startup still needs to do all the other block-and-tackle activities required to make a product.  While service providers like contract manufacturing organizations increasingly enable startups (as well as larger companies) to outsource much of this work, operationally, there’s just so much to get right.

One manifestation of the broad focus of large pharmas can be seen in their approach to technology innovation.  I learned this the hard way after I arrived at an R&D technology strategy role at a large pharma, spoke in depth to researchers across the organization, and identified a number of unusually precocious digital innovators. Delighted by the talent I identified, I proposed that the organization invest additional resources behind these stars and expand their individual efforts. 

Yet this turned out to be, from the perspective of top R&D leaders, including the head of R&D, exactly the wrong answer.  These innovators, I was told, were obviously on the right track and of course should be acknowledged, but the real strategic goal was to bring everyone in R&D up a notch.  A global improvement of even 5% in facility with emerging technologies, I learned, was considered far more useful to the organization than supercharging those who were already ahead. 

Incredulous, I asked the brilliant founder of a leading AI-driven biotech startup for a second opinion, and I was surprised to hear a similar perspective.  The founder told me that in the tech industry, “a single individual, or even a very small team, can leverage technology to move very quickly… and make huge amounts of progress.” 

But drug discovery, the founder continued, “is very much a team sport. A single individual or even a small team are rate limited by the pace at which they can do biology or chemistry experiments. Conversely, if you accelerate the entire organization…then that can be very value creating.” 

This mindset (which I understand, though not yet fully embraced as I continue to believe in the value of investing behind pioneers) may also explain why large pharmas are increasingly moving towards shared, enterprise platforms (“foundational enterprise capabilities,” in the words of consultants Lamare, Smaje, and Zemmel), and are leery of isolated tech solutions.

Challenge 3: Need to “pick winners”
Advantage: Neither

Biopharma remains an exception-based, hit-driven business, largely living off of infrequent, outsized successes. This is a domain ruled by the power law, not the normal “bell curve” distribution.

To the consternation of all, our ability to identify the rare “winners” seems as elusive as ever (see here, here); many blockbusters have come from products that weren’t initially recognized as especially promising. Examples here include Merck’s pembrolizumab (Keytruda) (as I discussed at length here), and also Millenium’s bortezomib (Velcade), acquired in the LeukoSite transaction that was focused primarily on a different product, Campath (see here, also here).

On the other hand, the GLP-1 obesity products so much in the news these days emerged from decades of meticulous and deliberate work in both academia and leading diabetes companies, Lilly and Novo Nordisk. Notably, these pharmas also had the resources and conviction to conduct the essential but often daunting long-term cardiovascular outcome studies that discouraged many other companies (large and small) from investing in the field at all.

Even so, the magnitude of the drug effect – both in terms of weight loss and in terms of cardiovascular benefit – is likely well beyond what most optimists probably imagined.  Not surprisingly, many pharmas who largely shunned obesity are urgently now trying to acquire their way into this market.

Given the importance of identifying “winners,” I’ve been struck by how many senior drug developers with whom I’ve spoke have confided to me that they think R&D strategy (in terms of what to go after) tends to be overrated. 

One veteran told me that while a strategy can be useful for attracting early investors to a startup, or facilitating communications in a larger organization, in practice, success tends to depend less on any particular strategy, and more on how astutely you respond to what you encounter (see also Challenge 5, below).

This skeptical and pragmatic attitude to strategy may represent the pharma equivalent of U.K. Prime Minster Harold Macmillian’s famous response when asked about “the most troubling problem” he faced during his tenure.  Macmillan’s answer: “Events, my dear boy, events.”

Challenge 4: Navigation of nascent science & initial prosecution of promising molecules
Advantage: Smaller biotechs (though less so in down market)

A key advantage that belongs to (well-funded) startups and small biotechs is their exceptional focus and agility.  Because their aperture is typically so narrow, small companies tend to be exquisitely attuned to challenges their programs face, and can generally respond more rapidly, and adjust more nimbly, than large biopharmas.  There also tends to be a remarkable degree of organizational alignment – it’s much easier to get everyone to row in the same direction, since everyone is palpably invested in the same outcome.

Startups and small biotechs often have a relative flat organizational structure, conducive to fluid communication and fast decisions.  In the presence of sufficient funding (obviously not a given in the current difficult environment), startup scientists can pursue novel science, and biotech development teams can respond to unforeseen challenges, with an urgency and flexibility that tends to be far more difficult to come by in large companies, with their elaborate decision procedures and rigid processes. 

In contrast, large biopharmas are astonishingly complex organizations.  They are unimaginably, almost anachronistically hierarchical. Information, like authority, cascades down, rather than diffuses across. Because of their size, there is extensive reliance upon, and deep reverence for process (“trust the process” tends to be an earnest aspiration), and decisions often require not just consensus but also a stultifying number of preliminary meetings to ensure all proposals are thoroughly socialized, and all senior stakeholders are suitably aligned. 

One consequence: in large companies, decision-making tends to be both painfully slow and incredibly risk-adverse, as Safi Bahcall in particular has documented (see here, here).

Effectively navigating intricate corporate structures also requires a facility with the sort of organizational power politics that authors such as Stanford’s Jeffrey Pfeffer and USC’s Kathleen Kelley Reardon astutely describe. 

Challenge 5: Exploitation of winners
Advantage: Large biopharmas

As difficult as it can ordinarily be for anything to get real momentum in sprawling bureaucratic biopharmaceutical companies, their ability to execute effectively on a global scale when they actually hit upon someone promising is extraordinary. Pfizer’s development of the COVID vaccine is one compelling example; Merck’s exploitation of pembrolizumab (Keytruda) is another. 

In these and other cases, once a large biopharma decides to go “all in” on something, and the opportunity seems authentically compelling (rather than desperate), the ability of these massive organizations to execute on a global scale is extraordinary to behold.  Everyone in the organization understands the opportunity and the imperative, and the result can be mind-blowing. 

Of course, the pursuit of promising data motivates and energizes biopharma companies of all sizes. The difference is that large pharmas are uniquely positioned to drive these programs forward at scale.

AI and the Biopharma Productivity Paradox

I couldn’t have asked for a better way to wrap up 2023 than to listen to Microsoft’s Peter Lee discuss GPT-4, and generative AI more generally, earlier this week at a Dean’s Lecture at Harvard Medical School.

Peter Lee, Corporate Vice President,
Microsoft Research

Lee, readers will recall, co-wrote the book The AI Revolution in Medicine: GPT-4 and Beyond, together with Harvard professor Zak Kohane and veteran journalist Carey Goldberg, who were both in attendance. 

A year or so into the GPT-4 era, Lee seemed as excited by the promise of GPT-4, and as mystified by its mechanism, as he was when he first wrote the book (and when all three authors discussed it with me in May at Harvard’s Countway Library – video here, transcript here).  It’s abundantly clear that although we’re still in the earliest days of generative AI, the technology holds exceptional promise, and of course significant risk. 

Perhaps Lee’s most enduring message was one of the last points he made, citing a poignant and personal example that Kohane offered in the book.

“My first patient died in my arms,” Kohane wrote. “I was a freshly-minted doctor in a newborn intensive care unit, and despite maximal efforts with the best that medicine had to offer at the time, I had to hand a baby boy’s lifeless body to his parents within 24 hours of his birth.”

Kohane observed that “At the time, the death was an unavoidable tragedy.” Yet within a year, a new treatment approach was found to be effective in similar patients. 

“It became standard practice a year later in the very same nursery where my first patient died,” Kohane writes. “He would likely have survived if he had been born just a little later.”

Or if the therapy arrived a year earlier.

Kohane acknowledged the many different steps required to bring a therapy forward. If AI can be applied productively to even a few of them, he wondered, how big a difference might that make in accelerating a treatment’s evaluation and approval? 

The story of the baby boy who was one year away from a lifesaving intervention is a highly resonant example. It points to the importance of all the different tasks that medical product approval requires – and accordingly, all the opportunities for optimization and improvement.  It reminds us of the importance of saving time – months matter, and a year or more of process improvement can be the difference between life and death.

Phrased differently: we tend to hope AI somehow comes up with new brilliant treatments.  But even if AI “just” accelerates paperwork and increases process efficiency, that boost could still meaningfully hasten the delivery of improved therapeutics to patients. 

Given the many areas of opportunities for improvement in both healthcare and biopharma, the pressing question is whether AI will actually drive rapid improvements in productivity?  

Top management consultants, naturally, tend to say “Yes, and leading companies have already demonstrated this, why are you lagging?”  

In biopharma at least, these assertions lack credibility.  

For example, when consultants enthuse aspirationally that “a GenAI model can be applied to a massive pharma molecule database that can identify likely cancer cures,” most experienced drug hunters and scientists will just roll their eyes.

Those with a historical perspective on technology remind us of the “productivity paradox” and say it’s always taken longer to achieve technology’s promised benefits than anticipated – i.e. think about Kahneman and consult your priors.

With this in mind, I’ve explicitly discussed why, based on previous experience, we should cautiously manage our expectations for AI in the context of biopharma. 

Nevertheless, many experts hope and expect that this time will be different. Such earnest optimism was expressed for AI in healthcare delivery by UCSF’s Robert Wachter and Stanford’s Erik Brynjolfsson in the latest JAMA.

These authors argue that “the ability of the digital tools to rapidly improve and the capacity of organizations to implement complementary innovations that allow IT tools to reach their potential—are more advanced than in the past.” 

They also emphasize (as I’ve described in detail here and here) the importance of reinventing processes, noting that “great gains will only come when implementation is coupled with significant changes in the design of the work.” 

Lamare, Smaje, and Zemmel also explicitly emphasize the need for companies to “fundamentally rewire” how they operate.

I appreciate the optimism of Wachter and Brynjolfsson, and recognize the extraordinary promise and rapid improvements in AI. At the same time, I am mindful of the magnitude of the intrinsic biologic, human, and organizational complexities that must be addressed in biomedicine.

In biopharma, a question of particular interest in whether AI can help us become not only fail more efficiently but succeed more frequently – i.e. increase our probability of success by improving how we select targets, indications, and patient populations.  Already, there are seemingly hundreds of startups all claiming they can help with this (I’ve spoken with several in just the last few days). 

These assertions – that an algorithm or model can impact the overall probability of success – can be tricky to evaluate. Given the many ways a drug can fail, it’s going to be challenging for early adopters of AI methodologies to critically assess the impact (if any) the AI is having. 

Yet, how exciting to consider the possibility that at least in some cases, it might be possible to leverage existing data to make better decisions than the typical eminence-based approach.

More generally, the challenge and opportunity for R&D leaders of today is figuring how to effectively integrate emerging biological modalities with powerful but still nascent digital and data tools, in a fashion that leverages these methods without fetishizing them.

Amy Abernethy

A final note on the challenge of developing health technology solutions: the brilliant Amy Abernethy (well-known to regular readers of this column) announced this week that she’ll be stepping away from her role as the president of product development and chief medical officer at Verily, essentially to approach the challenge of evidence generation from a different perspective. 

The departure of Abernethy represents a tremendous, possibly catastrophic loss for Verily and their aspirations to demonstrate the ability to deliver concrete solutions in healthcare, including biopharma. Despite a preponderance of super smart engineers, the company just can’t seem to covert this brilliance into tangible commercial healthcare products.

As one health tech leader tartly told me, “Verily is such a hot mess. Never has a company been so well funded for so long with no clear mission as to why it even exists.”

And now it feels like the key experiment has been done, seeing if the transplantation a new visionary nucleus — Abernethy — into the existing structure could help the organization at last become a competitive health product company.  

The answer, sadly, seems to be: No.

Nevertheless, both Verily and Abernethy are right to recognize the promise of emerging technology to address enduring challenges in healthcare delivery and drug development. 

Let’s hope that in 2024, we spend less time fantasizing, catastrophizing, and rhapsodizing about the extent to which AI ethereally “changes everything,” and instead use our energy to develop more tangible examples of AI palpably improving something in the way new medicines are discovered, developed, and delivered to patients.

Best wishes for a creative, joyful, peaceful, and impactful 2024!

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