The Frontier of Epigenetic Editing: Chroma CEO Catherine Stehman-Breen

Today’s guest on The Long Run is Catherine Stehman-Breen.

Catherine is the CEO of Boston-based Chroma Medicine.

Catherine Stehman-Breen, CEO, Chroma Medicine

Chroma is working on therapies that control gene expression through epigenetic editing.

People have heard a lot about editing of the genome with CRISPR, and then subsequent refinements of the technology known as base editing and prime editing. The question at Chroma is a newer one. It boils down to whether it possible to achieve a similar kind of effect – with the potential for single-shot cures — by making edits to the epigenome? Can you achieve the same kind of life-changing result by leaving the underlying DNA sequence intact, but then just altering the expression of genes?

The work is still in the early stages. Chroma hasn’t publicly disclosed its targets, indications, or the preclinical results it has achieved thus far.

The company came out of stealth mode with a $125 million Series A financing with a prominent set of scientific founders and investors. I wrote about it then for on TimmermanReport.com.

Over the next year, the company did make enough progress in its first year to secure a $135 million Series B financing led by GV, and which included all of its existing investors. I expect to hear some scientific presentations later this year which might explain why that investment group chose to double-down, even in a difficult financing environment for biotech startups.

Catherine is a physician by training, and nephrology was her specialty. She started out in academic medicine at the University of Washington, and then worked her way up in clinical development roles at Amgen and Regeneron. She found new challenges in the biotech startup world in Boston / Cambridge a little over five years ago. It’s a confluence of skills, experiences, and network that have put her in position to run this interesting and ambitious young company.

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In Support of FDA’s Authority to Regulate Medicines

Shehnaaz Suliman, CEO, ReCode Therapeutics

On Friday, April 7, a federal judge with no scientific training fundamentally undermined the bipartisan authority granted by Congress to the Food and Drug Administration to approve and regulate safe, effective medicines for every American.

District Judge Matthew Kacsmaryk issued a decision that overturns the FDA’s 23-year-old approval of mifepristone, the primary medicine used in abortion and miscarriage care, and which has been proven by decades of data to be safer than Tylenol, nearly all antibiotics and insulin.

Amanda Banks, MD

The decision ignores decades of scientific evidence and legal precedent. Judge Kacsmaryk’s act of judicial interference has set a precedent for diminishing FDA’s authority over drug approvals, and in so doing, creates uncertainty for the entire biopharma industry.

As an industry, we count on the FDA’s autonomy and authority to bring new medicines to patients under a reliable regulatory process for drug evaluation and approval. Adding regulatory uncertainty to the already inherently risky work of discovering and developing new medicines will likely have the effect of reducing incentives for investment, endangering the innovation that characterizes our industry.

Jeremy Levin, CEO, Ovid Therapeutics

Judicial activism will not stop here. If courts can overturn drug approvals without regard for science or evidence, or for the complexity required to fully vet the safety and efficacy of new drugs, any medicine is at risk for the same outcome as mifepristone.

While the drug development, approval and monitoring process is not perfect, the Agency’s framework has resulted in decades of unsurpassed medical innovation and in statutory mechanisms to remove drugs from the market if, among other reasons, they fail to maintain the anticipated safety and efficacy profile.

As an industry dedicated to improving human health, and as members of the biopharma industry, we add our signatures to this letter and stand together to unequivocally support the continued authority of the FDA to regulate new medicines.

Paul Hastings, CEO, Nkarta Therapeutics

In the face of laws and rulings that aim to undermine the evidence-based and legislatively sanctioned authority of federally mandated institutions such as FDA to protect public interests, and by putting an entire industry focused on medical innovation at risk, we cannot stay quiet.  

We call for the reversal of this decision to disregard science, and the appropriate restitution of the mandate for the safety and efficacy of medicines for all with the FDA, the agency entrusted to do so in the first place.

Click here to join us.

Shehnaaz Suliman, MD


ReCode Therapeutics

Amanda Banks, MD

Advisor, Board Member

Co-founder and former CEO, Blackfynn


Jeremy Levin, MD


Ovid Therapeutics


Paul Hastings

NKarta Therapeutics

John Maraganore

Former founding CEO at Alnylam Pharmaceuticals


Julia Owens, PhD


Ananke Therapeutics


Peter Kolchinsky, PhD

Managing Partner

RA Capital Management


Ted Love, MD
President & CEO
Global Blood Therapeutics
Eric Dube, PhD

Travere Therapeutics

Dr. Albert Bourla

Chairman and Chief Executive Officer



Deborah Dunsire MD

President and CEO 

H. Lundbeck A/S


Alisha Alaimo



Robert Langer, PhD



Daniel Swisher

President and COO
Jazz Pharmaceuticals

Christopher Tan

Exec Director, BD&L, Infectious Diseases & Vaccines

Merck & Co, Inc


Paula Soteropoulos

Chairman of the Board



Steven Holtzman


Camp4 Therapeutics

Peter J Pitts


Center for Medicine in the Public Interest

Angie You


Architect Therapeutics

Jon Martin

Associate Vice President 



Jeb Keiper


Nimbus Therapeutics

Paul J Sekhri

President and CEO

Lyv Advisors LLC

Grace E. Colón, Ph.D.

Former CEO, InCarda Therapeutics; Board member, Voyager Therapeutics, CareDx, BIO, MIT


Michelle Werner


Rene Russo 


Xilio Therapeutics 


Barbara Duncan


Ovid Therapeutics

Ramani Varanasi

Managing Director

ReVive Advisors


Maria Soloveychik 




Nancy Whiting, PharmD


Recludix Pharma

Rekha Hemrajani

Board Member

BioAge Labs

Hanadie Yousef 


Juvena Therapeutics 


Deborah Geraghty



Patrice Milos

Board Member, VP Scientific Operations

Proof Diagnostics

Yvonne Linney PhD

Board Director

Linney Bioconsulting 


Julie Krop

Chief Medical Officer

PureTech Health

Rhonda F. Farnum

CBO, SVP Commercial & Medical Affairs

Theravance Biopharma, Inc.

Stephanie Oestreich




Sylvia McBrinn

Former CEO

Axerion Therapeutics

Christine Miller

Biopharma Executive

Wendye Robbins, MD


Red Tower Partners


Meg Alexander

Chief Corporate Affairs Officer

Ovid Therapeutics


Melita Sun Jung


Structure Therapeutics

Katherine Bowdish

CEO & President

PIC Therapeutics


Joanne Dove Kotz


Jnana Therapeutics

Jenny Herbach 


Adventris Pharmaceuticals 

Lavi Erisson 



Bob Coughlin

Board Member, Former CEO



Kristine C. Mechem

Chief Corporate Development Officer

Craif Inc

Jason Tardio

Chief Operating Officer 

Ovid Therapeutics 


Nina Kjellson

General Partner

Canaan Partners


Tara Nickerson

Biopharma Executive


John Kolljins

President & CEO

Satsuma Pharmaceuticals


Ashley Zehnder


Fauna Bio Incorporated

Mark Frohlich


Indapta Therapeutics

Cristina Ghenoiu 


RA Capital 


Emily Minkow


Stylus Medicine

Rajeev Shah

Managing Partner

RA Capital

Lori Lyons-Williams 
CEO, Abdera Therapeutics  
Ron Cohen, MD

President and CEO

Acorda Therapeutics


Elizabeth Jeffords


Iolyx Therapeutics

Emily Drabant Conley, PhD


Federation Bio

Amit Rakhit

Flare Therapeutics


Ken Drazan

Chairman & CEO

Arsenal Biosciences

Bernard Coulie

President and CEO

Pliant Therapeutics 


Sabrina Martucci Johnson


Daré Bioscience 


Zachary Hornby

President & CEO

Boundless Bio, Inc.

Eric Easom

Founder & CEO

AN2 Therapeutics


Mark Lappe

CEO and Chairman


Kevin Pojasek


Enara Bio

Srini Akkaraju

Managing General Partner

Samsara BioCapital


Jack Elands


Emergence Therapeutics

Kristen Fortney


BioAge Labs

JJ Kang, PhD


Appia Bio

Elena Itskovich


Nest Catalyst


David Meeker

Chairman and CEO 

Rhythm Pharmaceuticals 


Bonnie H Anderson


PinkDx Inc


Michael Gladstone


Atlas Venture

Ivana Magovcevic-Liebisch

President & CEO

Vigil Neuroscience

Polly Murphy


UroGen Pharma 


Matthew Hammond


RA Capital Management

Linda Phelan Dyson

Founder and Principal

Dunn Street Strategies

Marcelo E. Bigal


Ventus Therapeutics


David Grayzel


Atlas Venture

ShiYin Foo

Arvada Therapeutics

Jason Braun




Jason Rhodes


Atlas Venture

Bruce Booth


Atlas Venture

Erika Smith


ReNetX Bio


Kevin Bitterman


Atlas Venture

Joao Siffert


Design Therapeutics 


Peter Strumph 


Parvus Therapeutics 


Daphne Zohar



Alex Harding, MD

Head of Business Development

CRISPR Therapeutics

Zach Scheiner


RA Capital

Camille D Samuels 




Faraz Ali


Tenaya Therapeutics

Gisela A. Paulsen, MPharm

Former President & COO, Oncocyte Corporation

EIR, DigitalDX


Nicolas Tilmans



Michael Gilman


Arrakis Therapeutics

Pearl Freier


Cambridge BioPartners


Alan Fuhrman

Chief Financial Officer

Tyra Biosciences

Christy Oliger

Board Director


Katherine Vega Stultz 


Ocelot Bio


Paul D Rennert


Aleta Biotherapeutics

Thomas J. McGahren, MD JD

Managing Director

Griffin Securities


Yael Weiss


Mahzi Therapeutics


Kenneth A. Berlin

President & CEO

Ayala Pharmaceuticals, Inc.

Rob Shaffer

Chief Operations Officer

Vrata Therapeutics

Patrick Heron

Managing Partner 

Frazier Life Sciences


C Gordon Beck III

Founder and Managing Director

Princeton Biomedical Consulting LLC


Rebecca Frey

President and CEO

Siduma Therapeutics

Doug Drysdale




Nerissa Kreher, MD

Chief Medical Officer

Entrada Therapeutics

Sarah Boyce 


Avidity Biosciences 

Safia Rizvi


CILA Therapeutics


Zen Chu


MIT Healthcare Ventures

Bruce Goldsmith


Aureum Bio

Nabil Uddin

Corporate Development 

Concert Pharmaceuticals, Inc.


Paul Peter Tak, MD PhD

President & CEO

Candel Therapeutics

Catherine J. Mackey, Ph.D

Retired Sr. VP R&D


Samuel D Waksal

CEO and President 

Graviton BioScience Corporation 

Gautam Kollu


D2G Oncology

Sun Altbach 





Nima Farzan


Kinnate Biopharma


David de Graaf

President & CEO

Reverb Therapeutics

Brook Byers

Biotech Founder and Board Member

Byers Capital


Peter Barrett


Atlas Venture


Art Krieg

Adjunct Professor

University of Massachusetts Chane Medical School


Peter Smith


Remix Therapeutics

Holly Weng


HW MedAdvice

Michael Raab

President & CEO

Ardelyx, Inc.

Jean-Francois Formela


Atlas Venture


Todd Harris


Tyra Biosciences


Richard Colvin, MD, PhD

Chief Medical Officer

bluebird bio

Ronald A. DePinho, MD

Professor & Past President

UT MD Anderson Cancer Center

Steve Derby


General Ventures Inc.


David Campbell

President and CEO

Janux Therapeutics

Amir Nashat


Paratus Sciences 

Nick Mordwinkin

Chief Business Officer

Kezar Life Sciences


Heather Turner


Carmot Therapeutics, Inc.

Leslie Williams

CoFounder President & CEO

hC Bioscience, Inc

Mark Benjamin

President & EVP Business Development 

Cyrus Biotechnology 


Douglas Fisher, MD


Revelation Partners

Gerald Commissiong


Todos Medical

Diala Ezzeddine

Co-founder & COO

Differentiated Therapeutics


Daphne Koller

Founder and CEO


Hannah Brie Gordon

VP, Product

Enveda Biosciences

Sanjeev Redkar

President & CoFounder

Apollomics Inc.


Rick Lundberg 

President and CEO

Eikonizo Therapeutics 

Rajesh Devraj

President & CEO

Rectify Pharmaceuticals

Raul Oliva

CEO & Co-Founder

Sidekick Bio, Inc.


Ty Howe

Biotech advisor 

Marsh USA

Jeff Jonker


Belharra Therapeutics


Adel Nada




Tess Cameron


RA Capital

Florian Brand

CEO & Co-Founder

atai Life Sciences

Daniel Bradbury

Executive Chairman

Equillium, Inc


Robert Hughes




Rohan Palekar


89bio Inc 


Chris Francis


Wave Life Sciences


Stephen Benoit

President & CEO

MDI Therapeutics

Mary Rozenman



Derek DiRocco


RA Capital


Hong Wan

President & CEO

Tallac Therapeutics

Aoife Brennan



James McArthur

President & CEO



Glenn Rockman

Managing Partner

Adjuvant Capital, L.P.

Daniel Bensen


Tyra Biosciences


Ali Fawaz

General Counsel

Tyra Biosciences


William S. Marshall

Chief Scientific Officer

Elsie Biotechnologies

Laura Stoppel 


RA Capital

Allison Kemner

VP Clinical Sciences and Operations

Tyra Biosciences


Piyush Patel

Chief Development Officer

Tyra Biosciences

Ronald Swanson


Tyra Biosciences

Ben Wang

Cofounder and COO

Chimera Bioengineering


Jessica Sagers

Head of Engagement

RA Capital

Michael Mendelsohn

Board Chairman

Cardurion Pharmaceuticals

Imran Nasrullah

VP and US Head Collaborate to Cure Hub, BD&L/OI

Bayer Pharmaceuticals


Karen LaRochelle


Aleta Biotherapeutics 

Clifford Stocks



Xiaobing Li

Chief Development Officer

Rectify Pharmaceuticals


Ram Aiyar


Korro Bio


Sarah Honig

VP Corporate Development and Strategy

Tyra Biosciences



Stephanie Engels


Korro Bio, Inc


Eli Berlin

Chief Financial and Operating Officer

Terray Therapeutics 


Micah Benson


KSQ Therapeutics

Robert Hudkins


Tyra Biosciences


Laura Shawver


Capstan Therapeutics

Adam Kolom


Related Sciences

Jonathan Moore


Rectify Pharmaceuticals


William J. Newell


Sutro Biopharma


Reid Huber


Third Rock Ventures

Arthur T. Suckow


DTx Pharma


Suha Jhaveri


Leyden Labs

Viswa Colluru


Enveda Biosciences

William J. Rieflin


NGM Biopharmaceuticals


Michael Rosenblatt, M.D.

Senior Advisor

Several life science funds and boards

Eileen McCullough

Board member, CEO, and Company Builder

Stealth-stage Biotechs


Jing Liang

Managing Partner



Bassil Dahiyat



Isan Chen, MD


MBrace Therapeutics, Inc.

Kabeer Aziz


Adjuvant Capital


Adam Gridley

President & CEO

Allay Therapeutics

Ryan Daws


Obsidian Therapeutics, Inc.

Emilie Besnard 

Senior Scientist

Dorian Therapeutics 


Drew Volpe

Managing Partner

First Star Ventures

Sheila Gujrathi

Chair of Ventyx, ADARx and ImmPACT Bio

John Hood


Endeavor Biomedicines 


Mary Ann Gray


Gray Strategic Advisors, LLC

Roger Frechette

Principal and Founder

New England PharmAssociates, LLC

Karim Dabbagh


Second Genome, Inc


Blake Mandell

CEO and Co-Founder

Transcend Therapeutics

Brian Gallagher

Managing Partner

Trekk Venture Partners


Ginger Cooper

VP Sales

Artificial, Inc


Wendy Nelson

President & Founder

Boston Biotech Forum

Amit Jolly




Jacqueto Zephyr


Nimbus Therapeutics

Alan Horsagee

President & CEO

Duet BioTherapeutics

Bharatt Chowrira



Jens Eckstein Ph. D.

Managing Partner

Jens Eckstein Ph. D.



Dominique Verhelle


NextRNA Therapeutics

Arthur Klausner

Executive Chairman

Concarlo Therapeutics, Inc.

Anna French


Qiming Venture Partners USA


Aetna Wun Trombley


Lycia Therapeutics

Sean McClain

Founder & CEO


Jessica O’Leary

VP, Corporate Development



Hiroomi Tada MD PhD

Chief Medical Officer

Tyra Biosciences

Glenn Schulman

SVP, Investor Relations 

ProKidney Corp

Loren Beck

Chief Legal Officer 

HDT Bio Corp. 


Andrew Farnum


Variant Bio

Kenny Storch

Vice President


Benny Sorensen

CEO & President 

Hemab Therapeutics 


Jason Lettmann

General Partner

Lightstone Ventures

Philippe Lopes-Fernandes

EVP, Chief Business Officer


Cedric Francois




Leslie Stolz

Senior Vice President, Regulatory Affairs
Verve Therapeutics


Renato Skerlj


Expansion Therapeutics

Chi-Ting Huang

Vice President CMC

Pheon Therapeutics


Samantha Truex


Upstream Bio

Jeff Marrazzo

Co-founder and former CEO

Spark Therapeutics 

Hilary Malone


Certego Therapeutics

Greg Naeve

Chief Business Officer

RootPath Genomics

Alicia J. Hager

Chief Legal Officer



Nadir Mahmood



Mark Leuchtenberger 



Catherine Stehman-Breen

Chroma Medicine

J. Mike Smith

Managing Principal

Back West, Inc 


Robert Michael Poole
PresidentNW Biomedical Consulting, Inc.
Kenneth Moch


Euclidean Life Science Advisors, LLC 


Matthew Gall


iTeos Therapeutics, Inc.

Linda Rockett

General Counsel

Wave Life Sciences


Laura Tadvalkar

Managing Director

RA Capital

Bernat Olle


Vedanta Biosciences


Eric Marcusson

Co-Founder, Providence Therapeutics & Northern RNA

Marcusson Consulting


Marcos Milla

Venture Partner

Samsara BioCapital, LLC

Michele Libonati


Pacylex Pharmaceuticals, Inc.


Dolca Thomas

Venture Partner, BOD

Samsara, Ventus, Chinook

Susan Dillon
CEOAro Biotherapeutics 
Flavia Borellini

Biotech Executive, Board Director


Nancy Simonian


Syros Pharmaceuticals

Svetlana Lucas
CBOScribe Therapeutics Inc.
Eef Schimmelpennink

President and CEO

LENZ Therapeutics


Sumant Ramachandra

President and CEO


Fredrik Wiklund


Bright Peak Therapeutics 

Simon Read

CEO and Founder

Mariana Oncology


Sarah Kurz

Executive Vice President

Partner Therapeutics

Debanjan Ray



Michele Libonati


Pacylex Pharmaceuticals, Inc.


Dolca Thomas

Venture Partner, BOD

Samsara, Ventus, Chinook

Susan Dillon
CEOAro Biotherapeutics 
Flavia Borellini

Biotech Executive, Board Director


Nancy Simonian


Syros Pharmaceuticals

Svetlana Lucas
CBOScribe Therapeutics Inc.
Simon Read

CEO and Founder

Mariana Oncology


Sarah Kurz

Executive Vice President

Partner Therapeutics

Debanjan Ray




Jeffrey Smith

VP, Program Management


Eric Dobmeier

President & CEO

Chinook Therapeutics, Inc.


Thomas J Novak

Chief Scientific Officer

Autobahn Labs, Inc.

Stefani Wolff




David M. Epstein

President & CEO

Black Diamond Therapeutics

Tawni Koutchesfahani 

Executive Director, Manufacturing



Chris Varma

Frontier Medicines


David-Alexandre Gros


Eledon Pharmaceuticals

Patrick Trojer


TRIANA Biomedicines

Behzad Khosrowshahi

President & CEO

DRI Healthcare


Theron Odlaug, Ph.D.

Operating Partner

Signet Healthcare Partners

Saif Rathore, MD PhD

Former SVP Strategy, Cellarity

Andrew Hirsch

President & CEO

C4 Therapeutics


Laura Lande-Diner
CBOSatellite Bio
Amy Hummel

Associate Director, IND/IDE Management

Yale Center for Clinical Investigation


George Vlasuk

Board Member

Nimbus Therapeutics


Cara Tenenbaum


Strathmore Health Strategy

Daniel van der Lelie


Gusto Global LLC. 

Philip R. Johnson


Interius Biotherapeutics


Dave McDonald

Head of Life Sciences Investment Banking

Lake Street Capital Markets

Joseph Horvat

US General Manager

MorphoSys US, Inc.

Matt Ottmer

CEO & President

Kisbee Therapeutics, Inc


Seth Ettenberg

President and CEO


Edwin H Gordon


4c Advisors, llc

Andrew Funderburk

Managing Director

Kendall Investor Relations


Rita Balice-Gordon


Muna Therapeutics

Jonathan Leff


Deerfield Management

Mary Kay Fenton

Chief Financial Officer

Talaris Therapeutics


Kieren Marr


Pearl Diagnostics

Ananya Zutshi


Guardian Bio


Susan Sobolov


RIGImmune Inc


Amy Conrad


Juniper Point

Jacob Stangl

Founder and Director

OrisDx, Inc.

Mario David Saltarelli MD PhD
CEOGABA Therapeutics Inc



Ellen Leinfuss 

SVP, Commercial 


Ed Burgard PhD


Dignify Therapeutics




Tech, Pharma, and the Uneven Distribution of the AI-Enabled Future

David Shaywitz

The worlds of technology and entrepreneurship are captivated by recent advances in generative AI and large language models (LLMs). 

The arrival of ChatGPT, developed by OpenAI (a startup partnered with Microsoft), caused Google to declare a “Code Red,” akin to “pulling the fire alarm,” the New York Times explained. The latest class of startups at Y Combinator are reportedly flocking to AI. Students in the Harvard MS-MBA biotechnology program I advise tell me they are using ChatGPT constantly in section, and say the page is always open. I’ve also heard many medical trainees are routinely using it.

But if the future has arrived, as science fiction writer William Gibson famously observed, it’s not evenly distributed.

“People in tech are freaking out about LLMs, but not in science yet,” writes University of Rochester chemist and AI expert Andrew White.

Andrew White

“AI hype may be too high,” White observes, “but we’re missing hype on smart people + AI…. this will be the biggest transformation in science since the internet. Universities must be completely rethinking education and research.”

White’s onto something. There is an absolute frenzy of activity in tech, and a rash of startups seeking to apply AI to some aspect of biopharma, often drug discovery. 

But the view from within established biopharma companies tends to be more reserved. 

Far, far more reserved. 

Curiosity, wariness, weariness, and concern

As best I can determine, the view of incumbent biopharmas reflects a combination of curiosity, wariness, weariness, and concern. 

There’s authentic curiosity around ChatGPT and AI more generally, wariness about the newest new thing, weariness about successive cycles of technology hype and disappointment, and concern about the many unknowns.

No one in the pharma C-suite wants to miss the AI train. Then again, no CEO wants to explain to the media how confidential company information was inadvertently leaked – as recently happened at Samsung. Biopharma also must be serious about patient confidentiality and strict adherence to regulatory process. Not surprisingly, the industry is loath to engage in anything that could put these vital priorities at risk.

Consequently, many biopharmas are taking a cautious approach, considering generative AI the way they routinely evaluate other emerging technologies. Rigorous guidelines for use are established, highly specified pilot projects are proposed, reviewed and subject to tiers of approvals. Once clear guardrails are established, the new technology is gently prodded and poked. The potential is gingerly explored.

It’s not just senior executives who are risk averse. Most of my colleagues in biopharma are skeptical. 

After successive cycles of hope and disappointment, many seasoned drug developers just aren’t smitten by what seems like the latest shiny tech object. (I was probably in this camp as well before I started speaking with grounded AI experts like Zak Kohane and Peter Lee, who had early access to GPT-4, and began to appreciate over time that the technology represents something profoundly different.)

Many are still trying to understand what this technology can do. For instance, a colleague this week told me he tried GPT-4 for search and concluded “Meh. I’m still going to use Google.”

Playing around (or not)

What’s abundantly clear to me from Kohane, Lee, and others who have invested time in understanding GPT-4 is that:

  1. To really understand what GPT-4 can do, you need to spend a lot of time just playing with the technology, trying out all sorts of things, particularly in your area of expertise (like medicine).
  2. The more time you spend with GPT-4, the more it starts to feel like you’re developing a relationship with an extraordinary alien intelligence – powerful, imperfect, mystifying, intriguing.

Ideally – as one expert I spoke with this week suggested – the best way, in theory, for pharma colleagues to fully leverage GPT-4 would be to play around with it. This exploration would help determine the extent to which the technology could enable everyday tasks, and eventually contribute more profound insights. 

Given the concerns about risk, I don’t see this happening in biopharma. While data scientists like Cloudera co-founder Jeff Hammerbacher famously aspire to “party on the data,” this unfettered, playful approach tends not to be the dominant mindset of large biopharmas, given their abiding concerns around potential downside consequences.

One way GPT-4 is likely to arrive in pharma is through consultant service companies like Tata Consulting Services, Accenture, and Cognizant, to use the three examples highlighted by Chamath Palihapitiya on the “All In” podcast. As Palihapitiya notes, these companies do coding-for-hire work at scale, and are thus likely to be the first to operationalize tools like GPT-4 (which can assist and enable coders) so these firms can accomplish more with fewer people. 

GPT-4 will also come to pharma through applications, ideally from established, trusted vendors.  Familiar Microsoft Office products supercharged by GPT-4 will be an early example. For many emerging tools, generative AI will operate under the hood, largely invisible. Users, understandably, are likely to focus on the capabilities an application is providing — the job to be done — rather than on the underlying technology making this possible.

Culture Contrast

The contrasting attitudes of established companies and startups towards emerging technology — including, but hardly limited to, GPT-4 — reflects radically different goals and relationships to perceived risk.

Large established companies are defined by their ability to execute reliably at scale. In biopharma R&D, this means being able to manage a portfolio of complex programs globally. Included: everything from the consistent manufacturing of a range of products to the safe, responsible, and efficient conduct of clinical trials to navigating different regulatory procedures across the world. 

It’s a huge challenge to orchestrate these activities in parallel. The work requires a deliberate focus on establishing and optimizing repeatable processes, and making careful, deliberate choices – often involving multiple stakeholders – to ensure any risks to the established business are identified and hopefully mitigated.

Startups typically can’t, and don’t, work this way. Wall Street Journal technology columnist Chris Mims recently highlighted the prismatic example of Noam Bardin, a startup CEO who was absorbed into Google after his company, Waze, was acquired.

Noam Bardin

“What seems natural at a corporation,” Bardin said, “multiple approvers and meetings for each decision—is completely alien in the startup environment: make quick decisions, change them quickly if you are wrong.”

Bardin also described to Mims the differences in incentives he noticed before and after the acquisition.  “Before the sale,” Mims reports, “everyone’s financial interest was aligned with the performance of the company’s products. Once Waze was a subsidiary, getting ahead was all about getting promoted.”

As I’ve discussed (see here, here) a nearly identical description is found in Safi Bahcall’s Loonshots. The author, a former biotech executive, explains how disruptive innovation can be stifled by corporate processes dominated by risk-aversion and enlightened careerism. 

Suffocating processes designed to reduce risks are reportedly what caused Google to fall behind OpenAI and Microsoft in generative AI, according to the WSJ. “Now Google, the company that helped pioneer the modern era of artificial intelligence, finds its cautious approach to that very technology being tested by one of its oldest rivals [Microsoft],” the Journal reports (also covered nicely in this WSJ-associated podcast).

The risk aversion of large, established companies creates an opportunity for risk arbitrage. Startups can naturally shoulder more risk because they have less to lose and potentially more to gain. As I’ve discussed, this is reportedly how PayPal was able to defeat eBay’s attempt to develop a rival online payment product with Wells Fargo (called Billpoint). It is almost certainly why the most important generative AI applications for biopharma are likely to be developed by someone else. 

Bottom Line

While many technology companies view generative AI as essential technology that must be adopted as an existential, urgent imperative, established biopharma companies are taking a more cautious approach, curious about the opportunities, but wary of the many uncertainties and risks. 

Additional Astounding columns on generative AI:


New Book Contemplates How Generative AI Will Serve Man

David Shaywitz

In 1935, Astounding Science — the premier science fiction magazine of the day, and perhaps ever — published “Proxima Centauri.” It was a short story envisioning an encounter between a voyaging earth spacecraft and a ship from a nearby star system.

Written by Murray Leinster (William Fitzgerald Jenkins), the tale features the original use of the phrase “first contact” in science fiction. Think Close Encounters of the Third Kind, or perhaps more appropriately the “To Serve Man” episode of The Twilight Zone, since Leinster’s aliens turn out to be carnivorous plants who quickly develop (as alien plants often do) a taste for human flesh.

“First contact” is also the phrase Microsoft’s head of research Peter Lee selects to describe his initial encounter with GPT-4, in The AI Revolution in Medicine: GPT-4 and Beyond, the engaging and timely new book he’s co-authored with Harvard physician-scientist and

AI researcher Zak Kohane and journalist Carey Goldberg, documenting the trio’s early experience with this emerging, intriguing technology.

Lee’s phrase seems apt. When I asked GPT-4 to provide the first paragraph of a blog post on the subject, written in the style of The New Yorker, it responded:

The phrase “first contact” conjures up images of flying saucers and green men, of awe and wonder, of fear and loathing. It is the ultimate fantasy—or nightmare—of humanity’s encounter with the alien Other. But what if the Other is not from another planet, but from another machine? What if the first contact we are about to make is not with a distant civilization, but with a new form of artificial intelligence that surpasses our own in linguistic prowess and creativity? This is the prospect that looms over us as we await the arrival of GPT-4, the latest and most advanced iteration of a technology that can generate coherent and convincing texts on any topic, given only a few words or sentences as input….

GPT-4 even provides a cogent opinion on the popularity of “first contact” stories in science fiction, suggesting it may reflect the interplay of curiosity, fear, hope, and imagination.

Lee and Kohane have worked on AI their entire careers – yet neither seemed prepared for their encounter with GPT-4. Both described losing sleep as they contemplated the implications of what they describe as an “alien intelligence” with whom they each formed a “relationship.” Both are struck by its capabilities,yet acknowledge its limitations. 

Lee describes GPT-4 as “at once both smarter and dumber than any person you’ve ever met.”  He is particularly captivated by its ability to “imagine emotions and perhaps even empathize with people.”

Lee and his colleagues also present a series of specific, formalized challenges to GPT-4, examining its common-sense understanding, its moral judgement, and even its ability to navigate “theory of the mind” tests, exploring GPT-4’s ability to intuit what others might be thinking. The performance of the technology was extraordinary, Lee reports. 

Responding to one question involving two roommates who shared a cat that was moved from one place to another when one roommate left the apartment, GPT-4 not only correctly anticipated the likely reaction of each roommate, but even offered an opinion on what the cat in the scenario might be thinking – namely that the two roommates were “very rude and confusing because they keep moving it from one place to another without asking.”

As discussed in my last column, Kohane was especially impressed by the GPT-4’s clinical reasoning skills, and by the way it approached complex medical cases and suggested reasonable next steps. On the other hand, GPT-4 would also make some fairly basic mistakes (especially involving math), and would often confidently assert it was correct even when it demonstrably was not.

Having established GPT-4’s bona fides, Lee, Kohane, and Goldberg devote the balance of their text to a question that even the technology itself might struggle with: how do you solve a problem like GPT-4?  Each of the three authors seems focused on slightly different aspects of the challenge.

Lee appears especially preoccupied with the underlying existential question of what GPT-4 is, and whether at some level it can “understand” and “empathize.” He seems consumed by GPT-4’s capabilities, particularly since so many of these, “were not programmed by humans. Instead, they emerged into existence – sometimes unexpectedly – as its neural network grew.”

He continues, “how on earth can it be that the next-word prediction can possibly do… all the things that we’ve seen…unfortunately, we simply do not know the answer to this question.”

Kohane seems hopeful the technology can be used as a partner or co-pilot for healthcare providers, reducing burnout, administrative burden, and medical error, while allowing providers to practice at the top of their license. He delights in the possibility of physicians able to focus once more on the complex reasoning and human relationships that had first attracted so many of us to the profession.

Carey Goldberg

Projecting forward, Kohane imagines a next-generation large language model, fancifully called “Dr. One-With-Everything,” encompassing “protein structure, other basic biological databases (like gene regulation and human genetic variation), preclinical studies, and the design and conduct of clinical trials.”

This model, Kohane suggests, “will be likely the central intellectual tool for biomedical research by the mid-2030’s.”

Goldberg, meanwhile, offers the most pragmatic and in some sense relatable perspective on how GPT-4 will be used. She recognizes that “because GPT-4 appears to be such an extraordinary tool for mining humanity’s store of medical information, there’s no question members of the public will want to use it that way – a lot.” 

Already, Goldberg writes:

“health-related web searches are second only to porn searches, by some counts. Surveys find roughly three-quarters of American adults look for health information online. It’s not hard to predict a massive migration from WebMD and old-style search to new large language models that let patients have a back-and forth for as long as they want with an AI that can analyze personal medical information and seems almost medically omniscient.”

Moreover, she adds, patients want this capability now. While awaiting access to GPT-4, she writes, “My ‘everypatient’ emotion has tended to be impatience. Sure, I get the risks of hallucinations and other little-understood distortion, but I’ve still felt mainly the AI-delay frustration of people on the waiting list for chatGPT: ‘I get it – it’s not perfect. I’ll manage – just give me access!’”

The promise of democratizing this powerful technology is easy to appreciate.  As Microsoft AI expert Karmel Allison tells Goldberg, “If the internet and the mobile age were about putting information in the hands of everyone across the planet, the AI age is about putting intelligence into the hands of everyone across the planet.”

Karmel Allison

At the same time, the co-authors all recognize that there are clearly risks involved in deploying this powerful technology. Kohane, for example, asserts “GPT-4 cannot be used in medical settings without direct human supervision.”

Kohane and Goldberg also suggest that this is the “moment for broad, thoughtful consideration of how to ensure maximal safety and also maximal access,” and emphasize the need for “guardrails to keep patients as safe as possible.” But they also recognize it’s a “tricky balance,” adding:

“those safety measures must not mean that the great advantages that we document in this book end up unavailable to many who could benefit from them. One of the most exciting aspects of this moment is that the new AI could accelerate healthcare in a direction that is better for patients, all patients, and for providers as well — if they have access.”

None of the co-authors seem to seriously contemplate pausing ongoing work in generative AI – as Elon Musk and others have recently proposed.

Kevin Scott

Collectively, the authors’ perspective seems well-summarized by Microsoft Chief Technology Officer Kevin Scott, who tells Goldberg, “The technology will exist. It will have an enormous amount of possibility. I think it will be incredibly useful and powerful. And then society has to choose how it’s going to use it.”

It’s a thrilling future to envision, to anticipate, and (as many of us hope) to help create.

Unless, of course, the technology breaks away, and chooses how it’s going to use us. 

How To Serve Man? It was a cookbook.


Jan Skvarka, former Trillium CEO, on Driving a Turnaround

Vikas Goyal, Managing Partner, Trekk Venture Partners

Jan Skvarka isn’t a household name in biotech. Maybe he should be.

Skvarka was previously the CEO of Trillium Therapeutics, where he led a remarkable turnaround of the Canadian small cap biotech into a leading immune oncology player. Trillium had a market capitalization of $16 million when he started. Over the next two years, he led it to a $2.26 billion acquisition by Pfizer.

The acquisition gave Pfizer access to TTI-622 and TTI-621, two potentially best-in-class CD47 inhibitors now in development for multiple cancer indications, and a team of more than 50 expert drug developers.

Prior to Trillium, Jan had a long career as a strategy consultant at Bain & Co, an experience that would help him in many ways during Trillium. He is currently the executive chairman of DEM Biopharma, and a board member of Zentalis Pharmaceuticals and Monte Rosa Therapeutics.

Jan Skvarka, former CEO, Trillium Therapeutics

Jan spoke with me about why he is so excited about the CD47 mechanism, the situation when he joined Trillium, and how he approached the strategy, culture, and vision for the company.

How did you get involved with Trillium and what was the situation when you arrived?

I have always been fascinated by the success of T cell checkpoint inhibitors. It’s one of the biggest success stories in the history of medicine, delivering cancer cures, winning the Nobel Prize, and soon to be the largest drug class ever.

But, T cell checkpoint inhibitors engage only the adaptive arm of the immune system, and typical response rates are about 20-40 percent. My aspiration was to help create a novel checkpoint inhibitor therapy that would target the innate arm of the immune system, and – ultimately – in combination with T cell checkpoint therapies, to have a complete immunotherapy regimen that engages both arms of the immune system, and would challenge chemotherapy as a frontline approach in cancer

[When I joined Trillium in 2019,] CD47 was arguably the most promising innate immune system checkpoint inhibitor in clinical development. Trillium had two CD47 blockers with promising safety profiles and monotherapy activity.

Importantly, the molecules did not bind red blood cells and hence didn’t cause anemia, a major potential liability with some of the other CD47 targeted approaches in development. Trillium’s lead molecule also had stellar monotherapy activity, with over 90 percent of cutaneous T cell lymphoma (CTCL) patients showing lesion improvement within three weeks of treatment in an ongoing Phase 1 study.

Trillium had a great core executive team in Canada, comprised of CSO Bob Uger, CTO Penka Petrova and CFO James Parsons. They were highly capable in their respective functions, smart, loyal and dedicated.

But the company was facing numerous challenges.

One, the company’s lead program was intratumoral treatment of CTCL. Neither the delivery route nor the indication had any commercial legs. So this was an ironic situation — the clinical data was incredibly strong, but strategically the program had little commercial potential, and as such no appeal to partners or investors.

Operationally, the phase 1 study was stuck in its fifth year of crawling patient enrollment.

On the financial side, the stock price was down from a high of $30 to $0.40 per share. There was almost a complete exodus of quality investors save for NEA. We were only a few months of cash away from hitting Going Concern, and the company was about to be delisted from NASDAQ.

Nevertheless, the scientific foundation was there. And with this foundation, and the core executive team, I felt we had a shot at rebuilding.

What was your plan?

Given the challenging situation, I spent about six months on a diligence of the underlying science and Trillium’s assets. I wanted to be sure my conviction in the scientific foundation was solid.

I also wanted to be sure I was aligned with the board on what to do.

So I wrote a memo before I joined, outlining: (1) my analysis of the situation, (2) strategic options, and (3) plan and hypothesis for how to proceed. I presented the memo to chairman Bob Kirkman and, with his support, spoke to every member of Trillium’s Board. Once we had alignment, I was in.

It would end up being a two-year journey which I describe in three stages.

Stage one I’ll call the Emergency Room, stage two was Transformation, and stage three was The Build Out.

Stage one, the Emergency Room, took the first three months – the fourth quarter of 2019. We approached the situation like a patient in an ER, when you have to stop the bleeding. First, to address the cash burn, we had to lay off 40 percent of the staff. Second, we had a complete reset of strategy — we discontinued the lead intratumoral CTCL program and refocused on the intravenous route while prioritizing larger hematologic indications and solid tumors.

We also decided to resurrect the backup molecule, TTI-622, which would eventually become the molecule that drove Pfizer’s interest. By the way, I also believe that this decisiveness and speed helped us later rebuild investor confidence.

Stage two, the Transformation, took about 15 months, spanning 2020 and the first quarter of 2021. It was a lot of systematic blocking and tackling, touching every single aspect of the company.

On the people side, six out of eight board members and five out of eight executive team members, including myself, joined as part of the turnaround. We created a world class SAB and six indication-specific Key Opinion Leader panels.

We moved the headquarters from Canada to the US (Cambridge, Mass.), and transitioned from a foreign to a domestic filer. We raised $300 million across two rounds. We secured an equity deal with Pfizer for $25 million and added their chief scientific officer of oncology, Jeff Settleman, to our scientific advisory board.

At the first signs of COVID, we bought two years of manufacturing capacity in advance, a critical decision that helped us execute clinical studies without any delays.

On the clinical development side, we accelerated patient enrollment despite COVID, completed Phase 1 studies, declared recommended Phase 2 doses, and – critically – showed best-in-class monotherapy activity with intravenous delivery, and strong tox profiles.

We also did a lot of work in the trenches with investors. This was a turnaround and we needed to rebuild confidence. We had over 400 investor meetings in 2020! We recruited Paul Walker and Ali Behbahani from NEA to our board, which sent a strong signal to the investor community. And even with magrolimab’s good data at ASH 2019, it was only with our significant effort to communicate our new strategy that we got any read-through benefit.

In April 2021, we entered Stage three, The Build-out. With money in the bank, board and executive teams in place, and two molecules with class-leading monotherapy activity, we launched a broad Phase 2 program with nine clinical studies across multiple indications in both hematologic malignancies and solid tumors, while doubling the size of the organization within the next year.

Why did Trillium want Pfizer as an investor and how did that relationship evolve?

The initial $25 million Pfizer investment was not about the money – it was about validating our work, building relationships, and getting access to Jeff’s expertise.

Let me step back to January 2020, just as we exited the “ER”. At that time, we announced a new strategy transitioning TTI-621 from intratumoral to intravenous delivery, and from CTCL to larger hematological malignancies.

A few months later that year, our back-up program TTI-622 started showing strong monotherapy activity with a very good tox profile, while TTI-621 was experiencing thrombocytopenia issues. We made a strategic decision to transition the strategy a second time, making TTI-622 our new lead program while deprioritizing TTI-621. I was worried about how this new transition would be perceived by investors.

The Pfizer equity investment gave us an important validation for the shift to TTI-622. On Sept. 8, 2020, at 4 pm, we announced the new data for TTI-622. Two hours later, at 6pm, we announced the Pfizer deal. The day after, we announced we were going to do a public fundraising offering. Then on Sept. 10, we closed the round for $150 million.

At this time, with Phase 1 studies of both TTI-621 and 622 ongoing, we weren’t looking for a partner. We were in a great place to continue building the data and building the company, and we had high confidence in our assets. However, come May 2021 and the stock price started coming down, partly due to the markets getting nervous about biotech, and partly due to some retail investors selling out of their Trillium positions.

I approached John DeYoung, Pfizer’s head of business development for oncology, to ask if Pfizer would consider another $25 million equity investment, given that we had generated [substantial additional] Phase 1 data since Pfizer’s initial investment in September 2020. John said “let us have a look at the data” and Pfizer started the diligence. While they were looking at the updated Phase 1 results, Phase 2 data started coming in, including from some very tough multiple myeloma and AML patients, two indications of strategic interest to Pfizer.

It was at this point that Pfizer shifted their interest from a simple equity investment to a full buy-out.

How did you manage the culture through all those changes?

I’m not a believer in lengthy meetings about culture and putting lots of buzzwords on the wall. Buzzwords are cheap – after all, even Enron had “Integrity” engraved on their headquarters entrance wall. I think culture is shaped organically through how we make decisions, who we recruit, and how we treat employees. It has to be with respect, transparency and honesty, while always keeping patient impact in mind.

It is critical to have a vision and be crystal clear about the company’s direction. And not just clarity about who you are. It’s also equally important to be clear about who you are not. Without this clarity, companies and executives get distracted, they get pulled in different directions.

The toughest part of my time at Trillium was Stage one, the emergency room. Turnaround situations require decisive leadership and speed. There is no room for hesitation. You cannot procrastinate. Maybe you can still pay severances if you move today, but if you prolong things six months the company could run out of cash. And the team is deflated and maybe considering moving on to other opportunities – so staff are already anxious to hear where we are heading. So, we did these changes with speed, balanced with respect and transparency.

It was this respect and transparency with our staff that allowed us to rehire several laid-off employees once we were stabilized.

What were some of the keys to your successful relationship with Pfizer?

Trust is key. Don’t oversell, always be honest and transparent. In our case, Pfizer had about 150 people on the due diligence, and they turned over every stone. So, if there are any problems, just be transparent about them, disclose them upfront, as you don’t want them to come up later in the diligence and then play defense.

Relationships have been important to your success. Can you talk about some that have been pivotal for you?

That’s a great question. I believe there are two parts to it – relationships that contributed to our success at Trillium, and relationships that were formative to who I am as a person and an executive.

On the Trillium part, we had a truly outstanding team. In addition to my Canadian executives who I mentioned before, we later added Ingmar Bruns, a talented, brilliant chief medical officer; Lisa Fiering, an excellent human resources executive; Ben Looker, an outstanding general counsel; and Rose Harrison who thoughtfully led our strategy efforts.

Paolo Pucci, our lead director, masterfully guided the board through its M&A considerations and was always there for me as a great coach and mentor. Jason Fenton of Cowen (now with Oppenheimer) played a critical role in our fundraising efforts, especially at a time when no other banker would have touched Trillium. Eric Tokat of Centerview was much more than just our M&A banker – he was also a true advisor who guided several of our major strategy and BD decisions even before we were an actual M&A candidate.

I would be remiss not to mention also the Pfizer oncology leadership team – Jeff Settleman, Oncology CSO, who as our SAB member greatly contributed to some of our most critical clinical development decisions; Chris Boshoff, oncology chief development officer, who did a phenomenal job at pre-merger integration and squarely deserves the credit for achieving a 100 percent acceptance rate of the Trillium staff who were offered to continue with Pfizer after the acquisition; and John DeYoung, oncology BD head, a master communicator and someone who just gets things done.

Beyond Trillium, I have been incredibly lucky to have great mentors who took personal interest in me, helped me grow as an executive, and navigated me in many tricky situations. In particular, I owe enormous debt to three people who I worked with as a CEO of Tal Medical prior to Trillium – Steve Paul, Tal co-founder and Board chair, former head of R&D at Lilly, who coached me in my transition from a Bain consultant to a life sciences CEO; John Abele, Tal senior advisor, co-founder and former chair of Boston Scientific, who taught me how to build industry relationships and manage people; and Bob Langer, co-founder of Tal’s parent company PureTech and MIT professor, who helped me navigate several complex business and career situations.

Last but not least, I’d like to mention Chuck Farkas, senior partner at Bain & Company, under whose thoughtful mentorship I grew from a fresh MBA grad to one of the lead life sciences partners at Bain. It is my aspiration to help other life sciences executives by passing on the knowledge I learned from these great individuals.


Timmerman Traverse for Life Science Cares is Back

Luke Timmerman, founder & editor, Timmerman Report

The next biotech team adventure is here.

I’m thrilled to announce the Timmerman Traverse for Life Science Cares 2023.

We’re on a mission to raise $1 million. We’re giving it all back to the most vulnerable people in the communities where we live and work.

This trip involves shared sacrifice. We will cover 20+ miles and gain 8,000 feet of net elevation on the Presidential Traverse in New Hampshire. The expedition is set for Aug. 20-23, 2023.

Sweat will be involved. Legs will be tired. The weather may get rough. Teammates will need to lend each other a hand.

The difficulty is what makes it so meaningful. Over the past two years, this initiative has raised a combined $1.7 million to fight poverty.

Awareness of Life Science Cares and its outstanding network of community nonprofits is on the rise. Relationships among scientists, executives and investors have been forged on the trails. Sometimes these relationships translate into new professional and business opportunities.

Who’s on the Team?
  • Luke Timmerman, founder & editor, Timmerman Report
  • Art Krieg, founder and former chief scientific officer, Checkmate Pharmaceuticals
  • Samantha Truex, CEO, Upstream Bio; board of directors, Life Science Cares
  • Lydia Meyer-Turkson, senior director, early innovation partnering, Johnson & Johnson
  • Ted Love, entrepreneur, former CEO, Global Blood Therapeutics
  • Tim Springer, Professor of Biological Chemistry and Molecular Pharmacology, Professor of Medicine, Harvard Medical School; founder, Morphic Therapeutic, Scholar Rock
  • Andrea van Elsas, partner, Third Rock Ventures
  • Lalo Flores, CEO, Century Therapeutics
  • David Schenkein, general partner, GV
  • June Lee, venture partner, 5AM Ventures
  • Katherine Andersen, Head of Life Science & Healthcare
    Corporate Banking and Relationship Management, SVB
  • Ben Portney, investment partner, Andreessen Horowitz
  • Kaja Wasik, co-founder and chief scientific officer, Variant Bio
  • Yael Weiss, CEO, Mahzi Therapeutics
  • Heath Lukatch, managing partner, Red Tree Venture Capital
  • Raju Prasad, CFO, CRISPR Therapeutics
  • Kaye Foster, senior advisor, executive coach, BCG; venture partner, ARCH Venture Partners
  • Sandra Glucksmann, biotech entrepreneur, former CEO, Cedilla Therapeutics
  • Uciane Scarlett, principal, MPM Capital
  • Sheila Gujrathi, board chair, ImmPACT Bio
  • Hamid Ghanadan, founder and CEO, The Linus Group

The Life Science Cares network is brimming with excellent nonprofits who are entrepreneurial problem-solvers. Some provide basics like food and shelter. Others concentrate on on-ramps to a better life in the long term, through science education and job training. They are smart, caring, inspirational, resilient people.

Our resources are concentrated in biotech industry clusters — Boston, San Francisco, San Diego, Philadelphia, and New York.

Everyone who goes on this expedition must raise a minimum of $25,000. Many raise more. Each hiker has his or her personal reasons for stepping up to the challenge. I encourage you to look over their personal statements and donate to their campaigns on JustGiving.org.

Corporate sponsorship opportunities for this year’s Timmerman Traverse for Life Science Cares are available. See Mathias Vialva mathias@lifesciencecares.org for more information. If you are interested in joining the hike, see me. luke@timmermanreport.com.

These trips are a wonderful way to enjoy nature, get fit, give back, and make new friends.

Biotech entrepreneurs can do amazing things when focused on a tough challenge.

Let’s roll up our sleeves and fight poverty together.


See what alumni of the Timmerman Traverse have to say:

“We started as industry colleagues with an aligned philanthropic goal. We finished as friends, deeply connected through an experience none of us will ever forget and all of us will work to rekindle in our lives.” — Reid Huber, partner, Third Rock Ventures

On the top of Mt Clay, there are no hierarchies, job titles, favored sons, or favored daughters. You are driven by your personal grit, your fellow climbers, and the beauty and challenges in front of you. We climbed for ourselves, we climbed for each other, but most importantly we climbed for the community being served by Life Science Cares. It was a bond we will never lose.” — Dave Melville, founder and CEO, The Bowdoin Group

It was amazing to see leaders across our biotech industry come together to raise funds to help bridge the unfortunately real gap between the medicines we develop, and the patients and communities who need access to them.” – Vineeta Agarwala, general partner, Andreesen Horowitz


Members of the Timmerman Traverse for Life Science Cares 2022. At Crawford Notch.



Treating a Common, Underappreciated Disease: Eric Dobmeier on The Long Run

Today’s guest on The Long Run is Eric Dobmeier.

Eric is the CEO of Seattle-based Chinook Therapeutics.

Eric Dobmeier, CEO, Chinook Therapeutics

Chinook is seeking to develop drugs for kidney diseases. About 10 percent of people on Earth are estimated to have some degree of chronic kidney disease. It ranges from mild forms all the way through end-stage renal disease that requires dialysis. America spends $130 billion a year on managing and treating kidney disease.

The therapeutic options are pretty limited. Chinook is developing a Phase III drug candidate, atrasentan, for IgA nephropathy – a disease of localized inflammation in the kidneys. That’s a small molecule. It also has an antibody drug candidate for IgA nephropathy in Phase II, aimed against a target called APRIL.

The founding thesis of the company was to use some of the tools of precision medicine – which have successfully changed the way many types of cancer are treated. That vision hasn’t exactly materialized yet. But the FDA has shown some willingness to consider surrogate endpoints, biomarkers, that make clinical trials a bit more practical to run. Kidney disease has become more attractive for drug developers who have to look at the time and expense required, and probability of success of various disease categories, before deciding where to invest.

During a biotech financial downturn, Chinook finds itself in the fortunate position of having late-stage clinical assets that will deliver meaningful data readouts within the next year.

Eric comes to this opportunity after a long career on the business side of biotech. Eric, a lawyer by training, made his way from basic contracts to more strategic business development, and eventually other functions – investor relations, communications, manufacturing, and corporate strategy. He was there 15 years, as the company grew into the leading maker of antibody-drug conjugates for cancer. Seagen has now agreed to be acquired by Pfizer for $43 billion.

Eric’s had quite a career already, and he’s an area with a lot of patient need, and a lot of potential for biotech to help people live better lives.

And now for a word from the sponsor of The Long Run.



Occam Global is an international professional services firm focusing on executive recruitment, organizational development and board construction. The firm’s clientele emphasize intensely purposeful and broadly accomplished entrepreneurs and visionary investors in the Life Sciences. Occam Global augments such extraordinary and committed individuals in building high performing executive teams and assembling appropriate governance structures. Occam serves such opportune sectors as gene/cell therapy, neuroscience, gene editing, the intersection of AI and Machine Learning and drug discovery and development

Connect with Occam

Now, please join me and Eric Dobmeier on The Long Run.



Welcome to the AI Irruption

David Shaywitz

Biopharma, like the rest of the world, appears to be on the threshold of profound, technology-induced change. Incredible advances in artificial intelligence, manifested most recently in GPT-4, are here. 

This technology, Ezra Klein explains in the New York Times, “changes everything.”  Bill Gates describes it as “the most important advance in technology since the graphical user interface,” and declares, “the age of AI has begun.” Similarly, Times columnist Thomas Friedman argues:

“This is a Promethean moment we’ve entered — one of those moments in history when certain new tools, ways of thinking or energy sources are introduced that are such a departure and advance on what existed before that you can’t just change one thing, you have to change everything. That is, how you create, how you compete, how you collaborate, how you work, how you learn, how you govern and, yes, how you cheat, commit crimes and fight wars.”

At an entrepreneurship salon at Harvard this week, I discussed GPT-4 with Dr. Zak Kohane, Chair of the Department of Biomedical Informatics at Harvard University (disclosure: I’m a lecturer in the department), and Editor-in-Chief of the soon-to-be-launched NEJM-AI.  

Kohane received early access to GPT-4. He has just completed a book, The AI Revolution in Medicine: GPT-4 and Beyond, to be published in mid-April, about the impact of emerging AI technology on healthcare. I read an advanced, draft copy of the book. Kohane’s co-authors are Peter Lee, Corporate Vice President and Head of Microsoft Research, and Carey Goldberg, a distinguished journalist. 

From both the book and the salon, the three most striking features of GPT-4 seem to be:

  1. Its ability to reason;
  2. Its ability to communicate and engage with people in natural language;
  3. The fact that no one really understands how it works.

How did GPT-4 impress Kohane? For starters, it performs spectacularly on standardized exams like the medical boards, and seems to be able to reason thoughtfully, Kohane says.

Zak Kohane

For example, we discussed the ability of GPT-4 to respond to an apparent paradox that Kohane says stumps the vast majority of the non-physician data scientists. The question: why is a low white blood cell count between midnight and 8 am associated with far worse outcomes than a low count between 8am and 4 pm? 

GPT-4’s top suggestion, Kohane says, was the correct answer: the issue isn’t so much the low blood count but rather the existence of a blood draw in the middle of the night. That signals the patient is experiencing some sort of medical crisis. 

GPT-4 can also provide sophisticated differential diagnoses, Kohane says, and suggest relevant next steps. 

He posed GPT-4 a question from his own specialty, pediatric endocrinology:

“I gave it a very complicated case of ambiguous genitalia that I was actually called for once back in my training. And it’s able to go through everything from the clinical presentation to the molecular biology. It had a disagreement with me and was able to cogently disagree with me, and it was also able to articulate concerns for the parents of this child and for the future engagement of the child in that discussion. So, on the surface it’s acting like one of the most sensitive, socially aware doctors I’ve ever met. But we have no guarantee that it is such.”

The ability of GPT-4 to engage in such a human-like fashion is one of the most striking, and disarming, characteristics of the technology. Many who engage with GPT-4 over time describe the sense of developing a close relationship with it, in a fashion that can feel dislocating. Kohane, Lee, Friedman and others all describing losing sleep after spending time with GPT-4. They are overwhelmed, it seems, by the power and possibility of what they’ve experienced.

 “GPT-4’s abilities to do math, engage in conversation, write computer programs, tell jokes, and more were not programmed by humans,” wrote Lee, of Microsoft Research. These capacities emerged unexpectedly, he wrote, “as its neural network grew.“

Peter Lee, Corporate Vice President,
Microsoft Research

This creates what Lee calls a “very big problem.” He writes: “Because we don’t understand where GPT-4’s capabilities in math, programming, and reasoning come from, we don’t have a good way of understanding when, why and how it makes mistakes or fails….”

The implications are dizzying. As Kohane writes, “I realized we had met an alien agent and it seemed to know a lot about us, but at the moment, I could not decide if it should be given the keys to our planet or sealed in a bunker until we figured it out.”

Implications for Healthcare

Some AI experts, like University of Toronto professor and author Avi Goldfarb, said the AI technologies will serve as a democratizing force in healthcare. He suggests, in a podcast interview with Patrick O’Shaughnessy, it will be able to “automate diagnosis,” with the consequence of “upskilling” the “millions of medical professionals” like nurses and pharmacists. The consequence, he suggests, is that:

“There’s hundreds of thousands of doctors in the U.S. and their special skill in diagnosis is going to go away. They’ll have to retool and figure out how to deal with that. But there’s millions of other medical professionals who are now going to be able to do their jobs much better, be more productive. And that upskilling provides a lot of what we see as the hope and opportunity for AI.”

I asked Kohane about this, and (to my surprise) he seemed to largely agree, albeit with a slightly different framing.  He notes that we have a crisis resulting from a shortage of  primary care doctors. Massachusetts (as the Boston Globe has recently reported) is being hit particularly hard. While we may have an idealized view of how the best primary care doctors can treat patients, Kohane argues, this is generally not the lived reality, and suggests that a nurse practitioner or physician assistant, coupled with AI, could generally offer a higher level of care for patients than a typical primary care doctor without AI. Given the shortage of trained medical professionals, AI can help improve the quality and quantity of available care.

It’s also clear that patients will have access – and, through Bing (which works with GPT-4 when accessed from Microsoft’s Edge browser), already have access – to this knowledge and information. 

Many patients and caregivers are eager for this capability, as Goldberg writes in the book. The problem is that GPT-4 (like surgeons and Harvard grads) tends to be frequently correct but rarely in doubt. It still suffers from the problem of “hallucinations,” making up information that sounds plausible but isn’t accurate. Like humans suffering from the Dunning-Kruger Effect, it can insist that it’s correct, when it’s wrong. I saw that when GPT-4  tried to persuade me that Goose, not Merlin, uttered the line “That MIG really screwed him up,” in the original Top Gun

For now, everyone seems to acknowledge the hallucination problem, and call for “human in the loop” approaches. But what happens as we gain more confidence in GPT-4 and, motivated by both convenience and cost, are increasingly tempted to take the human out of the loop?

Stepping Back

What seems clear is that we are truly experiencing what economist Carlota Perez has described (see here) as the “irruption phase” of emerging technology. We recognize that there’s something promising and incredibly exciting, and now everyone is trying to figure out what to make of it, and how to apply it.

These days, it feels like every healthtech person I know who hasn’t started their own VC fund (as noted here) is either starting their own health+AI company or writing a book about health+AI, and in some cases both. Microsoft Office programs are about to be boosted by GPT-4. Other companies, such as the regulatory intelligence company Vivpro – are already offering GPT-powered tools. Every consultancy is offering executives frameworks and navigation guides to the new technology.

The truth, of course, is that no one has any idea how things are going to evolve. The pharma company of the future, the healthcare system of the future, the payor of the future, perhaps even the FDA of the future: all are likely to be profoundly changed by technologies like GPT-4. 

The technology will likely first arrive as incremental, point solutions, says Goldfarb, of the University of Toronto. Eventually, however, the real productivity gains arise from more fundamental change.  The classic example here, as I’ve discussed, and as Goldfarb also cites, is that dropping electric generators into factories built around steam power didn’t have much impact. But reconceptualizing the structure of factories from the ground up, in a fashion enabled by electricity, was transformative.

As Microsoft AI expert Sebastien Bubeck observes in Kohane’s book, “GPT-4 has randomized the future.  There is now a thick fog even just one year into the future.”

What an amazing, terrifying, thrilling, and hopeful time to be alive.  For those of us in medicine and biomedical science: what an opportunity, and profound responsibility, to be in the arena, actively shaping the future we hope to create and aspire to inhabit.


The Future of Neuroscience Drug R&D: Ryan Watts on The Long Run

Today’s guest on The Long Run is Ryan Watts.

Ryan is the co-founder and CEO of South San Francisco-based Denali Therapeutics.

Ryan Watts, co-founder and CEO, Denali Therapeutics

Denali is one of the prominent development-stage biotech companies working on treatments for neurodegenerative diseases. It has a pipeline with seven drug candidates in clinical development. It’s developing small molecules and large molecules against a range of neurodegenerative diseases that includes rare diseases such as Hunter Syndrome and ALS, as well as more common maladies such Alzheimer’s disease and Parkinson’s.

Ryan is a scientist by training. He did his PhD at Stanford University and spent the first part of his career running labs at Genentech. He joined with former Genentech colleagues Alex Schuth and Marc Tessier-Lavigne to co-found Denali in 2015. The company secured a Series A financing of $217 million – which was big then, and is still big now. The company doesn’t yet have any products on the market, but it has amassed $1.34 billion in cash as of the end of 2022, and has established a broad base of support for its R&D through partnerships with Sanofi, Biogen, and Takeda Pharmaceuticals.

This is a wide-ranging conversation that includes Ryan’s path into biotech and neuroscience, some of the classic challenges of the field, and reasons why he’s optimistic that significant progress is coming to neuroscience R&D.

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Now, please join me and Ryan Watts on The Long Run.