2023 Best Books
Designing therapies, building companies, developing agency
Five of my favorites, in alphabetical order:
Altered Fates by Jeffy Lyon & Peter Gorner
For Blood and Money by Nathan Vardi
The Founders by Jimmy Soni
Living Medicine by Frederick Applebaum
Scaling People by Claire Hughes Johnson
Altered Fates by Jeff Lyon & Peter Gorner
Cell and gene therapies are rapidly changing the practice of medicine, and it seems likely that the prevalence of these modalities will only increase with time.
How did this happen?
I realized earlier this year that even after a decade working adjacent to and within the field, I have never encountered a concise, clear narrative on how the first gene therapies trials came to pass or how the tools of the trade were discovered. There are a fairly small number of delivery vectors and cognate cellular targets in common use — where did they come from? How did the field’s various dogmas about the suitability of a given tool for a given tissue develop? Many of the details seem to have been lost from the community’s collective conscience and pedagogy.
Altered Fates was the history I yearned for. Lyon & Gorner wrote much of their work contemporaneously with the execution of the first FDA approved gene therapy trial, and they were able to perform personal interviews with the majority of players in the field at the time.
It would take a much longer post to encapsulated everything I learned from Fates, but in brief form, the following details of gene therapy history were a surprise to me:
The first gene therapy trial occurred in 1969 (!) with a leporine virus
Early gene therapy trials were really cell therapy trials, as all editing was performed ex vivo
The first FDA-approved gene therapy trial in 1990 actually worked and helped patients, contrary to a popular narrative that much of the early work was premature
The National Cancer Institute (NCI) was once the world’s most prolific gene therapy center, centralizing many of the practitioners and resources. Legislative changes in 1985 (Gramm-Rudman-Hollings) led to a diaspora of talent and decentralization of expertise into industry and smaller academic settings, setting the stage for our modern industry.
Regulatory precedent from the first trial in 1990 unlocked a rapid expansion of trials (32 trials in 1992, 59 by 1994 — geometric growth), highlighting the importance of a legible regulatory path for new medicines.
I look forward to writing up a more complete summary soon. Fates is easily in my top 10 books about therapeutics and their development.
For Blood and Money by Nathan Vardi
For Blood and Money belongs alongside Billion Dollar Molecule, Her-2, and Breath from Salt on your drug development bookshelf.
Vardi follows the story of Imbruvica (ibrutinib), an inhibitor for the Bruton’s tyrosine kinase (BTK) protein that serves as a critical signaling axis in B cells of the immune system. Ibrutinib was the first among a class of drugs targeting BTK that have proven effective for treating certain blood cancers. The story is unconventional in a half-dozen ways, and highlights the sheer serendipity that often enables new drug development.
Ibrutinib was originally acquired by Pharmacyclics from Craig Venter’s Celera Genomics for pennies as part of a broader IP deal, then went on to be the centerpiece of an eventual $21B acquisition by AbbVie. Along the way, the company was led by a charismatic CEO who had no biotech background, but among other successful business ventures, created the McDonald’s chocolate chip cookie recipe.
Celera had left the drug on the cutting room floor because it was a covalent inhibitor, going against a common drug development dogma that suggests covalent binders are often toxic. Pharmacyclics found in early trials that imbrutinib radically reduced cancer burden in chronic lymphocytic leukemia (CLL) patients, so much so that blinded clinical trials became challenging because physicians could trivially see the benefits for patients receiving the drug relative to a placebo. At this stage, Pharmacyclics knew that they had a winning medicine, but they still needed to develop it. They went from molecule to drug candidate in an extraordinarily short time.
For Blood is a unique story for exactly this reason. Most of the other tomes in the biotech canon cover the early discovery phases of medicinal invention, but shed less light on the people and patients who make clinical trials and eventual commercialization possible. The Pharmacyclics story provides Vardi a vehicle to “skip to the end” of the development process and explain the fractal complexity of bringing a molecule from the lab to the world.
The Founders by Jimmy Soni
The formation of the Paypal Mafia is one of the founding stories from Silicon Valley’s first internet wave. It’s easy to find a dozen articles outlining how unlikely it is that so many successful entrepreneurs and investors would all work together, purely by chance, on the same payments startup. Surprisingly, it’s hard to find any that go a step deeper and ask why so many members of the early Paypal team went on to succeed in diverse fields.
The Founders is an excellent, rapidly paced answer to this question. The story itself feels like reading a thriller novel. Soni manages to capture the emotional intensity of building a company in lucid prose, even when the real life events he was given as substrate involve moving about an office building and staring at computers. Most of the triumphs and crises occur primarily in the team’s heads.
If I were to summarize the core explanatory argument of Founders in three lines:
Everyone at early Paypal learned to exercise outlier levels of agency.
Individual exceptionalism was further amplified when the principals collectively found a game where hard work translated directly into impact, rewards, and power with a tight feedback cycle. They learned that agency is rewarded if you find the right place to apply it in a manner that is difficult to teach outside experience.
The agency the principals developed through this experience explains much of the success they experienced downstream.
For those curious about early Internet history or the agency production function, Founders is a great read.
Living Medicine by Fredrick Applebaum
Hematopoietic stem cell (HSC) transplants (“bone marrow transplants”) can offer life saving treatment for many forms of blood cancer and inherited disease, treating more than 20,000 patients/year in the US alone. Living Medicine is the story of Don Thomas (Nobel, 1990), the man who invented the technique. It is also the story of the patients who bravely participated in early trials against all odds, and the downstream technologies that have blossomed as a result.
In the early years transplantation, Thomas’ patients were all terminally ill with blood disorders and had no other hope for treatment. At the time, medicine was still naive to the incredibly complex biology of histocompatibility, so Thomas’ patients unfortunately failed to engraft, then passed away time and again. He was widely criticized as a barbarian and accused of promising patients cures that he could not deliver, yet he persevered against conventional wisdom to unravel the mysteries that separate one body from another.
Thomas eventually prevailed and learned to match donors with recipients using clinical diagnostics, eventually leading a specialized transplant ward at Pacific branch of the Public Health Service hospital system in Seattle. His ward and its physicians eventually served as one of the nucleating agents for the Fred Hutchinson Cancer Center (“the Hutch”), one of molecular biology’s most differentiated research organizations.
Living Medicine was a reminder for me that often the best ideas look incorrect, even foolish at first blush.
Scaling People — Claire Hughes Johnson
Johnson’s Scaling is perhaps the most important entry into the management canon since High Output Management. Like Grove before her, Johnson is wonderfully tactical in her guidance, eschewing the high level pseudo-philosophy that too often plagues management advice.
Scaling is all the more valuable because it’s one of the few entries in the management literature that isn’t primarily a restatement of Taylorism. Scientific management principles are often strictly superior to ad-hoc decision making, but there are clearly many cases in modern knowledge work where the management tools developed for manufacturing businesses in the early twentieth century fall short. Scaling provides answers to questions like: How should I instrument a fundamentally creative process like product development or design? How do I measure progress in a non-linear R&D environment?
Highly recommended for anyone building or operating within an ambitious organization.