David Shaywitz

Pharma colleagues: does this complaint sound familiar?

This company is too bloated. It’s too slow. We have all these layers and layers of bosses where leaders at the top would decide on the strategy, and then it would just trickle down to the people who actually did a lot of the day-to-day work…. I am 10 layers below the CEO and I have ideas for how this company could be better, but they’ll never be heard because there are just so many people above me who are making those decisions.

According to Wall Street Journal reporter Chip Cutter, it’s exactly what newly installed Bayer CEO Bill Anderson heard when he joined the company last June and embarked on a listening tour.

A seasoned pharma veteran who was previously CEO of Genentech and then CEO of Roche Pharmaceuticals, Anderson had become “disillusioned over the years by the many approvals and endless rounds of meetings required to get anything done at large companies,” Cutter reports.

Bill Anderson, CEO, Bayer AG

Anderson heard the same gripes at Bayer.  He was told that “launching a new product takes years instead of months,” Cutter writes.  “Disputes between departments take too long to resolve. He learned that company rules and procedures fill 1,362 pages, he said, ‘longer than War and Peace, and a lot less exciting.’”

At the same time, Cutter also points out that “Modern corporate hierarchies have persevered because they largely work and attempts to subvert them haven’t.”

Nevertheless, Anderson is trying to “rewire” the company culture, focusing on “fewer bosses, fewer rules.”  The plan – built around a principle Anderson calls “dynamic shared ownership” — involves self-assembling groups of employees deciding on priorities, and working together to accomplish projects for 90 days, and then repeating the self-assortment process. 

The idea, as “The Journal” podcast co-host Ryan Knutson explains, is “to empower employees to make big decisions without having to get the approval of layers and layers of management.”

To guide the process along are leaders/advisors, in roles called “’visionaries,’ ‘architects,’ ‘catalysts’ and ‘coaches,’ positions focused on longer-term strategy and guidance-giving,” according to Cutter.

It’s a radical departure from the usual way of conducting business in large companies, Anderson recognizes.  “The first go round, it’ll be a little messy,” Anderson says, “but that’s okay because the thing is, the thing we’re comparing to is a system that doesn’t work very well. So this is the thing. We don’t actually have to be that good to beat the current system.”

Cutter describes an example of the new way of working, focusing on a self-assembled team focused on expediting the launch of a new line of vitamins.

The team didn’t spend time creating a polished PowerPoint presentation to show company higher-ups. Executives were instead periodically invited to the Garage [a dedicated innovation area] to look at designs and ideas on the walls and offer any suggestions.

Typically, the timeline for a product launch takes into account the multiple layers of approval needed for each stage of the rollout. If eight people gather from different departments, each of them would spend much of their time getting their individual bosses to sign off on an idea.

“They’ve got to convince eight people,” Anderson said. “And when one or two of them says, ‘No, no, actually, I like this better,’ then the other six have to go back and convince their managers about the new plans.”

Not any more, Anderson said, gesturing with cupped hands and making the sound of an explosion. 

The team “hit its mark,” Cutter writes.  “Bayer’s new line of One a Day vitamins, packaged in a palette of pink and purples, went on sale in March, a year ahead of schedule.”

As Cutter observes, “Anybody who has gotten an early taste of this, a lot of former CEOs, management thinkers, and others, they are all captivated by what happens here because Bayer is touching on problems that are so familiar throughout corporate America and so if this works, it could be dramatic.”

The Challenges of Scale, The Drive For Control

Whether or not Anderson’s solution sticks, he is unquestionably getting at a real problem in large corporations: the tendency of entrenched bureaucracies to inhibit agility and dampen innovation (or, to put a somewhat finer point on it: to crush the souls and extinguish the spirit of often highly innovative employees drawn to industry by the desire to have an impact and make a difference).

This challenge also is highlighted in my favorite management book: former Pixar CEO Ed Catmull’s Creativity Inc., as I’ve discussed here.  (An expanded edition was recently released, as Catmull discussed with the WSJ here.)

Ed Catmull

As Catmull sees it, “full creative engagement” requires us to “uncouple fear and failure – to create an environment in which making mistakes doesn’t strike terror into your employees’ hearts.” 

This sounds great as a mantra, Catmull acknowledges, but in practice, managers also are typically told “the success of our enterprise depends on your group doing its job on time and on budget.”

Consequently, he says, if managers “have to choose between meeting a deadline and some less well-defined mandate to ‘nurture’ their people, they will pick the deadline every time.”

Managers, Catmull explains, “typically want two things: (1) for everything to be tightly controlled, and (2) to appear to be in control.”

And now we get to the crux of the issue:

But when control is the goal, it can negatively affect other parts of your culture.  I’ve known many managers who hate to be surprised in meetings, for example, by which I mean they make it clear they want to be briefed about any unexpected news in advance and in private.  In many workplaces, it is a sign of disrespect if someone surprises a manager with new information in front of other people.  But what does this mean in practice?  It means there are pre-meetings before meetings, and the meetings begin to take on a pro forma tone.  It means wasted time.  It means employees who work with these people walk on eggshells.  It means that fear runs rampant.

I suspect most pharma veterans will recognize these behaviors.  (See also Safi Bahcall’s Loonshots – my WSJ review here, and additional biopharma discussion here.)

The question is whether these patterns of behaviors are inextricably tied to the smooth functioning of massive sprawling corporations, with their need for alignment, their reliance on hierarchy, and their instinctive prioritization of tight control to drive consistency, efficiency, repeatability, and standardization? 

One alternative, presumably, might be a more trust-based cultivation of originality and creativity that Catmull champions. 

There are other challenges related to company size: in a smaller organization, the relationship between your individual contribution and the mission and success of the company is much easier to discern, and often immediately palpable.  But in massive, incredibly complex companies, most of the time, your sphere of control can feel far removed and often detached from the overall trajectory of the company as a whole.  Hence the tendency to keep your head down and focus exclusively on your specific deliverables, which you rely on to maintain your bearing.

Adding to the challenge, employees in large companies typically operate in the disorienting miasma of corporate buzzwords and platitudes, constantly repeated. 

Terms like “innovation” tend to be invoked so often, and applied to the most pedestrian activities, that they quickly lose all meaning in what can feel like a “Successories”-inspired world.   Minor accomplishments, particularly those in line with high profile management initiatives, receive outsized recognition, and highly burnished “success stories” are celebrated and socialized. 

One result of all this is a remarkably hermetic environment within large companies, sort of an alternative, self-consistent universe with its own rules and customs, sustained in large measure by the established structures and defined hierarchy.  Truth is what your manager, and his or her manager, says it is, and you challenge these orthodoxies at your peril.

Speculation

First, I’d argue that big companies lean into process and control because it feels more reliable and scalable than creativity.  Indeed, Catmull’s core thesis, as he tells WSJ reporter Emily Bobrow, is precisely that there is not a “formula” for success, and you need to reinvent yourself creatively each time. 

As I’ve frequently noted, this is the exact antithesis of what anyone in large pharma companies wants to hear or is prepared to hear.  Instead, pharmas characteristically overindex on perceived “success factors,” and may doom future projects by applying with excessive rigor the putative lessons learned from previous blockbusters.

Second, big pharmas will continue to search for tools (including potentially AI) that essentially enable them to leverage their size and process, and industrialize innovation. This basically means they seek to use brute force to produce superior medicines.  So far, based on the high fraction of pharma products born elsewhere, this hasn’t proved especially successful, but the hope is always there.

Third, since I don’t think the cultures of most big pharmas are likely to change meaningfully, I anticipate we will continue to see the pharma version of “the big sort,” the demographic self-assortment that leads to the geographical clustering of like-minded people (e.g. progressives moving to blue states and conservatives moving to red states).  Drug developers who find comfort in process, control, caution, and stability will migrate to and remain in large pharmas, while those who prefer living a bit out over their skis will choose smaller biotechs – provided market conditions enable early-stage companies adequate opportunity to find their footing.  

Most of the top creative physician and scientists I know in drug development are now working in small biotechs – often after previous roles in large pharmas. We have seen a long-term trend of talent migration from large pharma to startups – see Luke’s column from September 2017 on “How’s It Going for Big Pharma Vets at Startups?”

Fourth, remember that while smaller biotechs may be more innovative (or at least embrace more risk), most drug development efforts fail; even with the most creative people in the most supportive environment, science is incredibly, unfathomably, brutally unforgiving.  The single biggest advantage big pharmas have (see here) are the resources to remain in the game long enough to absorb the many inevitable failures – and then run with the very rare success, whenever it arrives.  

Even the most innovative small biotechs struggle to remain independent, and are generally acquired by big pharmas; Genentech, memorably, was fully acquired by Roche in 2009. 

Pixar, incidentally, was no different.  As Pixar Chair and majority shareholder Steve Jobs told Catmull when Jobs was contemplating a sale to Disney, “Pixar is a yacht.  But a merger will put us on a giant ocean liner, where big waves and poor weather won’t affect us as much.  We’ll be protected.” 

The challenge, of course – for Genentech, Pixar, Waze and others — is sustaining their distinct creative culture in the context of the larger corporation. 

Not surprisingly, as Bruce Booth of Atlas Ventures has described, a lot of top R&D talent tends to recycle into the startup ecosystem after an acquisition.  Given the challenges of maintaining (much less retroactively establishing) a culture within large pharmaceutical companies that truly supports creativity, let’s hope market conditions sustain and foster the virtuous cycle Booth describes, as this may most effectively enable the continued, essential cultivation of genuine innovation in the life sciences.

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.

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 90^th 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.”