Three Core Questions Underlying Durable Behavior Change

David Shaywitz

Each of us would be happier and healthier if we could adopt and maintain healthier behaviors. Many of us – including providers, organizational heads, community leaders, parents – hope to cultivate healthier behavior in others.   

The difficulty we experience attaining these common goals reflects three underlying questions around behavior change.

  • Is the most effective locus of intervention the individual or the community?
  • Is the key problem the lack of information or not knowing what to do with information?
  • Most fundamentally, is durable healthy behavior change achievable or futile?
Individual vs Community

The discrete health and wellness options with which we’re most familiar target individuals because it’s generally individuals who buy them, whether it’s the purchase of a Peloton, a subscription to Weight Watchers, or an app for mindfulness.

Yet, as the health and wellness of employees has become an urgent priority for corporate leaders (as discussed in my last column), there’s a lot more interest in how our work environment (and how context, more generally) can support worker health and wellness. 

For example, Richard Safeer and Judd Allen, writing in the Journal of Occupational and Environment Medicine, describe our “great opportunity to move employee health and well-being beyond interventions that until now have focused on the individual as the locus of change.” 

They emphasize the value of a “supportive culture,” but worry that employers are interested in adopting buzzwords like “culture of health,” rather than pursuing a deeper vision of a healthy work culture. Their concern is that “workplace health promotion vendors, journals, and researchers appear to be rebranding the existing set of workplace programs without modifying their work so they actually align workplace cultures with health. This is a missed opportunity.”

Safeer and Allen’s worry about corporate leaders who ignore these foundational issues aligns with benefits expert Josh Bersin’s in-depth evaluation of the subject, as we recently examined.

British health researchers Michael Kelly and Mary Barker have emphasized the need to layer in a deeper knowledge of social and contextual relationships into our efforts to understand and guide health behaviors. 

“The scrupulous analysis of behavior change techniques has produced a behaviour change taxonomy that has advanced our understanding of mechanisms and of supporting change in the behavior of individuals,” Kelly and Barker observe.

What’s needed now, they say, is more scholarship around a discipline called “social practice” which “sees the relations between individuals and groups and institutions as the starting point.”

In other words, they propose we take a more integrative, less reductive view of the factors contributing to behavior change, and pay more attention to the social relationships.

Esther Dyson

The idea of looking at factors beyond the individual has led visionary angel investor Esther Dyson to consider health at the level of the community, while Dr. Michael Joyner of the Mayo Clinic frequently emphasizes the contribution of our built environment to our health.

The health-promoting opportunities of the workplace in particular has started to attract increased attention, as was discussed in a fascinating book, The Great Indoors, by Emily Anthes, that I reviewed for the WSJ last year. Companies are increasingly contemplating features such as circadian lighting, for example.

Given the power and influence of environmental influences on our behavior, it’s encouraging to see increased interest in this opportunity for health promotion. At the same time, we must continue to offer improved opportunities to individuals, and recognize the exceptional power of human agency – including the ability we often have to adjust aspects of our own environment, and help create for ourselves heathier work and life spaces.

A Knowledge Problem Vs. A Doing Problem?

As a colleague who lived through this experience explained to me, the early days of digital health, and especially of wearables, were premised on the assumption that if people only had more and better information, they’d be more likely to pursue healthier behaviors. You can’t manage what you can’t measure, the hoary business maxim goes.

Some experts continue to believe this remains our greatest challenge for behavior change. As one academic epidemiologist recently shared with me, “the biggest unmet need is in risk communication itself.” He adds, “Risk often seems abstract to people. Making the implications of lifestyle choices tangible is often what people need for them to take action.  The only way I see to do this is to make the risk personal and precise.”

On the other hand, arguably one of the biggest lessons from the early days of digital health is the extent to which information often isn’t enough to drive durable behavior change, even given the inherent self-selection that means the information is provided to those who are most curious and presumably motivated. 

In some cases, it may be because the information is sterile, rather than especially useful or actionable, as many early quantified selfers discovered, to their disappointment (see here).

But even when we have really good information – smoking and fast foods are bad for you, say, or vaccinations are good at preventing severe illness and death – adopting more healthy behaviors can still be a huge problem.  

In general, according to several experts, this isn’t because we don’t have the knowledge, but rather that the behavior we’re pursuing meets another powerful need for us, one that those hoping to encourage healthier behaviors might do well to better understand. 

This is not only a perspective useful for health coaches, as John Berardi argues in Change Makers (discussed here) but it’s also what researchers Kelly and Barker suggest as well.

“Treating the people doing the behaviours, not as cultural dopes, but as knowledgeable actors whose understanding of their own conduct is important is the sine qua non of unraveling the connections.  This analytic and self-consciously academic approach turns on its head the idea that it is enough to give people information, however simple or plain the language, and tell them what they need to do to produce change in behaviour. As a consequence, we need to rethink the way we as health professionals work with the public.”

They describe a pilot approach in Southhampton, U.K., called “Healthy Conversation Skills,” that provides “individual support for patients and clients of health and social care services that steers away from information giving and towards empowering and motivating individuals to generate their own solutions to their problem.” 

So far, Kelly and Barker say, this approach – which seems to be a simplified version of motivational interviewing — “is looking promising.”

Based on my experiences in both clinical medicine and digital health, I recognize that while personalized data and relevant risk assessments can contribute to motivation, rarely is it enough. 

It’s true that if you tell someone they have a cancerous lump, and they can definitively treat it by immediate excision, there’s a good chance they’ll insist on the procedure. But tell someone suffering from type 2 diabetes that they will likely suffer a range of increasingly devastating consequences unless they dramatically change their nutrition and lifestyle, chances are they’ll want to modify their life but having trouble sticking with most meaningful adjustments.

Rather than focusing on data visibility, data visualization, or even the need for more precise knowledge of risk – as important as these are – we might do better if we turn our attention to the incredibly complex human dynamics of behavior change. This would include factors an individual can directly influence, like mindset and (as psychologist Wendy Wood emphasizes), habits, but also the additional interacting contextual social and environmental factors that may also play a critical role.

Hope vs Futility

A recurrent theme in these columns is how astonishingly difficult it can be to durably change health behaviors. As we saw in detail in the recent discussion of people with obesity, our bodies, and even more, as Dr. Fatima Stanford explained, our minds, seem determined to continuously conspire against us. 

And it’s not just our minds and our bodies, but also in many ways our environment that seems to be continuously making health more elusive. Our food, as many have discussed, is increasingly engineered to stimulate us to desire more. Social media and cable news, as Cal Newport has discussed in Deep Work, compete for our attention by stoking outrage (this book contributed significantly to my decision several years ago to no longer engage on Twitter).

You don’t have to be cynical by nature to look at the situation and ask how realistic is it to even aspire to promote positive behavior change when it’s getting easier and easier to opt for the less healthy choice. Just like when Netflix starts the next episode automatically, less healthy options have increasingly become the default. 

Given the ever more powerful forces and interests arrayed against healthy behavior, how can it possibly make sense to fight against this tide, especially when it seems the time and effort required to improve the situation far exceeds what’s required to further aggravate it. Are we essentially stuck rearranging deck chairs on the Titanic – unless or until there’s a solution that’s as easy to adopt as the original problem, say a magic pill to stifle appetite, or to replicate the health benefits of exercise?

The most thoughtful perspective I’ve encountered on these almost existential challenges is from Sam Quinones’s extraordinary The Least Of Us, a just-published sequel to Dreamland (2015), his remarkable account of the early days of the opioid epidemic.

Sam Quinones

In his current effort, Quinones looks at the evolution of the nation’s drug epidemic, tracing its evolution from relying upon products derived from plants (coca, poppy) to those synthesized in the lab. Many of these so-called “designer drugs” are potent, addictive, and deadly. 

The devastation these narcotics wreak upon individuals, families, and communities is heartbreaking, and Quinones brings us into this world with unassuming delicacy. Adept at showing without telling, he allows us to immersively experience the drama he describes. 

I’ve generally been cautious about comparing opiate addiction to overeating (much less excessive Twitter use). Quinones has no such reservations, and leans into this comparison. He highlights the (increasing) allure of a range of addictive behaviors, and interviews neuroscientists who suggest these addictions may share common biologic mechanisms.

Somewhat remarkably, despite all the misery he so poignantly describes, Quinones also manages to find reasons for hope. His optimism springs not from toxic positivity – Quinones takes pains to show how unfathomably difficult it is for those addicted to powerful narcotics to get clean and, especially, to stay clean. Relapse, it seems, is the tragic rule, and durable recovery, the rare exception. 

And yet, we meet individuals who are earnestly striving to get better, and see small communities come together in often unanticipated ways, to support and occasionally enable recovery.

We emerge from The Least Of Us with a sense of the dimension of the challenge of durably altering addictive behaviors, but also with the feeling that success, however exceptional, is possible. We appreciate the need for individual agency and the value of community support. We see that even the rare triumphs are often preceded by a series of wrenching stumbles and maddening setbacks. 

When we then contemplate the challenge of our own behavior change, we realize that we cannot afford to underestimate just how difficult these alterations are likely to be. With eyes wide open, we must resolutely pursue lasting change, recognizing our responsibility to tenaciously drive our own success, and appreciating the role each of us can play in contributing to the success of others.


Targeted Small Molecule Protein Degraders: Nello Mainolfi on The Long Run

Today’s guest on The Long Run is Nello Mainolfi.

Nello is the president and CEO of Cambridge, Mass.-based Kymera Therapeutics. Kymera is working on targeted protein degraders. These are orally available small molecule compounds. Many in biopharma are excited about them because they have a clever design that allows them to go after targets that have previously been out of reach for small molecules.

Nello Mainolfi, co-founder and CEO, Kymera Therapeutics

These compounds are sometimes called “heterobifunctional molecules.” They are “chimeras” or hybrid molecules of a sort, that engage a protein target of choice, while also recruiting E3 ubiquitin ligases. These ligases act as catalysts for the ubiquitin-proteasome system, which acts to drag proteins of your choice into the cellular garbage disposal system, where they get irreversibly degraded.

Instead of directly inhibiting a disease protein, you can latch onto it and drag it into the trash compactor. Pretty cool.

Nello is a chemist by training, and dove all-in as co-founder and VP, head of drug discovery at Kymera in 2016. It’s a pleasure speaking with him at length about this exciting area of drug discovery that doesn’t get as much media coverage as I think it should.

Today’s sponsor, Answerthink, has been consistently recognized by SAP, one of the largest enterprise software companies, as a top business partner for delivering and implementing SAP solutions for small and midsized life science companies. Their SAP certified solutions designed for the Life Science Industry are preconfigured, rapidly deployable and address fundamental business and IT challenges such as:

  • Integrating your business applications
  • Delivering validated reporting
  • Increasing your speed to market
  • Support for global rollouts
  • As well as delivering a fully compliant solutions that meets FDA’s strict standards.

Explore how Answerthink can streamline your business processes to ensure growth.

Visit Answerthink.com/timmerman and get a copy of the e-book- “Top Three Barriers to Growth for Life Science Organizations.”

That’s Answerthink.com/timmerman

Absci is all about creating new possibilities in the realm of protein-based therapeutics. What does this mean?

Absci has a fundamentally different approach to drug discovery. It designs and develops next-gen biologics of any modality, from antibodies to T-cell engagers to completely novel protein scaffolds, including a futuristic format it calls “Bionic Proteins.”

Because Absci conducts its screens in its scalable production cell line, it collapses several steps of biologics discovery into one integrated, efficient process. Absci also has a unique computational antibody and antigen discovery approach for isolating fully-human antibodies from disease tissues and using these antibodies to identify novel drug targets.

Absci does all this with a powerful combination of deep learning AI and synthetic biology technologies. Absci is already helping some of the best partners in biopharma translate their ideas into drugs. Check them out at absci.com and absci.ai.

Now please join me and Nello Mainolfi on The Long Run.


Corporate Health and Wellness Has New Urgency And Vision

David Shaywitz

Like no other event in our collective experience, the pandemic reminded us of the need for an integrative view of wellbeing beyond traditional measures of physical health. Focusing exclusively on cholesterol level and bone density, for example, would be hopelessly inadequate for the needs of today. 

I continued to be haunted by Zak Kohane’s description of the many children’s hospitals across the country that have stopped admitting patients for elective procedures.

This isn’t because the hospitals are overrun with COVID, Kohane says. Rather, the beds are filled to capacity with children whose mental health, exacerbated by the challenges of childhood in the era of COVID, now requires in-patient care. 

Many employers have apparently recognized the urgent health crisis. “Workplaces went through an accelerated digital disruption” as a consequence of the pandemic, Forbes columnist Brian Solis writes.  Corporate health and wellness offerings that used to be the sole provenance of HR are now getting the attention of senior leadership, talent management expert Josh Bersin explains

Particularly in the face of “the great resignation,” when many employees are seriously rethinking their priorities and commitments, keeping workers happy and physically healthy has become a top business priority.  The pandemic didn’t create today’s holistic view of employee health and wellness, but it dramatically accelerated and intensified employer interest. 

Today, let’s take a quick look at the evolution of workplace health and wellness, consider the dimensions of health and wellness that executives are now contemplating, and assess how well these efforts are likely to perform.

Evolution of Corporate Health and Wellness

The introduction of health and wellness to the workforce is generally traced to the 1950s, HR expert Cheryl Brown Merriwether explains. Early efforts tended to focus on “industrial hygiene” – monitoring “air quality and cafeteria sanitation.” 

In the 1970s, she explains, as the cost of healthcare assumed by companies climbed, employers looked to reduce these costs by promoting healthier lifestyles.

The first “modern” corporate wellness program is generally considered to be J&J’s “Live for Life.”  The effort launched in 1978 with two goals: encouraging healthy employees by promoting healthy behaviors, and reducing healthcare costs for the company.  

As Merriwether outlines, “Live for Life” was an onsite wellness program that

“included physical assessments, questionnaires, and provided employees with information on stress management, nutrition, and weight control.  The program also provided support for high-risk behaviors such as alcohol or substance abuse.”

Corporate wellness programs began to incorporate psychological wellbeing in the 1980s. Around that time, workplace fitness programs, sometimes including onsite fitness centers, became more widespread.

In the 1990s, the US Department of Health and Human Services advanced an initiative called Healthy People 2000, which encouraged employers to promote healthy behaviors. “It was widely believed during this period,” Merriwether says, “that workplace health and wellness initiatives benefited both employees and company, even though evidence and supporting data were hard to find.”

The deliberate focus on creating and fostering a positive corporate culture, which started to gain traction during 1990s, took off during the tech-fueled 2000s.

As Bersin explains,

“In 2007, Google created a course on mindfulness that was an overnight sensation. It was the most popular benefit on the Google campus and sparked the trend toward mindful thinking at work, in design, and even in engineering. We believe many of the new ideas about growth mindset, abundance mentality, yoga, and various other philosophies of growth prominent today stemmed from this root.”

Companies continued to look to health and wellness programs for healthcare cost-savings. Through the 2010s, companies increasingly searched for ways to persuade employees to avail themselves of perennially underutilized wellness services, and thereby unlock the (always elusive – see here) cost savings.

Corporate wellness programs continued to evolve in the 2010s. As Abraham and White describe in Health Affairs in 2017, there was a transformation in value proposition, from “return on investment (ROI)” to the more expansive concept of “value on investment (VOI).” 

As the authors explain, this means looking “beyond individually focused metrics of medical care cost savings or productivity gains,” and extending the scope “to include organizationally focused metrics such as employee engagement, turnover, retention, and satisfaction and even profitability.”

One health plan executive told Abraham and White that for employers, health and wellness may still be about healthcare costs, but it’s also increasingly about recruiting and retaining the most talented workers they can find. “It is way beyond ROI,” they say.

To address this need – a need obviously intensified by the pandemic – companies are creating “wellbeing care teams,” Merriwether reports. These teams are (or will be) staffed by “professional practitioners, both clinical and non-clinical, she says,” and “will include mental, behavioral, and integrative health practitioners working in partnership with health, wellness, and professional recovery coaches.”

Merriwether points out that the “market for health coaching services is $7B and growing,” and notes “there are currently more than 128,000 health coaches and educators who help clients establish lifestyle behavior changes.” (See here for my recent discussion of health coaches and technology.)  

Components of Health and Well Being

For some time, as Bersin notes, most companies have embraced a view of “wellbeing as a constellation of social, mental, physical, and behavioral health.” However, Bersin adds, over the last decade – particularly “as work has become ever more focused on always-on digital tools” – new dimensions have emerged: “sleep and rest, meaning and purpose, relationships with others, and even positive thinking.”

Bersin proposed a corporate health and wellbeing framework that includes six dimensions (plus enabling tech and HR capabilities); I’ve mapped this (imperfectly) onto the well being frameworks I’ve previously discussed (see here), and have also included a related but distinct set of six dimensions that McKinsey uses to categorize consumer interest in wellness.

Still Needed: Focus On Social Milieu

Today, Bersin points out, “nearly all companies have programs for resilience, wellbeing, mental health or stress reductions. Company leaders are adding new vacation policies, giving people apps and relaxation tools, and lavishing wellbeing benefits on their teams.”

So are these efforts working? If by “working” we mean creating a “healthy organization,” Bersin argues, then the answer is “no.” What’s needed, he says, is more than just “a set of benefits and wellbeing programs.”

Instead, he contends, what’s needed is “a top-down focus on job and work design, management, and rewards practices, a sense of psychological safety and fairness, and a commitment to listening to employees.”

What I think Bersin is getting at is a point that academic experts including Michael Kelly and Mary Barker have addressed as well: many well-intentioned “intuitive” solutions come up short because they fail to recognize and account for the complex social milieu from which behaviors originate.

In their instantly classic 2016 paper, “Why is changing health-related behavior so difficult?” Kelly and Baker highlight the failure of commonly-invoked approaches to behavior change. Among the examples they cite: “use common sense,” “it’s about messaging,” and “it’s about providing people with information.” They also explain why we can’t reliably be guided either by the assumption that “people act rationally” or by the view that “people act irrationally.”

What’s needed, they argue, is a view (called “social practice”) that “conceptualizes behavior not as something that can be reduced down to things that individuals do and think as if they were isolated from others.” 

Kelly and Baker emphasize the importance of “disaggregating broad behaviors” (like eating, drinking, smoking, etc), “breaking them down in time and place where different expression of these behaviors occur.” And of course, they remind us, more research is required.

Key Takeaways

For executives who need to help employees today, and for health-oriented entrepreneurs looking for a way to contribute, there are several takeaways.

First, it’s tremendously exciting and hopeful to see so many offerings targeting the many dimensions of health and wellness, a Cambrian explosion that would seem to increase the chance for the development of truly high-value products.  The diversity of wellness alternatives now available theoretically offers greater opportunity  for individual employees to find programs that best meet their particular needs.

But there’s a downside to this burst of activity. The volume of offerings makes it hard for employees to navigate the system and make good choices. (Full disclosure: I’ve worked in several large corporations and never managed to successfully navigate a benefits systems, which always seemed incredibly complicated, and to involve a series of nested options and endless passwords.)  

Apparently, I’m not alone. Bersin cites research that finds almost half of employees consider their multiple workplace wellness programs to be confusing. That’s a big roadblock that gets the way of using benefits. 

What matters most when it comes to corporate wellbeing solutions, Bersin says, are “simplicity and transparency.” 

Yet we should also not get so lost in the weeds of benefit deployment that we lose sight of what seems to be a really encouraging development – the increased recognition that our health and wellbeing is often closely tied to the environment we’re in: the nature of our work, the richness of our engagement with colleagues, the way in which our effort is recognized and valued. It’s also an area where genuine commitment and involvement by senior leaders can make a palpable difference.

Let’s dare to be hopeful for a moment. The increased availability of personalized corporate health and wellbeing options, from health coaches to fitness centers to mental health support, together with more integrative company-wide efforts that authentically promote and enable a healthy culture, offers exceptional promise.

We can begin to imagine what the future of work could, and arguably should, be.

Wellness, Not Woo Woo

One final point: it’s really important to recognize that the pursuit of wellness need not come at the price of hard work and exceptional performance. 

Phrased differently, wellness doesn’t have to be “woo woo.”

As the father of positive psychology, University of Pennsylvania professor Martin Seligman takes pains to explain, the “A” in his PERMA-V model  (a framework represented in column four of the previous table) represents “Achievement.”

Seligman further emphasizes that we feel best when we enter a state of complete absorption, termed “flow” by the late Mihaly Csikszentmihaly. We are most likely to experience “flow” when we are fully utilizing our core strengths. (Then again, when I took the test, my top three turned out to be “love,” “perspective,” and “curiosity,” so perhaps I should have become a rabbi.)

Flow may also explain why, as a recent WSJ article reported, entrepreneurs tend to be happier than wage-earning employees – even though entrepreneurs on average work longer, make less, and are more stressed. “All of those problems do take away from entrepreneurs’ happiness, of course,” the Journal acknowledges, “but the positives of running a business are so strong that they outweigh the negatives.”

The point: while it’s smart for companies to embrace health and wellness as a corporate value, it will be even smarter if leaders embrace and authentically support the remarkably diverse range of ways in which this worthy goal might be meaningfully pursued.


T Cell Therapies for Autoimmunity: Jeff Bluestone on The Long Run

Today’s guest on The Long Run is Jeff Bluestone.

Jeff is the president and CEO of South San Francisco-based Sonoma Biotherapeutics. Jeff has a long, distinguished history as an immunology researcher at the University of Chicago and UCSF. He learned over the years how to enlarge his impact by coordinating groups of scientists as an administrator at the Immune Tolerance Network and Parker Institute for Cancer Immunotherapy.

Jeff Bluestone, co-founder and CEO, Sonoma Biotherapeutics

Jeff took the startup plunge a couple years ago to build Sonoma Biotherapeutics. Many listeners of this show are quite familiar with the CAR-T cell engineering revolution that has brought forth some exciting new T cell therapies for cancer. Some of the same tools and concepts are being brought to bear now at Sonoma for a quite different purpose.

Instead of engineering T-cells to attack cancer cells, Sonoma is seeking to engineer T-regulatory cells to help bring the immune system into a balanced state, so it doesn’t attack healthy cells or “self.”

Listeners can learn more about the company from a February 2020 article on Timmerman Report about Sonoma’s Series A financing and founding vision.

Jeff is a brilliant scientific entrepreneur. This conversation provides a glimpse into how he thinks about using the tools of today’s biology to do things for autoimmune and inflammatory disease that would have been inconceivable a decade ago. 

Now, a word from the sponsors of The Long Run.

Answerthink has been consistently recognized by SAP, one of the largest enterprise software companies, as a top business partner for delivering and implementing SAP solutions for small and midsized life science companies. Their SAP certified solutions designed for the Life Science Industry are preconfigured, rapidly deployable and address fundamental business and IT challenges such as:

  • Integrating your business applications
  • Delivering validated reporting
  • Increasing your speed to market
  • Support for global rollouts
  • As well as delivering a fully compliant solutions that meets FDA’s strict standards.

Explore how Answerthink can streamline your business processes to ensure growth.

Visit Answerthink.com/timmerman and get a copy of the e-book- “Top Three Barriers to Growth for Life Science Organizations.”



Absci is all about creating new possibilities in the realm of protein-based therapeutics. What does this mean?

Absci has a fundamentally different approach to drug discovery. It designs and develops next-gen biologics of any modality, from antibodies to T-cell engagers to completely novel protein scaffolds, including a futuristic format it calls “Bionic Proteins.”

Because Absci conducts its screens in its scalable production cell line, it collapses several steps of biologics discovery into one integrated, efficient process. Absci also has a unique computational antibody and antigen discovery approach for isolating fully-human antibodies from disease tissues and using these antibodies to identify novel drug targets.

Absci does all this with a powerful combination of deep learning AI and synthetic biology technologies. Absci is already helping some of the best partners in biopharma translate their ideas into drugs. Check them out at absci.com and absci.ai.

Now, please join me and Jeff Bluestone on The Long Run.


Obesity Is Rising; Can Health Coaches & Tech Drive Durable Behavior Change?

David Shaywitz

As we enter the holiday eating season – quickly followed by the New Year get-in-shape resolution season – let’s look at obesity challenge head-on. 

Expert physicians who study obesity recognize the condition as a complex disease associated with profound health consequences. It also represents, for many health tech entrepreneurs, a high-value problem to be solved.

Obesity has been ratcheting upward for decades, representing a corrosive threat to national (as well as global) health. (See the data below from the National Health and Nutrition Examination Survey and read the full CDC paper from February 2020):

More than four out of 10 adults in the U.S. meet criteria for obesity (Body Mass Index of 30 or higher), and nearly one out of 10  adults would be classified as suffering from “severe,” or “class III” obesity, with a BMI of 40 or higher. 

The increase in obesity during this time period, interestingly, occurs despite the decrease in physical inactivity reported during this same time.

In other words, although more Americans seem to be getting off the couch, obesity rates keep going up.

Obesity in adults “is associated with a striking reduction in life expectancy,” according to UpToDate (an authoritative reference used in clinical practice). In addition, UpToDate reports, “obesity and increased central adiposity are associated with increased morbidity,” noting that “obesity has surpassed smoking as the number one cause of preventable disease and disability.” Significant comorbidities related to obesity include diabetes, hypertension, osteoarthritis, cancer, depression – and of course, COVID-19.  As UpToDate summarizes, multiple (observational) studies “link obesity with increased morbidity and mortality” from COVID-19.

Not only are individuals with obesity at increased risk from COVID-19, but for many Americans, the pandemic seems to have prompted a hefty increase in weight. An American Psychological Association survey from March 2021 revealed that 42% of us reported undesired weight gain as a consequences of the pandemic; individuals in this category said they gained an average of 29 pounds; the median amount they gained was 15 pounds. 

If there’s a silver lining related to obesity, it’s that, according to UpToDate, most of the “over 230 comorbidities and complications of obesity” that have been identified will improve when people lose weight. 

The Brutal Challenge Of Weight Reduction

Yet durable deliberate weight loss remains an incredibly difficult challenge – staggeringly, almost incomprehensibly difficult.

One factor, according to MGH obesity medicine expert Dr. Fatima Cody Stanford relates to “the organ that’s most important with regard to regulating our weight – and that is our brain.”  In particular, she says, the brain actively defends a weight set point, and gets “quite angry” when you lose weight, to the extent, she says, that it pushes you to return to an even higher set point – a particular problem for “weight-cycling” (i.e. “yo-yo dieting”).

Dr. Fatima Cody Stanford, obesity medicine expert, MGH

And it gets worse. For the vast majority of us – 97%, she says – the brain “doesn’t retrain” on a lower weight, no matter what you do. 

“Unless you do something that actually changes that brain-gut connection,” she says, citing the example of bariatric surgery, the brain “still wants to go back.” 

Consequently, outside of bariatric surgery – which Stanford describes “the most effective tool available for both children and adults that have severe obesity” – maintaining a healthy weight, for most people, is destined to remain a chronic, constant, difficult, daily battle; even those who have bariatric surgery generally must remain constantly vigilant, if they want to maintain the weight loss their procedure helps them achieve.

But wait – it (somehow) gets even worse. 

Six years after television’s “The Biggest Loser” competition, NIH metabolism researcher Kevin Hall, studied the 14 of the original 16 participants and discovered they had regained two-thirds of the weight they had lost during the show. 

Even more discouraging, Hall found that the people who continued to exercise the most (compared to original baseline) exhibited a lower(!) resting metabolic rate (RMR). Hall says he now believes these data may represent an extreme example of the “constrained energy expenditure model” proposed by Duke anthropologist Herman Pontzer.

Pontzer’s depressing insight – evident in Hall’s data – is that our bodies tend to exhibit metabolic adaptation, meaning that lots of physical activity seems to result in a disheartening decrease in RMR, with the apparent goal of keeping total energy expenditure fairly constant. In practice, this means that when intensive exercisers aren’t exercising, their bodies seem to burn calories at a slower rate – which seems like a miserable way for your body to thank you for exercising.

Herman Pontzer, associate professor of evolutionary anthropology, Duke Global Health Institute

If there is any vaguely hopeful message from Hall’s study, it’s that the contestants who continued to exercise the most did better at sustaining weight loss (despite the compensatory decrease in RMR) than other participants. The reasons for this, he writes, “remain to be fully elucidated.”

Given the stubborn biology – not to mention the consequences of our often-obesogenic environment – it’s not surprising obesity remains a challenging and profound chronic health problem.

The Training Gap

What may be more surprising is that, despite the prevalence of obesity, and the fact that (at least according to a 2006 study from Australia), many patients preferentially look to physicians for advice on healthy eating and weight management, most doctors are apparently ill-prepared to step up.

In 2019, Stanford published a study she led examining obesity education in medical schools, residencies, and fellowships around the world, a report that concluded “there is a paucity of obesity education programs” for these trainees “throughout the world despite high disease prevalence.” 

Or as she has phrased it more colloquially, “nobody learns anything about obesity as a disease, which means that even though it’s the most prevalent chronic disease not only in the U.S. but around the world, no one knows how to treat it.” 

Stanford has recently extended these findings to medical specialties, and found:

“Even on medical board exams, obesity is not well covered. I can tell you that as a doctor, if it’s not on the test, we don’t think it’s important. So it’s not on the test, which means we’re not learning about it, which means that if you as a patient often are going into to your doctor and wondering why they don’t know much about the disease, it’s because they didn’t learn and it’s not necessarily their fault.”

While Stanford cites the “over 5,000 physicians in the country that are board certified in obesity medicine” as progress, she says “it won’t cut it” in the face of the “over 100 million adults that actually have the disease and the tens of millions of children that have the disease.”

Poignantly, Stanford pleads, “We need everyone to understand the complexity of the disease, especially anyone that’s on the treatment side: doctors, physicians, assistants, nurse practitioners, and the list goes on and on. Or we’re going to continue to fail our patients.”

One area where I recognize first-hand that physicians tend to lack training is in guiding patients through behavior change. I don’t know any internist who emerges from their education with a real sense of how to even think about this, beyond perhaps a conceptual introduction to the Prochaska “Stages of Change” model. While doctors consistently advise patients to undertake lifestyle modifications like reducing smoking, and pursuing diet and exercise, few in medicine expect their advice to be heeded, and it often seems to be offered more for the sake of documentation – and justifying more aggressive interventions – than based on any expectation of progress.

A physician-scientist colleague recently described a formative, and probably not that unusual experience from his own training as a medical student. A cardiologist he was shadowing would routinely try his best to scare patients, warning them they could easily die before their next visit if they didn’t shape up soon. This approach seemed to please the physician, but, predictably, resulted in minimal change in behavior.

The Promise of Health Coaching 1 – DPP Data

On the other hand, the somewhat unexpected triumph of the “lifestyle” arm of the Diabetes Prevention Program (DPP), a NIH-sponsored study first reported in the New England Journal of Medicine in 2002, highlighted the untapped opportunity associated with more intensive coaching efforts.

As I described in Forbes in 2012, this study examined whether several different interventions could forestall the development of type II diabetes in an at-risk population. The study included two medication arms (one of which was discontinued); one “usual care” counseling and education arm; and one “lifestyle” arm in which participants were intensively coached around diet and exercise. 

The big finding was that while participants who received the medication – metformin – saw their risk of progression to diabetes cut by about a third, the lifestyle intervention group experienced a massive 58% reduction in risk. 

The DPP data emphatically demonstrated what some have long believed: effective health coaching can make a real difference. At the same time, this required a Herculean effort from the coaches, who intensively and consistently engaged with the participants in this arm of the study. 

One question arising from the DPP: can this approach be replicated at scale? Early efforts using group counseling, administered through a YMCA, seemed encouraging. These results, coupled with the rise of powerful personal technology, led to the birth of startups like Omada Health and others, companies seeking to combine a DPP-style intensive coaching approach with emerging technologies to achieve similar benefits at greater scale.

The Promise of Health Coaching 2 – Expert Experience

While the success of intensive coaching may have stunned some physicians, I suspect many dedicated coaches were appreciably less surprised. Given the difficulty of motivating behavior change, it makes sense to consider the perspective and experiences of those who seem especially good at it.

One example here: Canadian John Berardi, whose passion for coaching and health led him to a successful career as a coach, entrepreneur (he co-founded Precision Nutrition, and in 2017 sold 80% of his ownership in the company, then valued at around $200M), researcher, and thought leader.  Berardi’s recently published book, Change Maker, offers particularly relevant insight to the unique challenges and opportunities of health coaching.  (Disclosure: I have recently reviewed course materials for Precision Nutrition; I have never met or interacted with Berardi.)

As Berardi points out, “we sometimes confuse our passion for health and fitness with actual skill in helping others improve their own health and fitness.” He emphasizes that “while having knowledge is a good and necessary thing,” for health professionals, the “desire to display knowledge” can be counterproductive, since “you’re not in a knowledge-first business but a people-first business.”

Doubling down on that point, which may make some physicians and other health professionals bristle, Berardi argues:

“Unless you’re a full-time researcher or a professional philosopher, you’re not in a knowing profession, you’re in a doing-stuff-with-people profession. That means you’re accountable for how you are with people and how often those people get results (as opposed to how much you know, how smart you sound when sharing it, or how elegant your solutions seem on paper).”

John Berardi, co-founder, Precision Nutrition

(This also relates to the need for medical therapies to deliver real-world performance, vs clinical trial performance, as I’ve discussed here and elsewhere.)

Berardi also explains the importance of deeply understanding the people you are trying to help, of “asking great questions and then deeply, actively listening to the answers,” and of building upon what someone is already good at, versus telling them, in effect, their success requires they become someone else. 

Also useful, he says: focusing on “behavior goals” rather than “outcome goals”; “approach goals” rather than “avoid goals”; “mastery goals” rather than “performance goals.”

In addition, he describes a “5S” approach for goals: simple, segmental, sequential, strategic, and supported, and takes a very long-term view towards getting results, building on small, achievable victories. 

“The irony here is that ‘all or nothing’ doesn’t get us ‘all,’ it usually gets us ‘nothing.’  Which is why I like to practice ‘always something’ instead,” Berardi says.

The point here isn’t that Berardi, the DPP investigators, or anyone else has figured out some magic formula for driving behavior change. Rather, the takeaway is that motivating behavior change is extremely difficult, and seems to represent a critically important health promoting capability that is both desperately needed and difficult to locate anywhere in our health system. Most doctors lack the training, time, and perhaps forbearance needed to guide patients effectively down this difficult route. 

This has created an opportunity for someone – maybe a profession, maybe a company – to step into this gap.

Hurdles Ahead

Three hurdles await:

  • Driving durable healthy behavior change is intrinsically a wicked problem to solve.
  • The business model needs to work. Someone has to pay for the cost of driving the healthy behavior change. It’s a real challenge given the historically low probability of success, and the need to tangibly (and credibly, as Quizzify’s Al Lewis unfailingly points out) realize the financial benefits of improved health – often in a relatively (perhaps unrealistically) short time frame.
  • While technology offers the promise of scale, the power of health coaching seems closely tied to the close, trusted relationship and understanding that develops over time between coach and participant; while in theory, technology might offer the possibility of even more nuanced understanding and richer data collection, the power and intimacy of the personal relationship remains difficult to translate at scale.

This is the grand behavioral change challenge that brave health professionals, entrepreneurs, and technologists must now tackle, and upon which our collective health and well-being may depend.


Omicron Variant: the Latest Twist in the Pandemic

Otello Stampacchia, founder, Omega Funds (illustration by Praveen Tipirneni)

I hope you all had a wonderful Thanksgiving.

My Thursday started with me waking up in anticipation of a delightful meal with family (I love apple pie with gelato), at least partially reunited for a holiday meal together after so many months of caution and precautions. I was really looking forward to not having to do much else but drink (Barolo, of course) and be merry for a couple days.

That ended very quickly as soon as I opened my Twitter account.

As background, I do follow quite a few (several hundred by my latest account) virologists and epidemiologists there. They were all freaking out. In the literal sense of the word. (Yes, if you really thought all my previous writings came from “original” research, sorry to disappoint: the views below are more of a synthesis of data generated from the real experts).

As you probably all know by now, there is a new viral variant of concern (B1.1.529) detected in samples from various African countries (particularly South Africa and Botswana, which also happen to be the very few locations in Africa performing PCR testing and genomic surveillance for emerging variants of concern). The WHO in Geneva called for an emergency meeting about it, happening as I write. Also as I write, the new variant has been detected in Hong Kong (due to two returning passengers, at least one flying in from Johannesburg), and Belgium (passenger from Egypt) and Israel, in addition to other African countries.

Incidentally, the global community focused on pandemic surveillance has really stepped up its game in the last 18 months. The B.1.1.529 variant was only identified on Nov. 23. Within 3 days, with a lot of people doing a lot of work on it, information is flowing seamlessly through the global scientific community (which is not what happened early on in the pandemic). We have been helped by the good fortune that this variant can be easily identified by widely available PCR tests, without requiring deep genome sequencing.

I will attempt to summarize below why everybody who knows anything about the pandemic is in a tizzy about it, the potential implications for the long-term perspective for the pandemic, and then try to wrap all this up in my usual optimistic farewell message (note the sarcastic tone in the latter part of the sentence).

Omicron Variant and its properties

The variant was first detected in South Africa. It bears repeating that just because a variant is detected in a country, it does not necessarily originate in that country or that it is somehow the place to blame. South Africa is one of the very few African countries with a proper surveillance mechanism in place that can detect / sequence such strains. The irony of the situation is that countries that are “doing the right thing” sharing data and information in real time are often condemned / ostracized and bear the economic brunt of travel bans etc., instead of being congratulated and offered any support needed. The discussion on travel bans is above my pay grade, to be honest, but we cannot expect countries to collaborate in a global pandemic if their honesty is rewarded with economic shocks.

I would also like to publicly acknowledge and thank the (many) scientists working selflessly on the task: particularly Tulio de Oliveira (@Tuliodna, one of the best Twitter handles ever), Director of CERI (Centre for Epidemic Response & Innovation, South Africa). Developed countries need to continue and increase investments in collaborating with such centers across the world and providing them with resources. This is an absolute priority and the US and EU need to step up.
That said, and as mentioned previously (in July 2021 by both Larry Corey and yours truly here in Timmerman Report), Africa is a fabulous breeding ground for the virus, due to a large population (1.2 billion as of 2016), with low vaccination rates, and very high prevalence of HIV-positive people and other large immune-compromised, susceptible patient populations.

These conditions predispose some infected individuals to incubating the virus over a long period of time, increasing the probability of breeding viral escape variants. By the way, similar conditions also exist in several developed countries due to a meaningful percentage of the population with co-morbidities (diabetes, obesity, etc.), vaccine deniers etc. etc.

OK, so you knew all that, apologies: let’s get to the fun / scary / geeky part .

What then has all my virologist and epidemiologist “friends” in a frenzy?

Omicron has a lot of mutations (50) across its sequence: see graph below.

Just the spike protein (which binds to the ACE2 receptor on human cells) has 32 mutations across its receptor binding domain (RBD) and the furin protease cleavage site. It pretty much looks like all the “greatest hits” from Alpha, Beta, Gamma and Delta have been put together in a new “compilation”, plus some new “tracks” (mutations about whose potential effects we have no idea).

This unique and broad mix of changes in the spike protein comprises quite a few previously known to affect receptor binding and escape from neutralizing antibodies. There are many more mutations across other viral sequences associated with increase transmissibility and (quite possibly) more efficient evasion / escape from recognition by the immune system.

That alone would not have been sufficient to freak me (and many people way more knowledgeable than me) out. After all, there have already been several variants like Gamma (South America) and Beta (also from South Africa), for example, which had mutations that were supposed to provide an advantage in escaping the immune system.

They all got eventually outcompeted by Delta, which is extremely transmissible and produces many more viral particles upon infection due to its higher fusogenic (and other) properties. Delta, and its many offspring, was basically king of the land (and it still is pretty much everywhere). So far, however, we have been very fortunate that Delta hasn’t been able to evade the vaccines’ protective effect, at least over a 5-6 months period in healthy / young subjects.

What DID freak me out is the second graph below from the Financial Times: Omicron seems to be increasing its prevalence AND incidence very rapidly in a Delta prevalent background.

Daily COVID cases have more than tripled in S. Africa since Tuesday of this week, and apparently (take this with a pinch of salt) close to 90% of cases seem to due to Omicron in the province where it has been detected. That suggests it might be able to outcompete Delta and be more transmissible. See also this brilliant thread from John Burn-Murdoch, data scientists and visualization genius at the Financial Times.

If you want to escape your family obligations during this holiday, I also highly recommend reading the GISAID report on the new variant on Nov 23, or the just published UKHSA report and technical briefing (skip to page 18 if you are impatient like me): the number of mutations is mind-boggling indeed.

We obviously do not know for sure how much more transmissible Omicron is, or how effective currently approved vaccines and monoclonal antibodies will be against it. These experiments are lengthy and not trivial to perform. The in vitro experimental data should be available shortly, followed by animal “challenge” studies, but neither will be the last word on the key question — do the vaccines hold up against the new variant in people, especially over extended periods of time? We should hopefully have some answers within 2-3 weeks.

I’d like once again to remind people that, in a pandemic, an ounce of prevention is worth a pound of cure. Nature has a good summary of the known unknowns here.

Potential implications and the long-term perspective

First of all, I sincerely hope that Omicron will not be able to outcompete Delta globally. If it does, as I fear, and if it shows increased capability for immune evasion / escape, then we might be in real trouble. It would force the vaccine makers to create new vaccines purpose-built for the new variant, and they might have to be administered more frequently.

Luckily, we have had some much earlier warnings than we had with Delta, thanks to a strengthened global surveillance system (Delta was already all over the world by the time people started paying attention).

This could buy us a few weeks, perhaps a few months, if we are lucky.

We have also managed to somehow scale up the manufacturing capabilities for vaccines. But this would represent a big stress test. We would have to possibly re-vaccinate everybody with Omicron-specific additional doses. Were the new vaccine to require a 3-dose regimen over a 6-month period, as many virologists and immunologists would expect, it could be too much for our global manufacturing capacity. I do not think it is possible to have half yearly dosing for the whole world.

We are also still left with the problem of immune-deficient / compromised people as new source of variants: we are talking tens of millions of people, if not hundreds of millions, worldwide. Vaccines’ protective effects do not seem to last as long in these individuals. They will keep helping the virus get fitter and fitter by incubating it over months and allowing it to build much better versions.

In the hopeful case that I am wrong, however, this new variant should (if needed) raise the alarm to code red.

Up until (very) recently, most developed countries (US and Western Europe) have been lulled in a state of complacency, believing this pandemic was more or less over, with politicians being pushed by significant portions of their populations to remove / lighten up the various mitigating procedures that have proven successfully in containing the spread.

All this, just as we are entering the fall / winter period in the Northern hemisphere, with associated indoor spreading due to poor ventilation, and large portion of the population still unvaccinated (tragically so in Eastern Europe and large parts of the US with low levels of trust in public health authorities). And, for those of you who have forgotten this, this will be the first winter season with the highly transmissible Delta variant being the prevalent strain.

One silver lining: orally available polymerase inhibitor / protease inhibitor treatments from Merck and Pfizer (respectively) have so far delivered excellent efficacy and are likely to hold up well against the variants because of their different mechanism of action. These treatments are no substitute for vaccines in the general population, but they will provide an additional useful tool for global pandemic defense because of their ease of use, ease of manufacturing, and ease of distribution.

That said: they cannot be given to people in a chronic setting (like immune-compromised patients); Merck just announced very puzzling and honestly disappointing protection data from the second part of their study; AND, people would need to be diagnosed very quickly for the anti-virals to be effective. As a result, while invaluable, I do not think they will actually help meaningfully containing spread or the emergence of new variants.

Conclusions: the never-ending pandemic?

Practically, then, what to do right now?

I am afraid we do not have the luxury any more of caving to the (very vocal) minorities of vaccine deniers / libertarians imposing the (supposed) pre-eminence of individual liberties over public health considerations.

We should impose vaccine mandates ASAP, mask mandates in public / indoor places, mandate vaccine passes, improve PCR and rapid antigen testing infrastructure, etc.

In addition, we should:

  • Strengthen vaccine availability / vaccination rates in developing countries;
  • Make abundant foreign aid available (subject to vaccine adoption rates, perhaps);
  • Adapt and prepare our public health infrastructure for much broader testing requirements
  • Prepare for the very real possibility of yearly / half yearly vaccine shots with regularly updated sequences;
  • Turbo-charge antibodies / oral small molecule anti-virals research;
  • Expand monoclonal antibody manufacturing capacity for what is likely to be a huge requirement for prophylactic options for immune-compromised populations who are unlikely to mount an adequate vaccine-induced immune response.

And this, by far, is not an exhaustive list.

I am, however, exhausted just by thinking about it and by how much time and treasure, not to mention lives and livelihoods, has been wasted already.

My wish list above, similar to my requests to the Italian equivalent of Santa Claus as a child, is extremely unlikely to be granted, particularly the societal changes / mandates mentioned. It might have, perhaps, a slightly higher probability of happening in selected countries in Western Europe (I was very encouraged by the recent Austrian vaccine mandate across its population, for example: a first in developed countries). I just do not see this happening in the US or the UK.

This will likely condemn us to flare ups in cases / hospitalizations / deaths for years to come, particularly in the fall / winter months (and in the “air-conditioned” months in places with very hot summers).

While science has delivered above and beyond expectations, our society has shown itself unable to accept the sacrifices needed to effectively fight an enemy that exploits our medical and cultural vulnerabilities and becomes ever fitter. This is painfully particularly so in Western Democracies with our (just) emphasis on open debate and cultural diversity that is perhaps willfully manipulated by minorities / geo-political actors / lobbies using social media echo chambers.

We are all actors now, in a Darwinian evolution drama with many acts: the fittest, as always, will survive.


Follow Otello Stampacchia on Twitter: @OtelloVC

This article expresses the personal views and perspectives of the author. The views and perspectives expressed here do not necessarily represent the views or perspectives of Omega Fund Management, LLC or any officer, director, partner, member, manager or employee of Omega Fund Management, LLC or any of its affiliated entities.


Reviving Targeted Radiopharmaceuticals for Cancer: Ken Song on The Long Run

Today’s guest on The Long Run is Ken Song.

Ken is the CEO of San Diego-based RayzeBio.

Ken Song, CEO, RayzeBio

At RayzeBio, Ken discovered new opportunity in an area cancer R&D that had been long ago abandoned. It’s about creating targeted cancer therapies loaded with radioactive isotopes to give them extra tumor-killing punch. These aren’t the same thing as antibody-drug conjugates, in which a targeted antibody aims for tumors, and unloads a toxic chemical compound to kill the tumor.

This is targeted radiation, for short.

Scientists have been working on this type of treatment for decades, and have been stymied by failures of many kinds. Ken was surprised and excited to learn recently that some things have happened to change that narrative. He’s busy putting the pieces together to make not just one radiopharmaceutical for cancer, but to put together a platform for making many of them.

It’s a fascinating story, which I first discussed with Ken in October 2020.

This is a conversation with a very sharp scientific entrepreneur, thinking hard about how to create potent new tools in the toolbox against cancer.

Now, before we get started, a word from the sponsor of The Long Run – Answerthink.

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Absci has a fundamentally different approach to drug discovery. It designs and develops next-gen biologics of any modality, from antibodies to T-cell engagers to completely novel protein scaffolds, including a futuristic format it calls “Bionic Proteins.”

Because Absci conducts its screens in its scalable production cell line, it collapses several steps of biologics discovery into one integrated, efficient process. Absci also has a unique computational antibody and antigen discovery approach for isolating fully-human antibodies from disease tissues and using these antibodies to identify novel drug targets.

Absci does all this with a powerful combination of deep learning AI and synthetic biology technologies. Absci is already helping some of the best partners in biopharma translate their ideas into drugs. Check them out at absci.com and absci.ai.

Now, please join me and Ken Song on The Long Run.


Precision Health’s Next Great Challenge: Behavior Change

David Shaywitz

Humility may not be the first word you associate with “genetics,” “precision medicine,” and “Harvard,” but it was unquestionably the theme of the day at a fascinating panel this week convened by the Harvard Data Science Initiative.

The discussion (video here), was remarkably grounded. It reflected hard-earned learnings from experts who have tried to implement data-driven, “precision” health solutions outside the academy, and had scars to show for it. 

Five themes stood out for me in this conversation:

  • Appreciation for the successes of “precision medicine” – particularly in some cancers as well as in some monogenetic diseases;
  • Recognition of the limitations of precision medicine – i.e genetics are often just not that determinative, and generally are not especially useful or impactful in the prevention and management of disease;
  • Emphasis on the underappreciated implementation challenges associated with driving innovation into practice;
  • An urgent plea for improved approaches for the identification and effective treatment of mental health conditions;
  • A powerful sense that a key opportunity for improving health is the development of improved, ideally more precise, approaches to durable behavior change.

Because readers are likely familiar with my extensive discussion of precision medicine over the last 10+ years, I’m going to focus on the last three topics: implementation challenges, the mental health need, and behavior change opportunities.

Implementation Challenges

Tremendous advances in our scientific understanding and in the technologies we can deploy have invigorated researchers seeking to apply these advances to the study and treatment of human disease.  Yet the gap between theory and practice remains wide.

Priti Hegde, chief scientific officer, Foundation Medicine

Foundation Medicine Chief Scientific Officer Priti Hegde described an early experience she had when she started out in the pharmaceutical industry at Genentech. 

”We had this vision,” she said. “We should collect data from every patient on our clinical trials, and that data will transform drug discovery.”

So what happened?

“You won’t believe it, but it took us over five years just to get systems in place where datasets can be put in place in a manner that allows us to analyze data; that we need to have cloud compute architecture, that we need to have data access policies. These things may be kind of boring for a scientist, but critically important for us to get to a place where we can actually start to analyze the data and make something out of it.”

(As I’ve written, the challenges Hegde saw have also been publicly discussed at Novartis – see here, here – and Lilly – see here.)

Hegde has taken this understanding to her current role. “At Foundation Medicine, I realized I can innovate ‘til the cows come home. But if the insurance providers don’t see value in what we’re doing, and if we can’t demonstrate value for patients, there is no point in innovating. So it always comes down to the practical, boring, mundane things that drive true innovation.”

(For more on the importance of implementation see here, here, here.)

Harvard’s Mark Namchuk, a pharma veteran, also spoke eloquently, and plaintively, about the challenges of moving from the “pristine biology” of the lab to the complexities of clinical trial design and execution. “There’s this practical world that you’re going to run into,” he explained, and urged students and trainees considering careers in translation to seek out the perspective of experienced clinical trialists.

Duke bioinformatician Jessie Tenenbaum, who is Chief Data Officer for the North Carolina Department of Health and Human Services, also highlighted the need for pragmatism.

“It’s the implementation,” Tenenbaum said. “It’s how do you build that into a workflow that’s extremely entrenched with clinicians and providers and genetic counselors and everyone doing what they do?  Make sure to get it in front of them in a way that’s going to be digestible in the busy day that they have.”

Jessie Tenenbaum, Duke University; chief data officer, North Carolina Department of Health and Human Services

Tenenbaum also emphasized actionability – “what do we do” with the information, which requires a consideration of context. 

Tenenbaum shared an example from earlier in her career, when the genetics of warfarin metabolism were elicited. “When I was in grad school and learning about pharmacogenomics,” she said, warfarin was “the poster child for success” as researchers “figured out the genes and figured out the clinical guidelines based on the genes.” 

Her big revelation came afterwards, however, when she was at Duke. It arrived courtesy of cardiologist Rob Califf (who President Biden recently nominated to serve, for the second time, as Commissioner of the FDA).

As Tenenbaum tells it, Califf “made me get up at some ungodly hour, to round with him, to see the patients and how this [warfarin management] really worked. There was someone who was about to be prescribing warfarin, and Dr. Califf asked the doctor “did you think of doing the genetic test?” 

No, the doctor replied.

The patient “was an elderly person, had many other complicating factors…genetics just didn’t even play a role,” Tenenbaum recalled. 

(Indeed, most clinicians have found that dosing warfarin empirically, following the traditional “go low, go slow” advice, works well — especially since at least half the variation in dosing seems to depend upon factors besides the two genes implicated in warfarin metabolism.)

The point: it’s great to appreciate the ideal and abstract elegance of precision medicine, but to deploy it effectively, you also need to grapple with the messy reality of clinical care. 

The Mental Health Crisis

One particularly concerning reality of contemporary clinical care is the expanding mental health crisis sweeping the country in the wake of the pandemic.

The impact on children, in particular, was emphasized poignantly by Zak Kohane, a pediatric endocrinologist by training, who now chairs Harvard’s Department of Biomedical Informatics. 

“There is an unbelievable disaster happening in pediatric mental health right now,” Kohane explains.  “Our local hospital [i.e. Boston Children’s Hospital] is not accepting elective admissions — not because of COVID, not because of trauma, but because our psych wards are overflowing. And this is, by the way, not just us. It’s nationwide.”

Tenenbaum shares Kohane’s sense of urgency. Her research has focused on mental health, and she’s edited a forthcoming book, Mental Health Informatics

She points to several challenges in applying technology to mental health. 

First, she notes that “as opposed to cardiology, where we kind of understand how the heart works and how to quantify that, there’s just different epistemology of understanding what is knowledge.” 

She adds, “There are different concepts. They’re all self-reported and subjective, as opposed to something we can quantify. So there’s a huge number of challenges in that space.”

(There are some fledgling academic and industrial efforts to bring more quantitative data analysis to neuroscience R&D; see TR coverage of Neumora Therapeutics, Oct. 2021)

Tenenbaum also highlighted the profound need, in her current role in public health in North Carolina, to address mental health. It’s hard to make strides when essential data infrastructure is missing, she said.

When she started the role, she explains:

“We think about the sexy predictive analytics, machine learning, what can we do? And you get in and realize, ‘Oh my gosh, they’re using faxes, that’s where we’re at that.’ So data IT infrastructure, governance, quality automation — those are the things we need to get into place first, and then ask me next year about what we’ve managed to do with mental health and public health.” 

Tenenbaum hastens to add that many of the challenges in public health stem from efforts that “have been drastically underfunded for decades,” and notes that much of the fax reporting has now been automated.

John Quackenbush, a computational biologist at Harvard, also emphasized the unmet need represented by mental health, and expressed hope for the opportunities represented by “digital phenotyping,” a topic under investigation by the Onnela lab at the Harvard School of Public Health. 

The Onnela lab, Quackenbush said, was initially interested in the promise of wearables for neuropsychiatry, but more recently has focused on leveraging the passive data collected by smartphones. (I am somewhat cautious about this – multiple mental health startups were founded based on this exact principle, yet to the best of my knowledge, most ultimately pivoted away from it.)

Precision Behavior Change?

There was a strong emphasis from the panel on the urgent need to motivate healthier behaviors – precision behavior change, perhaps – but very little sense of how this can be done effectively, especially at scale.

All the panelists pointed out that for most people, you don’t need fancy assays to tell you how to live a healthy life. As Tenenbaum, put it, “I can tell you based on your genome what you should do. Eat right and exercise.”

Harvard’s Quackenbush tells me he offers people similar actionable advice based on their genomes: “Eat well, exercise, maintain a healthy weight, and don’t smoke.”

John Quackenbush, computational biologist, Harvard University

Obviously, we don’t need a genome sequence to tell us this.

Likewise, Namchuk emphasizes the lack of utility of microbiome analysis. He explains, “People are fascinated with the microbiome. I find the microbiome both fascinating and unbelievably frustrating because I have no idea what to do interventionally with the microbiome.”

Adds Tenenbaum, “So much of it comes down to eat right and exercise. And people can know that. And that doesn’t mean they’re going to do those things…we know in America there’s an obesity epidemic and we all know what we’re supposed to do, and it didn’t prevent myself and others I know from putting on that weight during COVID.”

The challenge, Tenenbaum says, is “figuring out the precision way to get people motivated to do it. I don’t know if we’ve cracked that nut yet.”

As Harvard’s Kohane summarizes:

“The sort of behavioral characteristics that we’re trying to modify turn out to be very hard. We don’t do it. Facebook knows a lot more than most of us know about how to modify behavior [see my discussion of ad-tech for health here], but the healthcare system doesn’t know how to modify behavior. Health insurance companies don’t know how to modify behavior.  They’ve tried all sorts of incentive programs for cigarette smoking, weight loss, and we just don’t know how to do that, and we’ve failed at scale.”

He adds, provocatively: “Do we have enough leverage to do behavior modification … or should we just say, you know, humans are weak-willed individuals, and if we really want to combat the biggest epidemic in our lifetime, namely obesity, we’re going to have to go pharmacologic?”

The takeaway: for most people, the key to improved health isn’t a diet or exercise program based on specious conclusions from sequencing your genome, analyzing your microbiome, or surveilling your smartphone. Rather, it’s figuring out how to motivate people to adopt and stick with basic healthy living behaviors. 

It’s really about consistent coaching, guiding people to lead healthy lives – in a customized fashion that maximizes the chances of success.

Companies like Omada HealthVirta HealthNoom, and Precision Nutrition, among others, are aspiring to do variations on this theme. (Disclosure: I’ve recently reviewed course materials for Precision Nutrition.) The challenge, from a business perspective, is finding a way to combine the power and value of one-on-one interactions with the technology that offers the potential for additional insight as well as the promise of solutions at scale. 

Hence health’s multi-billion dollar question: can technology truly enhance the power of health coaches, enabling health coaching to scale while providing customized insights and improving adherence? Or will the efficacy of health coaching inevitably be reduced and diluted in the insatiable drive to achieve exponential growth?

Our future health may depend on how this question is resolved.


A Trek in the Himalayas for Cancer Research

The biotech community can do extraordinary things when fixated on a goal.

Like curing cancer.

I’m excited to announce today that I’m taking a team of biotech leaders on a mission to raise $1 million for cancer research at Fred Hutch.

This group will come together on a trek to Everest Base Camp. It’s a legendary hike in the Himalayas of Nepal, up to 17,500 feet of elevation. We will be giving back to science, forming meaningful relationships, getting to know the local Sherpa communities, and appreciating the natural wonder of the highest mountain range in the world.

The trip is scheduled for Mar. 23-Apr. 8, 2022.

Each person is committed to raising at least $50,000 for cancer research.

Here’s who is on the team:

This trip will be guided by Eric Murphy of Alpine Ascents International. AAI has a 30-year history of guiding trips in Nepal. They were the guides I trusted on my Mt. Everest summit expedition of 2018.

Luke Timmerman with Everest guide Jangbu Sherpa at Everest Base Camp. 2018

If you’d like to personally support any of the people above, click on their names to go straight to their Fred Hutch fundraising pages. Your donation is tax-deductible, and you’ll automatically get a receipt.

If your company would like to sponsor this team, and align your company mission with this once-in-a-lifetime expedition, see me: luke@timmermanreport.com.

Thank you for your support in this moment of possibility against cancer.



Motivating a Modicum of Exercise: The Healthtech Opportunity

David Shaywitz

“It’s been a busy few weeks for product announcements in the world of fitness,” industry observer Anthony Vennare recently commented, citing the latest offerings from the Peloton, Mirror, Tempo, and other digital fitness platforms.

On the one hand, these developments are encouraging, offering customers pursuing fitness — and who are willing and able to afford the steep premiums — a greater range of options.

At the same time, when you look at these products – and the slick ads that often accompany them – it’s pretty clear that the target market is the already fit, or at least the fit-adjacent. While certainly some previously sedentary people have been inspired to start riding a Peloton or rowing a Hydrow, the inactive do not appear to be the main customers these digital fitness companies are pursuing.

Which, from a health perspective, is really too bad.

Here’s why.

Minimal Exercise Is Unreasonably Healthy

There are plenty of data arguing that exercise is good for you, and a huge amount of ink that’s been spilt trying to define the ideal weekly threshold.  But if you are really looking for the most bang from your buck – the most benefit for the smallest change in amount of weekly exercise – the data seem remarkably clear. 

Going from inactive to exercising a little bit each week seems to result in a disproportionate boost in your health, including specifically years of added life. The amount you benefit if you make this relatively small change in weekly exercise is roughly equal to the benefit you can expect to receive if you then go from exercising just a little to exercising intensively, all the time.

As Andrew Yang might say, it’s just math – and in particular, the shape of the benefit curves. (See Figure 1 of this 2012 paper by Steven Moore and colleagues at the National Cancer Institute, and Figures 2 and 3 from this 2017 review by Warburton and Bredin of the University of British Columbia.)

Earlier this year, I discussed what seemed like an important opportunity for digital fitness companies to target these customers – a need for what investment banking analyst Aarti Kapoor called the “Planet Fitness of the Digital World.” 

For Kapoor, this opportunity reflected a market gap revealed by her economic analysis, but if you layer in the disproportionate health benefit from serving this population, the need for such an offering seems that much more compelling.

Motivating Small Activity Is A Big Challenge

So why haven’t more digital fitness companies seemed to have targeted this demographic?

One reason: it’s easier to persuade someone who’s already active to try out a different product than it is to convince an inactive person to get off the couch in the first place.

A second reason might be the intangibility of the benefits: a previously sedentary individual who now exercises a little every week might be significantly better off from a health perspective, but might not feel all that different, or look all the different, and might regard themselves as still fundamentally deconditioned.

A related challenge is the Peltzman Effect – the tendency to compensate for a reduced risk by feeling more comfortable engaging in riskier activities. You can think of it like permissioning; for some, wearing a seatbelt justifies driving faster; a skateboard helmet makes it easier to contemplate more dangerous tricks. In the area of health and fitness, I imagine this tendency might be renamed the “Diet Coke Effect,” since making one healthy choice (like opting for a calorie-free beverage) often seems to justify indulgences (say a package of Yodels) that can more than offset the potential benefits of the first decision. 

While this challenge impacts all of us – it’s easier to justify ice cream after an intense workout – it’s easy to imagine that any potential health benefit of slightly increased exercise might be lost if the activity made it easier to justify additional caloric consumption.

There are also a range of what might be termed structural obstacles, as Dr. Michael Joyner of the Mayo Clinic pointed out to me, ranging from challenges in the built environment (e.g. “neighborhoods that are either not safe or not walking friendly”) to economic factors to limited opportunity for active transportation.

No one ever said it would be easy.

At the same time, it’s difficult not to be impressed by the engagement of emerging digital fitness technologies; Peloton is arguably a leading example of this, as I’ve discussed –also here).

Who Will Figure It Out?

So, first question: where will the digital health company serving the inactive come from? Will it emerge from a sophisticated digital fitness player like Peloton developing a new offering that targets a different demographic (with all the attendant risks to the brand), or from a company like Planet Fitness, developing digital offerings that deeply engage and encourage the currently sedentary?

Alternatively, might it come from a wellness and mental health brand like Noom, Headspace Health, or Happify Health, seeking to extend their program with a fitness hardware component? Or might the winning entry be something yet to be created?

Second question: if a company does develop a compelling offering, will the benefits delivered be robust enough, and achieved rapidly enough, to meaningfully reduce health costs – what I often think of as the Al Lewis test

This deceptively simple goal represents a remarkably difficult challenge, as I’ve recently discussed, but one that, if met, would obviously be of exceptional interest to self-insured employers, as well as payors seeking to promote disease prevention and encourage health maintenance.

Aarti Kapoor, CEO, VMG Consumer Acquisition SPAC

We may get some early visibility into the first question from Aarti Kapoor herself, who has recently left her investment banking job to become CEO of a SPAC — “VMG Consumer Acquisition Corp”— that went public just this week. The stated intention of this blank check company is ”to identify and complete a business transaction with a company in the high-growth consumer and retail industry.”

Given Kapoor’s previous interest in a digital fitness offerings focused on the less active, it’s exciting to contemplate the possibility that she might identify a promising high-growth company in this category.

Whether or not Kapoor invests here, the space remains compelling from both a business and health perspective. It represents an important opportunity for aspiring healthtech entrepreneurs.


A Remarkable Life in Science: David Baltimore on The Long Run

Today’s guest on The Long Run is David Baltimore.

David is one of the most accomplished biomedical scientists – and scientific citizens — of the past 50 years. He recently won Lasker~Koshland Award for Special Achievement. The award was granted “for the breadth and beauty of his discoveries in virology, immunology, and cancer; for his academic leadership; for his mentorship of prominent scientists; and for his influence as a public advocate for science.”

David Baltimore, president emeritus, distinguished professor of biology, Caltech

It would take way more than an hour to discuss all of this work in depth.

His fundamental work in virology led him down a whole set of interesting paths in immunology and cancer biology.

He won the Nobel Prize in 1975 at age 37.

Now at age 83, Baltimore is in a position to reflect.

In this conversation, we talk about his upbringing, the value of humanities training for scientists, some early career turning points, how he got involved with biotech, and the kind of opportunities he’d like to see open up for young scientists in the future. I think this conversation pairs quite well with the last episode with Tony Kulesa.

Now, before we get started with the conversation with David Baltimore, a word from the sponsor of The Long Run – Answerthink.

Today’s sponsor, Answerthink, has been consistently recognized by SAP, one of the largest enterprise software companies, as a top business partner for delivering and implementing SAP solutions for small and midsized life science companies. Their SAP certified solutions designed for the Life Science Industry are preconfigured, rapidly deployable and address fundamental business and IT challenges such as:

  • Integrating your business applications
  • Delivering validated reporting
  • Increasing your speed to market
  • Support for global rollouts
  • As well as delivering a fully compliant solutions that meets FDA’s strict standards.

Explore how Answerthink can streamline your business processes to ensure growth.

Visit Answerthink.com/timmerman and get a copy of their e-book- “Top Three Barriers to Growth for Life Science Organizations.“

That’s Answerthink.com/timmerman

And, I’m pleased to welcome a new sponsor this week – Absci.

Absci is all about creating new possibilities in the realm of protein-based therapeutics. What does this mean?

Absci has a fundamentally different approach to drug discovery. It designs and develops next-gen biologics of any modality, from antibodies to T-cell engagers to completely novel protein scaffolds, including a futuristic format it calls “Bionic Proteins.”

Because Absci conducts its screens in its scalable production cell line, it collapses several steps of biologics discovery into one integrated, efficient process. Absci also has a unique computational antibody and antigen discovery approach for isolating fully-human antibodies from disease tissues and using these antibodies to identify novel drug targets.

Absci does all this with a powerful combination of deep learning AI and synthetic biology technologies. Absci is already helping some of the best partners in biopharma translate their ideas into drugs. Check them out at absci.com and absci.ai.

Now, please join me and David Baltimore on The Long Run.