Controlling COVID in 2022: Masks, Treatments and Fast, Frequent Testing

Mara Aspinall, managing director, BlueStone Venture Partners; professor of the practice, biomedical diagnostics, Arizona State University

Over the past week I have been reflecting on what we know now, two years into a seemingly unending pandemic.

One of the biggest failures has been with testing.

At first, our only effective defenses were masking and social distancing. We were slow to ramp up testing, unable to give most people the timely information they could use to isolate and curb the spread.

As the first year went on, we got better and better at testing. First came PCR, then rapid antigen tests.

At the start of 2021, we began to think that testing was less necessary. Vaccination, many hoped, would bring the end of COVID all on its own. Masking became inconsistent and despised. Testing declined – to the extent that a major US rapid test antigen company began to wind down a manufacturing plant in the summer of 2021. 

Now at the end of 2021, it is clear that the virus has continued to evolve in dangerous ways.

It has kept pace, and in some ways is outpacing our best efforts. Rapid antigen tests are now reportedly in short supply in many parts of the country, right at the time they are needed most. New more transmissible variants are emerging every ~100 days. The newly emergent Omicron variant contains all the best/worst mutations of earlier variants that contribute to transmissibility and immune escape, plus an unprecedented number of mutations of which we know little or nothing.

Today, the CDC reported that Omicron makes up about 73 percent of new US cases. It took two weeks to reach that threshold. Delta needed four weeks to reach that level, and Alpha took 12 weeks. [Clarification, 12:40 pm PT Dec. 28: On Dec. 28, the CDC revised this estimate of Omicron incidence downward from 73 percent to 23 percent of new cases for the week ending Dec. 18.–LT]

In 2022, we will add effective treatments for the more seriously ill. But instead of putting all our eggs in one basket, we must mobilize all the tools at our disposal to return to “normal”, whatever that will turn out to be. Masking, vaccination, improved indoor ventilation, and the fast, low-cost and frequent self-testing that empowers individuals to manage their own health, their family health, and their community health.

Effective testing depends on how, when and where the virus replicates and the natural progression of resulting infections. A major challenge to our early understanding was that all our data came only from the sickest patients in hospital. 

How did testing become so much easier, simpler and cheaper? 

We have decent answers to four key scientific questions that put us in much better position than we were in two years ago:

  1. How is the virus transmitted? Primarily aerosols, less so bodily fluids, and rarely fomites.
  2. From where can we acquire a valid sample? Upper respiratory tract tissue secretions: mucus and saliva. There’s no need for more invasive or difficult to obtain biopsies or bronchoscopy.
  3. Which infection products are reliable analytes? mRNA and N proteins, much less so immune response markers such as IgM from blood or volatile metabolic by-products from breath.
  4. Are there easy to observe symptoms that are sufficiently reliable to act as a proxy for the infection itself? Unfortunately, no, not this time around, the only unique symptom is loss of smell or taste, but this is not universal. Temperature monitoring that worked well for SARS-CoV-1 in 2003 is largely futile “hygiene theater” for COVID-19. It’s not sensitive and not specific enough to be useful even as a screening test.

Stopping the chain of transmission requires tests that identify the infectious subset of the infected. If the upper respiratory viral load is high enough, secondary aerosol transmission can occur, especially in closed spaces where vocalization is happening (e.g. choirs, basketball arenas, bars and restaurants). 

High viral loads have been identified in all infectees: vaccinated or not; asymptomatic, pre-symptomatic, peak symptomatic, or early post symptomatic. This is to be expected, as the vaccines were designed to stimulate systemic immunity to save lives – they weren’t designed to prevent infection and transmission (although some scientists hoped they might do it all).

Optimizing the testing protocols for increasingly available rapid antigen tests depend on studies of the end-to-end natural history of disease in the same individuals over time (i.e. longitudinal, not cross-sectional) — from pre-infection, first positive test, peak infection, through viral clearance across all degrees of illness severity. This data is harder to find, mainly because it’s harder to collect than cross-sectional data.

But we do have some data to help guide us here.

A July 2021 Singapore study of hospitalized patients with Delta variant infections, who were previously given mRNA vaccines, showed that peak viral loads were similar between vaccinated and unvaccinated patients, but that the vaccinated had less severe illness and cleared the virus consistently faster (see adapted study Fig. 1).

Fig. 1. Virological and serological kinetics of SARS-CoV-2 Delta variant vaccine-breakthrough infections: a multi-center cohort study. MedRxiv. July 31, 2021. (Barnaby Edward Young et al National Center for Infectious Diseases, Singapore).

One caveat: only the seriously symptomatic were included in this study.

A December 2021 letter in the New England Journal of Medicine confirms these insights in the National Basketball Association’s 2020/2021 longitudinal screening program in a group of 173 healthy individuals (60% players/40% staff), PCR tested 19,941 times (before Omicron emerged):

  • On average, from first contact through viral clearance takes an average of 13 days for the vaccinated and 15 days for the non-vaccinated – 4 days from contact to 1st PCR+; 3.2-3.5 days to peak viral load; 5.5-7.5 more days for the unvaccinated to clear the virus. These estimates combine the results of a comprehensive study of a May/June 2021 Delta outbreak in Guangdong, China (30 million unvaccinated community PCR tests and 100% contact tracing of all 167 cases) that found that infectious contact to 1st PCR+ in the 25% who developed COVID took an average 4 pre-symptomatic days. These data from China are consistent with the NBA study results of 1st to last PCR dynamics, published in the NEJM. The NBA study found that 1st PCR+ to peak timing was similar for both vaccinated and unvaccinated but that the vaccinated cleared the virus 2.3 days faster, with less patient-to-patient variation (see adapted Fig 1D & E). Several unvaccinated patients (Figure S7) had particularly long clearance times with PCR-detectable virus up to 30 days post-peak.

Adapted Fig. 1 and 2. Viral Dynamics of SARS-CoV-2 Variants in Vaccinated and Unvaccinated Persons. NEJM. Dec. 1, 2021.


  • Peak viral load tops out around 100 million to 1 billion viral copies per ml (108 – 109cp/ml) and “…found no meaningful difference…” across all sub-groups sampled: vaccinated or not, and across variants (Wuhan A/B, Alpha or Delta – Figure 1F). However, through the wonder of exponential scales, it is worth noting that the 108.0 cp/ml in the vaccinated is still 20% less virus than the 108.1 cp/ml in the unvaccinated. In contrast to the NBA study, two earlier studies found greater differences in viral load: year-end 2020 Alpha surge data from Israel (May 2021 Nature Medicine) estimated 2.8-4.5x lower viral load in vaccinated patients (perhaps because mRNA vaccination was more effective at clearing Alpha variant infection?); and the Guangdong, China study found Delta peak viral load to be ~1,000x (103) that of the initial Wuhan A/B D614G strain (24 cycle threshold (Ct) versus 34Ct). Either way, there is no doubt today that we have to assume that all infected individuals can reach similar viral loads and be infectious whether vaccinated or not, and whether asymptomatic or not. In other words – test, test, test to detect infection early so people can isolate in a timely manner.
  • Rapid antigen tests are sensitive enough to detect transmissible individuals. A May 2021 study published in The Lancet showed there is a consensus that viral load drives transmission: the secondary attack rate (% contacts infected) was 24% if the index case viral load was >1010 cp/ml but only 12% if <106 cp/ml. The Roche Cobas PCR test used in the NBA data has a limit of detection of ~25 cp/ml (101.4 cp/ml), corresponding to ~35 cycle threshold (Ct) (see the study’s methodology in supplementary data). Rapid antigen tests are typically 10,000x less sensitive, i.e. are antigen positive >105.4 cp/ml. Laboratory culture of virus is typically unsuccessful <106 which implies a negative antigen test represents inability to transmit between humans, at the time of the test. This is evidence that the rapid tests are giving us valuable information – they tell us whether we are infectious at a given moment.
  • Frequent testing is essential because viral load increases fast. In the NBA group, each new variant has shortened the time from 1st PCR+ to peak viral load. The ramp-up is remarkably fast. The Wuhan D614G variant took an average of 4.2 days from 1st PCR positive to peak viral load; Alpha 3.4 days; and Delta 3.0 days. It is likely that Omicron will prove faster still – if so, the good news is a shorter pre-symptomatic but transmissible delay, but the bad news is that it enables faster surge growth. Billy Quilty, a researcher at the London School of Hygiene & Tropical Medicine demonstrated this by taking a rapid antigen test 4 times in 24 hours, which was likely Delta, but might have been Omicron (no sequencing or PCR SGTF was performed to confirm the presence of Omicron).

Based on these data, we can conclude a few things.

Vaccines are still extremely valuable tools, but they are one layer of protection out of many.

To curb the rate of spread and keep our hospitals from being overwhelmed, we need to massively increase both the number of people who test, and how often we test, while being highly diligent in masking – even for the vaccinated and boosted. Otherwise, we’ll continue to fly blind during another very long and painful winter.


Physician-Scientist-Biotech VC: Vineeta Agarwala on The Long Run

Today’s guest on The Long Run is Vineeta Agarwala.

Vineeta is a general partner with Andreesen Horowitz’s bio fund.

Vineeta Agarwala, general partner, Andreesen Horowitz

Vineeta has spent a lot of time on the front lines of an explosion in biological data, and efforts to analyze it to develop better therapeutics, diagnostics and digital health applications. Before coming to A16Z, she worked at GV and Flatiron Health, among other stops.

I first spoke with Vineeta in 2019 when she, along with colleagues at Flatiron Health and Foundation Medicine, published a paper in the Journal of the American Medical Association. The paper focused on non-small cell lung cancer outcomes for patients, based on their tumor genomic characteristics. It’s a fascinating piece of work, offering a glimpse into what might be possible for personalized medicine and a “learning” health data system.

See the full JAMA article here.

In this episode, Vineeta talks about her career journey this moment of possibility in biotech, how to make more use of engineering and computation in biotech, and some of the other challenges on her mind as she considers investments in early-stage startups.

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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 Vineeta Agarwala on The Long Run.


The Long War

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

I think I have seen enough. We cannot fight an exponential rise with linear thinking and processes. And yet, this is what we keep doing.

On that optimistic note, some background for those of you who are new to my cranky musings. As many of you know, I wrote here on Nov. 26 about the emergence of Omicron as an ominous new Variant of Concern.

What follows is a (fairly wonky) post to discuss how serious this new threat is. There were many “known unknowns” at the time: in the intervening period, some of them are now much clearer. I thought of sharing the evidence, completely unprompted by my gracious editor as well as by the (many) emails from readers.  

If you want the TL;DR version: get a third dose of a vaccine as soon as possible (and I mean now, really). And be very, very careful this winter in the Northern Hemisphere, and keep layering non-pharmaceutical interventions (masks, tests) to stay safe.

Previous unknown #1: is Omicron much more transmissible than Delta?

The circumstantial evidence was already fairly strong: S. Africa’s commendable genome surveillance effort noticed a rapid spread in a predominantly Delta background (over a very short period of time). There is now incontrovertible evidence that this is indeed the case: (FT coverage) in both the UK and Denmark, also countries performing an admirable job in genome surveillance and sequencing of viral infections, Omicron is going to be the predominant variant within a few days (again, on a Delta prevalent background).

The doubling time in cases in both UK and Denmark seems to track around 2 days. That’s shocking. The Rt for the virus (a measure of transmissibility) is estimated at ~6 with Omicron, which is (very roughly) a 400-500% increase over Delta (also a shocking statistic).

As I type this in the evening of Dec. 14, the Washington Post is reporting on the CDC warning that their modelling is showing worst-case scenario of Omicron spreading could overwhelm health systems by January, particularly in under-vaccinated communities. More on the un-vaccinated below.

Answer: yes, way more transmissible.

Previous unknown #2: Is Omicron able to evade previous immunity more effectively than Delta? AND: Previous unknown #3: Will the vaccine protect against Omicron?

Again, here the circumstantial evidence from South Africa was fairly strong: Omicron spread in the background of a population having undergone a massive Delta wave just several months prior, leaving an estimate of ~70% of the population recently exposed to Delta and therefore having (presumably) some meaningful level of pre-existing immunity. We now have more consistent data (still more to come) that show just how much is Omicron capable of evading the immune system.

Quoting from one of the many papers published over the last few days in pre-print servers:

“Using isolates of SARS-CoV-2 WT, Beta, Delta and most importantly Omicron we studied the capability of the BNT162b2 vaccine given in two or three doses to neutralize major SARS-CoV-2 variants of concern (VOC). We demonstrate low neutralization efficiency against delta and wild-type for vaccines with more than 5 months following the second BNT162b2 dose, with no neutralization efficiency against Omicron. We demonstrate the importance of a third dose, by showing a 100-fold increase in neutralization efficiency of Omicron following a third dose, with a 4-fold reduced neutralization compared to that against the Delta VOC. The durability of the effect of the third dose is yet to be determined.” (59425721 (medrxiv.org).

Another recent study using Pfizer/BioNTech vaccine showed that protection against hospitalization fell to 70% (from 93% with Delta) and against infection to 33% (from 80% with Delta).

Now, there is a lot to unpack here, so let me elaborate. Vaccine-induced antibody levels from two doses of the Pfizer/BioNTech COVID-19 vaccine, seems to drop substantially against Delta after 5 months from the second dose and to practically completely drop against Omicron.

Some caveats are in order: antibodies are not the only defense the body has against a viral infection (there are other arms of the immune system which are more difficult to monitor that have a significant role, see Dec. 14 Timmerman Report article from Harlan Robins). It is expected that some protection against hospitalizations and deaths will still be in place with a two-dose vaccine. Efficacy from therapeutic antibodies also seems to drop significantly against Omicron, with many losing their neutralizing effect against this new version of the virus. The good news is that a third dose of the vaccine restored very high level of neutralizing antibodies against both Delta and Omicron.

Answer: yes, able to evade existing immunity way more effectively than Delta. Vaccines (three doses, less so for two) appear to still be strongly protective against severe disease. A two-dose regimen seems to still show substantial reduction in efficacy against hospitalization (down to ~70% from >90% previously) at least in the few months following the last dose administered.

Still unknown #1: is Omicron “milder” than Delta or the other variants (or will it cause more severe disease)?

That is definitely still unclear. However, dark clouds loom on the horizon. Many people are pointing to data on hospitalizations from S. Africa in the current Omicron wave vs the previous Delta wave to state that, individually (crucial word, that one: we will come back to that), Omicron does not seem to cause more severe infections than Delta.

I would like to spare you the (by now routine) reminders that increase in cases precede increases in hospitalizations by 2-3 weeks, and hospitalizations precede increases in fatalities by 2-3 weeks. But these facts bear repeating.

South Africa might also provide us with a misleading comparison. It has a very young general population (average age of 27-28), it is in its late spring-early summer (with less mixing in indoor / poorly ventilated spaces), and it just had a massive Delta wave just a few months prior (during the end of their winter). All those factors could be contributing to a lower proportion of severe infections requiring hospitalization. As a counterbalancing argument, S. Africa has ~20% of its population infected with HIV, which should increase the severity of Omicron infections.

So, if South Africa might not be the right comparator, where should we look? The UK and Denmark should be considered the canary in the coal mine here: both have excellent genomic surveillance and sequencing (see above), they are now in winter, and have older population than S. Africa (~40.5 in UK and 42 in Denmark, thanks Wikipedia: the US is at roughly 37).

There are, of course, differences in public health measures between these two countries. The UK started its vaccination campaign with AZ’s vaccine, which does not confer the same level of protection as early as the mRNA ones (they are now boosting with mRNA). I do not know also the various % of people in vulnerable populations vaccinated in each country. Caveats abound.

Therefore, there is a gradient, or sliding scale if you will, to consider, when looking at the data coming in from those two countries in the coming days. That said, it is absolutely clear that the Omicron’s spread has taken authorities by surprise (not many virologists / epidemiologists, I have to say, but then, if the world listened to them, we would not be here). On Dec. 13, the UK reported an estimated 200,000 cases, with 20% attributed to Omicron, as well as the first death related to the variant. I am afraid this is only the beginning.

Answer: we still don’t know but it might not matter this winter (see below).

OK, skip the technical jargon and take us to the gloomy projections!

Let’s assume for a minute (and I emphatically do not believe this should be our base case) that Omicron does indeed cause mild symptoms and very few breakthrough infections in people who are fully vaccinated (and by fully vaccinated, I mean three doses).

Why am I writing this article in the middle of the night?? There is, shockingly, still a startling amount of misunderstanding about the impact of a fast spreading variant. Let me clarify.

Always known (and always forgotten) #1: a more transmissible / less severe variant is much more dangerous than a less transmissible / more severe variant.

Not to stray too far from the beaten path here, but compare Omicron (or even the original SARS-CoV-2 strain) to SARS-CoV-1 or the MERS virus (all coronaviruses): perhaps a 1-2% Case Fatality Rate versus ~10-15% for the first SARS in 2002-2003 and ~40-50% for MERS in 2012.

The first two coronavirus outbreaks caused an almost infinitesimally small number of deaths compared with SARS-CoV-2. The differences this time: much higher transmissibility and a large number of asymptomatic patients with SARS-CoV-2; and vastly more people travelling (• Global passenger air traffic each year, 2004-2022 | Statista).

The current death toll in the US from the pandemic has just touched 800,000. To put this in perspective, this is more than the US casualties from WWI, WWII, the Korean and Vietnam wars combined.

The latest data from CDC indicates only ~55 million people have been vaccinated with a three-dose regimen (that is ~17% of the population). People who have received two doses are roughly 61% of the US population: A large percentage of these people will be protected (especially if they have gotten their second dose recently).

People who have NOT received a single dose are 28% of the population. And these vaccines refuseniks concentrate in areas with a complete disregard for other mitigating public health measures (masks, no congregating indoor etc.). These are potentially very vulnerable not just to Omicron but to Delta, which is already prevalent. In general, even should Omicron result in a smaller percentage of non-vaccinated people progressing to severe disease, even a small percentage of a very large number is still a very large number!

There is simply not enough time, even assuming everybody who still has to be vaccinated will be miraculously convinced in the next couple of weeks, to vaccinate everybody before Omicron takes over. The US might have 1-2 weeks advantage vs the UK and Denmark but I find it increasingly difficult to believe we will escape this variant unscathed.

The other factor to consider is the following: because of its much higher transmissibility and spread, Omicron might overwhelm healthcare systems just by compressing a lot of cases in a very short period of time. Even with a smaller % of cases requiring hospitalizations, if you compress millions of cases in a period of weeks instead of months, many more people will need treatment.

This tsunami is coming at a vulnerable moment in healthcare. The never-discussed-enough fact is that healthcare professionals are exhausted and despondent after nearly two years of caring for a general population which has taken their selfless sacrifice and abnegation for granted. Nurses are leaving the medical profession in droves. It is frankly shocking how much we are demanding of and taking for granted from these incredible professionals, and how little we are willing to do as a country to support them.

What else is left to say? We have seen this movie already a few times. To quote Jon Levy, Prof. of Environmental Health at Boston University (@jonlevyBU):

“We keep making the same mistakes. We treat a global problem like a domestic one, and a public health problem like a medical one. We localize what should be national and individualize what should be collective. We forget about lags between cases and deaths, and ignore morbidity.”

In doing so, as aptly put by George Santayana, “Those who forget history are condemned to repeat it.”

Stay safe, and Buon Natale to you all. I do wish for all of you a merrier 2022 than what I am expecting.


The Other Side of The Story: Vaccines Must Produce Both Antibodies and T cell Immunity

Harlan Robins, co-founder and chief scientific officer, Adaptive Biotechnologies

It’s time to include T cells in the fight against COVID-19.

The scientific community brought novel vaccines to the world in less than a year. That heroic work saved millions of lives. These vaccines were designed specifically to induce antibodies that target the spike protein and disable the virus, blocking it from entering the ACE2 receptor on cells.

Like other vaccines, efficacy was largely measured by using tried and true technology — cheap, simple assays that almost any lab around the world can run — to count the number of neutralizing antibodies against the spike protein.

We knew the target (we thought). This strategy worked brilliantly with the original strain – even better than we had hoped. 

But much to our surprise, the virus started to mutate faster. Like other coronaviruses, SARS-CoV-2 is a long RNA virus with an enzyme that self-corrects errors in its genetic code. Therefore, we expected it to evolve slowly. Shorter RNA viruses such as influenza or HIV don’t have this error correction capability. They mutate regularly, which makes these viruses especially difficult moving targets for vaccine developers.

Now we know SARS-CoV-2 is a tough adversary for vaccine development. As the virus started mutating and moved through the Greek alphabet, it successfully evaded much of the neutralizing antibody response induced by vaccines or previous infection-induced immunity.

The neutralizing antibody response has fallen off dramatically – a 40-fold drop against the Omicron variant, according to an early report out of South Africa. But that worrisome development hasn’t yet translated into a real-world drop in vaccine efficacy. How could that be?

The current hypothesis is because of the T cell response, the other primary mechanism by which the adaptive immune system fights viruses. Antibodies prevent the virus from entering cells. T cells locate and kill cells that have been infected by a recognizable pathogen.

Evidence has been mounting in recent months demonstrating that T cells bind to more parts of the SARS-CoV-2 virus than antibodies, which makes it much more difficult for the virus to escape killer T-cells, also known as CD8+ T-cells. In fact, T-cell levels are correlating directly with real-world vaccine efficacy.

Sure, there were breakthrough infections by the time the Delta variant swept the world, but thanks to T cells, hospitalization and death rates among vaccinated individuals were extremely low.

Historically, antibodies have been used as the main measure of vaccine response because they are well-understood and easy to measure. As opposed to a simple blood-based serology test to measure antibodies, the traditional methods for measuring the T cell response require functional assays that use live cells. Since live cells are finicky, these assays are virtually impossible to standardize and run at scale. Also, functional assays require samples to be viably frozen, which is not possible in a global study. As a result, the T cell assessments that have been done on COVID vaccine studies to date have been done by special labs for a small fraction of participants in the vaccine studies.

But we are in a new age of medicine. The tools exist today to measure T-cell response quickly, at scale and cost efficiently. We now have molecular assays that can assess the T cell response using DNA from blood that is compatible with almost any sample handling and shipping protocols.

It’s time to start using them.  

Unfortunately, we are now sitting on the edge of efficacy with the present vaccines. With Omicron, we are seeing neutralizing antibody levels drop to less than 10% of the level seen with previous variants. Even T cell levels, which have held steady in vaccinated people for long past six months, are also starting to drop.

We at Adaptive Biotechnologies, along with colleagues at Stanford University, just published last week that the number of circulating T-cells that can kill Omicron has dipped to about 70 percent of the levels seen against the original strain.

Source: Adaptive Biotechnologies

This is predicted by determining which T cell epitopes – parts of the Spike gene that T cells bind – are impacted by the Omicron mutations. For each T cell epitope, we have measured the size of the T cell response. So, we can determine how much of the response is lost due to the mutations. 

A third shot of an mRNA vaccine six months after the first round of shots will likely provide a reasonable level of protection. But there is still high risk that the protection will drop even farther with the next variant.

It’s time to rethink vaccine design to take advantage of the T-cell response. If we continue to only focus on neutralizing antibodies as the measurement most predictive of vaccine efficacy, we will wind up with new vaccines designed for mutations that are no longer relevant. We cannot afford to make this mistake.

We need to look at both neutralizing antibodies, and T-cells, to get a more comprehensive view of the breadth and depth of immunity being elicited by new vaccine candidates. We need to take these measurements consistently and longitudinally. We need to know how long the protection is likely to last and we need to make sure that a robust T cell response is induced in everyone.

We – and others – have been raising the alarm about the importance of T cells for the last year and our pleas have fallen on deaf ears. As mentioned above, the T cell response was not practical to measure at scale and neutralizing antibodies for other vaccines served as a good correlate of protection. But we now have better measurement tools and SARS-CoV-2 vaccine efficacy is remaining strong even when antibodies are ineffective. The T cell response must be included at scale in all vaccine studies, and now it’s possible to do so.

This has life and death significance. It is imperative to leverage existing technologies to rigorously study the complete immune response to advance vaccine and drug development, inform public health and guide individual decision-making. Companies like Nykode and Gritstone are working on novel vaccines that consider the breadth of the T cell response. More should be following suit.

The world has changed. We should be nervous. We should be acting immediately to develop vaccines that consider both antibody and T cell responses systemically. The time is now.


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