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Alex Mayweg, managing director, Versant Ventures
Back in March — during the first wave — I reflected on the COVID-19 situation in Switzerland. This small country, at that time, was managing its outbreak and quickly getting it under control.
This was just as the federal government had begun coordinating a response, which had previously been left to local authorities. As I mentioned back then, while Switzerland is rarely the first to take measures or adopt something new, when the country does, it tends to take action extremely well.
Switzerland never formally and fully locked down, but the population adhered to the social distancing rules. And the results spoke for themselves — the numbers during May and the early summer faded to nearly insignificant digits. Switzerland’s flattened curve became the envy of many European countries.
While many Swiss citizens had cancelled the summer holidays they had planned to beautiful locations all around Europe, most (including me!) regretted doing so when the summer arrived and almost seemed — well — sort of normal. Perhaps a bit too normal.
The youth took the opportunity and enjoyed the warm sunny weather in Switzerland, hanging out with friends on the beautiful rivers, lake shores, and mountain resorts. And who would blame them after such a spring?
The mountain resorts recorded strong occupancy in the summer months. It almost seemed like most of Europe decided that hiking in the Swiss mountains might be a reasonable vacation destination, where social distancing — if needed — might be easier. Outdoor and camping equipment became extremely popular purchases.
And while some social distancing and hygiene measures certainly persisted, very few wore masks (except on public transport), as the federal government also returned the power back to the 26 local authorities – known as cantons. Each canton implemented its own measures — or lack of — which could be well justified as the case numbers remained low.
In August and September the numbers started creeping up. Cases rose particularly among the 20-29 year old age group. The famous R-value crept up and hovered just above 1, but after some weeks of increase, there were also brief periods of decreasing case numbers. Were we controlling the situation due to our heightened sensitivity, education and Swiss-efficiency hand washing?
Schools re-opened and mask wearing was still minimal. That changed when some cantons, such as Basel Stadt and a few others, reintroduced masks in supermarkets and shops but not in all public areas. Surprisingly, some cantons didn’t require masks in most public areas. The number of new cases was steadily increasing, but the curve was still pretty flat.
Since most of the cases were in young people, there was very little added pressure being put on hospitals. But even if corrected by age-group, the hospitalization and mortality rate looked much better now than it did during the initial first wave. Doctors were learning how to better treat patients in the hospital, and a couple of new medicines – dexamethasone and remdesivir – were available for those in need. Things seemed to be relatively under control.
Then the autumn school holiday break arrived. Again, the mountain resorts were packed. In many areas mask wearing was minimal. With cooling temperatures, guests were enjoying their meals or afternoon refreshments indoors or in mountain huts. Northern Italy was also a popular destination as the numbers there were even lower than in some parts of Switzerland — so why not go? You’ll never see Venice with this few tourists!
About two weeks later, cases shot up sharply. Suddenly, we saw a switch from local clusters of COVID-19 to a nationwide surge of cases. Hospitalizations spiked.
What were the factors driving this new nationwide spread?
Within two weeks, Switzerland went from one of the best in Europe to one of the worst, eclipsing the UK, Spain, the Netherlands and also France in new cases per 100K inhabitants.
About 10 days ago, when the sharp incline of the case curve surpassed many European countries, the federal government once again took back control from the inconsistent local authorities and introduced mask law in most public indoor spaces. Once again, the federal government issued a strong recommendation to work from home.
While this was important, I could not help notice that many other European countries had already taken these measures, or even tougher ones, a while ago.
On Wednesday, Oct. 28, the federal government announced further measures, such as requirement for mask wearing in certain public open-air areas, early closing times for bars and restaurants and further limitations for gatherings of certain group sizes. Rapid Covid-19 tests will also be rolled out.
The federal government stopped short of the anticipated “circuit breaker lock downs” that may still yet be implemented next to help flatten the curve as cases are spreading into higher age groups and hospital occupancy is going up.
The number of deaths, which usually increases a few weeks after a surge in new cases, is unfortunately once again following this sad, predictable pattern.
It is hard to know if too little is being done too late. The lack of measures and discipline in the summer are certainly an issue, but also understandable given the very low numbers of infections at the time. It’s difficult for people to remain vigilant when the threat isn’t visible.
The next weeks and months look to be a bumpy ride. We must do everything now to get this back to some reasonable control. But once again I have faith in my fellow citizens that with good discipline and by working together (albeit socially distanced!) we can hopefully manage this next wave as well or even better than the last.
My hope is that with our united best efforts over the next months and, at some point next year with the aid of emerging vaccines, new drugs, further refinement of treatment protocols, and perhaps a bit of “earlier than expected herd immunity” we can get on top of this virus.
If we do, we can eventually start the Roaring Twenties of this millennium.
Today’s guest on The Long Run is Peter Kolchinsky.
Peter is the managing partner at RA Capital Management. The Boston-based firm invests in public and private life sciences companies with a total of $6.8 billion under management.
Peter Kolchinsky, managing partner, RA Capital
Peter is a virologist by training at Harvard University. It’s obviously a valuable set of skills to have in a year like this. But he’s been spending more time lately on the future viability of the biopharmaceutical ecosystem itself.
The industry, as everyone ought to know, is in deep trouble. Public anger over high drug prices has been festering for years, with no real solution being offered by either party in Washington DC. Peter has seen the good that industry can do with creating new medicines, as well as the misdeeds that have been committed by those in the insurance industry and in pharmaceuticals.
In January, he wrote about some proposed solutions in his book, “The Great American Drug Deal.” It’s brilliant, unorthodox in its solutions, and easy for a layperson to read – unlike a lot of health policy books.
Peter hasn’t been content to just say his piece in a book – he’s now spearheading a nonprofit called No Patient Left Behind. It seeks to advocate for some of the ideas described in the book, urging biotech executives, leaders of industry trade groups, and members of Congress to get on board. He sometimes seeks to advance his thoughts as an occasional contributing writer for Timmerman Report.
In this conversation, I skipped Peter’s backstory. We talked about the crisis in biopharma and the broken profit incentives that have created this mess. He sees an internal battle within the industry between builders who develop innovative new drugs and other products, versus the landlords who are more interested in rent-seeking behavior to maximize profits of old blockbusters. He calls this a “battle for the soul of the industry” – perhaps adapting a phrase from a certain candidate’s rhetorical framework this election year.
One small note before we start: Peter was joined on this call by Chris Morrison, a veteran biotech journalist now working as an editor at RA Capital. You’ll hear Chris chime in at a couple of points, once to clarify a patent expiration date, and another time to remind Peter of the name of an author he was trying to cite.
Peter is brilliant and fiery in this conversation. Anyone who cares about the future of biotech ought to give this a listen.
Now, please join me and Peter Kolchinsky on The Long Run.
Ruth Etzioni, PhD, Full Member, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center
For a numbers person like myself, the SARS-CoV-2 pandemic is supremely frustrating. Even after 8 months, there are so many numbers that we still do not know. Even though there are thousands of researchers trying to fill in the gaps in our knowledge, the gaps persist.
As the officially recorded US death toll from SARS-CoV2 approached 200,000 last month (it’s now over 224,000), one missing number in particular began to disturb me. While I agreed with the many voices blaming the abysmal national response for the grim death count, I knew that even if we had responded optimally, the number of COVID-related deaths would not have been zero.
But how many deaths might we have expected had we responded quickly with sufficient testing, effective contact tracing and compliance with masking and social distancing?
I couldn’t find any published guesses. So I did it myself (with some help, acknowledged below).
I took as my model the country of Germany. It is frequently cited as having “crushed the curve” in March and April, because of a combination of rigorous contact tracing, quarantining, and near universal compliance with local and national lockdowns. In fact, Germany managed to keep cases and deaths ultralow through the summer.
But COVID-19 is a virus that tends to resist tidy narratives and easy explanations. Like much of Europe, despite its early accomplishments, Germany, too, is coping with a new spike in COVID-19 cases. On Sept. 22, when the official US death toll surpassed 200,000, Germany was still in good shape, recording new cases at levels only slightly higher than its summer nadir.
I asked the following question: If the US had been as successful as Germany in managing the virus, how many deaths would we have expected by September 22? By “as successful as Germany.” I meant, “if the likelihood of COVID-19 death in the US were the same as in Germany.”
It is not enough to simply translate the COVID-19 death rate per capita in Germany into a number of US deaths, because the age and demographic structures of the two countries are quite different. The vast majority of Germans are of European ethnicity. In the US, 18 percent of the population is Hispanic or Latino and 13 percent are African American. And the German population skews slightly older.
To accommodate the demographic differences between the two countries I used age-specific cumulative death rates in Germany from the Robert Koch Institute as my baseline for non-Hispanic whites. But African American and Hispanic/Latino populations in the US have had markedly higher COVID-19 mortality rates than non-Hispanic whites. Even if the US had responded properly to the pandemic, I do not expect that it would also have solved its persistent problem of racial disparities in underlying health, which makes minority populations especially vulnerable to a pandemic.
So, for these minority populations I inflated the Germany-based death rate using race-specific death rate ratios (relative to non-Hispanic whites) from the CDC. Putting this all together, I (and my co-authors) concluded that, had we been as successful as Germany at managing the virus, the US would have had 43,187 deaths rather than the recorded cumulative total of 200,000 on Sept. 22. You can read the abstract and full manuscript here at MedRxiv.
I stared for a while at this shocking result. It was much worse than anticipated. These findings suggested that almost 80% of the 200,000 lives lost – 160,000 people! – could perhaps have been saved by a response that met the gravity of the threat, a response that went all out to break the chain of community spread in order to protect American lives. Even though my result was just an approximation, I felt like it was an important data point. I wanted to publish it right away. But I knew better.
I have seen over and over again how science has been politicized during the pandemic. I wrote in these pages about inappropriate, politically motivated interpretations of the changing IHME COVID-19 model projections, and the appropriation of the Mayo Clinic convalescent plasma study for political expediency. I knew that my result could be used to support a variety of political stories. Mostly I was concerned that it would be dismissed by Administration supporters because of its limitations, chief among them being that the US is not Germany.
So I tried to make it politicization proof. I went through all of the relevant differences that I could think of between the two countries and explained why my result was still defensible. Yes, there are cultural differences, and greater trust in the government in Germany. Yes, Americans are more likely to be obese. And yes, it is possible and even likely that what counts as a COVID death in Germany is not the same as in the US. I re-classified my work as a “thought experiment designed to provide a first quantification of a best-case scenario in this country.” I still thought it deserved to be published.
Unfortunately, the journals that I submitted it to did not agree. I quickly received two flat-out rejections from journals that are known for publishing commentaries on the state of public health in this country.
Was the work simply too hot to handle? Were my methods at fault? Were the limitations deal breakers? Did the editors disagree with my message?
I’ll never know. But at least my science has been validated. This weekend CNN published an article titled: “Faulty US COVID-19 response meant 130,000 to 210,000 avoidable deaths, report finds.”
Finally! I breathlessly followed the link and arrived at a report from a very reputable group of researchers at Columbia University. They had exactly the same idea as I had, but they looked not only at Germany but also at South Korea, Japan, Australia, Canada, and France.
By the time they posted their report, the US death toll stood at 217,000. The report concluded that “had the U.S. government implemented an “averaged” approach that mirrored these countries, the U.S. might have limited fatalities to between 38,000 to 85,000 lives – suggesting that a minimum of 130,000 COVID-19 deaths might have been avoidable given alternate policies, implementation, and leadership.”
In academia, there is a term for when someone publishes your idea before you have a chance to do so. It’s called getting “scooped.” Normally, it’s painful. But this time I am not at all perturbed. I’m delighted that others agree that this information is urgently needed and that they are equally determined to unearth and disseminate it.
We have a number for the human cost of our disastrous national response to COVID-19.
Now we just need to make sure everyone knows it.
Thanks to my co-authors on the article, Ivor S Douglas MD and Elan Markowiz, future PhD.
Today’s guest on The Long Run is Daphne Koller.
Daphne is the CEO of South San Francisco-based insitro. The company is seeking to develop a new platform for drug discovery that leans on a combination of wet labs and machine learning algorithms to spot new biological targets for drug discovery.
Daphne Koller, founder and CEO, insitro
Artificial intelligence and machine learning have been stirring imaginations in biopharma, and generating more than a little hype, for a few years now. Smart people who know how complex drug discovery is, are pining for something to make drug discovery less risky, less time-consuming, and less expensive. Insitro represents one of the prominent wagers in the AI for drug discovery category, as it raised a $143 million Series B financing in May led by Andreessen Horowitz, and which included earlier investors like ARCH Venture Partners, Foresite Capital, GV, and Third Rock Ventures.
Daphne comes to this challenge with a fresh set of eyes. She was a math prodigy as a kid. She became a tenured professor of computer science at Stanford University. She became a successful entrepreneur, co-founding Coursera, the online learning platform. But when it came time to find challenging new problems to solve intellectually, and important problems to solve for humanity, she decided that tackling disease was the place to be for her next act.
We talked about her journey, and some of the key aspects of her strategy to make insitro succeed in this new frontier.
Now, please join me and Daphne Koller on The Long Run.
Please subscribe and tell your friends why it’s worthwhile. Quality journalism costs money. When you subscribe to Timmerman Report at $169 per year, you reward quality independent biotech reporting, and encourage more.
Ankit Mahadevia, CEO, Spero Therapeutics
The progress in developing therapies and vaccines for COVID-19 has been extraordinary, and has received extraordinary attention.
But there’s another good news story beginning to emerge, about our widening array of defenses against bacterial infectious disease.
On the clinical front in the past month, developers have announced positive Phase III trials in difficult diseases that have been marked with prior failure, such as C. Difficile gut infections and oral treatment of resistant, complex urinary tract infections (cUTI). As we have noted before in this column, the continued growth and sustainability of the antibacterial field depends on choosing medicines that have a high prevalance of unmet need and sustainable reimbursement in the current system (typically outside of the hospital DRG based payment system).
Those things are necessary to build a base upon which to develop new treatments for emerging diseases.
For infections (primarily hospital-based) that require reimbursement reform before we can develop economically sustainable treatments, the reintroduction of the PASTEUR Act last month in Congress is a welcome step in planning for our preparedness against future pandemics and infectious threats.
The Act would confer substantial upfront payments and payments over time (totaling hundreds of millions of dollars) to sponsors developing agents to treat current and future high-priority bacterial threats. This could provide the kind of steady, predictable revenue streams for future infectious threats that don’t exist in the market today.
Where do we go from here? The impact of infection, even at the highest levels of government, makes the wait for vaccines and therapeutics excruciating.
Certainly, a comprehensive, long-term approach to developing medicines for current and future threats before they’re in dire need is critical. Further, as an important part of the economy and the social infrastructure that supports it, the drug development community must be a driver in this solution as it has been with COVID-19, rather than waiting for someone else or another pandemic to propel us into action.
Each of us in the ecosystem has a part to play to keep driving ahead towards a solution in advance, so we won’t be stuck playing catch-up.
Those of us that select and prioritize investment in infectious disease portfolios have the highest responsibility to choose therapeutic needs that meet two related priorities: address a need currently not met by existing medications and have the economic potential to sustain a franchise.
Medicines reimbursed outside of the hospital tend to meet these criteria (see here for much more data behind a premise for a sustainable franchise).
When a company can generate enough product revenue to achieve scale, it then has the means to plow profits back into additional promising therapies. Cubist Pharmaceuticals (built based on the growth of daptomycin in the outpatient setting) and Pfizer (built in part on the growth of linezolid in the outpatient setting) are models for success.
When building off a stable foundation as in these cases, antibacterial developers can have enough wherewithal to acquire additional revenue-generating products, take advantage of some of the substantial regulatory and market exclusivity incentives that exist in this category, and fulfill our industry’s mission to be a source of cures for the most pressing needs of the moment and in the future.
The commitment of over $1 billion to the infectious disease sector by a consortium of larger companies, through the Antimicrobial Resistance (AMR) Action Fund, is a great start.
However, money by itself isn’t enough. Given that drug development is the answer to the challenge nature has posed to us with infectious threats, larger drug developers can continue to be central by directly advancing medicines.
The approach of being reactive to threats as they emerge is suboptimal, as evidenced by today’s pandemic. As with biotech, the first step is building these efforts around applications that have economic potential in the current health care environment and can form the basis for efforts at greater scale.
Recent investments by Roche and Pfizer, continuing investment in the field by Merck, as well as interest from new parties are positive developments. There’s also an increasing recognition of the opportunity to do well for shareholders and patients by using sustainable products to build a base for a pipeline.
It’s heartening to see the multiple, well thought-out proposals in legislatures around the world for investing in new anti-infectives. What’s required now is for all stakeholders to coalesce around the right solutions. No plan will be 100% perfect for all stakeholders, but doing nothing will certainly be imperfect for all of us.
In the meantime, the Biomedical Advanced Research and Development Authority (BARDA) has risen to the challenge of the COVID-19 response. It has also remained focused on infectious threats beyond COVID-19, marshaling its expertise, mandate, and national coordinating platform.
We can choose what we value in the health care system. Ultimately, all actors in our health care system follow the incentives created by reimbursement. Our industry has a vast number of pipeline medicines in play (many around the same targets) in oncology, rare diseases, and inflammation.
That is because our system — either intentionally or unintentionally — puts more financial support behind these endeavors. We have fewer medicines in play for psychiatry, and for infectious threats, for the same reason.
We have been spoiled by a very, very effective infrastructure against infections over the last 50 years. COVID-19, and the relentless, worrisome march of antimicrobial resistance suggests large holes in that armor.
All of the breathtaking innovation in our sector, including the cancer treatments, procedures, and approaches leveraging our immune system are built on an assumption that we already have a strong armamentarium for infectious disease prevention and treatment. The pandemic has exposed a weakness in our defenses, and opened up a new set of great opportunities for biotech to show what it can do. We’ve already made great progress in this most difficult year.
We encourage all of us in the industry to keep doing our part to prevent infectious threats of the future.
Special thanks to Tim Hunt, Aleks Enge of the Novo REPAIR fund, and the Spero Team for their contributions.
Please subscribe and tell your friends why it’s worthwhile. Quality journalism costs money. When you subscribe to Timmerman Report at $169 per year, you reward quality independent biotech reporting, and encourage more.
Karl Simpson, CEO, Liftstream
Over the summer, when George Floyd’s horrific death and the disparities of the pandemic combined to spur a new national reckoning with systemic racial injustice, many CEOs issued statements.
Many insisted they would do more than talk – they’d take action in day-to-day business against structural inequalities.
Those loud pronouncements of action are fading fast. The reverberations of their disquietude will soon give way to challenging questions from the intended recipients of those well-crafted statements opposing racism and promising equality.
While the large multinational companies led the way, many smaller companies joined the momentous wave of formal protest that crashed at the feet of those marching the streets in support of BLM, sweeping them along with hope and motivation because “this time was different.”
As the heat of summer subsides, and the mercury falls, the racial justice issue is still burning red-hot. Activists have lost none of the zeal for change. But what action have we seen?
It is too optimistic to hope for immediate change, especially given the historical intractability of the racial issue and the many other difficulties companies currently face.
I do not wish to serve up pre-packed excuses to CEOs. They need to be pressured to follow through with actions. As each day goes by without change, the impatience has undoubtedly intensified. Many ideas for how to bring greater equality aren’t new, so pulling together an action plan should not take too long, but we must allow time for thoughtful and considered action to be implemented.
Very few people would contest that dialogue is crucial to resolving this social tumult. At some point though, words must give way to deeds, and that time has arrived. In an earlier article I wrote for the Timmerman Report, I described the skepticism that follows corporate pledges on diversity. The words, or sentiment, often heartfelt and well-meaning, count for little unless they are linked to direct action.
The NYC Comptroller, Scott Stringer, set out this challenge to CEOs. At the beginning of July, he sent letters to 67 S&P 100 companies, asking the companies to provide evidence of their respective commitments to racial diversity, consistent with the public statements they had made. Among the 67 companies that received the letters were 10 pharmaceutical and biotechnology companies.
The NYC Comptroller, on behalf of the New York City Employees’ Retirement System, Teachers Retirement System of the City of New York and New York City Board of Education Retirement System, requested that the companies publicly disclose their consolidated EEO-1 data. They argue that without this disclosed data, stakeholders are unable to monitor, assess and benchmark a company’s progress and successful practices to hire, retain and promote black employees, other employees of color, and women. After all, it is data they are already obliged to collect under law.
The letters included the request that the companies disclose the consolidated EEO-1 report with the raw data, not percentages, such that it would provide a clear and trackable data set across 10 categories of employment, including senior management.
Investors who evaluate companies on financial metrics wish for this consistent formatting and full disclosure as to enable useful comparisons between periods, and among peer group companies. In response to this letter, about half of the companies — 34, to be precise — have committed to disclose their consolidated EEO-1 report. Abbvie, Amgen, Biogen, Bristol-Myers Squibb, Gilead Sciences, Medtronic and Pfizer are among those following through with disclosure.
This is an encouraging sign of leadership, which others can follow.
This action is in line with a broader effort by institutional investors to get companies to report on a range of human capital metrics and indicators, including diversity and inclusion. One such example is the Human Capital Management Coalition (http://www.uawtrust.org/hcmc) which filed a rulemaking petition with the Securities and Exchange Commission.
This coalition of institutional investors, with $5.9 trillion under management and co-chaired by the UAW Retiree Medical Trust and CalSTRS, are seeking improved reporting and disclosure by companies on human capital metrics, including diversity and inclusion.
Cambria Allen-Retzlaff, co-chair of the Human Capital Management Coalition and Corporate Governance Director for the UAW Retiree Medical Benefits Trust
“The Coalition has long viewed diversity and inclusion data from portfolio companies as critical to investors’ overall understanding about how well a company is managing its workforce. This is why workforce data – focusing on diversity among senior management – is among the four fundamental metrics we believe every company should report to shareholders. These metrics alongside the number of full-time, part-time, contingent employees, turnover in the workforce and total workforce costs, provide a more accurate view of a company’s human capital management and investment,” said Cambria Allen-Ratzlaff, co-chair of the Human Capital Management Coalition and Corporate Governance Director for the UAW Retiree Medical Benefits Trust. “Decisive data showing financial and performance benefits of a diverse workforce makes sense: Why wouldn’t a company seek talent from the largest pool possible?”
The regulatory and policy sands are clearly shifting, toward more disclosure on D&I, whether at the board, senior management, or organizational level. Proxy firm ISS (Institutional Shareholder Services) recently reported its 2020 policy survey results, in which they asked if corporate boards should disclose the demographics of the board members including directors’ self-identified race and/or ethnicity.
Nearly three quarters (73%) of investors agreed that companies should do this to the full extent possible.
Despite the winds of change blowing forcefully through the business landscape, and a powerful coalition of backers, this proposal for more transparency has stalled. On Aug. 26, the SEC rejected the opportunity to require companies, under Regulation S-K, to report racial and gender workforce data. The amendment to Regulation S-K does introduce principles-based human capital reporting on issues material to the company, which will not result in widespread and uniform reporting by issuers on D&I.
The Human Capital Management Coalition, along with many other institutional investors, will no doubt continue to push the SEC. More specifically, we can expect investors to press their portfolio companies for improved disclosure, and vote accordingly when they aren’t happy with the results.
Running concurrent with the SECs vote on Regulation S-K amendments, was a legislative process in the State of California where Assembly Bill 979 has been signed into law by Gov. Gavin Newsom. This law amends the Corporations Code and requires corporations to appoint directors from underrepresented groups based on the board size. The statute defines a director from an under-represented community as:
“an individual who self-identifies as black, African American, Hispanic, Latino, Asian, Pacific Islander, Native American, Native Hawaiian or Alaska Native, or who self-identifies as gay, lesbian, bisexual or transgender.”
The new law follows similar legislation on gender which has seen many women corporate directors appointed to the boards of life sciences companies throughout California. Companies will have until between 2021 and 2022 to comply, or face fines ranging from $100,000 to $300,000.
Board composition gets a lot of attention when discussing D&I because there is publicly available information, particularly on gender. This information offers an opportunity for analysis and gives advocates the data on which to base their case. The lack of data on diversity at all corporate levels means the board of directors will continue to be an indicator of an organization’s cultural tone.
While board diversity can only signal a correlation with financial performance, we know that it has specific business implications that show up in a company’s financial results. For example, close to half of women (45%) in biotech will reject a job if there are no women involved in their interview and the employer’s board and management are all males. It is not a massive leap to suggest that the same will be true of prospective candidates from racial minorities when people like them are missing from a company’s hierarchy. These data show a direct effect on recruitment, a material risk for many biotech companies, and value.
Any board of directors should act under the societal context in which the company is active. Diversity and equality are very much part of this current and future context, and the judgments that boards and CEOs take at this time will have long-term implications, possibly long after the directors have all moved on. The time horizon to which a board of directors is looking to formulate strategy has a bearing on material issues, and how highly they are prioritizing diversity. If the board has a long-term view, then it should be conscious of how its own diversity is seeding the firm’s cultural identity, and either enabling or limiting management’s ability to promulgate inclusivity throughout the company.
But board composition is not only limited to the skills around the table. Investors and proxy firms continue to pay attention to the issue of directors serving on too many boards. The specificity of biotech often demands directors with particular expertise and skills. It is, therefore, not uncommon to see directors serving on multiple company boards, both private and public, calling into question their ability to be effective in the role. Diversifying the candidate pool is seen as an obvious remedy to this over-boarding problem.
The trend of “over-boarding” also concerns institutional investors and proxy firms. Among public issuers, they see evidence of greater over-boarding in biotech, pharma and healthcare than in any other industry.
For example, Glass Lewis recommended against U.S. directors 235 times in 2019 for over-boarding, with over a quarter of these occurring at companies in the pharma, biotech and healthcare sector, double any other sector. While proxy firms are only concerned with directorships for listed companies, there remain significant opportunities in biotech to serve on private company boards. While the demands of board service for a company with a venture investor ownership structure may not prove as onerous as a public company, there are limits to what even the most talented person can manage.
Different conclusions can be drawn from this evidence of over-boarding. One is that biotech and pharma companies still favor appointing highly recognized and well networked directors who they believe to have incomparable experience. Another is that companies are not cognizant of appointing directors who are burdened by competing commitments, or care less about their level of engagement.
Replacing such directors by appointing diverse candidates is part of the solution. While they wait for attrition, companies can also expand their boards and add diversity this way too. But unless companies are adapting their approach for appointing board members, looking further afield and in new places, many diverse candidates will soon become over-boarded themselves.
As for private companies with venture ownership, they require incentives to do more on ED&I. Perhaps the action by Goldman Sachs to refuse to support any company’s IPO without board diversity, thereby limiting access to capital, will be one such incentive for biotechs.
The most significant current incentive though, is that clear evidence of a company’s diversity and inclusive culture will drive decision making among future employees, and influence employee retention. Companies that fail to hire and retain diverse employees will lose out on key talent, and will be taking on material operating risk.
The board and CEO can provide the first spark needed to light the fire. Their response to ED&I must be multifaceted but should include a series of well-described key measures, such as the adoption of a publicly stated diversity policy, containing a clear recruitment search policy for all board and management appointments.
Companies should expand the number of directors on the board to add diversity; even though the board may reduce in size again as terms expire. Companies should consider their governance structure, including the independence of the Chair of the board.
Research that Liftstream published in 2017 showed a correlation between greater board diversity and a separate CEO/Chair structure. Nomination and Governance committees need to have diverse candidates chairing this committee, or at least as members. Companies nearing IPO, or recently listed, should take advantage of any opportunity to add new independent, diverse directors to the board as investor directors rotate off. And boards and CEOs must look internally at how succession plans and internal promotion processes can be made to equally award black and minority employees.
There are many ways to act in the short term, and the long term. Let us hope those words begin to transfer to deeds, and that those deeds add up over time to the kind of change our society needs.
Please subscribe and tell your friends why it’s worthwhile. Quality journalism costs money. When you subscribe to Timmerman Report at $169 per year, you reward quality independent biotech reporting, and encourage more.
Dr. Jennifer E. Adair, PhD, associate professor, Clinical Research Division and Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, and research associate professor, University of Washington.
Early in the morning of Wednesday, Oct. 7, we heard news that buffered the impact of the chaos and tragedy of this year.
For the first time in history, women almost matched men for Nobel Prize awards across all categories.
One in particular stood out.
Two women shared the award in Chemistry: Dr. Jennifer Doudna of the University of California at Berkeley and Dr. Emmanuelle Charpentier of the Max Planck Institute for the Science of Pathogens in Berlin, Germany for their co-development of a method of genome editing.
Just writing that sentence brings tears to my eyes.
There are a couple reasons why. The 2012 discovery by Doudna and Charpentier, that CRISPR systems derived from bacteria and phages can be repurposed to re-write the DNA of nearly any organism, opened the door for a new era in biology. That discovery has helped fuel my own research in human gene therapy as an early-career faculty member at the Fred Hutchinson Cancer Research Center.
However, the reason that gets me running for the tissue box is that they didn’t have to share this award with a man.
Barbara McClintock in the lab, 1947.
To be clear, this hasn’t happened for a Nobel Prize in Chemistry since 1964. That year, Dr. Dorothy Crowfoot Hodgkin became only the second solo female laureate in history for her application of X-ray crystallography to solve protein structures. She was preceded by the only other solo female laureate, Dr. Marie Skłodowska Curie in 1911 for her discovery of the elements radium and polonium.
The Nobel Prize in Medicine has once gone unshared to a woman, Dr. Barbara McClintock in 1983 for her discovery of mobile genetic elements. No female laureate of the Nobel Prize in Physics has ever been honored alone, in fact all four female laureates in Physics have shared their prizes with two male laureates.
Between 1901 and 2020, a total of 931 Nobel laureates have been named. Only 58 (6.2%) are women. Women comprise only 15.9% of Literature laureates, 13.7% of Peace laureates, 5.4% of Medicine laureates, 2.4% of the Memorial Prize in Economic Sciences laureates and 1.9% of Physics laureates.
With this year’s announcement, the prize in Chemistry now boasts an impressive 1 percentage point increase in female laureates from 2.7% in 2019, to 3.8% in 2020 (seven women out of a total 186 Chemistry laureates).
That may not sound like much progress, but there is a long-term trend at work. About half of all the female Nobel laureates — 28 out of the 58 in history — were honored between 2001 and 2020. That sounds like significant progress, but it should be considered against the total number of laureates in the same 20-year time period. There were 232 total laureates counting men, women, and organizations, which means that women have only won 12.1 percent of the prizes in the 21st century. Only 12 of these laureates (5.2%) were awarded for Chemistry, Physics or Medicine.
To put this in perspective, women make up about 42 percent of PhD degree recipients in Science, Technology, Engineering or Mathematics (STEM) fields.
When Presidential candidate Joe Biden announced he would select a woman as his Vice Presidential running mate in 2020, responses were mixed, even among women. I heard echoes of the age-old argument, “Shouldn’t the best candidate win?”
The problem with this argument is that the meritocracy isn’t based on a level playing field – it is biased towards men.
Of all the evidence I could cite here, consider just a few recent findings. A 2019 study in JAMA showed that women in science receive less research funding than their male colleagues, even when grant scores are similar. Another 2020 study by researchers at Northeastern University found that women are biased against in peer-reviewed journals.
Two other studies objectively illustrate just how deep gender bias in science goes. The first was a randomized, double-blind study published in PNAS in 2012.
In this study, science faculty in chemistry, biology and physics were asked to review resumes for a lab manager position. Resumes were identical and were randomly assigned male- or female-associated names. Male-named applicants were consistently ranked higher than female-named applicants, despite identical merit on paper.
This bias was explored further in a more recent study published in Sex Roles last year. In this study, resumes were again randomly assigned names, but this time both gender and race were examined. The position for consideration was postdoctoral fellow. This study supported the known gender bias especially evident in Physics, and further underscored the intersectionality of race and gender as the most biased against across all sciences – again, in the context of equal merit on paper.
It is sad and unsurprising then that of the 22 Hispanic Nobel Prize recipients, only two are women and neither of whom are included in the six Hispanic laureates honored in Chemistry or Medicine. Only six Nobel laureates are known to have identified as LGBTQ. Exactly zero of the Nobel laureates in Chemistry, Physics or Medicine are Black.
The Swedish Academy of Sciences committee intended to grant the 1911 Nobel Prize in Chemistry to both Marie and her husband Dr. Pierre Curie, but Pierre died in an accident in 1906 and the award stipulations prevent posthumous award recipients, granting the historic award to Marie alone. With her default-solo Nobel in Chemistry in 1911 following her husband’s death, Dr. Curie also became the only woman in history to win a Nobel Prize twice. She shared her first Nobel Prize in Physics in 1903 with her husband and her doctoral advisor, Dr. Henri Becquerel. Initially only Pierre and Henri were nominated, but after learning of their nomination they decided to lobby the Nobel Prize committee for Marie to be included.
Dr. Hodgkin’s Nobel Prize nomination was solo from the outset, as she had solved both the crystal structures of penicillin in 1945 and Vitamin B12 in 1955. But her nomination didn’t come until two years after colleague Dr. Max Perutz shared the Nobel Prize in Chemistry with Dr. John Kendrew for solving the protein structure of hemoglobin, in 1959.
Indeed, Perutz has been quoted as saying, “I felt embarrassed when I was awarded the Nobel Prize before Dorothy, whose great discoveries had been made with such fantastic skill and chemical insight and had preceded my own.”
Dr. McClintock received her solo 1983 Noble Prize in Medicine more than 33 years after her discovery of mobile genetic elements. In her autobiography, she gives credit to Dr. C.B. Hutchison for inviting her to take his graduate level genetics course at Cornell University, Dr. Lester W. Sharp for his cytology course, and Dr. Rollins A. Emerson, who paired McClintock with fellow graduate students Marcus M. Rhoades and George W. Beadle, who became a Nobel laureate in 1958.
In these cases, and in all of the shared Nobel Prizes awarded to women, men had to open the door. Not only the men named above, but also the nominators, who must meet a set of stringent criteria which greatly favors men, and the prize committees, which have been made up entirely or predominantly of men throughout history. Today, less than 25% of Nobel Prize committee members are female.
When only one group has a majority seat at the table and owns the building the table sits in, they have the ultimate power to invite anyone else in to sit down. They have to actively push for others who do not look like or relate to them to join, and they need to do this by deconstructing their own perceptions of meritocracy.
Drs. Doudna and Charpentier didn’t just have to exceed peer-reviewed publishing standards and funding norms, they had to commercially advance their methodology and simultaneously become global advocates for ethical application of the technology. The result of this momentous effort is a tool that continues to rewrite not just DNA, but nearly all of the life sciences.
Since nomination and committee determinations for Nobel Prizes are made over the course of a year and sealed for a period of 50 years after the award is made, it will be a very long time before we have insight into the decisions behind this year’s awards. Regardless, it is a long overdue positive message to young female scientists like myself, and scientist-hopefuls everywhere.
There are many, many more exceptional candidates working incredibly hard, making groundbreaking discoveries, and waiting and hoping for their chance to someday get the call from Stockholm. Everyone must realize that to the newcomers, the rooms and tables and decorum are unfamiliar and will likely need to change.
True equity and inclusion requires many, many new steps and challenges beyond opening the door, pulling out the chair and sitting down. In short, everyone needs to get uncomfortable for at least some time. The sooner we start seeing and listening to one another at the same tables, the shorter the discomfort will be for everyone.
Even more important, beyond that discomfort lies an infinite number of new ideas whose benefits to the planet and humanity are exponentially diverse.
Dr. Jennifer E. Adair, PhD is an Associate Professor in the Clinical Research Division and Cell and Gene Therapy Program at the Fred Hutchinson Cancer Research Center, and a Research Associate Professor at the University of Washington, both in Seattle. Despite an unexpected pregnancy at 19, and another at 20, Jen completed her Bachelor of Science degree in Chemistry at Youngstown State University while on welfare in 2000.
She then went on to complete her doctoral degree in Genetics and Cell Biology at Washington State University in the laboratory of Dr. Raymond Reeves in 2005, during which she gave birth to her third child. After 2 years as a post-doctoral fellow in the laboratory of Dr. Kenneth Olden, the first African American Director of a National Institute of Health, Jen returned to the Pacific Northwest to start her career in gene therapy at Fred Hutch under Dr. Hans-Peter Kiem.
She started her independent laboratory in 2014 to develop tools and methods for delivering gene therapy to patients who need it, anywhere in the world. That same year she adopted her fourth child. In addition to science and science writing, Jen is an inventor, girls soccer coach and volunteer with Boys & Girls Clubs of America, including an interactive program to introduce children to gene therapy science. She is an advocate for the ethical application of gene therapy and diversity in science. Her research has been honored by TEDx, Geekwire and AAAS to name a few. In 2020, Jen was named the Fleischauer Family Endowed Chair in Gene Therapy Translation. You can learn more about Jen here.
Today’s guest on The Long Run is Pearl Huang.
Pearl is the CEO of Cambridge, Mass.-based Cygnal Therapeutics.
Pearl Huang, CEO, Cygnal Therapeutics
Cygnal is a startup dedicated to developing cancer drugs based on some fairly new understanding of the Peripheral Nervous System.
For years, scientists assumed that the PNS was merely a conduit of the central nervous system. But what if the PNS is not a passive actor in disseminating messages from the brain, but an independent force capable of propagating its own neural signals that help facilitate the growth and spread of cancer? Cygnal represents a wager that exoneural biology may be one of the keys to understanding oncogenesis, and one that’s been long overlooked.
Pearl comes to this work with a wealth of experience. She’s a scientist by training, and has worked her way up through the ranks at the Big Pharma companies Merck, GSK and Roche. In between there, she got her first taste for entrepreneurship as the scientific founder of BeiGene.
Pearl grew up in a small college town of the Upper Midwest, a place much like where I grew up. She has some interesting observations about the remote Upper Peninsula of Michigan, moving on to MIT when there weren’t many women around, and then later in life finding herself comfortable with taking on senior leadership roles. It all sets the scene for what drew her to the unorthodox approach to cancer being explored at Cygnal.
Please join me and Pearl Huang on The Long Run.
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David Shaywitz
The COVID-19 crisis created an urgent need for healthcare data.
For starters, it was necessary to characterize the spread of the pandemic. Quickly, reports were needed on the capacity of healthcare facilities responsible for care of the severely afflicted. Then there was the urgent need to assess the trajectory, and outcomes, of patients admitted to hospitals.
The profound difficulty our healthcare system has had responding to each of these needs – despite the often heroic efforts of so many dedicated individuals – has revealed critical gaps in the way healthcare data are gathered, shared, and analyzed.
The challenges of defining the spread of COVID-19 relates in part to existing deficiencies – “We don’t really have a public health infrastructure,” Walmart Health’s Senior Vice President Marcus Osborne explains.
The Centers for Disease Control and Prevention also made some high-profile blunders early on – perhaps most prominently, the distribution of a flawed initial test for the virus, which forced the country into catch-up mode from the start, as the New York Times and others have discussed. Also a key factor: the Trump’s Administration’s apparent distrust of, and disdain for, the established experts in the public health community; a representative headline, from Axios: “Trump’s war on public health experts.”
The failure experienced by hospitals in assessing capacity has been persuasively documented by Wall Street Journal reporters Melanie Evans and Alexandra Berzon.
The challenge of understanding collectively what happens to patients once they’ve been admitted to a hospital may be less visible, but remains equally problematic. We are far better at, or at least more diligent at, determining what a patient should be billed for than determining at the most basic level how they actually fared, both individually and for most categories of patients.
This represents the “feedback gap” I recently described, in the context of a July conference on “Establishing a High-Quality Real-World Data Ecosystem” organized by the Duke-Margolis Center.
Recently, the Margolis Center convened another meeting, focused specifically on “Applying Lessons Learned from RWE [real world evidence] in the Time of COVID-19 to the Future.” While the individual presenters were uniformly hopeful and optimistic, I emerged from the proceedings with the strong sense that the pandemic has thrown into sharp relief a number of persistent and long-standing challenges.
Those who are interested can watch the conference video on YouTube.
Several topics caught my attention.
First, related directly to the origin of the feedback gap I previously described, is the idea emphasized by UCSF’s Dr. Laura Esserman. In typical care, “we don’t get outcomes on everybody – that’s a problem with medicine.” She added, “We should track outcomes on everyone, and isn’t that just real-world data?”
She continued,
“Our current electronic health records are not organized for quality improvement and you shouldn’t have to go to the IRB to get permission to collect the data that allows you to do your job.“
In other words: how can we improve the care we routinely provide if we’re not routinely, and systematically, determining and analyzing how the patients we’re currently taking care of are doing?
Dr. Robert Califf – legendary cardiology clinical trialist, former Commissioner of the FDA, and now Head of Clinical Policy and Strategy at Verily – highlighted a consequence of this failure: the vast amount of clinical practice is not informed by high-quality evidence. He cited a recent study that reported how few of the cardiology guidelines (just 8.5% of the recommendations in the American College of Cardiology/American Heart Association guidelines) are based on the highest level of evidence (supported by multiple randomized controlled trials – RCTs). Unfortunately, this pattern that doesn’t seem to have changed in the last decade.
While we have a robust clinical trial enterprise, Califf explained, it isn’t meeting a number of critical needs. In particular, he says, “We are not generating the evidence we need to support the healthcare decisions that patients and their doctors have to make every day.”
Fixing this, he says, will require us to “deal with the fragmentation and misaligned incentives in our system.”
As I’ve argued, a key “reason the information isn’t tracked is, essentially, no one (besides the patient!) really cares, in the sense of being personally invested in (and accountable for) the outcome.”
The consequence of our failure to collect – and the lack of adequate motivation to routinely collect – the information we need to improve care, even at the level of most individual hospitals, much less the regional and national level, has been felt especially acutely by FDA Deputy Commissioner Dr. Amy Abernathy. An expert in real-world evidence from her Duke and Flatiron Health days, Abernathy has been seeking to organize the incoming COVID-19 data and analyze it through collaborative efforts such as the COVID-19 Evidence Accelerator (in which I’m a participant).
Reflecting on what she’s learned, Abernethy highlighted what struck me as the observational research version of Mike Tyson’s memorable epigram, “Everyone has a plan until they get punched in the mouth.”
In the case of learning from COVID-19 RWE, there was important methodological lesson to be learned from the challenges of even the seemingly most basic elements, such as defining “time zero,” determining what constitutes a hospital admission, and discerning whether a patient was receiving intensive or critical care.
Many of these issues were surfaced, Abernethy noted, at the Evidence Accelerator, when participants were encouraged to show their work, and get into the critical “nitty-gritty.” Some of these challenges were also highlighted by conference participants, including Harvard’s Griffin Weber.
Abernethy also pointed out that we’ve become relatively proficient at understanding at a glance what to look for in a high quality RCT, assessing attributes like adequate statistical power and how the blinding was managed. Now, she said, we need to develop this intuitive understanding for observational studies as well.
Abernethy also emphasized the need to refine our conception of RWE. We often tend to view RWE-driven studies as a “replacement product” for RCTs – but this framing may be misleading and distracting. Everyone would like to have robust RCTs to answer every question, she said, but that’s not possible, and we need RWE “to fill in the gaps.”
RWE, she emphasized, can be used for a range of purposes, such as understanding patterns of care, or deciding which RCTs should be conducted.
This is a critically important idea: the value of RWE is not as a substitute for RCTs, but rather to more effectively capture the totality of data in the healthcare system, and to provide information about healthcare as it’s actually practiced, within the acknowledged messiness of routine care, as I’ve discussed.
I was also struck by Abernethy’s focus on the importance of high-quality datasets, which would seem to be the cornerstone of meaningful analytics. Abernethy highlighted the problem of data gaps, and the need to link data sets and fill in missing data using different data sources, in effort to approach a level of “completeness” that would enable meaningful study. She noted that technology might be helpful here, in the form of “synthetic controls” (statistically generated comparators based existing data; a nice explainer from Jen Goldsack here) and the use of tokenization (an approach to de-identification of data permitting it to be shared; a useful white paper from Datavant, a leading startup in this space, here).
Abernethy also offered what I thought was spot-on advice regarding the development and application of technology, and some important advice about how healthcare could more effectively engage with technologists and tech companies.
There’s a pervasive problem, she said, with “vendor-think” – the idea that the healthcare stakeholder (hospital, payor, biopharmaceutical company, health services researcher) specifies what a vendor needs to provide, and then the vendor “builds against that list.”
She described with perfect clarity not just how many large healthcare organizations typically approach large projects, but also the mindset within healthcare organizations that I’ve witnessed and described, where data experts and statisticians are often treated as second-class citizens.
What’s needed, she persuasively argued, is for authentic collaboration, where you have at the same table not just the manager or executive, say, who’s sponsoring the project, but also healthcare domain experts, who understand the subtleties and context of how the data were generated, as well as the technologists – the data scientists and engineers who can build and refine the solution.
Such ongoing collaboration not only ensures a better mutual understanding of needs, but also enables the work to proceed iteratively, and to evolve as the participants refine their understanding of both the problem to be solved and the solutions that can be envisioned.
Achieving this balance is notoriously difficult, and vanishingly rare to see in practice. This barrier – a hurdle in organizational dynamics as much as technological expertise – also represents an exceptional opportunity for an integrative and empathetic leader who can not only bring the right people to the table, but (and this is the hard part) ensure their talents are fully elicited and authentically embraced.
Sarah Warren, senior director, translational science, NanoString Technologies
It’s worth looking back on what is known about the SARS-CoV-2 virus, which was first detected in the US in mid-January, when a man traveled from Wuhan, China to Seattle.
Nearly 10 months later, a tremendous amount of knowledge has been gathered about the virus, how it is transmitted, and the disease symptoms it causes.
We know, for instance, the risk factors that are associated with severity of infection, such as being elderly, or having certain pre-existing conditions like Type 2 diabetes. We are beginning to understand all the ways the virus can be transmitted, particularly through the air. And yet, much remains unknown about the virus, particularly its impact on the body at the molecular level.
Jason Reeves, senior scientist, NanoString Technologies
In our quest to gain a deeper understanding of the molecular and cellular pathology of the disease, investigators have been leveraging every tool and platform available. Applying spatial biology – a strategy for profiling the distribution of cells and molecular pathways within tissues – to samples collected from patients who died from the disease, represents a powerful way to understand at a local level how the virus is reshaping infected tissue and the subsequent immune response.
Our company, Seattle-based NanoString Technologies, recently hosted a virtual Advancing Spatial Biology Conference to feature the work of investigators who are using the company’s GeoMx Digital Spatial Profiler to address a variety of research questions. One of the tracks was dedicated to studies that addressed the impacts of COVID-19 in the lungs. Although the data are still early, the collective results presented by these investigators reveal insights into the underlying biology of the virus and will guide development of therapeutics, supportive care, and vaccines.
Some of the major findings from these studies are summarized below.
The GeoMx technology enables simultaneous profiling of 60-90 proteins, and up to 1800 RNA transcripts (today), from multiple regions of up to half a millimeter in diameter within a tissue section with a profiling area of 14×36 mm.
Capturing this much data, in spatial context from a tissue sample, enables the use of data analysis methodologies suitable for high-plex data to create a deep understanding of how the infection manifests in different patients.
What we see again and again is that the disease varies greatly between individuals. Several investigators during the track pointed out that lung tissue sections from COVID-19 patients were more variable than lung tissue sections from patients that died from other causes. Chris Mason and colleagues at Weill Cornell Medicine in New York were able to compare COVID-19 lung tissues to flu-infected lung tissues, to underscore the wider range of possibilities.
What might be driving this? Partly, the diversity is driven by different courses of the disease that are observed for each patient. Some people succumb rapidly to infection and pass away shortly after diagnosis and presentation in a hospital. These people tend to have evidence of active viral replication and strong interferon response.
Other people have a longer course of disease. They may survive the initial diagnosis but then die from secondary effects of the infection such as inflammatory cytokine storms or other dysregulated immune responses. The lung tissue from these patients tends to be characterized by more tissue repair signaling pathways, perhaps as the lungs attempt to heal themselves.
However, this dichotomization is not universal, so there must be other as yet unidentified causes of the diversity. Viral load may be one contributing factor. Intriguing data presented by Gordon Jiang from Beth Israel Deaconess presented showed that the levels of 5-lipoxygenase, an enzyme involved in the production of inflammatory leukotrienes, is expressed in proportion to viral load.
Despite this inter-patient variability, there were some common patterns of expression, especially in the immune response. Certain innate immune cells, such as macrophages and neutrophils, are activated by the virus and robustly recruited to the sites of viral infection early in the course of disease. The type I interferon response, part of the body’s first line of defense against viral infection, is consistently one of the strongest upregulated pathways.
This suggests that therapeutics targeting these pathways and currently in clinical trials, such as baricitinib, the JAK1/2 inhibitor developed by Lilly that blocks production of interferons, may be effective at tamping down runaway inflammation early in infection, if given in combination with antivirals to control viral load, such as remdesivir, or therapeutic neutralizing antibodies in development. Intriguingly, data presented by the keynote speaker, Dr. Peter Sorger from Harvard Medical School, suggested that similar pathways may also be upregulated in non-human primates infected with COVID-19.
It is also abundantly evident that the virus is impacting both the immune response and altering the underlying tissue architecture. Regions of the lung with high viral load are characterized by hyaline membranes, sheets of dead cells, surfactant, and proteins that are associated with acute respiratory distress.
These hyaline membranes can be visualized on tissue sections and are accompanied by hyperplasia (excessive growth) of type II alveolar cells. This is a key cell population in the lung that is a progenitor for the gas-exchanging type I alveolar cells. These cells maintain the lubricating surfactants, and recruit immune cells following injury, which are necessary to maintaining normal breathing ability.
Type II alveolar cells are recognized as a reservoir of COVID-19, where the virus hides out, allowing the infection to progress into the lower lungs. These type II alveolar cells provide a fertile breeding ground for the virus, as they express the ACE2 protein that acts as a viral receptor. Spatial profiling of the lungs revealed enrichment of collagen synthesis pathways and extracellular remodeling pathways in the Cornell cohort. Building on that finding, Asa Segerstolpe of the Broad Institute presented evidence of increased keratin expression in infected regions of the lung.
As previously mentioned, the immune response is dominated by interferon signaling and associated chemokine expression. This was accompanied by robust recruitment of myeloid cells, including monocytes, macrophages, and dendritic cells, to infected regions of the lung, whereas T cells and NK cells were more abundant in patients with high viral load but displayed less specificity for highly infected regions of the lung. In these studies, cell population abundance was inferred through gene expression deconvolution strategies to enable profiling of 14 different immune cell populations. Patients with high viral load also had expression of some immune checkpoints, including PD-L1 and IDO1, but mixed expression of other checkpoints including CTLA4, LAG3, and VISTA.
One of the most interesting observations from the COVID-19 studies has been the diversity of the localization of immune responses to infection. David Ting, from Massachusetts General Hospital, demonstrated that in addition to variation between patients who have high and low viral titers, there is also variation between regions of interest with high viral load and those without, but only for some signaling pathways.
For example, chemokines CXCL9, CXCL10, and IDO1, which recruit and regulate immune cells, are expressed at higher levels only in areas of the lung with detectable viral transcripts from patients with high viral load. In contrast, antiviral proteins IFITM1, IFIT3, and IFI6, are expressed at approximately equal levels in virus-high vs virus-low areas of the lung. Antigen presenting genes are displayed uniformly throughout the lung regardless of viral load. These observations are only possible with spatial biology tools that enable simultaneous profiling of a large number of targets in parallel.
As these studies and other mature, we are starting to better understand some of the mechanisms at play in COVID-19 infection. However, given the rarity of these samples and the not insignificant risk physicians must undertake to collect them, we must try to learn as much as possible from each sample we have.
Spatial biology represents a powerful tool to directly examine the infected tissue of COVID-19 patients and characterize its inherent complexity, rather than risk getting overly focused on a single variable that’s just one of many factors at work. By applying tools such as GeoMx and methods such as spatial profiling, we can deepen our understanding of the disease and accelerate the development of treatments and vaccines to mitigate the growing burden of this pandemic.
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Alex Dickinson, co-founder and executive chairman, ChromaCode
Our consumer electronics companies are constantly marketing the newest one-touch, automatic machine. They make it sound so simple, so alluring, so irresistible. Think of our smartphones and watches.
That might partly explain the administration’s instant embrace of the Abbott ID NOW point-of-care machine for COVID-19 testing. FDA commissioner Dr. Stephen Hahn touted the box’s features and benefits – a 6.6-pound box, the size of a toaster, that could deliver accurate yes-no test results in 15 minutes — at a Rose Garden news conference back in March. President Trump even seemed to cradle it briefly.
In late March, when horrific images from overwhelmed New York hospitals were dominating television, this seemed like good news that people wanted to hear. The call for the fast and simple answer was on display again this week, as the Trump Administration announced plans to distribute 150 million rapid antigen tests.
If there is a consistent pattern to this Administration’s response, it has been to put faith in quick fixes instead of strategic long-range plans that play out over a period of months. We’ve seen the unfortunate results of this excessive faith in the latest shiny technology object.
Like many things about the COVID-19 pandemic, the truth about point-of-care testing machines is more complicated than their coolly modern façades indicate. Whether these rapid testing instruments are molecular tests that look for the SARS-CoV-2 virus’ signature genetic material, or antigen tests that detect specific proteins on the virus’ surface, there are accuracy trade-offs with the rapid point-of-care tests, when compared with traditional real-time PCR platforms. Multiple academic studies have shown higher false-negative rates than what Abbott has reported on its ID NOW platform.
The issue of test inaccuracy hasn’t received much attention, but it has gotten some notice. Recently, the Governor of Ohio, Republican Mike DeWine, received a positive result from a point-of-care machine that detects antigens. Subsequent RT-PCR testing thankfully showed that the previous point-of-care test was a false positive.
The reliability of these sleek point-of-care machines is not the only thing that should concern us. These are highly automated, closed systems. That sounds good at first glance to most people, because it implies simplicity, speed and consistency. The term “sample to answer” is the diagnostic industry equivalent of “plug and play.” What’s not to like?
Besides the problems with accuracy, these closed systems create capacity constraints.
Our increasing reliance on these closed systems is hampering our ability to ramp up national testing effort to the scale it needs to be. Recent reporting from Reuters assigns blame for the U.S. testing shortfall on these closed testing systems.
These companies operate on the razor and razor blade model. They sell the machine first, and then supply the proprietary consumable supplies such as chemical kits and plastic sample plates and pipettes needed to make it run. It’s similar in concept to the branded printer cartridges in use on your HP or Epson home printer.
The rapid point-of-care COVID-19 diagnostic testing companies – four major manufacturers – simply can’t manufacture enough consumable chemicals, sample plates and pipettes in their special kits to keep their instruments running at full capacity nationwide. This is the primary cause of testing backlogs. And it’s not just the “printer cartridges” that are in shortage – many of these companies can’t make enough of the “printers” themselves to meet demand.
These closed systems can be useful and convenient under normal circumstances. During a typical flu season, hospitals can quickly determine whether a few patients are suffering from the flu or a different respiratory illness and treat accordingly.
But a pandemic is not a normal circumstance. And while some experts have recently called for an increase of less accurate antigen tests to more quickly track and contain the virus — essentially throwing “everything but the kitchen sink” at the problem because the U.S. has struggled to generate a comprehensive national testing plan — there’s no evidence that these manufacturers can produce the instruments and consumables at the necessary scale.
For our country to reasonably manage this pandemic, we need much more than just the test results for a few dozen patients at a time delivered by a quick, easy-to-use black box.
These point-of-care machines do have a role to play, however. They can be invaluable tools for COVID-19 testing in specific environments, such as daily testing of caregivers at assisted living facilities. But as a nation, experts say we need to be doing millions of tests per day — the latest estimate by Harvard’s Global Health Institute is 4 million per day. The network of discrete closed systems cannot handle that kind of volume, nor is it flexible enough to scale up and down as testing needs change.
Fortunately, we already have an open-system network that we can harness to produce the amount of testing needed to safely reopen our economy: an installed base of “old-fashioned” real-time PCR machines.
Every big central lab, government lab, hospital lab and research lab in the country has at least one open-platform real-time PCR instrument. Different manufacturers make these instruments, but they all run in basically the same way, using the same chemical supplies.
These systems aren’t as quick to deliver results and require trained technicians to operate. But they can handle tremendous volumes of tests. These traditional RT-PCR machines can handle 10-100 times higher throughput than the point-of-care tests, and are able to generate >1,000 results per day per machine. In contrast to ID NOW, they are the gold standard of accuracy.
Certainly, open-platform PCR instruments are currently handling a significant portion of the testing. But right now, only labs that are CLIA certified by the federal government are allowed to handle diagnostic testing. That leaves out most academic labs and many, many commercial research labs that are run to exacting specifications, but are not technically CLIA certified. Add to that a large number of PCR instruments that run diagnostics for our pets. We love our pets, but I think most people would agree to delay those diagnoses to free up capacity for the urgent COVID-19 demand.
The federal government could, and should, use its influence to requisition these instruments for use in COVID-19 testing. The capacity exists – it just needs to be properly directed and mobilized. It’s not too late to swing into action.
At a low estimate, the U.S. has 30,000 open-platform PCR instruments. If each instrument is leveraged to run the 1,000 tests per day it can run, that would give us 30 million tests per day. Capacity could be stretched further through the use of robots, pooled testing or the application of data science.
This is a robust infrastructure that will better meet the testing demands this pandemic calls for. Testing at high volume will help us find our way back to something closer to normal until we have a widely distributed vaccine.
The role for open systems is clear.
As Gary Kobinger, a Canadian researcher best known for his work on Ebola, argues in that same Reuters report that all diagnostics should be done on open platforms. “At one point there will be a new pathogen, and the company that makes the cassette that is controlling everything is not going to be able to supply you,” Kobinger said. “And this is where we are now, right?”
Right.
Alex Dickinson, PhD is the co-founder and executive chairman of ChromaCode. He is a life sciences executive with over 25 years of experience leading strategic initiatives that have transformed small companies and enabled large companies to penetrate new markets. Most recently, he was the Senior Vice President of Strategic Initiatives at Illumina, where his responsibilities included working with national governments and large institutions to develop precision medicine programs for healthcare systems.
Today’s guest on The Long Run is Jennifer Petter.
She is the founder and chief scientific officer of Waltham, Massachusetts-based Arrakis Therapeutics.
Jennifer is a medicinal chemist who has spent her career thinking about how to make small molecules with all the classic Lipinski “Rule of 5” characteristics against protein targets.
Jennifer Petter, founder and chief scientific officer, Arrakis Therapeutics
Five years ago, when she was looking for a new entrepreneurial challenge, she attended a Gordon conference. She saw a couple scientific presentations from Matt Disney at Scripps and Kevin Weeks at UNC Chapel Hill that gave her an idea. Might it now be possible to make small molecules against RNA targets?
She was inspired to get going on building a new drug discovery platform at what we now call Arrakis Therapeutics.
Arrakis took this work up several notches this spring, through a new partnership with Roche. The big drugmaker, seeing the possibility for creating multiple small molecules against RNA targets, agreed to pay $190 million upfront to Arrakis to work together on making it happen. Arrakis also recently described its work in detail in its first peer-reviewed publication in ACS Chemical Biology.
Jennifer also used to identify as a man, and was known as Russ Petter. She came out publicly as transgendered in June 2018. CEO Mike Gilman wrote about it on the company blog.
In this conversation, we spent the first part talking about Jennifer’s early life and key steps in her career leading up to her current work at Arrakis. At the end, we talked about her gender transition and how she handled that in the workplace. I think my questions are a little awkward, but it’s OK because the situation was awkward for a lot of people. It’s old news, but I think Jennifer has some timeless thoughts on handling the situation with grace.
Now, please join me and Jennifer Petter on The Long Run.
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Thong Le, CEO, Accelerator Life Science Partners
“I’m gonna have the halibut and chips. And a medium vanilla milkshake. What about you, Thong?”
I looked up at my towering companion as he peered down at me with a gentle smile. I’m about 5-foot-8, and he was about 6-foot-7. I quickly scanned the menu board, then made my choice.
“You know, Mr. Gates, I think I’m going to have the exact same thing that you’re having.”
“Please, Thong, call me Bill. And lunch is on me.” Unbeknownst to Mr. Gates (or to me for that matter), that first lunch meeting more than 20 years ago at Daly’s Drive-In, a burger joint in Seattle’s Eastlake neighborhood, would inspire me and alter the trajectory of my career.
Photo from Gates Notes.
As many know, Mr. Gates was a giant among giants. A tall and imposing figure, he made many lasting contributions to the communities that he so graciously served. He served our country during World War II, he established a prominent law firm (now known as K&L Gates), and he has given generously of his time and resources to help countless community organizations focused on global health, education, and the arts. His leadership at the Bill & Melinda Gates Foundation propelled the Foundation to tackle some of the world’s most pressing issues in global health and education, and to create better opportunities for the poor and vulnerable around the world.
Mr. Gates was also very forward-thinking when it came to the relationship between university research and its potential to catalyze progress. Shortly after the passage of the Bayh-Dole Act in 1980, he saw potential for the University of Washington to translate some of its research for the wider world. Not surprisingly, given his position in the community and his legal acumen, he played a seminal role in developing policies, initiatives, and a successful foundation dedicated to promoting and advancing technology commercialization in the region.
These accomplishments are substantial for any single individual, but they represent only a portion of the impact that Mr. Gates had on folks like me who were fortunate to cross his path. Beyond the highly visible ways he made an impact – like serving on Boards or leading fundraising campaigns – Mr. Gates also took a lot of time to meet with individuals like my younger self.
As generous as he was with his philanthropy, he was even more generous with his wisdom and counsel. He took an interest in hearing the stories behind an individual, and he went out of his way to open doors and inspire a spirit of selfless giving.
My story was one of the ones that seemed to have resonated with Mr. Gates. You see, I had no direct connection to him or to the many organizations that he was affiliated with. At the time, I was a young kid who had found the beginnings of a path to a better life. My parents had immigrated to this country from Vietnam at the end of the war while my mother was still pregnant with me. Upon arriving, my father was unable to find work to support the family, especially given his (then) limited grasp of the English language. He took jobs as a janitor and then as a television repairman in order to make ends meet.
As time went on, my father continued to strengthen his English, and began taking courses at a local community college. That helped him to land a job as a social worker, where he worked for more than 30 years to support our family of six. While we had little materially, because of my father’s example, we possessed a commitment to hard work, perseverance, and education.
Those family commitments led me to excelling in school, and eventually attending Harvard where I developed an interest in science and business. Those interests led me to join a biotech-focused management consulting firm after college that gave me the tools to solve difficult business problems. I also threw my energies behind a start-up company that I co-founded, which taught me what it meant to sacrifice everything to build something new.
Unfortunately, not all sacrifices pay off, and I had to extract myself from that startup before I could see it develop as I hoped it might. I moved back to the West Coast from New England, pondering where the next season of my career might lie. I wanted to know where there might be opportunities to combine my passion for science and my experience for business. I wanted to know where I might be able to grow as a business leader while also impacting those around me. I wanted to know where my future might be.
With the help of a business colleague whom I met through my management consulting work, I was able to obtain the contact information for Mr. Gates. I reached out to him, hoping he’d be interested in helping someone like me.
At that lunch meeting, Mr. Gates listened carefully, and wisely counseled me to look past the hardships of my past and to look ahead to the future. He encouraged me to focus on the positive, and to not dwell on those that took advantage of me. He advised me to surround myself with people that were mission-driven and full of integrity. And he inspired me to consider possibilities that I might not have otherwise considered, especially local ones in a growing Seattle sector. Seeing that my mind was full of questions about “where” and “when”, Mr. Gates was able to provide a lens to focus my passions and experiences to the “here” and “now.”
Were it not for Mr. Gates, I never would have made the connections that ultimately led me to join the team at Washington Research Foundation (WRF), a non-profit organization that Mr. Gates co-founded to translate university research into the business world, and which plowed back its proceeds into supporting scholarship and more research in Washington-based research institutions.
I joined WRF’s investment team (known as WRF Capital) in June 2000 — a few months after our lunch at Daly’s. Over the next 14+ years, I was fortunate to work alongside a team of talented professionals at WRF to identify and invest in breakthrough technologies. By the time I decided to leave WRF to lead Accelerator Life Science Partners, WRF’s collective efforts — through intellectual property licensing, returns from successful start-up investments, and philanthropy — had returned more than $500 million to the University of Washington alone. WRF’s impact in the region continues to this day, and I’m proud to have contributed to WRF’s successes as an organization.
My father died about 10 years ago. Before he passed away, he shared with my brothers and sister the story of his life leading up to his decision to risk everything at the end of the Vietnam War to immigrate to this country. And he shared with us a Vietnamese proverb that essentially says it is our duty and privilege to do everything we can to ensure that the lives of those we care about are better than the ones we have.
In the time that I knew him, Mr. Gates lived this philosophy out fully. Mr. Gates allowed me to stand upon his shoulders at a time when I needed it the most. He did so selflessly, without any expectation that doing so would benefit him in any way. It was only 90 minutes of his day in the spring of 2000. It didn’t cost him much. Yet that effort to inspire me and support his community in the Pacific Northwest made a very real impact.
And I know there are countless others whose stories are the same – stories about a giant of a man who did everything he could so that future generations are better off than the ones that came before.
Thong Q. Le is the President & CEO of Accelerator Life Science Partners, a venture firm that catalyzes the development and commercialization of breakthrough biotechnology innovations (for more information, please visit www.acceleratorlsp.com).
