Call Me Back - with Dan Senor - A Post-Delta World — with Dr. Sid Mukherjee

Episode Date: September 3, 2021

To find the published pieces discussed in this episode: “What the Coronavirus Crisis Reveals About American Medicine”, by Sid Mukherjee, The New Yorker (April 27, 2020) : https://www.newyorker.com/magazine/2020/05/04/what-the-coronavirus-crisis-reveals-about-american-medicine For all of Sid’s pieces published in The New Yorker: https://www.newyorker.com/contributors/siddhartha-mukherjee “What We Have Gotten Right in the COVID FIGHT”, by Yuval Levin, Commentary Magazine (September 2021): https://www.commentary.org/articles/yuval-levin/americas-record-during-covid/ 

Now the Delta strain is pretty much the single dominant strain in the world. And so we need to figure out, you know, whether these vaccines are working against Delta and to what extent. What are the clinical consequences for all of this? If yet another strain were to become dominant in the world, we would have to repeat all of this. And this is something, especially in the era of evolving viruses, that's something we have to be cognizant of and just swallow, as it were. Welcome to Post-Corona, where we try to understand COVID-19's lasting impact on the economy, culture, and geopolitics. I'm Dan Senor.

As we were all gearing up for a roaring return to normalcy, the Delta variant has, at best, tempered enthusiasm. Before Delta, we fought a virus and thought we may have won by developing a vaccine. Quickly. Warp Speed, and thank you to the ecosystem of life science startups and large pharma companies and the years and years of massive investment in the sciences that made all of this possible. But three dominant variants later, it looks like we're not fighting a virus as much as we are fighting the fundamental rules of evolution. From alpha to beta to gamma to delta, the virus is becoming more contagious. I should emphasize that its effects are also less severe if you're vaccinated. But what should all of this tell us?

What does this trajectory look like? Well, to help me understand how to make sense of the new ambiguity we're in, I checked in with Dr. Sid Mukherjee, who's a cancer physician, a stem cell biologist, and a hematologist. Sid is a New York Times bestselling author. He's written three books. The Emperor of All Maladies, a biography of cancer, was the winner of the Pulitzer Prize in general nonfiction when it first came out. In it, Sid tells the story of cancer from its first description in an ancient Egyptian scroll to now state-of-the-art labs and modern research institutions. Sid also wrote The Laws of Medicine as well as his latest book, The Gene, An Intimate History. That book has been turned into a four-part documentary series which Sid worked on with filmmakers Barack Goodman and Ken Burns. He's

also a writer for New Yorker magazine. He's an assistant professor of medicine at Columbia University and a cancer physician and researcher. He completed his internal medicine residency and an oncology fellowship at Mass General Hospital. A Rhodes Scholar, he graduated from Stanford University, the University of Oxford, where he studied immunology, and Harvard Medical School, where he got his MD. He's also behind a number of promising startups in the life sciences. As you can imagine, Sid's got a lot going on, not exactly an underachiever. So I was grateful to get a chunk of his time for this conversation. He's one of the

most thoughtful people I know in the worlds of medicine, science, and public health. And as a writer, he certainly has a gift for storytelling. I always learn a lot from him. So what I wanted to pick Sid's big brain about today is whether this pandemic fight we are in is winnable, or are we going to simply keep chasing these variants forever? And what does this mean for our lives and our economy? This is Post-Corona. And I'm pleased to welcome my friend Sid Mukherjee to this Post-Corona conversation. I'm hoping, Sid, you'll be able to tell us how we're going to get to Post-Corona. But before we get there, I just want to thank you for joining us. My pleasure. Thank you for having me. So, Sid, before I get into the substance, I do want to talk a little bit about your background

and all these projects and careers you have going on in one person. Because every one of the things you do seems like it could be its own career. So just as I mentioned in the intro, you studied biology at Stanford University, you were a Rhodes Scholar, you studied at Harvard Medical School, you're an associate professor, you are an entrepreneur behind several life sciences startups, and you are a writer for The New Yorker. So do you, I mean, I'm someone who has at any given moment, let's just say a few projects going on, and they all tend to kind of reinforce one another in my life, in my career.

So you get kind of a flywheel effect. But you, it's like a whole other level in terms of the number of things you have going on. So can you just describe how they all fit together? Well, I think this idea of a flywheel effect is exactly right. I think they all reinforce each other in very important ways. The work that I do as a writer, writing books or writing for The New Yorker, comes from my seeing patients. When I see patients, those patients inspire questions. Those questions convert themselves into laboratory questions or clinical trials. Those laboratory questions generate, in the best case scenario, medicines. Those medicines then become licensed.

If they're really any good, they become human medicines. Those medicines then lead to the startups of companies, where they allow these medicines to become, you know, really come into the real world. And those then generate a second series of questions, which I bring back to the laboratory that I write about, and that I explore, and they lead to a second series of medicine. So it all seems like a mad world from the outside, but inside there is, I think, a very deep level of connections, and each one reinforces the other. So it's not as if, I mean, just to tell you what it's not, I'm not a triathlete.

I'm not biking one day, swimming the next day, and running the third day. Although, of course, those are also interconnected. What I'm doing is I'm doing things that all emanate from the same kind of ideas, which are self-reinforcing. And often they're, you know, I'm helped by massive teams. So it's not like I'm doing any of this alone. When I form a company out of a medicine that's come out of my laboratory, you know, that can grow as a company called Vore has grown to 120 people in a year. And so there's an enormous level of self-reinforcement that happens while this is going on. So your passion for storytelling, which obviously there's the writing you do for The New Yorker, your two books that have, you know, kind of been extraordinarily successful bestsellers. There's your film project, the series you worked on with Ken Burns. All of these projects, you know, tell me you are like a, among other things, you are like a physician journalist.

And I've been somewhat, on this podcast, we've been somewhat critical of the quality of science journalism, particularly as it has manifested itself during the pandemic. It's been uneven at best. But physician journalism, A, strikes me as a different genre, A. And B, when it exists, it's typically not conducted by actual physicians. So I think that you being a physician and have this passion for storytelling puts you, I think, in a different sort of subgenre. You know, I think that the idea of, I really don't think of myself as a journalist in the traditional, I was never trained in journalism. I, you know, when I write for The New Yorker, they're usually thought pieces. I was among the first to identify the idea that the total viral inoculum for COVID, for instance, might have something to do with the severity

or the likelihood of you getting the illness. Very simple idea drawn from multiple other respiratory viruses, but somehow it had not been in the news. It was a thought piece. And I also brought up the idea of using viral load as a measure of whether you are capable of transmitting infection and potentially of the severity of your infection. So these are thought pieces. These are not usually investigative pieces. So I don't think of myself as a journalist in the traditional sense. I tell stories, often very long stories. The stories are connected to my patients.

They often have one patient or a group of patients at their center. I'm not a science journalist. I'm sometimes asked to write about topics regarding science journalism. I almost never do because of exactly that reason. When I write a book, my book is usually not a kind of polemic. I'm not writing, you know, a new fad diet. I'm not writing about a new kind of, I'm writing usually very large histories. They're often 600 pages long. And so, you know, I just, I find myself outside that realm of science journalism and have really never, really never done it. Okay. So now let's jump into the pandemic, where we are now and where it's going.

And just to frame the conversation, we're all consumed with the Delta variant, and we quietly seem to have fundamentally transitioned to a completely different phase of the pandemic. Initially, we fought a virus and largely won the fight by developing a vaccine, almost miraculously, in under a year. But three dominant variants later, it looks like we're not fighting a virus as much as we're fighting the fundamental rules of evolution. And that frame, if you will, makes me question whether or not this fight against COVID is ultimately winnable, quote unquote, the way we in the West like to think about things being winnable, you know, that sort of have a binary outcome.

What's your reaction to that? Well, I think there are two scenarios that will occur. But let's talk about evolution first, because it's important. As you very well know, we need to do a little bit of science speak, if that's okay. But mostly things that people will know. So everyone knows about the spike protein, and the spike protein is a protein that is used by the virus. Coronavirus is called corona because it comes from the word crown, like coronation. And that's because it has almost a crown-like envelope around it, and proteins that stick out of it. And those proteins are

the ones that bind to your cells. And that's what allows the virus to enter a cell. And of those, the one that's most well-identified is the spike protein. The spike protein is the one that concerns us the most because when that mutates, its capacity to bind a cell changes. It can increase the capacity to bind the protein to the cell or decrease it. But of course, evolution will make it want to bind it more strongly, more tightly and be internalized inside your body. Now, there are two camps of people in the spike protein world. One camp of persons, people, scientists, thinks that the spike protein will keep mutating and mutate and mutate and mutate and mutate, which it does, and will keep evolving and new strains will come up. And that's certainly going to be true.

The other camp says, yes, that's true. That must be true. That's true by evolutionary dynamics. But there are only so many mutations that any protein will tolerate, which still allows it to exist in three-dimensional space. So think about Lego pieces. You can mutate Lego pieces by making various combinations of them. But there are only so many combinations of Lego pieces that are stable, that can stand up. Spike, the mutations in Spike, the second camp believes, is, and this is absolutely true, is like a Lego piece that is standing up, right? It can mutate, you can make many, many variations of it. But the really

significant ones, the ones that really affect human biology in the most adverse manner, are mostly done. And delta is probably the endpoint of that or one endpoint of that. There'll be sub-delta mutations, and they're already coming up. But the big baddie ones are mostly done. How do we know that they're mostly done? Well, we can do that because of structural biology. So in other words, using structural biology,

using computations and computers, we can figure out how the extent to which any protein can change or mutate. And at a certain point of time, like the Lego blocks, it'll topple over. And so that's the basis of this kind of information. Now, it's hard to know. Of course, this is computational stuff. This is stuff that's made on a computer. So you could believe or disbelieve the computer. And computers can be right and the computers can be wrong. Our models can be right. Our models can be wrong. Our models can be right, our models can be wrong.

But let's continue the thought. That thought would say that delta is where it's at. There'll be more mutations for sure. And remember that spike is not the only protein or only gene that corona carries. It might acquire a gene that makes it even more resistant to immune attack, and so forth. But all of this said, I think that given how we're doing with vaccination, and given the fact that people are now establishing herd immunity if they're not

vaccinated, I think it's a winnable fight. I think the collateral damage, if you don't get vaccinated, is enormous. So the message is you should get vaccinated. The collateral damage is serious enough, even among young people who were previously less likely to be affected by the other strains. Delta is bringing down young people. It is putting them in ICUs. It's putting them in the ICUs in the American South. There's been waves of deaths in India. I know 30-year-olds, 40-year-olds who've been killed by Delta. So this is not a joke. We know, and we can talk about this in great detail, that vaccination will stop it. It may get you infected, but it will likely not allow Delta

to kill you. So I think it's a winnable fight in the following manner. I think that we will eventually acquire, hopefully by vaccination, but if not by vaccination, by just the spread of Delta, which I hope the Lego constructions, we will have a situation where most of the world is immune to Delta. And as I said, I hope through vaccination, I hope not by natural immunity given the collateral damage. And then what will happen is then we have a waiting pattern, a pattern in which either one of two scenarios happens. One is that the world acquires immunity to Delta, and that stops the virus in its tracks. The second is that there will be other mutations outside Delta that will continue to crop up, but they will be like small fires in local fires. And that's why we need a global

surveillance system in which we find those fires and quickly stamp them out by isolation, containment, vaccination, if possible, and quickly stamp them out. And we will stamp them out as fast as we can. And I think that's, you know, that's the second scenario. So in both scenarios, I think it's a winnable war. We just need to get shots into arms that will stop Delta in its tracks. And we need to get, you know, in the worst case scenario, as I said, we'll get herd immunity to Delta with all the collateral damage and deaths that will come with it. So on this point about young people, so from Alpha to Beta to Delta, the one trajectory we have seen is that the virus has become more contagious. I mean, they are not numbers, you know, delta relative to alpha are, you know,

two, three X, but they've become, they seem to not becoming more severe. Actually, the virus seems to be less severe. Is this your sense that, and this is the trajectory we're on, not just that they've become local fires that we have to put out. But just generally speaking, the mutations become more contagious, but less severe. I don't think they've become, I don't think we have evidence that they're less severe. I think that we have certainly a lot of evidence that they have become more contagious. The severity of an infection depends not just on the virus, but on the host as well. And we knew right from the top that the most compromised hosts, those with comorbidities such as hypertension, diabetes, obesity, and of course, if you're immunocompromised in any way, manner possible,

then if you got the virus, your outcome was likely to be very bad. With Delta, what we're seeing is, of course, a very high R0, so extreme infectiousness. But we're also seeing people in their 30s and 40s without comorbidities, you know, being admitted to the ICU and frankly dying. And so severity is much harder to pin down compared to an R0. An R0 is a number that is an absolute number. It's, as I said, relatively easy to calculate. Severity is a much harder thing to calculate because as the R0 changes, the population of people affected by a virus changes as well. And so

when we say severity, what we're really meaning is a host virus interaction. And that host virus interaction is changing because the population of people infected is changing. So the general opinion, as I said, seems to be that, you know, in the first wave of the virus, in the original sort of the wild type Wuhan wave of the virus, most people in their 30s and 40s got a bad infection, but were relatively spared. What we're seeing with Delta is a high R0, as you mentioned, but for the first time, we're seeing people in their 20s, 30s, and 40s being affected going to the ICU, and as I said, some people dying. So you mentioned what's happening in the Southeast. One thing we know is that the

pediatric wards in hospitals in the Southeast are at peak capacity. Yet nationwide, the kids, the data, there seems to be a discrepancy in the data, because nationwide it does not seem like kids' cases, the case count for children is through the roof. Yet everywhere you turn, at least, or everywhere we read about in the Southeast, the pediatric wards are peak capacity. And I know you were recently in London. We spoke during the summer.

My understanding is there's a similar dynamic going on with pediatric wards being jammed in UK hospitals. And now also they went back to school sooner than we did. So it's hard to know. It's not a perfect comparison. But how do you make sense of these children's cases and what's happening in the pediatric wards? So there are many potential explanations, and we don't have the right explanation. I think, you know, like all viruses, again, this is a virus-host interaction. In places where there's a lot of endemic viral transmission, and potentially, and I'll say potentially because I was one of the first to propose this hypothesis, but potentially it also has to do with the level of viral inoculum that a child receives,

the total amount of virus that you breed in essentially. So in places that are not masked and in places that have a very high viral load circulating, what is I think happening is that susceptible children, and the word susceptible is the important word here, people, children who have, for various genetic and other reasons, susceptibility to the virus are being, I hate to use the word, picked off by the virus virus and the pediatric wards

are full. In places like New York and other parts of the United States where there's a high level of vaccination, 60% and above especially, I think the exposure of children to a virus is much, much reduced. And that's because these vaccinated individuals are standing sort of like bulwarks against the children who are unprotected because they're unvaccinated. Which again brings me back to the point, if you're not vaccinated, you're not just being foolish to yourself. You're being selfish to your own children and to the children around you. Vaccination is not just a self-act. It's also a selfless act. If you don't form that bulwark, if adults who are capable of being vaccinated do not form the triangle of security around the children that are inside that triangle, then the children will be attacked and will be put into ICUs and pediatric wards. So, I mean, I tell, you know, anti-vaxxers this, don't just get vaccinated for yourself, get vaccinated for the next generation. Because, you know, these children

will suffer all the trauma of being in the hospital, being in the ICU, some dying. But also there's potentially, you know, long COVID, which we can talk about. And we don't know anything about the long term effects of COVID on children, especially severe COVID on children. And by now, we've collected enough information on vaccinated individuals that it doesn't seem to be the case, aside from the few side effects of vaccination that are very well documented, very rare. It doesn't seem to be that, you know, you are getting long-term effects of vaccination itself. So vaccination, you know, I often turn to the proverbial American West when at night circle of wagons around around a camp. And so that the most vulnerable people, the children are protected inside. And it's a selfless act. And if you're not vaccinating, it's not you're not just being foolish to yourself.

You're really you're really a short changing a whole generation of people, including your own children. So you talked about the evolutionary pressures impacting the virus's evolutionary path. You talked about the Lego metaphor, which actually is visually very helpful. I'm trying to get a sense of what human interventions are affecting the evolutionary pressures so obviously you're right now you're praising the you're singing the praises and the importance understandably of vaccines and social distancing and mask wearing but do all these human interventions affect the it's forcing the the virus to optimize to be, you know, more damaging in different ways.

I'm not making the case against any of these measures. I'm just trying to understand, do these measures have their own effect that could send the virus in a different direction that we're not, you know, anticipating? So, I mean, all of those things, the important thing about isolation, containment, social distancing, et cetera, is they reduce the total circulating population of virus, total amount of virus at a population level. And remember, evolution has one important law, which is that, I'll summarize it in a funny way and then tell you what it means. In cancer, we say that there are three zeros between

1 billion and 1 million. And that's important because people forget that distinction. Killing 1 billion cells is not the same as killing 1 million cells, because 1 million cells have 1 million opportunities to mutate. 1 billion cells have a thousand times more opportunities to mutate. One billion cells have a thousand times more opportunities to mutate. The same applies to viruses. You know, a total circulating population of virus, which is X, has X, you know, some factor of X, some function of X capacity to mutate. If that population increases, then its capacity to generate new mutants increases. If that population decreases, the capacity to generate new mutations decreases. So I think the human interventions that we're taking, the social interventions that we're taking, have a biological correlate. And the biological correlate is that they, you know, decrease the

capacity of the virus to mutate. Now, we know this very clearly because the virus wasn't born as Delta. The virus was born as the original Wuhan strain. Over time, as more and more people got infected and the total number of viral particles in the world, whatever it might be, increased exponentially, we began to see mutations that were selected that became better and better at infecting humans. That's what Delta is. Is Delta like reacting to what we're doing? And so it's trying to work around the systems we've set up.

We've had these human interventions to battle alpha, and so, you know, or beta or whatever, and then Delta comes in and says, okay, well, I'll try this. Well, you know, most evolutionary biologists would believe that Delta would have arisen anyway. It is part of the, if you think of the virus strains as a tree, Delta is a natural variant of the tree. I think we don't know enough about what the exact path was that led to the arrival of Delta. All that we do know is that its fitness for human reproduction, so reproduction in a human cell, and its capacity to bind the human cell is much greater, its infectiousness is much greater. I don't think that, at least, you know, again, there's an analogy with cancer here. I don't think that Delta arose because of something we did.

Delta arose because it lies within the evolutionary path of the virus in itself. It's not as if, you know, we pushed a button and therefore Delta learned to escape that button. But rather it is that Delta is a natural evolutionary consequence of the way viruses evolve. And the more virus there is, the more it will evolve. Had we been more capable of limiting the total viral numbers, some hypothetical number, you know, some several trillion in the world, we would have had fewer evolutionary changes. My belief is even if that was the case, as long as the virus circulated or circulates in the population, Delta would have arisen. It may not have arisen with the speed and with the breadth

that Delta took across many countries and continents, such as India and the southern United States, et cetera. It may have changed its trajectory, but Delta would have risen. I want to talk about some of these vaccines, and you just completed a study in Bahrain that looked at the impact of, I think, four vaccines, right? Two of the western vaccines, plus Sputnik from Russia and Sinopharm from China in a controlled population. I think Bahrain is the only country, the only population that has had all four of these vaccines spread throughout the population. So it gives you unique insights. So first, can you talk?

I know you just wrapped up the study. So can you first talk a little bit about the study, what you were trying to understand and what we can learn from it? Absolutely. The study is still in preprint, so it's not been peer reviewed. So there are several things that are still going on in the study. But let's take a step back. Bahrain has a total population of about 1.51 million, and it managed to vaccinate more than 1 million individuals.

And there were four vaccines that were available, Sinopharm, the Chinese vaccine, AstraZeneca or Covishield, Pfizer, and Sputnik V, the vaccine made in Russia. And the study looks at, in a very granular way, because Bahrain keeps data on every single individual who's either been vaccinated or unvaccinated and is capable, because of a very centralized database, is capable of asking the question, what happens to each of these individuals after the vaccination? Very carefully kept data, very meticulously kept data, and very granular data. This is what we call a real world or a phase four study. And unlike any previous phase four studies, there are several distinctions between this one. So for instance, if you compare

a phase four study from Israel, there they were using primarily the Pfizer vaccine, so it's not, so they were not able to compare vaccines against each other. So in Israel, you get the benefit of, we've talked a lot about the Israel experience on this podcast, in Israel, you get the benefit of a very diverse population. So you get a lot of biological demographic variability, but it was all tested and rich data. I mean, highly centralized data, so they could really track effects. But your point is it was all tested with just one vaccine,

just Pfizer. Correct, correct. So in contrast, in Bahrain, a lot of the vaccines, there were four vaccines, so we were able to track all four vaccines. Sinopharm was used the most, the Chinese vaccine, and it was also deployed the earliest. So one major confounding factor in this phase four study was that we had to eliminate the early vaccine recipients of Sinopharm. It's a very important point because you don't want to, you want to start the clock off with all, if you compare vaccines, you want to start the clock off at as similar a time as you can. So Sinopharm

and Pfizer, we started the clock off at the same time. And that was January 30th, after almost two months of, you know, high risk people and frontline health workers getting Sinopharm vaccine, we eliminated all of them. So January 30th, Pfizer and Sinopharm go off to the races, as it were, together. And of course, AstraZeneca arrives soon after, and Sputnik also arrives very soon after. There are some demographic differences between the vaccines. So Pfizer and Sinopharm, just by chance, the men and women ratio is very similar. AstraZeneca, probably because of some of this rare adverse effects, is more predominant in men, less in one, infections. Number two, hospitalizations. Number three, ICU admissions. And number four, deaths for all the four vaccines. And again, this is very important because this is real world data. This is not a clinical trial. This is a cohort study.

So we're asking in the real world, how are these vaccines performing? And the second difference with many of the studies, including the Israel study to some extent, is that we caught the delta wave right in the middle of the study, just by chance. So we were able to ask what happens during delta as well. So there are some confounders, and you can read about the confounders in a real-world study. You can't control for everything. The world is not perfect. People make self-choices about vaccines, etc.

But in the real-world study, the basic top-line finding is that all vaccines worked. During the Delta wave, it looks as if the Sinopharm vaccine, having eliminated the early vaccinees, the Sinopharm vaccine was the least able to prevent hospitalizations, infections, and deaths. Pfizer and Covishield performed very well. You still got infections. Obviously, they worked. So there was a reduced number of infections, reduced number of hospitalizations and deaths. But with Pfizer, I think there were overall, I think three deaths in total. With AstraZeneca, there was one, if I remember correctly, I don't remember the exact numbers, but they were highly protective against ICU admissions and deaths. And so it is a comparative study against four vaccines. And I talked about some of the potential confounders. We tried to eliminate as many confounders as we can. But it's one thing is clear that the vaccines work. They still work against Delta. But Delta is lethal. And some vaccines seem to protect you more than other vaccines, particularly the Pfizer and AstraZeneca vaccines were effective in protecting you.

The Chinese government has been obviously Sinopharm. The Sinopharm vaccine has been the predominant vaccine throughout China, but also throughout parts, large parts of asia africa uh it's been deployed in some parts some countries in eastern europe so while we're all consumed with our vac the vaccines that were that originated in the west the reality is sinopharm is is probably the the experience of using sinopharm is probably more common globally than what we've experienced here. If you're saying that your study has shown that Sinopharm is the weakest, which we knew, but this obviously gives us more information, especially as it relates, specifically as it relates to Delta, how worried should we be that that's the vaccine that's touching most of the world? Well, as I said, all the vaccines are protective and nothing, you know, something is better than nothing.

Pfizer is quite hard to transport, hard to deploy around the world. Because of the cold chain? Because of the cold chain, exactly. AstraZeneca seems to have performed very well. You know, I don't have any horse in this race, as it were, But this is what the real data shows. And we've left individuals and individual nations to figure out what risks they're willing to take with one vaccine versus the other. As I said, all four vaccines were protective. We are not making, and I cannot make, any political or medical recommendations. But the data is what the data is, and we let individuals and individual nations decide how to get vaccinated. And just to zero in on a point you alluded to, how does this experience with the Bahrain study that you worked on, how should it

inform our thinking generally about how we do clinical trials across the board for vaccines and in other drug approval processes? Well, it's a very important point, Dan. I'm a very big believer in what's called a phase four clinical trial. Phase four clinical trials are clinical trials that are done after a drug or a vaccine has been released in the real world. And these are real world trials. They can be done in many trials. They can be done in many ways. They can be randomized. If they're randomized, they're very powerful and very well controlled. The problem is that no one wants to pay for them. Because, you know, if you're the drug company that's made the drug, the last thing you want to do is to pay for another trial. And,

you know, the worst outcome is, gosh, you know, the effectiveness of the drug is actually less than what you found in the randomized trial. So every incentive is against it. But on the other hand, from a public health and population health perspective, it's the most important study, right? Because this is how it performs in the real world. So for drugs, I think it's very important to perform phase four studies, whether randomized or cohort or case control studies, different kinds of studies to determine whether they're really working, whether they're working across all populations. A good example is, you know, a drug might work very well in a phase three study, but it might be only because you enrolled white patients. Whereas, you know, African-Americans may have a completely different response to that drug and it may not work. So that would be a phase four study, post-approval study.

It could be, as I said, cohort, randomized or observational, anything. For a vaccine, it's very important because, as you very well know, the viral strains themselves are evolving. And so as the viral strains evolve, it's important to keep up with the vaccine studies so that we understand how those vaccines are performing in the real world in the context of the evolution of the virus itself. The original studies done by, for instance,

Pfizer and by Moderna and by AstraZeneca, et cetera, were all studies that were done before the Delta strain became dominant. Now the Delta strain is pretty much the single dominant strain in the world. And so we need to revisit this to figure out, you know, whether these vaccines are working against Delta and to what extent, what are the clinical consequences for all of this? If yet another strain were to become dominant in the world, we would have to repeat all of this. And again, and this is something, especially in the era of evolving viruses, that's something we have to be cognizant of and just swallow, as it were.

Because unless we do this, we will never realize, we will be using outdated information. And it's especially true for viruses because viruses are evolving. I want to now look a little retrospectively because you wrote a piece early on in the pandemic in The New Yorker about how the U.S.'s experience dealing with the pandemic has revealed some major structural flaws in our healthcare system and some broader kind of how our society is organized more generally. And that was just based on kind of early days. Now, I'm referring here, I want to refer to a piece by Yuval Levin from the American Enterprise Institute.

He wrote this piece, which is on the cover of the current issue of, the new issue of Commentary Magazine called, What Have We we gotten right in the covet fight uh he says that there's you know obviously plenty of coverage about what we got wrong but he focuses on what we've gotten right and what he says the difference between the he argues that there's a there's two ways to deal with the pandemic there's mobilization of discipline and there's mobilization of capacity and the u.s is generally in the early stages of any crisis really bad mobilization of discipline you saw mobilization of capacity and the u.s is generally in the early stages of any crisis really bad at mobilization of discipline you saw mobilization of discipline in like the asian democracies right and in asian countries generally where they're really good about telling people

what they need to do and people follow rules and they're disciplined but when it comes to the sort of next phase which is mobilizing capacity, whether it's mobilizing, you know, civic discipline, but through immense exertions of power, money, and energy, helps explain both why we often seem inept and rudderless at first in the face of major challenges, and why we often ultimately achieve astonishing practical feats in taking them on. It is also why we frequently fail to give our country credit for its triumphs, because what Yuval's arguing is that the narrative that's established about how America deals with the crisis is always the narrative that's formed and becomes indelible in the early phase of it. But the reality is we have these triumphs later on, but they become eclipsed by the mess at the

beginning. You wrote a lot about the mess at the beginning. So first, can you just spend a moment telling us what the mess was? And then do you agree with Yuval Levin that there's something about this next phase of dealing with the pandemic that is extremely impressive about what America has done? And maybe only America could have done that. So I will say, let's talk about the mess first. The first mess was in the supply chain. We ran out of masks. We ran out of personal protective gear. We ran out of ICU beds. We were at one point of time in danger of running out of ventilators. The supply chain issues emerge from, I think, a lack of attention

to the fact that much of the supply chain now depends on global supplies. And because global supplies are competitive, they can put in very competitive bids. For instance, if you're in China, you can say, I'm going to make N95 masks for 50 cents less than you can make them in the United States. We buy the bulk of our supply chain, bulk of a medical supply chain or some parts of our medical supply chain from places like China, India, and other producing countries. Those collapsed. And one lesson from that is that we must have a local supply chain. We also had a depleted federal stockpile. I spoke with the person who manages the stockpile,

and it was very clear that in the early days of the pandemic, we had underestimated the stock time we have a crisis, we'll continue to buy from you. So the guy ramps up his factory, expands his operations, hires more people. And then the next crisis comes along and some producer, let's say in China, I'm not singling out China, but some producer somewhere says, I can sell it to you for 50 cents less. And all the people go and say, okay, fine, I'm going to buy from them. And the guy has now 300 employees sitting without work. So he has to close his factory down. So one lesson we've learned just from supply chains, we need a local supply chain, and at least a percentage of it has to come locally. And that means that this is not a sort of made in America or make in America story. It is that for medical crises, we need a stockpile

and supply chain that will not disintegrate when there is a moment of crisis as we saw before. The second failing, I think, was in approval and deployment of early testing, containment, and isolation. You mean like a very easily accessible, commercially available test? We just didn't have them early on. Exactly. We did not have them early on for reasons that I outline in my piece. And they were rather, I would say, extraordinarily simple reasons. Basically, one piece of equipment, a primer to test the virus did not work for a while. And even though academic laboratories had already started making very good products, the approved test was still not ready. And there would be several days that would pass before the federal test was made ready.

And you in your piece cites, I think the numbers from the first case of COVID identified in the US, which I think was in Seattle, it was something like 40 plus days until there was... That's correct. That is correct. And that is... Until there was a test available. That is unacceptable because the test, in fact, is in fact a very easy test. And the researchers in Seattle, and I spoke with the researcher involved, had already devised a test that would work. But the test within the federal test, the mandated test, was still not working. CDC approved. The CDC approved one, exactly. So there are ways around it. Many countries have created ways around it, which is to identify upfront pre-approved laboratories and essentially recruit them very early on in the course of a pandemic or infection and say, look, you know, while we are devising our test, why don't you devise your test as well?

And the first one that gets it, you know, gets the test right, reliably speaking, you know, that's the test that we'll use rather than then relying on just one source for testing. So that was the second problem. The third problem was that we continued to allow untested passengers from foreign countries to enter. By that time, it was already too late. You know, we now know that by the time the first patient arrived in Snohomish County in Seattle, the country was already had several cases of the original variant of the virus from China. And very soon, within the 40-odd days that passed before even our first tests had come, the East Coast had been infected or begun to become infected with mostly European travelers. We know that because we can trace the lineage of each of these viruses. Now,

that could have been contained. That could have been contained by, for instance, devising an earlier test, making sure that passengers were tested. It may not have completely contained the virus, but it may have contained the spread of the virus to local areas where they could have been stamped out like local fires as opposed to spreading through the entire country very quickly. I'll give you a couple of examples of two other things that failed. I think our medical system of records was very poor at tracking infections. In fact, we relied more on Twitter to figure out what, you know, where the infections were moving, how the side effects of the infections were, how to spot early signs of the infection, because our current medical systems, including what we call the

electronic medical record, are very poorly searchable. I asked a colleague of mine, how easy would it be to figure out how many of my cancer patients were vaccinated or were at risk for COVID or had COVID already early in the infection. And basically, she laughed and she said, you know, it would take you several days to figure this out. Meanwhile, we have the among the most sophisticated medical record systems in the world. But unfortunately, we've devised those medical record systems primarily for billing purposes rather than exploratory purposes, such as figuring out sort of how to understand the dynamics of an infection as they move along.

So this is what Israel, I mean, this is what Israel was able to do. This is what many other countries were able to do. The UK to some degree through the NHS? That's correct. The UK through the NHS, Israel through its centralized system and so forth. And we are still unable to do it. We have to still rely on basically CDC and other records to do exactly that. So I think that that is a major concern.

So those were three things that I think, and if you read the piece in the New Yorker. Yeah, we'll post the piece. Yeah, Yorker. Yeah, we'll post the piece. Yeah, post it. We're going to post the piece. It goes into much greater detail than I'm telling you on a high level. Now, let me tell you, you know, what we did well. I think, obviously, what we did well was to invent vaccines. Two of the best vaccines, Pfizer and Moderna, came out of decades of science

that not only the United States, but also to some extent, credit must be given to the Germans as well in this. But, you know, this was a United States and to some extent, Germany led effort. The UK came up with its own vaccine. India came up with its own vaccine. You know, the UK vaccine is being produced, not mainly, but a large part in India. That's the AstraZeneca vaccine. So what we did well was, you know, the inventiveness and the innovation. And to your point, the decades of investment in medical science, in the human genome project, you know, which began two decades ago. I mean, all of these projects, we kind of benefited from the legacy of a lot of that work.

Exactly. And, you know, places, I'll just single out one place, the Broad Institute. You know, overnight, the Broad Institute was converted from a human genome sequencing laboratory to a viral genome sequencing laboratory. So all that innovation and the rapidity of that innovation was really reassuring. I think what we did very well was, you know, we were very early on the leaders in the vaccine deployment program. The whole world watched as America got vaccinated. You know, one of the companies that I've been involved with as a medical advisor was among the first to start vaccinating. We set up what was called vaccine super pods and we created the concept of a drive-in vaccine super pod.

You didn't have to wait in at the pharmacy to get yourself vaccinated because pharmacies would be overwhelmed. You know, no Walgreens has placed for, you know, a line going around 800 people in the middle of the winter for people to get vaccinated. But rather, we created a system, a digitized system by which you could, you know, you would be pinged when your turn was ready. You would drive up, be registered, vaccinated. And in fact, you could be vaccinated while sitting in your car, which was, you know, just a completely different model than many other places used. And in fact, the super pod model was then replicated across multiple places in the country

and was very good. So these were, you know, innovations that I think were very reassuring. But then we get back to square one, which is now we can't vaccinate people all over again because of, you know, other countries like the EU are reaching 60, 70 percent vaccination rates. We're stuck in the, you know, in the 50s, in some places, in the 30s, in some places, even, you know, in the 30s and 40s. And as I said, unless we create a bulwark against COVID, those children in those places, and of course, adults and people who are vulnerable will remain vulnerable until vaccination is reached. So

it's almost as if the pendulum swings one way, swings the other way in terms of innovation and deployment, and now has swung back the other way, and we have become once again laggards in being able to vaccinate. Just in wrapping up here, a couple longer term questions. So we were all amazed as you're talking about about the fast and innovative response with regard to mRNA technology and the new vaccines. Are there any other technologies in the pipeline

that could succeed in combating or eventually eradicating COVID that have, that are similar to mRNA and sort of, that if you were in the medical science world, you were, you were, you knew about mRNA, and you knew there was, there was, there was reason to believe in its promise, but if you weren't, if you were just, you know, regular not engaged in medicine or science, you kind of first learned about mRNA with COVID. Are there any other technologies in the pipeline that you foresee having that same trajectory?

Well, you know, the use of various viral vectors for vaccination has been around for quite a while. And by various viral vectors, I mean, other viruses that are able to carry spike protein or other proteins into the body and make it so that you can then, and so, so I can't, I won't name one of them because there's so many, but there have been many, many other ways of delivering vaccines. And of course, unfortunately, it's not been deployed yet, but the nanoparticle method of delivering vaccines would also be a very useful way of deploying vaccines in the future. The one thing we did not talk about was, of course, influenza. You know, these same technologies will be used and will be very useful against influenza, especially as new pandemics of influenza come around in the future, which they inevitably will.

Influenza is a very different kind of virus compared to COVID or SARS-CoV-2, I should say, partly because influenza is, SARS-CoV-2 has a continuous genome. And so it's, when it makes mutations, it makes mutations in, you know, in spots. It can't sort of one day sort of suddenly wake up one morning and flip out its entire genome and say, you know, I'm going to make a new variant of COVID, which doesn't look at all like the previous variant of COVID. Influenza, in contrast, has what's called a segmented genome. It's very unique in this way. It has, its genes are stored in pieces, which are separated, physically separated from each other, separate molecules. And so what influenza can do, which is very unique, is that it can mix and match. It's like taking two completely different socks out of your drawer, which are mixed and matched.

Now, COVID can't do that. It has only one sock. It can make changes, as it were, to push the analogy. It can put new dots or new spots on the sock, but it can't change the socks overall. Influenza can pull two totally different socks out of the drawer, and now it becomes a completely new influenza. Now, why am I telling you all of this? Because influenza, unlike COVID, is going to stay with us for the rest of our lives, for the rest of human history. And it's because of this ability, because, you know, it can pull two new socks out of its drawer. That's why we call them H something N something. H is one kind of sock, N is another kind of sock. The mRNA vaccines will, I think, really, really speed up our capacity to make anti-influenza vaccines. And because influenza changes its socks, as I said,

will really speed up the capacity to tackle influenza infections in the future. Speaking of flu shots, won't we eventually find ourselves in the same situation? Could we argue that we won't eventually find ourselves in the same situation with COVID that we find with flu shots, where there are so many variants, we'll just have to make bets and get shots for two to three variants out of dozens? I hope not. And as I said, it goes back to my conversation about the two camps and the Lego blocks. If it seems that COVID is done with its stable Lego blocks, then we will probably need Delta. We might need boosters later, but we'll probably need Delta as a shot against the Delta variant. And hopefully, unlike influenza, the virus will have no greater tricks to play. I'm saying hopefully because we don't know. These are based on

computational models. There are already new strains that are appearing, but they don't seem to have all the nasty, you know, they have the nasty things that Delta has and they're Delta plus. But it's not as if, you know, Delta was a massive increment in its infectiousness. So, you know, I think that that's what the big difference is. Last question. Some epidemiologists look back at the AIDS-HIV epidemic in the 1980s as a period in which, despite the human catastrophe, there were also great strides made in life sciences that we benefited from in a whole range of areas decades later. So first question is, do you agree with that retrospective view? And I think what you're saying, based on what you're just, these examples you're talking about right now with regard to flu, the influenza and other illnesses,

we could have a similar experience as a result of this terrible pandemic period we're experiencing now. There's no doubt that we will. And I already gave some examples of, you know, for instance, mRNA technology. But it's not just mRNA technology, you know, how to wrap mRNA, how to keep it stable inside the cell, how the, you know, cells normally, when you give them mRNA, get very irritated because they think that they're being infected by a virus. And they make lots of nasty things to prevent that. There was a trick that was used to trick the cells into believing that they weren't being infected by a virus.

Coating the mRNA in a particle that would deliver it into the cell was itself a huge accomplishment. And these accomplishments will lead to new vaccines, vaccines against, for instance, human papillomavirus, for which there's already a vaccine, but new kinds of vaccines. I told you the story of influenza and the capacity to mix and match very rapidly. So there's no doubt in my mind that this sad episode in human history, catastrophic episode in human history, has already led to innovations that will last for a very, very long time.

So on that mixed note, both recognition of how difficult the time has been, but some hope, we will end there. Sid, thank you for being so generous with your time and your insights. It was a tour de force, and we'll be following what you think and write and publish, and we will post a whole bunch of material in the show notes, including some of the pieces as it relates to Bahrain and in our show notes. But Sid, I just want to thank you. My pleasure. And thank you very much. That's our show for today. If you want to follow Sid, you can find him on Twitter. He's at Dr. D-R, at Dr. Sid Mukherjee, M-U-K-H-E-R-J-E-E. Sid has numerous pieces published in the New Yorker magazine. I highly recommend all of them, but especially the ones from this past year on the pandemic. You can track them down

at the New Yorker website. We'll post links in the show notes. If you want to purchase any of Sid's books, which I highly recommend, you can go to barnesandnoble.com or your favorite independent bookstores or that other e-commerce site. I think they're calling it Amazon. Also look out for that documentary series I mentioned that he's worked on with Ken Burns. You can find that through PBS. Post-Corona is produced by Ilan Benatar. Until next time, I'm your host, Dan Senor.