Dr. Akiko Iwasaki: Is Long COVID One Disease or Many?

Harlan Krumholz: Welcome to Health & Veritas. I’m Harlan Krumholz.

Howard Forman: And I’m Howard Forman. We are physicians and professors at Yale University. And we’re trying to get closer to the truth about health and healthcare. Harlan, what has caught your attention this week in healthcare?

Harlan Krumholz: Well, I was drawn to the issue of rejuvenation therapy. You know about this rejuvenation therapy, Howie?

Howard Forman: I don’t.

Harlan Krumholz: It’s a fountain of youth thing, baby! So there was a company that was formed called Altos Labs. And it’s a new biotech company that says it’s “dedicated to unraveling the deep biology of cellular rejuvenation programming.” So that’s a lot of fancy words to say. They’re seeking to roll back the years and to address the issues around aging by reversing disease, injury, disabilities. I mean, it’s this huge promissory thing that we’re going to help people be young. Now, the interesting thing about this is, one, is the CEO, who is the former head of research at Glaxo, Hal Barron, who is, actually, a Yale School of Medicine grad.

Howard Forman: Yale alum.

Harlan Krumholz: And Hal’s had an illustrious career, a wide variety of companies, including Genentech and at Roche. And now is leading this company. And then there’s a whole long list of Nobel laureates and highfalutin scientists who’ve joined the effort, people who’ve been interested in this, and they say, “this company”—I’ll tell you a quote—“to reimagine medical treatments while reversing disease for patients of any age as possible.” And I thought it was interesting to see this enthusiasm. They’ve raised billions for this company. I mean, there’s nothing to it yet, but it’s billions, and there’s, then there was a lot written about, Bezos is one of the investors, other billionaires, and then the media sort of jumped in and started weighing in.

One article was saying, it said that “young people dream of being rich, and rich people dream of being young.” And that’s what brought people like Bezos to the table to invest in it. These are some of the titles of articles: “Super-wealthy Fund Mysterious Lab to Unlock Immortality,” “Silicon Valley’s Quest to Live Forever Could Benefit Humanity,” “Meet Altos Labs, Silicon Valley’s Latest Wild Bet on Living Forever.” Anyway, I thought it was all quite interesting. We’ll see where it goes, but it’s a whole heck of a lot of money on a bet to say that we can actually reverse aging.

Howard Forman: Yeah. I agree with you. I mean, I think we’ve been searching for the fountain of youth for hundreds, if not thousands of years, but the best evidence is about preventive and protective measures that we already know about in terms of our extending our own lives.

Harlan Krumholz: Yeah. Absolutely. So how about you? What caught your attention?

Howard Forman: So, I’m going to go back to talk about COVID just briefly, but forces are aligning right now to push us to this new normal. And by that I mean there’s a large part of the country that has already put COVID behind them. Many people who are very afraid of COVID have now been fully vaccinated, including boosters when appropriate; others still have been vaccinated and already had COVID at least once, and while deaths and morbidity at this moment continue to pile up, the political will to push for any active measures is waning considerably at the same time that cases are now thankfully waning. So but this has been a traumatizing time for so many. You and I have talked about the effects on our family members and people near and dear to us, those with small children who are not eligible for vaccination thus far, those with elderly family members, who they may live with, those with immunocompromised family members and so on.

So it’s not at all irrational for those folks to be ill prepared for a time when masking is no longer expected indoors, vaccination requirements might wane, testing fatigue sets in, and so on. And the challenge, I think now for both our public health officials and for our workforce, is to provide real-time guidance and data to support changes in policy and help individuals understand risk. And that has been extremely difficult so far. We’re still seeing about 2,400 deaths per day, disproportionately among the unvaccinated. So I don’t pretend that we’re already at this new normal, but I expect that this is coming really soon. And by spring’s onset, we should be thinking about what our expectations are for schools, for workplaces, health facilities, private enterprises. And this is where I’m hoping that public authorities, mayors, governors, and so on, and institutional leaders, including our own employer, Yale University, and where we both work, at Yale New Haven Hospital, can make thoughtful evidence-based adjustments sooner than later. And I was heartened to see that Yale has returned to normal food service in the last few days, and we’re expecting to return to classroom on Monday. And I’m hoping that we’ll be able to have some frank discussions about masking and other measures we can take to get back to as close to normal as we can achieve with reasonable accommodation for those individuals who are still at higher risk.

Our guest this week is Akiko Iwasaki. Dr. Iwasaki is Waldemar Von Zedtwitz Professor of Immunobiology, a professor of molecular and cellular and developmental biology at Yale and an investigator at the Howard Hughes Medical Institute. Her lab focuses on how immune systems defend against viruses. Since the COVID-19 pandemic began, she’s become a trusted COVID-19 expert on Twitter, but more importantly, through her own lab, her collaborations with others, including you, Harlan, and her promotion of her colleagues, she has substantially advanced her understanding of this disease, long COVID, and the means to prevent and treat it. She’s also passionate about combating sexism in academia and advocating sponsoring and mentoring women scientists. Thank you very much for joining us, Dr. Iwasaki.

Harlan Krumholz: So, anyway, I get to start off. Thanks, Howie, for doing the introduction. So, one thing that I wanted to explore a little bit was your advocacy and also your use of social media to do it. By the way, folks listening: She has almost 170,000 followers on Twitter. The tweet that she pinned says: “Mentee: Should I avoid being pregnant while trying to secure a faculty position?” “Me,” meaning Akiko, says, “Be pregnant and go on interviews. If they don’t welcome you with open arms and offer childcare options, they don’t deserve you.” And I really love that. And in a Nature interview, she said, “We need to continue to tackle sexual harassment, implicit bias, unequal pay, lack of access to affordable childcare, lack of opportunities and support.”

Akiko, one of the things I wanted to ask was, because I saw that your mother was a, really an inspiration around this, is then that she had fought for women’s rights in Japan. And I wondered if you could just tell us, what was it like to step up like that to be bold and to be an advocate? And where did that come from? Can you tell us a little bit about your mom too, along the way?

Akiko Iwasaki: Yeah. Well, thank you, Howie and Harlan, for having me on your show. It’s really a pleasure to be here, and thank you so much for your kind introductions too. I’m blushing right now. Yeah. So yeah, my mother had a—both my parents had a very large influence on my life, and my mother worked for a large sort of media company in Japan. She worked there since before she got married. And usually at that time in Japan, as a woman who gets married, you’re sort of expected to leave the company. She didn’t do that. And she had her first pregnancy with me, and she was pressured to leave the company now that she’s pregnant, but she didn’t leave. And the second pregnancy, again, she got a lot of pressure to leave, but she didn’t. And so, and third pregnancy, she, again, stuck with the company, and she suffered a lot of harassment and enduring daily abuse at the company. And yet she persevered. And because of that experience, she had gathered other women around her and other men who were supportive of women who are pregnant or who have children to stay in the workforce and to create an environment that other women don’t have to suffer the same consequences. And so she enabled certain regulations to be in place in that company so that other women can succeed and stay in the workforce without such harassment that she suffered. And so that’s sort of the origin of why I became an advocate of women in science and underrepresented minorities who are also mistreated in academia.

Howard Forman: Wow. That’s terrific. So I want to pivot to talk about the science and so much that you’ve been working on. First, I’m just curious to know what it was like as the pandemic was just on our doorsteps to have pivoted to doing so much COVID work so suddenly. It’s one thing for somebody who’s having to shut down clinical trials to have to do something differently, but for you, you’re always doing ongoing wet lab research; to have to make such a big pivot is amazing. And you did it so swiftly and involving so many people. Can you tell us a little bit about how you do that and how you set your priorities for your research? Because they’ve been in such centrally important areas.

Akiko Iwasaki: Yeah. Thank you. So prior to COVID, my lab has always focused on infection by viruses and immunity, and most of that work was done in animal models. We had a couple of projects where we were looking at human immune responses, but that wasn’t the major part of the lab. So the entire reason that we were able to pivot so smoothly and so fast is because we had colleagues such as Dr. Albert Ko at the School of Public Health and Dr. Saad Omer, and a bunch of us actually got together early in February of 2020 to start thinking about building a biorepository so that we and others can benefit from having human samples to be able to study immune responses and viral replication kinetics and other issues around this new virus.

And so that launch of the IMPACT Yale Biorepository is what enabled us to pivot so quickly to do translational research. It’s really about having great colleagues around and people who are just sort of selflessly willing to put themselves in together with a group of people to create a platform where we can all benefit. So yeah, that’s really the reason we were able to pivot so quickly.

Howard Forman: And you got very much with Harlan as well—so I’ll let you both speak to that—involved with the idea behind long COVID before the mainstream. Did you realize that there was going to be a great need to follow patients that had persistent symptoms or delayed symptoms in many cases? Can you tell us a little about that work specifically and the types of work you’re doing in that area?

Akiko Iwasaki: Yeah, so as we began to study COVID, we first, of course, focused on the acute disease because that was what was happening in March of 2020, but then, as the months went by, we started to realize that there were so many people who were having lingering symptoms, even after they have had the sort of acute phase of disease. In some people, this acute phase of disease was quite mild. And yet it developed into this severe and prolonged symptoms, including very severe fatigue and shortness of breath and cognitive issues. There’s so many, over 200 different symptoms that are now reported for long COVID. And so I became aware of this post-acute phase of COVID early on during the pandemic and started to follow that mainly by reading articles and looking at Twitter feeds. And then I realized that there are so many people suffering from these kinds of issues and that most of those people were being ignored because there was no label back then, there was no PASC [post-acute sequelae of SARS-CoV-2 infection] or long COVID or any acronyms that people use now to describe this disease.

And so I became very aware and interested in trying to understand how a prolonged symptom or long-term symptoms can happen after an acute respiratory infection. And one of the things that I became struck by was the reports from patient groups showing that about 40 to 60% of the long haulers felt better after the vaccination, while about 20% of them felt worse. And this was not just one group reporting; there were multiple patient groups reporting similar numbers. And so that’s when I thought that maybe an immunologist like myself can contribute to this understanding because the vaccine is ultimately inducing antiviral immune response. And if that’s helping, does that indicate something about the disease? And so that’s sort of how I began becoming interested in getting involved in long COVID. And of course, when I was talking on one of the panels about this interest, Harlan was also on that same panel. And Harlan said to me that he really wants to help me realize this dream. And I thought he was just being really nice, and he is really nice.

Harlan Krumholz: No, no, no, no, no, not always, not always.

Akiko Iwasaki: But I thought, wow, that’s incredible, that Harlan just sort of.... You remember that panel, Harlan, when you said—

Harlan Krumholz: I do remember.

Akiko Iwasaki: That I’m going to help you get this done, and that’s what he is doing.

Harlan Krumholz: Well, look, it’s been remarkable to have the opportunity to work with you. And part of what our vision about this is, is to be in sincere and genuine partnership with people who are facing these health challenges and try to bring together people and work with them in a way that respects and honors their participation and try to get to the root cause of this. Akiko had come up, I don’t know, you might want to talk a little bit, but I mean, you have a hypothesis about what could be causing long COVID. Do you want to just say a few words about that?

Akiko Iwasaki: Oh, sure. I’d love to. So we’re following several hypotheses of how long COVID can happen after an acute infection with a virus. The first hypothesis is a persistent virus or viral reservoir or remnants of virus. That’s a chronically triggering inflammation, and that’s leading to this long COVID. The second hypothesis is that there may be autoreactive immune responses generated by the virus and after the virus infection, either because it’s triggering mimicry of antigens that mimic between the host and the viral proteins, or just bystander activation of autoreactive cells. And there are other hypotheses like the latent viral reactivation that happens in some people that could be triggering lung symptoms. There’s also tissue damage that’s caused by the virus that if it’s unrepaired or repaired inappropriately could be causing chronic issues. And inflammation in general can induce significant changes in the tissues that could also be contributing.

So we had these hypotheses, and now there are emerging evidence for many of these hypotheses to be true in at least a subset of patients. And long COVID is probably not one disease but multiple diseases that look very similar and depending on what triggered it and what’s chronically causing these symptoms, the treatment will obviously be quite different. So we need to really find out how many subsets of disease causes are there. And can we identify patients in these disease subsets so we can appropriately treat these people?

Harlan Krumholz: Yeah. A couple things really attracted me to what Akiko was doing. One is that her ability to develop immune signatures, take thousands of measurements of immune function and try to put into perspective a profile of someone’s particular immune system, both with regards to the cytokines and chemokines, the chemicals that are circulating the antibodies, the receptors on some of the cells, and so forth. And then the other thing, so there was, the science was attractive. I mean, she’s at the cutting edge of this. And I believe that what she’s doing can really crack the case on a lot of diseases and that this will just be the prototype. I mean, looking at COVID will open up a whole pipeline of research that may be able to help a whole range of people who are really suffering from overactivation of the immune system, sort of “friendly fire” as the immune system tries to fight against disease.

It ends up hurting itself often and hurting the person. But the other thing I, and I just want to say this quickly, which is that she’s such a great partner in this quest to change research, to have research be a method of empowering people who are participating in research, and again, this treatment of people as part of a team. And I know you’ve said team science, and often when people are talking about team science, they mean teams by other scientists. But I think you and I understand team science to be broadly inclusive of the people who are participating in the research, who are facing the health challenges and incorporating their wisdom and knowledge as we develop these studies so that we can move faster, learn quicker, and that we’ll return results and make sure that they know what we’ve learned along the way, so they can feel pride in the achievement.

And so there aren’t many people that you can come together with who want to embrace that. So in the course of that, we’re going to build a community of people who are facing... and interested in COVID and facing long COVID issues and just broadly want to contribute to COVID research. And we’re going to try to conduct it in a way that honors that proposition of empowerment for those who are working with us—not just subjects; they’re really part of the team. And that’s what we’re going to try to do.

Howard Forman: I want to, in our final minutes, I was wondering if you’d give us a little bit of hope maybe about what we might expect in the future about intranasal or mucosal vaccines and what that might mean for the future, either for this or future respiratory infections.

Akiko Iwasaki: Yeah. So mucosal immunity is what we’ve been studying ever since I started my lab here, and we focused on the mucosal surface because many pathogens, including SARS-CoV-2, enter our host through the nose and the mouth and mucosal surface. And if we can set up the immune barrier right at that surface, it is much more effective in preventing infection, transmission, and disease, everything downstream of the infection. And so we recently put up a pre-print where we came up with a strategy called “prime and spike.” This strategy takes advantage of existing immune responses that many of us have already because of prior vaccination or infection and turns it into a natural adjuvant. So all we have to do is nasally spray antigen, in this case spike protein from the virus, without any adjuvant and trigger the immune responses. That’s really robust and long-lasting within the nasal cavity because there is preexisting immune cells that can sort of stimulate the entire process of adaptive immunity without needing to rely on innate immune signals. So the prime and spike, when we used... this is in the mouse model so far, but it is very protective because it induces mucosal IGA response. IGA is the isotype of antibody that’s secreted into the mucus layer and can capture the virus as they are exposed at these surfaces and also provide long-lasting memory, tissue-resident memory cells in the respiratory tract, which allows them to be recalled very quickly after exposure to a virus. So unlike having soldiers inside the castle, we’re putting them outside the door. And so they can respond very quickly and limit the amount of infection that a person suffers from. And what that does is, you limit disease, and you also limit transmission from that person onwards. So we’re very excited about this prime and spike idea, and hopefully we can make this into reality soon.

Howard Forman: Yeah. Just for our listeners, because I’ll be honest with you, until somebody told me this a year ago, I didn’t know it from medical school. Can you tell us about what an adjuvant is, what that actually means in terms of vaccinations?

Akiko Iwasaki: Yeah, sure. So vaccines usually has two components. One is the antigen itself. So antigen is what the B cells and T cells see, and this is important because an antigen dictates what specificity you would generate with the vaccine. So, flu antigen or SARS-CoV-2 antigen. So that’s what the spike protein is. It’s the antigen, but the protein alone is not effective in triggering a robust immune response. You need the second component, which is called the adjuvant. An adjuvant triggers the innate immune response. And it’s the innate immune response that tells the adaptive immune cells what to do and how to do it well. So without this adjuvant, a vaccine is useless. It’s not going to trigger the right immune response. And right now the most common adjuvant is called alum, and it’s sort of mixed in together with the antigen, and it triggers this innate immune response.

There are sort of newer versions of adjuvants that are being developed because of the discovery of toll-like receptors that happened here at Yale, as well as its ligands. So those toll-like receptors are the sensors of these adjuvants. And because we know what the sensors are and what the ligands are, the newer version of adjuvants actually include these kinds of toll-like receptor agonists, and that’s being, coming into the market with the numerous set of vaccines. So with the immunogen, the antigen plus the adjuvant, you have a potent vaccine. And so that’s what I mean by “adjuvant.” But in this case, in the prime and spike case, we already have the adaptive immune response, and we’re using that as natural adjuvant in the absence of any innate ligand.

Harlan Krumholz: So you’re an innovator in vaccination, because I know you also had this “prime and pull” approach to HSV-2, and it’s really, I think, a tribute to you that you’re thinking about, like, how actually to apply this with people. I just had a quick question about this. A lot of your work was around how the body has cells that are sort of pattern recognition cells, so that when it sees one microbe, it sees another one, a little bit different, but it’s recognizing a pattern and it’s able to respond even faster, even though it’s not the exact same thing, but for SARS-CoV-2, it’s a coronavirus. We’ve seen coronaviruses our whole lives because of common cold. Why didn’t we have a pattern recognition response that helped protect us against SARS-CoV-2? And so why are these variants so pesky? Because they’re just a little different, and can’t our cells, these pattern recognition cells, like help us out and say like, “Hey, we see this. It’s a little different, but we can respond faster than we might have otherwise.”

Akiko Iwasaki: Yeah. So, Harlan, you’re getting at the difference between innate and adaptive immune response. So the pattern recognition, such as the toll-like receptor, is a pattern recognition receptor. What they see is something conserved within the pathogens. So in the case of toll-like receptors, they might see lipopolysaccharide from bacteria or RNA from viruses, but they can’t tell a difference between a flu and a coronavirus. These patterns are very conserved, evolutionarily conserved—

Harlan Krumholz: More basic, more basic.

Akiko Iwasaki: Exactly, more basic. And so those pattern recognition receptors trigger innate immune response to quickly mount defense, but they don’t remember, and they’re not specific against any given path.

Harlan Krumholz: And just so to people, this is really our primitive defense system. And this defense system is sort of not very specific. It’s helping us ward off, but it’s really not able to go against something very specific. And is that what you’re saying? So yeah, we’ve got that, and it could recognize it, but it’s so primitive, couldn’t truly protect us. Maybe helps slow it down a little bit, but it’s really not effective in that way. Is that it?

Akiko Iwasaki: Exactly. So the innate immune system is the first line of defense, but then innate immune response when it’s triggered in the right cells, called antigen presenting cells, that triggers adaptive immune cells, such as TMB cells, and the TMB cells have receptors that are specific to the pathogen, exact amino acid sequences that they see with their receptors. So they can distinguish a variant, alpha variant versus delta variant, for example, they can distinguish very minute differences within the amino acid sequences of a virus. And they’re great at recognizing specific antigen, but that is also a Achilles’ heel of the adaptive immune response, because they cannot recognize something slightly different.

Harlan Krumholz: Slightly different.

Akiko Iwasaki: Yeah. So—

Harlan Krumholz: And that’s why we get bedeviled by this, yeah.

Akiko Iwasaki: Exactly. So the variants are escaping this adaptive immune recognition along the way so that we now have more reinfection or breakthrough infection with the Omicron variant because they’re so distinct from the original virus now.

Howard Forman: I just want to say at this point, the one thing we’ve left out is what an amazing educator you are. And just going through this podcast reminds me to say that, because you’re not just a scholar, a scientist, a communicator, a sponsor, but you’re a teacher as well. And a lot of our medical students and students that work in your lab have learned so much from you. So I just want to thank you for educating us for our audience, for advancing the field of immunology and particularly helping us through this pandemic, both with your science as well as your communications. Thank you so much for being here.

Harlan Krumholz: And she’s won the Yale Teaching Award, you know that, right? Look, I told you, “Don’t invite Akiko. She’s too busy. We don’t want to have to distract her—”

Howard Forman: He did say that. But that was three months ago.

Harlan Krumholz: Yeah, yeah, yeah, yeah. But anyway, we’re so grateful to have you on. Thank you for joining us, and I look forward to continuing to work with you. It’s a great privilege of mine. Thank you.

Akiko Iwasaki: Thank you, Harlan. Thank you, Howie.

Howard Forman: Thank you so much. Harlan. What’s something that inspires you or keeps you up at night?

Harlan Krumholz: Well, Howie, this is something where Akiko talked a bit about her mother, and I want to just take a minute to talk about mine. This week, I was down in Florida visiting her for her 85th birthday, and she continues to inspire me. I mean, she has such really an upbeat attitude and is very much enjoying life. And one of the things I noticed was the degree to which she really works hard to connect with others. And that’s both friends and family and how she stays sort of integrated in the lives of others. And it, I was telling my wife, I really think that that’s one of the keys to the fountain of youth, that really is in the end, the sort of secret that a lot of people know, which is that having those relationships, those connections, keeps you going.

And she says, I talked to a bunch of her friends. So many of them told me, “God, we really love your mom.” And I just saw it’s because she makes that investment, gets herself out there. And one of the evenings I was there, there was a gathering outside of some of the friends, and there was some music and people were up, moving around and dancing around. And I just saw really the power of connection that way. And it was nice for me to spend a little bit of time with her. It’s great to see her at 85, so vibrant as you know, I lost my father this year. So it’s really, I think, emphasized for me the importance also of keeping close with my mom. But anyway, that’s what inspires me. She inspires me. My mom inspires me. And I just wanted to take a minute to say that. How about you, Howie? What inspires you or keeps you up at night this week?

Howard Forman: Well, first of all, I want to say that you and your mother inspire me also. And it just reminds me, our surgeon general and our former student, Vivek Murthy, wrote a book about togetherness and about basically loneliness as well. And there’s just so much evidence to support at what you just said, that we live fuller, better, healthier lives where we have people in them. So I’m thankful for you and for your mom. You know, I was struck a little bit, obviously I think we all were a little bit, that Justice Breyer announced his upcoming retirement from the highest court in the land. And President Biden has indicated that he’ll make good on his pledge to appoint a black woman to the Court, which is another first for the Court. And this has already drawn political lines, with some describing this as affirmative action and others noting that this is long overdue.

I happen to feel really strongly about representation mattering, and it matters a lot, in my opinion. It matters in how we make decisions about the conduct of clinical trials and research, and it matters in how we govern and how we adjudicate. And our experiences lived in otherwise influence us enormously. The 20th century saw the first appointment of justices who were Jewish, Louis Brandeis, 1916; Thurgood Marshall, the first African American in 1967; Sandra Day O’Connor in 1981, first female; Antonin Scalia, 1986, the first Italian American; and the first appointment of a Hispanic justice was in the 21st century with Sonia Sotomayor in 2009.

Black women make up around 7% of the total population. And until now, zero of the roughly 115 justices in our history. Judicial decisions are subject to an understanding of history and the law interpretation of words that were often written 200 or more years ago. And yes, lived experience in representation is very important on the highest court of the land. I’m also confident that there are many incredibly qualified people who could fill one of these important seats. So we’re not limited by talent. So I look forward to President Biden’s nomination and glad to see one more milestone in our nation’s history achieved.

Harlan Krumholz: Well, I’m also a big fan of this move and to see the representation, but I do wonder about the endgame of it. So are there seats now for different people? And then, what about an Asian seat? And are we going to do that? And what does it mean then for some, and it’s quite small it’s.... Anyway, it’s quite, there needs to be some balance in it, but certainly like things have been so out of balance for so long. This is just—

Howard Forman: That’s right.

Harlan Krumholz: It’s a long time coming. All right. Well, good points, good points, and interested to see the nomination. Be exciting to see next steps. You’ve been listening to Health & Veritas with Harlan Krumholz and Howie Forman.

Howard Forman: So how did we do? To give us your feedback? Keep the conversation going, you can find us on Twitter.

Harlan Krumholz: I’m at H-M-K-Y-A-L-E. That’s H-M-K, Yale.

Howard Forman: And I’m @theHowie. That’s at T-H-E-H-O-W-I-E.

Harlan Krumholz: Health & Veritas is produced with Yale School of Management. Thanks to our researcher Sherrie Wang and to our producer Miranda Shafer. Talk to you soon, Howie.

Howard Forman: Thanks very much, Harlan. Talk to you soon.