Dr. Steve Holland — Sussing Out Susceptibility to Sickness

>> Diego (narration): In this episode, we’re asking questions about susceptibility. Why do some people tend to get sick more than others? How can one person have a terrible time fighting off an infection while another doesn’t seem to fazed at all? What makes someone more likely to fall ill?

>> Dr. Holland: And that question that so many people ask, you know, why me? Why now? These are fundamental human questions.

>> Diego (narration): That’s Dr. Steve Holland. For him the mystery of why some people are more prone to disease is as much a curiosity as it is a calling.

>> Dr. Holland: These questions pervade every single aspect of medicine, whether it's infectious disease or cancer or rheumatology. There are things like melanoma, you know, skin cancers that are caused by sun exposure, and yet, everybody has some sun exposure. Why does some people get it more than others? I mean, pick anything else, tobacco exposure. We know that the rate of lung cancer is much higher in people who smoke, but not everybody who smokes get lung cancer, why is that? And so, that intrinsic level of variability is really what we're after.

>> Diego (narration): Dr. Holland is the director of intramural research and chief of the immunopathogenesis section at the National Institute of Allergy and Infectious Disease—the same institute where thirty years ago other NIH scientists found that susceptibility to HIV wasn’t the same for everyone.

Led by Dr. Phillip Murphy, the researchers studied people who knew they had been exposed to the virus but proved to be naturally resistant somehow. It turned out that these individuals had variants of a gene called CCR5 that had mutated and given them protection against HIV. Typically, CCR5 codes for a protein on the surface of white blood cells that HIV uses to grab hold and infiltrate the cell. But in the very rare occasion that there are two mutated copies of CCR5, the protein never reaches the cell surface—meaning no protein, no entry point, no infection.

>> Dr. Holland: It is certainly an inspiration to all of us that are interested in looking at population-based studies on the one hand and, you know, rare studies on the other. And I think Phil has done a beautiful job really integrating both of those.

>> Diego (narration): Like Dr. Murphy, Dr. Holland is trying to understand the differences in our biology that can influence a person’s susceptibility to disease. But unlike the case with CCR5, Dr. Holland is finding that some answers lie outside of genetic glitches. 

>> Dr. Holland: There are lots of ways to develop similar immune defects to those that we first identified as being genetic.

>> Diego (narration): These defects largely deal with interruptions to the chemical signals that immune cells use to communicate with one another. Those chemical signals come in the form of cytokines, which are small molecules released by one cell that then go on to trigger specific responses in the cells that receive them. They’re basically the alarm bells that alert the immune system of an attack. Without cytokines, the type of white blood cells that recognize an invader, known as lymphocytes, can’t call in the heavy artillery, like macrophage cells, that usually help wipe out an infection. And if that happens, pathogens, like viruses, bacteria and fungi can spread under the radar and cause serious illness.

Dr. Holland focuses on rare cases like this, in which immune alarms are silenced, and patients struggle to fend off life-threatening infections. During our conversation, he explained how sometimes the body can inadvertently thwart its own defenses by producing antibodies that block the very cytokines it needs to put up a fight.

[TRANSITION MUSIC]

>> Diego (interview): So Dr. Holland I understand that you first started to look for differences of susceptibility in patients who were infected with a type of bacteria that the doesn’t normally cause harm to the majority of the population.

>> Dr. Holland: Right. I started out in this about 30 years ago looking at people who had disseminated disease with nontuberculous mycobacteria—organisms that are intrinsically not pathogens for humans. We reasoned that if we look at things that aren't pathogens for normal humans and we exclude other possibilities like HIV infection and exclude, you know, drugs and other things that might be confounding factors, we ought to be left with some underlying features that we can understand. And so, we’ve used those rare patients to try and understand the genes underlying mycobacterial susceptibility with these nonpathogenic mycobacteria. But over the last few years, we've looked into some other areas. One of them has been with fungal infections. And the fungus we've gotten very interested in is called coccidioidomycosis.

>> Diego (interview): Yeah, I saw that, I couldn't pronounce it [laughs].

>> Dr. Holland: The easier name for it is Valley fever. And it's called Valley fever because it is in the San Joaquin Valley that runs through Southern California, through Arizona, down into the Rio Grande Valley. And this fungus has been living in the desert out there for thousands of years. And it only sort of, you know, goes to town when it gets into a mammalian host; prairie dogs, dogs, horses, humans. And then when the host dies, it goes back into the soil and desiccates and turns into a spore again. Well, we thought, you know, after we'd done all this work in mycobacteria looking at why some people get infected, we got interested in the story with this Valley fever because, you know, lots and lots of people get exposed to it. In some series, up to 130,000 infections a year. And yet, the number who get really sick is small. And that suggests, ah, big exposure, modest disease burden, but a small portion of people who get a big disease burden.

>> Diego (interview): So, is that why you chose to study these less common diseases? Because the disease burden is much heavier but in a smaller proportion of the exposed population, compared to something more widespread like the flu?

>> Dr. Holland: So, I think it's like staring at the night sky. You notice the brightest stars first, but as your eyes begin to accommodate, the more you see. You know, we're just humble investigators here and we start with what's obvious. And, and now, we're moving toward what's less obvious. By studying the rare, we can go back and understand the common.

I suspect that exactly the same principles are present in a whole host of infectious diseases, influenza, for sure. I mean, you look at that, you know, in the United States each year, between 30 and 60,000 people die of flu. And yet, the vast majority of us walk around, say, oh, come on, that's just the flu and we say, ‘oh come on, it's not a big deal. But for some people, it is a big deal.

>> Diego (interview): Right, yeah, and I was going to ask; that difference isn’t just the case between immunocompromised and healthy populations, right? There’s variation within quote, unquote healthy people.

>> Dr. Holland: Well, there must be variation within healthy people. So, part of what we're interested in is that some of this variation only gets brought out when you have the right encounter. So, this Valley fever or coccidioidomycosis is a terrific example of this. And it's an important example because the organism is limited to only the Southwest United States and a few other places. So that means that you could have some enormously predisposing genetic risk and live in Chicago or Maryland and be completely oblivious to the fact that your life was at risk from, you know, Valley fever. But you go to Tucson, to see a spring training or something, and all of the sudden, a completely otherwise healthy person could be exposed to this infection and get a severe or fatal case of it. And that's really what we're trying to understand. What about, what about these things that, 99.9% of the time, they're not important. But that point one percent, when you get that exposure, that's what we're after.

>> Diego (interview): Yeah.

>> Dr. Holland: And that's where we think that we can find genetic factors. And those genetic factors, why do we care? Because when you find a gene that causes something, that tells you, oh, that's the pathway that's essential. And when you know the pathway, then you can begin to say, okay, how can I interfere in it? How can I make it bigger, make it smaller? How can I intervene in some way? Go around it? How can I exploit that pathway for the purpose of getting people over their infection?

>> Diego (interview): But genetics is just one possibility, one door into the problem. Susceptibility to these diseases can also be acquired later in life. Is that right?

>> Dr. Holland: Absolutely. This has been one of the most interesting discoveries while looking the wrong way in the wrong place. After we had identified a couple of genes involved in disseminated nontuberculous mycobacterial disease, we became foolishly convinced that that would be the mechanism for all of these problems, which was just intellectually lazy. Eventually, we got steered because of observations from another group in Europe, there was a single case report of a woman who had antibodies against a cytokine called interferon-gamma. And interferon-gamma is how lymphocytes talk to macrophages to tell them to, you know, ingest and kill things. So these antibodies against interferon-gamma prevented people from doing that and we thought, ‘boy, that sounds a lot like some of the patients we had here who were getting these terrible infections, some fatal. And, you know, lo and behold, they had that, as well. And so, we realized that there was this other mechanism which was the development of antibodies against the mediators of immunity.

>> Diego (interview): Well, just to emphasize the point. So, basically these autoantibodies are getting in the way of your own immune system fighting off infection.

 >> Dr. Holland: Exactly, the things that one cell makes to talk to another cell are blocked. So it's functionally like you were missing the cytokine altogether or missing its receptor altogether. And as is often the case, the more we started to look for, the more we started to find autoantibodies against cytokines. And so when the COVID epidemic came along, we had already had a sense that they were biologically important. And so working with groups here, Luigi Notarangelo and others in Italy and France, New York, we were able to put together these cohorts of patients and show that about 10% of patients who have severe COVID actually have autoantibodies against interferon alpha.

>> Diego (interview): Oh wow.

>> Dr. Holland: And one of the more interesting things that we found in the last year or so is that these antibodies are dynamic; that is, they go up and down with some rapidity. They usually fall back down to normal within a few months of being sick, and that they clearly exist in some people before they get sick and don't have obvious associations, at least, not so far. I'm sure there will be associations but we're not sure what they are yet.

>> Diego (interview): So that begs the million question, why did those people develop antibodies against their own immune system?

>> Dr. Holland: Well, we're getting into this complex domain of risk versus cause. We know that driving without seatbelts is a risk for getting injured in an accident, but driving without a seatbelt doesn't make you get injured in an accident, it just makes it more possible. So what are the risks here? For the anti-interferon-gamma autoantibodies, there are specific risks in molecules that we think are being triggered by exposure to a fungus or something else in the environment that just so happens, coincidentally, to generate an immune response against the same sequence in interferon-gamma. That's the hypothesis.

So I think that there will be predisposing risk factors that allow people to get stimulated by environmental agents, maybe foods, maybe infections, maybe, you know, a respiratory viral infection triggers the development of an autoantibody that then goes on to make you susceptible to something else down the road. I think these are legitimate possibilities that speak to the very complex and dynamic situation of our immune system—constantly being stimulated, constantly revving up and then revving down. Just take vaccines for a moment. The whole idea behind developing these levels of antibodies against a vaccine is that the cells come in, they recognize a problem, they expand, they make the antibody, you get a fever or something—that’s all a sign of the immune response coming in and doing what it’s supposed to do. But, you know, the other side of that is what tells those cells when it's time to stop expanding? How do they know when to be controlled? And it turns out, there is a control mechanism. Just like there's a gas pedal, there's a brake. And we are now learning about breaking instead of just about accelerating. And it turns out, as you guessed from driving, you've got to have gas, brake, and steering. If you're missing any one of those your drive doesn't go very well.

>> Diego (interview): Yeah, that’s fascinating and equally puzzling how it all comes together; genetics, risk factors, the environment etc. So how do you study susceptibility? Like what do you look for in the lab and how do you translate over to clinical trials?

>> Dr. Holland: Right. So, we're trying to move into the modern world of really agnostic investigation. So rather than just say, I want to see if this cytokine blocked or this cytokine, we want to see all the things that might be blocked. And so we're taking at holistic look at these individual patients who have predispositions to autoimmunity. And so far, it's really quite fascinating. We've gone from single-gene sequencing to now we do whole genome sequences on everybody. Just because we recognize a syndrome, doesn't mean that we understand it. And, you know, the way I think about this, it's sort of like a limp, right? Saying somebody has a limp doesn't tell you very much about what's really going on. It could be anything from polio, to a stroke, to a fracture, to arthritis. And so, what we're trying to do is take an agnostic view. We start with the genetics, so everybody gets the full genetic sequencing, and then we're trying to expand our search for antibodies. We're collaborating to work on this entire human proteome—that is, you know, all the genes of the body on a chip—to see if we can recognize antibodies that we didn't even think about. So those are our research topics. And what we're looking to do is to integrate genetics with autoimmune phenomena.

I should just say that where we haven't probably been foresighted enough is in trying to integrate the microbiome with that; that is the bacteria and the viruses and the fungi that live in our intestines, on our skin, in our mouths. And these, for sure, are going to have important influences. But, you know, it gets complicated fast.

>> Diego (interview): Yeah, that’s a whole other can of worms. And I imagine it’s possible for those microorganisms to trigger an autoantibody response.

>> Dr. Holland: Some of them do. Well, they trigger all sorts of things. And they change. You know, they change when you change your diet, when you change your location, when you take antibiotics. And we are trying to study those things but, but I'm not good enough to incorporate that into the rest of my work yet.

>> Diego (interview): Understandably so. It’s mind boggling trying to consider all of it at once. Well out of curiosity, do you ever study people that have a naturally high resistance to pathogens as opposed to those that have a high susceptibility. I ask because I imagine that if you find something that really works in a person with a good immune system, it also kind of gives you clues as to how you can help those that have an immune system that's compromised.

>> Dr. Holland: Yes and no. The yes is, absolutely, if you can know that you've got somebody who was, you know, exposed and resisted an infection, then it's definitely worth studying. You know, I have been around long enough to have taken care of HIV before there were any drugs. And back then, it was a relentlessly progressive and fatal disease in a very short period of time. Now, it's completely different. But there are people who survive without treatment, and they have been studied. And for some of them, we know that there are genetic mutations like CCR5 that are protective. And for others, we know that there are other variants and other genes that are protective.

And so, when these genes around HIV resistance were discovered, they were discovered because men who had had multiple sexual contacts with people who died came forward to investigators and said, "I know I was exposed, I know my partner has got sick and died, but I know I'm not sick. Why not?" And it was their recognition of the fact that they were exposed and not sick that allowed people to do it.

>> Diego (interview): Could that be considered the case with asymptomatic COVID. People who know that they’re exposed but don’t get sick.

>> Dr. Holland: It’s kind of the case with COVID. For something like COVID or any of these respiratory viruses, where the fraction of asymptomatic or low level symptomatic is pretty high, it's very hard to pick out, for instance, if, I don't know, if 30% or 50% of people who get exposed to COVID are asymptomatic to start with. How am I going to pick up who's really resistant from who's just, you know, oblivious. And discriminating those is not so easy. That's why you need to get into mouse models where you can begin to look specifically at which mice get sick faster, which mice get sick slower, or are there some mice that never get sick at all. There, because we know the inoculum, we know the date, we can begin to really pick up discrete genes.

>> Diego (interview): Yeah.

>> Dr. Holland: In humans for COVID, I don't say it can't be done, I think it's just going to be hard.

>> Diego (interview): That makes sense. Well regardless of whether it’s COVID, or Valley Fever, or something else, what really grabbed my attention about your work is how you focus on the host side of the equation, like often I think for infectious diseases, people think, you know, the pathogen is what we blanketly just need to wipe out. But it seems like that’s a very limited perspective. To me, these microscopic organisms aren't necessarily or inherently bad themselves, especially those that don't cause disease in the majority of the population. And it's not like they have the freewill or are deadest on harming us. But it's the relationship between the host and the pathogen and how those two interact that determines the outcome.

>> Dr. Holland: Right. You're absolutely right. I trained in infectious disease so I started out as a pathogen-focused guy. And I still think pathogens are very important. But, most of the organisms we call pathogen, whether it's mycobacteria or even many respiratory viruses, are present in the water supply, they’re in soil, they’re easily aerosolized, and most of the time they don't cause trouble. Loads of people get exposed to them and either don't know it or never have a problem.

When I came here to study HIV in 1989, I had a chance to come over and work with John Gallin who was a lab chief here in NIAID at the time, and then the scientific director, and then became the director of the Clinical Center. And it was really working with John that I began to focus on the host side of things. John was a neutrophil guy who had put together a cohort of patients with chronic granulomatous disease and with Job syndrome. And he said, "Steve, you can work on anything you want, as long as it's neutrophils." And I, I said, "Well, thanks. Thanks a lot, John." I didn't know how interesting that could be. And I thought, well, it was a chance to have my own lab and he said, "You can have a lab that's 50 yards from the patients." And I thought, this is fantastic, this is what I want to do. And it absolutely transformed my career to start working on chronic granulomatous disease and then Job syndrome. And then it was an aberrant phone call from a pediatrician in Florida saying that he thought he had a child with chronic granulomatous disease who had disseminated mycobacterial infection. Well, I knew enough about chronic granulomatous disease to know that that probably wasn't the case. That is, they don't get disseminated nontuberculous disease like this child had. So, I brought that child up and it turned out his two maternal uncles had the same problem. And we treated them, studied them, I mean, I could bore you for hours about it. But it was from that, that I realized that studying these nontuberculous mycobacteria would be, you know, worth, worth focusing on. And really, that was when my boulder got pushed off the top of the hill and honest to God, I’ve never looked back.

>> Diego (interview): And I don’t want to put words in your mouth, but the NIH seems like the perfect place for, you know, these comprehensive studies because you have researchers and clinicians and pretty much any facility that you all need in one place. So how does that, you know, play into your work? Does it make it a lot easier? I assume.

>> Dr. Holland: Well, I don't think there's any place that I could do the kind of work that I feel driven to do other than the NIH. And I say that because the pressures of the world elsewhere are so strong to push people to do either, you know, fulltime medical care or fulltime laboratory work. And the opportunity to straddle those two worlds is increasingly difficult to come by. And it's precisely that ability to go back and forth from the lab to the clinic that I think makes the NIH such an extraordinary place.

>> Diego (interview): Absolutely.

>> Dr. Holland: You can live that integrated dream that everybody hears about. You know, you go to medical school, they say, oh, there's a scientific foundation for medicine and you can use that science to make the world a better place. But frankly, the practice of medicine doesn't take full advantage of that, doesn't even take partial advantage of that most days. And the prospect of being able to live that life here, oh, my God.

You know, I think that what makes the NIH so special in so many ways is what we refer to as the retrospective review of research. That is, you get funded, as a principal investigator, you get funded to work for four years. And at the end of that four years, you have to stand up and say, here's what I did. But during those four years, the privilege and the liberty to change your direction as the data come to you, to say, you know, I was working on mycobacteria but now, I think, I better work on Valley fever and now, I think, I better work on COVID without having to go back and write a grant. It's not that I'm against justifying what I do, I completely think that's important. But the most important person I have to justify it to is myself. And I'm thrilled to be held accountable for what I do. I'm proud of what I do, I love what I do. And I think that the system here is designed to make sure that we, the investigators have the opportunity to explore the science as it evolves. And it's not that there's not great science many places, there is—terrific universities, terrific scientists out there—but they live in a different world. And, you know, we all have to decide which world we want to live in. But this one has some extraordinary advantages. And I just can't imagine a better environment.

>> Diego (interview): Yeah, I mean, science is all about adaptability so it makes sense that a career in science should reflect that.

>> Dr. Holland: I completely agree.

>> Diego (interview): Great, awesome.

>> Dr. Holland: Thank you very much.