Dr. Michael Ombrello — The Rare Case of Beverly Gage

>> Diego (narration): Hello listeners! So glad you could join me for another episode of Speaking of Science, the podcast that explains the research and tells the stories of science-in-the-making in the Intramural Research Program of the National Institutes of Health, or as some of you may know it, the NIH IRP. I’m your host Diego Arenas and for this episode I’m bringing you a story about rare disease; what it’s like when your sickness is a medical mystery and what’s it’s like being the medical investigator on the case.

It’s the story of Beverly Gage, a patient who came to the NIH with a condition that had not been observed before, and Dr. Michael Ombrello, the clinical researcher determined to help her find answers. Where their paths cross, shows us the current challenges of diagnosing, treating, and living with disease that is new to science.

[TRANSITION MUSIC]

>> Diego (narration): Ok, let’s start at the beginning, on a crisp autumn day in the waters of the Long Island Sound.

[NATURE SOUNDS FADE IN: BREEZE, BIRDS, WAVES LAPPING ON THE SHORE]

Beverly Gage, a professor of history at Yale University and an avid swimmer, went for a mile-long swim..

[SOUND OF SOFT SPLASHES FADES IN]

…along the thin strip of Connecticut beach where distance swimmers like to gather.

>> Dr. Gage: That was something that I do pretty regularly.

>> Diego (narration): And everything in the water was as usual. Nothing seemed out of the ordinary, until…

>> Dr. Gage: I ran into a plant that scratched up my arm, kind of got some angry scratches and welts. And all of that went away, but that night I started to get a very itchy rash coming up from my ankles and then spreading over my body. You know, I just assumed it was poison ivy or any of the many other things one can get in the summer in the woods in Connecticut.

>> Diego (narration): But then more signs that something was really off started to come along.

[MYSTERIOUS MUSIC FADES IN]

 >> Dr. Gage: I started to get joint pain. At first it was in my neck and jaw, and that too, I assumed I had turned my head in a funny way or I had opened my mouth too wide to breathe when I was swimming and that that would go away too, but that then began moving around to different parts of my body and not going away.

>> Diego (narration): The joint pain and inflammation didn’t just persist, they worsened. It was hard to believe that all this came on so suddenly, especially considering that Dr. Gage didn’t have a history of serious health complications.

>> Dr. Gage: Up to this moment in my life I had not only been healthy, but really assumed that nothing too terrible was going to go wrong, at least for a long time.

>> Diego (narration): It was treacherous new ground, and in the months that followed, the constant agony began to take a mental toll.

>> Dr. Gage: We had been through—it was probably maybe six months into the whole experience, and I was really having trouble walking. One of the things that would happen if I was insufficiently dosed on steroids is that my knees would swell up. And they would get very painful to walk. I remember looking and trying to think about a life with, you know, kind of daily pain, some level of disability and thinking, you know, “I don't know if I want to—I don't know how and if I can live a life with this kind of pain and disability and uncertainty as a permanent condition."

>> Diego (narration): Being the historian she is, Dr. Gage documented the ups and downs of her condition in a journal she hoped would help her piece together the mystery of her illness.

[MYSTERIOUS MUSIC ENDS]

>> Dr. Gage: Most days it was a pretty practical journal. I wanted to have a record of what was happening. And I'm well aware as a historian that memory is not the same thing as actually recording thoughts, sensations, details, when they're happening.

I would record how I was feeling. You know, which limb was swollen, whether I could walk, all of those sorts of things. So that was one piece of it. And then of course there was a piece that was emotional. I wanted just kind of an outlet for my experience. There are all of these moments where you try something new. Okay. That drug didn't work. Let's try this drug. That diagnosis didn't work. Let's try this one. And of course, each time one feels this is going to be it. Maybe this is it. Maybe we fixed it, but over time as one doesn't work and the next doesn't work, I could see my hopefulness or despair changing from moment to moment. And that like becomes a pretty hard cycle to tolerate.

>> Diego (narration): Eventually, she turned her journal into a feature for The New Yorker titled “Nobody has My Condition But Me.” In it she describes how she pin ponged from one medical specialist to the next in search of answers that could tell her what was wrong.

>> Dr. Gage: I got to know all sorts of medical specialties that I had never given much thought to, you know, from internal medicine then to dermatology then to rheumatology, then to immunology, then to pulmonology, and infectious diseases, right? All of these specialties. And one of the kind of interesting things about the experience is to see the way that medicine is organized, but if you're in a position like I was trying to be your own coordinator can get pretty challenging.

>> Diego (narration): The more doctors she saw and the more they struggled to pinpoint a cause for her symptoms or provide a specific diagnosis that could lead to a tenable course of treatment, the more apparent it became that her condition was truly rare.

>> Dr. Gage: Once I entered particularly the world of immunology, I started doing tests and finding out all of these things that were in fact extremely rare, quite wrong, weirdly were not things that I was symptomatic from.

When we did a very, very basic work-up measuring my immunoglobulin levels, it turned out the findings were really quite bizarre. Some of them were extremely low. Some were very, very high. But all of them were out of whack and out of the normal range. And out of that came a diagnosis called common variable immune deficiency. And that is a coherent thing. It basically means you don't make antibodies very well. I have a few B cells. And usually when people have that disease the main thing that they've experienced are a series of chronic infections that they can't fight off very well. Usually respiratory infections, sinus infections, you know, people in great danger with something like COVID because they're not producing antibodies and their immune system isn't working properly to fight those off. I think the strange thing with me is that I actually didn't have any history of that.

>> Diego (narration): Because she didn’t have that history of recurring infections, the diagnosis of common variable immune deficiency, or CVID, didn’t align with her symptoms. Once again, the shoe didn’t fit. But, fortunately something did come from all that testing.

>> Dr. Gage: It did send me off down this immunology path and it's through that that I also had genetic testing found that I have this genetic mutation and it's really the genetic mutation that sent me on to the NIH.

>> Diego (interview): And what do you remember from when you first got here?

>> Dr. Gage: I drove down from New Haven where I live because this was still a moment when, you know, public transportation was not something one was doing because of COVID. This was the fall of 2020, so that was not great to discover that you have, you know, a kind of chronic rare incurable immune deficiency that means you don't respond to vaccines and you're highly susceptible to infection. And then it also meant getting down to the NIH and kind of coordinating all of that in person was difficult. So I drove down on a Sunday and got there Sunday night for an appointment on Monday morning with Dr. Ombrello and his team.

>> Dr. Ombrello: Hi, my name is Michael Ombrello. I'm an Adult and Pediatric Rheumatologist, and I'm the Chief of the Translational Genetics and Genomics Section in the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, or NIAMS.

>> Diego (narration): As a leading expert in rare inflammatory diseases, Dr. Ombrello, received word from Dr. Gage’s doctors at Yale about a patient with a unique genetic mutation they knew he had already been studying.

>> Dr. Ombrello: I first heard about Dr. Gage through her rheumatologist at Yale University, who had reached out to me because in her evaluation of Dr. Gage, she'd done a screening genetic panel to look for genetic variance in immune system genes that might help to explain what she had observed in Dr. Gage. And she had found a variant in the gene PLCG2, which encodes the protein phospholipase C gamma 2, which I happen to know a little bit about and have previously studied in immune dysregulation.

>> Diego (interview): Alright, so once you know a person has mutation in this very specific immune-related gene, what’s the next step? What sorts of questions do you begin to ask?

>> Dr. Ombrello: So, when I meet somebody who's got a mutation in PLC gamma 2, and we think that that mutation may be doing something, I start by asking questions about the immune system, questions about infections. Do they have a history of recurrent viral infections or bacterial infections or fungus infections or weird types of infections, like tuberculosis, or mycobacterial? Because most of the time, people don't come telling you that they have problem X or Y or Z with their immune system, but they know that they had infections.

Then I ask them about inflammatory diseases, whether they have any autoimmune diseases like rheumatoid arthritis or lupus, or whether they have any inflammatory diseases with inflammation inside of their eyes or inside of their lungs or their bowel, because these are frequent things that people with mutations in PLC gamma 2 can manifest. And I talk to them about allergies because about half of people with mutations in PLC gamma 2 have one of a variety of allergic types of characteristics; whether they have eczema, or other types of allergic skin disease, food allergy, whether they have allergy to household dust mites or environmental allergies, or a combination of all of these things. Because an allergy usually involves our immune cells, our white blood cells or our B white blood cells.

And so, we try to characterize the features of the different parts of the immune system to get a feeling for what these patients have. But in the case of Dr. Gage, her mutation was a new class of mutation.

>> Dr. Gage: The mystery with this mutation, as with the CVID diagnosis and surely these things are related to each other in some way, is that you would expect that I would have suffered from pretty serious and chronic infections for much of my life in a way that I didn't. And when I asked Dr. Ombrello, if he would expect to find a lot more of this kind of mutation. Like is it unique or is it just that we've only begun to look for these things and probably there are lots of them in the world? And he said he didn't think that there were lots of them in the world. And I asked why not. And, you know, in essence he said because most people in, you know, kind of earlier generations who had this probably wouldn't have survived very long. They probably wouldn't have survived due to infections. And so the mystery of me is why I just hadn't experienced those infections. But it was also a sign that probably, you know, I might be a one off for a while.

>> Diego (interview): What was that like? To, you know, hear you’re one of a kind, but not in the way you might have hoped?

>> Dr. Gage: It was a funny thing to experience as a patient because on the one hand I have to admit my first response was, "Oh, that's so cool." Wow. The government. NIH is going to be interested in me. And then I thought, "Oh, no. If they're getting the NIH involved, then really no one has any idea what's going on here." And we're in some kind of uncharted territory.

>> Diego (interview): Well, how did Dr. Ombrello explain what your mutation meant and how it manifested in the symptoms you were experiencing?

>> Dr. Gage: He said, first of all, that my mutation was unique. It wasn't something that had ever been seen before. He explained that this was a gene that was important for immune function and that essentially one of the copies of my gene didn't work and didn't work at all. It tried to fire. It tried to do its thing and just nothing happened.

[SOUND OF CAR PUTTERING]

>> Diego (narration): For the bio wonks in the room, Dr. Gage had a truncating mutation.

>> Dr. Ombrello: She had a mutation that caused her cells to stop making protein about halfway through. So, the entire second half of the protein wasn’t expected to be made.

>> Diego (narration): Normally, when this protein, phospholipase C gamma 2, is made in full, it travels to the inside surface of the cell..

[SOUND OF CAR PULLING UP TO GARAGE]

…where it causes a chemical reaction…

[CAR HONKS HORN TWICE]

 …that allows for calcium ions to flow from the outside in.

[SOUND OF GARAGE DOOR OPENING]

>> Dr. Ombrello: And so, PLCG2's job is essential to the generation of that calcium flux.

>> Diego (narration): For the less biochemically inclined, all this means is that the PLCG2 protein is part of the switch…

[SOUND OF CAR IGNITION]

…that works to activate the cells of the immune system.

>> Dr. Ombrello: B white blood cells, which are the ones responsible for making antibodies, require PLCG2 to work at just the right level. And slight increases or slight decreases in either the baseline amount of activation can lead the B cell to go down a different path. Instead of responding the way it's supposed to, it responds pathologically. Sometimes that can be too much of a response, and that can lead to an autoimmune or an allergic disease. Other times it can be too little of a response, and that can lead to an infectious disease predisposition.

>> Diego (narration): And so, to determine how Dr. Gage’s mutation altered the switch mechanism inside her cells, Dr. Ombrello used a technique called flow cytometry.

>> Dr. Ombrello: Flowcytometry is basically where you stimulate a bunch of cells on a plate and then you run them through a tube with a laser that shines on the cells. And if the thing that you're looking for is there, the laser will cause a different color to be released, and you'll recognize that the thing has happened. So, we put in a dye that binds calcium—like I was saying, the PLCG2 turns on the calcium. And so, using this flowcytometry, we can measure in real time, the concentration of calcium in each cell as it passes through the laser and the column. And so, when we put Dr. Gage’s mutation into cells, it actually had no fluxing. Her mutation is not able to turn the cells on.

>> Diego (narration): In B cells that means antibody production against possible infections was jeopardized. But keep in mind, PLCG2 is expressed all throughout the body. Many different types of white blood cells need the switch to work as it should so that they can carry out their specific jobs and maintain the body’s delicate balance.

>> Dr. Ombrello: The tuning of the light switch is cell-type specific. PLCG2's important in monocytes or macrophages, which are kind of the cleaner-upper of cells. They do phagocytose and ingest things. And in the natural killer cells, which are important cells for killing our host cells that are infected with viruses, and in fact, cousin cells of the macrophage cells are in our nervous systems and lay the insulation on our neurons. And people are showing that mutations in PLCG2 that affect those insulation-laying cells, are involved with Alzheimer's Disease.

And so, the number of cells in which PLCG2 is involved, is relatively large. And our knowledge about its specific role in each of these different kinds of cells is relatively limited.

>> Diego (narration): It’s importance in so many aspects of our biology, is the reason Dr. Ombrello has been researching PLCG2 for years, well before even meeting Dr. Gage.

>> Dr. Ombrello: Our story about PLC gamma 2 mutations began a pretty long time ago, 12 or 13 years ago, when we saw patients who had come to the clinical center because they had a bad inflammatory skin condition. But in investigating that group of people with the inflammatory skin condition, we realized that that was the tip of an iceberg. And the iceberg was actually people in the family that got hives when they were exposed to the cold. We call that cold urticaria. And we spent a lot of time studying the genetics of these people and found a very specific type of mutation in PLCG2, that essentially cut out a chunk of the protein, but it did it in a way that allowed the two ends to be put back together and still be viable. So, it essentially removed an important regulatory piece of PLCG2. We found three families who had this, and we called this PLC gamma 2 associated immune dysregulation, or PLAID. And we described these three families in the New England Journal of Medicine. And we set out for over a decade to look for more patients who had the same sort of cold-induced hives.

But as time went on, we identified the second class of mutation of PLC gamma 2, which were the ones that were gain of function mutations. These gain of function mutations led to a condition that at the time, we called A-PLAID, or Autoinflammatory PLAID because the features were very different from the PLAID patients. They had inflammation in their eyes and inflammation in their gastrointestinal tract, and inflammation in their lungs and their skin.

And then we started to find loss of function mutations. People like Dr. Gage, who had 75% of the normal amount of calcium activation, or 50 % of the normal amount of calcium activation and who also had these sorts of inflammatory features. And so, we hypothesize that different mutations lead to different constellations of symptoms.

>> Diego (interview): Well once you started to classify these gain of function vs loss of function mutations, so essentially ones that boosted the effects of PLCG2 and others that suppressed it, how did that change your understanding about the nature of this gene? And how to go about treating immune disorders that stem from it?

>> Dr. Ombrello: Now, that we've come full circle and have recognized that there's also a big group of people, maybe the most common group of people with loss of function mutations and that those people also have autoinflammatory features, we've taken a step back from the way that we originally classified this condition, right? We called the people with cold urticaria—with the cold-induced hives—PLAID. And then we called the people with the gain a function mutations, A-PLAID because they had autoinflammatory features.

But when we recognized that people with loss of function mutations might also have autoinflammation, it then became incorrect to use autoinflammation as a way to label the people with the gain a function mutation. So, the way that we brought all of this together at the end of the most recent paper, was to suggest that maybe the best approach would be to call all of the people who have immune system abnormalities with mutations and PLC gamma 2, PLAID, or PLC gamma 2 associated immune dysregulation, and then we should just specify what the subtype of gain a function or loss of function, or dominant negative cold sensitive.

Because at the end of the day, the reason we really want to classify the mutations is because the mutational effect may specify how we treat it. You would treat gain a function mutation different than a loss of function mutation. Depending on the things that a person is having, then we focus in on those parts of the immune system, and on the potential therapeutics that we can use to try to modulate those. And so, we proposed that we should change the way that we label these conditions as a result of that.

>> Diego: It’s interesting how when you broadened your search for all PLCG2 mutations beyond the ones that produced those cold-induced hives, you started to hear about more and more people suffering from immune abnormalities. So maybe mutations in PLCG2 aren’t that rare?

>> Dr. Ombrello: Well, so, it's not clear if it's actually rare. And that's one of the things that I think the study surrounding the paper has pointed out to us is that when you start to look for patients who have immune system abnormalities with variance in PLC gamma 2, there's a fair number of them. And so, this introduces the next level question. Now that we know that there's people with decreased function or increased function who have immune defects, how can we know when we see a mutation that's never been reported or that we've never identified, whether that's a relevant mutation? Today, the way that we do that is to create the mutation and put it in a cell and run a series of experiments and this takes time and money and effort. And in terms of clinically characterizing the mutations, that's really challenging. And that's, for PLCG2, that's the place where I'm stuck right now. If you have a disease or a set of mutations that are causing something, you have to come up with a way that you can test on a plate whether you can affect that thing happening, right? And so, of course I'm talking about our colleagues at the NCATS who have a large library of different pharmaceutical agents that are available for testing.

So, we're at a point when we really are seeking a way that we can, in a more high throughput manner, interrogate these mutations of PLC gamma 2 to try to make a clinically relevant assay, as opposed to a more research-based assay with a longer timeline.

>> Diego (narration): The story of Dr. Gage and PLCG2 reflects one of the harsher truths about nature and biology. From a human-centric perspective, mutations might seem like nature’s reckless experiment—as if it were moving the levers and dials that control our genes to test the boundaries for what is possible. Almost as if it were saying, “What happens if I crank this up? What if I turn it off? Or change it altogether?” All with no regard for the impact on a person’s health and quality of life.

But of course, we know, there’s no ulterior motive behind genetic mutations. Sometimes the change is silent and goes unnoticed. Sometimes its effects ripple throughout the body. And other times, it takes a chance encounter for the dominos to fall.

If Dr. Gage hadn’t grazed up against that plant during her swim, would she ever have developed any symptoms? Would the effects of her PLGC2 mutation ever surfaced? It’s hard not to wonder the “what ifs,” but it’s important not to dwell on them.

They’re only worth entertaining to appreciate the complexity and fragility of our inner workings and their interactions with the forces around us. With researchers like Dr. Ombrello at the helm, science is getting closer and closer to untangling the connections that govern human health. But progress is slow and having only pieces of the puzzle brings mixed emotions to those living with understudied diseases. For Dr. Gage, there was a sense of relief in learning what gene was responsible for her illness, but she still had to contend with the reality that there’s currently no concrete treatment or cure.

>> Dr. Gage: It was helpful in the sense that it was more information. And did give some explanation for why all of these systems seemed to be misfiring. It was also helpful to me because I—my first instinct and I think for a lot of people this is probably true was to blame myself, to think about things that I had done to cause this somehow. And so learning that there was a genetic basis I thought, oh okay, well I really didn't cause that. Right? Even though obviously, you know, genes interact with environment and behavior and all sorts of things to express or not. So, that was a relief in some sense. I would say the frustration was that it didn't really make a lot of difference in terms of the treatment. It pointed us in certain directions. We did some treatments that we hoped might work kind of based on this knowledge, but actually nothing proved to be effective. So that I think has just been sort of a situation of uncertainty, a certain kind of fragility, you know, facing of one's mortality.

And I think that that in many ways was what I wanted to get at in the "New Yorker" article was that we're just at a very particular moment in history it seems to me in which our knowledge has expanded so rapidly, so dramatically, particularly you know in the world of genetics and genetic research, and yet what any of it means, whether it's going to lead to useful treatments is more much ambiguous.

>> Dr. Ombrello: In these kind of situations, learning the gene is the beginning of the research process. And that's the frustration for the patient because when you have a research process, from identifying new gene with a link to disease, you know, 20 years is a pretty reasonable time to go from diseased gene discovery to disease specific treatment.

And so, I appreciate the fact that when patients are finding out that they or their family members have these mutations, they're reaching out to us and they're wanting to come participate. And I recognize on one hand, they're wanting to come get the best possible care, or take advantage of any cutting edge therapies that we may be thinking about, but at the same time, I'm very honest with them about where we stand in terms of treatment, and that maybe the treatments that I have to offer them are much the same as what their home allergist, immunologist, or rheumatologist might have. But people who have these variants, I think they see the writing on the wall, and they recognize that there are more of these than were previously noted.

[PENSIVE MUSIC FADES IN]

In the end, that's the most common answer that I hear, is even if we're not going to be able to find something that's specifically going to improve my case, or help my child, we want to help people in the future who may have this.

>> Diego (narration): While patients and researchers fight hand-in-hand for the future, there’s at least some solace in the now, knowing that rare doesn’t have mean alone.

>> Dr. Gage: One of the nice things about publishing something about this is that lots of other people have reached out and said not "I have what you have," but "I have my own weird rare hard to diagnose condition and I can sympathize." And that the article gave them some language, some perspective, some sense that we're not alone in this experience.