Abby: From the campus of Harvard Medical School, this is Think Research, a podcast devoted to the stories behind clinical research. I'm Oby.
Brendan: And I'm Brendan. And we are your hosts. Think Research is brought to you by Harvard Catalyst, Harvard University's Clinical and Translational Science Center.
Oby: And by NCATS, the National Center for Advancing Translational Sciences.
Brendan: As a clinical fellow in 2008, Dr. David Sykes met a patient presenting a strange constellation of symptoms that had gone undiagnosed. After years in clinical research, drug therapy, and biotech, Dr. Sykes has discovered a disease called TEMPI syndrome. And worked with patients around the world to improve treatment and quality of life. David Sykes is an assistant professor of Medicine at Harvard Medical School and a hematologist at Massachusetts General Hospital. Dr. Sykes, thank you for joining us and welcome to Think Research.
David Sykes: Thank you.
Brendan: You run a lab and your lab is focused on developing new treatments for patients with blood disorders. And that encompasses a wide array of diseases. Can you describe some of the research you lab is doing?
David Sykes: Absolutely I think most of my post-doctoral work was focused on the disease acute myeloid leukemia. And that's a disease where the development of your blood cells goes awry, and those cells that are normally supposed to mature, don't mature into their normal neutrophils or macrophages. And your blood is really a remarkable organ, which means that you're making hundreds of millions of new cells every day. And so understanding how that developmental process works, then understanding how that goes wrong in the setting of leukemia, is really a focus. And then beyond that, we've also looked at the normal development of particular cells called neutrophils with the idea of trying to understand better how neutrophils are made-- really with the ultimate goal of developing neutrophil transfusions some time off in the future.
Brendan: OK. So neutrophil transfusion-- what is that?
David Sykes: Boy, that's something that has been on the want list for decades now. But we're very capable of transfusing red blood cells for people who have anemia, low red blood cell counts. And of course we're capable of transfusing platelets if you have too few platelets and you're bleeding. But transfusing white blood cells has just been a much more difficult challenge. So decades of clinical trials have really struggled to show a real clear benefit for those. And so we're trying to take a step back, and instead of using the mature neutrophils, actually develop a system of transfusing neutrophil progenitors in the people that don't have enough neutrophils and are usually suffering from bad infections.
Brendan: OK. And so white blood cells are the cells that fight infection. And so being able to infuse those into people who lack them, what would the benefit be?
David Sykes: That's a good question. I think we think a lot about patients that might be immunocompromised or immunosuppressed. And usually those are patients that maybe don't have enough T cells. The classic is AIDS, so HIV infection, you don't have enough T cells and you're very sensitive to particular infections. But we sometimes forget about patients with neutropenia. So if you don't have enough neutrophils, you're neutropenic. And it turns out those patients are actually among the most heavily immune suppressed. And if you don't have enough neutrophils for a week or for two weeks, you're at a very high risk of lethal bacterial or fungal infections. And so the ability to support people during a period of neutropenia or neutrophil dysfunction would really be a holy grail of transfusion medicine. But actually getting neutrophils from one donor and into another donor, is just a very non-trivial type of approach. They have a very short half life, and the numbers that are required make it just technically, very challenging.
Brendan: You also discovered a disease called TEMPI syndrome. And I want to get into the story about that. Because when we spoke previously, I thought it was a really interesting story and a microcosm or an illustration of the kind of translational, or a pathway in translational, medicine. But kind of unusual too. So first, could you just tell us what is TEMPI syndrome?
David Sykes: TEMPI syndrome has been sort of a labor of love for the last decade or so. And TEMPI syndrome at its heart, now affects, we think 26 people worldwide. So it's a ultra rare disease. And it's an acronym, which we named after the salient features. The T stands for Telangiectasias, which are these unusual vascular malformations on the skin. The E stands for Erythrocytosis, and elevated erythropoietin, where patients make too much of the hormone erythropoietin, which drives red blood cell production. The M stands for Monoclonal gammopathy, which is the very common expansion of a monoclonal antibody in the patient plasma. The P for Perinephric fluid, where patients-- not all of them, but most of them, get unusual fluid surrounding their kidneys. And then the I is really the most debilitating. That's Intrapulmonary shunting, where patients-- the blood actually bypasses their lungs and doesn't get oxygenated, so their oxygen levels fall.
And this was a story that, really that borne out of curiosity. And we met a gentleman back in 2008 at the Massachusetts General Hospital with an undiagnosed medical condition. And I think just kind of stubbornly thought that we could try to diagnose, where other people have not been able to diagnose his medical condition. And here at the Massachusetts General Hospital, they have a really nice collaboration with the New England Journal of Medicine, where very unusual cases or patients with undiagnosed cases can actually have their case written up and presented to an expert audience. And we were able to do that in what's called the case records of the MGH.
And I think what was really fun about that, was at the end of the case report, it's still concluded with this is that a patient with an undiagnosed medical condition, but quite an interesting one. At the end of the case report, we convinced the editors to sneak in a little sentence that just said, if anyone else around the world has seen the case such similar as this, please contact me. And of course, the readership of the New England Journal of Medicine is such, that within a week of that publication we got two emails. One from a researcher in Belgium, and one from a physician in Los Angeles, that they had patients that were almost identical to the patient we saw. So it really started spurring some excitement around the fact that, hey, this was ultra rare, obviously. But that this was something that was probably not just a one off, but actually of more of a syndrome.
Brendan: Right. So tell us a little bit more about that first patient that you saw. You said that they had been struggling to find a diagnosis for some time. And how did they come to you?
David Sykes: Well it's always such a small world. This was a patient who lived in Memphis. But had already been seeking opinions at the Mayo Clinic and seeking opinions of New York City. And had, in this case, a cousin who knew my mentor at the time, Dr. Eyal Attar. I was a fellow at the time. Dr. Attar who's since gone off to industry, was working at the MGH and he was mentoring me as a fellow. And so we just saw him as a new patient in clinic one day. Went through-- I can still remember the stack of hundreds of pages of medical records of all the stuff he had done. And then we ended up admitting him to the hospital and trying to spend a couple of days, basically inviting a whole team of nephrologists, and a whole team of Internal Medicine doctors, and putting our heads together to try to think that through.
Brendan: And you talked about the case report in the New England Journal of Medicine. And convincing the editor to tack that little note on the end. Was that an unusual kind of thing to add into a case report?
David Sykes: It was. I think the case reports usually focus on cool diagnoses and the ability to come to a diagnosis. And oftentimes they're presented to someone who doesn't know the case, but who needs to, on the spot, come up with a diagnosis. Those are called the unknown cases. And then the other majority are focused on management, like how do you manage a complicated case. But quite rarely do they publish cases without an answer. It's very unsatisfying for the reader to come to the end and not have an answer. But one of the pathologists at the Mass General, Nancy Lee Harris, who's quite a famous pathologist and who was running the case records at the time, thought this was interesting enough. And it stumped enough people at multiple different institutions that she thought would be interesting to put this in. And then sort of at the last minute, I wanted to be sure we use the power of social media. Or in this case, the power of the readership of the New England Journal of Medicine, at least to put in that crowd-sourcing approach to diagnosis.
Brendan: So you ended up getting a couple of emails. And one was about a patient in Belgium. Can you tell us about that patient?
David Sykes: Yeah. So my colleague and now very good friend, Wilfred Tryon in Antwerp, Belgium. He had written this very impassioned email, just talking about how he also had a patient that he'd been caring for for more than a decade, with exactly the same constellation of symptoms. They're just too weird-- these five TEMPI symptoms are just too weird. It could not have been a coincidence. And unfortunately, his patient at the time was doing quite poorly from the breathing standpoint. The intrapulmonary shunting, the I of TEMPI, had led to the point where she would require 24 hour oxygen. And so I think there was both this kind of excitement around the fact that this wasn't an isolated case. And then a little bit of pressure to think of, how could we think of approaching this from a treatment standpoint to try to bring some relief to this patient.
And so along with Casey O'Connell, who was the doctor out in Los Angeles, we combed the medical literature and found three additional cases that had been published. Again as these undiagnosed cases in the medical literature. And then put together a very small case series of the six patients, the three living patients, and the three described patients in the literature. And decided that this had to be a new syndrome. So that was the first formal description of the TEMPI syndrome. Again, that was just published as a letter to the editor in a very small article. Just suggesting that something was really common to all these patients. And really what we focused on at that point, was the fact that they all had the M-- the Monoclonal gammopathy. And statistically speaking, that was just astronomically small, that six patients should all have a monoclonal gammopathy. And so that's what led us to focus on that.
Brendan: So you mentioned after the patient in Belgium who required 24 hour oxygen, that you started thinking about treatment. Was it finding the monoclonal gammopathy-- was that the thing that you started focusing the treatment plan on?
David Sykes: That's right. The medical teaching is that these monoclonal gammopathies are very common, which is true. Even more than 5% of people over the age of 65 have it. So there's millions of people with monoclonal gammopathies. And they're never felt to cause anything. That abnormal antibody is felt to be an innocent bystander. And that's been the medical teaching. But also, what we realize is, we had six patients within their 40s, 50s both alive and in the literature. Probably, there would only be a 1% chance that they should randomly have a monoclonal gammopathy. So the fact that you had six patients, 1% times 1% times 1%, just made it astronomically unlikely that that wasn't somehow involved in the case.
And so what we did was, we took a page from the cancer literature. Multiple myeloma is also a disease where those patients make abnormal antibody cell. And this is abnormal plasma cell production. And so we had to convince both ourselves, and the patient, and the insurance companies, that we wanted to treat these patients with myeloma therapy, even though they didn't have multiple myeloma. To try to kill off their plasma cells and to try to eradicate this monoclonal gammopathy.
Brendan: So tell us more about the early treatment attempts. And you mentioned your patient in Memphis who's still alive, I take it, and is doing well. How were those early attempts? And maybe talk about convincing somebody to take a drug that isn't approved for this, for a disease that didn't exist until they met you, really.
David Sykes: That's such an important question. Which is, here you've got three patients and three different, well, two different countries and three different locations. And now you've told them that they're not alone in the world, which I think they were immediately happy to hear about. That was just a fundamentally-- I think reassuring. And then honestly, I think this was just a good example of involving the patient in the treatment process. Which is, we don't know what you have, but we want to help you. And what can we do that doesn't seem too crazy that really has some potential to work?
And I think, one, we were blessed with very nice, just wonderfully thoughtful patients who understood the dilemma there. Both a diagnostic and a therapeutic dilemma, where you don't want to make anybody worse, but at the same time, you don't want people to go untreated. And then we were really fortunate. That first patient in Belguim-- we decided to move forward with a medication called bortezomib, which is a classic medication for multiple myeloma. And what was just amazing, was that she had a dramatic response to even first couple of doses of bortezomib. Which was really, I think in a sense, if she hadn't had that response this whole story would be very different. But she had a dramatic response. And within months had actually-- I mean, it seems crazy, but had had come off 24 hour oxygen and was back to riding her bicycle. It was just transformative at that point.
And then that really gave us the impetus to be like, wow, we seem to be on to something, and treated the other two patients. And of course that was a special case, because the patient that I had met, he didn't respond very well to bortezomib. So if he had been the first person, I think we'd have a different-- Though he then subsequently responded to another plasma cell directed therapy quite recently-- daratumumab, another myeloma drug. Just approved. Actually approved even after the time where we described the syndrome. That's just a lucky chance of the FDA approving a new drug for a different disease.
And then, same thing. He had tanks of oxygen in his work that he just sent back to the company. And he's been off in a clinical remission now for the last two years.
Brendan: Yeah. That's so interesting that if you had tried to treat your one patient, if you tried to treat the patient who-- tried to treat him first, maybe things might have gone differently. Do you think about that? Like would you have said, this isn't the right path or-- because that was your only option at that point.
David Sykes: This is it. I mean, this story has so much serendipity and just good luck in a sense. And that's right. Because when you're doing something that's not just a little outside the box, but way outside the box, you do want to be very thoughtful about it, and very careful that you don't hurt anybody. And then, I think this always falls into what I like to call-- this is not my word, but people call it a therapeutic challenge. Which means, let's try to make your diagnosis by seeing if you respond to a certain therapy. So this was clearly, huh, is that MGUS really involved? And if we take it away, if we eradicate it using this bortezomib or daratumumab, do the symptoms get better?
And in this case, we were just super lucky. They totally got better. Confirmed that this was a reversible disorder, that the damage was not permanent. Confirmed that this was not a congenital problem. This was something that had developed and could be then reversed or eradicated. And so that therapeutic challenge to make the diagnosis, became very satisfying. But also, full disclosure of course, very lucky for sure.
Brendan: So since then, you continue to treat patients-- I mean, there's only 26 patients that we know of worldwide. So tell us a little bit about the TEMPI syndrome community, and how you're involved, and what the ongoing work is like.
David Sykes: That's so true. It's almost funny to call it a community. It is such a tiny community. But now I think, and this is the last 20 years with, let's face it, with the advent of Google, and the advent of really a lot of online resources. This has been a perfect time to find an ultra rare disease. And so we, of course, put up a Wikipedia page. That's the first thing one should always do. But all kidding aside, it's interesting because once you get a bit of a web presence-- both on the rare disease networks and Wikipedia, now if patients just type in this-- sorry, if doctors or patients. But just type in the symptoms of the TEMPI syndrome. Actually, TEMPI syndrome comes up as a search. So we actually come up high on the list. And so about two times a year, three times a year, we'll get phone calls from someone who's typed in literally, telangiectasias, erythropoietin, or something. And then all of a sudden that comes right up. And it really has been a good advertisement.
And then we've also tried to be very prolific about publishing. Just even tiny little publications that then go on to Pub Med as basically little advertisement. Because every time we do that, another patient or two comes out of the woodwork. So just this last year in 2020, we had a small review article, and actually it was the TEMPI syndrome is now recognized by the World Health Organization. And it's in the coding system. So now it actually becomes billable and you can code for it. So it has become ultra rare, but now it's actually real, just because now it's in all the databases. And we hope that of course, we'll find-- well, we don't want anybody to have the TEMPI syndrome, but at least like to hope to find everybody, so that one can make a concerted research effort to try to really figure out what's going on.
Brendan: I wanted to ask you-- you talked about how it's not congenital, so it's something that develops and is reversible. Do you know, or do you have any thoughts about why or how it develops?
David Sykes: It's such a good question. We think it's bad luck. So if you have literally 5% of your population over the age of 65 that has one of these MGUS's, and if it's a 1 in 100 million chance that the MGUS can actually do something bad and cause the TEMPI syndrome, it might just be bad luck. At the same time, the patients are a little younger than you'd expect. And so one of the hypotheses has been that, it's a response to an unknown infection, that then leads to what looks like almost an autoimmune disease. This antibody is tickling something inside the patient's own body to cause these other symptoms. But how does an antibody cause high erythropoietin? We don't know. How does an antibody cause telangiectasias, cause perinephric fluid? We really don't know.
So that's been the focus of the laboratory research, which is, what is the link between an antibody that you didn't have when you were born. That you developed somewhere in your third or fourth or fifth decade. And it's now wreaking havoc, but if you get rid of the antibody, you can just reverse all those things. But that link is totally not understood and certainly one of the focuses of my lab.
Brendan: Yeah. And the intrapulmonary shunting. And it just seems so strange to me that the whole pulmonary, cardiopulmonary system, is to get blood through the lungs, and oxygenate, and get the carbon dioxide out. And then exhale, respirate. So how does the blood miss the lungs? That's what I want to know.
David Sykes: It is a fascinating thing. So any one of us typically has 1% of the blood that bypasses the lungs. That's actually blood that's supposed to feed the lung. And so it doesn't go through the gas exchange process. But you are supposed to oxygenate literally 99% of your blood every time it pumps around the body. And so we think-- but all hypothesis now, we think that the abnormal blood vessel production that leads to the telangiectasias in the skin, also leads to basically, we think telangiectasias in the lung. Where those are now abnormal blood vessels. And the patients that have had the worst intrapulmonary shunting have been up in the 25% range.
So 25% of the blood just goes right by and doesn't get oxygenated. And that's an astronomically high number, which, people just don't see. When we did the scans, we didn't even believe because they were so high. And typically only seen in kids with congenital heart disease. But this is a microscopic intrapulmonary shunting. What's ridiculous, was to watch those numbers get better on treatment, to go from 25% 18% to 12%, and then to normalize. But yeah, very striking how-- yeah, you definitely need your blood, all of your blood to be oxygenated as it goes by the lungs every time.
Brendan: Yeah. At least 99% of it.
David Sykes: At least 99%.
Brendan: Yeah. So what was it like that your patient in Belgium, who you started to see this sounds like pretty rapid improvement-- then she's able to get off oxygen, she's able to ride a bike. What is that like to see when you're in the dark for so long, and then somebody turns on the light?
Brendan: I think obviously we were, I mean, there's no question we were ridiculously excited. Just because as a doctor, one, you definitely just want to make people better. So even if you don't quite know why they're getting better, it's so satisfying. And then two, I think we were so worried that we were going to do something bad, that we were extremely relieved that we had not only not hurt her at all, but actually really led to such a dramatic improvement. And then she's just really a remarkable lady. Has been such a kind of a good advocate for trusting your physician and being part of the decision-making process. And she's involved in music therapy for children who are developmentally delayed.
So really such a very sweet, thoughtful, and artistic woman who was really-- I think she understands the dilemma we were in. Understood the uncertainty, but also embraced it as a chance to-- you've got a couple of handful of people now around the world, and we're kind of all in this together. Now let's try to learn something. And I think we've asked a lot of our patients, research samples, thinking, and making sure that they are part of that process. And really the patients have just been wonderful in terms of participating in that uncertainty. And the older I get in my medical experience, the easier I find it, the ability to say I don't know. And I think that's really important for a patient to realize, that maybe you don't know but you're going to try to work with them to figure it out.
Brendan: Great. Is there anything else you've learned from this process, from your work on TEMPI syndrome? And anything about translational medicine or how you approach the lab work you do, or the other work that you're involved in.
David Sykes: Yeah. I mean to wax a little poetic on this. I mean, I think this is an important example of just having curiosity driven research. And I'm not sure one can always do that, because time is busy, and certainly not every patient develops a new syndrome that's not been described before. And at the same time, I think we're surrounded every day with the realization that patients and their diseases can teach us something. We certainly don't know everything there is to know. There's a lot of biology still to be learned. And then that's coupled with the practical issues, which is there's no TEMPI granting agency. All of this research has been done by just gifts from the Department and the Massachusetts General Hospital has been very supportive. Wilfred's hospital has been very supportive.
But how do you study a disease that only affects 26 people, or try to convince someone that it's important? Though you could also then imagine, if you could understand how an antibody could cause all these symptoms, that's a whole area of biology that we don't know about. And maybe then that applies to other areas of biology. Or maybe that applies to some things we didn't expect. So I try to keep-- with my fellows, and medical students, and trainees, try to keep that curiosity and excitement always open. Not that everybody needs to figure out a new syndrome, but just to keep an open mind, and to realize that not everybody quite fits into the predefined boxes that we need to put them in on a day to day basis, just to kind of get through the day.
Brendan: Yeah. That's interesting about the basic science aspect of, if you figure out this antibody thing, who knows what else it could lead to.
David Sykes: And I think that's really the key, which is, yes, some people would say, why would you bother researching a disease that's so rare? But that's not the point. The is you have uncovered, because of its rarity, a whole new area of biology that was previously not even considered. Now-- again these are hypotheses, but the fact that now you have patients and their response, really puts you in the position of a testable hypothesis. And I think that's what I'm most excited about. That's the whole goal of a scientist, right. Is the nerdy scientist, I don't want to just do stuff other people have done. I want to learn new biology. And then when to be cool. If it wasn't just new biology, but it was actually new biology that could actually help somebody, that would be even more cool.
Brendan: Well Dr. Sykes, thank you so much. We really enjoyed having this conversation with you.
David Sykes: Thank you very much Brendan.
Brendan: Thank you for listening. If you've enjoyed this podcast, please rate us on iTunes and help us spread the word about the amazing research taking place across the Harvard community.
Oby: To learn more about the guest on this episode, visit our website, catalyst.harvard.edu/thinkresearch.