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Oby Uradike: From the campus of Harvard Medical School, this is Think Research, a podcast devoted to the stories behind clinical research. I'm Oby.

Brendan Keegan: 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 Uradike: And by NCATS, the National Center for Advancing Translational Sciences.

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Brendan Keegan: In immunology, the research is often computational as scientists strive to understand healthy versus unhealthy viruses, and how they impact the microbiome. As this work expands into opportunities for therapeutics and real benefits for patients, Doctor Kate Jeffrey is using her recent Harvard Catalyst pilot grant to expand her field. Kate Jeffrey is an associate professor of Medicine at Harvard Medical School and an immunologist and epigeneticist at Massachusetts General Hospital.

Speaker 3: So Kate, do you want to give a small introduction of yourself?

Kate Jeffrey: Yep, hello, my name is Kate Jeffrey. I am an associate professor of Medicine at Harvard Medical School. And my lab is based at Massachusetts General Hospital. I'm an immunologist and epigeneticist.

The overarching goal of the lab is really to understand human immune diseases better. And that in two flavors of how our environment influences these diseases, because we know it's not all genetics. And it also, you have that environment integrates into our epigenome and how that altered epigenome changes the behavior of ourselves. And so one aspect of the environmental component is something that we call the virome, which are viruses that exist within our gut. And how they may shape our immune system and contribute to disease.

Speaker 3: OK, great, so I know you applied for the microbiome opportunity that we had, I think was launched about three years ago now with this symposium, and so one of my first questions is, why did you apply? What was it about the opportunity that gave you that impetus or decision to say, OK, I'm going to apply for this.

Kate Jeffrey: Yeah, so I had, we had just embarked on the virome work, which was a fairly relatively new frontier for my lab. I had arranged access to clinical samples at MGH to look at the virome in patients and actually, at that time was when this pilot announcement, I saw the announcement. And actually, it was just almost perfect timing for us, because we just started. We just were accumulating preliminary data. And just to get that pilot grant, really before we had any other major funding towards this project, I mean, it was just perfect timing.

And so I applied and then went through the rigorous process of this presentation and Q&A and everything, and that was great. And I think, obviously, it was the call for microbiome, which most people work on the bacteria. But we had this new angle of the viruses that are part of that community and the rest is history.

Speaker 3: Yeah so--

Kate Jeffrey: We got it.

Speaker 3: Yeah, which is great, and in terms of the award, do you think that it helped you because this was a new area in which you were doing research, it wasn't necessarily, what your core focus was, Did you see it as a proof of concept grant?

Kate Jeffrey: Yeah, definitely, so all of my NIH funding at the time, was epigenetics and immunology. And so this was just to some funding for us to get the project properly I would say. Because I mean, to put things into context, you have people in your lab. But you actually need to find funds to pay these people in your lab. And so this really enabled my postdoc to have defined time towards this project.

And it also served a purpose for us to essentially define our project. Because what I really liked about the process was us constantly saying, well, what are our aims? What are we plan to do? And we constantly met as a group, and you continually refining the project. And I have to say as an academic, we all have great ideas. But I do think that project management is something that every academic could improve on. And I have to say, one really positive outcome from this was just achieving realistic goals in a realistic time frame.

What are we trying to achieve? And actually really truncating that down so it is achievable in that time frame. And I felt like that was a really positive experience for us.

Speaker 3: Oh, that's great that's great to hear. Because that's definitely something we strive towards in whatever small incremental fashion that we--

Kate Jeffrey: Yeah, I mean, think about-- think about an NIH grant. I mean, you write an annual progress report. That's basically it, right? And so actually, I found this process really refreshing. Because I think that it is good to be just reporting frequently and constantly thinking about where you are in the stage of what you proposed and what you need to do to achieve that. So yeah.

Speaker 3: Yeah. Yeah. Is it something that you've tried to apply to other projects as well?

[laughter]

Kate Jeffrey: Yes, all of a sudden, every project in my lab is perfectly managed in a timely manner. [laughs] No, but it is something that you think about. And I think that yes, I have tried to implement more definitive timelines on projects as a result.

And it doesn't need to be a huge achievement just by saying, I want this part of this project achieved by this date. I think it's definitely changed my way of thinking.

Speaker 3: Oh, that's great. That's great. You know, you kind of touched on it, but it was a new area for you to research. And what do you think is the importance of studying the virome?

Kate Jeffrey: Yeah, so-- well, there's two parts. I mean, I think we've all been obsessed with one virus over the last year and a half. And this concept that viruses are pathogens is quite clear with the outcome of the COVID pandemic or the SARS-CoV-2 Pandemic.

But this idea that viruses actually exist amongst us and many of them don't cause any pathology is a fascinating concept, right? Because it's almost like that goes against this idea that all viruses are pathogens and all out to hurt us. And not only are they not hurting us in the gut, there's this idea that many of them have just evolved with us for so long that our immune system and these viruses are just in a homeostasis relationship and actually can't survive, one without the other.

And so that, for me, is a conceptual thing about-- a conceptual aspect of the work. It's really interesting. But the other more tangible aspect is that we've started to identify viruses that are actually only in patients with inflammatory bowel disease.

And so now, you start to think about, OK, well, we can vaccinate against pathogenic viruses like SARS-CoV-2. What about trying to vaccinate against more chronic damaging viruses in IBD? And conversely, what about trying to replace that healthy virome in an inflammatory bowel disease patient for benefit?

So that's sort of the two main things that I get excited about-- is just that fundamental understanding of, what are viruses? We just think of them as these biological entities that need us to replicate. But they're not always damaging, and we actually have some beneficial relationships with them. And then, the converse-- can we find some causative viruses of these chronic immune disorders like inflammatory bowel disease?

Speaker 3: You know, you're talking about the environment in IBD and colitis and all those types of diseases. So what did you find?

Kate Jeffrey: So the crux of our findings was-- you know, I'm an immunologist, right? So I care about how these viruses educate our immune system in good and bad ways. Now, the virome has exploded in popularity in the last few years, but that explosion has been by sequencing.

And people are just sequencing all different tissues and all sorts of diseases and telling us, oh, yeah, there's changes in viruses in type 1 diabetes, in graft versus host disease, in patients with HIV. The list goes on. Many, many diseases have been looked at, including inflammatory bowel disease.

But I took a step back and was kind of like, yeah, but we-- it's all correlative. Like, we don't know what these viruses are doing to our immune system. And so we just took the reductionist approach as, OK, well, why don't we just figure out, is our immune system seeing these viruses in health? And is that a beneficial thing?

And when the virome changes in disease, is that actually contributing to disease? And so we took the immunological approach, where we isolated viruses, collected viruses, put them on immune cells, and just asked, what do these viruses do to immune cells?

And it turned out that viruses from a healthy gut actually amazingly triggered this very protective anti-inflammatory sort of program in innate immune cells. And conversely, viruses isolated from an inflamed inflammatory bowel disease gut very much provoked inflammation.

And that was the first evidence that these viruses can autonomously do something outside of the bacteria that they exist amongst. And secondly, that you can actually start to manipulate the immune system in good ways and bad ways with these viruses in the gut.

Speaker 3: So in my view, I think your project was successful pretty successful-- very successful, I think. And--

Kate Jeffrey: Yeah. we're still waiting on reviews. I just wrote to the editor now, but--

Speaker 3: Yeah. And you know, and relatively speaking, $50,000 isn't that much money. Yet, you were able to use every-- I don't want to say penny, but every cent of it, in a productive way. And so how do you think you managed that?

Kate Jeffrey: Yeah, so $50,000 is not it a lot of money, unfortunately. Paying salaries of postdocs and reagents and things, you know, it costs a lot of money. I think on average, now, it's suggested that every paper in publication in a top-tier journal costs about $1 million in funding to get done.

But this $50,000 was very valuable, because it enabled me to designate time, or part of the time of my postdoc, towards this project so I could designate that funds towards her salary. But it also enabled us to get the processing of these clinical samples done, and that was the defined part. We had this relationship formed with the colorectal surgeon at MGH, and this enabled us to just extract those viruses from those colon resections, and then start to do these experiments.

And then, other money started to trickle in. So you know, and as you just get those initial findings, then we go to an R21 NIH grant, and then some other funding. So I think 50 grand in isolation, there's no way we could have done this project.

But I think that it got things kick-started, because as I say, I could devote specific time of my postdoc to this aspect, and it enabled us to just sort of get extracting of these viruses from the colon resections.

Speaker 3: Yeah. Yeah, exactly sort of how we would want it to work. You got this small amount of money for a proof of concept, relatively high-risk project, let's say, because it's not sort of considered something that's in your field, necessarily. Yet, just by getting it and being able to devote the time to it, it's helped with pushing it on. And--

Kate Jeffrey: Yeah, definitely. I think it's also just a good thing to say that once you have money on something, the project becomes real.

Speaker 3: Yeah. Yeah.

Kate Jeffrey: Every scientist has a million ideas. And actually, my postdoc advisor once said something that was very profound, and that was, it's always easy to start a project. And that always stuck with me.

And I think, going back to the project management and all of those ideas, I think scientists have no shortage of ideas. I think it's just executing those ideas. And you need the funds to really be able to just make that project real and get it going.

Speaker 3: Yeah.

Kate Jeffrey: And then, ultimately finishing that project, getting it published, and yeah.

Speaker 3: I mean, where do you think you are now, and how do you think the future of this research is going to go?

Kate Jeffrey: Yeah, so it's interesting. I was a nobody in this field, like, four years ago. Like, who is this person? And I'm almost now considered, like, one of the major virome players. Like, it's kind of funny.

Initially, it was just an interest, and I thought, well, people aren't looking at the immune responses to this. So where is it going? I think that we're going to move beyond correlative aspects of the virome, and then now trying to implement this. Is this a real therapeutic window here?

Can we vaccinate? Can we inhibit some of these damaging viruses? Can we use healthy viruses akin to a healthy microbiome, and start transferring healthy viruses to a patient?

So I think that's going to be the next stage. We've gone beyond sequencing, beyond computational analysis, learning from the microbiome field of the last 20-odd years of research, and just getting beyond those correlations and asking those direct questions about, what are these viruses doing and how can we leverage this for the benefit for these patients.

Speaker 3: So I mean, you touched on it already about the project management piece, but there was also the part that when we get people in the same cohort together every four months or so to present to Capitalist Leadership, how-- did that help?

Kate Jeffrey: Yeah. Look, I'm a huge proponent of the-- more feedback one can get on any project before it's submitted for funding or submitted to publication, and more feedback on-- everyone's got their different strengths and weaknesses, right? And if you are the only one that's looking at your project and data the entire time, I do think that's a problem.

And some departments are better than others of mitigating that, right? So departments will have work in progress, and you've got more eyes on the data and the story. But I think that this forum definitely helped our project, because there was often-- you know, people are coming from a completely different point of view, and they would suggest something that-- oh, gosh, I didn't even think about that, or-- because I don't think about that generally. So I think any presentation to peers and colleagues is always beneficial for science.

Speaker 3: I have been asking this question to the other people I've interviewed, just because I recently finished reading this book, called Range, by David Epstein. And it sort of-- he basically compares the Tiger Woods of the world with the Roger Federers. You know, Tiger Woods was playing golf since he was a baby, and Roger Federer had played all these sports and came to tennis relatively late.

But Roger Federer was still able to get to the top of his game, because he had all this other experience playing those other sports. And one of the things that he mentions in the book as well is that there are those people who are the specialists, and there are all the people who are the generalists.

All the generalists, because they've come from a different background and they've done lots of different things before they've fallen upon their area of expertise-- that they are now able to use that diverse background and apply it to what they're doing in their particular career focus. I mean, what do you think about that?

Kate Jeffrey: From a scientist's perspective?

Speaker 3: Yeah, yeah, from your perspective, personal or scientist, you know. Yeah.

Kate Jeffrey: Look, I think, for any profession or particularly science, I think a well-rounded skill set and personality goes far. I think that everyone in science is smart, right? And some people thought they were going to do it from birth.

Others-- I didn't know. I mean, I was always really good at math and science at school, but I also liked art. So for me, it was a bit later. And it was more the research component that got me excited, actually.

But I would say, as a principal investigator, your success is so much more than the ability to do science. Actually, your job-- it's like that saying of, you get promoted to incompetence, where you're-- you know, many scientists are really good at science, and then they get a group to lead, and they don't know how to communicate, and they don't know how to manage, and they don't actually know how to write particularly well, and they don't know how to give good presentations.

And actually, those four things that I just mentioned are almost the crux of the success in the science career, in addition to the science. So the ability to communicate, the ability to manage the people, the ability to write-- like, it's just like a huge part of an ability to, I guess, be a good boss and mentor. Like, that's a sort of-- that's a huge aspect.

I mean, you hear all these horror stories about great scientists but awful mentors, right? And that's just unfortunate. Because I think that's people that have just been so narrowly exposed to things throughout their life. And I don't know, I feel like the--

I've always been really good at the bench work and the science work, and all that sort of stuff. But I feel like when I came into the next sort of foray, I felt like my world experiences and my life experiences of moving from Australia to the US and always traveling a lot and being independent and all these things have helped me with my science. So I'm certainly a specialist, but I'm a bit more of a generalist in my other skill set, I would say.

Speaker 3: Yeah, what kind of background do you have?

Kate Jeffrey: So I grew up in Australia, went to Melbourne University. And there, I was doing-- yeah, so Australia is not like the American college system, as you appreciate. You actually do a Bachelor of-- you know.

So I started doing a Bachelor of Science, Bachelor of Arts double degree. And then, it was-- I got into biochemistry, and got really into that. And then, when I started studying immunology, it was like, well, this is awesome.

But that's just book science. And you don't really know what science-- I didn't know what a career in science entailed. My parents are not academics. I didn't know anyone that had ever had a lab or run-- I didn't even know what that was.

And then, I sort got into doing research and, like, in the lab. And then, it was just like, oh, wow, there's this whole creative component of this. OK, so I could just do book science, and just remember stuff, and then go and do whatever degree.

But then, it was like, oh, you've got this whole creative aspect to research. Because actually, it's like lateral thinking and interpretation, and just learning to sort of-- it's not all black and white. And that was the stuff that really excited me.

And then, it was like, oh, cool, you can have this totally international life. You're not, like, stuck in a hospital in Melbourne for the rest of your life being-- you know. So that was appealing. And so then, I did what's called an honors year in science, so I did a year in a lab where I did a mini-thesis.

And then, I actually, in true Australian style, just put on a backpack and went around the world for nearly a year, living in China and Japan, and going around Europe and whatever. And then, I came back, and I actually got a fellowship to do my PhD.

And so that's when I did my PhD. I was actually looking to do my PhD overseas. But then a person that I really liked their work had come back to Australia, actually, from Boston. And so I joined his lab. That's Charles [inaudible].

And Charles basically taught me everything I know. And he is still a major part of my professional development to this day. And that-- not to be too on my soapbox, but that's-- for the younger scientists, choosing the right mentor is absolutely everything. And trusting and knowing that mentor is going to continue to support your career, pretty much, for the rest of your career-- that essentially made my career.

And so I hope to pay that back, of course, in my own mentees. So then, I moved to-- so I finished my PhD, and then, itchy feet, moved to New York. But I think in Australia, it's sort of-- it's like that inferiority complex or something.

I don't know why Australia has that, because it's actually an unbelievable country to live in, and there's fantastic science. But there's-- I always say that to my husband, who's American. Australians are very outward-looking. Americans are very inward-looking.

And Australians, it's like, go overseas. Get the experience. Go overseas. And so I went to Rockefeller University. Like, what else would you want to do? So I went to Rockefeller, and did my postdoc there under a fellowship from the Australian government.

And then, well, met my husband, and then we both moved to Boston to start labs. And yeah, so that's the path, I guess, in a nutshell. So--

Speaker 3: Yeah. Yeah. It's a winding path of--

Kate Jeffrey: Yeah, but I never had that, I'm going to be a scientist. Because I knew what I was good at, but I was only aware of the classic careers in that path, like being a medical doctor or doing-- what do you do? You be a science journalist, or you-- I didn't--

Speaker 3: Or a teacher.

Kate Jeffrey: Being a teacher, or-- I didn't know that there was this whole world that you could just do research. I mean, I did, but I didn't know what that entailed, actually. And it's interesting, because obviously, in the Boston area, you meet so many kids whose parents are professor, and those kids have seen their own parents and have that whole path, and they still choose it, which is amazing.

[laughter]

There was a certain naivete for me going into it. So yeah, I think you just sort of take the opportunities as they come along. I've always said, I'll keep doing science until someone tells me not to.

And I'll keep doing science while I find-- you've got to enjoy it. You've got to love it. Like, why else do it? Why else do anything?

And we are in a position of incredible privilege, because I don't make a profit for anybody. I don't-- you know, I have this complete freedom to just come up with, hopefully, good ideas and execute them. Like, what a luxury that is.

Speaker 3: Right. Exactly. Exactly. And so you said you were interested in art. You'd done your dual degree. Do you do anything in that creative arts side of things, even though I know science is creative?

Kate Jeffrey: So I always have had that in the back. I mean, obviously, like everybody, I read a lot and like art and whatever. But a lot of my friends are artists and filmmakers and things, and I get a lot of enjoyment out of that, because it's nice to get out of the science world-- although there's many, many parallels, actually, in those careers.

And so when I was in New York, I founded a film festival with a colleague-- the Imagine Science Film Festival. So that was trying to show films related to science, and trying to break down the stereotypes of science, because that was something very important to me.

It's like, oh my god, I'm not an old man in a lab coat. I'm still cool, and I don't like science being on the side. And so yeah, we tried-- we did the science festival, which was ended up being really successful. Because New York being New York, people have a large appetite for these types of things, and we got a lot of funding from various sources.

And Alexis Gambis who did the majority of the work on this festival-- he's finished his PhD and ended up going to NYU Film School. He just had a film picked up by HBO Max. Like, he's totally doing the filmmaking thing.

So that, for me, was the creative side of New York and doing that film festival. I would love to say now in my spare time I have all these creative ventures, but I'm a mom with two kids. So my creative thing is going to soccer on a Saturday morning.

[laughter]

Like, taking my kids to gymnastics or whatever. But yeah, I still read a lot. And I think, actually, reading broad literature always helps one's writing and ability to communicate. So--

Speaker 3: Yeah, but even having that experience of founding a film festival about science-- that is sort of something, let's say, the old man in the white coat would think was unnecessary or something, that didn't give you credibility.

Kate Jeffrey: I think I was told at the time by my post-doc advisor, this is a distraction. And I think there's probably some truth to that. But I think that was something that was making me happy and was filling-- not a void, but filling part of me that I didn't feel was being satisfied, particularly in a city like New York, where so much-- so many creative things are going on, and you just felt like this is a great place to do this. And it was super fun.

Brendan Keegan: 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 Uradike: To learn more about the guests on this episode, visit our website, Catalyst.Harvard.edu/ThinkResearch.