On this edition of FOCUS In Sound, we welcome a married couple of researchers, both of whom have been recipients of Burroughs Wellcome Fund grant support – Doctors Alice Chen-Plotkin and Joshua Plotkin. Of course, one of the major challenges in a scientific career is an ability to balance the demands of work life and home and family life, and you can multiply those challenges when you have two active scientific careers going on in one family. Add in a couple of kids to make it even more interesting, and you’ll see why the Plotkins’ story is downright inspirational. Both Alice and Josh conduct fascinating, valuable research, which we will hear about, and at the same time they’ve made it all work without compromise. Dr. Alice Chen-Plotkin is an assistant professor of neurology at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. Alice specializes in research on neurodegenerative diseases, particularly Parkinson’s disease and frontotemporal dementia. She was awarded a Burroughs Wellcome Fund Career Award for Medical Scientists in 2008. Dr. Joshua Plotkin is an associate professor of biology and computer science at the University of Pennsylvania. He was awarded a Burroughs Wellcome Fund Career Award at the Scientific Interface in 2005.
Transcription of “Interview with the Chen-Plotkins”
00;00;00;26 – 00;00;33;11
Ernie Hood
Welcome to Focus In Sound, the podcast series from the Focus newsletter published by the Burroughs Wellcome Fund. I’m your host. Science writer Ernie Hood. On this edition of Focus In Sound, we welcome a married couple of researchers, both of whom have been recipients of Burroughs Wellcome Fund grant support, DRS, Alice Chen Plotkin and Joshua Plotkin. Of course, one of the major challenges in a scientific career is an ability to balance the demands of work life and home and family life.
00;00;33;23 – 00;00;57;21
Ernie Hood
And you can multiply those challenges when you have two active scientific careers going on in one family. Add in a couple of kids to make it even more interesting and you’ll see why the Plotkin story is downright inspirational. Both Alice and Josh conduct fascinating, valuable research, which we will hear about, and at the same time, they’ve made it all work without compromise.
00;00;58;09 – 00;01;27;12
Ernie Hood
Dr. Alice Chen Plotkin is an assistant professor of neurology at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. She earned a B.A. in English at Harvard University and M.S. in Biology at Oxford University and her M.D. at Harvard Medical School in 2003. Alice specializes in research on neurodegenerative diseases, particularly Parkinson’s disease and frontotemporal dementia.
00;01;28;08 – 00;01;55;15
Ernie Hood
She was awarded a Burroughs Wellcome Fund Career Award for medical Scientists in 2008. Dr. Joshua Plotkin is an associate professor of biology and computer science at the University of Pennsylvania. He earned his A.B. in mathematics at Harvard, during which time he spent a year at Oxford as a visiting student. He received his Ph.D. in Applied and Computational Mathematics from Princeton University in 2003.
00;01;56;03 – 00;02;24;18
Ernie Hood
He was awarded a Burroughs Wellcome Fund Career Award at the Scientific Interface in 2005. Alice, Josh, welcome to Focus In Sound. We certainly want to discuss your scientific pursuits. But first, I think our listeners would really enjoy hearing your story as a couple. How you met, how you’ve managed to converge your careers and actually end up working at the same institution, and how you’ve managed to maintain a thriving family life at the same time.
00;02;25;05 – 00;02;32;15
Ernie Hood
So, Josh, I understand you and Alice met while you were in college, not even planning on academic scientific careers. Tell us about that.
00;02;32;19 – 00;02;42;21
Joshua Plotkin
Well, that’s right, Ernie. We met in college when it wasn’t even clear that we would become scientists. And as a result, we’ve known each other through thick and thin. As we became scientists over the past decade or so.
00;02;43;06 – 00;02;45;05
Alice Chen-Plotkin
More. Gosh. 15 years.
00;02;45;15 – 00;03;05;05
Joshua Plotkin
15 years? That’s right. And our past has taken us through different countries and all the way through graduate school, eventually landing us at the same university where we have jobs now. And it seems like it was very smooth, but in fact, it was more or less completely unplanned. It just happened to work out so well that we ended up together in the same place.
00;03;05;05 – 00;03;07;09
Joshua Plotkin
And a lot of it was fortuitous, I’d say. Would you? Well.
00;03;08;00 – 00;03;33;13
Alice Chen-Plotkin
I think there is a little bit more planning than you’re leading people to believe. I think we did make plans with other in mind from pretty much 2003 onwards. You think? Josh Before then we didn’t. But but from the time we got about a year into our marriage, we actually were long distance married for the first year and we decided this is just not how we want to live.
00;03;33;19 – 00;04;04;07
Alice Chen-Plotkin
And so from then on, I think that Josh or I, before we made a move, would always consider what the other person probably needed, both then and down the line. And so it meant that at certain points one of us had to make a decision about the next step in our career very early. Relative to our peers. But I do think there have been lots of times when we did something that wasn’t very planned.
00;04;04;15 – 00;04;16;21
Alice Chen-Plotkin
For instance, just somebody following somebody somewhere. And we thought that it wouldn’t be necessarily a great thing for the following end of the couple and it ended up being great. So that is the serendipity piece of it.
00;04;17;07 – 00;04;39;09
Joshua Plotkin
The best example of that is probably when I followed Alice to England when I met her. I was still a sophomore in college and Alice was a senior, so she was two years ahead of me. And of course she went on and graduated and won a fellowship to go to England. I was stuck back in Boston without her and eventually decided to get up and leave college and spend a year at Oxford, more or less just to pursue my girlfriend there.
00;04;39;16 – 00;05;02;26
Joshua Plotkin
But when she was there, she was in the zoology department, whereas I was in the math department and I started to spend afternoons over in the zoology department, just over tea and got to speaking to some evolutionary biologists there and found they had tons of fascinating questions to think about. And so the sum total of this is that I went all the way to England really just to pursue my girlfriend, but I came back in love with evolutionary biology as well.
00;05;02;26 – 00;05;11;13
Joshua Plotkin
And so that was completely fortuitous. How I fell into biological sciences was all tied up with how Alice and I stayed together through college and beyond.
00;05;11;24 – 00;05;27;29
Ernie Hood
Well, that that’s terrific. Alice, I did want to ask you another part of your story that I must work in on behalf of all of us English majors, where you actually started out specializing in poetry. So what what led you to turn to medicine and neuroscience?
00;05;28;00 – 00;05;54;17
Alice Chen-Plotkin
Yeah, So I was a writer, and that’s, I think, what Josh was referring to in terms of our having known each other before our present guises, which actually influences a lot of how we interact with each other. And I actually think if you speak to many neuroscience contests, it’s not at all confusing to them how somebody who was an English major, any kind of person in the arts might end up as a neuroscientist.
00;05;54;25 – 00;06;19;14
Alice Chen-Plotkin
What I mean by that is that I think the abiding interest was always in understanding human behavior. Right. I think that’s what as a writer I was interested in, and certainly that’s what informs what books I like to read. And I think that when you’re a creative writer, you are trying to understand your own experience and understanding the experiences of people you see.
00;06;19;14 – 00;06;41;18
Alice Chen-Plotkin
And you try to convince people that the reason that things are the way they are is because of a visceral feeling. And you’re able to convey that if your art is very good as a neuroscientist, you’re going about it sort of differently. You talking about it at the level of genes and channels, but the interest is the same.
00;06;41;18 – 00;07;00;13
Alice Chen-Plotkin
The interest is why do we behave the way we do? And I think that for me, I liked the rigor that science offers. And the other piece of it, why I became a doctor. That is a two part explanation. I think one part of it has to do with the fact that I came from a huge family of doctors.
00;07;00;13 – 00;07;32;08
Alice Chen-Plotkin
So there was a lot of emphasis on being a doctor, which I resisted for a long time. The other piece of it, though, and this is the piece that now as I have a family of my own, I think about is I want a sense of social good to come from my life’s work. And I think that the way that sort of interest in why we behave the way we do and interested in having social good coming out of your life and also just interested in making my parents happy.
00;07;32;08 – 00;07;37;10
Alice Chen-Plotkin
Converge was for me to become a neurologist neuroscientist, and I’m really happy doing it.
00;07;37;16 – 00;07;47;25
Ernie Hood
Well, that that’s terrific. So we’ve we’ve got you both in your actual scientific careers at this point. How did it work out that both of you ended up there at Penn?
00;07;48;03 – 00;08;10;28
Joshua Plotkin
We came back from England and Alice attended medical school at Harvard while I was attending graduate school at Princeton. And we were separated for that period of time, which was a bit painful, especially because we actually got married during that period of time that we were separated. I returned to Harvard to do a postdoc while Alice was doing her residency, and it was at that point that we decided we would never agree to a separation any further in the future.
00;08;10;28 – 00;08;36;27
Joshua Plotkin
And so we really planned our next move together. And since she needed to do a fellowship after residency and I’d already done a postdoc, it was time for me to look for a faculty positions. And at that point we really just constrained our search to places where we sort of could both be happy and found that University of Pennsylvania offered a wonderful ecology and evolution group for me, as well as a really rich neuroscience community for Alice.
00;08;37;08 – 00;08;57;21
Joshua Plotkin
And so I accepted a faculty position here, knowing that it would hopefully work out for Alice as well in the near term, in the near future. And we delayed actually coming here for two full years so that Alice could finish her residency in Boston before we actually made the move to the University of Pennsylvania and to Philadelphia at the exact same time, I should mention that we moved to Philadelphia.
00;08;58;03 – 00;09;02;14
Joshua Plotkin
We, of course, changed jobs. We bought a new house and Alice was taken with her.
00;09;02;15 – 00;09;04;04
Alice Chen-Plotkin
Unexpectedly pregnant and.
00;09;05;12 – 00;09;11;17
Joshua Plotkin
So essentially everything changed that first year. And but at the same time, we all sort of came together. And so it was wonderful.
00;09;11;23 – 00;09;38;26
Alice Chen-Plotkin
I came to the University of Pennsylvania as a postdoc and Josh came as a faculty member. So in 2010, when I was done with my postdoc and I was ready to launch a lab, there was a question of whether I would only look at the University of Pennsylvania or if we would then look around as a couple. And that’s a hard choice because it means that the other partner might have to think about uprooting what they’ve built over the last three years.
00;09;39;04 – 00;10;08;00
Alice Chen-Plotkin
But one of the deals Josh and I have had always for each other is that we would always consider our kind of the sum total. So as a consequence, Josh and I both looked again at places that would work for both of us, and it actually helped a lot in terms that I did stay at the University of Pennsylvania, but in terms of having that freedom to look around and to actually have other offers has actually influenced everything about my faculty career here.
00;10;08;00 – 00;10;19;27
Alice Chen-Plotkin
And so I think that for people who are academic spouses, just having that ability to help each other and with mobility if necessary is really very good.
00;10;20;09 – 00;10;21;26
Joshua Plotkin
And even if you don’t end up moving.
00;10;21;26 – 00;10;22;17
Alice Chen-Plotkin
Yeah, yeah.
00;10;23;05 – 00;10;39;24
Ernie Hood
Well that that’s terrific. And it’s great that it’s worked out so well for both of you. Now you’ve got a couple of kids now and flash forward to the present. How are things working out with both of you having demanding scientific careers and demanding family life as well?
00;10;40;00 – 00;11;09;04
Alice Chen-Plotkin
We have a five year old son. He was born right when I started my postdoc, a little bit unplanned, too, that he was coming so early. And then we have a seven month old daughter. I think that it’s always being negotiated. It’s always been sort of reinvented. But I think that you figure out what works. There are times that I am the person who does more of the child rearing.
00;11;09;04 – 00;11;16;07
Alice Chen-Plotkin
And for instance, right now our seven month old is still nursing. That just obviously cannot do that. Right. So I.
00;11;16;08 – 00;11;18;18
Ernie Hood
The sharing thing can only go just so far.
00;11;18;18 – 00;11;28;26
Alice Chen-Plotkin
Actually. Exactly. So I take care of that piece and it means I’m a little tired right now. But I think that what Josh does is he manages our five year old very much and that.
00;11;28;26 – 00;11;30;02
Joshua Plotkin
Takes some effort, I should say.
00;11;31;19 – 00;12;07;16
Alice Chen-Plotkin
And we often get asked stuff like, how do you have a work life balance or how do you separate out your life from your work? And and Josh and I actually don’t separate out our life from our work. And for better or worse, this works for us, meaning that our children have been in our labs and that has been necessary for various reasons or for interest, because our five year old now is actually very interested in science and similarly, I think that our family life, it’s influenced by the fact that we are scientists.
00;12;07;17 – 00;12;12;22
Alice Chen-Plotkin
I certainly I look at my children and I look at how they’re behaving and I think about what’s going on in their brains all the time.
00;12;12;27 – 00;12;32;26
Joshua Plotkin
So, yes, that’s right. And then especially Linus, who’s now five, knows a lot of the members of our research teams by name and maybe even requests to spend some time with him on the weekends, which is actually happened once or twice. And that’s because he comes into the lab once in a while, because, you know, he might have a doctor’s appointment or something and we might have some downtime where I just will bring in to the lab or Alice will bring him to her lab.
00;12;33;04 – 00;12;42;07
Joshua Plotkin
And since we live close enough to work, this all manages to work out and the people in the last year to enjoy it as well. So it’s not as if we have a work life balance. We just have a work life mixture.
00;12;42;16 – 00;12;59;12
Ernie Hood
Josh I understand that the funding each of you received from the Burroughs Wellcome Fund actually played a fairly pivotal role in this story. Tell us more about that. And I’m sure that the the Fund folks will be tickled to hear about these consequences of their largesse.
00;13;00;20 – 00;13;28;16
Joshua Plotkin
Oh, I’d be happy to do that. Only in part because it’s just such a joy to recount, as you said, of the Burroughs Wellcome Fund funding, which Alice and I each have slightly different flavors of grants and the best looking fund. But in both cases, their career awards that are specifically designed to help scientists transition from a post-doc period to their first faculty position, and I would say easily the funds that the Burroughs Wellcome Fund provided were in fact essential for both of our transitions to faculty members.
00;13;28;26 – 00;13;40;13
Joshua Plotkin
And largely that’s because it’s not so much the dollar amount of the funds, but it’s the way in which the Burroughs Wellcome Fund views how you can use these funds. It’s completely, in some sense unrestricted, and they support.
00;13;40;13 – 00;13;42;17
Alice Chen-Plotkin
It. They invest in the person, I think.
00;13;42;17 – 00;13;58;26
Joshua Plotkin
And that’s that’s right. They support they support the person more than the specific research project. And so they’ve had plenty of times where I’ve called the Burroughs Fund up and asked, well, could I use the funds for this purpose or for that purpose? And sometimes these are purposes it’s like to take the lab out for a retreat if they really need to celebrate this recent paper.
00;13;59;08 – 00;14;16;22
Joshua Plotkin
And those folks that the director said, Of course you can use the funds, however you think will further your research and your career. And that kind of flexibility is just priceless, honestly. And I would say every single DWF dollar I have is worth five NIH dollars. I have just because of the flexibility that at.
00;14;16;26 – 00;14;45;22
Alice Chen-Plotkin
On by so and I think it’s also the fact that it it comes early in your career and early in your career. You need to be launching many different things and maybe taking those kinds of risks. And and and the fact that you can do that as a postdoc, which is what happened to me is huge because it means that you can launch things that are all your own different from your post-doctoral mentors.
00;14;45;22 – 00;15;06;28
Alice Chen-Plotkin
And in my particular case, I stayed at the university of Pennsylvania, which is always kind of a tricky thing if you’re going to stay in the same institution you postdoc in. But because of my Burroughs Wellcome Funded projects, I had been able to do things that were sort of different in both methodology and flavor from the My Postdoctoral Lab.
00;15;06;28 – 00;15;11;08
Alice Chen-Plotkin
And so it was very easy to transition to being an independent investigator.
00;15;12;00 – 00;15;41;13
Ernie Hood
Folks, that is a terrific story and one that I’m sure will provide real hope and inspiration to many of our listeners who may be struggling with the types of issues you’ve been able to overcome so gracefully. Moving on, we certainly want to spend our remaining time focusing on your scientific pursuits. Alex, let’s start with you. As I mentioned earlier in your lab, you study two particular neurodegenerative diseases, frontotemporal dementia and Parkinson’s disease.
00;15;42;04 – 00;15;51;28
Ernie Hood
Tell us first about your work with frontotemporal dementia. What is that and how have you worked to identify a suspected risk gene for the condition?
00;15;52;18 – 00;16;27;11
Alice Chen-Plotkin
Frontotemporal dementia is the second most common cause of dementia in people under the age of 65, and it’s probably number three or number four for people older than age 65. So it’s actually fairly common, though it isn’t recognized frequently. Frequently people just call it dementia or people assume it’s Alzheimer’s, but it’s actually a different disease process. It manifests clinically differently because the the deficits that develop are primarily in language and in behavioral control as opposed to in memory, which is what you see in Alzheimer’s disease.
00;16;27;11 – 00;16;55;13
Alice Chen-Plotkin
The frontotemporal dementia work was actually the work that was funded by the Burroughs Wellcome Fund. And I had the great fortune of landing in a lab right at the time that they were discovering a protein that accumulates in the brains of people with frontotemporal dementia. So for a very, very long time, dating back 100 years or so, it was well recognized that people with this kind of dementia would shrink their frontal lobes and their temporal lobes.
00;16;55;20 – 00;17;28;27
Alice Chen-Plotkin
Therefore, the name and that if you looked at the brains under a microscope, you could see that there were inclusion bodies inside the neurons, but it was not known what was inside those inclusion bodies. And so at the time I entered my postdoc, my postdoctoral mentor had just through brute force, biochemistry and immunological methods, identified the protein in those inclusions, which, you know, had been a mystery for a long time as a protein called TDP 43 or tardive binding protein 43.
00;17;29;06 – 00;17;57;06
Alice Chen-Plotkin
And this actually revolutionized the field because it went from being a very heterogeneous, clinically heterogeneous, pathologically kind of disease to a situation where you could classify things with some knowledge of what might actually be the underlying cause. And so we took advantage of the fact that we could now classify this disease in a more precise way to do genome wide association study.
00;17;57;06 – 00;18;24;27
Alice Chen-Plotkin
These are very common, and the underlying idea is just you find a bunch of people or in this case brains from people who have a trait and a bunch of people who don’t. And we now live in an era where you have technologies that let you sort of saturation genotype so you can look at genotypes across the genome, a million markers at a time and see if some markers are represented more frequently in people with the trait versus without.
00;18;24;27 – 00;18;48;10
Alice Chen-Plotkin
And so we took this approach to frontotemporal dementia and as a consequence we discovered a genetic risk factor called transmembrane protein one, a6b, And if you are scientists, you can probably tell from the name that this is not a protein as well characterized. So it was pretty much minimally characterized. Even the transmembrane part of it was kind of putative.
00;18;48;20 – 00;19;17;14
Alice Chen-Plotkin
And so we had a new genetic risk factor for a disease that is incurable and fatal. And we did not know what it did and we did not know how it worked. What happened subsequently is that my lab has been trying to figure out both why there’s a genetic signal there. How can a variation in your code then translate into something that increases your risk for a disease?
00;19;17;24 – 00;19;42;13
Alice Chen-Plotkin
And it turns out that what is probably happening is that there’s a specific genetic variant that changes your expression levels of this protein, and we’re working out the exact mechanism and then we’re working out the consequences of two high expression, which is what we see with increased disease risk. And I’m excited about it because as I mentioned, genome wide association studies are very common.
00;19;42;13 – 00;20;02;23
Alice Chen-Plotkin
They’re probably one thousands of these done every issue of nature Genetics has genome wide association studies, but the follow through from genetic signal to causal variant to disease mechanism is very rare. That’s probably happened less than ten times and I think we’re going to do that. So that’s what we’re trying to do in FTD.
00;20;02;23 – 00;20;19;23
Ernie Hood
Okay. Well, that is very exciting. But you describe yourself first and foremost as a Parkinson’s disease, Doctor. I am. And you’re using but you’re using similar unbiased, genome wide approaches to discovering novel biomarkers for Parkinson’s. Tell us a.
00;20;19;23 – 00;20;45;22
Alice Chen-Plotkin
Little bit about that. Once I had labs on my own and enough resources to kind of have a diversified portfolio, I wanted one piece of it to be really related to my clinical life. And the thought was that we live in this incredible time where we can use technologies that let you look in an unbiased way at hundreds, thousands, tens of thousands, millions of signals and pick the best one.
00;20;45;27 – 00;21;24;04
Alice Chen-Plotkin
And I thought, why can’t we use this approach to look in Parkinson’s disease, too? But rather than looking for genetic risk factor, I wanted to do something very translational and I wanted to do something that I thought was going to influence my own patients within my lifetime, and even perhaps their lifetime, which is a harder goal. And so we have used these kind of unbiased screening approaches of, in this case, hundreds of proteins and blood to find what we think are the best markers for different disease states, different prognoses, and maybe even kind of a sense of modifiable risk in Parkinson’s disease.
00;21;24;19 – 00;21;33;08
Ernie Hood
Well, Josh, let’s turn to you. Would you give us a broad overview of the research agenda that you are pursuing based upon mathematical biology?
00;21;33;26 – 00;21;59;25
Joshua Plotkin
Sure. Well, it’s, of course, quite different from what else is pursuing. I work in the field of molecular evolution, which is studying how evolution proceeds at the molecular scale. The kinds of questions we ask, or I think the kinds of questions that anyone would ask about evolution. Most people who think about evolution. I immediately struck by how impossible it all seems, you know, how did something as complicated as a human or even just the vertebrate eye evolve from such simple things as a single celled bacterium?
00;22;00;24 – 00;22;21;25
Joshua Plotkin
How can we comprehend this sort of tremendous evolutionary transition which occurred over the course of 3 billion years, by the way? How do how do we address those questions? And fortunately, the main tool we have in our favor is DNA. The study that evolution went through a revolution of sorts when DNA was discovered, because DNA provides a kind of common currency for comparing individuals within and between species.
00;22;22;12 – 00;22;55;15
Joshua Plotkin
And as a result, evolution has moved slowly from a qualitative field like it was when Darwin originated the field to what is now becoming a much more quantitative subject that can even benefit from mathematics. So we can now precisely ask what mutations allow an organism to adapt to its environment and what determines the pace at which adaptation occurs, and how do mutations act in concert with one another to provide some sort of phenotypic change, either a change of the protein structure or some sort of macroscopic change in the cell morphology or the growth rate of a cell.
00;22;55;26 – 00;23;21;15
Joshua Plotkin
And my research is, is an attempt to develop mathematical models that allow us to pose these questions in very precise ways and then leverage experimental data to infer the answers to the questions. The data that we use typically comes from evolving microbes, either laboratory populations of bacteria or wild populations of viruses. And these types of organisms provide many advantages for studying quantitative details of evolution simply because they evolve so quickly.
00;23;22;08 – 00;23;47;12
Joshua Plotkin
Take flu, for example. In flu, the antigenic proteins that evolve the most rapidly have undergone about 30% of substitutions. 30% of their sites have substituted over the past decade or so, and that’s about the equivalent of ten of about 10 million years worth of evolution. In a typical mammalian protein. And so what we have compressed over a very reasonable timescale like a decade is a is a tremendous amount of evolution occurring right in front of us.
00;23;47;13 – 00;24;13;01
Joshua Plotkin
And better yet, since public health officials collect and sequence thousands of flu strains every year, we know the complete genetic record of all of the viruses evolutionary course and so finally, armed with this sort of high fidelity genetic record of evolution, we can hope to actually pinpoint what specific mutations or constellations of mutations allowed the virus to adapt, allowed it to escape the pressures of the human immune system or escape the pressures of drugs.
00;24;13;18 – 00;24;25;12
Joshua Plotkin
And so in the end, although the questions that I think we’re asking to begin with are fairly large and sort of philosophical, the kind of mathematical techniques we’re using, I think can even produce, hopefully in the end, some practically useful results.
00;24;25;24 – 00;24;42;04
Ernie Hood
Alice, Josh, you’re both doing great scientific work and you are living role models for balancing a thriving scientific career with a healthy marriage and family life. We wish you the best of luck for continued success. And thanks so much for joining us today. Our Focus In Sound.
00;24;42;24 – 00;24;44;04
Joshua Plotkin
Say thank you to Ernie.
00;24;44;15 – 00;24;53;24
Ernie Hood
We hope you’ve enjoyed this edition of the Focus In Sound podcast. Until next time, this is early heard. Thanks for listening.
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