Garbage In, Garbage Out

[AUDIO PLAYBACK] SPEAKER 1: And so with that, I want to introduce Dr. Lee.

[CHEERS, APPLAUSE]

FLORA LICHTMAN: A few months ago, a bunch of bigwigs assembled in a glassy atrium at Penn Medical School. There were deans, senior professors. They were honoring scientist Virginia Man-Yee Lee and her late husband and scientific partner, John Trojanowski. He died a few years ago.

– The only thing I feel sad about today is that John is not here with us.

FLORA LICHTMAN: This is Virginia talking.

– And he would be so delighted with this whole thing.

FLORA LICHTMAN: This whole thing was a portrait unveiling. It’s a picture of John with a wave of white hair, sitting, you know, kind of distinguished on a chair, looking very serious. And Virginia’s behind him, leaning on his shoulder, smiling. They’re both wearing lab coats. They look happy.

– Because I remember that this was years ago.

FLORA LICHTMAN: We’re about 30 minutes into the ceremony. And so far, it’s exactly what you’d expect– formal, polite, a little stuffy. But then Virginia leans into the microphone.

– We really did have a unique partnership. We literally sleep, eat, and shit science 24/7, literally.

FLORA LICHTMAN: This is a portrait unveiling with a bunch of university brass, and Virginia’s talking about shitting science. And that is the thing about Virginia. She just seems to flush away what other people expect of her. She’s been defying other people’s expectations her whole life.

– I am maybe the second woman to be on the wall in the School of Medicine. And I am probably the only Chinese– I am the only Chinese, or any Asian that is on the wall. So now you can understand what I would face in my career.

[END PLAYBACK]

FLORA LICHTMAN: This is The Leap, a series about gutsy scientists who’ve risked their careers, their reputations, and even their lives to make a breakthrough.

[BRIGHT MUSIC]

Virginia Lee is a badass biochemist. Over her 40-year career, she has shaped our understanding of a crazy number of neurodegenerative diseases, including Parkinson’s, ALS, Alzheimer’s. All these diseases have something in common.

Proteins in the brain misbehave. They fold wrong. They form clumps.

They destroy neurons. They muck up the brain’s signaling. And thanks in large part to Virginia’s work, we know what many of those proteins are.

Five years ago, Virginia was awarded the Breakthrough Prize, one of science’s most prestigious honors. It’s a moonshot for anyone, let alone someone with Virginia’s story. For Virginia, it was an uphill battle to even get into the lab, let alone climb to the top of her field. So how did she do it? How did she block out her doubters and find the confidence to become the person she did, when from the very beginning of her life, the odds were not in her favor?

[AUDIO PLAYBACK]

– I was born on the roadside. And I was born right after the Second World War. And so, my parents were running away from the Japanese earlier on when I was conceived. And my mother didn’t want to have me, because at that point, she already had two boys.

And so my mother said to my father, maybe we’ll abort this one and have other ones later, maybe. And my father said, absolutely not. And so we were going from Chongqing on the way to Guangzhou, so I just literally was born on the roadside.

– And almost not born at all.

– Right, almost not born at all. So I’m pleased that my father decided not to abort me. So That was a good idea.

– Yeah.

– Yeah.

[END PLAYBACK]

FLORA LICHTMAN: And that might have been Virginia’s dad’s most parental moment.

[AUDIO PLAYBACK]

VIRGINIA MAN-YEE LEE: So I actually more or less grew up on my own. I didn’t spend any time at all with my father, and even if you count seconds and minutes and not even a year or two of my life.

[END PLAYBACK]

FLORA LICHTMAN: Virginia’s mom wasn’t around so much either. By the time Virginia was 11, both her parents had moved to the US, leaving Virginia and her brother to be brought up by aunts and uncles in Hong Kong. But despite being thousands of miles away, Virginia’s mom had a specific vision for Virginia’s life.

[AUDIO PLAYBACK]

– My mother didn’t want me to be too educated because she was worried that I wouldn’t be able to find a husband. And she always complained that at that time, when I was young, I was tall for an Asian woman. And so she always said that, you’re too tall and you’re so talkative. And if you’re overly educated, nobody would want to marry you.

So that was the mantra of my mother. And so that’s why she wanted me to study piano and then married a professional, like a nice Chinese doctor and live happily ever after. So that was her dream for me.

– But it wasn’t your dream for yourself?

– No, it was not. I really didn’t have the patience to practice 3 to 8 hours a day. So I said to myself, I want to do something else. And I remembered that before I finished up in high school, I actually got a chemistry prize. I got the best score. And so I said to myself, well, if I was good at chemistry, maybe then I can go to university and major in chemistry.

– So you dropped out of London’s Royal Academy of Music and enrolled instead of University of London in chemistry.

– Yeah.

– Was that a risk for you? I mean, your mom wanted you to be a musician. Did you tell her? Did you have to get her OK? How did that go?

– So actually, she wasn’t very happy. But there’s one really good thing about Chinese family, OK. Chinese families like education. It doesn’t matter what you do. You stay in school, they’ll support you. And so that was my story. My father, particularly, and said to my mother, I support her if she wants to go to school.

– So one thing that’s really striking to me is that from a young age, you had confidence in your own trajectory or your own path.

– That’s right. That’s right. I want to be in control of my life, because my parents weren’t with me. That actually allow me to think about the fact that I have to be independent. I have to be able to make a living.

And nobody’s going to be there to support me. Some people are lucky because their parents have a bit of wealth, for example. And I wasn’t counting on it. So I was counting on myself to be able to make a living on my own.

[END PLAYBACK]

FLORA LICHTMAN: Science seemed like a way to do that. But there weren’t a lot of role models for Virginia on this career path. There were times in her education where she’d look around the room of 2,000 people and not see another woman, let alone a woman of color. But she didn’t just make it, she excelled. She got a PhD and made her way to Harvard for a postdoc.

Then the question was what to focus on, what scientific problem to tackle. And the answer came from a surprising place, a pickup bar in Boston, Massachusetts.

[AUDIO PLAYBACK]

– Yeah, John, I pick him up in a bar.

[LAUGHS]

[END PLAYBACK]

FLORA LICHTMAN: The other half of the portrait, John Trojanowski. He was 29. She was 30. He was a neuropathologist. She was a biochemist. They had a lot to talk about.

[AUDIO PLAYBACK]

– So he tried to impress me. He took me to this German club, to show off that he was speaking German. And then he took me back to his place, and that was it. That really was it.

[END PLAYBACK]

FLORA LICHTMAN: They dated, got married, and in a decision that would come to define their lives, they began working together too. And their research became their priority.

[AUDIO PLAYBACK]

– We decided not to have children. And in part, it’s because John was one of seven. And so he changed diapers when he was a teenager. So he didn’t want to go down that road. He said, I don’t want to go there.

– He’s done.

– Yeah. Yeah, so I said, I’m fine with it. And basically, we are together literally 24/7. And we talk about science all the time.

[END PLAYBACK]

FLORA LICHTMAN: As scientific partners, they recognized they were a powerful duo with just the right complementary skills. John was focused on brain diseases, Virginia had the biochemistry expertise, and they thought neurodegeneration was a field where they could make a real impact.

[AUDIO PLAYBACK]

– So really, at that time, when I jumped into disease research, there were very, very few basic scientists. And basically, these MDs don’t have the skill set to do some of this work. And so John realized that somebody like me with a biochemical skill set would be able to have a go at it. And he was right.

[END PLAYBACK]

FLORA LICHTMAN: They started with Alzheimer’s. And it was a super exciting time for the field. The disease was first identified in a 50-year-old woman in 1907. But it wasn’t until the 1960s that people started to realize that the same disease was causing dementia in older people.

By the ’80s, when John and Virginia got in, people knew that Alzheimer’s and other neurodegenerative diseases came along with signature changes in the brain, clumps of protein that shouldn’t be there. But what those proteins were, how they got there, how they spread through the brain, all of that was unknown. And that’s where Virginia’s biochemical skill set could be deployed.

[AUDIO PLAYBACK]

– What I aimed to do at the beginning was to identify all of the disease proteins that were implicated as pathological lesions in patients with different neurodegenerative diseases.

– That’s not a small goal.

– No, no. And people thought we were crazy, because the fact that we wanted to do all of the different neurodegenerative diseases, people were sort of like, wow, it’s a massive undertaking, and you probably won’t get there.

– Why did you go forward with it?

– Well, I think that we trusted each other’s instinct. I’m the basic scientist, but he really was a great organizer. So he knew right away that he needed to reach out to the neurologists because they see the patients. He said, well, all you need to do is– you see these patients anyways, all you have to do is ask them whether they want to donate their brain for research.

– You needed brains of people with these diseases?

– Yeah, we need the brains, exactly.

[END PLAYBACK]

FLORA LICHTMAN: John assembled a library of human brains from people who had suffered from different neurodegenerative diseases. And with these brains, Virginia got to work identifying what the lesions were made of. And they were off.

[BRIGHT MUSIC]

[AUDIO PLAYBACK]

– I remember visiting their lab at University of Pennsylvania and even had dinner at their house.

[END PLAYBACK]

FLORA LICHTMAN: This is Ken Kosik a neurologist and neuroscientist who has known Virginia and John since the very earliest days.

[AUDIO PLAYBACK]

– It was a busy lab with a lot going on, data coming all the time. They always had stuff that they wanted to show somebody.

– Would they pull you aside and say, come look at this?

– Oh, yeah, we were all starting our careers. So it was very exciting. We were starting our careers in a field that was young. It was almost every day you could make a discovery, because no matter what you did was new.

– I mean, it sounds a little bit like– I don’t know, like you’re explorers or something. It reminds me of the way people talk about deep sea explorers who are pulling up a net and saying, oh, my gosh, no one’s ever seen this tubeworm or whatever it is.

– I love your analogy. I mean, for all of us, the field was totally exciting because it was so young.

[END PLAYBACK]

FLORA LICHTMAN: Exciting, young, and contentious.

[BRIGHT MUSIC]

Back in the ’80s, a big argument bubbled up over what drove the disease. People knew that in the brains of people with Alzheimer’s, you could see plaques of protein that form between neurons. And scientists had figured out that they were made of a protein called “beta amyloid.”

But there were also these deposits called “tangles” inside of neurons. And a slew of researchers, including Ken and Virginia, helped establish that those tangles were made of a different protein called “tau.” And what followed was a schism about which of these proteins, beta amyloid or tau, was more important.

[AUDIO PLAYBACK]

– There’s no doubt about it. People had these very, very strong opinions that started to feel, for some people, a little bit religious.

– People called it a holy war.

– [LAUGHS]

Some people would call it a holy war, yeah. So that’s what they called them the “Tauists” and the Baptists, right?

– OK, so Baptists for beta amyloid and “Tauist” for the tau people.

– That’s right.

– And the Baptists had a leg up.

– They were funded much more. Their view was adopted by the pharmaceutical industries.

– Meanwhile, tau was the underdog, the thing barely mentioned at a scientific conference.

– Tau usually is the last session on the last day when everybody is gone.

– So there’s this holy war brewing, and Virginia steps right into the center of it. And she takes up the case for tau.

– What I think was very impressive thing about Virginia is she spoke her mind. And she would get up at conferences. And some people might think of it as being a gadfly. But in fact, she was pointing out something that is now something that people would really accept, that is the importance of tau in this whole disease process. And that view was not so readily swallowed at that time.

– So Virginia would get up and say, stop ignoring tau. And how would people respond? Would they boo her? What’s the scientific version?

– Well, people don’t really boo, generally, at scientific meetings. But you can sometimes get a feeling of ripple through the audience.

– Was she going against the grain by standing up?

– Yeah, oh, for sure, because people were not so pleased to always hear that point of view.

– It’s one thing to go against the grain when you’re established, when you have all this credibility. It’s another to do that when you’re just starting out, and when you’re the only woman and only woman of color in the conference room.

– Particularly when I was young, OK. Being female, being Asian, and being attractive– I was attractive when I was young. It’s not a good combination for a budding scientist at that time. And so a lot of people just don’t really take me too seriously. So there are a lot of doubters. And publicly, I would defend myself.

– You just stood up for yourself.

– I stood up for myself.

– Where did you get the courage to do that?

– I guess, in part, it’s because of the fact that John pushed me out there, and just keep pushing me. He was very important to me in early career, knowing that he’s behind me, he was around. And these things came along, and I dealt with it and moved on. I don’t dwell on things.

– You move on, and you focus your attention on the things that interest you.

– Exactly.

[END PLAYBACK]

[BRIGHT MUSIC]

FLORA LICHTMAN: These days, the “Tauists” are pretty much vindicated. It’s accepted that it’s an important part of Alzheimer’s disease. Virginia made many contributions to our understanding of tau.

And as she was making discoveries, the lab grew. Picture 40 people, John and Virginia as co-PIs. And Virginia is figuring out her style of leadership.

[AUDIO PLAYBACK]

– She loves to say, garbage in, garbage out.

– Yes garbage in, garbage out.

[END PLAYBACK]

FLORA LICHTMAN: This is Virginia’s former postdoc, physician-scientist, Alice Chen-Plotkin.

[AUDIO PLAYBACK]

– Alice, she sat in the little office right next to my office for three years. And particularly because she’s so observant, she probably was one of my trainees that knew me the best.

[END PLAYBACK]

FLORA LICHTMAN: So here’s the “garbage in, garbage out” translation.

[AUDIO PLAYBACK]

– What that means is that if the model you’re going to use or the samples you’re going to use is wrong, whatever you find is going to be wrong. But not everybody would say it like that, right? But that’s how she is.

– I’m a very straightforward person. I mean what I say, and I say it as it is.

[END PLAYBACK]

FLORA LICHTMAN: After tau, Virginia had other breakthroughs, not just in Alzheimer’s, but in Parkinson’s. And there’s a world where that could have been her whole contribution to science, and it would have been plenty. But Virginia seems to have this drive, something in her that makes her look at a big, messy, difficult problem and want to steer right into it. And that’s exactly what she did.

It began as a quest to figure out frontotemporal dementia, or FTD. This is a rare and devastating condition where parts of people’s brains begin to shrink. It can bring debilitating changes, like loss of language, inappropriate behavior, trouble connecting to loved ones.

Virginia spent a lot of time studying what proteins build up in people’s brains with this disease. And she found that 50% have tau pathology. But that only explained half the cases.

[AUDIO PLAYBACK]

– And I said, well, what about the other 50%? They look the same, except that those other 50% don’t stain for tau. So what is it? And so that’s basically when we decided to go after it.

– I know that this was a very hard problem to solve. Did you know going in that it was going to be tough to crack?

– Well, I think that the only way that I would know that it would be hard is because nobody has done it. Many labs working in neurodegenerative disease were doing the same thing. This was like the last protein that had not have been found.

– Wow, like the final frontier.

– Exactly the final frontier. And we worked for two or three years. We got nowhere.

– Was it particularly hard to find this protein? Or is purifying any protein in the brain difficult? Was there something that was particular about this problem that made it hard?

– Yes, yes, there’s something particular about this problem in the sense that the amount of pathology actually are much lower.

– So there’s less of it?

– There’s less of it, yeah.

[END PLAYBACK]

FLORA LICHTMAN: Like a lot less of it. Compared with tau or the protein they found in Parkinson’s, this mystery protein was scarce, a needle in a haystack. And trying to figure out its identity required that Virginian and team work through all these complex processes, like taking brain material, injecting it into mice, generating antibodies to the protein, which could be then used to figure out its identity. I don’t– maybe I’m making it sound straightforward. It wasn’t.

[AUDIO PLAYBACK]

– It was a huge effort, a huge– really, the biggest effort that I ever embarked upon, labor intensive. I mean, we had thousands and thousands of monoclonal antibodies, and then screened for them by tissue section. That was the first step, is to be able to have tools that you can use to look for the protein of choice. And really, it took a lot out of me. Towards the end, the last two or three years, it’s almost like I would do everything in my power to get there.

– Were you ever afraid you weren’t going to find it? Did that cross your mind as a possibility?

– Well, I was determined. I was determined. So I wasn’t going to give up. You learn from a failed experiment. And then you can plan the next experiment better. One thing about science, those “discoveries,” end quote, are far, few, and in between. And so unless you enjoy the process, you’re going to be disappointed a lot of the times.

– You liked the journey.

– I liked the journey. I still like the journey.

– Even though it was hard.

– That’s exactly right.

– Even though it was hard.

– Yeah.

[END PLAYBACK]

FLORA LICHTMAN: The joy of doing carried Virginia along. After five years, by the early 2000s, they thought they finally figured it out. They zeroed in on a protein called TDP-43. And it wasn’t just in the brains of people with FTD.

Even more surprising, they found this protein also accumulated in the brains of people with another neurodegenerative disease called ALS, or Lou Gehrig’s Disease. This is an illness that first presents with muscle weakness and trouble swallowing or slurred speech. So finding that these two seemingly very different diseases shared the same protein pathology was really surprising.

[AUDIO PLAYBACK]

– When we actually even published, people didn’t believe it.

– When scientists who reviewed the paper said.

– They said, well, if you’re wrong, then you’re going to be in the toilet. But it’s true. What he said is true.

– Where was that skepticism coming from?

– I don’t know. I guess maybe I’m not one of the ALS researcher. And I really never really worked on ALS. But we were very convinced that we’re right.

[END PLAYBACK]

FLORA LICHTMAN: And they were.

[AUDIO PLAYBACK]

– Her TDP work essentially changed everything about how we think about ALS and FTD.

[END PLAYBACK]

FLORA LICHTMAN: Here’s Virginia’s former trainee, Alice Chen-Plotkin again.

[AUDIO PLAYBACK]

– What happened when she discovered TDP-43 is that everything could now be organized in a way that made some biological sense. And that led to the realization that, man, all these neurologists everywhere had missed the cognitive impairment that’s in ALS. So all of a sudden, ALS and FTD became part of the continuum, united by TDP-43.

– I think that’s her most important discovery.

[END PLAYBACK]

FLORA LICHTMAN: Here’s Ken Kosik again.

[AUDIO PLAYBACK]

– That was a painstaking effort, a momentous biochemical job to do. And she did it.

– Why was she the one who was able to do that?

– Because she was a top-notch biochemist.

– So I don’t know anything about what skills make someone a great biochemist. I mean, I’m sure it’s a lot of things together. But is there a way to analogize what it takes to be really good at this particular thing?

– Yeah, I wonder about that a lot. I recently had a person in my lab who was one of these people who had magic hands. They do an experiment one time, and they get a beautiful result. And it’s a true result. They replicate it and replicate it, and it’s true.

One day, I decided I was just going to watch him a little bit. When he’s at the bench, it was almost like doing choreography. I mean, he had his pipette tips all lined up, he had his tubes, he had everything laid out so that there was a minimum of movements put together in this dance-like manner. So Virginia had magic hands. She could get things to work.

– [LAUGHS]

Well, I’m not sure that that’s entirely true, because right at that point, I wasn’t doing many of the experiments. But it is true that when I was younger, I enjoyed doing experiments with my own hands. I really did. And I know the nitty-gritty of the experiment, the detail, what to look for, and so on.

– Yeah, we heard that from Alice too, where she said that, in a 40-person lab, every single person felt like you knew exactly what was going on with their experiment.

– She was not one of those hands-off PIs. She was the person that, in your lab meeting, she might be like, well, maybe you should use this percentage of SDS in your buffer.

– Yeah, that’s me. Yeah, that’s me.

[END PLAYBACK]

FLORA LICHTMAN: Alice works at Penn, too. She walks by Virginia’s portrait all the time.

[AUDIO PLAYBACK]

– I think it means a few things to me. One is just, she is one of the only women, but she’s so kick ass. There’s no kind of question, is this a nod to women or something like that, because she’s so much better. So that’s really meaningful to just have this total baller. But, beyond that, the important development in my life is that I think I used to apologize for myself more.

I’m a Taiwanese-American girl. I grew up in Jackson, Mississippi. I was socialized to be a polite, more reserved, keep my opinions to myself type of person. But she doesn’t apologize for herself. And it was kind of incredible to see this person, who’s also a Chinese-American woman, who is just right out there.

And I love that about her. I love that she is exactly who she is. She created that herself. I don’t think it was that all these people encouraged her and said, you’re so great. She did that on her own.

[END PLAYBACK]

[MUSIC PLAYING]

[AUDIO PLAYBACK]

– Virginia, in hindsight, is there anything you would have done differently?

– That’s a very good question. I mean, if I had known in my teens that I’m capable of doing a lot of great things, I don’t know.

– What is it making you think right now?

– Well, I– I’m lucky that I ended up on this path. That’s all I can say. In terms of my story, I would say that the most important person that made it happen was John Trojanowski.

– I don’t want to take anything away from John. But the most important person is you.

– Yes, but I think that he provided me with that emotional support, which I’ve never had, because I have never felt loved, ever–

– Until John.

– Yep.

[END PLAYBACK]

[AUDIO PLAYBACK]

– Virginia Lee is my wife of 44 years and my lab partner of about 38 years.

My wife and I, Virginia Lee is my colleague. We bike to work every day.

My esteemed colleague and partner, both in work and in life.

– And if you’re not really happy, then you don’t know what you’re capable of doing.

[END PLAYBACK]

[SOMBER MUSIC]

[UPBEAT MUSIC]

FLORA LICHTMAN: The Leap is a production of the Hypothesis Fund. The show is hosted by me, Flora Lichtman, and produced by Annette Heist. Editing by Devon Taylor, Pajau Vanga, and David Sanford.

Fact checking by Nicole Pasulka. Mixing and scoring by Emma Munger. Music by Joshua Budo Karp. Thanks to Emily Rizzo, Michel Goedert, Eddie Lee, Lisa Toole, and Alison Ward. Thank you for listening.

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