An interest in neurodegenerative diseases drove Junying Yuan to study cell death as a graduate student at Harvard University. Now a full professor at the hallowed institute, Yuan is moved by the same interest in a new direction—the removal of misfolded proteins.

Text and Interview by Nicole LeBrasseur

Cellular suicide, or apoptosis, has its up side. It keeps cancer in check and helps prune extra cells during development. But at the wrong time or place, apoptosis can have devastating consequences, as seen in stroke victims and patients suffering from Alzheimer's and Huntington's diseases.

Among the first scientists who dissected the cellular mechanism of apoptosis was Junying Yuan, who cloned the first two genes needed for cell death in worms, ced-3 (1) and ced-4 (2). She found that ced-3 and its mammalian counterpart encode the cell's executioner—a cysteine protease (3) that is now known as the prototypical caspase.

Recently, Yuan received a Pioneer Award that unveiled her lab's new interest in the removal of misfolded proteins from a cell. We caught up with Yuan to discuss her interests, including how this new path intersects with cell death.

A REVOLUTIONARY EDUCATION

How did you get your start in science?
 Both of my parents and others in my family were involved in science—they were doctors and engineers. But that career option was not a possibility for me when I was growing up in China. That was during the Cultural Revolution, so essentially all the universities were closed. I was considering whether I wanted to be a farmer or a factory worker; those were the options.

But I was a good student, and I had a high school teacher, Mr. Lu, who believed that I should go to college somehow. Normally, someone from a family like mine—intellectuals—would have been sent to a remote farm to work, but he helped me stay in Shanghai, where I worked in a factory on heavy machines.

Fortunately, at that time, the Cultural Revolution was ending, and China reinstituted college entry exams. Mr. Lu asked me to study the old high school curriculum, from before the Cultural Revolution, because my education had been really basic and elementary. You know, every semester English started with, “Long live Chairman Mao” [laughs].

So I studied for four months really, really hard. They estimated that probably more than 100,000 people took the exam, and I actually scored the highest. And I went to Fudan University in Shanghai.

When I needed to decide what to study, my grandfather, who was a professor of organic chemistry, told me, “Study biology, it's good for girls. And chemistry is also very interesting.” He said the combination of chemistry and biology, meaning biochemistry, would be the thing of the future.

What made you decide to leave for the States?
 That was also a coincidence, because when I was in college, it wasn't really possible to leave the country to study. But my mother was a professor at a medical school, and she told me that she heard rumors that the best student in her college would be sent abroad to study. So I applied to graduate school in her medical college, and I again scored best on the entrance exam.

That qualified me to take another national test sponsored by Harvard. They had organized a program to bring Chinese students to top graduate schools in America. That's how I got to Harvard.

MORBID INTERESTS

How did you get interested in cell death?
 One of the courses I took at Harvard was called Neurological Diseases, and they actually brought in patients who had diseases like Alzheimer's and Huntington's. That left a really deep impression on me. Even today, I can remember exactly what that Huntington's patient looked like.

I also took a class on developmental neurobiology. At the time, classical work done by Ron Oppenheim and others had shown that up to 50% of neurons die during development. I was intrigued that cell death, something associated with disease, was also associated with a beautiful thing like development.

At the end of the courses, I concluded two things. The first was that all of these neurodegenerative diseases are caused by the selective death of specific populations of neurons that should not have died. I thought it was striking that early in embryonic development you can have very orderly, selective neuronal death. And later on in life, you can also have very selective neuronal deaths. It was a first-year student's fantasy, but I thought, “There may be some similarities between them.”

graphic

Aggregates (left) of mutant proteins (green) with polyQ expansions kill neurons. Preventing aggregation (right) saves neurons and might help treat diseases such as Huntington's.

YUAN/MACMILLAN

I even talked to some professors about it. But their response was always negative, because nobody believed that cell death was something interesting or regulated. They just thought neurons died in Alzheimer's because they were poisoned, and neurons died in development because they were starved to death by a lack of growth factors.

The second thing I concluded was that, although we were hearing lectures from eminent physicians, they really didn't know anything about these diseases in terms of mechanism. All they could tell the patient was which way they were going to die. And if I were the patient, I really wouldn't care which way it was; they were all pretty bad. That made me interested in cell death as a biological mechanism.

You got your Ph.D. from Harvard even though you worked in an MIT lab. How did that come about?
 Nobody at Harvard then was studying cell death. So I went to our graduate director, Ed Kravitz, and said, “I cannot find a lab that I want to work in here.” Thinking back, anybody else would probably have thought I was so arrogant—I'd just recently arrived from China, and I definitely didn't speak English well. “What do you mean? None of the hundreds of labs here would be good enough for you?” Fortunately, Ed was really nice to students, and he said, “Oh, if you can't find a lab here, you can work in Cambridge,” meaning on the Harvard main campus because I was at the medical school, “or you can even go to MIT.”

That made me really happy because I had just heard Bob Horwitz from MIT talk about cell death in C. elegans. He believed that there were cells that were determined to die, just like there are cells determined to be a neuron. It was striking to me that his ced-3 and ced-4 mutants had such specific defects in cell death, and nothing else seemed to be wrong with them. I thought those were the most interesting mutants I'd ever heard of. So I ended up in Bob Horwitz's lab, but with a degree from Harvard.

ENTERING A NEW FOLD

That's where you started your famous work on caspases and cell death. But you were recently given a Pioneer Award to study the removal of misfolded proteins. What's the connection?
 From all this work, I've realized that even though apoptosis and caspases are contributing to many neurodegenerative diseases—Aβ can induce apoptosis in Alzheimer's, PolyQ can induce apoptosis in Huntington's—for most of these diseases, inhibiting cell death will be too late for the patient. The disease actually starts with neuronal dysfunction caused by these proteins. In many cases, the mutant proteins manifest as an accumulation of misfolded proteins. So I think it's very important to learn how cells normally remove misfolded proteins.

Maybe the best example is Huntington's disease. The penetrance is 100% when they have PolyQ repeats longer than 40-something. The key, though, is why does this person live fine for 40 or 50 years, and then all of a sudden have Huntington's disease? It's not because these patients don't express PolyQ proteins when they're young. It's pretty much always around.

graphic

Disease-associated neuronal death can happen by apoptosis (left) or via an unusual pathway Yuan's lab named necroptosis (right).

YANG/MACMILLAN

So we're hoping to understand what tips the threshold. Because if we can push that back another 10 or 20 years, it will mean a cure for many of these people.

What are you learning about misfolding and disease now?
 I don't want to give away too much of our progress yet. But the key I think is accumulation. And what leads to accumulation must be the degradation mechanism—it's somehow defective.

Do you think the Pioneer Awards are a promising avenue for medical research?
 I think they are very good. What it does most for me is really free me from writing grants all the time instead of doing more productive work. I can follow the work in the lab better, I can really think more in depth about the projects. It gives me more time with my students and postdocs.

The Pioneer people are looking for someone to do things that are different from what they originally studied, but the hope is to spark creativities in the differences. The other thing they look for is a good track record of creativity, a willingness to stick your neck out and do something different. That pushed me toward working on a subject that I honestly wouldn't have worked on otherwise.

References

References
1.
Yuan, J., et al.
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2.
Yuan, J., and H.R. Horvitz.
1992
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Development.
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–320.
3.
Miura, M., et al.
1993
.
Cell.
75
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653
–660.