HomeOur ScientistsDavid C. Chan

Our Scientists

David C. Chan, MD, PhD
Investigator / 2008–Present

Scientific Discipline

Biochemistry, Cell Biology

Host Institution

California Institute of Technology

Current Position

Dr. Chan is also a professor of biology at the California Institute of Technology.

Current Research

Mitochondrial Dynamics in Development and Disease

David Chan studies how the dynamic behaviors of mitochondria within a cell are controlled and how they affect cell and tissue physiology. These studies have implications for a broad range of human diseases, particularly neurological disorders.

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Mitochondrial fusion protects against neurodegeneration...

Biography

Charcot-Marie-Tooth disease (CMT) is an awkward name for a puzzling genetic disorder. It was named in 1866 for its three codiscoverers who described it as a progressive, muscle-wasting disease. But CMT is not a disease of the muscles. It is a…

Charcot-Marie-Tooth disease (CMT) is an awkward name for a puzzling genetic disorder. It was named in 1866 for its three codiscoverers who described it as a progressive, muscle-wasting disease. But CMT is not a disease of the muscles. It is a neuropathy that degrades muscle indirectly by damaging the peripheral nerves, particularly the neurons that control movement and sensation of the distant toes and fingertips.

The neurons are directly affected in one type of CMT, called type 2. This is different from many other forms of CMT, where CMT-associated mutations affect the formation of the myelin sheath that electrically insulates the nerve axon. In 2004, researchers discovered that the gene most commonly mutated in patients diagnosed with type 2 CMT is Mfn2. Mfn2 affects the mitochondria——the cell's power plants——and that caught David Chan's attention.

Chan, a molecular biologist at the California Institute of Technology, is one of a small but growing number of researchers interested in mitochondrial dynamics. Mitochondria are ancient, but the field is not. Chan remembers presenting at the first international mitochondrial dynamics meeting, held in 2005, by which time he was almost an old-timer in the field. After all, he'd been in it for five years.

When Chan set up his lab at Caltech in 2000, mitochondrial dynamics wasn't so much a field as a puzzling observation: Why did the hundreds of mitochondria in the average mammalian cell constantly seek each other out, fuse, exchange contents, and then divide?

Among the organelles that populate human cells, mitochondria have always been a special puzzle. Mitochondria churn out the adenosine triphosphate (ATP) molecules that fuel everything in the cell, yet they have peculiar features. For one, mitochondria have their own DNA. It's a tiny, compact genome, 16 kilobases long, containing 37 genes but little noncoding, repetitive DNA. This is a suspiciously tidy genome for a eukaryote, especially in human eukaryotic cells, which carry in the cell nucleus a sprawling 3 billion-base genome that is about 95 percent noncoding. (To confuse matters, the nuclear genome contains many mitochondrial genes that have migrated there over the eons.)

Mitochondrial DNA reads more like the laconic genome of some ancient bacteria. Indeed, that's where many biologists believe that ancestral mitochondria originated a billion or more years ago. Captured by ancestral eukaryotic cells, the bacteria were kept as "endosymbiots," permanent houseguests earning their eukaryotic keep by cranking out ATP.

Visitors or not, mitochondria exhibit some noneukaryotic habits, including nonstop fusion and fission, both of which attracted Chan's attention. What do mitochondria gain from this strange dance? How do the many-membraned mitochondria merge and then separate? The mechanics were confusing enough, but first Chan wanted to see what happened to mitochondria that couldn't fuse. To do that, he created a mouse line in which he knocked out the mitofusins, the proteins necessary for fusion. With their mitochondria unable to mingle, cells from these mice rapidly lost energy and grew poorly. Mitochondria in a normal cell maintain a fairly uniform size and membrane structure. The nonmingling mitochondria lost that healthy uniformity.

Chan realized that the whole mitochondrial population of a cell has to constantly mix, mingle, and divide to keep individual mitochondria healthy. Whatever their evolutionary origins, mitochondria live as a community, averaging their strengths and weaknesses, including, as Chan also discovered, missing copies of mitochondrial DNA.

Like a stone thrown into a still pond, the revelation sent Chan's research interests radiating in all directions, from atomic scale x-ray crystallography to human medical genetics. Chan's lab is deeply involved in studying the basic molecular mechanics of fusion and fission. He has also followed the impact of lost mitochondrial dynamics in mice, finding severe impacts on placental tissue, on neurons in the cerebellum, and on skeletal muscle.

He has traced the connection of mitochondrial dynamics not only to human diseases such as CMT but also to neurodegenerative disorders, and most recently, in "natural" human aging. "It has been known for a long time that as people age, their mitochondrial DNA accumulates damage and their mitochondrial function declines," explains Chan. "It's been suggested as one of the reasons that we lose muscle strength as we age. But it's never been known if it's causative or secondary."

Chan now wonders if mitochondrial fusion itself is a controlling factor in how fast our brains and muscles age. Could aging cells be protected or rescued by boosting mitochondrial mixing? With good animal models, a strong lab, and now HHMI investigator status, Chan intends to find out.

Chan was born in Hong Kong but came to the United States when he was two, growing up in New York City and Baltimore. He was a student at Harvard College and an M.D./Ph.D. student at Harvard Medical School under former HHMI investigator Philip Leder. After Harvard, Chan went on to do postgraduate work on HIV with former HHMI investigator Peter Kim at the Whitehead Institute for Biomedical Research.

And then Chan changed directions. He'd never worked on mitochondria before, but the fusion-fission question fascinated him. His mentors worried that his new research subject was too drastic a detour into an unproven area. His family worried that he was lost to clinical medicine. Chan remembers just following his instincts. "When I started my lab, we were just working on the basic biology," he recalls. "There was no obvious disease relevance, but in the last two years there's been much more interest in the human biology of this and the relevance to medicine. It was not what I planned, but I'm very pleased that it's going in that direction."

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Education

  • BA, biochemical sciences, Harvard College
  • MD/PhD, genetics, Harvard Medical School

Awards

  • Ellison Medical Foundation Senior Scholar
  • Beckman Young Investigator
  • Mitochondrial Research Society Young Investigator