Developmental Biology, Genetics
Institute of Biophysics, Chinese Academy of Sciences
Dr. Zhang is an investigator at Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Caenorhabditis elegans as a Genetic Model System to Study Autophagy
Hong Zhang was in an enviable position. A postdoc studying genetics at Harvard, he had recently won a major award and his wife and two children were settled happily in the United States. But when the director of Beijing’s brand-new National Institute of Biological Sciences contacted Zhang, he agreed to go back to his native China for a job interview.
That was in 2004. “At that time it was not like now. People wondered, ‘Can China do good science?’” Zhang remembers. The risks of taking the job came sharply into focus when he walked through the near-empty building that housed the institute. Just setting up a lab there would be a challenge, Zhang realized—indeed, he later needed to strike a special deal with a supplier just to get basic equipment for his research. On the other hand, the institute, part of a nascent push by the government to beef up biology research in China, would provide generous annual funding with no need to apply for grants. Zhang saw that joining the institute would be a risk but knew that if he succeeded, he could be a pioneer in life sciences research in China. He took the challenge.
Zhang first decided to study biology when a childhood teacher of his was diagnosed with cancer—he found himself captivated by the mystery of the disease. But as he pursued further education in biology, he became more interested in genes than in tumors, so in graduate school at Albert Einstein College of Medicine he joined a lab that studied genes regulating the development of the worm Caenorhabditis elegans. As a postdoc in the Harvard Medical School lab of Daniel Haber, now an HHMI investigator, he continued to work with C. elegans while also branching out into mouse genetics.
Once Zhang got his lab in China up and running, his team began genetic screens on C. elegans, looking for mutants in which some cells didn’t develop correctly and then identifying the genes responsible. While looking for genes involved in the process by which cells acquire their characteristics during development, his team stumbled on something particularly interesting. They discovered a novel set of genes involved in breaking down unneeded parts of the cell, a process called autophagy.
Previous studies on autophagy genes had relied on yeast, with the belief that autophagy was similar in these single-celled organisms and in higher ones. But Zhang’s lab turned up a collection of autophagy genes that didn’t exist in yeast. One of these genes, SEPA-1, specializes in breaking down P granules, a type of protein clump. “It took me a while to realize this was a very important finding. … I didn’t know much about autophagy genes,” Zhang explains. “At that time no one knew how protein aggregates are removed.”
The exact function of P granules is not known, but they are normally found only in germline precursor cells—cells destined to become eggs or sperm. P granules are also found in some other cell types, but autophagy quickly clears them out. SEPA-1, as the first protein found to target a specific aggregate protein for autophagy, is an important clue to how aggregates might be removed from these cells.
Zhang has followed up his serendipitous finding with more research on genes that remove P granules and other types of protein aggregates from cells and on the mechanisms behind these processes. These questions have important medical implications, since buildup of other types of aggregates in cells can lead to diseases such as Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis (Lou Gehrig’s disease). Zhang is also scrutinizing the role of autophagy genes in shaping animal development. His lab generated mice deficient for the metazoan-specific autophagy genes Ei24and Epg5. They are using these mice to study the role of autophagy in mammals.
Less than a decade after accepting the offer to return to China, Zhang is confident he made the right decision. His publications showed for the first time that C. elegans is a fruitful system for studying autophagy, leading other scientists to follow suit. And Zhang estimates that about 20 labs in China now use C. elegans as their main model system, up from 0 in 2004. Yet Zhang’s core fascination is not with autophagy or C. elegans but with the genes that underlie them both. “I’ve always enjoyed the beauty of genetics,” he says. “It gives you interesting things that you can explore.”