Vilcek Prize for Creative Promise in Biomedical Science
Feng Zhang’s promise is readily apparent in his many accomplishments, but the young molecular biologist says he is only getting started. At the age of 36, Zhang, a professor of neuroscience at the Massachusetts Institute of Technology, has been painted a wunderkind in the popular press for work that was declared groundbreaking almost as soon as it was published. The youngest person to be appointed core member at the Broad Institute of MIT and Harvard in Cambridge, Massachusetts, Zhang developed transformative molecular biology tools that have boosted genetic engineering and neuroscience.
Born in China’s Hebei province, Zhang immigrated to Des Moines, Iowa, at age 11 along with his mother, who strived to provide a solid American education for her son; his father, who worked as a university administrator in China, joined them a year later. Arriving in Des Moines to a nurturing school environment, Zhang quickly got up to speed and learned English.
His interest in biology was piqued in middle school during a screening of Jurassic Park. The film’s premise—that dinosaurs are resurrected from fragments of ancient DNA preserved in amber—gained a hold over his imagination, sparking a lifelong fascination with molecular biology. “As a child, I always liked to take things apart and put them back together. So the fact that you could do it with living things was really exciting,” Zhang says. With the encouragement of an early mentor, he volunteered at a nearby gene therapy lab through an after-school program for gifted students. There, another mentor put him through his paces as he picked up molecular biology skills in double-quick time. Thanks to an Intel Science Talent Search scholarship, Zhang applied to Harvard University and was admitted to a bachelor’s program in chemistry and physics in the fall of 2000.
At Harvard, under the guidance of biophysicists Don Wiley and Xiaowei Zhuang, he further honed his skills. Around this time, Zhang’s close friend at Harvard began to suffer debilitating bouts of depression that forced him to take a hiatus from school. Impelled by his friend’s plight, Zhang resolved to study neuroscience upon graduating from Harvard in 2004. So he joined the Stanford University lab of another prodigy, Karl Deisseroth, whose star, like Zhang’s own, was on the ascendant.
Working with Deisseroth and fellow graduate student Ed Boyden, Zhang developed key elements of an approach dubbed optogenetics, which uses light to control the activities of brain cells in living animals. “If you can change the electrical potential on the membranes of brain cells using light, you can control the cells,” he explains. Zhang engineered light-sensitive proteins called channelrhodopsin and halorhodopsin into the neurons of freely moving mice using a virus-based gene targeting and delivery system. With this tool, neuroscientists can use light to trigger or suppress neuronal firing and precisely manipulate animal behavior, allowing them to map circuits underlying normal brain functions and study their dysfunction in mood and movement disorders.
Zhang returned to his alma mater in 2009, joining the Harvard Society of Fellows. There, he began to lay the groundwork for his next major contribution to science. Working with proteins called zinc finger nucleases and TALENs, Zhang attempted to edit the genomes of mammalian cells with a view to engineering them. Although he ultimately succeeded in this goal, he was painfully aware that those proteins were too cumbersome for many applications. In early 2011, as he explored other ways to achieve efficient and precise genome editing at the Broad, Zhang attended a talk by a fellow scientist, who described a natural genetic toolkit that some bacteria use to fend off invading viruses. Dubbed CRISPR-Cas9, the toolkit represents a rudimentary form of bacterial immunity, and Zhang realized at once that it could be co-opted for editing genes and perhaps made to work in human cells. The resulting CRISPR-Cas9 genome editing module was elegantly simple: A snippet of RNA guides the DNA-cleaving Cas9 enzyme to a matching sequence in the genome, whereupon the enzyme cuts the DNA, inactivating the target sequence. Cells stitch the genome back together using DNA repair mechanisms that sometimes rely on a reference template provided by researchers. By introducing a template containing a desired sequence, researchers can direct the edit, eliminating, for example, disease-causing mutations. Because guide RNA sequences can be designed to target any gene of interest, this engineered CRISPR-Cas9 system represents a powerful tool to edit genomes with breathtaking ease.
Several researchers made key contributions to the field of CRISPR genome editing, including molecular biologists Sylvain Moineau, VirginijusSiksnys, Emmanuelle Charpentier, and Jennifer Doudna. But it wasn’t until Zhang’s team demonstrated the use of engineered CRISPR-Cas9 to edit the genomes of living mouse and human cells in 2013 that its full potential became evident. In everyone’s view, Zhang’s article in Science is a landmark that transformed molecular biology. Today, thousands of researchers use this molecular scalpel to edit DNA for research and potential therapeutic purposes. For example, researchers have demonstrated that the method can be used to treat muscular dystrophy and glaucoma in mice, render human cells grown in lab dishes resistant to HIV, and help create food crops and livestock with desirable traits. A handful of clinical trials are planned or underway, including one for a rare eye disease called Leber congenital amaurosis type 10 that is on the horizon for Cambridge-based Editas Medicine, a company that Zhang co-founded.
Zhang and his team have continued to improve and expand CRISPR-mediated genome editing. In 2015, they reported the characterization of the enzyme Cpf1, which offers advantages such as simplified guide RNA architecture. A few years later, he harnessed Cas13a, a programmable RNA-guided enzyme that edits RNA, instead of DNA, expanding the CRISPR toolbox and providing a basis for developing molecular diagnostic tests for infectious diseases. Zhang’s contributions have earned him many honors, including Canada’s Gairdner International Award, Taiwan’s Tang Prize, and the Albany Medical Center Prize.
Zhang continues to apply his gift for molecular biology and penchant for neuroscience in studying the molecular underpinnings of neuropsychiatric diseases, hoping to identify novel therapeutic approaches. No doubt his uncommon talent was crucial to the success he enjoyed so early in his career, but the unwavering support he received in his new home in America was an important catalyst, he says: “This prize is a recognition of all the Americans who welcomed an immigrant into their society with open arms.”
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