Feature Story Fall 2012 Issue 25

Feng Zhang: A Voyage from Science Fiction to Science Fact

Feng Zhang in his laboratory with graduate student Patrick Hsu. Photo: Justin Knight
Feng Zhang in his laboratory with graduate student Patrick Hsu. Photo: Justin Knight

Feng Zhang was born in China in the early 1980s, a period of reform when the country was opening itself to outside influences, and its people were becoming fascinated with science. During that time, Chinese writers started dabbling in a new genre: science fiction.

Zhang, who joined the McGovern Institute in 2011, was hooked. “Chinese writers were opening their minds and imagining what the future might be like,” he recalls. In those days, if he wasn’t busy building things with Lego-like toys, he had his nose buried in sci-fi books.

Fast-forward twenty years or so, and Zhang’s work now reads as if sprung from the pages of a sci-fi novel. His first major research project, as a graduate student at Stanford, was to control the brains of mice using laser light. Now, he is adapting proteins from microorganisms and using them to edit the genome — a “find/replace” tool for DNA sequences, which he hopes will make it possible to change the genome of any organism, and to switch genes on and off at will. This would have profound implications for many fields of research, but Zhang himself hopes to use it to understand the brain. In particular he hopes to create new ways to study the origins of brain disorders.

To Boldly Go

Zhang, who holds a joint appointment at the Broad Institute, credits a high school mentor for setting him on the path to success. At age 11 he had moved from China to Des Moines, Iowa, and through a school science program he had the opportunity to work in a local lab that was researching gene therapy. His mentor gave him a piece of advice that has stuck with him ever since. “He told me I should work on things that are on the sexy side of practical,” recalls Zhang. “It was a good way to put it. I want my work to be useful without ever being dull.”

From Iowa, Zhang went on to Harvard, where he majored in chemistry and physics, bedrock subjects for modern science. But after graduation, he was ready for a new challenge and decided to study the brain. “Neuroscience seemed like a frontier,” he explains. “There was so much that was still unknown.”

He moved to Stanford University and in 2005 joined the newly formed lab of Karl Deisseroth, who along with Ed Boyden (now a McGovern Investigator) had recently begun to develop a revolutionary new method for controlling brain activity with light. The method, which came to be known as optogenetics, involved taking light-sensitive proteins from microorganisms and expressing them in neurons, making it possible to control the neurons’ electrical activity with extraordinary precision.

Zhang’s first assignment as a starting graduate student was to find a way to express channelrhodopsin reliably in neurons, using technologies based on gene therapy with which he was already familiar. The project succeeded beyond all expectations, and it transformed Zhang’s career. Within five years he had published 11 papers, an impressive track record for any student. His work attracted wide recognition; by the time he completed his PhD, optogenetics had been named by Nature Methods as its 2010 “Method of the Year” and by Science magazine as one of the most important tools of the past decade.

Fast, Cheap, and Ingenious

On the strength of his track record as a student, Zhang was awarded a prestigious Harvard Junior Fellowship, allowing him to bypass the usual postdoctoral apprenticeship and to begin to do independent research. Optogenetics had opened his eyes to the power of “synthetic biology,” the idea of engineering living organisms based on tools borrowed from nature. But to take full advantage of the potential of optogenetics, further technical advances would be needed. The brain contains hundreds, perhaps thousands, of cell types, packed together and connected in networks of extraordinary complexity. To make sense of this complexity, Zhang needed a way to specifically target the light-sensitive proteins to certain cells but not others.

The best way to do this was by modifying the genome, taking advantage of the organism’s own ability to express different genes in different cell types. While this was possible in certain species such as mice, it was still a painstaking process. Zhang wanted
a better method.

Structure of a TAL effector protein wrapped around a DNA double helix. Image based on data from Mak et al., Science 2012.

He chose to work with George Church at Harvard Medical School, a pioneer in DNA research and one of the leaders of the human genome project. On the lookout for ideas, Zhang learned through a pair of papers published in Science in 2009 about a protein from bacteria that infect rice plants. This protein, known as a TAL effector or TALE, is used by bacteria to subvert the plant’s natural defenses. It does this by binding to specific DNA sequences in the plant genome, switching on plant genes that are helpful to the bacterium. The protein was of particular interest because its DNA-binding domain had a simple modular structure — much like the Lego pieces Zhang played with as a child — raising the possibility that it could be artificially engineered simply by rearranging the order of the individual modules.

“We were hunting for something like this but never expected to find it in nature,” says Le Cong, a graduate student who collaborated with Zhang at Harvard and later followed him to MIT. Working together in Church’s lab, Zhang and Cong devised a way to build artificial TALEs with the modules assembled in any desired order. Their method was much faster and cheaper than any existing alternative, and it allowed them to uncover a set of simple design rules for building TALEs that would recognize any desired DNA sequence. “It was as if for any given lock we could design a key to fit,” says Zhang.

New Frontiers

The potential is enormous, and goes far beyond their original idea of targeting light-sensitive proteins to specific neurons. TALEs can be used to switch genes on or off, allowing cells to be reprogrammed. They can also be used as “molecular scissors” to make targeted cuts in the DNA sequence, and to introduce genetic changes that will be passed to the next generation.

There are many potential applications, but Zhang’s immediate goal is to enable basic research including the creation of new disease models. For example, once human disease genes are identified, Zhang’s method will allow researchers to express them in animals and to understand how they work to cause disease. TALEs may also be useful for creating stem cells that could be used to study, and perhaps even treat, human disease.

Perhaps the most exciting possibility is that TALEs could be used therapeutically to treat patients with genetic disorders, by silencing a mutant gene or activating its healthy counterpart, or even by editing the genome to correct the damaging mutation. Treating brain disease in this way will be challenging, but Zhang is undeterred. He points to the example of gene therapy, recently approved in Europe for the first time, to treat a rare metabolic disorder. “The idea of gene therapy in any form would have been considered science fiction until recently,” says Zhang. “We should not be near-sighted when looking to the future.”

Making History from Fantasy

Zhang with graduate student Silvana Konermann.

For all its engineering sophistication, Feng’s approach is simple in its essence. “To understand how biological systems work, we need tools to perturb them,” he says. “My goal is to make that possible.”

Guoping Feng, a long-time collaborator and now a McGovern colleague, says Zhang “thinks in terms of bigger questions than a single disorder, and he wants to develop tools across the board, not just for neuroscience.” He adds, “It fits his personality. He is ambitious, creative, and pragmatic.”

He is also a good citizen, making his methods freely available to other researchers. He created a website devoted to making TALEs widely available and to sharing his own lab’s expertise with other researchers worldwide. “As a tool builder, you want your tools to be used,” says Zhang. “Otherwise, what are you really contributing?”

His track record of innovation has landed Zhang many awards, including a McKnight Technological Innovations in Neuroscience Award, a National Institutes of Health Transformative Research Award, the Perl /UNC Neuroscience Prize (shared with Ed Boyden and Karl Deisseroth) and, most recently, in 2012, one of ten NIH Director’s Pioneer Awards, which aim to fund exceptionally creative scientists with pioneering approaches to research.

Meanwhile Zhang spends as much time as he can where he is happiest, working in the lab to test his latest ideas. He appreciates having lab space both at the Broad and the McGovern Institutes, surrounded by experts in both genomics and neuroscience, where ideas can be cross pollinated between different fields. “You never know where the next idea will come from,” he says. As someone who has made a career taking natural inventions from the microbial world and using them to manipulate the brain, Zhang’s own success provides strong support for his argument — and an illustration of how, in the hands of the right scientist, history can be created from fantasy.

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