Feature Story Winter 2016 Issue 36

Feng Zhang: Pioneer of CRISPR Genome Editing

Feng Zhang has launched a biotechnology revolution through his pioneering development of CRISPR genome-editing tools. Photo: Justin Knight
Feng Zhang has launched a biotechnology revolution through his pioneering development of CRISPR genome-editing tools. Photo: Justin Knight

Feng Zhang was not yet 30 when he arrived at MIT in 2011 to set up his own research group at the McGovern Institute and the Broad Institute of MIT and Harvard. In a previous interview with Brain Scan in the fall of 2012, he spoke with reserve, a quiet up-and-comer working on microbial genome editing tools called TAL-effectors.

A few months later, in January 2013, he dropped a bombshell. He published a paper in Science demonstrating a new genome editing method called CRISPR. Zhang’s paper, along with a parallel paper from Harvard geneticist George Church, showed for the first time that a bacterial enzyme called Cas9 could be used to change DNA sequences in human cells, far more easily than any previous method. Suddenly, it was possible to find and edit genes in the genome almost as simply as text in a Word document.

CRISPR was originally identified in bacteria, in which it provides protection against attack by viruses. AMI Images/Science Photo Library / Broad Institute

CRISPR was originally identified in bacteria, in which it provides protection against attack by viruses. AMI Images/Science Photo Library / Broad Institute

This feat was immediately recognized as a major breakthrough, and it unleashed a torrent of activity that continues to this day. The technology has now been used to engineer the genomes of mice, rats, flies, worms, zebrafish, dogs, and many other species, including human stem cells. Nearly 2000 papers on CRISPR have appeared since Zhang’s original publication, and several companies have been launched to commercialize the technology, attracting hundreds of millions of dollars in investments. CRISPR has generated a whirlwind of media attention and Zhang himself was profiled in the New Yorker and in the newly launched publication STAT, which described him as “the most transformative biologist of his generation.”The CRISPR technology has been so influential that it was named by Science as the top breakthrough of 2015.

It is no exaggeration to say that Zhang’s work has started a biotechnology revolution. But Zhang himself, who prefers the lab to the limelight, has remained focused, publishing over 40 papers since the seminal report in Science. In October, he surprised peers at a scientific meeting by presenting a second, alternative CRISPR tool that provides new functionalities compared to the earlier technology. The room rippled with excitement at the speed of his progress.

In addition to developing and sharing new tools, Zhang uses them in his own lab to study many diseases, including autism, schizophrenia, and Alzheimer’s disease. “We don’t just want to test tools, we want to use these tools in real-world applications,” Zhang says. “Understanding the limitations of the technology fuels our ideas for further development.”

Trend Setter

Zhang’s interest in genome editing traces back to his childhood. In 1993, at age 11, he moved with his mother, a computer engineer, from China to Des Moines, Iowa. He spoke only a little English, but within a year he had mastered the language and enrolled in a special molecular biology class offered by his middle school. As part of the class, he watched the movie Jurassic Park, in which dinosaurs are resurrected using the power of fantastical biological engineering. He realized that biology might also be a programmable system, similar the computers his mother coded.

Zhang was hooked. Through his school, he found an opportunity to volunteer in a local gene therapy lab, where he engineered human melanoma cells to glow by inserting a fluorescent green jellyfish protein, and then showed that the protein could protect the cells from DNA damage by absorbing UV light. The experience taught him that biological tools had great potential to fight disease.

Le Cong (left) and Fei Ann Ran were among the first to join Zhang's lab, and were co-authors on the first CRISPR genome-editing paper. Photo: Justin Knight

Le Cong (left) and Fei Ann Ran were among the first to join Zhang’s lab, and were co-authors on the first CRISPR genome-editing paper. Photo: Justin Knight

Following a degree in chemistry and physics from Harvard, a PhD in neuroscience from Stanford and a prestigious Harvard junior fellowship, he had just arrived at MIT and the Broad Institute and was starting to build his own group in 2011, when CRISPR first appeared on his radar. Zhang read a paper from a Canadian lab showing that CRISPR (which had been studied by many labs since its first discovery in 1987) uses short pieces of RNA to find a specific DNA sequence, and a single enzyme, now called Cas9, to cleave them. “This paper got me really excited,” Zhang says. “We were working on genome editing with TAL effectors, where the DNA sequence is recognized by a protein. But if we could use RNA instead, it would be much simpler to design because the code is much simpler.”

Indeed the matching of RNA to DNA is as simple as a child’s decoder-ring, substituting one letter for another. Zhang’s excitement grew as he read every paper he could find about CRISPR and began to envisage the possibilities. He recalls sitting at a kitchen counter and sketching a roadmap for development: First, understand the biology and improve the technology; second, develop applications; and third, share the tools widely with other researchers.

For step one, he enlisted the help of his earliest lab members, including then graduate students Le Cong and Fei Ann Ran. The team focused on a key goal: altering the bacterial CRISPR system so that it would work in human cells.

When they began, it was far from clear whether this goal was possible. The human genome contains 3 billion letters, equivalent to six feet of DNA, packed into every cell nucleus, so locating a single target site is like finding a needle in a haystack. Yet, Zhang and his team were able to engineer CRISPR to make precisely targeted changes with remarkable efficiency, as described in the pivotal 2013 Science paper, on which Cong and Ran were joint first authors. “I’ve been lucky to have amazing postdocs, students and colleagues,” says Zhang. “I feel like a kid in a candy store here at MIT.”

Use Cases

Step two of Zhang’s road map is to develop practical applications, particularly in the field of brain disease. Over the past few years, many studies have identified genes linked to autism, schizophrenia, bipolar disorder, and other disorders. Zhang wants to use CRISPR to speed the systematic study of these genes, to understand how they influence disease processes and how these effects might be reversed.

The Zhang lab is using CRISPR to study the effects of autism mutations in human neurons. Image: Neville Sanjana

The Zhang lab is using CRISPR to study the effects of autism mutations in human neurons. Image: Neville Sanjana

One example is autism, which Zhang’s lab is studying using human neurons engineered with CRISPR to carry mutations linked to the disorder. By studying these neurons in culture, he hopes to identify differences that may contribute to the development of autism and which could be potentially targeted in future therapies.

Zhang’s lab is also using CRISPR to study genes that may cause or protect against Alzheimer’s disease and to study the development of drug resistance in cancer. Another focus is on the creation of animal models of brain disorders. For example, he is collaborating with Mriganka Sur of MIT’s Picower Institute to create mouse models of Rett Syndrome and with McGovern Investigator Guoping Feng to create
models of autism and schizophrenia.

An important challenge for research and therapy is to deliver the CRISPR reagents to the relevant cells within the body. One way to do this is with viral vectors used for gene therapy, but the Cas9 enzyme is large and difficult to deliver. “We wanted to make it more compact,” Zhang says. “So we thought, maybe there are other, smaller alternatives out there in nature too.”

Zhang and his collaborators scanned the genomes of other bacterial species, searching for other proteins and systems that might be considered. One that appeared particularly attractive was a protein called Cpf1, and Zhang, along with his collaborator Eugene Koonin, announced last October that they had successfully harnessed Cpf1 for genome editing. Soon after this, Zhang, Koonin and Konstantin Severinov identified three additional CRISPR enzymes that could also be used for genome editing.

Sharing the Knowledge

As outlined in step three of his roadmap, Zhang has made it a priority to share his methods widely, and his CRISPR reagents have already been distributed over 27,000 times, at nominal cost, via a sharing service called AddGene. “New technologies need to be made accessible,” he says. “It’s very important to make sure what you build is easy to use and openly available.”

Biotech investors were also quick to recognize the potential of CRISPR, and several new companies have been launched to develop CRISPR for human gene therapy and other practical applications. With four other scientists, Zhang co-founded Editas Medicine, which has licensed his CRISPR-Cas9 patents from Broad and MIT and which hopes to develop CRISPR-based treatments for human genetic disease. An early target is retinal blindness—for which the company expects to begin human trials in 2017—and treatments for more complex disorders could follow. “It would be a dream to be able to treat diseases like ALS (amyotrophic lateral sclerosis), Rett Syndrome, or Parkinson’s,” says Zhang. “We think CRISPR could provide a completely novel way to treat these devastating and untreatable diseases.”

Step Wise

Since his arrival at MIT and the Broad Institute in 2011, Zhang's lab as now grown to more than 30 people. Photo: Justin Knight

Since his arrival at MIT and the Broad Institute in 2011, Zhang’s lab as now grown to more than 30 people. Photo: Justin Knight

The implications of CRISPR for science and medicine are exciting, but the notion of easy genome editing has also raised concerns about the prospect of “designer babies,” and unforeseen effects if engineered genes spread into the environment. CRISPR has already been used to engineer food crops, research animals and even genetically altered pets.

Well aware of the potential concerns, Zhang is among many scientists working with the National Academies of Sciences and Medicine to consider guidelines for the ethical use of genome editing. But he also remains inspired by the possibilities, especially for brain research. CRISPR has the potential to help scientists understand how brain diseases rob people of social connections, happiness and memories, and it could, someday, guide the way to new therapies. “My hope is that CRISPR will live up to its promise by being used responsibly,” he says.

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