The Unassuming Revolutionary

Asian Scientist Magazine catches up with the inventor of optogenetics and CRISPR gene editing, Zhang Feng.

AsianScientist (Jan. 26, 2016) – Few biomedical scientists would fail to recognize the name Zhang Feng, despite his relatively short career to date. Just six years out of his PhD program at Stanford University, he can already lay claim to not one but two of the most revolutionary biotechnologies of the decade: optogenetics and CRISPR-Cas9 gene editing. And judging from our recent interview with him, the 34-year-old is only just getting started.

Yet Zhang comes across as unassuming and understated in person, thankful for the recognition and quick to share credit, but more interested in doing good science.

“I’m pretty lucky to be working with students, postdocs and collaborators who share the same passion for science,” he replied when asked about whether the many accolades he has received has made it pressurizing to perform. “I think it’s pretty good.”

A serendipitous stumble into neuroscience

By any standard, Zhang’s meteoric rise has been much more than ‘pretty good.’ Born in China to parents with an engineering background, Zhang remembers following his parents to work and being exposed to computers from an early age.

“There was a huge emphasis on science and technology in China when I was growing up, that was right after China opened up to the Western world,” he recalls. “I knew I wanted to be a scientist and build technologies.”

His parents were keen to help him realize his goals, even at the expense of their own careers. While in the US as a visiting scholar, Zhang’s mother was impressed by the school system and sought an opportunity to bring him over.

“She realized that I might be able to benefit much more in an environment which doesn’t just focus on rote learning and memorization,” Zhang shared.

Leaving academia and taking on a job as a computer engineer in Iowa, she worked alone in the US for about a year and a half before being able to bring the 11-year-old Zhang over.

At the age of 18, Zhang won third place at the Intel Science Talent Search for finding a protein that could prevent retroviruses like HIV from infecting human cells. Entering Harvard University on a full scholarship the following year, he majored in both chemistry and physics, wanting to “build a foundation in areas of science that don’t change as quickly,” despite his early success in molecular biology.

When the question of graduate school came up, he had originally planned to follow in the footsteps of his undergraduate mentor at Harvard, Professor Zhuang Xiaowei, who had done her postdoctoral training under the 1997 Nobel Laureate in Physics, Professor Steven Chu.

“So when I got to Stanford, I tried to find him. But when I knocked on his door, Karl [Deisseroth] came out instead,” Zhang shared.

It turned out that Chu had moved to Berkeley because he had just been appointed director of the Lawrence Berkeley National Laboratory. Deisseroth had taken over his office and lab space, but because it had happened so recently, the tag on the door still read ‘Steven Chu.’

That serendipitous encounter turned out to be a life-changing one. Zhang, who had been trying to get into neuroscience but was getting rejected because of his lack of background in the field, found in Deisseroth a mentor who was willing to take the risk of a relatively green graduate student. And Deisseroth in turn found in Zhang a talented and unusually perceptive student, whose skills would be, in his own words, “absolutely essential” to the creation of optogenetics.

Named ‘Method of the Year’ by Nature Methods in 2010, optogenetics has transformed the practice of neuroscience labs across the world. Instead of slow acting drugs or imprecise electrodes, optogenetics allows precise control over the activation of specific neurons in a spatially- and temporally-regulated manner, qualities absolutely essential for studying lightning fast transmission in the brain. It works by delivering light-sensitive proteins into the target cells, which then allow the researchers to switch those cells on and off simply by using light.

Reaching a roadblock

Despite the phenomenal success of optogenetics, there were still some shortcomings with the method that left Zhang feeling dissatisfied.

“Optogenetics has three components to it: the light-sensitive proteins, a system for using laser to send light to the brain and a molecular biology approach for limiting the expression of the light-sensitive proteins to specific groups of cells,” he explained.

The first two were well established by the time he was a graduate student, and Zhang had worked out the molecular biology in mice.

“Unfortunately, our approach did not apply to other animals, such as rats or monkeys. I wanted to see if we could target these light-sensitive genes into the genome of any animal, so that led me to genome editing tools like zinc-finger nucleases and transcription activator-like effectors (TALEs).”

By this time, Zhang had been offered a position at the Massachusetts Institute of Technology (MIT), joining as the youngest core member of the Broad Institute. He got to work teaching his students how to build TALEs, modular DNA-binding proteins that could be engineered to bind to a targeted stretch of DNA. Though simple in theory, building and optimizing TALEs in practice was difficult and laborious, often requiring a PhD student’s entire tenure; far too long for Zhang.

“I felt that if we wanted to do neuroscience, we can’t have a system that was so difficult to learn, because we’ll never get to the real question,” he said.

Broad Feng_1381_LenRubenstein

The CRISPR game changer

As luck would have it, he didn’t have to wait long before coming across a promising alternative. In February 2011, two months into his position at MIT, Zhang attended the annual scientific advisory board meeting of the Broad Institute. It was there that he first heard the word ‘CRISPR,’ which he promptly Googled and started reading up on.

First discovered by scientists at Japan’s Osaka University in 1987 as an unusual pattern of repeats of unknown biological significance in bacteria, CRISPRs were only given their name—clustered regularly interspaced short palindromic repeats—in 2002, by a group at Utrecht University in the Netherlands. The Utrecht group also noticed that CRISPRs were invariably followed by a group of genes encoding DNA-cutting enzymes, which they termed CRISPR-associated genes or Cas for short, but nobody yet knew what their function was.

It took scientists working on yogurt bacteria to finally figure it out and put the CRISPR-Cas system to use. Working with Streptococcus thermophilus used to convert lactose into lactic acid for cheese and yogurt production, researchers at the food manufacturer Danisco discovered that exposure to bacteria-infecting viruses caused S. thermophilus to incorporate some of the viral DNA into the spacers of CRISPR sequences. This effectively ‘vaccinated’ the bacteria against the virus, as the CRISPR sequences would guide the Cas enzymes to the viral DNA.

For Zhang, CRISPR was not simply a solution for sickly bacteria but the very technique he had been looking for.

“I thought, ‘This is amazing!’ Why don’t we try to see if we can engineer the system so that instead of having to tweak a protein to recognize a new sequence we can just make a short RNA?”

Working independently, Professor Jennifer Doudna at the University of California, Berkeley and Professor Emmanuelle Charpentier at Umeå University in Sweden came up with the same idea, showing in their 2012 paper in Science that artificial guide RNA could be used to edit genetic material in vitro. Later that year, Zhang also submitted a paper to Science demonstrating the same effect in mammalian cells.

The promise and perils of gene editing

Since then, interest in the CRISPR-Cas9 gene editing system has skyrocketed, as shown in the exponential rise in the number of publications in the field. The key has been the system’s ease of use; what used to take entire teams years to do can now be completed by a graduate student in a matter of months.

And scientists have already begun to put CRISPR-Cas9 gene editing to use in a wide range of applications, from breeding mildew-resistant rice to pigs that have had 62 genes edited at once, possibly making them suitable as organ donors for humans. More controversially, researchers from the Sun Yat-sen University in China have even used CRISPR-Cas9 on 54 human embryos, albeit non-viable ones that could not have resulted in live births.

Zhang is emphatic on how the technology should be properly used.

“Given the current state of things, we absolutely should not edit human embryos,” he stated. “If anything, the embryo editing study highlighted the current limitations of gene editing, namely a low efficiency leading to genetic mosaicism and off-target effects.”

Enter the venture capitalists

But that isn’t to say that Zhang believes the technology shouldn’t be used in humans at all. Zhang’s cautious optimism hasn’t stopped him, or any of the other co-inventors of CRISPR-Cas9 technology, from starting multi-million dollar companies to capitalize on their findings.

Zhang’s own Editas Medicine has plans to carry out CRISPR-Cas9 clinical trials for Leber’s congenital amaurosis (LCA)—one of the most common causes of childhood blindness—by 2017, backed by over US$160 million in Series A and B funding. Editas also has a collaboration with Juno Therapeutics to develop novel chimeric antigen receptor (CAR-T) and high-affinity T cell receptor (TCR) therapies to treat cancer.

“The mission of Editas is to use the latest advances in genome editing to develop treatments for very grievous human disease. With the new funding, the goal is to make the technology specific enough to deliver it efficiently in the body or to cells that have been removed from the body,” Zhang said.

Of patents and prestige

As alluded to previously, Editas is not the only player in the scene. Although Doudna was one of the co-founders of Editas, she had licensed her own patent to a company called Caribou Biosciences, breaking off the relationship with Editas when Zhang’s patent application was approved before her own. Charpentier, on the other hand, has sold her share of the same patent application to yet another rival company, CRISPR Therapeutics.

The scientific community itself is also divided over the issue of who really ‘discovered’ CRISPR. Zhang may have won the patent, but it was Doudna and Charpentier who were recognized with the prestigious US$3 million Breakthrough Prize in 2015. All three, however, were awarded the Jacob Heskel Gabbay award in 2014.

But in 2015, Zhang discovered a protein that could make the debate over credit purely academic. Called Cpf1, the protein is smaller and simpler than Cas9, making it easier to deliver into cells. Furthermore, unlike Cas9 which requires two pieces of guide RNA, Cpf1 requires only one RNA molecule that can be much shorter.

“The second difference is that when Cas9 targets DNA, it needs a small motif we call the protospacer adjacent motif or PAM motif. For Cas9 there is usually a purine-rich sequence of guanine or adenine. For Cpf1, the sequence requires thymine instead, allowing us to target a completely different set of genes,” Zhang explained.

The most importance difference, however, is that Cas9 makes a blunt-ended cut through the DNA double strand while Cpf1 makes a sticky end, making recombination a much more controlled process.

“Cpf1 is just one example; there are going to be many more useful enzymes to be found in Nature. Some will target DNA, some may even target RNA,” Zhang excitedly added. “I think the way forward is to stay humble and look to Nature for inspiration; it’s like going on a treasure hunt, looking for powerful new tools to improve human health.”

Staying focused

It is Zhang’s relentless focus on improving human health that has perhaps seen him achieve so much in so little time. While working on optogenetics, he refused to get excited by his positive results in cell culture until he finally saw how it could change the behavior of live and awake mice. Similarly, he resisted what must have been great temptation to carry on in the very hot field of optogenetics but was driven instead to bring the technology closer to human applications.

“It’s fascinating how when you are looking forward, you don’t really know how things are going. But when you look back, you can perfectly connect the dots and see how everything is linked together,” he mused.

The birth of his first child 18 months ago has only strengthened his resolve.

“I’ve been very fortunate to have a healthy child. But seeing her uncomfortable with something as simple as a cold or fever makes me realize just how important health is and reminds me that the work we’re doing to improve human health is worth it.”

This article was first published in the print version of Asian Scientist Magazine, January 2016.

Photos: Len Rubenstein/Broad Institute Communications.
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Rebecca did her PhD at the National University of Singapore where she studied how macrophages integrate multiple signals from the toll-like receptor system. She was formerly the editor-in-chief of Asian Scientist Magazine.

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