蘑菇视频APP

Jason Pontin: What was your experience of moving from China to Iowa at the age of 11?

Feng Zhang: I was born in China, and I went to elementary school in China before immigrating to the U.S. with my parents. I feel very lucky to have immigrated to the U.S. The school system in China is very much about rote memorization, but in the U.S. the teachers encouraged us to pursue things that we found interesting. I liked to take things apart, and the school had plenty of classes and outside activities that encouraged kids to experiment and learn how to build robots or interesting devices.

JP: Can you recall what most startled you about America?

FZ: Of course China has many, many more people than the U.S. When I first moved to Iowa, I鈥檇 hardly ever see any people on the street. In China, I was used to seeing crowds of people walking or crossing intersections, and in the U.S., it was very different.

JP: If you were taking apart robots and interested in mechanical things, what led you to biology and your current research at the Broad [Institute]?

FZ: I went to a public school in Des Moines, Iowa. One of the programs was a Saturday enrichment program. They had Saturday classes for kids who wanted to just learn something different. One of the classes was on molecular biology. I hadn鈥檛 really known what molecular biology was before that, and in fact hadn鈥檛 enjoyed the biology classes I took in school. It had mostly been about memorizing things and dissecting smelly frogs, but going to that class, we did experiments like extracting DNA from strawberries. We to see what DNA looks like and we watched movies like Jurassic Park. It was that combination of learning about the fundamental principles of DNA and biology and watching a movie that showed how these concepts were not too unreal that got me really excited.

JP: It鈥檚 a miraculous moment鈥攁t least it was for me鈥攚hen you realize how molecular biology is at the one and the same time underpinned by extraordinarily simple principles and yet possesses an endlessly fascinating, blooming complexity.

FZ: Exactly. And seeing how there is a code for biology and how you can make sense of that code and use the code to do things that would help people鈥攃reating new genetic medicine, engineering plants that can give higher yield or be resistant to drought鈥攖hat just seemed really amazing.

JP: What is current focus of your lab, one of the largest and most active at the Broad Institute?

FZ: One of the main areas that we focus on has been to develop useful biotechnology for improving human health, and the approach that we take is by learning from nature. So far, I鈥檝e been fortunate to work on a few problems that have borrowed intricate and also powerful mechanisms that nature has evolved over billions of years, and turning those into tools. Those experiences taught me that nature is really the best inventor out there in terms of biotechnology, and it鈥檚 had a lot more time and a lot more experiments to help it develop its inventions.

We can learn a lot from nature. We are using computational approaches combined with experimentation to discover new mechanisms from nature鈥攏ew ways that bacteria or cells defend themselves against infection, or things that allow them to survive in interesting or very diverse environments, and also things that allow them to rapidly evolve, to be able to adapt to changes in the environment. And a lot of those mechanisms are some of the most robust mechanisms in life, because they are things that decide whether a cell survives or dies. Under that kind of strong selection, the molecular mechanisms that are developed are very robust. We have benefited from some of them鈥攔estriction enzymes for recombinant DNA, microbial defense mechanisms like CRISPR. They all came from these kinds of systems involved in providing survival mechanisms. We鈥檙e trying to find more, and some of these we鈥檙e hoping to also turn into new biotechnology to improve people鈥檚 lives.

JP: You are most associated with CRISPR-Cas9. What is it, and why was it such a breakthrough over previous gene-editing techniques like TALENs or zinc fingers?

FZ: Since the sequencing of the human genome, one of the things that scientists wanted to do is to be able to go into the DNA of cells and be able to change those DNA letters. That way we can ask questions like What does one DNA sequence do? or What is the mutation that leads to disease? If we can figure out what causes disease, then the hope is to also correct the mutation, to undo the disease, to improve health. And for that particular problem, several iterations of technologies have been developed. But most of them were very difficult to use. It鈥檚 very challenging to have to engineer a complicated protein to be able to home in on a specific mutation in the genome. CRISPR, on the other hand, is a much simpler mechanism. Rather than engineering a protein, we can simply specify the mutation that we want to change in the DNA by synthesizing a new piece of RNA. This is nowadays something that you can go online and order from a company. Once you type in the sequence, you get a FedEx envelope a couple days later. And it鈥檚 that simplicity that makes the tool significantly more accessible, and also that simplicity made it possible to develop it for many other applications that we couldn鈥檛 do with previous technologies. For example, we can now target every single gene in the human genome in one experiment and ask questions like Which gene is involved in the metastasis in cancer? or Which genes are involved in driving increased growth rate or transformation and differentiation into a different type of cell? And that kind of scale and accessibility opens up new ways to study biology.

JP: What is CRISPR best at?

FZ: I think CRISPR is a very broadly useful technology. Scientists are applying CRISPR to study anything from the basic biology of how cells divide and replicate all the way through to understanding diseases like cancer, psychiatric disease, and diabetes. Because CRISPR is so much easier to use and more scalable than anything before, it is making science much faster. Just to give you one comparison, scientists use mice as a model to study disease, and oftentimes they would make a transgenic mouse by modifying a gene in the mouse to see what happens. Using previous approaches, it would take maybe a year, or a couple of years, to make a mouse. Now with CRISPR you can do this in three weeks.

JP: What are the limitations of CRISPR as a technology, and how does your work address those limits?

FZ: CRISPR-Cas9 is like a pair of molecular scissors: It can cut DNA at a specific place. Once you cut DNA, you can disrupt that DNA. So it鈥檚 good for inactivating a gene. But there are even more sophisticated changes we want to do. We may want to swap out something, or we may want to insert a large piece of DNA. CRISPR-Cas9 by itself is not so effective at doing those other things. Scientists are working on developing new ways to be able to make more complicated changes. So, for example, just earlier this year we reported a new mechanism: It's called a , and it provides a new way to be able to insert large fragments of DNA precisely into the genome. And that will open up opportunities for engineering cells for therapeutic applications or for research applications. The field is still moving quite rapidly: I think there are more natural mechanisms we鈥檒l discover, and some will help us .

JP: Does CRISPR have off-target effects, and are they predictable?

FZ: CRISPR is known to be able to not only target where you program it to target, but also go elsewhere in the genome鈥攖hat鈥檚 called off-targeting. And depending on the specific CRISPR system that the scientist uses鈥攏owadays there are many more systems besides Cas9; there鈥檚 also CRISPR-Cas12, Cas12a, Cas12b, and so forth鈥攕ome are more specific than others, especially for therapeutic applications. This is a major area that needs to be further developed, because we want to be sure that we can be very precise at changing only what we want to change.

JP: Can these gene-editing techniques be used for neurons to treat neurodegenerative diseases like Parkinson's and Alzheimer's?

FZ: I think that鈥檚 one of the really exciting potential applications. Using the standard CRISPR-Cas9 system, it鈥檚 possible to disrupt genes. So if a specific gene is mediating disease, we can try to get rid of that gene and then treat the disease鈥攆or example, maybe a gene that鈥檚 involved in the glycogen storage disorder. And then as we develop more systems, we may be able to fix mutations in neurons, maybe treat things like Huntington鈥檚 disease or replace big pieces of DNA for different forms of genetic neurological disease.

JP: Somewhat unbelievably, you are still in your late thirties. Where do you think these biological controls will be in, say, 25 years?

FZ: The more we know, the more we can do, and the more we can help treat disease. But it鈥檚 hard to predict what will happen 25 years from now. It鈥檚 easier to see what may happen in five to 10 years. In the next 10 years the whole area of genetic medicine or cellular medicine is going to take off. Our ability to modify genes or cells is providing a new way to be able to get at the root cause of disease. So rather than just treating the symptom, we can correct the underlying cause of the mutation, so that the person gets one treatment and is cured. At the same time, the ability to engineer cells鈥攅specially cells that we can transplant into the body, whether they鈥檙e immune cells or stem cells鈥攑rovides new ways to be able to treat illnesses by restoring function in the body. So, for example, if someone has a liver disease, we may be able to put back into the person liver cells that have been repaired, and they can regenerate liver tissue. Or if someone has cancer, there鈥檚 already great progress in immuno-oncology, engineering immune cells to get rid of cancer cells.