麻豆传媒

[UPDATE: After this article went to press, it was announced that Emmanuelle Charpentier and Jennifer Doudna had been awarded the 2020 Nobel prize in chemistry for pioneering the CRISPR gene-editing technique.]

IT IS no exaggeration to call Feng Zhang one of the most groundbreaking scientists working today. In his 20s and 30s, he helped develop two revolutionary technologies. The first, known as optogenetics, involves inserting genes into brain cells to allow them to be switched on and off by shining a light on to them. This technique has helped us understand how the brain works and is being explored as a potential treatment for some neurological conditions.

The second, CRISPR, is a gene-editing technology that promises to correct a near-limitless list of human diseases. These days, Zhang has a dual appointment at the McGovern Institute for Brain Research and the Broad Institute, both in Massachusetts, and is often spoken of as a future Nobel laureate.

Powerful tools can be used in different ways, however, and when it comes to CRISPR, there have already been some worrying developments. Two years ago, biophysicist He Jiankui was widely criticised 鈥� and eventually handed a prison sentence 鈥� for using CRISPR to gene edit human embryos. Many researchers, including Zhang, feel his actions were an ethical overstep.

Meanwhile, Zhang is party to an ongoing dispute over who should own the patent for CRISPR. Other scientists were first to publish details of the technology, but he was quickest to show it works in human cells.

麻豆传媒 caught up with Zhang to discuss those controversies and to get the low-down on the future of CRISPR. These days, Zhang is optimistic that the technology may help us in the battle against covid-19 and that it may have applications that go far beyond medicine.

Jessica Hamzelou: What are the most promising applications of CRISPR in the works today?

Feng Zhang: One of the tantalising possibilities is to use it to correct DNA sequences so that we can restore genes and treat disease. I co-founded Editas Medicine with several other colleagues and, earlier this year, the company began human trials using CRISPR to treat a rare, inherited eye disease called Leber congenital amaurosis. A harmless virus carrying the CRISPR tools is injected into the eye, where it modifies cells to restore normal function of a faulty gene.

Another company called CRISPR Therapeutics has been using the system to treat people who have beta thalassaemia, a disorder in which the blood has low levels of haemoglobin. They found that one patient responded very well and no longer needs blood transfusions.

Because you can use CRISPR to target many genes at once in human cells, scientists have been using it to carry out screens to find genes that are involved in specific disease processes. Then we can potentially edit those genes too.

So CRISPR is already showing promising results. How does it make you feel when you see that?

It is really exciting to be part of building something that can have a huge impact on people鈥檚 lives, but it also makes me realise that there is a lot more that we need to do. Seeing these promising early results really motivates me to want to do more.

What needs to be done before these become approved treatments?

We need to make CRISPR work more efficiently and precisely. One risk is that it will not only make edits that you want, but, by random chance, it also edits something else. We have started on this by engineering new versions of the system that are much more specific. We also need to develop the tools so that they can make many more types of changes in the genome and influence how genes work in different ways.

We are also working on new ways to deliver the CRISPR enzymes. We have developed a protein from Staphylococcus aureus bacteria, which is much smaller than the first CRISPR system we reported. The more compact the package is, the easier it should be to get it inside cells where it can do its work. We have already found that this system can edit genes efficiently in mice.

Are there any conditions that you are particularly interested in?

I have had an interest in mental illness and psychiatric conditions since I was a college student. People around me have been affected by these illnesses. CRISPR is already being used to better understand how they affect the brain and how we might develop more effective treatments.

But all diseases are important. Each affects people in different ways, biologically, but also emotionally. In terms of negatively affecting their lives, it鈥檚 the same 鈥� it is a toll on people鈥檚 quality of life. This is why I have focused on developing the technology for gene editing as a broadly applicable platform.

You are involved in a patent dispute over CRISPR. Does it matter who owns the rights to the technology, as long as it is being used for good?

It is important that this technology is developed safely and responsibly, and shared in a way that everyone can benefit from. The patent holder has the privilege and obligation to ensure that the technology is made accessible. The Broad Institute will continue to do this.

What do you think the next breakthroughs are going to be?

We will continue to see a lot of exciting applications in therapeutics. Cell therapy, where clinicians take cells out of a patient, repair them, and put them back, has a lot of potential. Integrating CRISPR with other technologies, like stem cells, could be especially powerful. These approaches could be used in everything from blood diseases all the way to liver, muscle and brain diseases in future.

One possible way to do this is to use stem cells to derive microglial cells, which are brain cells that respond to infections and damage. These cells could be engineered to restore or introduce genes. You could then transplant them into patients so that they can take residence in the brain and treat conditions. In the long run, we might treat neurodegenerative diseases in this way.

Have there been any uses of this technology that have worried you?

Absolutely. One of the things I was very concerned about was the use of CRISPR in editing human embryos. Less than two years ago, scientists described using CRISPR to edit two human embryos and then using them to create two genetically modified babies. I think it crossed many ethical bounds.

There has been lots of talk about how to regulate the technology, both before and after that incident. How should we do that?

I have been involved in a number of discussions about this, but the world is complicated. There isn鈥檛 a single type of ethics or culture or governing system. This means we have to reach agreements through international collaborations. People must come to an understanding of the potential impacts of these technologies before we get a consensus on using them.

The technology is still nascent and there is much about its performance and safety that we don鈥檛 fully grasp. To jump ahead and begin to apply this to a modified human embryo could have unintended consequences. On top of that, we don鈥檛 understand the biological mechanism that causes a lot of things that we want to treat. So, even if the technology was perfect, we wouldn鈥檛 know what edits to make to the genome. This is why we can鈥檛 yet use CRISPR to treat conditions like 础濒锄丑别颈尘别谤鈥檚 or cancer.

There are also tangled issues surrounding consent. Who has the right to consent to the use of this? How will availability of these technologies affect the human race going forward? When people think of changing the genome, they often think of genetic enhancement. We鈥檝e all seen enough dystopian science fiction to know that a society like that would be terrible for humanity.

鈥淲e鈥檝e all seen enough dystopian science fiction to know that genetic enhancement would be terrible for humanity鈥�

What do you think gene-editing technologies will look like in 10 years?

We will probably begin to see the technology applied to diseases that affect a large number of people, like cancer or even brain conditions. I suspect gene editing will be used beyond medicine, for example in agriculture, to create more drought-resistant and higher-yielding crops to help fight global hunger. We might also see CRISPR used in biological computing or as part of the response to climate change.

How could the technology help with climate change?

Some scientists are working out how to use CRISPR to engineer plants so that they can sequester more carbon. Others are looking at ways to engineer fast-growing cells like cyanobacteria to get them to take in and store carbon faster. These are some starting ideas to tackle climate issues. I am sure people will use their creativity to come up with more.

We can鈥檛 afford to ignore the climate, but we also have a pandemic to deal with. Can CRISPR help with that?

My team has spent a lot of time developing CRISPR-based diagnostics. One of the critical things for helping us fight the covid-19 pandemic is the ability to test more people, more rapidly and in more places in the community. So we have been working on something we called the . The main advantage of a CRISPR-based test is that it doesn鈥檛 require sophisticated laboratory equipment 鈥� you just need a water bath at 60掳C. You put your sample vial into the water bath and then, within an hour, you can dip in a test strip and get a result.

How soon will it be ready?

Another company I helped found, called Sherlock Biosciences, has been developing similar CRISPR-based technology for detecting coronaviruses. In May, this received emergency use authorisation from the US Food and Drug Administration. So now people in clinical labs in the US can begin to use that technology for detecting coronavirus, which should help expand our testing capacity.

My lab has also distributed STOP covid test kits around the world. One of our collaborators in Thailand got approval from the Thai government to use it in his hospital and will be screening surgery patients for coronavirus, so that they can better triage and isolate people who test positive for the virus.

You were also involved in the invention of optogenetics, another groundbreaking discovery. What is your secret to spotting the next innovation?

I am always curious about the way things work 鈥� or don鈥檛 work in the way they should. I have those questions in mind whenever I think or read about something. I always cross-check with the scientific problems I am interested in and see whether I can create a new connection.

The other thing I do is look at nature, which has done way more than we can imagine. CRISPR proteins are examples of things that nature has created through billions of years of evolution that have amazing applicability.

Also, when I was growing up, my parents always told me that I should make myself useful and not waste time. That probably has something to do with it.