西溪书社

Hi everyone. I would like to introduce you to Laika. To most of us, Laika is simply a very cute pig. However, to hundreds of thousands of patients in need of a lifesaving organ Laika is a symbol of hope. You see, ever since the 1970s, when organ transplants became a real option for patients with kidney failure and other organ diseases, organ supply has been an issue. Over the last few decades, the issue only worsened as organ demand has exponentially increased. Currently in the US, there are close to 115,000 patients in need of a lifesaving organ transplant. By the end of my talk, one more patient will be added to this list.

Today, about 100 people will get a new organ, a chance to start their life anew, and yet by the end of today, 20 others will die waiting. The situation is heartbreaking for patients, for their families and for the doctors who want to do more.

In some parts of the world, the situation also becomes a disturbing social issue. In Asia, for example, media outlets reported that desperate patients are obtaining organs from the cruel black market. It is clear that a solution is needed to this crisis. Human lives are at stake.

As a biologist and a geneticist, it has become my mission to help solve this problem. Today, I am optimistic to say that we are on our way there, thanks to Laika. Using gene editing technology, it’s now possible to exquisitely create a human-transplantable organ that can be safely grown in pigs.

Before we jump into the incredible science that makes it happen, let’s have a better understanding what xenotransplantation is. It’s a process of transplanting animal organs into humans. You may want to ask, why pig organs? Because some pigs carry organs with similar size and physiology to human organs.

Over the last half a century, pioneers of transplantation have tried hard to make it happen, but with limited to no success. Why is that? Two fundamental hurdles stood in the way. First is a problem of rejection. When our immune system sees a new organ as foreign, it will reject it. Second, and this one is specific to the organs from the pig, every pig carries a virus that is benign to the pig, but can be transmitted into humans. It is called the porcine endogenous retrovirus (PERV), and this virus has the potential to cause a viral epidemic similar to HIV. Without an effective way to address these issues, the field of xenotransplantation has been on hold for more than one decade. Little progress has been made, until now.

Let me share with you how I got here today with Laika. My journey started from Emei Mountain in China. That is the place well described in a lot of legendary stories, like the “Crouching Tiger, Hidden Dragon.” That is the place I call home. Growing up in the mountain, I started to have a strong connection with nature. This is me when I was seven years old standing in front of an ancient Buddhist temple with a monkey on my shoulder. I still vividly remember how my friends and I would toss peanuts around to distract the monkeys so that we could cross to hike through the valley.

I love nature. When it was time to choose a field of study, I chose to study biology at Peking University in Beijing. However, the more I learned, the more questions I had. How could our genetic makeup be so similar to animals and yet we look so different? How is our immune system capable of fighting off so many pathogens but smart enough not to attack ourselves. Questions like this tormented me. I know it sounds nerdy, but you know I’m a scientist.

After college, I decided I didn’t want to just ask the questions, I wanted to answer them, so I did. In 2008, I was lucky enough to be accepted into the PhD program at Harvard University and worked with Dr. George Church. While working in Church’s lab, I started to learn and experiment with the genetic makeup of mammals. Among all the experiments, one particular one took me closer to Laika. In 2013, my colleagues and I made changes in a human cell using a tool you may have heard about called CRISPR. We were one of the first two groups to report the successful use of such a tool in changing our DNA. It was an exciting moment in scientific discovery. The gene-editing tool CRISPR has two components. It has a scissor called the enzyme CRISPR and what is called a guide RNA. Think about it as genetic scissors with a microscope. The microscope is a guide RNA, which brings the scissors to the place we want to cut and says, “Here it is,” and the enzyme CRISPR just cuts and repairs the DNA in the way we want.

Shortly after we reported our study, physicians at Mass General Hospital were intrigued by the medical applications of our research. They reached out to us, and together, we began to see the potential to use CRISPR to solve the organ shortage crisis. How do we do it? It is simple, yet very complex. We started by making changes in a pig’s cell to make it virus-free and human-immune-compatible. The nucleus of that cell is then implanted into a pig egg and allowed to divide into an embryo. The resulting embryo is then placed into the uterus of a surrogate mother and allowed to divide into a pig. Basically, it’s a process of cloning. The piglet then carries organs whose genetic makeup hopefully wouldn’t be rejected by the human immune system. In 2015, our team decided to tackle the viral transmission problem first. We wanted to take out all 62 copies of the PERV virus from the pig genome, but at the time, it was nearly mission impossible. Even with CRISPR, we could only do one or two modifications within a cell. The record for number of modifications we can do in a particular cell was five. We had to increase the throughput by more than tenfold to achieve that. With very careful design and hundreds of trials, we successfully took out all the virus, broke the record. More importantly, our studies showed that we could eliminate the possibility of this dangerous virus being transmitted into humans.

Last year, with a modified cell and cloning technology, our startup, eGenesis, produced Laika, the first pig of its kind born without PERV.

(Applause)

Laika represents the first critical step in establishing safe xenotransplantation. It is also a platform that we can do further genetic modification on to solve the immunology problem. Since then, we have created more than 30 pigs without PERV, and they may be the most advanced geno-modified animal living on earth. We named Laika after the Soviet dog who was the first animal to orbit the earth. We hope Laika and her siblings can lead us into a new frontier of science and medicine.

Imagine a world where patients who suffer from liver failure can be saved with a new liver without having to wait for a donation or another human to die. Imagine a world where people with diabetes do not have to rely on insulin after every meal because we can provide them with good pancreatic cells that can produce insulin on their own. And imagine a world where patients with kidney failure do not have to face the burden of dialysis. We are striving to create that world, a world without organ shortage. We finally have the tool to tackle the problem we could never tackle before, and Laika is just the beginning of our journey. We have to be very humble in front of nature, because there are more issues to be addressed, including immunology and things we couldn’t even anticipate at this point. However, it is our responsibility to translate the cutting-edge science into medicine to save the lives of all the patients who are waiting.

Thank you very much.

(Applause)

Chris Anderson: I mean, Luhan, this is extraordinary work here. Come forward. So what’s the next steps here? You’ve got rid of the virus. The next steps involve trying to get to the point where a human body won’t reject a transplant. What’s involved in solving that?

Luhan Yang: It’s a very complicated process. So we need to take out the antigen of the pigs. In addition, we can learn a lot from cancer. How can cancer invade or circumvent our immune system so that we can utilize the trick of cancer and implement that on the pig organ to fool our immune system to not attack the organ.

CA: When would you estimate, when do you hope that the first successful transplant would happen?

LY: It would be irresponsible for me to give you any number.

CA: We’re at TED. We’re always irresponsible.

LY: But we are working day and night trying to make this happen for the patients.

CA: So not even, you won’t say that you think it could happen within a decade or within five years or something?

LY: For sure we hope it happens within one decade.

(Laughter)

CA: So there’s a lot of people here who would be very, very excited at that, the potential is extraordinary. There will be some other people here who are going, “That pig is too cute. Humans shouldn’t be exploiting something so cute for our benefit.” Do you have any response to that?

LY: Yeah, sure. So imagine one pig can save eight people’s lives. In addition, similar to human donation, if we only harvest one kidney from the pig, the pig can still be alive, so we are very mindful about the issues, but I think our goal is just to address the unmet medical need for those patients and their families.

CA: Plus, no one can say that to you if they eat bacon, right?

LY: That’s a good point.

(Laughter) CA: Luhan, thank you so much. LY: Thank you so much. (Applause)