"there is now adoptive cell therapy for solid tumors, which is a development trend in the future and our best opportunity, not only to make it a chronic disease, but also to make it curable.

As an oncologist, I am still very optimistic. "

"if we conquer all the cancers, our life expectancy will only increase by 3 to 4 years. Historically, the biggest change in paradigm is not to really deal with and conquer these diseases, but to solve a physiological problem of aging behind it. "

There is no doubt that China will become a global leader in biotechnology, and Sequoia hopes to serve as a bridge between scholars and researchers as well as practical applications. "

These are the views expressed during the dialogue by Shen Nanpeng, Sequoia Capital's global managing partner, and Richard D.Klausner, founder and CEO of Lyell Immunopharma.

During the wonderful summit dialogue, the two men discussed the latest tumor treatment technology and the future development direction of biotechnology.

In the future, what new ways will medicine use to help us cure diseases? What is the average life expectancy of human beings by 2100? Can science and technology keep us young forever? The summit dialogue between the two bigwigs will open up new ideas for tumor treatment and life extension.

The following is the full text of your conversation:

As an oncologist, I am still optimistic about turning cancer into a chronic disease or even a cure.

Shen Nanpeng: it is a great honor to introduce you to our audience. There are many CEO of the medical industry, many research scholars and many big names in the industry.

But it seems difficult to introduce Richard, and frankly I admire you very much. You are the leader of a well-known research institution, you have founded two great companies, Juno Therapeutics and GRAIL, and you are an investor, and the key is to look so young (laughter). So I really don't understand, how do you do everything? As a researcher, please share your experience with us.

In addition, you have many years of research experience in the treatment of the whole cancer, and you have also led the National Cancer Institute (National Cancer Institute). We know that it may be difficult to achieve a complete cure of cancer in the short term, but is there any hope of turning cancer into a treatable chronic disease? How far do you think we are from this day, or what challenges do you think we need to experience?

Richard: in fact, there has been a lot of progress in cancer research, and some cancers have become chronic diseases bit by bit.

When I led the National Cancer Institute in the early 1990s, we were at a critical turning point. We are excited to think that we have really understood how it works at the molecular level, and we can already imagine how precision medicine will be applied to the treatment of cancer, and we have done so. When we look back at molecular targeted therapy over the past 25 years, it is both exciting and satisfying, but also disappointing.

We used to think that as long as we mastered the tumor mutation factor (driver mutations) and developed targeted drugs that made tumor cells Oncogene addiction and apoptosis, we could make better progress in cancer treatment. Of course, we have made some achievements, such as the longer asymptomatic survival (PFSorOS overall survival) of lung cancer patients, but only a small number of patients. In addition, we are not fully prepared to face a situation, that is, if there is drug resistance (molecular resistance) in cancer treatment, what should we do?

In the face of this situation, we take the same approach as we did in the treatment of HIV more than 20 years ago, that is, a combination of multiple drugs. Twenty-five years ago, the first anti-cancer drug of this type, Gleevec, was approved to be put on the market, but so long ago, we have made only minor progress in this direction, and the therapeutic pressure caused by cancer mutations, as well as the evolutionary ability of cancer itself, makes molecular targeted therapy more difficult than we thought.

I still remember when we went to Congress in 1994 to tell you that we were in a new era, but what we didn't foresee at that time was the development of immunotherapy.At the time, a large number of colleagues at the institute were focused on immunotherapy, including Dr. Steven A. Rosenberg (Note: Steve Rosenberg was awarded the Edogawa NICHE Award in 2019 for his pioneering work in the development of effective adoptive cell therapy drugs and genetically modified T cells), but the field of immunotherapy was still a backwater and there was little time for immunotherapy at various cancer conferences. But the most encouraging and influential progress we have made in cancer diagnosis and treatment over the past decade is immunotherapy (Immunotherapy). Of course, we are still at an early stage in this respect, and we are going a little further in checkpoint therapy (Checkpoint Therapy represented by PD1).

My personal interest is mainly in studying the development potential of cell-based immunotherapy, which I firmly believe plays a significant role in the treatment of hematological malignancies (hematologic malignancy).Although we are still in the early stages of our research, it has shown superior ability to treat such malignant tumors, such as 30% or more than 40% of leukemia or lymphoma (Lymphoma). For me, the real challenge is how to break the boundaries of adoptive cell therapy, such as how to treat solid tumors. I think immunotherapy gives us the best chance, not just to make cancer a chronic disease, but to really cure it. As an oncologist, I am still optimistic about this.

Cell therapy for solid tumor is just around the corner.

Shen Nanpeng: with regard to the last point, that is, about cell therapy and how to treat solid tumors, could you expand it again? We all know that cell therapy has made a lot of progress in the field of hematological tumors. When do you think we can use cell therapy to treat solid tumors with the evolution of technology?

Richard: I think we're going to have a way forward, and we're looking at the way forward, which is to understand why adoptive T-cell therapy can't treat solid tumors like hematological tumors. We have now begun to understand the fundamental difference between immune cells in solid tumors and hematological tumors. I don't think tumor cells can always avoid being hit by T cells. We can study and understand the reasons from a deeper molecular level, so as to adjust T cells so that T cells do not have to suffer from the so-called "fate" of T cell depletion (T-cell exhaustion) in the treatment of solid tumors.

This is not a vague term, but a very clear, transcription factor-driven differentiation pathway. This is a remarkable finding-- a T cell can also treat hematological tumors from one differentiation pathway, but when used to treat solid tumors, it goes to another differentiation pathway. Now we begin to learn how to prevent T cells from going to another differentiation pathway. We're probably going to see these clinical trials hit the ground in the next few years, and we're showing a variety of different abilities to control the function of cells in the body, and we're now moving into a new field of cell therapy. this field starts with T cells, and we're going to see areas that we completely thought impossible 15 years ago, such as regenerative medicine, and now these things are happening.

It may be more important to figure out why it failed.

Shen Nanpeng: it sounds like you are very optimistic. Do you mean that T-cell therapy is more of a physical problem than a biological problem?

Richard: in fact, we have been naive about immune cells for many years, including myself. We just put immune cells in the patient, close our eyes and pray that they work.

But it wasn't until recently that we began to ask a question, not in the hope that they work, but when they don't work. What's the reason? This allows us to seek more detailed answers at the molecular biological level.

I think molecular targeted therapy is actually the same for cancer. We need to think about the mechanism behind this precise transformational therapy and medicine. Why is this intervention effective? Why didn't it work? What was the reason when it didn't work? The latter, I think, is more important, learning from mistakes.

For example, sometimes a clinical trial fails and a drug doesn't work, then we need to review it and see why it didn't work, so as to open the door to precision medicine.

Problems to be solved in RNA Technology at present

Shen Nanpeng: when it comes to cancer and other treatments, there is another model, such as mRNA, which is also used in the field of vaccines. We know that mRNA technology is a hot topic, including Musk. What do you think of mRNA's technology? What is the possibility of a breakthrough in this area?

Richard: I think this is a very interesting field. I was studying RNA about 40 years ago, which is a career that I pay close attention to and love very much.

Although it looks like we have a revolution in RNA, it is actually a revolution in the delivery mechanism of macromolecules. How can we get these wonderful RNA vaccines? First of all, we need to make sure that RNA is not degraded and does not provoke our immune system to respond to RNA and chemical modification (chemical modification).I think the real breakthrough is that lipid nanoparticles (lipid nanoparticles) can wrap RNA, then deliver it to human cells, and then play a role.

Although everyone is talking about RNA, for me, the real technological breakthrough-- whether it's Moderna Inc or BioNtech-- is to find innovative delivery media that allow us to transport some functional macromolecules (functional macromolecules) to specific locations. The theme of today's conversation is related to paradigm and science. I think the paradigm change that we have been waiting for for a long time is how to successfully control the delivery of macromolecules to living cells. The problems with macromolecular delivery show that there is a big difference between what we can do in the laboratory and what we can achieve in the real world in vivo.

Will there be some new enterprises in the industry to catch up?

Shen Nanpeng: macromolecular delivery is indeed a major challenge we face, and it is also the direction of hard work for enterprises like BioNtech and Moderna Inc.At present, this field is still in the early stage of exploration, do you think many startups still have a chance to catch up and come up with new ideas to improve the mechanism of macromolecular delivery?

Richard: I think there will be a new, selective delivery combination that will be more controlled, more secure and more accurate. But it takes a lot of work.

I think this area has a lot to do in terms of the evolution of the delivery mechanism, and it's going to be a huge industry. The key is what you choose to deliver. It's not just the delivery of encoded mRNA, which is great, but we can also imagine successfully delivering editorial molecules (editing molecules), whether DNA or RNA, in the body. I believe that in vitro gene editing technology can become very powerful in continuous evolution, but I think how to solve the delivery of macromolecules is still one of the biggest challenges we face.

We still see some progress, in this process, with the advance of research and development, there will be the emergence of new enterprises.

Mobile phone plays an important role in the treatment of mental illness.

Shen Nanpeng: there is a Chinese proverb called "Great minds think alike".

We just heard from Robert Nelsen about his love of neuroscience, and I know that you have also founded Mindstrong Health, and you have been studying or exploring new ways to treat mental illness for some time.

I would like to ask you what kind of thinking in this field, through Mindstrong Health, what major breakthroughs you would like to see can provide us with some new solutions?

Richard:Mindstrong Health, as Robert mentioned before, does not mean to delve deeply into neuroscience-- of course, neuroscience research needs to continue to advance-- but we thought it was possible that mobile phones are a very good tool to help us deal with mental problems, and online diagnosis and treatment can have great potential value for mental health.

The goal of Mindstrong Health is to use mobile phones as an intermediary, not only to provide health services, but also to take advantage of its rich data and evaluation indicators in the process of using mobile phones.

We know that friends with mental and psychological problems may use mobile phones more often, for example, to check some of these problems, and they prefer to interact with mobile phones than to interact with people or doctors. In fact, we can collect very detailed data on the mobile phone, and we can learn about this individual or inter-individual data.

In terms of mental health, the most important thing is to be able to detect and intervene as soon as possible, so that we can enter and intervene before he goes downhill.

We know that early intervention may be the most important part of the whole mental health process, reducing admission rates and reducing brain damage, especially the impact of multiple seizures.

So Mindstrong Health hopes to turn mobile phones into an assessment and delivery service for these serious mental illnesses.

Shen Nanpeng: this kind of mobile technology has become a part of our process of overcoming many difficult problems. It can be used to monitor the behavior patterns of patients.

Richard: yes, I think the beauty of the phone is that it is a passive, continuous use, and sometimes it has become a new ecology for you.

People with mental illness do not commit suicide when they see a psychiatrist, and if they do, it is often when they are alone, so I think that if we use mobile phones to strengthen the continuous attention, monitoring and treatment of this group, it will have a revolutionary effect.

Shen Nanpeng: when you have this data, you will develop some algorithms or artificial intelligence functions, and then constantly improve the services provided to patients, right?

Richard: that's right.

I think this project is very complex, it needs the assistance of machine learning and AI, there are two levels, the first level is to make new discoveries. Second, make the use and interaction of mobile phones more efficient.

If all our signals are random, for example, if you use your phone to go to a counselor or a psychiatrist, you also need to know which signals are signals and which are noises. I think this needs AI and machine learning to help you.

What is the competitiveness of Chinese enterprises in the world?

Shen Nanpeng: we have a lot of similar applications in China. Mobile phones are more popular and used in China, and mental illness is a difficult problem that Chinese health departments hope to solve.

Speaking of China, I know you have a lot of attention and investment in Chinese biotechnology companies. Some of the enterprises you have invested in the United States also want to come to China and bring some technologies and products to China.

How competitive do you think China's leading biotechnology companies are in the world?

Richard: I think there is a substantial change in the past five years, that is, Chinese enterprises are becoming more and more competitive.

If you look at some infrastructure needs, I think China's progress is faster, especially in the clinical system, I think it will definitely become more systematic, data sharing and access will be easier. This part is where I think it lags slightly behind the United States at present, but the progress will also be rapid.

But in the past five years, we can see that the growth of China's biotechnology industry is impressive, both in terms of personnel quality and innovation.

Another discovery, which I think will be interesting for China, including Sequoia, is that the biotechnology industry needs to learn from the technology industry.We are seeing the best first-class companies in biotechnology these are platform companies, but not what we call usual platform companies, such as contracted outsourced processing or technical tools, but companies like Moderna Inc that are expansive and can produce "killer applications" (killerapps) for ordinary consumers in the field of APP and even biotechnology.

I think we will see a group of more ambitious and expansionary biotech companies that will not just rely on a good product to quickly "sell" to large pharmaceutical companies, but will rise like technology companies.

In addition, a trend is the integration of technology and biotechnology, which is also very important.

Finally, we can already see some precedents in biotech companies, but not nearly as much as in technology companies, where the inventor of technology is also the founder of the company.

I personally like this very much. Traditionally, VC investors like me would go to universities and research institutes to find some new technologies and turn some good technologies into good enterprises, but the inventors of these technologies did not follow us.

In fact, I think the most effective and valuable thing is not the intellectual property rights of these technologies, but the wisdom behind them. I think we will see more and more technology inventors become the founders of good companies.

The ultimate mystery: how old can human beings live in the future?

Shen Nanpeng: you are a very good example in this respect. In the first conversation today, I talked to Professor Li Feifei about a very interesting trend, that is, the integration of biotechnology and information technology, as you mentioned cross-border.

Richard: you mentioned GRAIL, a company I founded, and we have also successfully launched a pan-cancer early diagnosis and screening service, which cannot be achieved without combining some sequencing techniques as well as clinical and biological technologies with deep machine learning.

More interestingly, it poses new problems for regulators. We use deep learning instead of the traditional detection limit (Limit of Detection) method, which is equivalent to the development of a new language. It would not have been possible without this integration of biology and information technology. This was also a challenge for Grail at the time, because the integration of different cultures was not always easy.

Shen Nanpeng: I still remember when I had my first meeting with Grail, you said that you aimed at a company like Alphabet Inc-CL C to build your own business, not a pharmaceutical company. I think this is a plan that can change the rules of the game, and it is also a very profound insight.

There's one more question. I remember that two years ago, we talked about how health care can change human life. We also talked about many factors that affect life expectancy, such as economic and nutritional factors.

According to the data, the average life expectancy was only 32 years in 1900, 65 years in 2000 and 71 years in 2020. How high do you think our life expectancy will be in 2100?

Richard: I think the biggest paradigm shift hasn't really happened yet, or we're still waiting for it, and I think it's scientifically possible for us to rethink all the diseases we're facing right now.

In fact, if we conquer all the cancers, our life expectancy may only increase by 3 to 4 years. The biggest change in paradigm is not that we conquer these diseases, but that we can solve the real problem-aging.

If we only focus on the disease in the aging process, we may be able to reduce mortality, extend some life expectancy, and we can live to 110 or 120 years old, which is also good.

But by 2100, my prediction is that we need to understand, and have a deep understanding of time and aging.We have always accepted the idea that aging is a natural process that occurs gradually with age, but this is actually wrong.Aging is indeed embedded in life genes, and different species have different lifespans. I think one of the most profound paradigm changes is that in the next 100 years, if your cells have some properties and can stay active at the age of 20 or 30, how many cancers will we reduce? How many diseases will be reduced? How much longer will there be?

So if we are not talking about 2030 or 2040, but about a period of time like 2100, the decisive factor may be whether we can finally understand the ultimate meaning of biology itself, and then we will discover what the secret of eternal youth is.

Evolution of biotechnology companies, China VS overseas, Sequoia: hope to become a bridge

Richard: I know that you have invested in many enterprises related to life sciences and health care in China, and you also have a rich international perspective. Can you compare the development of biotechnology in China and overseas?

Shen Nanpeng: I think China is still under the stage of catch-up.As you said, we have a group of very talented CEO, some of whom have overseas education and work experience, and many of them have returned to China because the market here is ready to accept these innovative technologies. We believe that they should first develop the domestic market, but gradually they may become world-class companies that can produce good global products.

We also need to rely on Chinese universities and scientific research institutes to transform scientific and technological achievements. In this regard, many countries and regions in the United States and Europe are worth learning and imitating. You mentioned a good point, sometimes we need some entrepreneurs, and they are also the most outstanding researchers, it is not easy to find the combination of the two, but we hope to find more such talents in China.

I believe that there is no doubt that China will become a world leader in biotechnology and medicine in the future.

So I hope Sequoia can become such a bridge that connects scholars and researchers on the one hand and real applications on the other.