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7.17

Intellectuals

The Intellectual

Introduction

In China, academia has traditionally been a pure ivory tower, surrounded by solid walls that isolate "pure" research from industry. However, Xu Tian, ​​vice president of West Lake University, told us that the power of technology plus finance is too strong.

He graduated from Fudan University in 1982, received his Ph.D. from Yale University in 1990, and completed his postdoctoral studies at the University of California, Berkeley in 1993. For the next 25 years, Xu Tian taught at Yale University and served as an Edward Hughes Research Fellow. He served as associate director of the Department of Genetics at Yale University and advisor to the president of Yale University.

In the ivory tower, Xu Tian was one of the earliest pioneers in the field of growth regulation. His laboratory had discovered the most important regulatory genes and signal transduction pathways in growth regulation. Xu Tian was also keen on the research and development of new technologies. The fruit fly mosaic genetic analysis method and mammalian PB transposon technology he created have been widely used in laboratories around the world.

Outside the ivory tower, Xu Tian co-founded the Rothberg Institute with his schoolmate, entrepreneur, and father of a rare disease patient, Jonathan Rothberg. This is a deep incubation converter that targets the challenges of the small market for rare disease patients and the difficulty in industrializing basic research results. There, they combine cutting-edge basic research with industrialization and effectively transform scientific research results. This institute/converter has incubated a series of world-first innovative products, including the world's first gene sequencer-454, which has spawned emerging industries. Of the 10 high-tech companies incubated there, 9 have been listed or acquired. In addition to the Rothberg Institute/Converter, Xu Tian has also created a number of other high-tech companies that transform scientific research results to promote the diagnosis and treatment of cancer and a variety of rare diseases.

In April 2018, Xu Tian joined Westlake University full-time as a professor of genetics and vice president. We had a conversation with Xu Tian at that time (see the article by Intellectuals: "Xu Tian Returns to China Full-time: Why I Chose Westlake University"). Six years later, at the 2024 Global Rare Disease Research Forum in Shanghai, the university president at the top of the ivory tower had another long talk with The Intellectuals. This time, he talked about technology, finance, and rare diseases.

Participating in the biotechnology revolution from the end of the last century to the beginning of this century, Xu Tian was surprised to see that scientific research results could be transformed from laboratories into products, and then create an industry from scratch and influence society. The driving force of these waves - the core technology transformed from basic research - shocked him even more and triggered his thinking about how science can influence society through transformation.

Xu Tian said: When sequencers appeared, all biologists doing sequencing became anxious because sequencing became too easy. "But this does not mean that geneticists have nothing to do, because the automation and cost reduction of sequencing have given geneticists more room to do things, and many people have been able to use sequencing results for diagnosis and other industrial applications." By the same token, this biologist who has embraced artificial intelligence since 2013 believes that the popular protein structure prediction tool Alpha Fold will not worry real structural biology, because there are many biological things behind the relationship between structure and function, which cannot be accomplished by simply predicting a structure, and a large number of structural analyses can promote industrial applications.

Witnessing the progress of technology, it took only more than ten years to reduce the cost of sequencing the human genome from about 10 billion US dollars to a few hundred dollars for sequencing an individual genome, which has led to a wide range of industrial applications. While believing in the power of science and technology, this scientist also deeply understands the huge role of financial power in the transformation of scientific research results. At the Second China Rare Disease Research and Translational Medicine Conference in May this year, Xu Tian, ​​co-founder of the Rare Disease Ruiou Foundation and chairman of the conference, told The Intellectual: Today, the biggest pain point in the development of rare disease drugs is cost, and the emergence of artificial intelligence has given us a ray of hope to reduce costs and benefit more patients.

Oral｜Xu Tian

Compiled by Li Shanshan and Li Lu

Quit your position as a Yale professor to start a business?

“My father would have killed me.”

My story begins with a technology.

In the late 1980s, when I just went to Yale as a graduate student, I sequenced the Notch gene, which is a very important gene for the development process. It is 10.5kb in length. Two graduate students before me had been sequencing this gene for two years, but the progress was slow. When I rotated into the laboratory, I tried the new deletion method at the time and quickly sequenced the remaining 7.5kb sequence. We found that this is a cell surface protein that can explain the principle of participating in cell interactions to determine cell fate. This result was published in Cell and widely reported by mainstream media. As a fledgling student, I was able to do it faster and better than several graduate students who had been doing it for several years. This made me realize that new technologies are too important.

When I was at Yale, I met Jonathan Rothberg. Like me, he was very fond of new technologies, so as soon as he entered the lab, we became good friends. We both had many whimsical ideas and often messed up the lab. For example, after seeing the "gun" for plant genetic modification, we wanted to use guns to genetically modify fruit flies. We brought Jonathan's brother's hunting rifle to the lab, but were kicked out. However, we did not give up and decided to do experiments at my house. When my wife came home and opened the cabinet door, a long gun fell out, and she was scared to death.

Jonathan is Jewish, and his family has many bankers and CEOs. During holidays, I went to his house and listened to his family talk about profits, stocks, and industries at the dinner table. One day, Jonathan said to me: Let's start a biotech company together, and then he started looking for investors.

Jonathan raised money for a long time, until I got the assistant professor position at Yale, he called me and told me: "I got the money" - he couldn't raise money outside, but his family gave him 2.4 million US dollars to start a biotechnology company. He called me because he wanted to find me to start a company, he said: we both like new technologies, we can tinker with things we like.

When I received the call, I told him that I was crazy to quit my professorship at Yale and start a business with him. According to our Chinese thinking, I, a new immigrant, had just got an assistant professorship at Yale, which was equivalent to a scholar-official position "within the system". I quit my job and started a company with him (which was obviously impossible).

I told him on the phone, "If I start a company with you, my father who is a teacher will definitely kill me."

Jonathan answered me: We have the technology, we can definitely do it, the two of us can definitely do it together. He said: In the future, we will have enough money, we can do whatever we want, you don’t have to apply for research funding anymore, we can do so many crazy experimental ideas…

Thinking back now, I had no idea about the upcoming biotech boom. I was still in the dark. At the same time, I didn’t have the adventurous spirit that Jonathan had. I had just managed to make ends meet and came to the United States to study with $50. I didn’t have the adventurous spirit in my mind.

I chose a compromise - Jonathan and I continued to work together as before, I still provided him with ideas, and we worked together to determine whether something could be done, but I only served as a consultant, and my main job was still to be a teacher at Yale.

After that, one day, I was working at Yale, and Jonathan called me again. He said that we had just gone public. Just think about it, if you had come at that time, your shares would be worth at least tens of millions of dollars. I told our mutual friend Michael Snyder (currently the head of the Department of Genetics at Stanford University) about this, and he said that you should call Jonathan quickly and tell him, "You are happy."

Jonathan's daughter suffers from a rare disease.

Is it God's will that we should solve this problem?

In the late 1990s, when Jonathan's biotech company was doing well, his first daughter was diagnosed with a rare disease, TSC (tuberous sclerosis complex). Soon after, this gene also appeared in the genetic screen of fruit flies in my laboratory. I was shocked, that is, if there were scientists who could do something to understand and treat this disease, my laboratory would definitely be one of the most likely (laboratories). At that time, I even wondered, is this God's arrangement for us to solve this problem?

Tuberous sclerosis is a rare multi-system congenital disease with an incidence of about 7-12 people per 100,000 people. Benign tumors and other problems may occur in the patient's brain, lungs, heart, kidneys, skin or other organs, leading to symptoms such as epilepsy, developmental delay or facial sebaceous adenoma.

At that time, our laboratory was studying growth and development regulation, which was not a popular topic at the time. The more popular topic was cell division. In comparison, at that time, everyone felt that growth regulation was not so important.

We study the regulation of growth and development, and why the organs of animals grow so large and why the organs are in a certain proportion to the body size. We hope to find the relevant regulatory genes. To find these regulatory genes, traditional methods are not enough, because the development process of these organs is too important for the development of the entire organism. If you mutate the relevant regulatory genes, the animal may die.

We invented a new method at that time - mosaic genetics, which means that most somatic cells have normal genes working, but the genes are mutated in a few cells of certain organs. Using this method, the animals are still alive, but we can also mutate genes in cells to find related functional genes. In this way, we found a series of important genes that regulate growth.

This method can also be used to study other important biological processes and related genes. These were later widely used around the world. Almost all laboratories studying fruit flies used it. This concept was also applied to mice, and methods such as conditional knockout (of a certain gene) emerged.

At the same time, just when I was doing very well as a professor at Yale University and even became a Hughes Fellow, a tenured professor, the chairman of the US-China Frontier Scientific Exchange Committee, and an editorial board member of Cell magazine, my twin children were born prematurely and were starved in the incubator. A little hand grabbed my finger and cried until they lost their voice. I just wanted someone to save my children. From then on, my research was not just an interesting exploration of the unknown, but also about solving problems.

We and the Hariharan lab at Berkeley University first discovered that TSC is involved in regulating growth, but the entire pathway (signal transduction pathway) was first studied by our lab. With this pathway, we found a way to inhibit the pathogenic pathway, so that we can make potential therapeutic drugs. It is this pursuit of helping our loved ones to relieve their pain that makes our lab's work not only stop at understanding the biological phenomenon of growth regulation, but also further unravel the pathway.

At present, the aforementioned pathway we found has been proven to be highly conserved in animals and humans. In addition to rare diseases, more than 70% of human cancers have mutations in this pathway, so it is of great significance to the understanding of the mechanisms of rare diseases and cancer and to drug development.

This is also a case where research on rare diseases helps us understand the mechanisms of common diseases and develop drugs. This is why we now attach great importance to research related to rare diseases. Many discoveries in rare diseases can be very inspiring for research on common diseases and even our understanding of biology.

From rare diseases to rapid gene sequencers,

Technology plus finance is too powerful

Jonathan and his family took our research results very seriously, and they began to hope to donate $30 million to Yale to study the diagnosis and treatment of rare diseases in children. As I said before, Jonathan's family and I felt that our encounter with rare diseases was like fate, and we had to do this.

But at the time, the dean of our (Yale) Medical School wanted to invest the money in building a building. Jonathan's family disagreed with this arrangement, and I also felt that we really needed to do something for the diagnosis and treatment of children with rare diseases.

Later, we used the money to find a house by the sea in the town where we lived and established the Rothberg Institute for Childhood Diseases. Jonathan was the chairman of the board and I was the chairman of the scientific committee. In this house, we began to conduct translational research on the diagnosis and treatment of rare diseases. To develop diagnostic instruments and drugs, a lot of money is needed. Only successful industrialization can truly develop instruments and drugs. Therefore, the institute/translator has incubated 10 companies and a number of world-first diagnostic instruments and drugs.

Speaking of the 454 sequencer, I would like to say a few words about Alpha Fold. It is very powerful. After the emergence of this tool, biologists basically have nothing to do with simple protein structures. The changes brought about by Alpha Fold are somewhat similar to those when the 454 sequencer was developed.

When 454 first came out, all biologists who did sequencing were anxious because sequencing had become too easy, and if a scientist only knew how to do sequencing, they would not be able to do subsequent scientific research. But this does not mean that geneticists have nothing to do. On the contrary, the emergence of this machine has given geneticists a wider space to do things, because the sequencing work has been automated, and a large number of gene sequences can allow geneticists to find the mysteries of genetics. The same is true for Alpha Fold for structural biology. Structural biology now studies the relationship between structure and function. There are many biological things behind this, and it is not something that can be accomplished by simply measuring a structure. Therefore, if it is said that structural biology is no longer viable now that Alpha Fold3 is here, this does not make sense. On the other hand, it is easier to obtain structures, allowing structural biologists to do more advanced work and have more important things to do.

Back to the Rothberg Institute, this institute is a non-profit organization, tax-exempt. Starting with Jonathan's $30 million donation, it mainly does research and transformation work. But after some new technologies are developed and commercialized, we set up a company, which can make a profit. Part of the company's profits will be injected into the foundation, and the US federal government and state governments will also provide some support.

At the Rothberg Institute, our first project was about SARS. Shortly after the institute was established, the SARS outbreak occurred in early 2003. At that time, I discussed with Jonathan that we should do something (to deal with this infectious disease), and he also agreed. Later, we found scientists from various fields to brainstorm. Among them, a computer expert mentioned that personal computers could be connected to the Internet and everyone's remaining computing power could be used to design drugs, so we did so. It was actually one of the earliest cases of cloud computing in the world. At that time, because the epidemic was very urgent, we wanted to do something for China and the world, so we did not apply for a patent or set up a company. Solving problems, influencing society, and helping our loved ones have always been our philosophy.

The 454 sequencer was launched in 2005. As soon as it appeared, the cost of sequencing began to drop by a million times. The main idea at the time was to reduce costs by miniaturization and high throughput, and to "mechanize" sequencing using micropore technology. The work done by each micropore was equivalent to the work of "running gel" by one person. In this way, everything from labor costs to material costs (chemical reagents) was reduced, and the speed was also increased.

Before 454, the commercial value of sequencing was not obvious. It was not until the emergence of 454 that the sequencing industry worth hundreds of billions of dollars was truly launched. Later, Roche acquired 454 for 155 million US dollars, but this was a hostile acquisition. The valuation at the time should have been 500 million US dollars. After the acquisition, Roche drove out Jonathan and other core R&D personnel. They thought they didn't need these people, but they were wrong. So later their products could not be upgraded. This led to the later Illumina. Three years later, Illumina's sequencer came out and quickly occupied the market.

After 454, the Rothberg Institute developed the world's first chip sequencer (Ion Torrent). Now 60% of the world's clinical sequencing is done using Ion Torrent. Later, Ion Torrent was sold to Thermo Fisher for US$2.4 billion.

Each of these companies founded by the Rothberg Institute/Converter has turned the results of basic research into commercial products for the first time, so the Rothberg Institute is a converter rather than a simple incubator.

We later did a lot of things. In 2012, I saw a news report about Professor Andrew Ng's Google Brain Project, where AI learned what a cat is. I was shocked by artificial intelligence. Although I had no computer foundation, I decided to learn AI myself. We did a lot of projects combining artificial intelligence with biomedicine in the laboratory and the Rothberg Institute. Butterfly Network is the world's first intelligent portable ultrasound machine. It not only uses chips to generate and receive ultrasound, but also uses AI to judge ultrasound images. It is the world's first approved artificial intelligence biomedical product. Hyperfine is the world's first mobile nuclear magnetic resonance machine, which uses artificial intelligence to distinguish signals and noise, so that the nuclear magnetic signal does not need to be so strong, which reduces the size of the entire nuclear magnetic resonance machine.

For rare diseases,

What else can we do?

AI Therapeutics, a company that Jonathan and I co-founded, aims to treat rare diseases. In this company, we began to use artificial intelligence for the first time to predict which drugs can treat corresponding diseases.

Because there are few patients for rare disease drugs and the market is small, we must think of some innovative ways to reduce costs in order to promote related research and development. In the past, drug research and development, from designing molecules and cell experiments to animal experiments, and then to clinical phases I, II, and III, was extremely expensive. It took an average of ten years to develop a drug, which was too long.

If we can introduce artificial intelligence to predict which drugs may be able to treat rare diseases and help develop drugs, we can greatly reduce costs and the situation will be very different. The principle is that if there is a drug that changes the direction of gene expression in the opposite direction of the gene expression of a certain disease, then this drug may be able to cure the disease because it is equivalent to correcting the problem caused by the disease.

However, it is not enough to use biostatistics alone to predict and find such drugs, because gene expression is too complex, and artificial intelligence is the best way to solve complex data. We started using neural convolutional networks to calculate, but it didn't work. Later, we developed a multi-dimensional fully connected network and trained this tool with the gene expression data of many people. In this way, we can predict the effect of drugs. Then we look for some drug molecules that failed to be developed by other companies. Generally, they are molecules that have passed the first and second phases of clinical trials and are non-toxic, but are ineffective in the third phase of clinical trials and have been abandoned. We use our artificial intelligence method to analyze and find those that may be useful and "advance" for the correct indication. At present, this method seems to be quite effective. We have four drugs in clinical trials, two in the second phase of clinical trials and two in the third phase, targeting rare diseases such as ALS. In April last year, the ALS drug passed the second phase of clinical trials and is now in the third phase of clinical trials.

One of the challenges facing China is the aging population and the increase in medical costs, which is also a global problem. About 20% of the US GDP is spent on the health sector. At Westlake University, we are combining artificial intelligence with low-cost traditional Chinese medicine, combining cutting-edge technology with the wisdom of the Chinese nation's thousands of years of fighting against diseases, promoting the modernization of traditional Chinese medicine, and opening a new path for the treatment of rare and common diseases.

One of the great inspirations I gained from my experience in academia and industry over the years is that research and finance are very powerful and can really change the world. Today, the biggest pain point in the development of rare disease drugs is cost, and the emergence of artificial intelligence has given us a ray of hope, reducing costs and benefiting more patients.