Serial Entrepreneur Allen Guo: Beyond Boundaries
date:01/01/2024
"Failure is our partner in growth, accompanying us along the way to transcend boundaries, transcend losses and transcend ourselves."
-- Allen Guo
"Do you have a motto?"
Allen: "No, I don't set boundaries for myself. Theoretically, life is not always aging, for example, 18 years old is not aging than 10 years old, but on the contrary stronger. It's just that at some point in time, a signal in our body tells us it's time to get old, can we change that signal? I'm trying to say to step outside the boundaries of what we had before and do something that we couldn't envision before and was challenging. Of course, another way to put it is to always be curious and keep learning new things."
"Do you mean no limits in life?"
Allen: "That sounds a little bit like chicken soup, haha ...... Although I don't set boundaries for myself, I do have an idol - Musk. It's a blessing of the times to have an entrepreneur like Musk on the planet, who is doing what we ordinary people can't reach but aspire to. Someone in the crowd has to think about how to jump out of the earth. If in a thousand or even ten thousand years, human beings can only survive in the same way on earth, it would be too boring. One day in the future, if I have the ability, I would like to do something similar, and that should be what many technology-based entrepreneurs and start-ups would like to do."
This is a conversation near the end of the interview.
His mind was very jumpy during the interview, and the experiences he recounted were full of ups and downs. He was twice a PhD student and twice a dropout, and he has been through N startups before embarking on his N+1st.
I don't know how to define him, "serial entrepreneur" is obviously just a label for him. In the interview, I was not surprised by his "crazy" sounding ideas, but I was touched by the hidden enthusiasm behind those ideas.
Such a person, no matter how old he is, is a teenager.
"Putting up posters near the school in the middle of the night to recruit students, earning myself travel expenses to study in the U.S., this was my first real business venture"
In 1991, Allen Guo was admitted to the Engineering Physics Department of Tsinghua University from Liaoning Experimental High School. There was a very popular saying in the last century - learn mathematics, science and chemistry well, and you will not be afraid to go anywhere. Becoming a scientist was the dream of many high school students in those days, and becoming a physicist like Albert Einstein was also Allen Guo's dream from his high school days into college.
"It took me 12 years to finish elementary and middle school, plus a five-year undergraduate degree at Tsinghua, so it took me 17 years to complete my studies, but my passion for physics was slowly drained away in college. In the early 1990s, when there was a wave of people going abroad, I was not sure what I wanted to do in the future, so I prepared to go abroad like other students. Thinking that it would take several years to study abroad, I set myself a Gap year".
After graduating from Tsinghua in 1996, Allen Guo returned to his hometown of Shenyang to set up a TOEFL and GRE training school. That was his first real venture.
"I just finished the TOEFL and GRE myself, so if I look for a formal job, I can't actually do anything in a year's time. I pirated the teaching materials of Yu Minhong of the New Oriental, and rode my bicycle with my buddies, and put up posters near major schools in the middle of the night to recruit students. We taught ourselves and taught more than 400 students in a year's time, and also earned ourselves travel expenses to study in the United States."
"Nasdaq collapsed, Silicon Valley was in mourning, out of TS investors have no news, this is my first Internet venture"
In 1997, Chunlong Guo moved to the University of California, Berkeley to study nuclear engineering, and a year later transferred to the EECS (Electrical Engineering and Computer Science) Department to pursue a PhD in wireless communications and semiconductors. Soon after, he was pulled in by the same group of mentors to join the start-up of China Star Microelectronics, later the first Chinese chip design company to go public in the US. At that time, there were three founders of MSE, one graduated from Stanford and two graduated from Berkeley.
"When I first arrived in the U.S. I had two eyes, I just wanted to see the world and didn't know what to do in the future. I may have a tradition of inactivity in my bones, and that restlessness was easily discovered by people who were equally restless, so I was pulled on board and became the first part-time employee outside of the three founders of MSE. Putting on a suit and a borrowed tie, I started to talk to TSMC and UMC about foundry business. That experience was memorable and was my first step into the Silicon Valley entrepreneurial and venture capital community."
Although his time at MSI was short, it opened a door to a whole new world for Chun-Long Guo's life.
At the turn of the century in Silicon Valley, the Internet tide was surging. In the early 2000s, he pulled together a few students from Berkeley and began exploring geolocation-based local services.
"GPS commercial services were far from mature 20 years ago. We then pushed users information about cafes, restaurants, barber stores, etc. within a certain area based on cell phone numbers, which was quite avant-garde at the time. Soon after, NASDAQ collapsed, Silicon Valley was in mourning, out of the TS (Term Sheet, investment intention letter) investors also no news, we can only rest. This is my first Internet venture."
That summer, Chun-Long Guo became the first Mayfield Fellow at Berkeley and joined an Israeli-founded wireless communication technology company, wireless-onlineInc. invested by Mayfield Fund, responsible for the marketing strategy of intelligent wireless station series in Europe and Asia. 2001, Chun-Long Guo, as a Haas School of Business In 2001, as a Hitachi Fellow, he worked part-time to provide technical and strategic consulting for Hitachi's entry into the U.S. market for the world's smallest RFID chip.
"From Heyou to Baihe is like a long march, first to survive and then to grow"
In 2002, the second wave of the Internet reared its head.
"At that time, there was a social networking site called Friendster, which was 'on fire half the time'. At that time, Google went to copy it, made a Orkut, the number of users once more than 100 million. But soon after that, it was killed by Facebook and My Space, which were in the ascendancy. The metabolism of the Internet industry in a period of great development is really too fast!
In the early years of the Internet, the world followed the law of the jungle. -The leftovers were king, and the first Chinese social network imitators soon suffered more than half of their casualties. Heyou.com was unwilling to give up and kept trying, and in 2005 it transformed into China's first real-name Internet dating service platform, Baihe.com, before finally surviving.
"From Heyou to Baihe is like a long march, the long march is forced out, first to survive and then may develop."
In 2018, Allen became the owner of Baihe.com.
"After I recovered from my injury and returned to China, I started Youcast Music Network, which is dedicated to the personalized recommendation of Chinese music."
After arriving in the U.S., Chunlong Guo fell in love with snowboarding, and in the winter of 2003, he was seriously injured while snowboarding at LakeTahoeHeavenly, suffering a triple crush fracture of the lumbar spine and undergoing two major surgeries. After the second surgery, he needed to continue to recuperate from his injuries, and Allen Guo had to stay in Silicon Valley.
Lying in bed with nothing to do, Allen Guo listened to many songs. At that time, there was a website called "Pandora Music Box" in the United States, whose slogan was "automatically pushing songs based on users' music DNA". To a certain extent, this was the predecessor of the recommendation engine behind today's Jitterbug, which automatically pushes the content that users are most likely to like based on their preferences.
Allen Guo, who has a technical background, was very sensitive to this, and in 2006, after recovering from his injury and returning to China, he founded Yobo Music Network, which is dedicated to personalized recommendations for Chinese music.
"Looking back now, it was a bad decision. There was a huge market for personalized pushing of favorite content to users through engines and algorithms, but choosing the music market as an entry point in China at the time was a mistake. Music had made Baidu's search traffic, and its content dividend on the web had been squeezed out by the giants, making it difficult for any other small company to survive. The pay-per-view model is a dilemma, and it's a very awkward situation for users to end up in."
Allen Guo also talked about a fact that sounds "unbelievable" today: 80% of the Chinese music industry's revenue was supported by China Mobile because of "colorful bells". Almost all musicians, whether lyricists or songwriters or distributors, were paid by China Mobile, which had the largest number of subscribers at the time, and had a fee-based model.
In 2011, Youcast Music signed a cooperation agreement with the Chengdu branch of China Mobile Music Base, and the business was eventually sold to Music Base, and Allen Guo left after a year with his team in Chengdu. Allen Guo, who returned to Beijing, felt that this ending was "really nothing to be proud of".
"There are still a lot of things I want to try, and there are still some dreams in my head that I haven't realized."
"I didn't know what I could do before I went abroad, and there were not a few people who felt the same way. After arriving at Berkeley, a wave of 'restless' buddies gathered around me, and a few people got high and sprang up a 'Chinese Student Entrepreneurship Forum', which felt similar to the Salvation League more than 100 years ago."
Even after years away from school and several setbacks, the attraction of entrepreneurship for Allen Guo continued unabated, and in 2012, when he returned to Beijing, he chose to continue his business, "because there are still many things I want to try, and there are still some dreams in my head that I haven't realized."
As a child, Guo loved to draw and paint, another of his hobbies besides physics when he was young. He wanted to try to connect the Internet with art, so he rented a studio in Beijing's 798 Art District, which he found to be an impractical idea after just six months.
"Because the Internet and art are completely two extremes. The Internet pursues scale, openness and interoperability; art is the opposite, a top luxury product, very personalized. Without rules there would be no Matthew effect, and I found myself cognitively biased and limited. It seems obviously problematic now, but at that time, I thought I was right. Isn't that how people grow?"
Allen Guo has also made many different attempts, some of which are rarely mentioned anymore.
Heyou.com once carried Guo's dream of being a social network, and although it later evolved into Lily.com to survive and thrive, his desire to be a social network has remained "intact". When WeChat first appeared, Allen Guo was eager to move again.
In 2013, WeChat was already in the ascendancy, "but not so much as to be untouchable". At this time, Allen Guo had the opportunity to contact with 360 founder Zhou Hongyi, at that time, 360 cell phone assistant and cell phone guard two APP users together more than 200 million, Zhou Hongyi want to do a social app, Allen Guo also have this knot. Later, Allen Guo took a team as a 360 consultant, and the goal was to combine WeChat and SMS functions together, taking into account telecommunications and network communications. Unfortunately, the two people who are used to leading are too insistent on their own views and do not compromise with each other, and eventually ended with Allen Guo quit.
"The product called 'SMS Pass' is forever submerged in history. We all put a lot of effort into it, and it was a pity that the project was stillborn. Two years later, and the old week in the United States hunting and get together again. In retrospect, if we could be more tolerant and flexible, so that the project could be put on line, but also to fulfill a wish, perhaps, today will not be WeChat alone. There are many potholes on the road to entrepreneurship, the biggest obstacle, or their own hearts."
"Once the buddy money is big it's hard to close the mouth again, and this is my last attempt in the Internet field"
Building a social network has always been a knot in Guo Chunlong's heart, and he has been exploring areas where it can be applied.
"One side of traditional lending is the individual and the other side is the financial institution. Why can't rich friends finance those who don't have money? Couldn't the trust between friends be quantified into something freely circulating? I wanted to combine lending with social networks, and in 2015, the social finance app 'Friends Money' was born."
Friends Money tries to break the judging standards of the traditional credit system and provide a fun and convenient social finance platform to young people who are not covered by banks and mainstream financial institutions, allowing funds to flow efficiently among those who need them.
"The idea was quite good in theory, and there was a great opportunity at the time in terms of response from all sides, but it wasn't long before we discovered the possible problems. If millions or tens of millions of users are involved, and everyone has a lending relationship with each other, it is actually very scary. This thing is very difficult to close the mouth again once it gets big, and this is my last attempt in the Internet field."
On September 4, 2019, the Leading Group of Internet Finance Risk Special Rectification Work and the Leading Group of Internet Credit Risk Special Rectification Work jointly issued the Notice on Strengthening the Construction of Credit System in the Field of P2P Network Lending, which supports the access of operating P2P network lending institutions to the credit system . In mid-November 2020, the actual operating P2P network lending institutions in the country will be completely zeroed out.
"The life sciences are starting to be digitized, and this is interesting."
In 2016, Chun-Long Guo went back to Silicon Valley to enter a university called Singularity. This university had two founders, one from Google and the other claimed to be the inventor of the cell phone. There is no way to verify the founders' backgrounds, but their ideas were very forward thinking.
Chunlong Guo's class brought together a large group of people who also love to cross borders, including a former Canadian deputy prime minister, a Dutch air force commander, professors, investors, entrepreneurs, artists, pastors, and more. They gathered in Silicon Valley to discuss space technology, nanotechnology, new energy, life sciences, and other topics that will shape the future of the world. Chunlong Guo is most concerned about the life sciences, which have begun the process of digitization.
"Many people who study physics have great interest in life sciences, and I don't know why. Schrödinger in the last century, a Nobel Prize-winning physicist, wrote a book called What is life in his later years, after influencing many physicists to turn to the study of life sciences. If life science research still relies on the traditional laboratory bottles and jars, I am not very interested. But the gene sequencing that happened in 2000 is the combination of life sciences and computational science, life sciences began to be digital, this is interesting."
Singularity, which means "singularity" in Chinese, comes from the founder's prediction that the "singularity" of humanity was about to happen. This "singularity" has two meanings: one is that from a certain moment artificial intelligence will surpass the sum of human intelligence, and the other is that humans will attain immortality in some form at some point.
"There are many different forms of immortality, one of which is a completely digital immortality, where the memories and consciousness of the brain are transferred to a chip. I have little interest in the Singularity founder's wish for immortality per se, but in a vitalistic sense, it seems perfectly possible to me that humans will achieve some form of immortality. He was predicting a time about 30 years in the future, whether it would be 2046 or 2048, who knows? I chose the number 2048. people in IT have a good sense of the Nth power of 2. 2016 is 32 years away from 2048, 32 is the 5th power of 2, 2048 is the 11th power of 2."
This is also the origin of the name "2048 Capital". This experience at Singularity also laid the groundwork for Guo Chunlong's later founding of Mizuki Future.
In January 2018, French President Macron visited China for the first time. The short 3-day trip was intense, but he still appeared at the Sino-French Artificial Intelligence Forum to witness the signing of a framework for cooperation on artificial intelligence between Chinese and French higher education institutions. Enabling this cooperation was 2048 Capital.
In fact, Guo Chunlong started to focus on investment after returning to Beijing from Singularity in 2016, and subsequently established 2048 Capital to focus on artificial intelligence and life sciences.
"You can't find a better partner than Hong Wei in the world."
VR was very hot in 2016, and Guo Chunlong looked at a bunch of VR projects, for which a closed-door roundtable was held specifically. He invited Wang Xiaochuan, the founder of Sogou, the director of the School of Cinematography at the Film Academy, the chairman of Taiwan's Hershey Technology, an expert in AI computing, and Wang Hongwei, the president of the Tsinghua School of Life Sciences, to discuss the future prospects of VR applications in various fields.
"I didn't expect Wang Hongwei to be most interested in this matter, and he called me a week after that roundtable, excitedly suggesting that we do a project to help scientists observe and study biological macromolecules with VR, expecting that we could visualize the world of biological macromolecules after wearing VR glasses. This VR project later became the first Tsinghua University life science research result transformed by Mizuki Future, although our business has long been much more than that. So, entrepreneurship many times is not planned out. Although electron microscopy was Wang Hongwei's expertise and today is one of the core technology platforms of Mizuki Future and is in high speed development, cryoelectron microscopy was not yet ready for commercialization."
Hongwei Wang and Chunlong Guo have been friends for twenty years. Chunlong Guo came to Tsinghua in 1991 to study nuclear physics and went to Berkeley for his PhD after his undergraduate degree; Hongwei Wang came to Tsinghua in 1992 to study biology and went to Berkeley for his postdoctoral research after his PhD at Tsinghua.
After returning to Beijing from Singularity, Chunlong Guo was always looking for and exploring new opportunities, and he talked to Hongwei Wang about the many possibilities for new opportunities.
"Hongwei is very specialized in the field of research, but at the same time he is a very broad-minded person. He also has a very active mind about emerging technologies in different fields. Science fiction is a common passion of ours, and we started talking about it from Yun Tianming in Three Bodies, exploring how to freeze brains and put them in Earth orbit. We talked about a lot of ideas that sounded crazy, and that was one of the big reasons why we both got together."
At the time, Chun-Long Guo had a vague idea that life sciences were unstoppable once they started to be digitized, even though any industry or technology that is digitized is very slow to start. He found it interesting that on the one hand, he could use his years of experience in the IT industry, and on the other hand, life sciences was still in the early days of digitization, which meant that this could go on for 30 years.
Wang Hongwei and Guo Chunlong have strong complementary skills. Guo Chunlong's professional cross from nuclear physics to semiconductor wireless communications and then to do IT Internet companies, always curious about new things; Wang Hongwei has been doing research in the field of life sciences, from the beginning of his doctoral studies at Tsinghua University has been focused on cryo-electron microscopy research, very dedicated.
"Mr. Jin Qinxian, the then director of Tsinghua University Research Institute for the Transfer of Scientific Research Results, paid special attention to the transformation of scientific research in the field of biomedicine at Tsinghua, and he gave us great support. Without anyone pulling anyone, we urged each other and decided to start a company. Entrepreneurship depends on the general direction, and the core team is the most crucial. We could not find a more suitable partner than Hong Wei. In addition to the complementary experience, skills and expertise, our years of acquaintance and trust are especially important. He is the soul of the company's science and technology, and I am in charge of the company's operations and commercialization."
"In the era of three-dimensional structures of biomolecular complexes, Mizuki expects to contribute more than 50% to the world"
In late 2016, Wang Hongwei and Guo Chunlong began planning to start their own business, only to register their company a year later - Beijing Shuimu Future Technology Co. The name, at a glance, is certainly related to Tsinghua.
Waterwood was given two missions when it first started: one was to take cryoelectron microscopy from the lab to industry, just like how gene sequencing technology has evolved over the past 20 years; the other goal was to drive the digitization of drug development based on the electron microscopy platform and AI computing, to crack human diseases that are difficult to treat, and even to slow down aging.
Chunlong Guo has excitement and awe for such a new field.
"I told Hong Wei, 'structure + computing' thing enough to do 30 years, there is no rush, I first go to another life science PhD, the company is temporarily looking for someone to run. I have been in the fickle Internet industry for a decade or two, feel that it has been consumed, before entering a new battlefield need to update the knowledge base, so I want to go back to school to recharge.In the summer of 2017, I returned to Tsinghua Park as a doctoral student in the School of Life Sciences, according to Yan Ning later said, I was the first on the day of the interview."
In late 2017, the Nobel Prize in Chemistry was awarded to three scientists, Jacques Dubochet, Joachim Frank and Richard Henderson, for their contributions to the development of cryoelectron microscopy techniques for the high-resolution structure determination of biomolecules in solution. The announcement of the Nobel Prize brought cryoelectron microscopy to the attention of the entire industry, and the drug discovery field began to realize the value of electron microscopy.
Chunlong Guo also sensed that the time might have come for the development of electron microscopy. In the year that followed, applied research in cryoelectron microscopy developed rapidly.
There was no proven model for cryo-electron microscopy commercialization in the U.S., and we had to figure out how to break through. In the spring of 2019, Chunlong Guo felt that he could not delay any longer, and that the commercialization of the electron microscopy platform needed to be fully accelerated, and he officially became CEO of Waterwood from May.
"I'm afraid I can't continue my studies at Tsinghua, and I'm currently on hiatus. I twice to study for a PhD, maybe twice to drop out of school. In another 20 years, I hope to choose a new field to get a doc title."
In 2020, Mizuki completed seed and angel rounds of investment by Banyan Tree Capital, Puhua Capital, Mint Angel Fund and Hotang Venture Capital. 2021 saw the completion of Pre-A round of financing with the addition of shareholders such as Tongchuangweiye, Byte Jump, and Tsinghua Infinite Qihang SeeFund Fund.
"After two years of mapping and building, we all began to see the unique entry point of Waterwood in the field of electron microscopy and the business model that can build a competitive barrier. Our team has also grown from 3 people in 2019 to over 70 people now, and is still growing. [...]
Talking about the future, Guo Chunlong admits that Shui Mu's strategic planning is in three steps. The first step of the goal has been achieved, that is, two years to complete the electron microscopy services from 0 to 1 breakthrough, "with a 300 kV electron microscope run beyond the current output of any other similar laboratory on earth, including resolution, success rate and efficiency."
The second step is to take the electron microscope platform from 1 to 10 and 100 in the next two years, so that the technical advantages gradually become industrial scale advantages. Mizuki's stage goal is to become the world's largest high-throughput biological structure resolution platform, "in the era of three-dimensional structure of biomolecular complexes, we expect to be able to make more than 50% of the world's contribution".
With enough biomolecule structure data, the best AI prediction model can be trained, which has been verified on AlphaFold 2. The third step is what Mizuki really wants to achieve in the future - a data-driven drug discovery platform.
"Imagine a future where high-throughput structure-based outputs will drive a whole new drug pipeline every year far beyond current human levels, including a large number of completely new targets that were previously completely unavailable as drugs. Drug design based on high-resolution structures and AI computation may be slower and get off to a tough start than traditional methods initially, but once a certain tipping point is passed, it will show exponential growth. In the future, all drug development, small molecules, large molecules, gene therapy, etc., cannot be done without electron microscopy and computation."
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NingJing: The strategic plan of Mizuki is expected. Currently positioned as an electron microscopy service platform, from the perspective of business model can we understand that we start from CRO?
Chunlong Guo: China's CROs started 20 years ago and are positioned to take on business that others can do, but at a much lower cost for Chinese people to do. Mizuki is promoting a new technology that has just made a breakthrough but is not yet very mature, which is not the same as traditional CROs.
It is not as simple as water for any new technology to be widely accepted. Based on electron microscopy and computation, we can provide more than just structural services, we can also provide customers with complete products from target to PCC and IND, especially for a large number of difficult target innovation drugs that are basically impossible to become drugs without electron microscopy. Of course, due to the downstream development capability, a large number of projects are developed through collaboration or license-out at different stages.
Many Chinese biopharmaceutical companies are exploring cross-border and innovative business models in CRO and Biotech, a typical case is the launch of "Thousand Mice, Ten Thousand Antibodies" antibody drug development platform by Biosetu, founded by Dr. Yuelei Shen. I appreciate that they have chosen such a big path, and Shen is a biopharmaceutical entrepreneur with an Internet mindset.
Serenity: As a scarce technology, how does cryoelectron microscopy work? What are the main fields it is currently used in?
Chunlong Guo: Cryoelectron microscopy is actually a large microscope, and the main difference between it and conventional optical microscopy is that it uses electrons as the medium, and the sample is placed at ultra-low temperature. The wavelength of electrons is much smaller than that of visible light, so the resolution or clarity that can be observed is theoretically much greater than that of optics.
What we usually think of as room temperature, in the physical sense, is a heated state with violent molecular motion, while the biological sample in solution is not conducive to improved resolution. If rapidly frozen to liquid nitrogen temperatures, the sample enters the glassy state, where biomolecular motion is much reduced, which can dramatically improve the quality of imaging. Scientists have also tried freezing to lower temperatures with liquid helium, but liquid helium is too expensive and costly. Air, which is 70% nitrogen, is available in a constant supply for us to extract, so liquid nitrogen can be produced industrially in large quantities, even cheaper than mineral water.
Cryoelectron microscopy is currently mainly used in the structural analysis of biological macromolecules, but also applied to some special materials, such as lithium batteries, the study of lithium-ion batteries is the core technology of electric car batteries, so cryoelectron microscopy is also important in materials, energy and other fields.
Tranquility: What are the unique advantages of cryoelectron microscopy in the field of life science research? How does it work?
Chun-Long Guo: Cryoelectron microscopy is an important tool for structural biology research, capable of observing the microstructure of proteins, nucleic acids, etc., and resolving the atomic composition and spatial position relationships of organic macromolecules.
In recent years, the speed and resolution of cryo-electron microscopy has increased due to continuous improvements in hardware and algorithms. It used to take an average of 2-3 years to resolve a structure, but now it is reduced to weeks or even days, and in the future it will only take a day or even a few hours. Breakthroughs are also being made in the resolution of structures with smaller molecular weights. Traditional X-ray crystallography mainly resolves protein structures with molecular weights below 100,000 daltons, and cryo-electron microscopy has broken through this limitation.
In addition, compared to conventional X-ray crystallography, cryoelectron microscopy requires very small sample volumes without the use of long crystals, which is closer to the normal state in living organisms.
One of the applications of cryoelectron microscopy, which is moving from research institutions to the pharmaceutical industry, is to rapidly and precisely decipher the structure of potential targets of drug action. For example, a team of researchers at the University of Texas at Austin used cryoelectron microscopy to resolve the S-protein structure of the neo-coronavirus for the first time in the world in early February 2020 and found that the ACE2 protein has 10-20 times more affinity for the neo-coronavirus than the SARS virus. This, to a certain extent, reveals the reason for the strong infectivity of the new coronavirus.
In mid-February 2020, Xinquan Wang's group at the School of Life Sciences, Tsinghua University and Linqi Zhang's group at the School of Medicine collaborated to resolve the crystal structure of the receptor binding region of the spinosomal glycoprotein on the surface of neo-coronavirus in complex with the human receptor ACE2 protein. One day later, Qiang Zhou's group at Westlake University announced the use of cryo-electron microscopy to resolve the full-length structure of the ACE2 receptor and the structure of the S-protein receptor structural domain in complex with the ACE2 full-length protein. Thus, structural biologists provide an important basis for drug and vaccine development in the battle for the new crown.
In the resolution of new drug targets for general diseases, cryoelectron microscopy also plays an important role in the structural resolution of larger molecular weight proteins such as membrane proteins, ion channels, and G protein-coupled receptors (GPCRs). In particular, GPCR is the largest class of superfamily membrane proteins in human cell membranes, with more than 800 kinds, and is an important way for cells to sense external signals, and is also the most known drug target. It is also an important direction in which Mizuki's team will have technical advantages.
In addition, cryo-electron microscopy can analyze the different states of proteins in solution, including the conformational changes before and after the binding of proteins to drugs and during the binding process, so it can more accurately understand the interaction between drugs and targets, which is especially suitable for antibody drug development, and can help transform antibody drugs that better meet clinical needs.
Serenity: Based on the unique advantages of cryoelectron microscopy, has Mizuki also identified the corresponding commercial application direction?
Chunlong Guo: In fact, there is a 40-year history of new drug discovery based on structural analysis. There are three major tools in structural biology: X-ray crystal diffraction, nuclear magnetic resonance (NMR), and cryo-electron microscopy (Cryo-EM). Of these, X-ray crystal diffraction has been dominant, with crystal structures accounting for approximately more than 80% of the total in the PDB database, and electron microscopy structures have accelerated in recent years, but are still well below 10%. Cryoelectron microscopy-based new drug discovery is still in the early stages of development.
As the technical advantage of high efficiency and high resolution of cryoelectron microscopy becomes apparent combined with molecular computational capabilities, Mizuki has gradually identified several commercial applications.
In Me-too or Me-better drug discovery, cryo-electron microscopy can resolve the structure of target complexes of proprietary drugs, medicinal chemists can then design molecules using strategies such as molecular hybridization, and computational chemists can obtain high-quality computational models. It can also improve the efficiency of drug discovery by allowing for the reconstruction of proprietary drugs with known targets and the screening of more accurate and effective lead compounds.
In First-in-class drug design, early probe molecule structures are resolved and combined with CADD, DNA-encoded compounds, and computational chemistry to enable the discovery and design of novel structures.
In antiviral vaccine and drug development, we provide a basis for drug development by resolving the 3D structures of key proteins and interactions during virus infestation, and provide a basis for vaccine development by structural analysis to compare the antigenic proteins of recombinant protein vaccines with viral antigenic proteins.
Mizuki's electron microscopy and computational platform has already entered into strategic partnerships with research institutions such as Beijing Biological Structure Frontier Research Center, Beijing Institute of Life Sciences, Institute of Pharmaceutical Sciences, Chinese Academy of Medical Sciences, and many innovative pharmaceutical companies including Biosetu.
Serenity: One of Mizuki's missions is to take electron microscopy from the lab to industry, what makes it possible to have this capability as a startup company? When do you think the electron microscopy technology will be widely used or enter a boom period?
Chunlong Guo: Tsinghua is a global leader in cryo-electron microscopy in life science applications. Of course, the electron microscope equipment is not made by Tsinghua, all the electron microscope equipment in China is imported so far, it needs a professional team to operate the hardware and software. Mr. Shi Yigong applied for research funding as early as 2010 to purchase the first 300 kV electron microscope for Tsinghua in the Asia-Pacific region.
There was a breakthrough in electron microscopy technology at the end of 2013, and when everyone started to think about using electron microscopy for scientific research, Tsinghua was already one step ahead by switching from traditional X-ray crystal diffraction to electron microscopy. Around 2016, a large number of Tsinghua papers on electron microscopy were published in Cell, Nature and Science, and Tsinghua became the global No.1 in the field of electron microscopy and structural biology.
Because of the background of Tsinghua University as a backing, the speed and ability of Mizuki to build cryo-electron microscopy platform is more advantageous than its peers. As the first startup company in the field of electron microscopy, Mizuki is positioned as a technology service platform company at the moment. With the support of Beijing Municipal Science Commission, we purchased our first electron microscope. With the support of Tsinghua University leaders and faculty, Mizuki became the first commercial company in Asia to realize its own 300 kV cryo-electron microscope.
Recently, more teams have entered the field of cryo-electron microscopy, which shows that people see the future of cryo-electron microscopy commercialization, and it is good to have competition for the development of technology and market.
It takes a long time for any new technology to go from immaturity to maturity and market growth. I often take Tesla analogy, more than ten years ago, if someone told you that the future of the road running all electric cars, I guess not many people believe, and today there is no one doubts. Tesla's market value has exceeded the sum of Toyota, Honda, Mercedes-Benz, BMW. But why is the road still dominated by gasoline cars? Because even if it is recognized by the market and the public, it will take a long time to really become mainstream.
Tranquility: Just now you talked about the initial creation of Mizuki with Tsinghua as the backbone, what are the current policy level guidelines or constraints for university teachers to participate in enterprises?
Guo Chunlong: This is a very important issue. In China, university participation in enterprises has undergone a series of reforms. 2017-2018, the government level made it clear that universities need to focus on teaching and research, and the school-run enterprise model was transformed into a new market-oriented model for the transformation of research results. The scientific research achievements of university teachers can be commercialized into companies in the form of IP shares, which is a more advanced model and similar to the international model of innovative start-up companies.
One of the major problems of the Chinese research system is the low efficiency of transformation. From the Ministry of Education to the Ministry of Science and Technology to the central government are aware of this problem, so they vigorously encourage scientists, professors and experts to transform their research results. Mizuki is the first enterprise that Tsinghua Life Science Institute tried to explore with the model of transforming research results, and implemented exactly according to the new rules allowed and approved by the policy.
The implementation has also encountered some problems, such as the state capital shares representing the university in the external fundraising review process is too long, it is difficult to respond flexibly to the market fundraising. I believe the whole mechanism will be smoothed out soon and will be more conducive to the transformation of scientific research results in universities.
Serenity: Your professional background and past experience are not in the life science field, how can you bring value to Mizuki and this industry?
Chunlong Guo: People who study physics have a commonality, they are more daring to enter any new industry or discipline. Physics is the study of the basic laws of things, whether it is the stock market, marketing or life sciences, the most important thing is a modeling problem.
My accumulation and thinking in the IT industry over the years has allowed me to see more clearly the technology trends that transcend market fluctuations and the so-called windfall. Specifically, one by one, disciplines and fields are being digitized, and life sciences are being digitized has become an inevitable trend.
Drug development has made great progress and breakthroughs in the past hundred years, but the method of making drugs is still very traditional, mainly by blind screening. If we can clearly see how molecular interactions occur in terms of the underlying biological structure, it will bring revolutionary changes. Whether small or large molecules, the underlying mechanism is molecular interaction, which is not beyond our knowledge for those who study physics.
The digitization of life sciences is within the reach of current technology, except for gene sequencing, which is electron microscopy. Electron microscopy is by far the newest and most powerful tool for quantifying biological macromolecules, and a critical infrastructure for the future of biomedicine. Still using Tesla as an example, without it, electric cars would have definitely become a global standard, but because of it, the popularity of electric cars has probably been advanced by at least 10 years. I hope that the driving role of electron microscopy in the field of drug discovery will be advanced by 10 years because of Mizuki Future.
The key core components of the electron microscope all involve engineering physics, for example, the electron gun (light source) requires a gas pedal major, and the most central high-speed electron imaging device requires nuclear electrons, which is exactly what I was majoring in when I was an undergraduate at Tsinghua. The electron microscope equipment itself was also invented by physicists. At the right time, we can promote the development and production of electron microscopy equipment, especially the core components, to end the history of China's structural biological research equipment rely on imports. People who do biology are less willing to enter equipment development, and those who study physics are more daring.
Cross-border teams have another advantage - they use new methods and dimensions to solve problems that people in the industry are not familiar with. Drug R&D is still facing a big bottleneck, and until today there is no chip company dedicated to drug computing, while future drug R&D will rely more and more on computing. In Mizuki's planning, we also consider optimizing the arithmetic base chip to make drug computation efficiency increase by several orders of magnitude after the structure problem is solved.
Serenity: I looked up your profile online before the interview and found that almost all your hobbies except photography are adventurous, such as flying, diving, mountain climbing, skiing, are adventure and challenges very attractive to you? If you put aside the meaning and value of your work, what would you most like to do?
Guo Chunlong: It's interesting how one grows up. In fact, I was weak and sickly as a child, and from elementary school to college, I always struggled to get a passing grade in sports. It was only after I came to the United States that I discovered my true passions, especially the feeling of skiing which is as fascinating and addictive as a bird in flight. The drive to find unprecedented pleasure in a sport I hadn't experienced before was overwhelming.
A hobby can switch a person from being a stick in the mud to being able to relax, but turning a hobby into a job is not necessarily a good idea. As I've gotten older, I've been more inclined to subtract. I used to be curious about everything, and when I was young I liked to read a lot of books and travel a lot of miles, but now I prefer to devote my limited time to one of the most important things.
The ultimate challenge of life science is about the nature of life, about aging and death, modern life science from the molecular level has made great progress, I hope that in my lifetime, before 2048 at least solve the mystery of aging, design drugs to slow down or even reverse aging.
This is not simply the pursuit of immortality. In the foreseeable future, human beings leave the Earth to enter the interstellar voyage, relying on the current body will certainly not work, not to mention the huge changes in the environment, our life expectancy is too short. With the fastest speed that human beings can currently achieve, it will take 18,000 years to reach the nearest Proxima. So, on a longer-term scale, whether we want to or not, humans must transform their physical bodies.
The cost of reproducing and educating the next generation is too high. If a person can live 1000, 10,000, 1,000,000 years, he or she can do many remarkable things that today's humans cannot do, and truly become an interstellar species. Mizuki's work in these 30 years may be able to do something from the perspective of life enhancement in conjunction with the icon Musk.
Of course, that sounds pretty crazy. Personally, I think any person or group of people still needs to have some long-term goals beyond the mundane, otherwise it's pretty meaningless to live alone for decades.
Curiosity, nurtured by natural selection, has become an essential element of our survival. We are not capable of predicting the future, and catastrophes often sneak up on us without our knowledge. The survival of a person, a group, or even a race may be determined by a restless few, and we are drawn to undiscovered lands or new worlds by a longing that is difficult to articulate and understand. Melville writes in Moby Dick on behalf of wanderers in all directions throughout the ages: An eternal quest for things far away distresses me, and I love to go sailing on very treacherous seas.
-- Allen Guo
"Do you have a motto?"
Allen: "No, I don't set boundaries for myself. Theoretically, life is not always aging, for example, 18 years old is not aging than 10 years old, but on the contrary stronger. It's just that at some point in time, a signal in our body tells us it's time to get old, can we change that signal? I'm trying to say to step outside the boundaries of what we had before and do something that we couldn't envision before and was challenging. Of course, another way to put it is to always be curious and keep learning new things."
"Do you mean no limits in life?"
Allen: "That sounds a little bit like chicken soup, haha ...... Although I don't set boundaries for myself, I do have an idol - Musk. It's a blessing of the times to have an entrepreneur like Musk on the planet, who is doing what we ordinary people can't reach but aspire to. Someone in the crowd has to think about how to jump out of the earth. If in a thousand or even ten thousand years, human beings can only survive in the same way on earth, it would be too boring. One day in the future, if I have the ability, I would like to do something similar, and that should be what many technology-based entrepreneurs and start-ups would like to do."
This is a conversation near the end of the interview.
His mind was very jumpy during the interview, and the experiences he recounted were full of ups and downs. He was twice a PhD student and twice a dropout, and he has been through N startups before embarking on his N+1st.
I don't know how to define him, "serial entrepreneur" is obviously just a label for him. In the interview, I was not surprised by his "crazy" sounding ideas, but I was touched by the hidden enthusiasm behind those ideas.
Such a person, no matter how old he is, is a teenager.
"Putting up posters near the school in the middle of the night to recruit students, earning myself travel expenses to study in the U.S., this was my first real business venture"
In 1991, Allen Guo was admitted to the Engineering Physics Department of Tsinghua University from Liaoning Experimental High School. There was a very popular saying in the last century - learn mathematics, science and chemistry well, and you will not be afraid to go anywhere. Becoming a scientist was the dream of many high school students in those days, and becoming a physicist like Albert Einstein was also Allen Guo's dream from his high school days into college.
"It took me 12 years to finish elementary and middle school, plus a five-year undergraduate degree at Tsinghua, so it took me 17 years to complete my studies, but my passion for physics was slowly drained away in college. In the early 1990s, when there was a wave of people going abroad, I was not sure what I wanted to do in the future, so I prepared to go abroad like other students. Thinking that it would take several years to study abroad, I set myself a Gap year".
After graduating from Tsinghua in 1996, Allen Guo returned to his hometown of Shenyang to set up a TOEFL and GRE training school. That was his first real venture.
"I just finished the TOEFL and GRE myself, so if I look for a formal job, I can't actually do anything in a year's time. I pirated the teaching materials of Yu Minhong of the New Oriental, and rode my bicycle with my buddies, and put up posters near major schools in the middle of the night to recruit students. We taught ourselves and taught more than 400 students in a year's time, and also earned ourselves travel expenses to study in the United States."
"Nasdaq collapsed, Silicon Valley was in mourning, out of TS investors have no news, this is my first Internet venture"
In 1997, Chunlong Guo moved to the University of California, Berkeley to study nuclear engineering, and a year later transferred to the EECS (Electrical Engineering and Computer Science) Department to pursue a PhD in wireless communications and semiconductors. Soon after, he was pulled in by the same group of mentors to join the start-up of China Star Microelectronics, later the first Chinese chip design company to go public in the US. At that time, there were three founders of MSE, one graduated from Stanford and two graduated from Berkeley.
"When I first arrived in the U.S. I had two eyes, I just wanted to see the world and didn't know what to do in the future. I may have a tradition of inactivity in my bones, and that restlessness was easily discovered by people who were equally restless, so I was pulled on board and became the first part-time employee outside of the three founders of MSE. Putting on a suit and a borrowed tie, I started to talk to TSMC and UMC about foundry business. That experience was memorable and was my first step into the Silicon Valley entrepreneurial and venture capital community."
Although his time at MSI was short, it opened a door to a whole new world for Chun-Long Guo's life.
At the turn of the century in Silicon Valley, the Internet tide was surging. In the early 2000s, he pulled together a few students from Berkeley and began exploring geolocation-based local services.
"GPS commercial services were far from mature 20 years ago. We then pushed users information about cafes, restaurants, barber stores, etc. within a certain area based on cell phone numbers, which was quite avant-garde at the time. Soon after, NASDAQ collapsed, Silicon Valley was in mourning, out of the TS (Term Sheet, investment intention letter) investors also no news, we can only rest. This is my first Internet venture."
That summer, Chun-Long Guo became the first Mayfield Fellow at Berkeley and joined an Israeli-founded wireless communication technology company, wireless-onlineInc. invested by Mayfield Fund, responsible for the marketing strategy of intelligent wireless station series in Europe and Asia. 2001, Chun-Long Guo, as a Haas School of Business In 2001, as a Hitachi Fellow, he worked part-time to provide technical and strategic consulting for Hitachi's entry into the U.S. market for the world's smallest RFID chip.
"From Heyou to Baihe is like a long march, first to survive and then to grow"
In 2002, the second wave of the Internet reared its head.
"At that time, there was a social networking site called Friendster, which was 'on fire half the time'. At that time, Google went to copy it, made a Orkut, the number of users once more than 100 million. But soon after that, it was killed by Facebook and My Space, which were in the ascendancy. The metabolism of the Internet industry in a period of great development is really too fast!
In the early years of the Internet, the world followed the law of the jungle. -The leftovers were king, and the first Chinese social network imitators soon suffered more than half of their casualties. Heyou.com was unwilling to give up and kept trying, and in 2005 it transformed into China's first real-name Internet dating service platform, Baihe.com, before finally surviving.
"From Heyou to Baihe is like a long march, the long march is forced out, first to survive and then may develop."
In 2018, Allen became the owner of Baihe.com.
"After I recovered from my injury and returned to China, I started Youcast Music Network, which is dedicated to the personalized recommendation of Chinese music."
After arriving in the U.S., Chunlong Guo fell in love with snowboarding, and in the winter of 2003, he was seriously injured while snowboarding at LakeTahoeHeavenly, suffering a triple crush fracture of the lumbar spine and undergoing two major surgeries. After the second surgery, he needed to continue to recuperate from his injuries, and Allen Guo had to stay in Silicon Valley.
Lying in bed with nothing to do, Allen Guo listened to many songs. At that time, there was a website called "Pandora Music Box" in the United States, whose slogan was "automatically pushing songs based on users' music DNA". To a certain extent, this was the predecessor of the recommendation engine behind today's Jitterbug, which automatically pushes the content that users are most likely to like based on their preferences.
Allen Guo, who has a technical background, was very sensitive to this, and in 2006, after recovering from his injury and returning to China, he founded Yobo Music Network, which is dedicated to personalized recommendations for Chinese music.
"Looking back now, it was a bad decision. There was a huge market for personalized pushing of favorite content to users through engines and algorithms, but choosing the music market as an entry point in China at the time was a mistake. Music had made Baidu's search traffic, and its content dividend on the web had been squeezed out by the giants, making it difficult for any other small company to survive. The pay-per-view model is a dilemma, and it's a very awkward situation for users to end up in."
Allen Guo also talked about a fact that sounds "unbelievable" today: 80% of the Chinese music industry's revenue was supported by China Mobile because of "colorful bells". Almost all musicians, whether lyricists or songwriters or distributors, were paid by China Mobile, which had the largest number of subscribers at the time, and had a fee-based model.
In 2011, Youcast Music signed a cooperation agreement with the Chengdu branch of China Mobile Music Base, and the business was eventually sold to Music Base, and Allen Guo left after a year with his team in Chengdu. Allen Guo, who returned to Beijing, felt that this ending was "really nothing to be proud of".
"There are still a lot of things I want to try, and there are still some dreams in my head that I haven't realized."
"I didn't know what I could do before I went abroad, and there were not a few people who felt the same way. After arriving at Berkeley, a wave of 'restless' buddies gathered around me, and a few people got high and sprang up a 'Chinese Student Entrepreneurship Forum', which felt similar to the Salvation League more than 100 years ago."
Even after years away from school and several setbacks, the attraction of entrepreneurship for Allen Guo continued unabated, and in 2012, when he returned to Beijing, he chose to continue his business, "because there are still many things I want to try, and there are still some dreams in my head that I haven't realized."
As a child, Guo loved to draw and paint, another of his hobbies besides physics when he was young. He wanted to try to connect the Internet with art, so he rented a studio in Beijing's 798 Art District, which he found to be an impractical idea after just six months.
"Because the Internet and art are completely two extremes. The Internet pursues scale, openness and interoperability; art is the opposite, a top luxury product, very personalized. Without rules there would be no Matthew effect, and I found myself cognitively biased and limited. It seems obviously problematic now, but at that time, I thought I was right. Isn't that how people grow?"
Allen Guo has also made many different attempts, some of which are rarely mentioned anymore.
Heyou.com once carried Guo's dream of being a social network, and although it later evolved into Lily.com to survive and thrive, his desire to be a social network has remained "intact". When WeChat first appeared, Allen Guo was eager to move again.
In 2013, WeChat was already in the ascendancy, "but not so much as to be untouchable". At this time, Allen Guo had the opportunity to contact with 360 founder Zhou Hongyi, at that time, 360 cell phone assistant and cell phone guard two APP users together more than 200 million, Zhou Hongyi want to do a social app, Allen Guo also have this knot. Later, Allen Guo took a team as a 360 consultant, and the goal was to combine WeChat and SMS functions together, taking into account telecommunications and network communications. Unfortunately, the two people who are used to leading are too insistent on their own views and do not compromise with each other, and eventually ended with Allen Guo quit.
"The product called 'SMS Pass' is forever submerged in history. We all put a lot of effort into it, and it was a pity that the project was stillborn. Two years later, and the old week in the United States hunting and get together again. In retrospect, if we could be more tolerant and flexible, so that the project could be put on line, but also to fulfill a wish, perhaps, today will not be WeChat alone. There are many potholes on the road to entrepreneurship, the biggest obstacle, or their own hearts."
"Once the buddy money is big it's hard to close the mouth again, and this is my last attempt in the Internet field"
Building a social network has always been a knot in Guo Chunlong's heart, and he has been exploring areas where it can be applied.
"One side of traditional lending is the individual and the other side is the financial institution. Why can't rich friends finance those who don't have money? Couldn't the trust between friends be quantified into something freely circulating? I wanted to combine lending with social networks, and in 2015, the social finance app 'Friends Money' was born."
Friends Money tries to break the judging standards of the traditional credit system and provide a fun and convenient social finance platform to young people who are not covered by banks and mainstream financial institutions, allowing funds to flow efficiently among those who need them.
"The idea was quite good in theory, and there was a great opportunity at the time in terms of response from all sides, but it wasn't long before we discovered the possible problems. If millions or tens of millions of users are involved, and everyone has a lending relationship with each other, it is actually very scary. This thing is very difficult to close the mouth again once it gets big, and this is my last attempt in the Internet field."
On September 4, 2019, the Leading Group of Internet Finance Risk Special Rectification Work and the Leading Group of Internet Credit Risk Special Rectification Work jointly issued the Notice on Strengthening the Construction of Credit System in the Field of P2P Network Lending, which supports the access of operating P2P network lending institutions to the credit system . In mid-November 2020, the actual operating P2P network lending institutions in the country will be completely zeroed out.
"The life sciences are starting to be digitized, and this is interesting."
In 2016, Chun-Long Guo went back to Silicon Valley to enter a university called Singularity. This university had two founders, one from Google and the other claimed to be the inventor of the cell phone. There is no way to verify the founders' backgrounds, but their ideas were very forward thinking.
Chunlong Guo's class brought together a large group of people who also love to cross borders, including a former Canadian deputy prime minister, a Dutch air force commander, professors, investors, entrepreneurs, artists, pastors, and more. They gathered in Silicon Valley to discuss space technology, nanotechnology, new energy, life sciences, and other topics that will shape the future of the world. Chunlong Guo is most concerned about the life sciences, which have begun the process of digitization.
"Many people who study physics have great interest in life sciences, and I don't know why. Schrödinger in the last century, a Nobel Prize-winning physicist, wrote a book called What is life in his later years, after influencing many physicists to turn to the study of life sciences. If life science research still relies on the traditional laboratory bottles and jars, I am not very interested. But the gene sequencing that happened in 2000 is the combination of life sciences and computational science, life sciences began to be digital, this is interesting."
Singularity, which means "singularity" in Chinese, comes from the founder's prediction that the "singularity" of humanity was about to happen. This "singularity" has two meanings: one is that from a certain moment artificial intelligence will surpass the sum of human intelligence, and the other is that humans will attain immortality in some form at some point.
"There are many different forms of immortality, one of which is a completely digital immortality, where the memories and consciousness of the brain are transferred to a chip. I have little interest in the Singularity founder's wish for immortality per se, but in a vitalistic sense, it seems perfectly possible to me that humans will achieve some form of immortality. He was predicting a time about 30 years in the future, whether it would be 2046 or 2048, who knows? I chose the number 2048. people in IT have a good sense of the Nth power of 2. 2016 is 32 years away from 2048, 32 is the 5th power of 2, 2048 is the 11th power of 2."
This is also the origin of the name "2048 Capital". This experience at Singularity also laid the groundwork for Guo Chunlong's later founding of Mizuki Future.
In January 2018, French President Macron visited China for the first time. The short 3-day trip was intense, but he still appeared at the Sino-French Artificial Intelligence Forum to witness the signing of a framework for cooperation on artificial intelligence between Chinese and French higher education institutions. Enabling this cooperation was 2048 Capital.
In fact, Guo Chunlong started to focus on investment after returning to Beijing from Singularity in 2016, and subsequently established 2048 Capital to focus on artificial intelligence and life sciences.
"You can't find a better partner than Hong Wei in the world."
VR was very hot in 2016, and Guo Chunlong looked at a bunch of VR projects, for which a closed-door roundtable was held specifically. He invited Wang Xiaochuan, the founder of Sogou, the director of the School of Cinematography at the Film Academy, the chairman of Taiwan's Hershey Technology, an expert in AI computing, and Wang Hongwei, the president of the Tsinghua School of Life Sciences, to discuss the future prospects of VR applications in various fields.
"I didn't expect Wang Hongwei to be most interested in this matter, and he called me a week after that roundtable, excitedly suggesting that we do a project to help scientists observe and study biological macromolecules with VR, expecting that we could visualize the world of biological macromolecules after wearing VR glasses. This VR project later became the first Tsinghua University life science research result transformed by Mizuki Future, although our business has long been much more than that. So, entrepreneurship many times is not planned out. Although electron microscopy was Wang Hongwei's expertise and today is one of the core technology platforms of Mizuki Future and is in high speed development, cryoelectron microscopy was not yet ready for commercialization."
Hongwei Wang and Chunlong Guo have been friends for twenty years. Chunlong Guo came to Tsinghua in 1991 to study nuclear physics and went to Berkeley for his PhD after his undergraduate degree; Hongwei Wang came to Tsinghua in 1992 to study biology and went to Berkeley for his postdoctoral research after his PhD at Tsinghua.
After returning to Beijing from Singularity, Chunlong Guo was always looking for and exploring new opportunities, and he talked to Hongwei Wang about the many possibilities for new opportunities.
"Hongwei is very specialized in the field of research, but at the same time he is a very broad-minded person. He also has a very active mind about emerging technologies in different fields. Science fiction is a common passion of ours, and we started talking about it from Yun Tianming in Three Bodies, exploring how to freeze brains and put them in Earth orbit. We talked about a lot of ideas that sounded crazy, and that was one of the big reasons why we both got together."
At the time, Chun-Long Guo had a vague idea that life sciences were unstoppable once they started to be digitized, even though any industry or technology that is digitized is very slow to start. He found it interesting that on the one hand, he could use his years of experience in the IT industry, and on the other hand, life sciences was still in the early days of digitization, which meant that this could go on for 30 years.
Wang Hongwei and Guo Chunlong have strong complementary skills. Guo Chunlong's professional cross from nuclear physics to semiconductor wireless communications and then to do IT Internet companies, always curious about new things; Wang Hongwei has been doing research in the field of life sciences, from the beginning of his doctoral studies at Tsinghua University has been focused on cryo-electron microscopy research, very dedicated.
"Mr. Jin Qinxian, the then director of Tsinghua University Research Institute for the Transfer of Scientific Research Results, paid special attention to the transformation of scientific research in the field of biomedicine at Tsinghua, and he gave us great support. Without anyone pulling anyone, we urged each other and decided to start a company. Entrepreneurship depends on the general direction, and the core team is the most crucial. We could not find a more suitable partner than Hong Wei. In addition to the complementary experience, skills and expertise, our years of acquaintance and trust are especially important. He is the soul of the company's science and technology, and I am in charge of the company's operations and commercialization."
"In the era of three-dimensional structures of biomolecular complexes, Mizuki expects to contribute more than 50% to the world"
In late 2016, Wang Hongwei and Guo Chunlong began planning to start their own business, only to register their company a year later - Beijing Shuimu Future Technology Co. The name, at a glance, is certainly related to Tsinghua.
Waterwood was given two missions when it first started: one was to take cryoelectron microscopy from the lab to industry, just like how gene sequencing technology has evolved over the past 20 years; the other goal was to drive the digitization of drug development based on the electron microscopy platform and AI computing, to crack human diseases that are difficult to treat, and even to slow down aging.
Chunlong Guo has excitement and awe for such a new field.
"I told Hong Wei, 'structure + computing' thing enough to do 30 years, there is no rush, I first go to another life science PhD, the company is temporarily looking for someone to run. I have been in the fickle Internet industry for a decade or two, feel that it has been consumed, before entering a new battlefield need to update the knowledge base, so I want to go back to school to recharge.In the summer of 2017, I returned to Tsinghua Park as a doctoral student in the School of Life Sciences, according to Yan Ning later said, I was the first on the day of the interview."
In late 2017, the Nobel Prize in Chemistry was awarded to three scientists, Jacques Dubochet, Joachim Frank and Richard Henderson, for their contributions to the development of cryoelectron microscopy techniques for the high-resolution structure determination of biomolecules in solution. The announcement of the Nobel Prize brought cryoelectron microscopy to the attention of the entire industry, and the drug discovery field began to realize the value of electron microscopy.
Chunlong Guo also sensed that the time might have come for the development of electron microscopy. In the year that followed, applied research in cryoelectron microscopy developed rapidly.
There was no proven model for cryo-electron microscopy commercialization in the U.S., and we had to figure out how to break through. In the spring of 2019, Chunlong Guo felt that he could not delay any longer, and that the commercialization of the electron microscopy platform needed to be fully accelerated, and he officially became CEO of Waterwood from May.
"I'm afraid I can't continue my studies at Tsinghua, and I'm currently on hiatus. I twice to study for a PhD, maybe twice to drop out of school. In another 20 years, I hope to choose a new field to get a doc title."
In 2020, Mizuki completed seed and angel rounds of investment by Banyan Tree Capital, Puhua Capital, Mint Angel Fund and Hotang Venture Capital. 2021 saw the completion of Pre-A round of financing with the addition of shareholders such as Tongchuangweiye, Byte Jump, and Tsinghua Infinite Qihang SeeFund Fund.
"After two years of mapping and building, we all began to see the unique entry point of Waterwood in the field of electron microscopy and the business model that can build a competitive barrier. Our team has also grown from 3 people in 2019 to over 70 people now, and is still growing. [...]
Talking about the future, Guo Chunlong admits that Shui Mu's strategic planning is in three steps. The first step of the goal has been achieved, that is, two years to complete the electron microscopy services from 0 to 1 breakthrough, "with a 300 kV electron microscope run beyond the current output of any other similar laboratory on earth, including resolution, success rate and efficiency."
The second step is to take the electron microscope platform from 1 to 10 and 100 in the next two years, so that the technical advantages gradually become industrial scale advantages. Mizuki's stage goal is to become the world's largest high-throughput biological structure resolution platform, "in the era of three-dimensional structure of biomolecular complexes, we expect to be able to make more than 50% of the world's contribution".
With enough biomolecule structure data, the best AI prediction model can be trained, which has been verified on AlphaFold 2. The third step is what Mizuki really wants to achieve in the future - a data-driven drug discovery platform.
"Imagine a future where high-throughput structure-based outputs will drive a whole new drug pipeline every year far beyond current human levels, including a large number of completely new targets that were previously completely unavailable as drugs. Drug design based on high-resolution structures and AI computation may be slower and get off to a tough start than traditional methods initially, but once a certain tipping point is passed, it will show exponential growth. In the future, all drug development, small molecules, large molecules, gene therapy, etc., cannot be done without electron microscopy and computation."
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NingJing: The strategic plan of Mizuki is expected. Currently positioned as an electron microscopy service platform, from the perspective of business model can we understand that we start from CRO?
Chunlong Guo: China's CROs started 20 years ago and are positioned to take on business that others can do, but at a much lower cost for Chinese people to do. Mizuki is promoting a new technology that has just made a breakthrough but is not yet very mature, which is not the same as traditional CROs.
It is not as simple as water for any new technology to be widely accepted. Based on electron microscopy and computation, we can provide more than just structural services, we can also provide customers with complete products from target to PCC and IND, especially for a large number of difficult target innovation drugs that are basically impossible to become drugs without electron microscopy. Of course, due to the downstream development capability, a large number of projects are developed through collaboration or license-out at different stages.
Many Chinese biopharmaceutical companies are exploring cross-border and innovative business models in CRO and Biotech, a typical case is the launch of "Thousand Mice, Ten Thousand Antibodies" antibody drug development platform by Biosetu, founded by Dr. Yuelei Shen. I appreciate that they have chosen such a big path, and Shen is a biopharmaceutical entrepreneur with an Internet mindset.
Serenity: As a scarce technology, how does cryoelectron microscopy work? What are the main fields it is currently used in?
Chunlong Guo: Cryoelectron microscopy is actually a large microscope, and the main difference between it and conventional optical microscopy is that it uses electrons as the medium, and the sample is placed at ultra-low temperature. The wavelength of electrons is much smaller than that of visible light, so the resolution or clarity that can be observed is theoretically much greater than that of optics.
What we usually think of as room temperature, in the physical sense, is a heated state with violent molecular motion, while the biological sample in solution is not conducive to improved resolution. If rapidly frozen to liquid nitrogen temperatures, the sample enters the glassy state, where biomolecular motion is much reduced, which can dramatically improve the quality of imaging. Scientists have also tried freezing to lower temperatures with liquid helium, but liquid helium is too expensive and costly. Air, which is 70% nitrogen, is available in a constant supply for us to extract, so liquid nitrogen can be produced industrially in large quantities, even cheaper than mineral water.
Cryoelectron microscopy is currently mainly used in the structural analysis of biological macromolecules, but also applied to some special materials, such as lithium batteries, the study of lithium-ion batteries is the core technology of electric car batteries, so cryoelectron microscopy is also important in materials, energy and other fields.
Tranquility: What are the unique advantages of cryoelectron microscopy in the field of life science research? How does it work?
Chun-Long Guo: Cryoelectron microscopy is an important tool for structural biology research, capable of observing the microstructure of proteins, nucleic acids, etc., and resolving the atomic composition and spatial position relationships of organic macromolecules.
In recent years, the speed and resolution of cryo-electron microscopy has increased due to continuous improvements in hardware and algorithms. It used to take an average of 2-3 years to resolve a structure, but now it is reduced to weeks or even days, and in the future it will only take a day or even a few hours. Breakthroughs are also being made in the resolution of structures with smaller molecular weights. Traditional X-ray crystallography mainly resolves protein structures with molecular weights below 100,000 daltons, and cryo-electron microscopy has broken through this limitation.
In addition, compared to conventional X-ray crystallography, cryoelectron microscopy requires very small sample volumes without the use of long crystals, which is closer to the normal state in living organisms.
One of the applications of cryoelectron microscopy, which is moving from research institutions to the pharmaceutical industry, is to rapidly and precisely decipher the structure of potential targets of drug action. For example, a team of researchers at the University of Texas at Austin used cryoelectron microscopy to resolve the S-protein structure of the neo-coronavirus for the first time in the world in early February 2020 and found that the ACE2 protein has 10-20 times more affinity for the neo-coronavirus than the SARS virus. This, to a certain extent, reveals the reason for the strong infectivity of the new coronavirus.
In mid-February 2020, Xinquan Wang's group at the School of Life Sciences, Tsinghua University and Linqi Zhang's group at the School of Medicine collaborated to resolve the crystal structure of the receptor binding region of the spinosomal glycoprotein on the surface of neo-coronavirus in complex with the human receptor ACE2 protein. One day later, Qiang Zhou's group at Westlake University announced the use of cryo-electron microscopy to resolve the full-length structure of the ACE2 receptor and the structure of the S-protein receptor structural domain in complex with the ACE2 full-length protein. Thus, structural biologists provide an important basis for drug and vaccine development in the battle for the new crown.
In the resolution of new drug targets for general diseases, cryoelectron microscopy also plays an important role in the structural resolution of larger molecular weight proteins such as membrane proteins, ion channels, and G protein-coupled receptors (GPCRs). In particular, GPCR is the largest class of superfamily membrane proteins in human cell membranes, with more than 800 kinds, and is an important way for cells to sense external signals, and is also the most known drug target. It is also an important direction in which Mizuki's team will have technical advantages.
In addition, cryo-electron microscopy can analyze the different states of proteins in solution, including the conformational changes before and after the binding of proteins to drugs and during the binding process, so it can more accurately understand the interaction between drugs and targets, which is especially suitable for antibody drug development, and can help transform antibody drugs that better meet clinical needs.
Serenity: Based on the unique advantages of cryoelectron microscopy, has Mizuki also identified the corresponding commercial application direction?
Chunlong Guo: In fact, there is a 40-year history of new drug discovery based on structural analysis. There are three major tools in structural biology: X-ray crystal diffraction, nuclear magnetic resonance (NMR), and cryo-electron microscopy (Cryo-EM). Of these, X-ray crystal diffraction has been dominant, with crystal structures accounting for approximately more than 80% of the total in the PDB database, and electron microscopy structures have accelerated in recent years, but are still well below 10%. Cryoelectron microscopy-based new drug discovery is still in the early stages of development.
As the technical advantage of high efficiency and high resolution of cryoelectron microscopy becomes apparent combined with molecular computational capabilities, Mizuki has gradually identified several commercial applications.
In Me-too or Me-better drug discovery, cryo-electron microscopy can resolve the structure of target complexes of proprietary drugs, medicinal chemists can then design molecules using strategies such as molecular hybridization, and computational chemists can obtain high-quality computational models. It can also improve the efficiency of drug discovery by allowing for the reconstruction of proprietary drugs with known targets and the screening of more accurate and effective lead compounds.
In First-in-class drug design, early probe molecule structures are resolved and combined with CADD, DNA-encoded compounds, and computational chemistry to enable the discovery and design of novel structures.
In antiviral vaccine and drug development, we provide a basis for drug development by resolving the 3D structures of key proteins and interactions during virus infestation, and provide a basis for vaccine development by structural analysis to compare the antigenic proteins of recombinant protein vaccines with viral antigenic proteins.
Mizuki's electron microscopy and computational platform has already entered into strategic partnerships with research institutions such as Beijing Biological Structure Frontier Research Center, Beijing Institute of Life Sciences, Institute of Pharmaceutical Sciences, Chinese Academy of Medical Sciences, and many innovative pharmaceutical companies including Biosetu.
Serenity: One of Mizuki's missions is to take electron microscopy from the lab to industry, what makes it possible to have this capability as a startup company? When do you think the electron microscopy technology will be widely used or enter a boom period?
Chunlong Guo: Tsinghua is a global leader in cryo-electron microscopy in life science applications. Of course, the electron microscope equipment is not made by Tsinghua, all the electron microscope equipment in China is imported so far, it needs a professional team to operate the hardware and software. Mr. Shi Yigong applied for research funding as early as 2010 to purchase the first 300 kV electron microscope for Tsinghua in the Asia-Pacific region.
There was a breakthrough in electron microscopy technology at the end of 2013, and when everyone started to think about using electron microscopy for scientific research, Tsinghua was already one step ahead by switching from traditional X-ray crystal diffraction to electron microscopy. Around 2016, a large number of Tsinghua papers on electron microscopy were published in Cell, Nature and Science, and Tsinghua became the global No.1 in the field of electron microscopy and structural biology.
Because of the background of Tsinghua University as a backing, the speed and ability of Mizuki to build cryo-electron microscopy platform is more advantageous than its peers. As the first startup company in the field of electron microscopy, Mizuki is positioned as a technology service platform company at the moment. With the support of Beijing Municipal Science Commission, we purchased our first electron microscope. With the support of Tsinghua University leaders and faculty, Mizuki became the first commercial company in Asia to realize its own 300 kV cryo-electron microscope.
Recently, more teams have entered the field of cryo-electron microscopy, which shows that people see the future of cryo-electron microscopy commercialization, and it is good to have competition for the development of technology and market.
It takes a long time for any new technology to go from immaturity to maturity and market growth. I often take Tesla analogy, more than ten years ago, if someone told you that the future of the road running all electric cars, I guess not many people believe, and today there is no one doubts. Tesla's market value has exceeded the sum of Toyota, Honda, Mercedes-Benz, BMW. But why is the road still dominated by gasoline cars? Because even if it is recognized by the market and the public, it will take a long time to really become mainstream.
Tranquility: Just now you talked about the initial creation of Mizuki with Tsinghua as the backbone, what are the current policy level guidelines or constraints for university teachers to participate in enterprises?
Guo Chunlong: This is a very important issue. In China, university participation in enterprises has undergone a series of reforms. 2017-2018, the government level made it clear that universities need to focus on teaching and research, and the school-run enterprise model was transformed into a new market-oriented model for the transformation of research results. The scientific research achievements of university teachers can be commercialized into companies in the form of IP shares, which is a more advanced model and similar to the international model of innovative start-up companies.
One of the major problems of the Chinese research system is the low efficiency of transformation. From the Ministry of Education to the Ministry of Science and Technology to the central government are aware of this problem, so they vigorously encourage scientists, professors and experts to transform their research results. Mizuki is the first enterprise that Tsinghua Life Science Institute tried to explore with the model of transforming research results, and implemented exactly according to the new rules allowed and approved by the policy.
The implementation has also encountered some problems, such as the state capital shares representing the university in the external fundraising review process is too long, it is difficult to respond flexibly to the market fundraising. I believe the whole mechanism will be smoothed out soon and will be more conducive to the transformation of scientific research results in universities.
Serenity: Your professional background and past experience are not in the life science field, how can you bring value to Mizuki and this industry?
Chunlong Guo: People who study physics have a commonality, they are more daring to enter any new industry or discipline. Physics is the study of the basic laws of things, whether it is the stock market, marketing or life sciences, the most important thing is a modeling problem.
My accumulation and thinking in the IT industry over the years has allowed me to see more clearly the technology trends that transcend market fluctuations and the so-called windfall. Specifically, one by one, disciplines and fields are being digitized, and life sciences are being digitized has become an inevitable trend.
Drug development has made great progress and breakthroughs in the past hundred years, but the method of making drugs is still very traditional, mainly by blind screening. If we can clearly see how molecular interactions occur in terms of the underlying biological structure, it will bring revolutionary changes. Whether small or large molecules, the underlying mechanism is molecular interaction, which is not beyond our knowledge for those who study physics.
The digitization of life sciences is within the reach of current technology, except for gene sequencing, which is electron microscopy. Electron microscopy is by far the newest and most powerful tool for quantifying biological macromolecules, and a critical infrastructure for the future of biomedicine. Still using Tesla as an example, without it, electric cars would have definitely become a global standard, but because of it, the popularity of electric cars has probably been advanced by at least 10 years. I hope that the driving role of electron microscopy in the field of drug discovery will be advanced by 10 years because of Mizuki Future.
The key core components of the electron microscope all involve engineering physics, for example, the electron gun (light source) requires a gas pedal major, and the most central high-speed electron imaging device requires nuclear electrons, which is exactly what I was majoring in when I was an undergraduate at Tsinghua. The electron microscope equipment itself was also invented by physicists. At the right time, we can promote the development and production of electron microscopy equipment, especially the core components, to end the history of China's structural biological research equipment rely on imports. People who do biology are less willing to enter equipment development, and those who study physics are more daring.
Cross-border teams have another advantage - they use new methods and dimensions to solve problems that people in the industry are not familiar with. Drug R&D is still facing a big bottleneck, and until today there is no chip company dedicated to drug computing, while future drug R&D will rely more and more on computing. In Mizuki's planning, we also consider optimizing the arithmetic base chip to make drug computation efficiency increase by several orders of magnitude after the structure problem is solved.
Serenity: I looked up your profile online before the interview and found that almost all your hobbies except photography are adventurous, such as flying, diving, mountain climbing, skiing, are adventure and challenges very attractive to you? If you put aside the meaning and value of your work, what would you most like to do?
Guo Chunlong: It's interesting how one grows up. In fact, I was weak and sickly as a child, and from elementary school to college, I always struggled to get a passing grade in sports. It was only after I came to the United States that I discovered my true passions, especially the feeling of skiing which is as fascinating and addictive as a bird in flight. The drive to find unprecedented pleasure in a sport I hadn't experienced before was overwhelming.
A hobby can switch a person from being a stick in the mud to being able to relax, but turning a hobby into a job is not necessarily a good idea. As I've gotten older, I've been more inclined to subtract. I used to be curious about everything, and when I was young I liked to read a lot of books and travel a lot of miles, but now I prefer to devote my limited time to one of the most important things.
The ultimate challenge of life science is about the nature of life, about aging and death, modern life science from the molecular level has made great progress, I hope that in my lifetime, before 2048 at least solve the mystery of aging, design drugs to slow down or even reverse aging.
This is not simply the pursuit of immortality. In the foreseeable future, human beings leave the Earth to enter the interstellar voyage, relying on the current body will certainly not work, not to mention the huge changes in the environment, our life expectancy is too short. With the fastest speed that human beings can currently achieve, it will take 18,000 years to reach the nearest Proxima. So, on a longer-term scale, whether we want to or not, humans must transform their physical bodies.
The cost of reproducing and educating the next generation is too high. If a person can live 1000, 10,000, 1,000,000 years, he or she can do many remarkable things that today's humans cannot do, and truly become an interstellar species. Mizuki's work in these 30 years may be able to do something from the perspective of life enhancement in conjunction with the icon Musk.
Of course, that sounds pretty crazy. Personally, I think any person or group of people still needs to have some long-term goals beyond the mundane, otherwise it's pretty meaningless to live alone for decades.
Curiosity, nurtured by natural selection, has become an essential element of our survival. We are not capable of predicting the future, and catastrophes often sneak up on us without our knowledge. The survival of a person, a group, or even a race may be determined by a restless few, and we are drawn to undiscovered lands or new worlds by a longing that is difficult to articulate and understand. Melville writes in Moby Dick on behalf of wanderers in all directions throughout the ages: An eternal quest for things far away distresses me, and I love to go sailing on very treacherous seas.
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