"I really don't like people asking me what I want to do after achieving financial freedom."
I don't remember where I heard such a story or paragraph, to the effect that an entrepreneur with a successful career is always asked such a question in his life, which makes him feel very confused.
Stories are stories, and paragraphs belong to paragraphs. However, in real life, those entrepreneurs who have truly achieved wealth freedom do not shy away from telling everyone about their new ideals for a new stage of life.
Last year, Pinduoduo CEO Huang Zheng, ByteDance CEO Zhang Yiming, Sogou CEO Wang Xiaochuan, three Internet giants have stepped down, to say that they have nothing in common, in addition to the same as the CEO of the big factory, the rest is the pursuit of life sciences.
Wang Xiaochuan said that in the next twenty years, he wants to make a contribution to the development of life sciences and medicine and make a little contribution to public health; Zhang Yiming believes that the impact of life sciences on human life has dawned; Huang Zheng has chosen protein robots and plant synthetic proteins (artificial meat) as research directions.
Looking further ahead, Jobs realized at the end of his life that "the intersection of biology and technology will be the biggest innovation in the 21st world." ”
Synthetic biology, as an interdisciplinary discipline involving biotechnology, genetic engineering, molecular biology, microbiology, biophysics and computers, is a "sharp weapon" in life sciences.
Origins and breaking the cocoon
In 1939, on the eve of the outbreak of World War II, in Lviv, on the border between Poland and Ukraine, a young man named Waclaw Szybalski, who had just graduated from high school, was enthusiastically preparing to become a freshman at the Aviation Academy, and building airplanes had always been his dream.
Shibalski was born into a family of intellectuals, and most of his friends with his parents were university professors, which gave him the opportunity to deal with different fields of science from an early age. Among them, aeronautical engineering is one of his most interesting disciplines. If all goes well, the young man's name today could appear in textbooks on aeronautical engineering all over the world. Shortly after the outbreak of war, the Soviet Union occupied Lviv, aeronautical engineering was banned due to its political sensitivity, and Shibalski had no choice but to transfer to chemistry and studied under a professor in the department of biotechnology, eventually becoming a microbial geneticist.
--- In 1978, the Polish geneticist used the term "Synthetic Biology" for the first time in the title of a paper published in an academic journal.
Fast forward to the first year of the 21st century, Stanford University Professor Eric T. Kool once again used "synthetic biology" at the 2000 American Chemistry Annual Conference to describe the synthesis of non-naturally occurring functional organic molecules in biological systems, and combined with the results of systems biology and genetic engineering, redefined the concept of synthetic biology, so that synthetic biology as a new discipline for the first time received attention and recognition by the academic community.
In terms of timeline alone, synthetic biology has been developing in the United States for 20 years, and at this point, China has been pulled away a lot.
Dr. Zhang Guochang from Amyris shared his "survival path" in synthetic biology for more than a decade at huachuang Capital's recent "Chuang Enjoy" synthetic biology special event.
Zhang Guochang stayed at Tianjin University for ten years, from undergraduate to doctoral degree. According to his recollection, when he was an undergraduate student more than ten years ago, his major was not called synthetic biology, but called biological engineering, because at that time there was no concept of synthetic biology in China. After graduating with a doctorate, Zhang Guochang found it difficult to find a professional counterpart job in China, which made him a little depressed, how did he choose such a major in the first place?
But Zhang Guochang still firmly believes that the 21st century will be the century of biology.
After several consultations with his family, he applied to the United States to continue his postdoctoral studies, determined to go all the way to "black", but for Zhang Guochang, who had just arrived in the United States, there was still some anxiety, after all, the 21st century had just begun.
Fortunately, there are some forerunners who are headwinds forward, they have slowly done the synthetic biology industry in the United States, and pioneering companies such as Amyris, Zymergen, Ginkgo and other pioneering companies have gradually been recognized by the market, giving many practitioners like Dr. Zhang Guochang a chance to settle down, and also giving some domestic investors and entrepreneurs confidence and inspiration.
Open the investment menu of Ma Rui, a partner of Fengrui Capital, in 2016, and you will see the name of Sapphire Microbiome (hereinafter referred to as Sapphire). Ma Rui very frankly told Investment Montiqi that in fact, before encountering sapphire, he did not know much about synthetic biology.
To this end, Ma Rui and his colleagues went to the United States to take a walk around and found that synthetic organisms are so hot in the local area. How did you throw so much money in? This gave him a big impact, and the teachers who returned to China to find synthetic biology were all acquainted, and immediately discovered the early trends in synthetic biology technology from the investment logic.
"You know that these smartest and most well-educated people in the world are willing to sink their hearts into doing this, and it's definitely a direction worth betting on." Marie said.
Later, Blue Crystal got three rounds of financing in one year, and the valuation is said to have exceeded 4 billion, becoming a star project in the industry. It has been favored by many investment institutions such as Gaoling Venture Capital, China Renaissance Capital, Country Garden Venture Capital, Lightspeed China and so on. Feng Rui has invested from the first round of tens of millions of yuan valuation to today, a total of seven rounds, the original judgment on the development of synthetic biology, has given the answer from the book return.
Another company with eye-catching financing results is The State Creation Biotechnology (hereinafter referred to as State Innovation), which was only established last year, and has received four rounds of financing of more than 100 million US dollars in only one year, which has also attracted the attention of the industry. Its founder, Zhang Zhiqian, told Investment Montiqi that when he visited Yale in 2017, he was inspired by a lot and returned to China to do his own laboratory.
As a post-95, Zhang Zhiqian has also been thinking, since he is so young, why not try to do this? See what kind of changes your team's technology can bring to society. So after the laboratory technology was relatively mature, Zhang Zhiqian began to attach importance to the landing of products, and also established a state innovation.
A hot wind of synthetic biology in the United States has blown the development of the country to some extent.
Are synthetic creatures really on fire?
In 2022, we are saying that synthetic organisms are on fire, and some even say that synthetic organisms are simply a bubble of capital popularity. But is that really the case?
First of all, a fundamental question needs to be asked, are synthetic creatures really on fire?
Theoretically, synthetic biological fire is not unreasonable: in 2020, CRISPR- Cas9, a gene editing system known as the "Hand of God", won the Nobel Prize of that year; in 2021, the consumption track was cold, and everyone began to turn upstream; in 2022, carbon neutrality promoted green biomanufacturing, and all of this pointed to synthetic biology technology.
According to the August 2021 McKinsey Synthetic Biology Report, in principle, 60% of the world's products can be produced by biological methods, and one-third of them are originally substances extracted from nature, and synthetic biology has changed the way they are produced. It is expected that the synthetic biology market related to materials, chemicals, and energy will have space of $200-300 billion in the next 10-20 years.
Wang Xiao, founder of Jiuhe Venture Capital, said to Meng Tiqi that the synthetic biological track is optimistic that there is its underlying technical logic, such as breakthroughs in the next generation of DNA synthesis technology, gene editing technology, bioinformatics technology, high-throughput biological experiment technology, etc., making it possible to obtain various types of biological data. Between 2010 and 2020, biological data has increased by more than 50 times, covering the sequencing and clinical data of various omics data such as genome, transcriptome, proteome, etc. These combined with the rapid development of computer technology make us hope to achieve new breakthroughs based on computational methods, and the collection of computing and biotechnology will generate huge opportunities.
Mi Lei, founding partner of Zhongke Chuangxing, also expressed that synthetic biology is indeed a subversive technology worth looking forward to for human development.
Although investors acknowledge the future prospects of synthetic biology, and even some investors bluntly say that synthetic biology is a track that must be seen, they are still very cautious to really transfer money from the account, after all, vision is not equal to reality.
As of now, there are 12 synthetic bio financing incidents in 2022, which is still some distance from the real sense of the explosion.
Ding Zhebo, managing partner of Woyan Capital, told Investment Montiqi that synthetic biology is still in the early stages of development, and fire is not a relative concept. However, there are definitely more and more people participating now, especially at the corporate level, so there will be a little virtual fire in the heat of capital, which is beyond doubt. In the past, a company could not raise a round for two or three years.
As for whether synthetic organisms are bubbles? In Ma Rui's words: "I don't feel like it's even on fire yet, and it seems like everyone is starting to prepare to take it back." ”
"It's really hard."
Why isn't synthetic biology on fire? The main card is in one word: difficult.
The difficulty of synthetic biology is well understood, as long as you compare it horizontally with other industries, the degree of difficulty is clear at a glance.
Ma Rui gave an example: if you only focus on one element in a biological system, such as DNA, then it is a sequencing company, as early as 2015, there was a wave; if you only focus on proteins, it is the proteomics direction that has been hot in China and the United States from 2020; or only focus on the interaction between components, such as proteins and small molecules or proteins and protein interactions, then you are an AI pharmaceutical company, and you have just made a wave. Then the complexity of synthetic biology is that you need to pay attention to the regulation of a string of proteins and other elements and their interactions, but also put in a pathway, and then put into a platform organism to achieve effective expression, the difficulty here has exceeded many of the previous cases, this is only the strain construction, let alone amplification and production.
Lan Yuxuan, co-founder of the microstructure factory, once said in an interview that the industrial amplification of synthetic biology is not a one-time process. In fermentation facilities, the environment faced by microorganisms is extremely complex, and the stability is difficult to ensure, and it is necessary to constantly explore and optimize the proportion of inoculation, the formulation of medium, dissolved oxygen control and feeding methods. It took four years to achieve the desired results from a small test of 10 liters of fermentation tanks to a pilot test of 5 tons of fermentation tanks.
When you solve these problems, a new problem comes, that is, selection.
Zymergen once designed a foldable optical film that is ideal for folding mobile phones. When Zymergen successfully produced this optical film over the difficulties, it found that the mass production was far less than expected, and what was more fatal was that the folding mobile phone did not get market recognition, becoming the last straw that crushed the camel. Zymergen's stock price plummeted as a result, which is a lesson for the past.
Selection is a difficult and important thing, and Investment Montić has compiled a selection suggestion based on the interview content:
Wang Xiao, founder of Jiuhe Venture Capital: Within the scope of the ability that technology can achieve, choose as high added value as possible, and the market is as large as possible.
Ma Rui, partner of Fengrui Capital: If the future of biomanufacturing is the general direction, then the really smart enterprises have begun to lay out upstream. For example, the raw material for manufacturing a certain product is glucose, the forward is starch, and then the corn is corn, it is likely that the future development is limited by China's corn yield, and the company needs to find a sustainable raw material, so going upstream is a better investment position and way for early investors.
Mi Lei, founding partner of Zhongke Chuangxing, added that the Tianjin Institute of Industrial Biotechnology of the Chinese Academy of Sciences has made major breakthroughs in starch synthesis, and for the first time in the world, the de novo synthesis of carbon dioxide to starch has been realized in the laboratory. Solving the problem of raw materials for biomanufacturing is also a good direction.
Ding Zhebo, managing partner of Woyan Capital: The correlation between products in the pipeline is very important, is there any commonality and synergy effect of the underlying biosynthesis route? In the future, we hope that more companies will see the scale effect, which can gradually reduce the marginal cost of R&D and production.
In fact, the selection of products is a logical inversion, and companies cannot focus on only one parameter. You have to think clearly about what the market needs, whether the market is big or not, and whether this product has high added value? Then think about whether the technology can be achieved or breakthrough, and finally consider the degree of correlation between the selections.
The "difficulty" of synthetic biology can be imagined, enterprises must have a full-link thinking, and any link error may be fatal.
Investment relativity
Of course, not all companies can solve the "difficult" problem at the first time, after all, there is no perfect start-up, there are always shortcomings that they cannot eliminate.
For example, the early state creations have encountered walls everywhere. Zhang Zhiqian said in an interview that when he first contacted the institution, when it came to synthetic biology, everyone would feel great and magical, but at that time, only technology had no products, and investors would find it difficult to judge.
But Zhang Zhiqian is very confident in the technology of synthetic biology and state creation, and has raised millions of dollars as start-up funds. Wang Xiao told Meng Tiqi that it was Zhang Zhiqian's firmness that impressed him, so Jiuhe became the earliest batch of investment institutions behind The State Chuang.
Entrepreneurs who understand technology and are determined to be business are very difficult to find even now. This is probably also the reason why Blue Crystal impressed Ma Rui in the first place.
Along the way, Blue Crystal has not been smooth sailing, and the industry environment faced in the early stage of entrepreneurship is much more difficult than it is now. In the round of valuation of 150 million yuan, Sapphire melted for a year and a half, and this valuation may only be the valuation of the seed round of many synthetic biology companies now. In order to survive, Sapphire also did a side job for a while --- trained high school students to participate in the iGEM (International Synthetic Biology Competition). Ma Rui told Investment Montiqi that the education business once accounted for 70% or 80% of Blue Crystal's revenue. The team has done a lot of iterative upgrades in business, products, technology, markets, and fundraising, and has suffered a lot before insisting on achieving the current results.
In Ma Rui's view, investment depends on the product, but can not wait for the product to come out before making a judgment. If you invest in the "show me the product" way, the investor's judgment is worthless.
"We are not willing to invest in the kind of enterprises with high certainty, but not so idealistic and emotional, we are more willing to invest in difficult things, but once they are done, there are huge economic benefits and social benefits." Marie said.
In fact, since the synthetic biology track was concerned, the voice of the to VC has not been broken, to which Ma Rui laughed and said: "I don't care if you are a To VC, you just have to get me." The reason why I can confidently say this sentence, I think the confidence stems from the experience accumulated by Ma Rui and Lan Jing in the past six years of jointly upgrading and fighting monsters.
In the primary market, there is no shortage of stories of Bó Lè Soma and will meet good talents, especially in the field of science and technology. Interestingly, a group of people with money and resources to invest in another group of people with high-tech skills have an absolutely consistent end goal, that is, a return on investment, but sometimes have different, even relative, decision-making logic.
Ding Zhebo's investment rules are different from Ma Rui's, in his view, it is completely possible to avoid the To VC project from the product.
"I'm not going to vote for you just because you're from Harvard, MIT, Berkeley or any other top college, and the right background is a necessary condition, but it's not a sufficient condition." I will not be because synthetic biology is very popular in the United States, there are Zymergen, Ginko and other SPAC listed companies in China to find a benchmark. Ding Zhebo always believes that the core of investment is still in product capabilities.
"You said that you have the underlying core capabilities, and you have established a product pipeline, and all the ideas are on paper, but there is no product output, then aren't you a PPT company?" Why should a truly powerful company want To VC? Ding Zhebo asked rhetorically. You have to make the product and compare it to the existing competitors, and the advantage is cost, performance or purity. ”
He then added: "At least two or three products in the pipeline should enter the pilot stage, and then tell me the schedule of large-scale production of products, the stability of the current strain, and how to solve the details of the challenges such as separation and purification in the yield process." ”
Of course, investors also have a place to reach consensus, for example, synthetic biology companies are roughly divided into two types of platforms and products, and most investors are more optimistic about product-based enterprises.
Wang Xiao's advice to start-ups is to try not to pay too much attention to platform data, and to focus on strain research and development and product landing first. The complexity of biological systems makes the prediction and modeling process very difficult, and most teams do not have algorithms + biological crossover backgrounds to identify which ones can be modeled.
This is not to say that platform companies are not good, in the long run, their malleability is very good, in the future there is a chance to grow into a very innovative large-scale company, but in the short and medium term, their self-hematopoietic ability is to play a question mark.
Ma Rui believes that there is no special good or bad between the two, the platform should do real innovation, the product should do the real value, investors do not mean that the investment platform does not invest in the product, and vice versa.
From the valuation level, Ding Zhebo told investment Montiqi that the valuation system of synthetic biological enterprises is actually affected by many factors, and some people may deliberately confuse the two, but in general, platform-based enterprises will expect more of its future development space and vision, so the valuation will be slightly higher than that of the product, but it still depends on the specific situation.
Looking to the future
The late arrival of synthetic organisms in China for more than a decade has indeed led to a certain gap with the United States, but in the long run, investors still have a very optimistic attitude towards the development of domestic synthetic organisms.
However, the biggest challenge at present is that talent, especially experienced talent, is very scarce in China.
Ding Zhebo said that now the people who do synthetic biology are relatively young, most of the practitioners are from overseas universities, from the research institute, many do not have much practical work and mass production experience, have not really operated a biochemical enterprise, and even a chemical plant of a certain scale may not have gone in, can only continue to explore based on the original laboratory research, from the trial to mass production, are still feeling the stones across the river. This is not to say that it must not work, but it will take a long time, and it will miss some market opportunities, which will have a greater impact on the commercialization of future products.
Xiao Han, a doctoral student in basic medical immunology, became very interested in synthetic biology when he participated in iGEM at the undergraduate level, and his classmates around him also paid attention to it. Xiao Han told Investment Montiqi that for many undergraduates, participating in iGEM is more like an attempt at different research fields. iGEM's programs, which cover the process from basic research to application, can help participants understand how synthetic biology products are created, which is also beneficial for cultivating new talents in the industry.
Although after the competition, there are not many students who continue to focus on synthetic biology, it should also be noted that synthetic biology has been widely used in basic research and achievement transformation in the field of life sciences, so maintaining attention to synthetic biology is also of positive significance to personal development to a certain extent.
Statistics show that in the 2021 iGEM competition, the number of high school teams Chinese mainland is 65, while the number of teams participating in the entire United States is only 50. In the future, with the increase in the experience of domestic practitioners and the increase in the number of new talents, it is believed that the talent gap will soon be made up.
In addition, the accessibility of synthetic biology, i.e., public awareness and commercial acceptance, needs to be improved. Wang Xiao said that strengthening accessibility will help promote data sharing and open source on the basis of protecting patents and inventions, allow more developers to join the industry, further reduce the threshold for development, and make it develop rapidly into a mature engineering discipline.
The good thing is that the domestic synthetic biology industry is developing at a high speed, and in the past few years, the Synthetic Biological Innovation Research Institute led by the Shenzhen Advanced Institute and the Research Center of Tianjin Institute of Industrial Biotechnology of the Chinese Academy of Sciences are trying to establish a synthetic biological ecosystem. In addition, the establishment of a synthetic biology industrial park in Baoshan District, Shanghai, and the Hangzhou Economic Development Zone have also laid out many synthetic biology-related enterprises, which are also things in the past two years.
From the external environment, capital began to have a certain enthusiasm, there will certainly be more people involved, any emerging track will experience a period of fanaticism, and then fall into a cooling off period and depression period, and finally return to the channel of rational development.
Interdisciplinary innovations like synthetic biology are interesting, because the real tipping point for the industry is in other disciplines. For example, what triggered the accelerated development of synthetic organisms to an inflection point is that the breakthrough of gene editing technology and AI machine learning capabilities has greatly reduced the cost of gene sequencing. No one can predict where the next technological "singularity" that detonates the industry will be.
Now, we can see a large number of overseas technicians returning to join the tide of domestic entrepreneurship. As long as it is close to the Chinese market and uses technology and innovation to meet the needs of Chinese customers, it must be promising. However, we must not only look at future development, but not solve practical problems, and be vigilant against the phenomenon of "synthesis" for the sake of "synthesis".
Ding Zhebo reminded that the irrational heat will definitely fade, and in the end, the most hurt is actually the enterprise, so I hope that enterprises and investors can be more pragmatic, find the expectations of mutual adaptation, do things more solidly, and do not make the entire market a chicken feather.