He was the first to develop a machine learning technique to predict continuous torsion angles for direct construction of protein backbone structures, which paves the way for the development of end-to-end protein structure prediction by deep learning and the subsequent AlphaFold2 revolution. Having lived abroad for more than 30 years, he was tenured professors in three universities in the United States and Australia.
In addition to his scientific research, he is a million-level “Internet celebrity” blogger on ScienceNet.cn. His blog on raising children has attracted wide attention, especially after his two daughters were admitted into Harvard University and MIT, respectively.
As a person approaching the age that many would plan for retirement, Dr. Zhou chose the most vibrant city in China to “do what was previously thought impossible”.
Surprisingly, he did not post his “Nature” paper but two papers published in less known journals as his representative publications on the official website of Shenzhen Bay Laboratory.
As for the reason behind it, Dr. Zhou said bluntly: “The significance of a scientific research is not directly related to whether or not it was published in a journal with a so-called high-impact factor.”
Returning to China: “Step outside the comfort zone and break through the bottleneck”
During his postdoctoral study at Harvard University, his mentor, Martin Karplus, said that: he once considered to change jobs every 5 years.
The 2013 Nobel Laureate in Chemistry moved from University of Illinois Urbana Champaign to Columbia University, then to Harvard University. He stayed at Harvard because Harvard had the best research environment.
Although he has no intention of “deliberate imitation”, Dr. Zhou seems to have “inherited” his mentor’s job-hopping habit. His scientific career can be characterized as “on-the-move”. After he was awarded a tenured associate professor at University of Buffalo, he was successively joined Indiana University and Griffith University as a tenured full professor. In March last year, he became a senior principal investigator and associate director of Institute of Systems and Physical Biology at the Shenzhen Bay Laboratory.
“After staying in one place for too long, I can feel that my thinking and social circle are gradually being rigidified; it seems to be trapped in a fish tank, making the future a little too comfortable, overly stable and too predictable. Without making a change, my scientific research would reach a dead end,” Dr. Zhou said.
To break the deadlock, he “forces himself to change”. A sudden change in the working environment would provide a shock needed to jump out of the comfort zone and break through the bottleneck. “It’s very much like finding the global optimum in mathematics, and a strong perturbation must be given to escape the trap of the local minimum,” he said.
However, it is entirely possible to jump from one local trap to another.
How to “avoid the trap”? He practices “democratic decision-making”. Every time before moving, he always seeks the approval of his family and the opinion of his team members. “I will move only if the family supports and my colleagues are willing to move along with me. This is the only way to ensure the continuity of scientific research.” he said.
That was the case when he moved to Shenzhen from Australia last year. Three of his colleagues at Griffith University also joined him at Shenzhen Bay Laboratory. This seeded the growth of his multi-disciplinary team to 25 strong with expertise ranging from biology, physics, chemistry, artificial intelligence, computational biology, software and to hardware. He is eager for having more young talents to join the team.
As for why he joined a new type of research institution like Shenzhen Bay Laboratory, Dr. Zhou said that he agreed with the idea of Dr. Yun-Dong Wu, Executive Vice Director of Shenzhen Bay Laboratory: scientific research needs stable support so that scientists can conduct original and exploratory research with peace of mind. In addition, in a new research institution, it is possible to participate in shaping the research culture, making it a fertile ground for promoting innovation.
“I also particularly like Shenzhen, a vibrant and thriving city; living in Shenzhen, I feel more energetic and braver to do what was previously thought impossible.” he said.
Scientific research: “One success is worth, and two successes are a win”
Dr. Zhou and his team currently conduct research in three major areas. The team’s basic research will continue to build around their expertise in protein/RNA structure prediction, hoping to go beyond AlphaFold by combining computing and high-throughput experiments. In applied basic research, they will mine biological and medical big data by using AI and deep learning, hoping to design new biological drugs and nanobodies against viruses and cancers, and accelerate discovery and application of new drugs. They are also working on translational research by designing a new generation of western blot imaging systems and self-evolution instrument, with the goal of surpassing the current-state-of-the-art equipment.
Whether going beyong AlphaFold, developing new drugs, or developing new equipment, all constitute great challenges.
Dr. Zhou is mentally prepared for the challenges. On the official website of Shenzhen Bay Laboratory, you can see his motto: “Success is built on accumulation and fermentation of many failures”. This is his personal experience after countless “failures”.
Dr. Zhou still remembers the “darkest moment” in his scientific career: He began his graduate research on computational liquid-state statistical-mechanics theories. For a whole year, no matter what he calculated, the result always turned out to be the opposite of what was expected. He could not remember how many projects he had changed, and began to seriously doubt about himself: “maybe I am not suitable to be a scientist”.
Later, even his mentor was not sure what to do. He asked another professor to join the supervising team. Perhaps because the new mentor had a different mentoring style and the specific research area was a better match, he suddenly felt something clicked and solved one problem after another. During his doctoral studies, he was highly productive, with more than 20 peer-reviewed publications, some of which are pioneering studies in the liquid-state theory. “Without the accumulation of multiple failures, there would have been no later smoother success.” he recalled.
Years after having his own research team, performing biological experiments provided him a new insight into setbacks: Difficulties associated with doing computational biology would be nothing compared to the challenges faced in biological experiments. There are simply too many variables that could go wrong. It usually takes a long time to figure out the reason and to correct them. During this slow process, someone else published on the same idea that they have investigated for a long time. Sometimes, because positive and negative control experiments were not well designed, experiments had been tried for a long time before being corrected.
There were too many lessons like that. All experimental work were completed after many failures. Many more ideas had to be abandoned. It has always been a narrow escape. ” Dr. Zhou said.
After experiencing setbacks so frequently, he became immune to the hardship and more determined to get the job done.
Zhou Yaoqi and his team
In a little over one year, Dr. Zhou and his colleagues have established two methods for screening inhibitors of SARS-Cov-2 papain-like protease, and found some initial leads; An engineering prototype for the new generation of Western-blot imaging system has been built and is being optimized. In addition to Shenzhen Bay Laboratory, he has obtained research funds from the Department of Science and Technology of Guangdong Province, and the Ministry of Science and Technology of China. His team also seeks private capital to attract more talents to accelerate innovation and translation. Currently, they have secured some investment and are expected to establish an innovative drug-discovery company soon.
“We are in the right place at the right time, and we are getting more and more right people as well.” Dr. Zhou is confident about the future. However, he does not expect all projects to succeed. After all, he is doing something that no one else has done before, which requires to search in the dark.
“If one project were successful, it would be a worthy effort. If two projects were successful, we would feel like to have won a lottery.” he said.
Scientific evaluation: High-impact factor papers may also be “sought after”.
Although he did have a publication in Nature, Dr. Zhou’s two representative publications posted on the official website of Shenzhen Bay Laboratory were not published in “high-impact factor journals”.
One paper focused on the development of a new type of antibiotic peptides that are achieved after 8 years of efforts. It was only published in the Journal of the Federation of American Societies for Experimental Biology with an impact factor of 5. Another paper on the first end-to-end RNA secondary structure prediction method was published in Nature Communications.
In this regard, Dr. Zhou believed that if a research was published in a high-impact factor journal, it simply means that certain aspects of the work were recognized with news values, but the work is not necessarily original. “An original 0-to-1 research, just like an ugly duckling, is often not perfect. Such a study can only be published in specialized journals, and requires many years of further studies to make it perfect. ”, he said.
In 2007, Dr. Zhou and his colleagues were the first to predict the real values of torsion angles of the protein backbone by using the neural network. The prediction errors were large at the time and the work was published in Proteins with an impact factor of 3. It was later demonstrated through continuous improvements that continuously distributed angles could be predicted accurately, which laid the foundation for the end-to-end prediction of protein structure through the angles by deep learning, including AlphaFold.
In addition, his most influential work, a new statistical energy function for proteins proposed by his team, was only published in Protein Science with an impact factor of around 2, but it has received more than 1,000 citations.
Although he himself published a paper in Nature as a post-doctoral fellow, he said that the paper was neither the best work, nor the most cited ones among his publications.
“Understanding the principles of chemical physics is very challenging, and the journals like Nature are not interested in that. For them, discovering the function of a molecule is more newsworthy. ” Karplus once told Dr. Zhou. Karplus had four papers with 1,000+ citations, only one of which was published in the high-impact factor journal Science.
“New ideas and new methods are very important. It often takes a long time to know whether they will have a great impact. It cannot be judged by the short-term impact factor represented by the average three-year citation for a journal. ” Dr. Zhou said. He suggests to change the way that an impact factor is calculated, instead of being misled by the factor.
For scientific evaluation, Dr. Zhou advocates anonymous peer review based on multiple indicators, including the trend and innovation of recent publications, rather than relied only on the impact factor of the journals in which the papers were published.
“Shenzhen Bay Laboratory’s evaluation criteria for scientific research or scientists are being established, and I firmly believe that there will be a method based on the profession.” he said.
Zhou Yaoqi and his team
First impression of returning to China: “Age Discrimination is a ‘formidable obstacle’”
After returning to China for more than a year, Dr. Zhou, as a cross-cultural scientist, is deeply impressed by the soaring scientific research quality, and improved research culture and environment in China.
“There is a fast flow of scientific research information. The Chinese translation of major international scientific discovery is almost instant. It is very convenient for people to communicate and cooperate with each other, just by convening in a WeChat group. More and more people are friendly and open for cooperation. The governments at all levels, from national, provincial, municipal, to district government, knew the importance of scientific research. They established various research grant schemes for scientists and scientific projects.” he said. More importantly, young people are highly talented and self-driven. The future for scientific research is highly promising.
However, there is no perfect place in the world. Dr. Zhou thinks that some areas need to be improved.
For example, in terms of career development, the time for a postdoctoral fellow is too short. The salaries for postdocs are subsidized by the government for two years only. As a result, many people think that the two years are enough for doing the postdocs. However, the postdoctoral period is the most important time to develop independent thinking skills. It was in his five years of postdoctoral training that he really knew how to think big and start small in scientific research.
In research project grants, some guidelines are too specific. In these cases, scientific discovery projects were treated as large engineering tasks that somehow can be solved by using big teams. Some projects set quantitative evaluation measures such as the number of papers published and the number of patents applied. These measures restrict creativity and suppress competitiveness.
For the career development of scientists, governments at all levels have various talent projects, but indiscriminate age cutoff is a ‘formidable obstacle’ for many. All scientists, regardless of their gender, age, or status, must be equal before scientific truth to bring out their full potential. In this regard, China still has a long way to go. In addition, recognize truly talented scientists is urgently needed for improvement.
From Dr. Zhou’s point of view, the key for a meaningful life is to find what you really love to do. After he completed his graduated study, he participated in starting up a company with his friends. Only then, he realized how much he loved scientific research. At the start of his next research chapter, Dr. Zhou hopes that his past research experience can lead to new research progresses benefiting the mass.
“When your work is what you really love, it is no longer a job, but a career. You will have the patience and perseverance, to overcome whatever the challenge you are facing. You will feel fulfilled,” Dr. Zhou said.
Currently, on the streets of Shenzhen, you might run into Dr. Zhou, who went to work every day by riding a shared bicycle for a 15-minute joyful trip.
Explore more about Dr. Zhou Yaoqi and his research: http://zhouyq-lab.szbl.ac.cn/
