Interview with Cheng Yifan, "Golden Partner" of the New Kono Award

Interview with Cheng Yifan, "Golden Partner" of the New Kono Award: We are always asking more questions

Interview with New Kono Award "Golden Partner" Cheng Yifan: We are always asking more questions Interview with New Kono Award "Golden Partner" Cheng Yifan: We are always asking more questions

In 2017, the Nobel Prize in Chemistry was awarded to Cryo-EM (Cryo-EM) technology; in 2021, the Nobel Prize in Physiology or Medicine was awarded to two American scientists David Julius and Arden Pataptian (Ardem Patapoutian), in recognition of their contribution to the "discovery of temperature and tactile receptors
.

"

Looking through the stories behind these two Nobel Prize achievements, we will find that there is a Chinese scholar who is closely connected with them
.

Professor Yifan Cheng of the University of California, San Francisco, an academician of the American Academy of Sciences , is a leader in the technological revolution of cryo-electron microscopy.

Academician of the Academy of Sciences

"David and I have been working together almost since 2009, always thinking that he should win the prize one day, so I am very happy
.

" Cheng Yifan was still unable to conceal his cooperation in an interview with The Paper ( The excitement and joy of the partner winning

Cheng Yifan graduated from the Department of Physics of Wuhan University in 1982 and Master in 1987
.

Entered China in 1987 Kexue Yuan Institute of Physics, follow Lifang Hua academician PhD, he engaged in electron optics, learning theory and experimental techniques of imaging and high-resolution electron microscopy theory, research and application

Academician of the Academy of Sciences

In 1996, at the age of 34, Cheng Yifan transferred from the field of physics to the field of biology.
He continued to do postdoctoral studies in the United States and Japan.
He became very interested in cryo-electron microscopy and used cryo-electron microscopy to study two-dimensional crystals and membrane protein structures
.

In 2006, Yifan Cheng became an assistant professor at the University of California, San Francisco, established his own laboratory, and received tenure in 2012

Academician of the Academy of Sciences

Cheng Yifan once claimed to be the oldest junior professor at the University of California, San Francisco, and it took 15 years to become an assistant professor after graduating from his PhD
.

This calm and pureness is also reflected in the interview, "Of course, David and the others won the award this time not because they solved the structure, but because of their long-term protein research, but we who are doing structural biology are also very excited.

Just recently, Cheng Yifan also shared on social software that he finished the 125th Boston Marathon in 3 hours, 17 minutes and 50 seconds, and he is already looking forward to the coming year
.

He who likes to run marathons has similar attitudes towards scientific research.

This is just like what he mentioned to The Paper reporters that technical means and scientific issues are actually promoting each other.
The advancement of technology allows you to try to ask some deeper questions, "After answering deeper questions, it will also It triggers you to think about a deeper level of problems.
At this time, further technical means are needed
.

"

Does Nobel Prize achievement need clinical application? "This is not the only standard"

Does Nobel Prize achievement need clinical application? "This is not the only standard"

At about 17:30 on October 4th, Beijing time, the Karolinska Institutet of Sweden announced in Stockholm that the 2021 Nobel Prize in Physiology or Medicine will be awarded to David Julius and Arden Pataptian.
Recognize their contributions in "discovering temperature and tactile receptors
.

"

"David Julius discovered TRPV1 in 1997.
He first found a molecular receptor that senses temperature.
Then Arden Pataptian was in 2010.
The laboratory discovered Piezo1 and Piezo2 one after another.

Mediates the stimulation of mechanical force .

" Xiao Bailong, who conducted post-doctoral research in Pataputian's laboratory from 2007 to 2012 and is now a dean professor at the School of Pharmacy of Tsinghua University, is being interviewed by The Paper ( Shi once said, "These are all very important physiological functions, and it is very important to be able to reveal its molecular mechanism
.
"

Dean

Cheng Yifan told The Paper at the first time, “The work of the two winners is basic research, which also illustrates the importance of basic research, especially groundbreaking basic research!” Press release issued by the University of California, San Francisco In, Julius himself also talked about the importance of basic research.
These studies did not have specific treatment goals at the beginning, but may eventually help treatment
.

"Most of the major advances in understanding the mechanisms of medicine actually started when scientists followed their own curiosity without knowing in advance that the work they were doing might one day be useful for treatment
.
" Julius said, "I am very Fortunately, we have public institutions and schools such as the National Institutes of Health that provide funds to me and other researchers.
We are exploring some basic questions, and we don't know whether it is'useful' or will be transformed at some point
.
"

Regarding the awards of Julius and Pataptian, Cheng Yifan commented, “I personally think it’s not early.
In many cases, basic research can indeed improve our understanding, and whether clinical applications can be applied or not.
It is not the only purpose of doing basic research
.
" He was deeply moved.
"I think this is a very big affirmation of basic research, including all those who do basic research
.
"

In Cheng Yifan's view, in recent years, most of the Nobel Prizes have been awarded to discoveries with major clinical applications, but many times in history they have been awarded to breakthroughs that are entirely basic science
.
For example, he mentioned that the Nobel Prize in Chemistry in 2011 was awarded to the field of quasicrystals.
The 70-year-old color scientist Daniel Shechtman won the award for his contribution to the discovery of quasicrystals.

.
By definition, quasicrystals are ordered solids that do not have translational symmetry and periodicity, but have rotational symmetry that ordinary crystals do not
.

"When I was a Ph.
D.
, my thesis was a quasicrystal research.
The quasicrystal hasn't been applied until now, but it is a breakthrough in cognition
.
" Cheng Yifan said, of course, many studies may eventually produce some clinical results.
Application, "But this is not the only standard
.
"

In fact, some pharmaceutical companies have targeted new pain-relieving therapies that target TRP receptors
.
For example, chronic pain has a great impact on the quality of life of patients, and currently widely used opioids in clinical practice are addictive
.
A new idea is to directly target the receptor that produces pain, the TRP receptor protein
.

Of course, for now, none of the TRP receptors or Piezo channels involved in the Nobel Prize has yet been discovered that can be used clinically
.
Cheng Yifan said, "TRPV1 has been developed as a drug target for pain relief, but it was unsuccessful because of the effect of the drug on thermoregulation
.
" Xiao Bailong also mentioned, "Our laboratory is also working on the discovery and development of its drugs.
, But this may take time.
It is very difficult to design and develop new drugs for such new targets
.
"

"Golden Partner": Understanding the function and regulation mechanism of the TRP channel from the structural point of view

"Golden Partner": Understanding the function and regulation mechanism of the TRP channel from the structural point of view

Nobel Committee will respect the official interpretation of the award-winning, wrote the basis for our perception of heat, cold and touch vital for survival, which is why we interact with the world around them
.
In daily life, we take these feelings for granted, but how are nerve impulses generated so that temperature and pressure can be sensed? "One of the biggest mysteries facing humans is how we perceive the environment
.
"

Committee member

In the course of historical development, scientists have continued to explore the above-mentioned mysteries
.
However, before Julius and Pataptian’s discovery, there was still a fundamental unanswered question about how the nervous system perceives the environment: how temperature and mechanical stimuli are transformed into electrical impulses in the nervous system.
?

Julius’ contribution is that since he joined the University of California, San Francisco in 1989 , Julius and his laboratory students, postdoctoral researchers, and other researchers have been exploring how neurotransmitters, drugs, and natural products regulate the nervous system
.

1989

They used various toxic substances produced by plants and animals, including toxins from tarantulas and coral snakes, capsaicin, a molecule that produces "hot" in peppers, and the chemicals behind the irritation of horseradish and mustard to try to understand what is responsible for temperature and pain.
How signals are transmitted to the brain through neural circuits
.

The red pepper was the inspiration for Julius' ion channel research, and it became one of the background pictures of the Nobel Prize celebration party
.
His work finally revealed that TRPV1, a special ion channel located at the outer end of the sensory nerve, responds to capsaicin in peppers and temperatures above 110 degrees Fahrenheit, and is activated as a heat sensation to the brain
.
This protein plays a central role in the perception of pain and heat
.

Cheng Yifan mentioned that Julius' contribution goes beyond this
.
The team also identified and studied different TRP channels responsible for other types of sensations
.
In 2002, Julius’ laboratory used peppermint and related compounds to identify the TRPM8 channel, which responds to low temperatures
.
They also discovered that TRPA1, also known as the "wasabi receptor", can respond to the irritating compounds of mustard and is also involved in inflammatory pain
.

The cooperation between Cheng Yifan and Julius' laboratories began around 2009, when he had only established his own laboratory for three years
.
"David's laboratory has been doing physiological research before.
Since they discovered the TRPV1 protein in 1997, the TRP channel field has developed very fast in the later period, but the structure of the TRP channel is limited
.
" Cheng Yifan recalled the research needs at that time "Everyone feels that it is necessary to have a good understanding of its function and regulation mechanism from the structural point of view
.

In fact, before the two collaborated, related laboratories were already trying to analyze the TRP channel structure, and Julius paid particular attention to it
.
"They tried to use crystallization to make structures during that time, but the crystallization method is actually more difficult
.
Our laboratory is also doing structural biology, but we use cryo-electron microscopy
.
" Cheng Yifan mentioned, "I am Before working with David, to be honest, I had no idea about TRP channels
.
"

In 2009, at a meeting organized by the department, Cheng Yifan listened to Julius’s speech, “We both chatted together and discussed using cryo-electron microscopy.
The method at the time was not enough.
The degree to which the atomic resolution structure can be solved, but we are the laboratory that has been doing methodological research
.
" Later, the two laboratories worked together to continue to improve the method while constantly trying to analyze the structure
.

Today, it is not an exaggeration to call Cheng Yifan and Julius "golden partners"
.
Among the published results on the page of Julius Lab, many of his collaborative papers with Cheng Yifan are listed
.
"Our laboratory has collaborated on more than ten articles, and there has been a lot of cooperation now.
Several students and postdoctoral fellows have also been jointly cultivated
.
"

In a press release issued by the University of California, San Francisco, Cheng Yifan’s name was also highlighted: In recent years, Julius has turned his attention to a better understanding of the structure of TRPV1 and related molecules, hoping that this information can drive new The design of painkillers
.
In a scientific breakthrough in 2013, he and his colleague Dr.
Cheng Yifan used cryo-electron microscopy to determine the structure of TRPV1 at a scale close to the atom
.
In 2015, Julius and Cheng Yifan used cryo-electron microscopy to determine the structure of the "mustard receptor" TRPA1
.

It is worth mentioning that in addition to the long-term contributions of the Nobel Prize winners, the real arrival of the era of cryo-electron microscopy has also benefited from the advancement of various technologies such as sample preparation technology, the invention of a new generation of electronic detectors, and software algorithm optimization
.
The development of the "direct detection camera" by Cheng Yifan and others finally set off the "resolution revolution" of cryo-electron microscopy in the biological field
.

"It took several years and some very good progress was made by the end of 2012.

" At the end of 2013, the top academic journal "Nature" published their research results.
Cheng Yifan and Julius two teams cooperated and used it for the first time.
Cryo-electron microscopy analysis obtained a high-resolution three-dimensional structure of the membrane protein TRPV1 at 3.
4 angstroms close to the atomic level
.

Once the research was published, it caused a huge sensation in the scientific community, and this result was regarded as a landmark
.
"It was the first time that cryo-electron microscopy was used to analyze the structure of membrane proteins, and it was also the first time that cryo-electron microscopy was used to solve completely unknown structures.
Of course, it was also the first structure for the TRP channel, so the work at that time had a great influence
.
"

Cheng Yifan also mentioned that for the entire structural biology, the results at that time were also far-reaching
.
Before their results were published, although some laboratories had increased the resolution to about 3 angstroms, everyone felt that cryo-electron microscopy resolved structures that had been previously obtained by X-ray crystallographic imaging
.
"Up to that time, I had never done an unknown structure, so it had a great impact on the entire structural biology.
The original laboratory for crystallography started from that time and switched to cryo-electron microscopy
.
"

Since then, the trend of improved resolution in structural biology has been set off.
In 2017, cryo-electron microscopy technology won the Nobel Prize, which also affirmed the development of technology in this field
.
"Of course, the Nobel Prize this time is not because of solving the structure, but because of their long-term protein research, but we who are doing structural biology still feel very excited, because structural biology has indeed played a certain role in promoting the development of this field.

.
"

He also talked about the Piezo study of Pataptian, another Nobel laureate
.
In 2015, Xiao Bailong's team reported the structure of Piezo1 for the first time
.
Since then, Xiao Bailong and Pataptian have successively reported higher resolution structures
.
In 2019, Xiao Bailong's team further obtained the structure of Piezo2
.

Always ask more questions, technology will bring more profound impact

Always ask more questions, technology will bring more profound impact

The cooperation between the two laboratories is exploring from structural analysis to deeper issues
.

"We have always been very interested in the mechanism.
Up to now, as far as the TRP channel is concerned, how heat causes its activation is still unclear.
Of course, many people are studying this aspect, so we also hope to make more changes.
More research
.
” Cheng Yifan said, in terms of protein structure, most of the research on TRP channels now focuses on the channel itself.
“There must be many in-depth or broader issues
.
”

On September 7th, less than a month before the results of the Nobel Prize were announced, the top academic journal "Cell" published another collaborative research paper by Cheng Yifan's team and Julius's laboratory.
The research team was applying different natural stimuli.
Using single-particle cryo-electron microscopy technology to analyze a series of intermediate state conformations and activation mechanisms of TRPV1 under the conditions of objects and simulating different physiological environments, a variety of closed and open states were observed
.

This study reveals the structural elements related to the coupling of multiple ligand action sites, compares the protein behavior when cations of different sizes pass through, explores the quantitative relationship between agonists and endogenous lipid molecules competing for binding sites, and also describes The protein conformation rearrangement under acidic conditions is improved
.

Cheng Yifan said that whether scientific research is difficult or easy depends on the questions we ask
.
"For example, in the past, we thought that by solving a structure, we knew what a protein was like
.
But proteins are dynamic, so now we are not only solving its structure, but wanting to know how the protein functions.
What kind of form is it in the dynamic state, what kind of transition does it have, and what kind of process does it go through from one state to another?"

It is this kind of progressive exploration.
Since 2013, the two laboratories have cooperated and published 4 articles on TRPV1 alone.
“We are thinking of studying these more questions step by step, how is this channel? Deactivated
.
"

In Cheng Yifan’s view, technological means and scientific questions are actually promoting each other.
The advancement of technology allows you to try to ask some deeper questions.
"After answering deeper questions, it will also cause you to think more.
For a deeper problem, further technical measures are needed at this time
.
"

"We have not paid too much attention to some things outside the channel itself.
It is also because the technical means have not yet reached there.
Now that there is further improvement in technology, we can more analyze this dynamic process.
This is for our understanding.
It is of great help
.
"

Similar bottlenecks will not completely disappear.
"The questions you ask deeper, then your questions may appear more difficult under the existing technical conditions.
Therefore, we need to promote more technological progress to be able to answer some of them.
More profound issues
.
" Cheng Yifan said that the alternating and deepening of technical means and scientific issues are all integrated with each other, and it is difficult to separate them
.

Cheng Yifan even mentioned that at this stage, at least his own laboratory has not focused on drug discovery
.
"If we have a good understanding of its mechanism, maybe we can think of a way to suppress the pain caused by a certain factor without affecting other functions
.
But whether it can be done, it is still Is unknown
.
"

However, he also believes that the development of this kind of basic research may eventually provide some new ideas and clues for the research and development of drug discovery
.

It is worth mentioning that cryo-electron microscopy technology shocked the scientific community in 2013, and now it has only been 8 years, and some of the people in it have begun to "shake in the military
.
" DeepMind, an artificial intelligence company under Google, made a major investment in December last year.
They developed a new neural network-based model AlphaFold2 that defeated their opponents and reached close to human experimental results in terms of protein structure prediction accuracy, which shocked the entire structural biology community
.
Since the beginning of this year, the continued progress of artificial intelligence in predicting protein structure has caused the outside world to ask: Are structural biologists really going to be "unemployed"?

As a leading figure in the field of structural biology, Cheng Yifan took the initiative to mention this latest trend
.
"In the past year, cryo-electron microscopy, or structural biology, has actually been greatly affected.
Many people who are engaged in experimental structural biology, especially students, feel that there may not be a great deal in this field in the future.
The future, but in fact it is often not the case
.
"

In his view, if the purpose is only to solve the structure, then I am afraid the above-mentioned worries are established
.
"Because almost all protein structures can be predicted in the future, even if the prediction is wrong, it means that its prediction is wrong, or that it will not be very accurate, nothing more
.
"

But if the purpose is our question about biology, then structure is only an intermediate means, and structural biology will certainly have its long-term significance
.
Cheng Yifan added, “In the past, many people may have been satisfied with solving a structure and publishing a good article.
Now and in the future, they should pay more attention to problems.
What kind of problems do you want to study?”

Cheng Yifan firmly believes that from the perspective of structural biology, technology will still bring many more profound effects
.