Gene Editor CRISPR Co Inventor Cong Le: Why Did Zhang Feng Miss The Nobel Prize?

On October 7, 2020, the Royal Swedish Academy of Sciences decided to award the 2020 Nobel Prize in chemistry to Dr. Emmanuelle Charpentier of the Max Planck Institute of etiology in Germany and Dr. Jennifer doudna of the University of California, Berkeley.

Two female scientists are famous for their co discovery of CRISPR cas9 gene editing technology, which has laid an important foundation for gene editing in human and other animal cells.

For a while, the professional technology of gene editing has become the focus of public attention. However, Zhang Feng, a Chinese scientist who also invented CRISPR technology for gene editing, missed the Nobel Prize. While the scientific community regrets and regrets, it also discusses why he did not get the Nobel Prize. However, Zhang Cong, an assistant professor of science and technology of Stanford University, expressed his regret for the fact that Zhang and his associate of the Nobel Prize for technology in the 21st century could not share the influence of the Nobel Prize for technology in the 21st century.

It is understood that Zhang Feng laboratory has been carrying out research on CRISPR gene editing of human cells since 2011. From concept proposal to technical design, repeated trial and error, and final realization of human cell gene editing, it is earlier than and not dependent on the publication of 2012 Nobel Prize winning papers.

"Like the results in many fields, sometimes different research groups and different scientists independently discover / develop similar or related results in different places and at similar times. In the history of the Nobel Prize, because of the limited number of people and other reasons, a large number of outstanding scientists missed it, including more than one Chinese scientist. "

He pointed out that, no matter how many top-notch Chinese scientists have been investing in this field, they have made great contributions to the development of Chinese industries, including those in China.

Why didn't Zhang Feng win the prize?

On October 8, Cong Le published an article on Zhihu that the two female scientists deserved the prize, but at the same time, he was very sorry that Zhang Feng failed to share the Nobel Prize.

Cong Le pointed out that, like the achievements in many fields, sometimes different research groups and different scientists independently discover / develop similar or related results in different places and at similar times. However, due to the limited number of people and other reasons, a large number of outstanding scientists will miss the Nobel Prize. In fact, in the field of CRISPR biology, European pioneers such as virginijus shivik ? NYS, Rodolphe barrangou, Philippe Horvath and other pioneers have made outstanding contributions.

Cong Le graduated from the Department of biology and electronics of Tsinghua University under the guidance of academician Yu Rao Zihe, and then went to Harvard Medical School to study for a doctor. He was the first student of MIT / Broad Institute Zhang Feng laboratory. After graduation, he completed his postdoctoral under the guidance of Professor Aviv Regev of MIT. He is now an assistant professor at Stanford University School of medicine.

It is understood that in 2009, when Cong Le just went to George church laboratory, one of the inventors of second-generation sequencing, as a graduate student, Zhang Fenggang did junior fellow (a position with independent PI qualification) in the laboratory. In this process, congle found a more advanced gene editing technology in genomics.

Cong Le has been doing CRISPR research in Zhang Feng laboratory since 2011, and has realized CRISPR gene editing in human cells for the first time (the paper was finally published in 2013), and is also a co inventor of some related gene editing patent applications (a series of CRISPR patents are controversial, and the legal scope cannot be commented).

When Cong Le first came into contact with the field of gene editing, many early articles were not published in top journals. They often encountered difficulties in finding the original literature, but these are very important starting points for research. A series of research findings from 1993 to 2011 by early research groups in Japan, Spain, Hungary, Austria and the United States helped them understand what CRISPR is and how it works in bacteria.

Congle said that due to years of scientific accumulation, these groundbreaking CRISPR biological studies have made them know that CRISPR protein represented by cas9 is a DNA cleaver as early as 2011. In 2007, for example, scientists had discovered that CRISPR could cut off phage DNA and protect bacteria from spoilage.

"However, one of the essential differences between these early works and subsequent gene editing studies is that they did not focus on the use of CRISPR for gene editing. Therefore, these biological understandings lay a theoretical foundation for CRISPR gene editing technology, similar to our biological understanding of stem cells, and laid a foundation for the induction of stem cell IPSC. Four famous genes Oct4, Sox2, KLF4 and cmyc (oskm) are used to induce stem cells. Although it is very important to study the biology of these four genes, the key step of IPSC technology is completed by scientists who realize the induced stem cell technology. " Cong Le pointed out.

In 2009, Cong Le met with gene editing for the first time while working with Zhang Feng, sriram kosuri and Paula arlota in the George church laboratory. In the beginning, they mainly studied ZFN / tale gene editing technology, which was the previous generation of gene editing technology earlier than CRISPR. In 2011, they first implemented the tale gene regulatory editing in mammalian / human cells (the paper was published in Nature Biotechnology in 2011), and a similar talen technology was developed by Miller et al. A lot of work in the field of gene editing is carried out independently by several research groups.

At the beginning of 2011, Zhang Feng proposed that CRISPR could be used to replace tale for gene editing. After long-term efforts and trial and error, the team worked to achieve this expectation.

Cong Le said that despite the great potential of CRISPR concept, before 2012, scientists had only successfully detected the editing activity of CRISPR in prokaryotic cells or in vitro in vitro experiments (including the important papers of the Nobel Prize winners in 2012), but they were most interested in gene editing of mammalian animals and human cells.

The structure and environmental complexity of human cells is much higher than that of bacterial cells. Therefore, in the history of biology, although a large number of technologies are suitable for bacteria or in vitro, they have not been realized in human cells. Dudena, the Nobel Laureate of this year, also mentioned his key papers published in 2012 on other occasions, saying that "technologies for making these modifications in animals and humans have been a big bottleneck", and their team encountered "a lot of setbacks" at that time.

In Zhang Feng laboratory, the team began to develop CRISPR system that can edit genes in human cells in 2011. In 2012, the team submitted a paper and finally published it in Science in 2013. In fact, Zhang Feng laboratory had the conceptual design of CRISPR gene editing technology for eukaryotic cells in February 2011 (with public archival proof).

Therefore, this part of the work from the concept to the technical design, and then to repeated trial and error, and finally the realization of human cell gene editing, are earlier than and not dependent on the publication of 2012 Nobel Prize winning papers.

Due to the complexity, uncontrollability and originality of CRISPR gene editing in eukaryotic cells, this paper published in 2013 has received a lot of attention and congratulations, and laid a solid foundation for a series of studies to promote CRISPR gene editing. The gene editing kit developed by Zhang Feng's team based on this work has been widely used in research and gene therapy by a large number of laboratories and companies. So far, this breakthrough paper is also the most cited article in CRISPR gene editing field.

Therefore, Zhang Feng is one of the most likely winners of the Nobel Prize.

Challenges and opportunities coexist

On October 7, Rao Yi, President of Capital Medical University, expressed the following views in his public account "Rao Yi science":

"Original originality is more elegant than close competition, and discovery and invention are more important than publication and display."

The Nobel Prize for artemisinin was announced by the media as early as 2015.

At that time, Rao Yi saw that someone in the wechat circle of friends forwarded the post-80s Chinese academic bully: will he win the Nobel Prize tomorrow? 》That is to say, I am afraid Zhang Feng's work so far has not reached the level of winning the Nobel Prize. It is a good wish to hope that the Chinese will win the prize, but objectivity and justice should not be ignored.

But Rao Yi also stressed that Zhang Feng was young, promising, intelligent and diligent, and it was not impossible for him to win Nobel prizes and other honors for his outstanding research work in the future.

In Cong Le's opinion, the recognition of the Nobel Prize for gene editing technology also reveals the influence and importance of this technology.

In fact, gene editing has brought great influence on the cure of human diseases and animal and plant research. It is reported that in June 2015, a 1-year-old baby girl in London, UK, entered the countdown due to leukemia. In the case of complete failure of traditional therapy, the doctor tried to inject the gene edited blood cells into her body. Unexpectedly, she created the miracle of the world's first case of infantile leukemia.

As for the application of gene editing in the future, Cong Le told the 21st century economic report that, like the growth of most new technologies, gene editing has broad prospects, but there are still many challenges in the technology and application level to be solved.

"From the perspective of the development of science and technology, gene editing is still in the early stage of maturity, so there will be potential problems such as overheating, being too fast but not reaching the target. For example, before problems such as long-term safety, editing accuracy and human social ethics are solved, too fast application may produce reverse effects. Therefore, I very much agree with the country's steady and orderly treatment of this emerging technology. " Cong Le analyzed.

In addition, Cong Le pointed out to the 21st century economic reporter that gene editing is both a challenge and an opportunity. For example, for the scientific research support of gene editing technology such as agriculture and environment, including the exploration of gene editing and treatment for rare and serious diseases, Chinese scientists and some start-up enterprises have been in the forefront of the world. It is understood that a number of gene editing companies in China are growing rapidly, such as Craig gene and Boya Jiyin.

"There are a lot of Chinese scientists at home and abroad. They are among the top in terms of research level and promotion of industrial development, including the support from industrial investment institutions. Therefore, I am looking forward to seeing the contribution of Chinese in this field. As a member of young scientific research workers, I hope you will continue to pay attention to and support." Cong Le said.

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