This article is from the public number:Back to Park (ID: fanpu2019), Lecture: Arnold J. Levine, Translator: Xian Jie (Yu Mengqian), cover from: Oriental IC
Reduction The crisis in biology, although not as profound as physics, is much broader. People with lofty ideals have already felt a lot: molecular biology is dead (G.Stent, 1970); biology is composed of concepts rather than mathematical formulas (E. Mayr, 1982); Is molecular biology still a science?(J. Maddox)? It is true that moving towards the whole is the general trend, and the question is how to go. In the fall of 2019, Arnold J. Levine, Emeritus Professor of the School of Natural Sciences at the Princeton Institute of Advanced Studies, gave a speech explaining two major changes in the biological paradigm.
Note: Gunther S. Stent, 1924-2008, Professor of Molecular Biology, University of California, Berkeley, one of the early phage biologists to study the neurobiology of bacterial metabolism and waterlogging and the history of writing biology Known for philosophy.
Ernst Mayr, 1904-2005, one of the leading evolutionary biologists of the 20th century, Emeritus Professor of Zoology at Harvard University.
John Maddox, 1925-2009, British science writer, physicist, has been the editor of Nature magazine for 23 years.
Arnold Levine (in the middle of light blue clothes), Emeritus Professor of Natural Science at the Princeton Institute of Advanced Studies, established the Simons System Biology Research Center, Theory Physicists, cancer biologists, mathematicians, and computational biologists conduct cross-disciplinary studies in molecular biology and physical science.
In the summer of 1968, a young assistant professor came out of the California Institute of Technology and came to Princeton University. In the first seven years of his academic career, the education and training he received was a method of reductionism – molecular biology from Watson and Crick. He then went to the Moffett Lab at Princeton University to study how the world’s simplest organism, the virus, causes cancer in mice or hamsters. Specific questions include: How many genes does the virus need to trigger cancer? How do the proteins encoded by these genes initiate and maintain tumor growth? What is the molecular mechanism? In 1909, Princeton University established the (John James Audubon, 1785.4.26-1851.1.27, a famous American painter and naturalist, his bird illustrations were drawn Called “American National Treasure”.) Used plates have been used to print his beautiful bird figures and books. The long evolution left these animals, their diversity attracts attention, highlights the unity and harmony of all living organisms, and sings the core principles of geology and biology.
This is a great biology museum that demonstrates the biological processes from 1859 to 1953. In 1859, DaErwin published The Origin of Species; in 1953, Watson and Crick published an article on DNA structure. During this time, a new generation of young biologists experienced a paradigm shift from Thomas Kuhn’s (Thomas Kuhn): from Gu Yao Te The organism biology that the museum admires is transformed into molecular biology, that is, observing life and asking questions from the molecular level, and less considering the organism itself, the natural life cycle of the organism, or the interaction between the organism and the environment. A new generation of molecular biologists are looking forward to studying evolution by studying the sequence of DNA constituents.
In 1953, Watson and Crick used the X-ray diffraction pattern of Rosalind Franklin (Rosalind Franklin) and Irvine The Chagoff rule (ie, the basic component of DNA or RNA consisting of nitrogenous bases, five carbon sugars, and at least one phosphate group) contains the decision Information on the sequence of amino acids in proteins, and ultimately the structure and function of proteins (genetic code) – In 1961, Nirenberg and Matthaei stated a codon (UUU, The presence of phenylalanine) of. In this way, the founders of molecular biology use the simplest organism (bacteria and virus), using genetic tools, establishing intracellular molecular circuits The model invented new methods needed to explore DNA, RNA and proteins at the molecular level.
The transformation of this research paradigm has brought about multiple levels of change. Molecular biologists became blue-collar workers, working hard in the laboratory day and night, seven days a week, and repeatedly using a pipette to aspirate. The experiment is so difficult and seems to never succeed, and if it succeeds, it must be guaranteed to repeat every time. Between 1965 and 1975, Princeton welcomed the first molecular biologists who received academic training at Stanford, Berkeley, Pasteur Institute, Geneva, Cambridge, and Caltech, rather than cultivating many seniors. Ivy League School of Biology. They like Bob Dylan and rock music, oppose the Vietnam War, and resist the decisions of their own country. They voted for women to enter the Ivy League school (Princeton University began receiving female undergraduates in 1969), and also took time to listen to black students at Princeton Discuss equality issues.
These molecular biologists like long summer vacations. From June to September, they either stay in the lab or meet in Cold Spring Harbor. Most senior teachers are in Woodshall (Woods Hole, a world-class marine research and education base, a small coastal village with a rich diversity of species) spent the summer, while others retired to write books. Molecular biologists seem to exude a little arrogance, they believe that they will change human understanding of life, understanding of life processes, and thus change the world.
Their ideas cannot be said to be completely wrong.
In the 1970s, genes were cloned and isolated, and the nucleotide sequence revealed the proteins encoded by the genes, which were finally expressed and produced in bacteria. Change is coming quickly, but not without fear and opposition. People strongly question whether it is safe to transfer genes to another species. A common question is: “What can the reductionism teach us when we leave the biological organism?” Jacques Mono (Jacques Monod ) replied: “The same thing applies to E. coli.” The answer is like a blind person – you are studying the elephant’s tail or nose, and you think it is an elephant. All of you, your knowledge of elephants is limited to this. The future of biology has become a tense problem. What kind of content is suitable for teaching the next generation? What kind of research method is worth investing time and money to develop future biology?
[Annotation] JacquesJacques Lucien Monod (1910.2.9-1976.5.31), a French biologist, and François Jacobs discovered the regulatory role of proteins in transcription, which was later known The lactose operon, the two together with André Lviv won the 1965 Nobel Prize in Physiology or Medicine. In addition, he predicted that there were mRNA molecules as mediators between gene information and protein products, and this theory was later confirmed. Source: Wikipedia
At Princeton, these issues are presented in an interesting and complex way. In the biology and biochemistry class, first-year graduate students come together to discuss how researchers choose their own research topics to build a laboratory. Through the discussion, the freshmen know each tutor and their research work one by one. They have plenty of time to explore the methods and reasons why the mentors determine their research direction. The discussion class is arranged in the evening, two teachers each time, so that students can be exposed to different perspectives and ideas.
One year, I partnered with John Tyler Bonner, Director of the Department of Biology. John is a talented scientist, a true gentleman, a dean who is respected by everyone. He studied at Harvard University and worked on the biological study of cell bacterium, Dictyostelium discoideum. In the process of completing this viscous bacterium, he made a real breakthrough, proving that an important part of the life cycle of Dictyostelium discoideum – from single-cell amoeba to a fused multicellular structure – utilizes a Chemokines. At Princeton University, John demonstrated that the chemical signal that causes cell aggregation is cyclophosphazate (cAMP), these organisms are in a single cell The transitional phase of evolution to multicellular organisms.
On the evening of our discussion with the graduate students, John spoke first and told the students why he had studied this muctomy mold throughout his career and how he studied it. He first outlined the life cycle of this bacterium: a large number of single-cell amoeba swimming and crawling in ponds or laboratory culture dishes, using bacteria as a food source, asexual reproduction like amoeba. When the bacteria are consumed, an amoeba will emit a chemotactic signal that attracts other amoeba and fuses into a large fertilized egg cell. The fusion of a large number of amoeba triggers a reproductive cycle (these molds have three genders), and the large cysts that form the diploid nuclei undergo a subtraction Split and mitosis. When the bacteria reappear in the environment, the haploid amoeba is released from the large capsule, harvesting nutrients and re-producing the asexual reproduction to begin the next life cycle. John emphasized that he is interested in the complex life cycle of this slime mold and its interaction with the environment. His entire research career, from undergraduate and graduate students to becoming a teacher, has been devoted to the study of this organism and will continue because there are still many issues to be resolved. It is clear from his description that he is deeply obsessed with this work and this organism. This is undoubtedly a fascinating speech.
Then it’s my turn to show my lab research direction. I pointed out at the outset that when I was a high school student, I was fascinated by the virus: they are so simple. The virus I studied at Princeton has only six genes, but it has a program that can replicate itself in cells by borrowing some cellular functions. How do the genes of the virus and the cells themselves replicate themselves by taking over the cells? But more importantly, after injecting the virus into newborn hamsters for 6 to 9 months, it usually causes cancer. Each cancer cell has a copy of the viral DNA integrated into the chromosome of the cell, and the integrated viral DNA expresses a set of virally encoded proteins. I want to figure out which genes and their proteins replicate the virus, which genes and their proteins cause cancer, and how they cause tumor formation. As soon as I figure this out, I will turn to another organism and another research direction.
I think John and I are aware of the difference in our research philosophy. We are us, we cannot be anyone else, but it is good for students to be exposed to different levels of thought, method and analysis. Although the training I have received and received is at the molecular level, as an experimental scientist, exposure to organic biology, evolutionary biology and ecology is good for me. I am not sure, when I have the answer to the yearIt is still so easy to become a department head and a senior professor when a light person floods into Princeton. Quoting John in his book “Princeton’s biology (1947-2012) (this is a book on the history of biology) “Molecule A sentence in the chapter on war: The view of molecular biologists is that “all biology must now be classified into molecular biology, and all those engaged in other forms of biological research have found the wrong target – the tree of the target has It is a dead wood.” Of course, Princeton is not the only university that has experienced a paradigm revolution. Most schools, like Princeton, solve this problem by setting up two biology departments, one called “Ecology and Evolution” and the other called “Molecular Biology”. Today, both systems have contributed and flourished.
The irony is that this is not the end of the story. With the rapid development of the last three decades of the twentieth century, the development of new technologies has enabled people to detect thousands of genes in a group of cells, as well as all transcripts in a single cell, at the transcriptional level, while large-scale genome sequencing It reached its peak in the 2001 Human Genome Sequencing Program. Today, we study evolution by sequencing and studying thousands of genomes in different organisms; we track the relationships and evolution of genes in various organisms; we build new life-form tree diagrams (tree of life); we also observe the new evolutionary process. DNA contains a lot of information we need to know.
How does a genotype translate into a phenotype? A deeper explanation has already begun. How do genetic functions, biological organisms, and biological populations respond to the changing environment of more than a billion years? Research is ongoing. We explored the origins, migrations, and ethnicity of humanity in Africa for hundreds of thousands of years. We use a hundred years as a time scale to sequence infectious disease pathogens to study epidemics. We studied viruses that cause cancer in animals and found human oncogenes and tumor suppressor genes. Many researchers are no longer investigating the virus and instead focus on gene function and genetic mutations that cause cancer in humans. Cancer, like evolution, shows us how a combination of genes in a genome changes. We have collected a lot of information and now we need to extract meaningful parts from it. However, we now find that general molecular biologists do not have sufficient quantitative analysis capabilities to process these big data, extract information from it, and map this information to the behavior and morphology of the organism. Life science research is turning to the storage and organization of information, the reading of information, the stabilization and restoration of information, and the selective use of information to address the problems caused by farming, nutrient intake and environmental stress.
The current research paradigm shifts back to general biology or systems biology, bringing together people in the fields of physics, computer science, mathematics, and engineering—they learn biology and do experiments or clinical research. Biologists work together. This collaborative science, called “fusion (chemical or physical signals as a series of molecular events in the process of cell-to-cell transfer, such as cellular responses caused by protein phosphorylation) /span> to determine which genes in a cellular network contain the maximum entropy (a measure of information or association). Various neural networks have been designed to solve biological problems and to enable machine learning to explore associations and paradigms that have not been previously discovered. Machine learning is creating new technologies that will change the way we study biology. Some biology undergraduate and postgraduate programs require applicants’ quantitative analysis capabilities, although quantitative analysis currently does not have much application in molecular biology. Scientists who have been trained in physics or computers begin to do biology, learn the skills of biological research, and prepare for solving biological problems. Time will tell us what impact these disciplines will bring and where biology will go.
The twentieth century, physicists and mathematicians stepped into the field of biology, and some people had a considerable impact. In most cases, “fusion” can’t last long. But will this be different? Will “fusion biology” become a branch of biology? Does systematic biology replace molecular biology as the most common research method? The problems that need to be explored now are extraordinary, and the depth of information to explore these problems is unprecedented, so young scientists are interested in life sciences.The attraction is obvious. The tools invented by molecular biologists at the turn of the century led to a revolution in bioinformatics. What is needed now is to analyze and understand them, and this requires new skills. Biology tools will be integrated with computer science, physics and mathematics, and practitioners of biology will undergo another paradigm shift.
If it is difficult to experience a paradigm shift in biology, then two such changes prove the speed at which science is progressing and changing.
The author: Arnold Levine, who was appointed Emeritus Professor of the School of Natural Sciences in 2004, founded the Simmons System Biology Center at IAS, by theoretical physicists, cancer biologists, mathematicians, and computational biology. The family conducts research between the fields of molecular biology and physical science.
Levine was one of the first researchers to independently isolate the p53 protein in 1979. The discovery of p53 produced about 50,000 papers in the first 30 years. In a 1991 paper by Nature, Levine and his collaborators reported that p53 mutations are the most common single-gene genetic variation observed in human cancers, and researchers are already at 100% ovarian cancer. P53 mutations were found in 70% – 90% of lung and colon cancers and up to 33% of breast cancers.
In his career, Levine has worked in the biological sciences from virology and immunology to molecular biology and genetics, and has guided non-mathematicians.
This article is from the public number:Back to Park (ID: fanpu2019), Lecture: Arnold J. Levine