The Journey with Max Delbrück

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In 1937, a German physicist, Max Delbrück, made a short trip to the U.S. for discussing the burgeoning research in the genetic factors- the term “molecular biology” had not been invented yet at that time. He was born in an elite family in Germany. However, witnessing that the Nazis rose to power and took over his fatherland, he decided to stay in the U.S. so got hired by Vanderbilt University as a faculty. A few years later, his brother, sister and brother-in-law were executed for their failed plot to assassinate Hitler.

One year later, in 1938, an Italian physician, Salvador Luria, got funded from the U.S. to join Delbrück's research team in Tennessee. He was mentored by two Nobel Prize winners in medical school and then served as a military doctor after graduation. However, because Mussolini banned Jews from academic research, he had to flee to Paris and eventually came to the United States. 

In 1943, at the dark climax of fascism with no sight of light at the end of the tunnel, Delbrück and Luria were thinking about an important biological question in their cozy, quiet office in Tennessee.  Bacteria develop resistance to phages due to genetic mutations. Do such mutations preexist or occur spontaneously after their exposure to the bacteriophages? In other words, is the resistance caused by the Darwinian selection or Lamarckian adaptation? 

At that time, the structure of DNA had yet to be discovered, let alone the analysis methods such as PCR or gene sequencing that are so common today. Genes are just concepts and factors, invisible and intangible. In fact, Delbrück was actually the professor of physics at Vanderbilt University, and studying biology was just his hobby. The "invisible and intangible" factor was not a problem at all for him. Luria suggested that the inconsistency of the frequency of the resistance can be used to distinguish pre-existed or induced mutation. Based on Luria’s insight, Delbrück established a statistical model of mutation distribution models to predict the frequency of phage-resistant bacteria (see the attachment).

Luria was an excellent experimentalist. He designed experiments based on Delbrück's statistical model.  The results confirmed that gene mutations occurred spontaneously in bacteria before their exposure to phages. The duo wrote an elegant paper together, most of which was to explain the statistical model. The experimental data consisted of two tables and one figure, and it was published in the journal Genetics. The current Science Citation Index (SCI) of this journal is less than 6 (https://academic.oup.com/genetics/article/28/6/491/6033179). Delbrück would probably have problems getting tenured today. However, this is the first time in the history of biology that someone performed an experiment to prove Darwin's theory of evolution by natural selection. The two duo were awarded the Nobel Prize in 1969. Today this model is well known as the "Luria-Delbrück distribution".

Molecular biology had its root in physics. This was initiated by Schrödinger whose book "What Is Life?" influenced the whole generation of physicists like Delbrück. Before the term "molecular biology" was invented, most molecular biologists had good training in quantitative genetics. However, in 1953, a physicist and an ornithologist worked together to change this tradition. Since then, molecular biology has been separated from genetics, and training in mathematics became rare among molecular biologists.

The new duo were Francis Crick and James Watson, who discovered the double helix structure of DNA. They further derived the central dogma of molecular biology: DNA is transcribed to RNA and RNA is translated into protein. The development of genetic "scissors and glue" (restriction enzymes and ligase) in the coming decades would completely transform molecular biology into a crash course for genetic engineering. In the next 50 years, genetic manipulation and signal transduction prevailed in biological research, and the "Luria-Delbrück distribution" quietly lay in the corner of general biology textbooks. The usual practice in research is to focus on one gene and design experiments around it, so as to prove it is the most important factor in the system. In many researchers’ minds, biomedical research doesn’t have to see the forest for the tree.

In the 1960s, while Luria and Delbrück continued to study genetic factors in bacteria, a young Israeli, Isaiah J. Fidler, came to the United States to study in school of veterinary medicine and then received a Ph.D. Later he started his first independent research job at NCI-Frederick. There he identified a melanoma from an aged C57BL/6 mice, making it a cell line- this is none other than the famous B16 cell line. In 1983, he asked an old question in cancer research: is metastasis caused by the spreading-capable cells that pre-exist in the primary tumor, or is it caused by cells accidentally drifting to other organs and adapting to the local environment?

How similar this is to Delbrück's question of origin of bacterial resistance to phages! Fidler said that he immediately thought of “go Delbrück”. Following Luria and Delbrück’s approach, he used the technique of cell cloning to generate 10 single cell-derived sublines. They are the most famous mouse cancer cell line series: B16F0 to B16F10 (Dr. Fidler told me “The F stands for Fidler”). He then injected these cell lines, one by one, to the tail vein of the mice. Each one of them exhibited distinct metastatic potential in the mouse lungs, appearing to be Luria-Delbruck distribution. The results clearly show that cells with the ability to spread arise spontaneously before metastasis (https://www.science.org/doi/pdf/10.1126/science.887927). This resolves a century-old debate about tumor progression. Dr. Fiedler's approach was later applied by many researchers, resulting in many discoveries such as  "metastasis gene" (e.g. https://www.nature.com/articles/nature03799, https://www.sciencedirect.com/science/article/pii/S1535610803001326). 

After I received my Ph.D., I went to work for Glenn. The first project he gave to me was to build a mouse model of metastatic melanoma. Most of the experiments have to be performed at the Frederick Campus. At that time, I didn’t understand that I was also replicating Dr. Fidler's approach at the same place where he designed it. Since then I kept applying the same strategy in studying the effect of tumor heterogeneity on drug resistance and building multiple organ-specific metastasis models. I have been observing the tumor heterogeneity in the manner of Luria-Delbrück distribution again and again.

In the recent two decades, advances in genomic and epigenetic analyses have made it possible to study cancer in a theoretical work frame of evolutionary biology. For example, the selection of a mutated gene can be evaluated by dN/dS method, the subclonal evolution can be traced by single cell sequencing. When I looked for papers in this field, they were full of Luria-Delbrück distribution (e.g. https://www.nature.com/articles/nature22794), along with many new methods to test all the old ideas in evolutionary biology. As my own research is turning to the new page, I am so happy that we are returning to the old tradition of genetics.

Attachment:


m: mutation rate

T: time

𝜇: mutation rate per cell per unit time

𝛽1: cell growth rate

If a mutation occurs randomly (Darwinian) rather than induced by the environment (Lamarckian), its proportion in the cell population will follow this formula. 

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