75 Years of Molecular Biology

In the November 1943 issue of the journal *Genetics*, Salvador Luria and Max Delbrück settled a long-running but arcane debate among bacteriologists. The original paper is freely downloadable, and is an amazing document to read today.

There’s a delightful innocence in the simplicity of the experimental design, the lengthy explication of the theory behind the work, and the humbleness of the authors’ conclusions. There is no hint that the paper is describing the dawn of molecular biology, a field that would revolutionize humanity’s relationship with nature in ways that are still unfolding 75 years later.

Luria and Delbrück didn’t set out with such grand ambitions. The question they wanted to address was simply how bacteria became resistant to infection with bacterial viruses, or phages. There were two competing theories at the time, based on previous experiments.

One school of thought was that a culture of bacteria grown in the absence of phages would acquire random mutations over time, some of which would by chance confer immunity to a phage. Once that particular phage was introduced, only bacteria with pre-existing resistance to it would survive. That aligned nicely with traditional evolutionary processes observed in “higher” (more complex) organisms.

The other theory was that bacteria could acquire resistance as a result of a phage infection. In this view, a more deterministic mechanism was at play, in which the selective pressure itself (phage) actually caused the adaptive mutation. If this model was correct, it would mean bacteria followed a fundamentally different evolutionary playbook from more complex organisms. That may sound like a weird idea today, but because of the way previous experiments had been designed, a lot of the early data actually seemed to favor it. Luria, in fact, was an enthusiastic supporter of this theory.

To test these two hypotheses, the researchers devised a brilliantly simple experiment. They grew separate cultures of bacteria, each originating from a single cell, then exposed these distinct populations to bacteriophage T1.

If the resistance was due to random mutations arising beforehand, one would expect tremendous variation between cultures, with some having a lot of survivors and some being wiped out completely. Essentially, the bacteria would be playing slot machines. There would be a lot of losers but occasionally some really, really big winners.

If the bacteria exhibited acquired immunity as in the second model, however, one would expect a consistent proportion of the population from each independent culture to survive the phage infection. Here, the bacteria would be investing in the bond market. The outcomes would be distributed in a boring, highly consistent pattern.

The results were absolutely clear. There was immense variance between cultures, proving that resistance was arising randomly before the bacteria encountered the phage. Bacteria, in other words, underwent the same natural selection and evolution process as more complex organisms.

That conclusion settled the eggheaded debate the authors had started with, but its echoes reached a lot farther. Luria and Delbrück’s result implied that all life, from bacteria to humans, operated on the same fundamental principles. We could study the chemistry of biology in easily cultured bacteria and extend those conclusions to everything else. Furthermore, we could quantify things like evolution, using organisms that could be grown to immense populations – millions or billions – in small containers over a period of hours. We could use statistics to analyze those results, and draw robust conclusions from them. These microscopic life forms would let us put life under a microscope.

A year later, Avery, McCarty, and McCleod, using another bacterial species, demonstrated that DNA was the genetic material. Researchers could then purify and study the molecule of inheritance, the blueprint on which natural selection and evolution acted.

After the close of World War II, other researchers in the burgeoning field of molecular biology quickly standardized their work, agreeing to focus on a few easily-grown laboratory strains of bacteria and their associated phages. Following Delbrück’s lead, they also adopted rigorous quantitative techniques and set standards for analyzing their results. What had begun with a curious question about how bacteria evolve, turned into a fundamentally new approach to life science.

The impact of Luria and Delbrück’s work continues to ripple through society. We’re sequencing our genomes, modifying our crops, identifying perpetrators, creating new drugs, and may soon take the first steps toward directing our own evolution, all because these pioneers showed us how. There’s no telling where biology will go in the next 75 years, but one thing seems clear: the discoveries driving it will come from asking eggheaded questions.