Biology is often seen by many as the least B impressive of the STEM subjects and hopefully this review shall show that genetics in particular has had its fair share of intrepid genius explorers that put their careers on the line in pursuit of answers to crazy questions. This article shall explore three of the greatest questions in biology and review a revolutionary approach devised in the 1980s to tackle them.
Our story starts at Columbia university in 1908 with a 42 year old scientist called Thomas Hunt Morgan. Those of you familiar with genetics will know why Thomas Morgan is an important geneticist. He was the first person to start working with the fruit fly or Drosophila Melanogaster in a meaningful way. He started a lab that would eventually come to be known as Morgan’s Fly lab and could be seen by some as the place where modern classical genetics was born. Thomas Morgan used his fruit flies to study heredity and did a large number of genetic crosses, eventually linking chromosomes to inheritance. He also tried inducing mutations using radium and X-rays but his method to identify mutants was not sensitive enough to pick all of them up. Eventually, T.H Morgan would go on to win the Nobel Prize in Physiology or Medicine in 1933 precisely for establishing this link and discovering how chromosomes convey hereditary information.
One of the most important breakthroughs that T.H Morgan came up with was the idea of crossing over. He came up with this idea to explain a curious phenomenon that we would now define as gene linkage. This is the concept that some genes seem to always be inherited together and others less so. If genetic material could be exchanged from one chromosome to another during a process such as crossing over, then genes that are close together are less likely to separate compared to genes that are closer together.
The above breakthrough led a 19 year-old undergraduate student in Morgan’s lab, Alfred Sturtevant, to suggest that a mathematical formula could be determined to predict the distance between two genes. Moreover, if the distance between several genes was determined, you could create a kind of genetic map to visualise where genes are found relative to one another. The unit of distance in these genetic maps is the ‘Morgan’ and is equal to the crossover or recombination frequency, expressed as a percentage.
Thomas Morgan and Alfred Sturtevant ushered in a golden age for genetics and would make it possible for a new generation of scientists to tackle a wide range of new problems. The next important player to enter onto the stage were the phage biologists and they would later become known as the Phage group. These include Salvador Luria, Max Delbruck, James Watson and Seymour Benzer, the latter of which will become of vital importance later in the story. These scientists would start the field of molecular biology. However, these fascinating scientists seem to have become all but forgotten.
The phage group was started in the 1940s by the German, Max Delbruck. He initially trained as a physicist but he was inspired to study biology by Niels Bohn and Wolfgang Pauli. Max Delbruck started his work in biology by looking at how mutations work and he wanted to find a simple biological system to do this. Bacteriophages, which are viruses that infect bacteria, seemed like the perfect system to study. Soon after, Delbruck met Salvador Luria, a fellow physicist turned biologist in 1940 and they both started working on the phages.
Delbruck and Luria studied several aspects of phage biology, from their replication patterns to their effects on cells. In particular, these two scientists studied these processes in a quantitative way, thus making their science far more precise. This allowed for the scientists working in phage biology to start thinking mechanistically and this would pave the way for what would soon be a golden age in molecular biology. Some of the basic phage biology they discovered some of you will have heard of, including how the lytic and lysogenic phases of bacterial replication work, how to identify mutations and they described the viral life cycle.
The above work made both Delbruck and Luria legends in the genetics world and inspired other scientists to enter the field. One of the first to join was Alfred Hershey, a chemist who studied antigens. The three men informally collaborated a great deal and they had as their base the biology lab at Cold Spring Harbour in Long Island, New York. Prior to this landmark experiment, Hershey discovered that phages have several different genes and that phages can undergo genetic recombination. In 1952, Alfred Hershey and Martha Chase discovered that only nucleic acids were transmitted from viruses to bacteria and were the genetic material of bacteria, ending the idea that genes are made of proteins.
Moreover, in 1945, Erwin Schrodinger published his massively influential book, ‘What is Life?’ which described how biology might need a new kind of physics to be explained. Schrodinger argued that several biological phenomena seemed to go against the most fundamental laws of physics, in particular the second law of thermodynamics which states that the universe tends towards a greater level of disorder (entropy). This book would attract a multitude of physicists into biology, including names such as Seymour Benzer, Francis Crick and Maurice Wilkins. In many ways, this one book opened up the path for the discovery of the structure of DNA.
We can now turn to the scientist who in many ways is the protagonist of our story. A man who hated standing still and who felt the need to go from one obscure field to another and shed a beam of insight onto it, opening the door to follow in his footsteps. His name is Seymour Benzer. In 1947, two years after ‘What is life?’ was published, Benzer was finishing his PhD in physics from Purdue University where he was working on solid-state physics. In fact, his research would contribute to the development of the transistor, a central electronics component that would open the way for the creation of computers.
Benzer met Max Delbruck at Caltech and even did a 2 year postdoc working under him. This completely converted Benzer to the world of the phage. He then went to the Laboratory of Molecular Biology (LMB) at Cambridge where he met Francis Crick and worked with him for a bit. It was at around this time that Benzer made his first major contribution to biology. He made a genetic map of the rII phage’s genome and discovered that genes were composed of different bases and were not indivisible units themselves. As some of you might have guessed, the method Benzer used to do this was Alfred Sturtevant’s technique of gene mapping.
However, around this time, many scientists had caught on to the formidable potential of molecular biology, which led Seymour Benzer to leave the field. He then decided to tackle an even more formidable question: how genes influence behaviour. Benzer’s approach to this question would be completely revolutionary. He wanted to find a model organism with which it would be possible to identify the relationship between single genes and the changes in behaviour that these genes might cause, which was a massively risky approach because scientists were not convinced that single genes could lead to behavioural changes. The risk therefore was ending up with fly mutants that actually had mutations in a large number of different genes and that would yield very little insight as to the exact proteins and cellular mechanisms controlling behaviour.
The scientist that would end up helping Benzer in this quest was Roger Sperry. It was thanks to Sperry that Benzer got to work with a large number of model organisms and in the end, he settled with using Drosophila. This was hardly a surprising choice considering that Drosophila had already made significant contributions to genetics in the past, in particular through the work of T.H Morgan. It was therefore at Caltech, with Seymour Benzer, with immense skepticism from Benzer’s colleagues, that the field of behavioural genetics or neurogenetics was born. This field, as the name suggests, is interested in uncovering the genetic basis of behaviour.
One of the first behaviours that Benzer chose to study was that of how fly phototaxis, or how flies move with regards to light. The ‘normal’ response flies have to light is to move towards it. However, Benzer’s idea was that certain mutant flies might exhibit a different response. To test this hypothesis, he developed an apparatus which he called a countercurrent machine (see figure 1). Once Benzer was satisfied with his apparatus, he then used EMS (Ethane methyl sulfonate) to induce mutations in the flies. This method is called a mutagenesis screen and is still used in molecular biology and genetics labs today. This method allowed Benzer to identify a large number of light avoiding fly mutants such as photophobe.
Figure 1 A sketch Benzer’s countercurrent apparatus to study phototaxis in Drosophila (taken from Benzer, 1967).
The power of Benzer’s method started attracting other scientists to his lab, notably Ronald Konopka. Konopka was particularly interested in understanding how organisms can have a sense of time, and had worked with an expert in the field of chronobiology, the study of how organisms develop a sense of Time. This meant that Konopka knew exactly the direction he wanted to take when he came to work with Seymour Benzer. Amazingly, flies have a sense of time since they only emerge from their eggs at dawn. This meant that by isolating flies that did not follow this pattern, it might be possible to isolate the gene responsible for this phenomenon.
Konopka managed to isolate several of these mutants which then became known as clock mutants. What Konopka discovered was that several of those had a mutation in a single gene that Konopka appropriately named the period gene. This had a very profound implication in that it suggested that circadian rhythms are controlled by a very small number of proteins. This discovery was published in a landmark paper in 1971 that is now seen as one of the most important papers in the field of chronobiology (the study of cyclical physiological patterns biology). It would take another 15 years before the period gene was fully cloned.
As shown above, Benzer’s method did not provide direct mechanisms to explain why the mutants had the change in behaviour observed, but it did provide a starting point for other scientists. Behavioural genetics allowed scientists to answer questions that had never really been reachable before. For instance, scientists studying Drosophila could not help but be amazed by their intricate courtship rituals. In the 1960s, certain mutant Drosophila individuals were observed behaving in a strange way: they would court with both males and females but would not copulate, resulting in the mutant being named fruitless.
A scientist who became fascinated by this fruitless mutant was Jeffrey Hall, an eccentric American who was known as a keen scholar of the American Civil War. Jeff Hall worked with several researchers who had been Alfred Sturtevant’s students. Hall initially was very interested in the period gene and he collaborated extensively with Michael Young’s lab and both Hall and Young managed to isolate the gene. Hall then collaborated with Michael Rosbash to understand how the period gene works. Hall, Young and Rosbash all would go on to win the Nobel Prize in medicine in 2017 for their work on circadian rhythms.
Another observation that Seymour Benzer had made in the 1960s was that Drosophila has a rudimentary ability to learn and remember. Benzer devised a screen to detect mutants that differed in their ability.
This takes us to the end of our exploration of behavioural genetics. It is clear that this field has made accessible a wide range of research topics and its potential has certainly not been fully fulfilled yet. From understanding how organisms sense time, to how they fall in love to how they learn, all of what makes life so beautiful can be explored just by the power of genetics. We are still the most complex system that we know of and I hope that I have revealed the magic lying in the biological sciences.
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