I recently attended a reunion of the lab in which I did my postgraduate work. It’s provoked a bunch of thoughts—about scientific progress, about the paths people take through life, about mentorship, and about myself.
Of these, it’s far and away the easiest to talk about science. This fact was borne out again and again over the two days of short presentations by thirty years’ worth of grad students, technicians, post docs, and principals. We all wanted to acknowledge our debts to each other and how important our advisors and peers were in our lives, and we all, every one, got choked up doing so. Several people hastily moved to data slides after dissolving into tears on acknowledgements and were only able to compose themselves in company of dry facts. Since one of the things I learned in grad school is to attack the easiest parts of a problem first—and they will be hard enough!—I will begin with science. I swear I’ll do my best to make it more about humanism and less about jargon.
My thesis advisor’s field of study is roughly three-quarters of a century old, depending upon exactly which set of experiments you chose as its initiation. This field—I’ll call it “molecular genetics”—analyses a whole cell on a molecular level. It seeks to understand the interactions of thousands of genes and proteins and other molecules as the cell grows, or as it responds to its environment by modifying itself. The preeminent model organism in this field, from the very beginning, has been the bacterium E. coli; this bacterium is afflicted by a virus, known as lambda, and sometimes it carries a spare bit of parasitic DNA that spreads itself from cell to cell, called “F factor.” To say that these three have been intensely studied is an understatement; since the the first work on them in the late 1940’s, they have been the subject of sustained intensive thought and experiment by thousands of the smartest people in the world, and me. One would think that a 10 micron cell and its two parasites, with some 3,500 genes, would have no secrets left after such attention. One would be wrong.
Some of the genes and proteins in the E. coli cell are less important than others, and perform one small task which makes the cell a small amount more healthy under a limited set of circumstances. Others are quite the opposite—they affect literally every single part of the cell, all the time, being responsible for the creation of every single component of the cell. The activity of these central genes is understandably important to the cell, and over 35 years ago, my thesis advisor set out to study the control of their expression. It was known that there was a molecule in the cell, given the jokey name “magic spot,” that affected their regulation under stress, but the details were murky; when I joined the lab 30 years ago, it was already an old problem, but seemed soluble.
During the eight years I was in the lab, it became clear that magic spot was not absolutely essential for the regulation of these central genes. In fact, my thesis is titled “Redundant Regulatory Regimes Render […] Regulation Remarkably Robust,” as I studied one of the alternative regulators of these central genes. But magic spot was still there, and others in my cohort made progress in describing how it did its job; while magic spot may not have been necessary for regulation, they showed that it was capable of the task.
Historians study the dead, and their continued efforts can paint ever-fuller pictures of their subjects in spite of the stillness of their tongues; the more time historians have had to dig into a dead person’s life, the longer the biography. So it was with my fellow students and researchers in my advisor’s lab, studying the silent E. coli over decades. They found details about the molecular interaction between magic spot and the protein at the center of the problem. Then they found another factor, called “DksA”, that seemed to have a greater effect on that same protein than magic spot, and once again it seemed that magic spot was less relevant. Then they found that DksA actually interacted with magic spot to have an even more dramatic regulatory effect. The molecular interaction behind this regulation was completely different from the molecular interaction with magic spot by itself—yet the effect was qualitatively similar. And so, while E. coli could no more speak about the details of its own history than a dead president, its biography grew ever thicker, and our understanding of the web of relationships between proteins and genes in the cell grew more detailed.
Very recently, the people in my advisor’s lab made an even more interesting discovery. We now know the complete DNA sequences of thousands of organisms. Even better, if we know one gene from our super-detailed study of E. coli, we can look at these thousands of organisms and find similar genes, and test to see if they make similar proteins that do similar things. So, people in my advisor’s lab looked for things similar to DksA—and found them. In F factor. And Lambda. Where they had been for the whole history of molecular genetics, known and yet unknown: we were aware of their presence, but unaware of their role. Like “Terra Incognita” in the maps of early explorers, these genes were labeled “unknown function” in the atlases of F factor and Lambda.
While DksA is a regulator of a centrally important process for the health of the cell, these similar proteins from F factor and lambda are detrimental to the cell. Both F factor and lambda are parasites. F factor utilizes cellular resources to spread itself from cell to cell, and lambda is a virus that can completely monopolize the machinery of the cell to make dozens of copies of itself and then explode the cell. In a healthy bacterial cell, DksA interacts with magic spot to reduce expression of other genes to conserve energy during lean times. The DksA relatives from F factor and Lambda look like DksA with magic spot already attached to it—and they reduce expression of other genes, not to save energy, but so that more energy can be spent on making more F factor or lambda viruses.
So it is that the in the map of these long-studied organisms, another piece of “Terra Incognita” gets properly colored in; genes, known for decades but always described as “of unknown function” can finally be understood, because of decades of work on a tangentially related problem.
This finding gives me a very warm feeling about the practice of science, even though I am no longer in this field at all (as a goat farmer I am in a very different and much more literal field). I feel a connection, no matter how slight, to a dedicated quest for knowledge that has been ongoing since my dad was in high school. I also feel some small pride in having had even a microscopic role in that effort.
More strongly, I feel a reverential awe for the subject, an insignificant bacterium and its two parasites. They seem so simple, the bread-and-butter of basic biology classes, and after 75 years of work they should be passé—yet, as Prokofiev noted, “there are still so many beautiful things to say in C major.” Indeed, the symposium’s closing remarks were equally about what had been found and what remains mysterious. The study of these simple cells, like an inexhaustible mine, continues to reward hard work with philosophical treasure.
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(I have omitted names, in an effort to center the process, rather than the persons; but in truth, the people are the creators of this story, and it is their intelligence, perceptiveness, and perseverance that have made this little portion of the map of life better known. My advisor is Richard Gourse; he and his advisor, Masayasu Nomura, charted out the initial forays into this territory. Wilma Ross has overseen much of the navigation through over 30 years of exploration, translating Rick’s directions to concrete action as well as plotting courses of her own; and of course, many students and post docs performed the hard labor of exploration, most notably Tamás Gaál, Kathy Josaitis, Melanie (Barker) Berkmen, Saumya Gopalkrishnan, Jonathan Jagodnik, and Rachel Salemi. I have a strong and enduring affection for the field, obviously, but such gifts as I have are not in laboratory research, and it’s for the best that I labor elsewhere.)
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