Sunday, August 21, 2022

Notes on the Gourse Lab reunion, August 2022–Part I

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.  


—————


(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.)  







Thursday, May 12, 2022

Wednesday wordage (slightly late) another neologism edition

 Shartcut:  a particularly awful, shoddy, egregious bit of avoiding doing the job right.  

Wednesday, April 20, 2022

Wednesday Wordage Neologism edition

 Fruckus: a noisy but meaningless skirmish or fight.  A portmanteau of fracas and ruckus.  Spontaneously uttered when asking your livestock guardian dogs what the heck they are doing wrassling with each other when they should be out watching over your goats.  

Wednesday, May 15, 2019

Wednesday Wordage, text edition

A neologism: Inthummunicado—being unable to send or receive text.

Wednesday, February 20, 2019

Wednesday wordage, Yiddish Edition

The classic, classic definition of the Yiddish word “chutzpah” is murdering your parents and then pleading for leniency before the court because you’re an orphan.  This has been superseded by a new definition provided by Matt Schlapp, chairman of the American Conservative Union and a “loyal supporter of Donald Trump,” in an interview with NPR’s Mary Louise Kelly:

KELLY: You're saying you agree that the situation at the border is a national emergency.
SCHLAPP: I agree that the situation at the border is an emergency. It's a humanitarian crisis, and America needs to solve the problem.
KELLY: And I - and I'm just trying to square that because when we interview members of Congress - Republicans and Democrats who represent the border - they say it's not an emergency.
SCHLAPP: Well, then why did two kids die?

Yup, there you have it.  We killed a couple of kids, and therefore we need to have a national emergency to build the f***ing wall so we stop killing kids.  
AAAAAAAAAAAAAAAAAAAAARRRRRRRRRRGGHHHHHHHHHHHH!!!!!!!

Monday, December 17, 2018

Monday Musical Offering Bah! Humbug! Edition

So it’s mid-December, Hanukkah has been and gone, and the radio is playing a lot of Christmas music.  It gets tiresome.  To explain why, let me try an analogy, which is not meant to be offensive to anyone of any Christian confession, but to illustrate how someone who is decidedly not Christian can feel at this time of year.

Christmas music is a deep catalog of advertising jingles for hair spray.

Music has been associated with religion, pretty much all religion, since the get-go, and for good reason.  If nothing else, it helps you remember words; if well done, music makes the words more appealing; better, words and music can act synergetically to poke at the parts of your brain that generate strong emotional responses.  There’s large chunks of the Jewish liturgy that I remember only with music, and that the music and words together can make me feel the presence of the ineffable.  Music sells religion like nothing else.

If you want to sell anything, whether Jesus or Jeeps, you’re going to want to hire the best tunesmiths, and you are going to want to really make a strong association between your product and the jingle.  And really, in the case of religion, that’s been done.  I can’t think of the words of the Kyrie without thinking of Bach, the Dies Irae without Verdi, and so on.  Similarly, I can’t think of the music of Mozart’s Requiem without thinking of the words, and then thinking, at least on some level, of confutatis maledictis and other bits of Catholic dogma.  Mostly, though, the music is good enough that I can tune out the dogma and focus on the music—it’s good enough to cast shade on the dogma.

Christmas music, though, is more like pop—catchy, sometimes very good, but by no means great or profound.  Which means that it’s harder to ignore the words, and thus harder to ignore the message.  Go ahead, try to think about “I’d like to teach the world to sing...” without having Coke come fizzing up in your head.  I’m not a big fan of Coke, but it’s not irrelevant to me.  I drink it, rarely, and in small amounts, and actually derive some pleasure from it.  And that jingle is a perfect catchy pop song.

What drives me batty about Christmas music is that there are scores and scores of nearly perfect pop song-jingles; they have been played more relentlessly than any advertising jingle ever; and, they are all selling a product that is irrelevant to me and that I kind of don’t even like and think may be doing some harm in how it is used—let’s say, hairspray.

Both for philosophical and historical reasons, I have problems with Christianity (and I really don’t care for the artifice of beehive hairdos, and how historically half of humanity has been taught that it needs to value itself for its appearance).  I find the concept of the Trinity kind of absurd (not to mention the idea of hair glued into weird shapes).  True, it may work and provide meaning for some people (and the right hairdo may be instrumental in finding Mr. Right), not me.  I can’t damn all of Christianity, but in the present the rise of fundamentalism is doing serious social and environmental harm (And aerosols contributed to the hole in the ozone layer, not to mention how spray cans contribute to pollution).

So this is why I am frustrated by the flood of Christmas carols.  By living in this society, these incredibly catchy songs are burned into my brain.  I don’t like their message, but I can’t help but have it playing in my head when I hear them.  They are perfect jingles.  I would really be OK never hearing them ever again.

Friday, November 16, 2018

Friday flora frosty edition

Snapdragon, Spiders, Silk, Frost.