Archive for the ‘Science’ Category

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The mentor gratitude project

August 28, 2019

In a recent post, I expressed regret at having failed to directly and fully thank my primary Ph.D. adviser while he was alive.

This regret has been useful in motivating me to identify and (when possible) thank others who have been unusually helpful and influential in my professional development. I’ve previously discussed a couple of them on this blog: George Kosaly (a former research collaborator) and John Peterson (a high school social studies teacher). Here’s the rest of my (imperfect, incomplete) list:

  • Pete Farwell. My college running coach, who was great running-wise but also encouraged my creative endeavors (poems and songs) for team gatherings.
  • Dan Lynch. My undergraduate research mentor, who demystified the enterprise of laboratory research for me.
  • Mary Lidstrom and Wes Van Voorhis. My postdoctoral research supervisors. Very different styles, but both excellent scientists who also found ways to support my interest in teaching.
  • Doug Meyer. My junior high school vocal music teacher, who gave me an excellent grounding in ear training and music theory.
  • Do Peterson. A friend who, in addition to introducing me to my now-wife, has been a musical mentor to me ever since we recorded Take Me to the Liver in 1996.
  • My parents. My dad especially for informing my development as a writer, and my mom especially for being my first teacher role model.
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…And my other Ph.D. adviser, Martin J. Kushmerick

July 14, 2019

MJKPhoto

image taken from http://depts.washington.edu/tcmi/

In my haste to note the passing of Kevin Conley, my primary graduate school adviser, I failed to mention a sad coincidence, which is that my OTHER graduate school adviser had just died eight days earlier.

Marty Kushmerick was, in a word, brilliant.  He knew a lot about a lot of things; breadth and depth coexisted happily in his brain.  Though his field was muscle biology, he taught himself way more thermodynamics, mathematical modeling, and nuclear physics than the average muscle biologist (e.g., me) could ever dream of. This allowed him to ask all sorts of scientific questions and collaborate with all sorts of people, who found his brilliance both charming and useful.

Kevin was one such person.

Two of Kevin’s greatest studies (Conley et al. 1997 and 1998) dismantled the prevailing model of the control of glycolysis in skeletal muscle. These studies were based on the fact that glycolysis produces lactic acid, which lowers the pH, which can be measured with 31P NMR spectroscopy, our lab’s primary technique at the time. However, it’s awfully hard to calculate precise RATES of glycolysis, as Kevin needed to do. I don’t think Kevin could have navigated the arcane details of proton stoichiometry on his own; fortunately, he had Marty to do the math (Kushmerick 1997) and thus provide the foundation for his own work.

While Kevin and Marty had distinct strengths and personalities, they shared a sincere and profound enthusiasm for the day-to-day work of scientific research. This was obvious to all who knew them.  They were visibly excited when they found an insightful paper in the literature or thought of a new experiment to try. It was fun to be in their lab in the late ’90s and early ’00s in part because THEY were having fun.

Fifteen-plus years later, it’s hard for me to conjure up that atmosphere, to remember what it felt like. This song helps, though. (Marty makes a cameo at 2:33.)

 

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My Ph.D. adviser, Kevin E. Conley

July 1, 2019

Last night I received the news that my Ph.D. adviser had just died of cancer.

For me, this was one of those moments of asking myself, “Did I ever thank this person adequately for what they did for me?”

Kevin and I had a complicated relationship. As a scientist and as a mentor, he had his share of blind spots, and as a graduate student, I had numerous deficiencies of my own.  What is indisputable is that he took his advising role very seriously, and gave it his full attention, and did everything he could to help me along my path, which he accepted as different from his own.  He treated me, above all else, with kindness and generosity.

Technically, I had two graduate advisers: Kevin and Marty Kushmerick. Kevin did almost all of the actual advising, but he knew that it was useful for me to be associated with Marty, a more senior and more famous scientist. Thus, at conferences and such, I would always say, “I work with Kevin and Marty.” Kevin never objected to this, though he surely deserved more credit than that.

In the winter and spring of 2000, my work was not going well, and Kevin and I were finding it hard to have productive discussions. I suggested that I spend the summer at a high-altitude training study that had accepted me as a research subject. A greedier adviser would have stopped me from going — shouldn’t I be in the lab, generating more data for him? But Kevin, to his great credit, let me go.  I had an experience that was useful scientifically (I got to see first-hand how complex human studies are conducted), and that also helped reset our relationship. When I returned, we were able to communicate with less frustration.

A final act of selflessness on Kevin’s part came when I was wrapping up my dissertation. There was one chapter that he found unconvincing (for reasons that I never really understood). He was not willing to have the paper published with his name on it; however, he did let me publish it. If this seems like a no-brainer, it wasn’t; research leaders are often VERY conservative and controlling about the papers that come out of their labs.

The above examples stick out in my mind, yet they fail to capture what might have been most important of all, which was simply that Kevin allowed me to barge into his office and ask for help whenever I wanted. This wasn’t necessarily an efficient arrangement for getting work done or helping me become more resourceful and independent, but it certainly indicated the extent of Kevin’s commitment to me.

Years after I left the lab, I wrote an odd little parody of the classic Bob Dylan song Knockin’ On Heaven’s Door.  The lyrics were, most directly, about the frustrations of doing research. But the subtext of “Knockin’ On Kevin’s Door” was that, as an often-rudderless graduate student, I was very fortunate to have an adviser who was always, always, always willing to make time for me.

I should have told him this more directly, with more explicit gratitude.

I hope he got the message anyway.

Kevin_Conley_1

[image from UW Dept. of Radiology website]

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When is it fun to be married to a biostatistician?

April 27, 2019

Always, if that biostatistician is Leila. But especially during scenes like the following….

It’s dinner time for 7-month-old Ben, and two types of orange mush are on the menu: sweet potatoes and peaches.

Ben likes the peaches much better because they are sweeter, but Leila is trying to get him to eat both.

With a twinkle in her eye, she says, “This calls for … randomization!” And proceeds accordingly.

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Previewing my first lab at my new job: an internal monologue

January 5, 2018

OK, in this part the students will add a drop of sheep blood to different solutions to see whether/how those solutions affect the shape of the red blood cells.

…SO HOW COME I CAN’T SEE ANY RED BLOOD CELLS?  WHERE ARE THE CELLS?

Is this microscope bad?

No, I can’t see any cells under this other microscope, either.

Has my microscope technique deteriorated so badly that I can no longer find blood cells in blood?

Let’s try a pre-prepared slide.

OK, I can see THESE cells just fine.  So what the hell is the problem with my newly made slides?  Is the saline diluting the cells too much, or something?  Let me try a drop of pure blood.

Good grief. I CANNOT FIND ANY FRIGGIN’ BLOOD CELLS IN A DROP OF PURE BLOOD.  I’m sorry, Everett — your new physiology instructor cannot, at a microscopic level, tell the difference between blood and water. That’s just too much to ask, apparently.

Nothing else to do but put the blood back in the fridge and ask for help on Monday….

Wait a minute. Here’s another bottle of sheep blood.  Why does it look so different from the one I was using — so much brighter?  And it hasn’t been opened yet….

Maybe I should try this bottle.

Hey, THIS blood has actual cells in it!  Lots of them!

And they shrink when put in hypertonic saline!

Maybe I am sort of qualified to teach this lab after all.

And now, for my next act, I will weigh this dialysis sac all by myself.

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Special announcement: an online conference devoted entirely to educational songs!

May 1, 2017

Here is something I’ve been working on behind the scenes for a while:

VOICES: Virtual Ongoing Interdisciplinary Conferences on Educating with Song

I’ve made a few quick comments about this at my other (equally neglected) blog … but I mostly want you to go to the VOICES website and explore that. And ask me questions, if you have them!

2017_03_07_main_logo_piece

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Marshall & Warren: cinematic science

January 13, 2017

Portrayals of science and scientists on television and in movies are often hilariously fanciful. In the generally wonderful BBC/PBS series “Sherlock,” for example, the title character sees the chemical structures of individual molecules through an ordinary light microscope. I guess peering into a ‘scope makes for more compelling and succinct visuals than, say, running samples through an HPLC and laboriously comparing them to standards. (“It’s UNCANNY, Watson! The retention time in THIS solvent is 9.72 minutes — HIGHLY suggestive of a halogen-substituted phenol!”)

Every so often, though, you come across a real-life science story that has an undeniably cinematic arc. Such is the tale of Australian physicians Barry J. Marshall and J. Robin Warren, who won the 2005 Nobel Prize in Medicine or Physiology for discovering the bacterium Helicobacter pylori and showing that it causes most cases of gastritis and peptic ulcers.

As recounted by Marshall (2001), his work with Warren drew upon four previously disparate strands of biomedical ideas and evidence. These strands, as of the late 1970s, were as follows. (1) Spiral-shaped bacteria had occasionally been found in the stomachs of various mammals, including humans. But these bacteria were not widely suspected of causing any particular disease. (2) Gastritis –- inflammation of the stomach -– was a well-known problem generally attributed to stress, which supposedly induced secretion of excessive acid into the stomach. But some patients developed gastritis despite an impaired ability to secrete acid. (3) An enzyme called urease, which breaks urea into carbon dioxide and ammonia, had been found in the stomach; some evidence suggested that it had been produced by bacteria. But urease’s importance, if any, was unclear. (4) Formulations containing bismuth, a heavy metal, had been used to successfully treat nonspecific gastrointestinal problems. But the mechanism of action and the importance of the bismuth itself were not clear either.

In pivotal studies conducted mostly in the early 1980s, Marshall and Warren synthesized these four strands into a coherent theory, as follows. Gastritis was not caused by acid secretion problems per se but by the spiral bacterium, H. pylori, which burrows into the mucus lining the stomach and causes inflammation. While most bacteria cannot survive the low pH of the stomach, H. pylori produces and secretes urease, which helps it weather the acidic environment by producing ammonia, which serves as a buffer. Finally, bismuth can cure gastric problems by serving as an antibiotic, killing H. pylori and ending the corresponding inflammation.

This was an exciting story in and of itself, but there was more. Not only does H. pylori cause the acute condition of gastritis, it turns out to be the main culprit in the chronic conditions of stomach ulcers and stomach cancer. Antibiotics were found to cure ulcers as well as gastritis (Marshall et al., 1988), and to drastically reduce the incidence of stomach cancer.

Marshall and Warren were initially ridiculed and dismissed. One can debate the extent to which this skepticism on the part of the scientific community was appropriate, because the preliminary evidence produced by Marshall and Warren was clear, but not overwhelming. A perfect example of this is the study in which Marshall et al. (1985) fulfilled Koch’s four postulates for identifying the causative agent of an infectious disease. Meeting the postulates is strong evidence that a disease’s cause has been found (Evans, 1976), so Marshall et al.’s (1985) study could be considered strong, yet — spoiler alert! — it was conducted on only one subject, Marshall himself, who gave himself gastritis by drinking a broth of H. pylori taken from another patient. Marshall believed this necessary because he had not been able to get H. pylori to cause disease in a healthy animal (Marshall & Adams, 2008), the usual way of fulfilling Koch’s third postulate. The study was not published in an elite journal but rather The Medical Journal of Australia, whose middling reputation may have also limited awareness and acceptance of the conclusions. Moreover, the idea that bacteria could cause disease in the stomach was considered implausible by many physicians, who assumed that the stomach’s high acidity kills essentially all microbes (Weintraub, 2010).

Another major, slightly comical step forward came during Marshall and Warren’s first big clinical study, in which they checked 100 gastritis patients for the possible presence of H. pylori in their stomachs (Marshall & Warren, 1984). They had no luck with the first 34 patients, but — spoiler alert! — sample #35 came back positive after incubating over a long holiday weekend, which gave the slow-growing H. pylori extra time to reveal itself. (It was actually during Easter. How perfect is that? On the third day, the bacteria appeared again. They were alive after all! Alive, I say!) After this, all samples were incubated for four days rather than two, and most were found to contain H. pylori.

It really is a great story. Why hasn’t it been turned into a movie?

REFERENCES

Evans, A. S. (1976). Causation and disease: the Henle-Koch postulates revisited. The Yale Journal of Biology and Medicine, 49(2), 175-195.

Marshall, B. J. (2001). One hundred years of discovery and rediscovery of Helicobacter pylori and its association with peptic ulcer disease. In H. L. T. Mobley, G. L. Mendz, & S. L. Hazell (Eds.), Helicobacter pylori: Physiology and Genetics. Washington (DC): ASM Press.

Marshall, B., & Adams, P. C. (2008). Helicobacter pylori: A Nobel pursuit? Canadian Journal of Gastroenterology, 22(11), 895.

Marshall, B. J., Armstrong, J. A., McGechie, D. B., & Glancy, R. J. (1985). Attempt to fulfil Koch’s postulates for pyloric Campylobacter. The Medical Journal of Australia, 142(8), 436-439.

Marshall, B. J., & Warren, J. R. (1984). Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. The Lancet, 323(8390), 1311-1315.

Marshall, B., Warren, J. R., Blincow, E., Phillips, M., Goodwin, C. S., Murray, R., … & Sanderson, C. (1988). Prospective double-blind trial of duodenal ulcer relapse after eradication of Campylobacter pylori. The Lancet, 332(8626), 1437-1442.

Weintraub, P. (2010). The Dr. who drank infectious broth, gave himself an ulcer, and solved a medical mystery. Discover Magazine, March 2010.

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Recent videos

December 5, 2016

As long as I’m using this blog to support family causes such as my parents’ anti-fluoridation work, I should also throw in a plug for my sister’s company’s new video, which nicely showcases their customizable dresses and headbands for girls 3-7 and their dolls. Great fun for those who enjoy spontaneous, open-ended accessorizing!

Other recent videos of possible interest: my song Cranial Nerve Functions, performed by Do Peterson; my song Kidney Wonderland, performed by me at the UW Nephrology holiday party.

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Fluoridated drinking water is not an elegant 21st-century solution

December 3, 2016

In a previous post, I explained why, overall, I approve of the anti-fluoridation movement. Now I want to address one specific aspect of this that is partly scientific but partly philosophical and aesthetic.

First, a bit of personal context. In the lab-research phase of my career, I spent about 7 years working on the development of new drugs for infectious diseases like malaria. To my great disappointment, my work did not contribute much to the fight against these diseases. However, as I worked in this sphere, I was dazzled by others’ advances, such as the following:

(1) A project led by Meg Phillips (UT-Southwestern) and Pradip Rathod (University of Washington) has intensively studied dihydrooroate dehydrogenase (DHODH), an enzyme thought to be a good malaria drug target. In other words, if a drug impairs this enzyme in malaria parasites (Plasmodium falciparum and related species), the parasite should die and the infected person should be cured of malaria. Over the past 15+ years, DHODH has been characterized in almost obsessive detail, enabling the design of chemicals that strongly block the Plasmodium DHODH without messing up the human DHODH or other human enzymes. A new drug based on this work, DSM265, is currently undergoing clinical trials.

DSM265
Figure (taken from Phillips et al., Science Translational Medicine 7: 296ra111, 2015) showing how the drug DSM265 nestles among specific amino acids of DHODH, thus disrupting its function.

(2) Among already-approved malaria drugs, artemisinin-related compounds are the best ones we have. However, isolating artemisinin from its natural source (the plant Artemisia annua) is costly and time-consuming. A team led by Jay Keasling developed an intricate “semi-synthetic” process, involving both genetically engineered yeast and chemical engineering technology, by which artemisinins can be made cheaply in the lab from simple starting materials.

Artemisin synthesis, part 1
Artesinin synthesis, part 2
Figures (taken from Paddon et al., Nature 496: 528-532, 2013) showing how artemisin can be synthesized in a chemical engineering lab.

To me, these projects represent the pinnacle of modern biomedical science. They were exceptionally hard, but years of relentless detail-oriented work by large groups of talented scientists — not to mention generous funding from government and nonprofit groups — led to practical advances that could save uncountable lives.

When held up against such thorough, painstaking work, the strategy of fighting tooth decay by dumping fluoride into drinking water strikes me as really lame.

For the sake of this argument, I’m not taking a stand on the strength of the evidence that fluoride reduces the formation of dental caries (cavities). Let’s assume that it does. The key point here is that according to most pro-fluoridation experts, fluoride acts topically (i.e., at the surface of teeth) rather than systemically (i.e., by passing through the blood and the rest of the body).

The Fluoride Action Network argues, “If fluoride works topically, there is no need to swallow it, and therefore no need to add it to the water supply. This is especially so when considering that (1) fluoride is not a nutrient, and (2) fluoride’s risks come from ingestion.” This reasoning really speaks to me as a scientist.

As illustrated above, we live in an age of remarkable biomedical resources. With the efforts of our best scientists, we can achieve great things like cure malaria with the best precision drugs mankind has ever known. In this can-do environment, do our most sensible and sophisticated cavity-fighting efforts really involve delivering fluoride to the wrong place in the body (the gastrointestinal tract) and hoping that the right amount of it trickles to the right place (the teeth)?

Fluoridated water’s relative safety or lack thereof is, in some ways, beside the point; it’s simply not the best option that we have. As scientifically literate, non-superstitious people, if we want fluoride to act on our teeth, we should put it on our teeth (e.g., with fluoride toothpaste), then spit it out. Period.

In closing, I want to acknowledge a counterargument to which I am sympathetic. People with limited incomes are least likely to get regular professional dental care and are also least likely to be able to afford fluoride toothpaste or be aware of its value. Shouldn’t we fluoridate water to give these vulnerable people the benefits of fluoride even if they’re not brushing regularly with fluoride toothpaste?

I think it’s a reasonable question. But if I were the mayor of a fluoridated-water town, I’d redirect all fluoridation funding into programs to aggressively distribute fluoride toothpaste to all low-income people who need it. And if I were a dentist, rather than lobbying for water fluoridation, I’d focus on this more intelligent route of fluoride delivery.

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I’m not an ecologist, but sometimes I play one on the Internet

December 2, 2016

This fall, I’ve been teaching introductory ecology & evolution labs for BBio 180 at UW-Bothell. It had been quite a while since I had worked directly with eco-evo material, so it was interesting to look at it with fresh eyes, sort of as my students were doing.

As the quarter progressed, I got the urge to contribute something to the excellent Dynamic Ecology blog run by bona fide ecologists, including my friend Jeremy Fox. So I pitched Jeremy a post on teaching with imperfect analogies, featuring eco-evo examples, which he liked and published.

With eco-evo analogies on my brain, I then started applying them to the realm of academic job searches, which led me to write another piece, which is posted below.

Ecology analogies for the academic job market

Dear Tenured People:

The academic job market continues to suck. Most of your students will be unable to land stable faculty jobs. Please discuss this fact, repeatedly, with your students and trainees. Explicitly acknowledging the extreme difficulty of getting a prized professorship is a vaccine against complacency and self-delusion, both in them and in you, the mentors who send them forth into the world. Since these discussions can be boring and/or dreary, you might consider enlivening them with the analogies below.

Sincerely,

Aging Adjunct

* * * * * * *

Analogy #1: Net reproductive rate R0

I began a recent UW-BERG seminar on job searches with an odd “hook”: a worksheet on net reproductive rate, R0, defined as the average number of female offspring produced by each female parent. (Females are the focus here because males are usually not limiting to reproduction.)

From the definition of R0, it follows that, in the absence of other changes (e.g., in lifespan), the population declines if R0 is less than 1, holds steady if R0 equals 1, and grows if R0 is greater than 1.

We can then move, as the worksheet does, to the concept of the academic reproductive rate as defined by Larson et al. (2014) and Gaffarzadegan et al. (2015). The academic R0 can be considered to be the average number of PhD students graduated by a tenure-track faculty member.

Gaffarzadegan et al. have a nice graph showing that, since 1980, the number of biology PhDs has increased dramatically while the number of tenure-track faculty positions has barely changed, causing the biologist R0 to rise from 2.4 (1980-90) to 6.3 (2010-2015).

With this additional information, discussions of academic job prospects can proceed in any of several directions. At my seminar, for example, I asked attendees to use the R0 model to make predictions about the quantity and experience of applicants for teaching-centric faculty positions. We then compared the predictions to actual job search data.

For me, those data are a mixed bag. The number of applicants per position was lower than I would have guessed. However, it is sobering that even the ad-hoc temporary openings attracted many experienced candidates.

Anyway, I find the R0 analogy useful in several ways.

(A) The R0 analogy underscores that mentors’ trainees are, in some sense, their “children,” i.e., people for whom they bear some responsibility. And that professors, departments, universities, and countries should not take on more children than they can reasonably expect to support.

(B) The rise of the biologist R0 so far above 1 is a sign that our entire training system may be fundamentally unsustainable, as argued by the scientific “dream team” of Alberts et al. (2014).

(C) The focus on a single easy-to-grasp number, R0, helps us contemplate the problems underlying it, as well as possible solutions. For instance, I said “MAY be fundamentally unsustainable” above because a high R0 would be acceptable if most PhDs used their academic training as an intentional springboard to wonderful non-academic careers. However, since most biologists would prefer to stay in academia (Sauermann & Roach 2012), a high R0 is a symptom of a serious problem. Partial solutions, then, might include training fewer PhDs and/or convincing more of us to give more serious consideration to non-academic options before we put all of our eggs in one basket.

And speaking of nascent forms of life….

Analogy #2: The soil seed bank

While I liked the R0 analogy enough to feature it in my UW-BERG seminar, I almost used an alternative analogy suggested by my colleague Cynthia Chang.

The basic idea of the soil seed bank is that soil contains deposits of seeds from many different species, any of which could potentially germinate, but few of which actually do.

So what are the implications of considering newly minted PhDs as “seeds” with potential to “germinate” into full-fledged faculty members?

Well, to start with, most seeds will not ever germinate, an obvious point also illustrated by the R0 analogy. But the soil seed bank analogy can be extended to make several related points.

(A) Germination may occur after a prolonged lag, but most seeds do lose their viability over time. People may hang on as postdocs and as adjunct faculty for quite a while, but after so many years, the odds of making the transition to full-time permanent faculty are quite low. Still, the lack of a firm “expiration date” makes it hard to know when to give up.

(B) Different conditions favor different seeds. Each species of seed has its own optimal germination conditions in terms of moisture, temperature, sunlight, etc. Which seeds actually germinate at a given time depends on local conditions at that time. Similarly, within a diverse crop of youngish biology PhDs, those whose strengths match the current needs of specific departments will be most likely to lay down roots.

(C) Seeds’ success or failure depends strongly on luck. A corollary to (B) is that, as conditions change from year to year, the species that sprout will change as well. If a fire happens to sweep through a given region, fire-resistant seeds will subsequently be favored. If instead the region happens to be hit with, say, a flood, different seeds will instead win the germination sweepstakes. The job-search parallels should be clear: whether a given candidate ultimately blossoms depends not only on their personal robustness, but whether they happen to enter the job market at a time and place that happens to favor their particular strengths.

This last point is often hard for hard-luck applicants to swallow. Words to the effect of “It’s not about you, it’s just an issue of fit,” while well-intended and true, are not necessarily comforting. Having had the persistence to come this far, we figure that if we can just hang in there, we will eventually have our day in the sun.

Indeed, some of us will ultimately be great oaks or sequoias, impressive and enduring, the giants of our fields.

For now, though, we are but tiny vessels of unrealized potential and uncertain fate, weathering harsh environments, hoping against hope for a favorable wind and a soft landing.