StemCell Therapy

Graduate and medical school interviews are not democratic spaces. Whatever the interviewer says during that 30 minutes, is the rule of law.

Surely there were policies about the legality of certain questions, but those often arent operational during the interview. Those of us in the chair only hope that the questions arent too difficult, that the interviewer doesnt focus on (or conjure) a flaw in our application, spend the 30 minutes of our engagement berating us for it, breaking our self-esteem for all of eternity.

One interview day during the fall of 2001, however, was special. Interviewer Z, as we will call them, had a different agenda than most.

Across a wooden desk they sat, their attention focused on a computer slightly off to my left. They tilted the monitor so that we could both see it, and walked me through a few of the things that they had worked on.

Interviewer Z was a physician turned basic scientist who made a name for themself as a virologist. In the last several years, they had moved into studying adenovirus-associated vectors (AAV) that were being used as delivery vehicles for gene therapy.

They told me that I was a promising researcher and were curious why I wanted to bother with clinical medicine at all (they were onto something). In light of that, they preferred to spend our interview time teaching me how to build a successful scientific career.

Their tips to building a career? Identify somethinga gene, a protein, a pathway, perhaps an organismand study a feature of it that no one has, in great depth. Study it well enough to publish results in a reasonably well-regarded journal. Present broadly on this topic. Talk to multiple audiences, make a case for why the thing you work on reveals everything about everything.

The advice they were giving me was about how they were able to be nimble, relevant and well-funded. I sat and listened closely.

With your microbiology background, you need to find a way to cash in on the human genome craze. Us virologists are going to win a Nobel Prize for it, you know.

They learned over and said, almost under their breath:

This is how we win.

THE NATURE AND NURTURE OF A SKEPTIC

Before this interview, I had never thought about scientific ambition in such organized terms. My scientific mentors until that pointa young physical chemist named Vernon Morris, and bacterial geneticist Susan Gottesmandidnt appear to work that way. That is, while each had their strategies (like all successful scientists do), they didnt describe their scientific ambitions like a military operation: no fields to take over, no one to defeat, nothing to win.

From my vantage point (nave at the time), they seemed to love the ideas, loved working with people, and only wanted to do good in the world (their behaviors reflected that).

My experience with Interviewer Z took place less than a year after the announcement of the completion of the first draft of the human genome. The announcement shook the world but was especially exciting for me because it was something of a local affair. I was working at the National Cancer Institute (NCI) at the time, on the campus of the National Institutes of Health (NIH) in Bethesda, Md. (where the Human Genome Project lived and where I commuted to work, while pursuing my degree at Howard University in nearby Washington, D.C.).

The months that followed the February 2001 announcement would be defined by as much scientific evangelism as you will ever see. The claims? That the completion of a draft of the human genome was our moon landing, our generations moment when we transcended possibility, forever saw the universe in a different light.

But while this hyper-optimism certainly lived in the vapors of the NIH campus, it didnt follow me into the laboratory where I worked.

My advisor, Susan Gottesman, barely spoke of the announcement. Not because she denied its importance, but rather, because she had other things to do and think about.

Her research program almost functioned as the anti-announcement: she studied gene regulation in Escherichia coli, the most unpretentious of model systems. Biology didnt operate further from the spectacle of human biology than the vagaries of E. coli and phage genetics. But these were her instruments, where shed built an international reputation for genetic approaches to understanding how proteins are managed inside of cells, how microbes respond to stressful environments.

Rather than grand statements about what understanding a genome could do in a fight against superbugs across the universe, Gottesman would speak directly about how studying single sets of genes, in a single species of bacteria (E. coli) could tell us about the quirks of microbial metabolism and physiology, how they operated like a board of modules and switches.

So detailed and pure in thought was she that she barely made reference to disease in her work, even though her discoveries absolutely applied to pathogenic organisms (for example, the small regulatory RNAs that she helped to discover in E. coli have now been found to regulate virulence genes in pathogens like Vibrio cholerae).

But her greater gospel, that I learned by osmosis (we didnt talk much about matters not directly about the work), is that the details matter at least as much as the hifalutin concepts do.

This was an important spirit to be around at that time. I was a college activist, who was consuming and reciting big ideas in the genus of social justice (ideas I stand behind, even today). My favorite writers were James Baldwin and Stephen Jay Gould, both authors of bold and beautiful manifestos (even in short essay form).

And it was all of these forces, a nonlinear mix of nature and nurturemy politics, my background (a young, financially disadvantaged African American, raised in a single parent home), and the environments in which my scientific ethics were madethat made me a natural skeptic of big announcements, big pronouncements and scientific grandstanding.

And yes, this included the notion that the draft of the human genome was our moon landing.

LESSONS FROM GELSINGER

After Interviewer Zs advice on how to win, I tried my hand at offering a real response in the form of a question.

Given recent events, did they plan on pivoting away from the study of adenovirus-associated viral vectors for delivering gene therapy? I asked it with a rebellious buzz in my chest, but it was a perfectly reasonable question.

In September 1999, roughly two years before that interview, a young person named Jesse Gelsinger had died while enrolled in a clinical trial for gene therapy run by the University of Pennsylvania. Gelsingers death had a large effect on me: we were close in age, and his death happened less than two years after the release of Gatttaca, a film about a perilous future defined by genetic discrimination.

Since the Gelsinger death, I had noticed a subtle signature of virology programslike the one run by Interviewer Zmigrating away from a gene-therapy focus vectors and into other areas of virus biology.

The brand of gene therapy that had been in voguenear the turn of the millenniumwas one where the corrected form of genes were delivered to the site of interest using viral vectors. Thousands of viruses have evolved machinery to integrate their DNA into their hosts. The logic followed that this aspect of viruses, where they can deliver genes to certain parts of the host genome, could be manipulated for our own goodwe can fix gene variants associated with disease. And after some early promising results, clinical trials were set up to test this in patients.

Gelsinger died during a clinical trial to cure ornithine transcarbamylase deficiency, a genetic condition that he suffered from. After injection with an adenovirus vector, Gelsingers body mounted a large immune response against the virus, which led to a cascade of events culminating in his death.

The Gelsinger death, combined with my personality, experiences and developing ethics, was the reason that the announcement of the completion of the first draft didnt land on me the way it did many others. I had already seen big ideas in science rise and fall.

Twenty years later, I can say that some of my skepticism was poorly founded and misguided. I can proudly admit that almost every field of biology has been irreversibly changed, if not revolutionized, by technology that sprung from that announcement.

We now understand more about the origins of species, the ones that Darwin speculated on, than we ever have.

We have almost real-time outbreak pictures of bacterial and viral genomes creeping through sequence space, sometimes landing on jackpot solutions that facilitate adaptations (but more often landing nowhere, and quite often, off a cliff towards genetic doom).

Genomic technologies driven by the announcement allow us to assess our risk for many important diseases and afflictions.

We can even quantify, to some degree, the magical biodiversity that populates our planet.

The completion of the draft of the human genome helped to democratize the technology, through making genomic sequencing more affordable. You no longer need to study a well-funded human genetic disease in order to afford the tools to sequence and analyze DNA. People who study rainbow trout use genomics. People who study archaea use genomics.

But while some of my young takes might have been sophomoric, others were mature and responsible (even wise).

Among the central messages during the last two decades of genomic science is that the relationship between genotype and phenotype does not function like the pieces of a puzzle. Genes and mutations speak to each other and the environments in which they operate, in surprising ways that defy any existing analogies.

Weve learned that resolving phylogenetic relationships between species and organisms can be a nightmare because biology doesnt operate according to the categories that make it easy to understand. (To put this in perspective, we cant even agree on the very basics, like whether there are two or three domains of life)

Weve learned that genes for disease A often dont cause disease at all. And paradoxically, many people with disease A dont have any identifiable genetic predisposition.

And Homo sapiens? Were an even messier story than we ever predicted: not only are social ideas like race unhelpful for understanding anything essential about the species, they are plainly in the way of a full grasp of the increasingly complex picture of our true origins. Genes from several nonhuman species are peppered throughout our genomes in nontrivial amounts, telling a story of wanderlust and widespread copulation.

As it turns out, my education about the rules of biology over the past two decades has functioned a lot like my education about the rules of real life.

With regard to the latter, there are truths that I can and will hold onto: nice people are great. Greed is bad, and so is racism.

But life isnt that simple.

Because Ive also learned that some people are mean for a reason, greed might happen by accident, and maybe weve all been raised to be bigoted in one way or another. Ive learned the challenge and joy in being empathetic, recognizing our privileges, and dealing with our own biases.

Similarly, DNA is the most fascinating and important string of information in the universe. It tells powerful stories about this bizarre collection of matter that we call life on earth. And it is a privilege to be a part of the species that can study and discuss what it is and how it works.

But it isnt everything. Because life isnt that simple.

And this is what Interviewer Z has since learned. Opportunism around big announcements didnt land them where they hoped. And ironically, the discovery that created the modern face of genetic modification and was awarded a Nobel Prize in 2020CRISPRwas the product of tinkering in microbes in a manner that resembled Susan Gottesmans methods, more than it did Interviewer Zs Art of War tactics.

Months after the interview, I would begin a two-decade-long scientific adventure, where Ive since engaged insect ecology, medicine, biophysics, evolutionary biology and othersalmost entirely (I believe) based on inspiration.

I have landed as an academic who runs my own research program in infectious disease, and am not much younger today than Interviewer Z was at the time of our 2001 interview.

But the advice I give young people today is much different than theirs:

Who the hell knows where the next big discovery will come from? Just hustle and flow, enjoy learning, and ignore the fads and big announcements.

More:
The Human Genome and the Making of a Skeptical Biologist - Scientific American

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