I walked out of my advisor’s office, defeated. Did most grad students cry uncontrollably for 10 minutes after every meeting with their advisor? I told myself this was normal. It’s disturbing how certain phrases get stuck in your head. I could still hear “Jack, the only viruses you manage to synthesize are the ones coming out of your nose.” The memory still stung, each reliving an echo of the original. I had wanted to scream at Dave, but I focused on my toes instead, just like my therapist taught me. At least she’ll be proud of me.

I joined Dave’s synthetic virology lab at Penn just six months ago. We design viruses for gene therapies that have the potential to bring sight to patients with inherited progressive blindness. I thought I would love the work, but it quickly became clear that I wasn’t going to cut it on my own. Every cell line I touched molded, every PCR reaction I ran fizzled, and every criticism from Dave’s lips cut me to the bone. I started weekly sessions with a therapist soon after my first one-on-one meeting with Dave. 

I can’t remember having a single dream since I joined the lab. My therapist calls it terminal insomnia, which sounds worse than it is. It just means every day I wake up around 3 or 4 instead of 7 or 8. At first, I would roll over and fight in vain to go back to sleep. Now I just get up. I usually get dressed and make the 10 minute walk to lab, still dark outside. It’s nice being in lab when no one else is. This is when I can work on my side project.

I never thought of myself as someone who needed therapy. I was by far the most successful of my three siblings, the one my parents brag about. But between leaving my family and undergrad friends behind in Arizona and the stress of the new lab, I haven’t had a chance to really get to know anyone in Philly. I felt close with my therapist, but last week she rattled me when she said “this is the last counseling session that the university will cover. After this, you will need to pay a copay. I believe you would really benefit from a few more months of counseling. What do you think?” I considered it, but the weekly copay was too high for my grad student starvation salary that barely covered rent.

Still, I was desperate for a way out of this nightmare. While I zoned out at a lecture covering the history of infectious disease, I realized the solution. I resolved to begin the side project that would definitively prove to Dave that I am a competent scientist, even if it killed me. I found the sequence for smallpox on GenBank. I divided the sequence into ten fragments and ordered the fragments online from different gene synthesis retailers. I adapted our lab protocols to recombine the fragments together in a human cell line. It was all surprisingly easy. The next step was just to send the viral DNA out for sequencing to confirm I put it together right. I was so close.

“Hey Jack, you sure get in early.” Jessie walked past me to her lab bench at 4:17 am. “I’m presenting at our group meeting today and was so excited I couldn’t sleep,” she said. “Thought I would get in some extra practice.” Jessie was everything I was not. She was successful in lab (with multiple papers already published), she baked cakes that everyone savored on lab birthdays, and she and her girlfriend recently adopted a dog. 

But she was close with Dave and I didn’t want her tipping him off to my project. 

She wandered over to my bench and said, “Whatcha working on? This doesn’t look like our usual old adeno-associated virus.” She glanced more carefully at the GenBank page. “Smallpox? Is this like smallpox smallpox? Like the smallpox that killed 500 million people before being eradicated in 1979¹? Whoa, does Dave know about this?”

Shit, I thought, should have closed that tab.

I tried to play it cool and said, “He’ll know soon,” but I wasn’t able to keep the smirk from my face. Although there was fear in Jessie’s eyes, there was also admiration, something I hadn’t felt for a long time. I looked around and remembered that our lab kept a bottle of chloroform on hand as a solvent. I’d only seen it done in movies, but I heard a big whiff of the stuff can knock a person out. I walked towards the chemical safety cabinet.

“Jack, I have some questions about your project.” 

“You don’t think I can do it?” I asked.

“I’m worried you will succeed, but not like you think. You’ve had a lot of shit luck recently, but you’re a talented experimentalist. When you present your work to our lab, it’s clear you can predict when an experiment will fail or work. But if you succeed with smallpox, how do you see this actually improving your relationship with Dave?”

“Once Dave realizes I’m a competent scientist, he will start believing in me. Anyway, I’m already so close, what else could I do at this point?” My hand floundered inside the safety cabinet until I found the chloroform. 

“I’m worried that your reasoning has become tainted by your shitty relationship with Dave. Right now, you are believing what is convenient, rather than asking what’s true and will actually work. At the same time, I know you’re logical and receptive to new ideas. Let me try a thought experiment on you. Let’s say that I was the one with the beef with Dave. What would I do in this situation?”

“You’re asking me?” I said. “I guess you would try to hash things out with Dave, just by having the balls to speak your mind. You would tell him that your work is valuable, and if he can’t see that you’ll find an advisor who can.”

“Mmm-hmmm…so why do you do the same?” asked Jessie.

“Well,” I thought aloud as I unscrewed the lid from the chloroform, “you’re so much better at that kind of stuff than me. I don’t know anything about talking to supervisors. My brain just goes blank, my eyes get wet, and then I can’t say anything without choking up.”

“Six months ago you didn’t know how to make smallpox, and now look at you. I’m sure you could learn to be honest with Dave without shitting yourself. Let’s try another thought experiment: What’s the worst that could happen if you chatted with Dave and told him that this just wasn’t the right place for you? How does that compare to the worst that could happen if you managed to create smallpox?”

“Well if I talked to Dave about leaving the lab, it would be incredibly uncomfortable for me. I would dread having that conversation, and after I would feel like a complete failure. I would feel too embarrassed to talk to anyone in the lab ever again.” I found a few paper towels to soak with chloroform.

“Okay, how does that compare with giving Dave smallpox?”

“Whoooooaaaa! I wasn’t going to give him smallpox, I was just going to prove that I could make it.”

“Sure you were,” Jessie said, nodding slowly.

“As they say, the proof is in the pustule” I cracked. “But really that wasn’t my plan. I guess there is a teenie tiny chance that someone could get smallpox. But it’s so small, I wouldn’t even consider it further.” I pressed the paper towels against the mouth of the chloroform bottle.

Jessie got close to me. “But think about it,” she said. “If there was just a 1 in 1,000 chance of a meteor hitting the earth and killing everyone, shouldn’t we make sure it doesn’t happen, since the cost is so high?”

I hadn’t considered this. A gigantic risk, when adjusted by a small chance of happening, is still a huge risk. 100,000,000 deaths multiplied by 0.001% is still 1,000 people likely to die. I put the chloroform down. Could Jessie be correct? Was I making a mistake? I didn’t even know the lethality of smallpox, or how contagious it is. Maybe Dave could die, which didn’t bother me that much. But maybe I could die, or if it got out of control, other people too. 

Jessie could see my gears spinning. “Jack, I’m not asking you to change your mind completely, just to update how strongly you believe in this project. Maybe, before this conversation, you were 99% sure that you’re making the right choice. Now maybe you’re 90% sure. It doesn’t have to be black and white.”

After that conversation, Jessie and I chatted daily about my smallpox project. It took a lot of talks, a lot of patience, but I eventually updated my certainty from 90% to 70%, from 70% to 50%. Once I dropped below 50%, I stopped working on the project.  She encouraged me to return to therapy, despite the financial costs. She helped me find some campus clubs where I could make new friends. I joined the Penn Effective Altruism club and became a club officer. After practicing with Jessie, I worked up the courage to talk frankly with Dave. I eventually transferred to another lab where my mentor supported me and where I thrived.

The ‘final’ smallpox case was in 1979. The eradication of a disease is one of humanity’s greatest accomplishments. But with recent advances in biotechnology, we are approaching a world where a single miserable grad student could bring smallpox back—or engineer something even worse. These scenarios, called Global Catastrophic Biological Risks, are recognized as one of the most pressing problems facing humanity. Just like Jack, we too must consider the worst case. There are tens of thousands of grad students around the world who work in biology, and one-third are at risk for a mental health disorder². They won’t all have a Jessie looking out for them. There are evidence-based methods to support these young researchers and reduce the chance that one of them could try to do something terrible. This includes: considering graduate mentorship as part of faculty performance reviews, increasing funding for graduate student mental health, reducing stress around qualifying exams and the dissertation defense, promoting diversity, equity, and belonging, and normalizing a healthy work-life balance³. These are simple interventions that can be put in place today at a reasonable cost. An ounce of prevention is worth a pound of cure. And we don’t have a cure for smallpox. 

¹https://forum.effectivealtruism.org/posts/jk7A3NMdbxp65kcJJ/500-million-but-not-a-single-one-more   This essay is referenced in the title.

² Levecque, K., Anseel, F., De Beuckelaer, A., Van der Heyden, J. & Gisle, L. Res. Policy 46, 868–879 (2017). https://doi.org/10.1016/j.respol.2017.02.008

³ Council of Graduate Schools & the Jed Foundation. Supporting Graduate Student Mental Health and Well-being (CGS, 2021). https://cgsnet.org/graduate-student-mental-health-and-well-being-0