Women's History Month Q&A with Nicole Paulk

Women’s History Month celebrates the achievements and contributions of women in many fields. To celebrate Women’s History Month with ASGCT I interviewed Nicole Paulk, Ph.D., assistant professor of biochemistry and biophysics at University of California, San Francisco, an exemplary scientist and powerful voice for new investigators in the field. 

Paulk received a Bachelor of Science in microbiology from Central Washington University. Following that, she worked in Markus Grompe’s lab at Oregon Health and Science University. It was during this time that she says she “fell into” gene therapy after she became interested in the idea of using viruses to treat liver disease. 

“This wasn’t a popular concept at the time,” she says, “but Markus liked my hard work ethic and asked me to join his lab as a graduate student. I sort of said ‘okay, but I want to work on viruses’ and he agreed. 

“My first couple Ph.D. projects worked out well, and then the ball was off and rolling and before I knew it, we had six papers in four years and I was hooked. I was a viral gene therapy lifer after that.”

ASGCT: What is your proudest accomplishment in gene therapy?

Nicole Paulk: Hands down, discovering that AAV capsids have post-translational modifications. I’ll never forget it. I was at the ASGCT Annual Meeting and I heard folks presenting on a failed clinical trial. Nobody knew why there wasn’t any expression in these patients when all the preclinical data had looked great. I agonized about it the whole flight home and wondered if in fact the preclinical vector made in human cells was fundamentally different from the vector used in the trial that was made in insect cells. But the dogma in the field at the time said AAV had no post-translational modifications and thus the capsids couldn’t/shouldn’t be any different. 

I became convinced that the different species of cells we use to manufacture this virus were producing different viruses, with modifications, and that maybe this was contributing to the functional differences seen clinically. I walked over to the mass spectrometry core facility with a vial of AAV and asked, “will you do a full mockup of this with me?” A week later I got a spreadsheet back with the litany of viral capsid modifications … and fell out of my chair.

ASGCT: Did you have any mentors who helped you/are helping you along in your career? What do you think is the most helpful thing they did/do for you?

NP: I’ve been fortunate to have several phenomenal mentors during my career. Many have been formal mentors (Joseph DeRisi, my K01 mentor at UCSF) and others have been informal mentors who I sought when I needed advice (Andy May, Paula Cannon, Thomas Rando, Kathy High, Mark Davis, Jeff Glenn, Karla Kirkegaard, former labmates, and so many more). 

One of the most important lessons I’ve learned from my mentors is the importance of choosing your mentors wisely. You really need to ensure that this is someone who has your best interests at heart, who has time for you, and who has a history of championing their mentees. A supportive mentor can make all the difference between struggling and thriving. Ideally, you’ll have more than one too, this way you’ll have diverse viewpoints on issues when you seek guidance. A good mentor can shepherd you through any storm, brainstorm with you on the most intractable problems, place those critical phone calls that will make hurdles disappear, and be your champion near and far for your entire career. A poor mentor will not only do the opposite but may actively try to derail you. Due diligence beforehand here is key. A good mentor is worth their weight in gold.

ASGCT: What can we do to better promote women in the field of gene therapy?

NP: I’d like to see more women in the senior editorial roles in all the big gene therapy journals (Molecular Therapy, Human Gene Therapy, Gene Therapy, etc). It still strikes me as bizarre that for how big our annual meeting has become that we still don’t have basic necessities for working parents like on-site daycare. 

We need more women in leadership roles in each of the places in the gene therapy pipeline where women are under supported so that they can act as shepherds to the next generation of women coming up the ladder: more tenured female PIs in academia, more women in key administrative roles within academia (Dean, President, Chancellor, Provost), more female founders of gene therapy startups, more female CEOs specifically (not CMO, not CIO, the C-E-O), more women sitting on SABs and BODs, more women investors in gene therapy companies, more women in leadership roles at CBER and the FDA, and more women running our various gene therapy societies. Until we reach gender parity in our representation at each of these critical points in the career paths for women in our field, we will continue to see disparity in pay, promotion, recognition and retention that ultimately harms the field gene therapy, and thus the patients.

ASGCT: What is the next decade going to look like for gene therapy?

NP: The next decade in gene therapy is going to be positively wild! With the current rate of trials and treatments in the queue for approval at the FDA, it’s predicted that we’ll have approved viral gene therapeutics to treat, and in some cases cure, about five to 20 new rare diseases per year in the next several years. 

In a decade, it’s not inconceivable that we’ll have beaten back 200 diseases. Just think about that! This will be the biggest transformation in medicine since antibiotics and vaccines. That’s how unprecedented this moment in medical history is. I’m personally committed to curing two of those diseases myself. One will be a common disorder that really moves the needle on global health. And the other I want to be ultra-rare. I got my start working in rare liver diseases with kids, and I owe it to those families to follow through, even if I have to self-fund it. This never really gets old for me, it’s still so cool. It’s why I’ve dedicated my entire career to this, it doesn’t feel like work. I get paid to do the coolest thing I can imagine.

ASGCT: What concerns do you have about the gene therapy field?

NP: I’m worried how comfortable gene therapists are with financial conflicts of interest. Our field has exploded with new therapies recently, and this is a remarkable achievement to celebrate. However, with those successes has come a lot of money, and money can be a poison. 

I can’t name a single gene therapy professor who doesn’t have financial conflicts of interest. Whether its lucrative patents, spin-off companies, paid board positions and speaking gigs, industry consulting, grants directly from big pharma and more. And while none of these are necessarily bad, if they go undeclared, or even worse unmanaged, these can lead to all sorts of problems we’ve seen in the field: pressure to falsify or hide damaging data, misleading the public, harassment and retaliation against trainees, and even harming patients. We need to enforce the declaration and management of these conflicts as our field swells with success. Integrity is paramount.

Dr. Pfister is assistant professor at the University of Massachusetts Medical School and chair of the ASGCT Communications Committee.

Related Articles