A Fireside Chat with Dr. Siddhartha Mukherjee

Last month at the 26th Annual Meeting, I had the pleasure of attending a fireside chat between Pulitzer Prize-winning author and physician-scientist Siddhartha Mukherjee, MD, and the panel of Hans-Peter Kiem, MD, PhD; Fyodor Urnov, PhD; and Maria Grazia Roncarolo, MD. Having read and enjoyed The Gene: An Intimate History, I was eager to hear what a conversation with Dr. Mukherjee was like, especially at a meeting centered on gene and cell therapy.

Urnov started the chat by commenting on Mukherjee’s emotionally transparent style of writing in his latest work The Song of the Cell, to which Mukherjee remarked, “The physician is a vulnerable person, a human being treating human beings… we try to invent therapies… but in doing so, you are exposing yourself to an enormous degree of vulnerability… it’s important to remember that there’s a human being at the receiving end of that therapy.” Mukherjee went on to say that this personal approach to writing helped create a sense of relatability with the greater public. Kiem agreed, saying “It gives us that vision and mission to see what we can do for our patients… it’s very gratifying… this has been a driving force to really accomplish that [developing gene/cell therapies].”

Looking back, I realized that these remarks pretty much framed the entire conversation for me, this idea of recognizing the humanity of both the physician/scientist and the patient. One of the topics in the fireside chat that really brought this to mind was the story of Emily Whitehead, the first pediatric patient to receive CAR T-cell therapy for acute lymphoblastic leukemia, and who has now been living cancer-free since treatment in 2012.

Mukherjee recalled the gripping circumstances of Whitehead’s therapy. “Here’s this child, desperately sick, relapsed while waiting for a bone marrow transplant… the tension is incredible… the nurses are tense, the doctors are tense, and then she’s put on this [CAR-T cell] trial and she gets her first infusion. Things seem to go well and then in the middle of the night, she crashes.” They later found out that it was caused by a cytokine storm and were eventually able to treat it. Whitehead survived and as we now know, the therapy worked. But it was a nail-biting time for CAR T-cell therapy. “Carl June [clinical team lead for Whitehead’s treatment] said to me, very frankly, that if Emily Whitehead had died, the entire field would have gone into a frozen winter,” Mukherjee said.

CAR-T cell therapy has risen to great heights since then. However, one challenge to overcome, as is commonly associated with gene and cell therapies, is that of accessibility. What use is a therapy if the people who need it don’t have the means to receive it? “Aside from Israel and China, there is a cell and gene therapy desert that goes from the Middle East or even further down in Eastern Europe all the way to the Far East… that is where much of the world’s population lives… it’s on the order of 3-4 billion people, virtually half the population of the Earth,” Mukherjee said. Mukherjee is currently involved in expanding access to CAR-T cell therapy in India, which has seen much early success: “It’s a landmark moment for the Indian ecosystem of science… it inspires the confidence that we can deliver cell and gene therapies to people in developing nations.” Mukherjee explained that there were definitely still hurdles to jump, especially related to cost reduction, but researchers are actively working to come up with innovative solutions to this problem. “It’s not around the corner, but I think that we will get there,” Roncarolo added, after sharing findings from one study that the cost for producing customized gene and cell therapies could potentially be reduced ten-fold.

While the treatment of disease is certainly reminiscent of our vulnerability as human beings, which Mukherjee stressed at the beginning, the fireside chat did go on to discuss another aspect of humanity in this age of gene and cell therapy: the desire to improve one’s self. When asked by Dr. Kiem on the subject, Dr. Mukherjee answered, “There is the temptation to use cell and gene therapy to make better versions of ourselves… the line between what is disease and what is not disease, what is emancipation [from disease] and what is enhancement is always blurring.” Mukherjee stressed the importance of discussion on this topic, involving not just scientists but a broad range of experts. “Making a better version of a human being invades on many fundamental questions that we have about who we are and what we are going to become,” he added.

As you’ve read, the fireside chat touched on a lot of issues in the field of gene and cell therapy. It was a stimulating discussion between luminaries, and one that definitely made me think. I have to say though, my favorite part was when they talked about moments in their careers when an idea on paper was eventually realized. Dr. Mukherjee recounted how one of his inverted drawings (e.g., chalk on black paper) led to the development of a new way to do CAR T-cell therapy for acute myeloid leukemia. Basically, existing CAR T-cell therapies were targeting an antigen that was present on both healthy and cancer cells, which led to unwanted off-target effects. Dr. Mukherjee’s inverted drawing inspired the idea of targeting healthy cells instead of cancer cells, by genetically deleting this antigen in healthy cells so that the therapy can become specific to cancer cells. The exciting part is that preliminary data from human studies are showing that this is actually a promising strategy. “This diagram becomes life, it becomes a patient, it becomes a human being. There’s no joy like it… there’s a mixture of anticipation, passion, nervousness, but also this joy,” Dr. Mukherjee expressed.

To end, I’d like to share a few words from Dr. Mukherjee towards the latter part of the chat, which I feel is important for any researcher to hear: “This idea of what E.O. Wilson called consilience, that many ideas come together, they meet and percolate in the community and lead to this new dream being born, it’s very important… it’s important for physicians and scientists to read broadly outside their fields… it’s really important for the public to understand that’s how science happens.” Indeed, sometimes the best ideas come from the most unlikely of places—a drawing while on a remote island in Mexico, a species of bacteria happily living in our guts, or a dish that got contaminated by fungi while you were on vacation. So, if you ever get stuck on something, maybe all you have to do is to look up, look around you, or, better yet, take a vacation! 

Download your certificate of attendance from the meeting here. On-demand sessions will be available in late 2023.

Dr. Lim is a postdoctoral reseracher at Washington University in St. Louis and a member of ASGCT's Communications Committee. His research areas of interest include muscular dystrophy, antisense therapy, and gene therapy.

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