Lab Meeting: Stuart Schreiber

“I want to wake up every morning and ask myself, what is the most fascinating thing I can think about? I just want to make it a life worth living, you know?”

Stuart Schreiber’s initial affinity for chemistry was aesthetic. Seeing his college chemistry professor draw d-orbitals for the first time he thought: “it blew me away. I didn’t know what it was, but I knew it was beautiful, artful and I had to know what it meant.” He describes feeling like a chemical “choreographer” after running his first successful organic chemical reaction, realizing: “I’ve learned the rules and I can make them [molecules] dance. My dance!”

Schreiber shifts effortlessly between discussing classical “Woodwardian” synthetic organic chemistry, theories of consciousness, advances in genetic genealogy, the Iliad and Odyssey, reimagining clinical research structures, and his current work on molecular glues, ferroptosis and neurodegeneration. He discusses each in a thoughtful, and at times poetic, way—his calm and measured cadence betraying Southern roots.  He describes a scientific mentor, W. Clark Still, as a true “renaissance man” – a term as easily applied to Schreiber himself.

Like Clark Still, Professor Stuart Schreiber is a card-carrying member of the organic chemistry elite. Trained under R.B Woodward and Yoshito Kishi (EJ Corey was his department head), Schreiber quickly made a name for himself by developing creative methods to make complex molecules—culminating in the synthesis of the immunosuppressant, FK-506. Among the first to realize that selective cell-penetrant small molecules can be used probe the “black box” of signal transduction, his subsequent work mapped calcineurin-NFAT, mTOR and histone deacetylases pathways, and paved the way for countless findings in immunology and cancer biology. This work, and his advances in small-molecule screening approaches, earned him election to the National Academy of Sciences in 1995, the Wolf Prize in 2016 and election to the National Academy of Medicine in 2018. He is the co-founder of the Broad Institute, and currently an HHMI investigator and the Morris Loeb Professor of Chemistry and Chemical Biology at Harvard University.

To advance his work in the clinic, he has co-founded several biotech companies including Vertex, ARIAD Gene Therapeutics, Infinity Pharma, Forma Therapeutics, H3 Biomedicine, Jnana Therapeutics, and more recently Magnet Biomedicine, Kojin, Belharra, and Kisbee (see Q #6). In addition to his groundbreaking work in organic synthesis and cell signaling, he is a pioneer in uniting academia, industry, and venture capital (on the SAB of F-Prime) to enable new therapies to reach the clinic.  

Since first meeting Dr. Schreiber when I was an undergraduate, I have wanted to sit down with him to discuss his views on life, science, medicine, and the development of new therapies. Below are excerpts from an interview with Dr. Schreiber in July 2022:

1.     Name an overlooked scientist, whom you feel strongly that every grad student (or med student) should know well enough, to be able to describe their major findings. What were the killer experiments? 

I’ll answer this in a very personal way. There is a scientist that very few people know that was transformative in my field, but more selfishly was a person who just opened my eyes to a way of thinking. His name is Clark Still, he was a professor at Columbia and an organic chemist. Everything about him is fascinating to me, including his cerebral calm. He had a soothing voice—he was this Georgian almost with an FM radio voice. But far more important, he was trained in synthetic organic chemistry. At that time in the 1970s synthetic organic chemistry was dominant, and people like my advisor R.B. Woodward and my department head EJ Corey won the Nobel Prize, and they were giants in the field.

I first learned about Clark because he was so good at doing what I was interested in [synthesis of complex molecules] but very quickly he moved in directions that were radically different—he developed what he called macrocyclic stereo control. He thought about macrocycles and acyclic systems and used fundamental conformational analysis. It was a big leap, and I loved conformational analysis. But the bigger leap was he started wondering about non-covalent interactions, molecular recognition, and he brought computation science to bear. He made it available to everybody by developing a program called Macro Model—people don’t know about it today, but it was the beginning of all of the computer-assisted structural analyses. It was like bringing a Mac to the world of computers, suddenly you had this GUI that was immediately accessible to everybody.  Computational science had been only for the experts and seemed so esoteric, and suddenly it was at everybody’s fingertips.

Clark Still. He was a savant. His deep intellectual curiosity and deep tenderness…he wasn’t interested in the ruthless, cutthroat, competitive atmosphere of the academy. Everybody knew he was on another plane, and they were jealous about that. He shocked the world at 49 or 50 and retired from Columbia. I asked him: ‘what do you want to do?’ He said: ‘I’m building a barn in upstate New York, and I’m going to build an airplane from scratch.’ This was classic Clark Still.

From Clark I decided, I’m going to wake up every morning and ask myself, what is the most fascinating thing I can think about. I just want to make it a life worth living, you know?

2.     What are you reading in your free time?

I really love science, so my reading is mostly about science. There are three areas that fascinate me that are not my research, but also touch something deep inside me. One is consciousness. How can we have a conversation with ourselves inside of our brains? What is that ghostly image when I conjure up the face of my beloved mother? I see something real that moves and is dynamic, what is that? How does this come about, and is it learned? Books in this area, The Origins of Consciousness and Breakdown of the Bicameral Mind, written by a local psychologist called Julian Jaynes. I don’t think his theory is right, but it got me thinking a lot. Another one I am in the middle of is The Idea of the Brain by Matthew Cobb.

Another area I am interested in is the deep history of humans made possible not only by anthropology but today by genetic anthropology. A book I have read three times is Who We Are and How We Got Here by David Reich at Harvard Medical School. It is so profoundly important to know who we are…if everybody knew what we can know from this topic I don’t think we’d be sitting here talking about the far right and far left.

The third topic is related and is very personal for me. Through genetic genealogy we can gain unbelievable insights and levels of resolution. For example, I know I descend from Emashapa Panyouasas she is my G7 grandmother. Her ancestors were Mayans who moved up through Mexico, the gulf coast and then settled in Mississippi. She was the princess daughter of the chief of the Choctaw nation. My mother and I didn’t know our families. Through genealogy I’ve figured out who my father was, and I’ve found out all kind of things…I discovered that living next to her [mother] were her two sisters, and they actually bumped into each other, and didn’t know it at the time. I later became very close with my Mom’s sister who died recently. Like my mother she was a Cajun angel who was a clone of her…I’ve met family after family after family. It’s amazing…I have over 4,500 family members that I can now infer from my descendants.

I am going with my wife to Northern Ireland where my grandmother is from. I’ve learned every home she lived in and all the families and all the relationships. And I’ve been reaching out to them, and they are so anxious to meet the “young lad” from Boston that cares about his Irish roots, which makes them so happy. That one is not a book, but I voraciously read many books about family relationships and new analytic genealogy technology.  

[Dr. Schreiber’s answers here are personal, profound, extensive and deserve a standalone article. Indeed in a 2019 Harvard Magazine article, he wrote a piece about his childhood, his ongoing quest to discover his family past and the scientific advances he made in the field of genealogy. It’s incredible]

3.     What was your first taste of science? Briefly, what about this initial experience drew you in? Who was your first great scientific mentor? 

I was not an academic at all. Getting to college was a fluke. I went to the University of Virginia and I quit after three weeks. My sister who I love very much asked me why. My advisor said you can’t study chemistry because you haven’t had it in high school. And she said you can quit if you want but not for that reason. So, I went into my first chemistry class, and my professor was drawing what turned out to be d orbitals in blue and white chalk. And it blew me away. I didn’t know what it was, but I knew it was beautiful, artful and I had to know what it meant.

The first time I did an experiment I knew about chemical reactivity and NMR spectroscopy, but performing my first chemical reaction, pulling a proton off of a methyl group, next to a carbonyl and condensing it with an electrophile—I couldn’t see any of the molecules but I could see in my mind the tetrahedral intermediate…and then I got the NMR spectrum and it was the compound I had imagined. It was then I had this idea, I’m a molecular choreographer. I make molecules. I can’t even see them, but I’ve learned the rules and I can make them dance—to my dance. And that’s how I became a synthetic organic chemist.  

4.     What has been your scientific high point? — What do you consider to be the most exhilarating discovery or set of discoveries you have been involved in?

There are maybe four or five things related to signal transduction, one to chromatin and gene expression, APOE and brain health and cancer resistance and ferroptosis. But it makes you feel bad picking one. But for me it was the discovery of molecular glues. That compounds can induce protein associations, which I called molecular glues. That set off a sequela of discoveries…pulling together a target and an E3 ligase to degrade a protein is a modern instantiation of this concept. It’s gone full circle now; you can find molecular glues to do anything you want. It’s quite amazing.

5.     What set of research questions or projects has you most excited about coming into lab today?

What I’m doing in my lab today is largely trying to solve this problem: can we have a completely generic solution to the goal of making drugs only work in the diseased tissue. Tissue-specific drugs that are given systemically.  If you pick a ‘presenter’ protein only expressed in the diseased tissue and you find a therapeutic target in the diseased tissue, and a molecular glue that requires those two, well then it can only work where you want it to work.

6.     Who are a couple of up-and-coming scientists (lab < 10yr old) in your area, or more broadly, whom you think we should watch? Why is their work so exciting to you?

Things are changing. Some of the most extraordinary scientists in my lab in the last few years have gotten offered academic jobs and declined them. They wanted to take their discovery and impact human health. They realized that by working with the venture community they could tackle major problems and have the resources to do so that they couldn’t do as an assistant professor.

The two examples I would give you. Dr. Vasanthi Viswanathan discovered that cancer cells have plasticity and undergo a cell change when they become drug-resistant. In doing so they become vulnerable to ferroptosis and evade apoptosis. From this discovery she founded a company called Kojin therapeutics.

Very similarly Dr. Emily Ricq joined my lab and pursued a problem about APOE. We knew that distinct alleles provide risk, neutrality or protection to Alzheimer’s Disease. But now we know that these alleles are risk or protection against acute brain injury—recovery from a coma, MS flair, traumatic brain injury, recovery from anesthesia. Emily figured out the mechanism by which APOE has this function. Everything about it was stunning and surprising.  She figured out that by working with the venture community she could continue this work, so she founded Kisbee Therapeutics.

These are next-generation scientists on their way to changing the world.

7.     What is one piece of advice for a young scientist aspiring to have a career in academia, and make some important discoveries?

I’ll go full circle. I’ll paraphrase what I learned from Clark Still. Think big and bold and follow your passion. Don’t listen to people who tell you what you can and cannot do. They don’t know you, only you know yourself. If you are passionate about something and have basic problem-solving skills, you can do it. Don’t walk away from something because you are not ‘trained in the area.

8.     [Prior to the interview questions, we discussed trends in medicine, science and discovery. Below is an excerpt of how Schreiber views the past, present and future of translational medicine, and a potential reimagining of medical/scientific structures]

The world in biomedicine has been put into these two bins. The academy and pharma/biotech. But keep an open mind and be on the lookout. Things are beginning to change and there is stuff bubbling up. The pandemic had a lot to do with this where policy makers, scientists and the ultra-wealthy got together to think—this led to discussion of what can we do to make the system more efficient from policy to investment to creative thinking about organizational structures.

If you want to do biomedical research with the immediate impact of altering human health and disease, first you would create a different structure: you would make a discovery and the next day you would ask is the discovery robust, scalable, relevant to the human condition. And have a pool of money already present to do all of those. There would be no company-formation phase where you have to in-license stuff and negotiate…it’s just done the next day. A lot of barriers will go away, and the process will be rapidly accelerated towards new medicines. I think the role of computational science, artificial intelligence and machine learning will grow in the future in unpredictable ways. We have some examples right now, the most successful is in predicting protein structures, but that will soon move to interactomes, protein-protein interactions, drug-macromolecule interactions and fold in molecular dynamics and empirical machine learning…the way this will be done is in the hybrid structure I alluded to.

The 21st century is the century of human biology, which is the ultimate validation for taking a physician–scientist path in training. How else are you going to learn about human biology – physiology and pathophysiology – if you don’t have access to hospitals and patients? Increasingly, we will see experiments designed from scratch that are longitudinal and involve measurements in humans, not unlike in the Framingham heart study decades past. It’s very exciting.