#32 - Siddhartha Mukherjee, M.D., Ph.D.: new frontiers in cancer therapy, medicine, and the writing process
Dr. Siddhartha Mukherjee, a Pulitzer Prize-winning physician and scientist, discusses his writing process, the three laws of medicine for critical thinking, and exciting advancements in cancer immunotherapy. He also shares crucial findings from his recent animal study on combining a ketogenic diet with a PI3 kinase inhibitor for cancer, emphasizing important caveats.
Deep Dive Analysis
15 Topic Outline
Sid Mukherjee's Background and Early Career
The Genesis and Impact of 'The Emperor of All Maladies'
Sid's Writing Process and Tenets
Upcoming 10-Year Update to 'The Emperor of All Maladies'
The Role of Obesity as a Cancer Risk Factor
The Search for Preventable Chemical Carcinogens
The Three Laws of Medicine: Law #1 - Strong Intuition vs. Weak Test
The Three Laws of Medicine: Law #2 - Normals Teach Rules, Outliers Teach Laws
The Three Laws of Medicine: Law #3 - Human Bias in Medical Experiments
The Excitement and Impact of Immunotherapy and Checkpoint Inhibitors
The Story of Gleevec and Targeted Therapy
Metabolic Oncology: How Body's Metabolic State Affects Cancer
Exploiting Drug Sensitivity with Nutritional Intervention
Ketogenic Diet and PI3 Kinase Inhibitors in Cancer Treatment
Sid Mukherjee's Approach to Balancing Life and Work
5 Key Concepts
Bayesian Idea
This concept, originating from Thomas Bayes, suggests that one can only interpret a test or event in light of its past predictions or prior probabilities. It emphasizes that the world has a history (priors) that should inform our understanding of future events or test results, rather than treating each event as de novo.
Laws of Medicine
A framework for medical thinking comprising three principles: 1) A strong intuition is much more powerful than a weak test, 2) Normals teach us rules; outliers teach us laws, and 3) For every perfect medical experiment, there is a perfect human bias. These laws encourage skepticism, historical context, and attention to exceptions in medical practice and scientific inquiry.
Checkpoint Inhibitors
A class of drugs (e.g., targeting CTLA-4 and PD-1) that block specific factors on cancer cells or immune cells, preventing cancer from inactivating the immune system. By 'driving nails through' these factors, the immune system can recognize and attack cancer cells, leading to durable remissions in some patients.
Targeted Therapy (Gleevec)
A treatment approach where a specific chemical molecule is synthesized to 'jam' a cancer's engine, often a mutant gene product like BCR-ABL, in a cancer-specific way. This allows the drug to inhibit cancer growth without significantly affecting normal cells, as exemplified by Gleevec for chronic myelogenous leukemia.
Hyperinsulinemia in Cancer Resistance
The phenomenon where certain anti-cancer drugs, such as PI3 kinase inhibitors, can induce a pre-diabetic or hyperinsulinemic state in the body. This elevated insulin then paradoxically feeds the cancer, allowing it to become resistant to the drug and undoing the therapeutic benefit.
6 Questions Answered
The idea came during his medical training when a patient asked, 'Where are we going with all of this? Why are we here? How did we get here?' This prompted Mukherjee to explore the full, unwritten history of cancer.
Mukherjee views his scientific and writing selves as integrated, using writing as a process of thinking to inspire new ways of understanding the cancer world. He follows tenets like ensuring human stories are central and making his books readable by everyone, regardless of their background.
The Nobel Prize recognized the identification of specific pathways that cancer cells use to inactivate the immune system, and the subsequent development of drugs that block these pathways. This breakthrough provided a 'first crampon' in the fight against cancer, making previously non-linear problems linear and opening new avenues for research into resistance mechanisms.
Cancer cells have distinct metabolic pathways compared to normal cells. Some anti-cancer drugs can induce a hyperinsulinemic state in the body, which cancer cells can exploit to become resistant to the drug, essentially 'feeding' the tumor despite the therapy.
Yes, animal studies show that a ketogenic diet can paralyze the resistance mechanism caused by drug-induced hyperinsulinemia. By blunting the insulin response, the diet can restore the effectiveness of certain anti-cancer drugs like PI3 kinase inhibitors.
Mukherjee is a question and project-driven person who emphasizes taking the first step (e.g., writing the first line, doing the first experiment) and persistently working at it. He also highlights the importance of being open enough to let the work 'speak back' to him, allowing experiments and ideas to guide the next steps.
13 Actionable Insights
1. Identify and Challenge Biases
Actively seek out and identify the inherent biases that may be influencing every claim or idea, as recognizing these biases is crucial for skeptical and scientific thinking in all aspects of life.
2. Apply Bayesian Thinking
Interpret new information or test results by considering past performance and prior probabilities, as the past is a strong guide for understanding the future in many aspects of life and decision-making.
3. Learn from Outliers
While generally applying Bayesian thinking, pay close attention to rare exceptions or ‘outliers’ because they can reveal fundamental laws and deeper understandings not apparent from normal cases.
4. Start and Persist on Projects
To achieve ambitious goals, initiate by ’throwing something at the world’ (e.g., the first line, experiment, or idea) and then persistently iterate and refine it, continuously asking questions.
5. Let Your Work Speak Back
Cultivate an openness in creative or scientific pursuits to allow your work or experiments to ‘speak back’ to you, engaging in a skeptical conversation with the emerging results to guide your next steps.
6. Ground Complex Information in Humanity
When communicating complex scientific or technical information, ensure a human element is present every few pages to make the content relatable and clarify its real-world payoff.
7. Craft Content for Broad Appeal
Design content for universal readability and multiple layers of interpretation, enabling diverse audiences to find it engaging and relevant from their unique perspectives.
8. Focus on Applied Research Impact
When evaluating or discussing scientific research, prioritize findings that have a clear manifestation in human medicine, such as new drugs, treatments, or fundamental reconceptions of disease management.
9. Address Obesity as Cancer Risk
Take the link between obesity and certain cancers seriously, as it is becoming a significant preventable risk factor, though the underlying mechanisms (endocrine, inflammatory, metabolic) are still being understood.
10. Ketogenic Diet: Specific Cancer Context
Do not self-prescribe a ketogenic diet for cancer prevention or treatment, as current animal studies show it is effective only in specific contexts (e.g., combined with PI3 kinase inhibitors) and can even accelerate some cancers when used alone.
11. Utilize Podcast Show Notes
Review the podcast’s meticulously prepared show notes, especially for challenging or technical content, as they contain comprehensive information and links to enhance your understanding.
12. Join the Podcast Email List
Sign up for the podcast’s weekly email list to receive valuable content, including interesting papers and observations, shared every Sunday morning.
13. Provide Podcast Feedback
Leave a constructive review (positive or negative) on Apple Podcast Reviews if you enjoy the podcast, to provide feedback and support the show’s continued improvement.
5 Key Quotes
If you look carefully through that book, every five to seven pages, the story comes alive in a human story, in a scientific story, and in a scientist's story. They all intersect.
Sid Mukherjee
The important thing is once you drive a single stake through cancer's heart, it's like placing the first crampon on a climb. You see, if there's no crampon that's placed on the climb, you can't climb a mountain. It seems like a wall. It's a blank wall and you don't know where to go left or whether to go right or what to do. Once you plant that first crampon... you all of a sudden, the whole face of the mountain becomes... it's a different mountain now.
Sid Mukherjee
The job in science is not to fool yourself. And you're the easiest person to fool.
Peter Attia (quoting Richard Feynman)
The first one was that there will be no scientific abstraction. At no place or point shall you go through five pages or three pages without there being a human being in the middle of this.
Sid Mukherjee
Normals teach us rules; outliers teach us laws.
Sid Mukherjee