#244 ‒ The history of the cell, cell therapy, gene therapy, and more | Siddhartha Mukherjee
This episode features Dr. Siddhartha Mukherjee, an oncologist and Pulitzer Prize-winning author, discussing his book "The Song of the Cell." He covers the evolution of cells, cell and gene therapies like CRISPR, ethical dilemmas in gene editing, and personal insights into his writing process and mental health.
Deep Dive Analysis
18 Topic Outline
Where The Song of the Cell Fits in Sid Mukherjee's Work
The Discovery of the Cell and Germ Theory's Impact on Medicine
The Evolutionary Drive for Multicellular Life
Ratcliffe's Yeast Experiment on Multicellular Evolution
Four Types of Cell Therapies
The Jesse Gelsinger Gene Therapy Tragedy and Its Aftermath
CAR T-cell Therapy for Cancer Treatment
Cost Reduction in CAR T-cell Therapy
Gene Therapy Approaches for Sickle Cell Anemia
The CRISPR Gene Editing Revolution
Ethical Questions Around Human Germline Gene Editing: The Case of JK
The Complexity of Genetics in Mental Illness
Two Types of Problems in Science: Eye in the Sandstorm vs. Sand in the Eye
Understanding Neural Networks and Synaptic Communication
The Importance of Learning by Doing in Science and Medicine
Sid Mukherjee's Unique Writing Process
Falls as a Liability of Multicellular Existence and Organ Failure
Sid Mukherjee's Decision to Open Up About Depression
9 Key Concepts
Gene as a Score
The human genome, or any genome, is likened to a lifeless score of music, a chemical code (DNA). It requires a 'musician' to bring it to life, which is the cell.
Cell as a Musician
The cell is the entity that brings the lifeless genetic code (the gene) to life. Without the cell, the encoded information would be useless, much like a musical score without a musician to play it.
Disease vs. Desire
This is a critical distinction in gene editing ethics. 'Disease' is fundamentally linked to human suffering, while 'desire' refers to the aspiration to ameliorate suffering even when no suffering is present, or to enhance traits.
Shove Genes
These are powerful genes that strongly push an individual in one direction for a trait or condition, such as the single gene mutation in Marfan syndrome causing extreme height. They are relatively rare.
Nudge Genes
These genes contribute incrementally to a trait or condition, moving an individual 'little by little' towards a phenotype. Most mental illnesses are thought to be consequences of hundreds of these small genetic nudges rather than a single shove gene.
Eye in the Sandstorm Problem
A type of scientific problem where existing information or theories no longer fit observations, requiring a completely new paradigm or fundamental shift in thinking, similar to the transition from Newtonian to quantum physics.
Sand in the Eye Problem
A different type of scientific problem where almost everything fits within a theory, except for one specific fact. This indicates the theory is nearly correct but has an important missing piece, like the discovery of synapses in neuronal transmission.
Synapse
The space between neurons where an electrical signal is converted into a chemical signal, and then back into an electrical signal. This conversion allows for the 'weighting' or modulation of signals, enabling complex learning networks and functions like consciousness.
Body as a Citizenship
This metaphor describes the human body as a complex network where different organs and cell types depend on each other to function. The failure of one part, like a broken bone, can cascade through the system, leading to overall collapse and organ failure.
10 Questions Answered
It is part of a 'Life Series' trilogy/quartet. It follows 'The Gene' (the smallest unit of information) and precedes 'The Emperor of All Maladies' (the dysfunctional aberrant cell), explaining how the cell brings the gene to life.
Multicellularity evolved independently multiple times, likely driven by advantages in predation (being bigger, having specialized defenses, mobility) and better access to food and resources, despite single-celled organisms being extraordinarily successful.
The four types are: 1) using a drug to change cell behavior (e.g., antibiotics), 2) transferring unmodified cells (e.g., blood transfusion), 3) using cells to synthesize substances (e.g., insulin, antibodies), and 4) genetically modifying cells for therapeutic reasons (e.g., CAR T-cells).
Jesse Gelsinger, a teenager with a mild genetic liver enzyme defect, died from a severe, hyperactive immune response to the adenovirus vector used to deliver the corrected gene, leading to a decade-long freeze in gene therapy research.
Earlier methods involved inserting a new, foreign page (gene) into the genome, which could be recognized as foreign and inserted in unintended places. CRISPR allows for extraordinarily precise changes to a single word (gene) within the existing genetic 'library', either deleting or changing it, leaving the rest intact.
A Chinese scientist, JK, used gene editing to make embryos HIV-resistant, despite the children having zero risk of HIV infection via IVF. This was deemed unethical because it crossed the line from treating disease (suffering) to fulfilling a 'desire' (scientific aspiration) without medical necessity.
Most mental illnesses are not caused by single 'shove genes' with high penetrance, but rather by 'nudge genes' – hundreds of small genetic variations that cumulatively increase risk. Current gene editing technology is limited to one or a few genes, making it impractical for such complex polygenic conditions.
This conversion at synapses allows for modulation and 'weighting' of signals. Instead of a simple 'on/off' electrical impulse, the chemical signal can be adjusted in strength, enabling complex learning networks, discrimination, and the nuanced 'music of the brain'.
Textbook knowledge provides foundations but doesn't teach how to troubleshoot failures, select patients for clinical trials, manage complications, or address unexpected issues like contamination. This practical, experiential learning is crucial for translating science into human medicine.
He made a conscious choice to challenge the stigma and 'victimhood' associated with mental disorders. He aims to frame depression as an 'organic disorder' involving dysfunctional mood-regulating neurons, akin to type 1 diabetes being a pancreatic cell dysfunction, thereby normalizing it as a physiological problem.
10 Actionable Insights
1. Practice Rigorous Hand Hygiene
Insist on rigorous handwashing, especially in medical settings, to prevent the transfer of “material substance” (germs) that cause infection and dramatically reduce mortality rates, as demonstrated by Semmelweis’s historical discovery.
2. Prioritize Patient Self-Diagnosis
When diagnosing a patient, always ask them, “What do you think the problem is?” because patients often provide crucial insights into their condition that doctors frequently overlook, aiding in more accurate diagnoses.
3. Embrace Experiential Learning
Recognize that practical skills in medicine and science, such as troubleshooting failures and managing complex projects, cannot be learned from textbooks alone. Actively engage in “learning by doing, learning by being, learning by experiencing” and seek guidance from peers who have practical experience.
4. View Mental Illness Organically
Challenge the notion of “special victimhood” associated with mental disorders by understanding the brain as a cellular cluster with physiology, similar to other organs like the pancreas or heart. This perspective helps remove blame and opens avenues for treating dysfunction in mood-regulating circuits.
5. Ethically Weigh Disease vs. Desire
When considering interventions like gene editing, differentiate between addressing “disease” (fundamentally linked to suffering) and fulfilling “desire” (ameliorating suffering where none exists). Prioritize interventions that alleviate actual suffering over those driven purely by scientific aspiration or enhancement.
6. Adopt a Holistic Writing Process
Use writing as a method for thinking and understanding, drawing from diverse sources like history, mythology, philosophy, and personal experiences. Combine memoir, journalistic, and travel writing to create a comprehensive and personal narrative that invites readers into your perspective.
7. Deepen Health Knowledge via Membership
To take your knowledge of health and wellness to the next level, consider joining a membership program that offers more in-depth, exclusive content, as suggested by the podcast host.
8. Read Mukherjee’s Science Books
For a profound understanding of life, cells, and medicine, read Siddhartha Mukherjee’s books, particularly “The Song of the Cell,” which offers a captivating journey through the history and future of cellular biology.
9. Strategic Reading of Science Trilogy
When reading Siddhartha Mukherjee’s “Life Series” (The Gene, The Song of the Cell, The Emperor of All Maladies), consider reading them chronologically as they appeared for a story that progressively delves deeper into medical mysteries, or start with “The Gene,” then “The Cell,” and finally “The Emperor of All Maladies” to understand the progression from information to life to dysfunction.
10. Understand Biophysical Size Limits
To understand the natural biophysical limitations on creature size, seek out Stephen Gould’s essay that discusses the volume-to-surface area ratio and its impact on an organism’s ability to sustain aerobic living.
7 Key Quotes
Every function that we carry out, regardless of its origin or regardless of what that function is, is a consequence of cellular physiology. We ourselves and everything that we do is cellular, is a consequence of something happening in some cell.
Siddhartha Mukherjee (quoting Rudolf Virchow)
Every illness is the consequence of some cell behaving incorrectly.
Siddhartha Mukherjee (quoting Rudolf Virchow)
The most important question that you ever ask in medicine, when you're trying to diagnose a patient is to ask the patient, what do you think the problem is?
Siddhartha Mukherjee
Gene therapy is really cell therapy. If you put the gene in the wrong cell in the wrong place at the wrong time, you get nothing. You get the disaster.
Siddhartha Mukherjee
The human genome is a library. Imagine the human genome as a massive library. If it was printed in normal text, it would contain 80,000 books, a massive encyclopedia, stretching across a massive library.
Siddhartha Mukherjee
Disease is fundamentally linked to suffering. When we talk about disease, we talk about human suffering. When we talk about desire, we talk about the idea or aspiration to ameliorate suffering, even where there's no suffering involved, as far as we can tell.
Siddhartha Mukherjee
Troubleshooting your way out of failure is the most standard way that we think about medicine and biology.
Siddhartha Mukherjee
1 Protocols
Ratcliffe's Yeast Multicellularity Experiment
Siddhartha Mukherjee (describing William Ratcliffe's work)- Take single-celled yeast and culture them.
- Allow the yeast to grow.
- Collect the sediment, as anything multicellular will sink to the bottom of the flask.
- Allow the collected sediment to grow again in another cycle of evolution.
- Repeat this process for about 30 to 40 cycles.