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Peter Attia MD244 ‒ The history of the cell, cell therapy, gene therapy, and more | Siddhartha Mukherjee
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CHAPTERS
- 0:02 – 3:43
Where The Song of the Cell fits in the Life series
Peter Attia asks how the new book fits with Siddhartha Mukherjee's earlier work. Mukherjee describes a Life series on The Emperor of All Maladies, The Gene and The Song of the Cell. He explains that genes are lifeless without the cell, likening the genome to a musical score and the cell to the musician.
- •The books form a trilogy, possibly a quartet, on how we understand and manipulate life
- •A gene is an inert molecule; the cell brings it to life, like a musician playing a score
- •The books can be read in order of publication or in a different logical order
- •The series moves from the history of cancer to genes to the cell
- 3:43 – 9:14
Why cell biology advanced without genetics' long silence
Peter Attia says the characters in the cell story amazed him because of their limited tools. Mukherjee contrasts the forty years of silence after Mendel with the steady growth of cell biology after the microscope, including Virchow's claims that all function and all illness are cellular. They also discuss the craft of grinding lenses for early microscopes.
- •Genetics had about forty years of silence after Mendel
- •Cell biology developed continuously from the 17th-century microscope
- •Virchow claimed every function is cellular and every illness is a cell behaving incorrectly
- •Mukherjee tried to build one of Leeuwenhoek's single-lens microscopes and found it a disaster
- 9:14 – 18:47
From witchcraft to germ theory: Semmelweis's story
Peter Attia frames the shift from Medicine 1.0 to 2.0 and says germ theory depended on understanding the cell. Mukherjee agrees and tells the story of Semmelweis, who linked doctors' unwashed hands to deadly maternal infections before microbes could be seen. Semmelweis was ridiculed and died impoverished.
- •Germ theory and antibiotics moved medicine out of the era of witchcraft
- •Microbes were imagined in the abstract long before they were seen
- •Semmelweis found much higher maternal mortality in the ward run by doctors who went between autopsies and deliveries
- •Handwashing with a diluted bleach solution cut mortality sharply
- •He was ridiculed, sent to an asylum and never vindicated
- 18:47 – 26:03
Why multicellular life evolved and Ratcliff's yeast experiment
Peter Attia raises the evolutionary drive for multicellular life. Mukherjee notes how successful single-celled organisms are, that multicellularity evolved independently many times, and that predation is a leading hypothesis. He describes Ratcliff's yeast experiment, where selecting sediment produced snowflake-like multicellular yeast with specialized cells.
- •Single-celled organisms thrive in extreme environments and remain dominant
- •Multicellularity evolved multiple times, so it was a minor transition
- •Predation and access to food are leading ideas for why it arose
- •Ratcliff's yeast formed multicellular snowflakes within 30–40 cycles
- •Cells in the middle commit purposeful death so the snowflake can split and reproduce
- 26:03 – 29:20
Dinosaur size and biophysical limits
Peter Attia wonders whether dinosaurs show multicellularity swinging too far toward size. Mukherjee says this is outside his expertise and notes several extinction theories. He points to a Stephen Gould essay on how volume-to-surface-area limits cap body size.
- •Mukherjee says dinosaur questions are outside his field and mentions many extinction theories
- •Smaller mammal-like creatures became more adaptable
- •Gould's essay describes a biophysical limit on size from volume versus surface area
- •Surface area must deliver oxygen and nutrients for aerobic life
- 29:20 – 32:49
Four types of cell therapy
Peter Attia asks about the four types of cell therapy in the book. Mukherjee lays out a typology of using cells as medicines, from drugs that change cell behavior to genetically modified cells. He stresses that gene therapy is really cell therapy.
- •Drugs such as antibiotics change the behavior of cells
- •Unmodified cells are transferred, as in blood transfusion
- •Cells are used to synthesize products such as insulin and antibodies like Herceptin
- •Genetically modified cells include CAR T-cells and CRISPR-edited bone marrow
- •A gene put in the wrong cell at the wrong time gives nothing or a disaster
- 32:49 – 42:10
Jesse Gelsinger and the early gene therapy failure
Peter Attia asks about Jesse Gelsinger, an early gene therapy patient. Mukherjee explains that Jesse had a defect in an enzyme involved in ammonia processing and was treated with a modified adenovirus carrying the corrected gene. He died of a massive immune response, which froze the field for almost a decade. They also cover what a virus is and the strategies developed to make gene therapy safer.
- •Jesse had an enzyme defect related to ammonia processing; the therapy used a modified adenovirus
- •Viruses are not considered living because they cannot reproduce without a host cell
- •Jesse likely suffered an immune rampage, possibly from prior exposure to adenovirus
- •Safer approaches include immune-privileged sites like the retina, dampening the immune response, novel viruses and small fractionated doses
- 42:10 – 48:25
CAR T-cell therapy and the cost of cell therapies
Peter Attia asks about CAR T-cells as a gene therapy success. Mukherjee explains that T-cells are extracted and weaponized to attack cancer, mainly in blood cancers. They discuss why costs are so high in the US and how his group is working to cut them 10- to 20-fold in India.
- •T-cells are removed, weaponized against cancer cells and re-infused
- •CAR T works in lymphoma, leukemia and myeloma but not yet well in solid tumors
- •Emily Whitehead was treated at seven and is now cured
- •The virus and sterile GMP manufacturing make CAR T intrinsically expensive
- •Cheaper virus production, less R&D burden and lower hospital costs cut the price in India
- 48:25 – 52:54
Gene therapy approaches for sickle cell disease
Peter Attia uses sickle cell anemia as an example of treating a germline mutation. Mukherjee describes three approaches: adding a corrected beta globin gene, editing the mutated gene back to normal, and reactivating fetal hemoglobin in adults. All three are in trials, and he expects a cure in our lifetime.
- •Sickle cell results from a single amino acid mutation that clogs small blood vessels
- •One approach edits bone marrow cells to correct the gene and reinfuses them
- •Fetal hemoglobin is better at extracting oxygen and prevents sickling
- •All three approaches are in trials with various measures of success
- 52:54 – 1:02:13
CRISPR and the library analogy for gene editing
Peter Attia introduces CRISPR and its bacterial origins. Mukherjee explains the genome as a library of 80,000 books and describes how CRISPR can change one word precisely. He contrasts this with the old virus-based approach, which inserted a foreign page that the body's immune response, the librarian, rejected.
- •Doudna, Charpentier, Zhang, Church and others developed a bacterial system for precise editing
- •CRISPR can delete or change a single letter, such as verbal to herbal
- •Earlier viral methods inserted new genes, possibly in the wrong place, and drew immune attacks
- •CRISPR can be applied to embryonic cells, bone marrow cells and T-cells
- 1:02:13 – 1:13:34
Germline editing ethics: He Jiankui and disease versus desire
Peter Attia asks about the CCR5 embryo editing case. Mukherjee explains He Jiankui's work on embryos intended to resist HIV, when the children faced essentially no HIV risk. He frames the issue as disease versus desire, and the two then discuss where the line falls for Huntington's disease and less penetrant genes.
- •He Jiankui edited embryos to make children HIV resistant, though IVF meant their risk was effectively zero
- •Mukherjee distinguishes disease, tied to suffering, from desire
- •The result was cruder than the precise edit hoped for, and informed consent was questioned
- •The community would be more accepting for high-penetrance diseases like Huntington's
- •Peter Attia raises APOE4 and other less penetrant genes as harder cases
- 1:13:34 – 1:20:34
Shove genes, nudge genes, and the genetics of mental illness
Peter Attia raises mental health as the hardest area for gene editing. Mukherjee distinguishes rare shove genes with large effects from many nudge genes with small effects, using height as an analogy. Most mental illness is the result of many small nudges, and many of those genes haven't been found, so editing is not feasible.
- •Peter Attia notes autism and schizophrenia have large genetic components but raises societal risks of altering them
- •Shove genes, like Marfan syndrome for height, push strongly and are rare
- •Nudge genes involve hundreds of small effects
- •Most mental illness is described as death by a thousand cuts
- •Editing is limited to one to three genes, so embryo mental-health editing won't happen soon
- 1:20:34 – 1:33:17
Eye in the sandstorm vs sand in the eye: synapses and neural networks
Peter Attia asks about two kinds of scientific problems. Mukherjee explains that a sandstorm problem needs a new paradigm, while a sand-in-the-eye problem is one stubborn fact in an otherwise fitting theory. He uses the synapse and the electrical-chemical-electrical signaling as an example, drawing an analogy to weighted neural networks, and both use musical analogies.
- •Eye in the sandstorm problems need a paradigm shift, like the move from Newtonian physics to relativity
- •Sand in the eye problems are cases where one fact won't fit
- •The synapse converts electrical signals to chemical signals and back
- •Chemical transmission allows weighting of signals, analogous to neural networks
- •Peter Attia compares digital signals to an orchestra limited to maximum volume or silence, and Mukherjee ties modulation to the music of the brain
- 1:33:17 – 1:38:46
Learning by doing: lessons beyond the textbook
Peter Attia asks what a doctoral lab, and his mentor Enzo, gave Mukherjee that medical school could not. Mukherjee says textbooks don't teach troubleshooting failure, running clinical trials or handling contamination, which come from peers and experience. He wrote a chapter about learning by doing.
- •Textbooks lay foundations but don't teach how to troubleshoot experiments
- •Nothing in textbooks covers selecting patients for clinical trials or managing their complications
- •Contamination and similar problems are solved by asking peers who have done it before
- •Mukherjee wrote about learning by doing because it can't be found in any book
- 1:38:46 – 1:44:34
Mukherjee's approach to writing
Peter Attia asks when Mukherjee realized he could write so well. Mukherjee says writing is a way to think and that he draws on history, mythology, philosophy and conversation. He blends memoir, journalism and case history so readers can see what it is like to be him.
- •Writing is hard for Mukherjee and is a way of working through his thoughts
- •Analogies and metaphors serve his own understanding
- •He draws on history, mythology, philosophy and interviews
- •He deliberately erases the lines between medical writing, memoir and journalism
- •He wants readers to experience both the exhilaration and the depression of his work
- 1:44:34 – 1:49:05
Falls, Virchow's death, and the body as a citizenship
Peter Attia connects Mukherjee's father's fall, Virchow's death after a broken femur, and the high mortality of falls in older adults. Mukherjee explains this through Virchow's idea of the body as a citizenship, comparing it to a city where one failing department causes cascading collapse. He says this is the liability of multicellular existence.
- •Falls are the leading cause of accidental death, with substantial mortality after a hip fracture
- •Virchow himself died after a fall and broken femur
- •The body is a citizenship in which parts depend on each other
- •Failure in one part can cascade, as when a transport shutdown stops a city
- •This interdependence is a liability of multicellularity
- 1:49:05 – 2:00:13
Depression, stigma, and closing thoughts
Peter Attia asks why Mukherjee wrote openly about his depression. Mukherjee says it was a conscious choice made after talking to his family, and argues depression is an organic disorder of mood-regulating circuits like type 1 diabetes is of pancreatic cells. The conversation turns to psychiatry lacking biomarkers, and ends with plans for a future conversation.
- •Mukherjee says depression can be an organic disorder, comparable to type 1 diabetes
- •He says mental disorders carry a punitive sense of victimhood because the brain is seen as separate from the body
- •Psychiatry lacks biomarkers, yet Mukherjee says clinicians recognize depression when they see it
- •He mentions possible therapies such as diet, medicines and electrical stimulation
- •Peter Attia proposes a part three covering the immune system, epigenetics and the culture of anti-science
