What is the historical difference in scientific progress between genetics and cell biology?

Genetics, starting with Mendel, experienced significant periods of silence, sometimes decades, where little progress was made. In contrast, cell biology saw a continuous 'blossoming' of science from the 17th century with the invention of the microscope, leading to audacious statements about cellular physiology before similar leaps in genetics.

How did the understanding of the cell contribute to modern medicine's shift from 'witchcraft'?

The deep understanding of the cell, particularly in the context of germ theory, was crucial. Before microbes could even be seen, their existence was imagined, leading to practices like sterile surgery (Lister) and handwashing (Semmelweis). This understanding of material substances causing disease transformed medicine from vague theories like 'bad humors' to a scientific, evidence-based approach, dramatically reducing mortality rates.

What is the evolutionary reason for multicellular life, given the success of single-celled organisms?

Single-celled organisms are incredibly successful, living in diverse extreme environments. Multicellularity evolved independently multiple times, suggesting a strong evolutionary drive. Leading theories for this transition include increased protection from predation due to larger size and specialized defense systems, and enhanced access to varied food and resources.

What are the four main types of cell therapy discussed in the book?

The four types of cell therapy are: 1) Using drugs to change cell behavior (e.g., antibiotics). 2) Transferring cells directly from one body to another without modification (e.g., blood transfusion). 3) Using cells to synthesize therapeutic substances (e.g., insulin production). 4) Genetically modifying cells for therapeutic reasons (e.g., CAR T-cells, CRISPR-edited bone marrow cells).

What happened in the Jesse Gelsinger gene therapy trial, and what were the consequences?

Jesse Gelsinger, a teenager with a rare ammonia processing defect, received gene therapy using an adenovirus vector to correct his liver cells. He mounted a severe, hyperactive immune response to the virus, leading to his death. This tragic event halted gene therapy research for nearly a decade while scientists worked to understand and prevent such immune reactions.

How does CAR T-cell therapy work, and why is it so expensive in the US?

CAR T-cell therapy involves extracting a patient's T-cells, genetically modifying them in a lab to recognize and attack cancer cells, and then re-injecting them. This 'weaponized' T-cell therapy has shown miraculous success in blood cancers. High costs in the US are attributed to expensive virus manufacturing, labor-intensive processes, stringent quality control in sterile GMP facilities, and the recuperation of R&D costs for many failed drugs.

What are the current gene therapy approaches for Sickle Cell Anemia?

Multiple gene therapy approaches for sickle cell anemia are in trials: 1) Gene correction using new technologies to change mutated genes to normal ones in bone marrow cells. 2) Using gene editing to directly revert the gene to its normal form. 3) Reactivating fetal hemoglobin in adults, which effectively carries oxygen and prevents sickling without needing to correct the original gene defect.

How does CRISPR gene editing differ from older gene therapy methods, using the 'library' analogy?

Older gene therapy, like the one used for Jesse Gelsinger, was akin to inserting a new, foreign page into a massive library (the human genome), often without knowing where it would land and risking an immune rejection. CRISPR, by contrast, is like going to a specific page in a specific book and precisely deleting or changing a single word, leaving the rest of the 'library' intact and minimizing unwanted interventions.

What was the ethical controversy surrounding He Jiankui's CRISPR babies?

Chinese scientist He Jiankui controversially used CRISPR to genetically modify human embryos (Lulu and Nana) to create HIV resistance, which was then implanted. The scientific community was incensed because the children had zero risk of HIV infection via IVF, making the intervention medically unnecessary and driven by 'desire' (to be first) rather than 'disease' (ameliorating suffering).

How do 'shove genes' and 'nudge genes' relate to mental health conditions like autism and schizophrenia?

Some rare 'shove genes,' like those causing Marfan syndrome for height, can powerfully push an individual toward a condition like mental illness with high penetrance. However, most mental illnesses are likely due to 'nudge genes'—hundreds of small genetic variations that incrementally increase risk, making precision gene editing for these conditions currently very difficult due to their complex, polygenic nature.

What is the 'sand in the eye' problem in neuroscience, and what did it reveal about neural communication?

The 'sand in the eye' problem occurs when almost everything in a theory fits except one fact. In neuroscience, it was the discovery of synapses (spaces between neurons). The 'madness' of converting an electrical signal to a chemical one, then back to electrical, was eventually understood as crucial for 'weighting' or modulating signals. This allows for complex learning, inhibition, and profound functions like consciousness, similar to how neural networks assign weights.

Why is it important to learn science through lab experience rather than just textbooks?

Textbook knowledge provides foundations but doesn't teach troubleshooting, managing clinical trial complications, or dealing with unexpected failures like contamination in drug development. Lab experience offers learning by doing, being, and experiencing, fostering practical skills and problem-solving abilities that are essential for making scientific discoveries translate into human medicine.

How does Dr. Mukherjee view and approach writing about personal experiences like his own depression?

Mukherjee views writing as a way to think and work through ideas, blending personal memoir, journalism, philosophy, and history to create a new genre. He consciously chose to write about his depression to challenge the 'victimhood' associated with mental disorders and to highlight that brain dysfunctions, like mood-regulating circuits, are organic, similar to pancreatic or cardiac dysfunctions.

How does a fall in an older person lead to higher mortality rates, and what cellular processes are involved?

Falls in older adults, particularly those resulting in a broken femur, often lead to a 10-30% mortality rate within 12 months. This is because the body acts as a 'cellular citizenship.' A seemingly localized injury can trigger a cascade of events—like bone cell (osteoclast/osteoblast) dysfunction preventing healing—that ultimately stresses the entire system, leading to organ failure and systemic collapse, much like a critical transportation system failure in a city.

Key Moments

244 ‒ The history of the cell, cell therapy, gene therapy, and more | Siddhartha Mukherjee

Peter Attia MD

Science & Technology5 min read121 min video

Feb 27, 2023|31,794 views|662|68

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Key Moments

TL;DR

Siddhartha Mukherjee discusses cells, gene therapy, and the future of medicine, highlighting historical breakthroughs and ethical considerations.

Key Insights

The cell is fundamental to life, bringing DNA's genetic code to life and enabling complex functions.

Understanding cells transformed medicine from 'witchcraft' to a scientific era, underpinning germ theory and treatments.

Multicellularity evolved independently multiple times, driven by factors like predation and resource access.

Cellular therapies offer diverse approaches, from simple drug interventions to complex gene editing like CAR T-cells.

Gene therapy's evolution, marked by early challenges like the Jesse Gelsinger case, has led to more precise tools like CRISPR.

CRISPR allows precise genetic editing, revolutionizing potential treatments for genetic diseases like sickle cell anemia.

Ethical boundaries between treating disease and pursuing enhancement are crucial in gene editing discussions.

The brain's complexity, involving electrochemical signaling and 'sand in the eye' problems, requires new paradigms in neuroscience.

Writing about science requires a synthesis of personal experience, history, and philosophy to create relatable narratives.

The decline in physical health due to falls in older adults and depression highlight the interconnectedness of cellular function and overall well-being.

THE CELL AS THE ESSENCE OF LIFE

Siddhartha Mukherjee's "The Song of the Cell" positions the cell as the fundamental unit that animates DNA's genetic code. Unlike DNA, which is a lifeless molecule, the cell acts as a 'musician,' bringing the genetic 'score' to life and enabling all biological functions. This trilogy, including "The Gene" and "The Song of the Cell," explores life from its informational basis (genes) to its operational unit (cells) and then to the consequences of cellular dysfunction, particularly in cancer.

HISTORICAL LEAPS: FROM GERM THEORY TO CELLULAR BIOLOGY

The understanding of cells fueled a critical leap in medicine, moving it from 'witchcraft' to a scientific discipline. The invention of the microscope in the 17th century allowed for the visualization of cells and, later, microbes, directly leading to germ theory. This era saw audacious statements like Rudolph Virchow's in the mid-19th century, positing that all physiological functions and all illnesses are consequences of cellular activity, a concept that advanced rapidly, unlike the slower progression in genetics during the same period.

THE EVOLUTIONARY DRIVE TOWARDS MULTICELLULARITY

The transition from single-celled organisms to multicellular life was not a singular event but evolved independently multiple times. While single-celled organisms are remarkably successful, the drive towards multicellularity is thought to be linked to advantages like increased size for defense, the capacity for specialized movement against predators, and more efficient access to food and resources, as demonstrated by experiments like Richard Ratcliffe's with yeast, which evolved into complex multicellular forms with specialized cellular suicide for reproduction.

A TYPOLOGY OF CELLULAR THERAPIES

Modern medicine utilizes cells as therapeutics in four primary ways. The first involves using drugs to alter cell behavior, such as antibiotics targeting microbial cells. The second is the direct transfer of unmodified cells, like blood transfusions. The third is using cells to synthesize therapeutic substances, such as antibodies. The fourth, and most advanced, is genetically modifying cells before therapeutic use, exemplified by CAR T-cells and gene-edited bone marrow transplants, blurring the lines between gene and cell therapy.

THE EVOLUTION OF GENE THERAPY: FROM CHALLENGES TO PRECISION

Early gene therapy efforts, like the Jesse Gelsinger case, faced significant setbacks due to immune responses against viral vectors. This led to a decade-long pause, prompting the development of safer strategies such as targeting immune-privileged sites (e.g., the retina), using less immunogenic vectors, or dampening the immune response. The advent of tools like CRISPR, discovered through studying bacterial defense mechanisms, revolutionized gene therapy, enabling precise edits within the genome rather than simply inserting new pages, as was the earlier approach.

CRISPR AND THE ETHICAL FRONTIER OF GENE EDITING

CRISPR technology allows for highly precise genetic modifications, offering new hope for treating genetic diseases like sickle cell anemia through gene correction or reactivation of fetal hemoglobin. However, its power raises profound ethical questions, as seen in the controversial case of editing human embryos for HIV resistance. This case highlights the critical distinction between treating disease and pursuing enhancement, emphasizing the need for careful ethical considerations when altering the human germline, especially for non-medically necessary interventions.

UNDERSTANDING THE BRAIN: 'SAND IN THE EYE' AND LEARNING

The brain's complexity presents unique scientific challenges, often described as 'sand in the eye' problems—where a single anomaly challenges an otherwise coherent theory. The discovery of the synapse, the gap between neurons, was such a problem, revealing that neural transmission involves a switch from electrical to chemical signals. This electrochemical signaling with 'weights' allows for modulation, learning, and complex functions like consciousness, analogous to how neural networks operate and enabling the brain to process information dynamically, like a sophisticated musical composition.

THE SCIENCE OF WRITING AND PERSONAL EXPERIENCE

Mukherjee views writing as a process of thinking and understanding, drawing from history, philosophy, mythology, and personal experience. He aims to create a new genre of medical writing that integrates scientific rigor with personal narrative, inviting readers into his world to experience the exhilaration of success and the despair of failure. This approach acknowledges that understanding complex biological and medical concepts requires not just factual knowledge but also an appreciation of the human element and emotional landscape involved.

CELLULAR BREAKDOWN AND THE CHALLENGE OF AGING

The consequences of multicellular existence are starkly illustrated by events like falls in older adults, which can lead to broken femurs and subsequent organ failure. This phenomenon underscores the interconnectedness of bodily systems, where the failure of one component, influenced by cellular processes like osteoclast and osteoblast activity, can cascade through the entire 'citizenship' of the body. This highlights the liabilities of a complex, interdependent system, where the decline of one part can compromise the whole.

DEPRESSION, DISEASE, AND THE BRAIN'S PHYSIOLOGY

Mukherjee advocates for treating mental health conditions like depression as organic disorders rooted in brain physiology, akin to diabetes or heart disease. He challenges the societal tendency to associate victimhood and blame with mental illness, arguing that the brain, like other organs, has distinct physiological circuits. By framing depression as a dysfunction of mood-regulating neurons, he aims to destigmatize it and pave the way for more effective, scientifically grounded treatments, emphasizing the need for biomarkers and a deeper understanding of neural circuit function.

Mentioned in This Episode

●Software & Apps

●Organizations

●Books

●Concepts

●People Referenced

Common Questions

Siddhartha Mukherjee's 'Life Series' aims to explain how we understand and manipulate life. It includes 'The Emperor of All Maladies', 'The Gene', and 'The Song of the Cell'. They can be read in chronological order of appearance, delving progressively deeper into the mysteries of cancer and cell biology, or in a thematic order starting with 'The Gene'.

Topics

Health & Longevity Neuroscience & the Brain Science & Mathematics Mental Health Cancer Treatment Evolutionary Biology Scientific Ethics Gene Therapy Medicine & Clinical Cell Biology Medical History

Mentioned in this video

Books

Emperor of All Maladies

Siddhartha Mukherjee's first book, described as part of his 'life series' trilogy, focusing on the history of cancer and cancer therapy.

The Song of the Cell

Siddhartha Mukherjee's most recent book, completing his 'life series' trilogy, which focuses on the cell as the 'musician' that brings genetic scores to life, and its role in health and disease.

The Gene

Siddhartha Mukherjee's second book in the 'life series', which delves into genetics as the smallest unit of information, explaining that genes are lifeless without cells.

People

Jesse Gelsinger

A young patient who died at 18 during an early gene therapy trial in 1999 at the University of Pennsylvania, due to a severe immune response to the adenovirus vector used to correct an enzyme defect in his liver.

Antonie van Leeuwenhoek

Pioneered the invention of the single-lens microscope in the 17th century, enabling the visualization of microscopic forms and driving the early advancements in cell biology.

Charles Darwin

His evolutionary principles of natural selection were simulated in Ratcliffe's yeast experiment, described as 'Darwin in a bottle' due to the rapid evolution of multicellular forms.

Jennifer Egan

Author of 'The Goon Squad', mentioned in an analogy to illustrate the lack of precision in old gene therapy methods, like inserting a random page into a specific book.

He Jiankui

A Chinese scientist who controversially created the first genetically modified human embryos (Lulu and Nana) using CRISPR, aiming for HIV resistance, despite no medical necessity.

William Osler

A prominent physician from 125 years ago, mentioned to contrast the difficulty of diagnosing heart and liver failure in his era with the ease modern medical students have today.

Thomas Hunt Morgan

Mentioned as one of the scientists who picked up Gregor Mendel's work in genetics after a long period of silence.

Feng Zhang

Scientist mentioned as assisting in the development and application of CRISPR technology, contributing to the genetic revolution.

Joseph Lister

The great surgeon who began sterilizing his instruments, connecting to the idea of microbes even before they were widely seen, and contributing to the transition of medicine from 'witchcraft' to modern practice.

Ignaz Semmelweis

A junior obstetrician in Vienna who discovered that doctors were transmitting microbes, leading to high maternal mortality rates. He insisted on handwashing with bleach, drastically reducing deaths, effectively founding germ theory in the abstract.

Lulu and Nana

The pseudonyms for the twin girls whose embryos were controversially genetically modified by He Jiankui using CRISPR, making them the first gene-edited human babies.

Emmanuelle Charpentier

Co-discoverer of the CRISPR-Cas9 gene editing technology with Jennifer Doudna, which revolutionized the field of genetics.

Helen Mayberg

A researcher known for her work on electrical stimulation therapies to treat psychiatric problems, mentioned in the context of new approaches to mental health.

Jennifer Doudna

A key scientist whose discoveries, along with Emmanuelle Charpentier and others, revolutionized genetics with the CRISPR system, enabling precise gene editing.

Siddhartha Mukherjee

Host Peter Attia's guest, an oncologist and author of 'The Emperor of All Maladies', 'The Gene', and 'The Song of the Cell', discussing his work on the 'life series' of books.

Stephen Jay Gould

An essayist and paleontologist known for discussing natural biophysical limitations on size, specifically the volume to surface area ratio, which can impact a creature's ability to sustain aerobic living.

Charles Dickens

Author mentioned in an analogy to explain the precision of CRISPR, contrasting it with crude gene therapy that would be like inserting an irrelevant page into his book.

Emily Whitehead

A patient who was successfully treated with CAR T-cell therapy at age 7 for leukemia and is now 16 or 17, completely cured, serving as an example of the therapy's miraculous potential.

Walter Isaacson

Author of a biography on Jennifer Doudna, which explores the complex relationship between science and philosophy, particularly regarding gene editing ethics.

Rudolf Virchow

A key figure in cellular biology who made audacious statements in the mid to late 19th century, asserting that all bodily functions and illnesses are consequences of cellular physiology and dysfunction.

Abraham Lincoln

Mentioned in speculation as possibly having inherited the Marfan gene due to his notable height, illustrating the effects of 'shove genes'.

Gregor Mendel

A pioneer in genetics whose work experienced a long period of silence before being picked up by others, contrasting with the continuous development in cell biology.

William Ratcliffe

A professor who studies the evolutionary transition from single-cell to multicellular organisms, famous for his simple experiments culturing yeast to evolve into multicellular, snowflake-like forms with specialized functions.

George Church

Scientist mentioned alongside others for his contributions to the genetic revolution and the development of CRISPR technology.

Carl Deisseroth

A medical school classmate of Peter Attia, described as brilliant and author of a fantastic book that addresses the complexities of mental health and the lack of biomarkers in psychiatry.

Andrew Solomon

An author who has written extensively about depression and mental illness, referenced in the discussion about psychiatric diseases.

Concepts

CRISPR

Revolutionary gene editing technology (originating from a bacterial system) that allows for extraordinarily precise changes in the human genome, such as deleting or changing a single word/letter in a massive 'library' of genes.

CAR T-cell therapy

A type of gene therapy where a patient's T-cells are genetically modified into 'weaponized' CAR T-cells to recognize and kill cancer cells, showing significant success in blood cancers like lymphoma and leukemia.

CCR5 gene

A gene in the human genome that, when modified, can make cells resistant to HIV infection. This gene was targeted by He Jiankui in his controversial CRISPR embryo editing.

Huntington's Disease

A devastating, 100% penetrant genetic disease that shortens life and causes immense suffering, discussed as a strong candidate for germline gene editing due to clear medical necessity.

Adenovirus

A type of virus used as a vector in early gene therapy trials, including Jesse Gelsinger's case. It can cause common colds and, when used in large doses, trigger a fatal immune response.

Rhodes Scholarship

A prestigious international graduate scholarship, which Siddhartha Mukherjee received to study at Oxford where he learned immunology.

Sickle Cell Anemia

An ancient genetic disease caused by a single amino acid mutation, leading to sickled red blood cells, clogging, and micro-strokes. Discussed as a target for multiple promising gene therapy approaches.

Marfan Syndrome

A genetic disorder caused by a single 'shove gene' mutation, resulting in extreme height and other complications, used to illustrate how powerful single genes can be.

Organizations

Oxford University

Where Siddhartha Mukherjee pursued his PhD as a Rhodes Scholar, learning immunology in a lab environment.

Harvard Medical School

Mentioned as a place where one receives a great medical education, but it is contrasted with the practical, hands-on learning acquired in a laboratory setting.

Studies & Research

University of Pennsylvania

The institution where the ill-fated gene therapy trial for Jesse Gelsinger took place around the year 2000.

APOE4

A genetic risk factor for Alzheimer's disease, mentioned as an example of a less penetrant gene compared to Huntington's, raising complex ethical questions for gene editing.

Locations

India

Siddhartha Mukherjee's laboratory is conducting CAR T-cell therapy trials here, aiming to dramatically reduce the astronomical costs seen in the United States, by 20 to 50 fold.