Siddhartha Mukherjee: History of the Cell, Cell Therapy, Gene Therapy

The Life Series Trilogy

• The Emperor of All Maladies
• The Gene
• The Song of the Cell

The Gene

• Smallest unit of information
• Encoded in DNA, but lifeless without the cell
• The cell is the musician that brings the gene to life

The Song of the Cell 

• Focuses on the cell and its importance in life
• Cells bring genes to life and are responsible for all functions and illnesses

History of Cell Biology 

• Microscope invented in the 17^th century
• Gradual blossoming of the science
• Rudolph Vercou made audacious statements in the late 19^th century 
  • Every function is a consequence of cellular physiology
  • Every illness is the consequence of some cell behaving incorrectly

Microscopes and Visualization 

• Lewin Hooke’s single lens microscope
• The lens is smaller than the size of an eyeball
• The microscope allowed for the visualization of microscopic forms

Transition from Medicine 1.0 to 2.0

• Introduction of the scientific method in the late 15^th century
• Germ theory and the understanding of microbial agents
• Reduction in human mortality due to the reduction of death from infectious diseases

The Importance of Antibiotics 

• Life-​​saving effect on procedures such as childbirth and surgery
• Microbes were imagined in the abstract before they were seen

Semmelweis and the Discovery of Microbes 

• Junior obstetrician in Vienna
• Discovered that doctors were transmitting microbes
• Importance of listening to patients
  Semmelweis and Germ Theory
• Semmelweis, a junior obstetrician in Vienna, noticed high maternal mortality rates in one ward compared to another 
  • Ward 1: run by doctors who performed autopsies and delivered babies without washing hands
  • Ward 2: run by nurses who did not perform autopsies, had lower mortality rates
• Semmelweis hypothesized that doctors were transferring a “material substance” from dead bodies to the women they were examining 
  • Insisted doctors wash their hands with a diluted bleach solution, which led to a decrease in mortality rates
  • Semmelweis essentially founded germ theory, although he did not have a microscope to confirm his findings

Evolutionary Drive for Multicellular Life

• Single-​​celled organisms are incredibly successful, living in a wide range of environments
• Multicellular organisms evolved from single-​​celled organisms multiple times independently 
  • Possible reasons for multicellularity: 
    • Predation: harder for predators to eat multicellular organisms
    • Access to food and resources
• Multicellular organisms still make up a small portion of life compared to single-​​celled organisms

Ratcliff’s Experiment with Yeast

• William Ratcliff conducted an experiment to study the transition from single-​​celled to multicellular organisms 
  • Cultured yeast and collected sediment, allowing it to grow in multiple cycles
  • After 30–40 cycles, yeast evolved into multicellular, snowflake-​​like forms
  • These new multicellular yeast continued to propagate and developed specialized functions
  • Ratcliff has conducted similar experiments with other organisms, such as algae

Evolution and Dinosaurs

• Dinosaurs were large multicellular organisms that existed millions of years ago
• It is unclear whether their size was an evolutionary advantage or a correction in the evolutionary process
• Factors such as volcanic eruptions and changes in food availability may have contributed to their extinction, allowing for the rise of other life forms
  Jesse Gelsinger and Gene Therapy
• Jesse Gelsinger had a genetic disease related to the processing of ammonia in the body
• The idea was to create a virus containing the corrected version of the gene and infuse it into Jesse’s body 
  • The virus would infect his liver cells, insert the corrected gene, and reverse his disease
• However, Jesse’s immune system mounted a vigorous response against the virus, leading to his death 
  • The field of gene therapy was frozen for almost a decade as researchers tried to understand the cause and how to prevent it in others

Safer Approaches to Gene Therapy

• Safe harbors in the body: places where the immune system doesn’t easily reach 
  • Examples include the retina and testes
• New drugs can dampen the immune response, preventing a severe reaction to gene therapy
• Hiding the virus: researchers can engineer the virus to be less recognizable to the immune system, reducing the risk of a severe immune response
  Gene Therapy and Immune Response
• Strategies to prevent hyperactive immune response: 
  • Use a novel virus that won’t raise a brisk immune response
  • Give gene therapy in small doses (hyperfractionation)
• CAR T‑cells: a special example of gene therapy 
  • Extract T‑cells from a cancer patient
  • Use gene therapy to weaponize T‑cells to attack cancer cells
  • Reinject weaponized T‑cells into the patient
  • Successful in blood cancers like lymphoma, leukemia, and myeloma
  • Not as successful in solid tumors

Reducing the Cost of CAR T‑cell Therapy

• Reasons for high cost in the United States: 
  • High failure rate of drugs, pharmaceutical companies recoup R&D costs
  • CAR T‑cells are intrinsically expensive to make
  • Quality control and sterile environment required for production
• Cost reduction strategies in India: 
  • Cheaper virus production
  • Reduced patent burden
  • Changed machinery and cell harvesting methods
  • Lower hospital treatment and therapy costs

Gene Therapy for Sickle Cell Anemia

• Three approaches to gene therapy for sickle cell anemia: 
  1. Express the corrected version of the Betaglobin gene
  2. Use gene editing technology (e.g., CRISPR) to change the gene back to its normal form
  3. Reactivate fetal hemoglobin in adults to correct the hemoglobin defect
• All three approaches are in trials and have shown various measures of success

CRISPR and Genetic Revolution

• CRISPR allows for precise changes in the human genome 
  • Discovered by Jennifer Doudna, Emmanuelle Charpentier, Feng Zhang, George Church, and others
  • Derived from a bacterial system evolved millions of years ago
  • Can delete or change specific words in the “library” of the human genome
  • Has the potential to revolutionize gene therapy and genetic editing
    Gene Editing and Ethical Considerations
• CRISPR technology allows for precise gene editing 
  • Can change specific genes to their normal or wild type versions
  • Can be done with embryonic cells, stem cells, bone marrow cells, and T cells
• Distinction between disease and desire 
  • Disease is linked to human suffering
  • Desire is the aspiration to ameliorate suffering, even when there’s no suffering involved
• Controversial case of Chinese scientist He Jiankui 
  • Edited embryos to make them HIV-​​resistant, even though they had no risk of HIV infection
  • Raised ethical concerns about informed consent and the necessity of the procedure
• Drawing the line between ethical and unethical gene editing 
  • Huntington’s disease: high penetrance, devastating effects, altering embryos could be seen as ethical
  • APOE4 gene: risk factor for Alzheimer’s disease, but not as penetrant as Huntington’s, raises questions about where to draw the line
• Balancing the potential benefits of gene editing with ethical considerations and potential risks
  Biomedical Community on Genetic Editing
• Genetic editing raises ethical questions on disease vs. desire 
  • Enhancing intelligence or physical traits falls under desire
• Mental health is a complex area for genetic editing 
  • Autism and schizophrenia have genetic components
  • Simplifying these conditions could have unintended consequences

Genes and Mental Health

• Two types of genes related to mental health: 
  • Shove genes: strongly push towards a specific outcome (e.g., Marfan syndrome)
  • Nudge genes: small influences that accumulate (e.g., height)
• Most mental illnesses are influenced by nudge genes 
  • Difficult to change hundreds or thousands of genes at once

Complexity of the Brain

• Two types of problems in science: 
  • Eye in the sandstorm: a paradigm shift is needed to understand a phenomenon
  • Sand in the eye: a single fact doesn’t fit the current understanding
• Neuronal transmission is a sand in the eye problem 
  • Neurons have spaces between them called synapses
  • Electrical conduction changes to chemical signals between neurons
  • Allows for weighting and modulation of signals
  • Analogous to neural networks in computing

Neural Networks and Learning

• Neural networks assign weights to different layers of communication 
  • Allows for discrimination between different inputs (e.g., dogs vs. cats)
• Brain’s electrical-​​chemical-​​electrical signal conversion allows for learning and processing 
  • If the brain were only electrical signals, it would be a “box of wires” without learning capabilities
• Understanding of this process is still developing in the field of science
  Digital vs. Analog Processes in the Brain
• Digital: completely on or completely off, no modulation
• Analog: modulation of sound, crescendo and decrescendo, more complex and dynamic
• Evolution figured out the importance of modulation in the brain 
  • Music analogy: tempo, pace, loudness, softness, rhythm
  • Produces a mature output of the score, the “music of the cell” and the brain

Learning in the Lab vs. Textbook Knowledge

• Textbook knowledge lays the groundwork and foundation, but has limitations
• Learning in the lab involves: 
  • Troubleshooting and problem-solving
  • Recognizing failure and learning from it
  • Gaining experience and knowledge from peers
  • Practical application of knowledge in clinical trials and experiments
• Lab learning is essential for understanding the complexities of medicine and biology

Writing Process and Style

• Writing is a way to think and work through thoughts
• Use of analogies, metaphors, and various sources (history, mythology, philosophy, conversations, interviews) to create a unique and personal style
• Breaking down barriers between different genres of writing (memoir, case histories, deep history, journalistic writing)
• Goal is to show readers the author’s world and experiences, both the highs and lows

End of Life and Falls

• Connection between falls in older individuals and the end of life
• Author’s father and Virtuo both died as a result of falls and subsequent complications
• Falls are the leading cause of accidental death in older individuals
• Importance of considering and addressing this issue in medicine and healthcare
  Mortality and Cellular Processes
• Mortality in older individuals can result from falls and broken bones 
  • Example: A person over 65 who falls and breaks their femur has a 10–30% mortality rate at 12 months
• Cellular processes play a role in these situations 
  • Osteoclasts, osteoblasts, and the matrix of the hip contribute to organ failure
  • The body is a “citizenship” where different parts depend on each other
  • Example: If the Department of Transportation shuts down, it can lead to a chain reaction of negative consequences

Depression and Mental Disorders

• Depression is often viewed differently from other medical conditions 
  • People may associate victimhood with mental disorders
  • This can lead to blaming the victim for their condition
• The brain is an organ with physiology, like other organs in the body 
  • Depression can be seen as a dysfunction of mood-​​regulating neurons in the brain
  • This is similar to how type 1 diabetes is a dysfunction of insulin-​​regulating cells in the pancreas
• The goal is to challenge the idea of victimhood and responsibility in mental disorders

Diagnosing and Treating Mental Disorders

• Psychiatry currently lacks biomarkers and radiographic findings for diagnosis 
  • This makes diagnosing mental disorders more challenging than diagnosing physical conditions
• However, clinical decisions can still be made based on observation and experience 
  • When a person is clinically depressed, there is a clear dysfunction in their neural circuits that regulate mood
• There is potential for new therapies and treatments for mental disorders 
  • These could include alterations in diet, medicines, and electrical stimulation

Future Discussions

• Topics for future discussions include the immune system, epigenetics, cellular reprogramming, and the culture of antiscience 
  • These topics require more in-​​depth exploration and discussion