podcast Peter Attia 2023-02-27 topics

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

Audio

Show notes

Siddhartha Mukherjee is an oncologist, Pulitzer Prize-winning author, and previous guest on The Drive. In this episode, Sid discusses many of the subjects of his latest book, The Song of the Cell , including the incredible discovery of the cell and how it transformed medicine. He explains the evolutionary drive to go from single-cell to multicellular life and unpacks the four different types of cell-based therapies and the problems they are attempting to solve. He also provides the latest in gene therapy, such as CRISPR, and the ethical questions around human gene editing. Additionally, he touches on a number of fascinating topics, such as the challenges of medical science, the human brain, learning styles, his writing process, mental health, and more.

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We discuss:

How the cell brings the genome to life, and how Sid’s recent book fits into his prior work to tell a story [2:30];
How the germ theory of disease and an understanding of the cell fueled a big leap in medicine [9:45];
What is the evolutionary drive for multicellular life? [17:15];
Four types of cell therapies and the challenges of gene therapy [26:00];
CAR T-cell therapy: promising gene therapy for cancer [36:30];
The possibility of using gene therapy to treat germline mutations like sickle cell disease [41:45];
The incredible revolution of gene editing with CRISPR [45:15];
Ethical questions around human gene editing [52:30];
The complex role of genetics in mental illness [1:01:30];
Two types of problems in science: the “eye in the sandstorm” problem and the “sand in the eye” problem [1:06:15];
Understanding neural networks: an example of the “sand in the eye” problem being solved [1:08:45];
Importance of learning by doing: comparing the learning styles of a doctoral student to a medical student [1:16:30];
Sid’s unique and brilliant style of writing [1:20:45];
Falling as the leading cause of accidental death: a liability of multicellular existence [1:25:00];
Sid’s struggle with depression and his desire to change the stigma around mental illness [1:29:15]; and
More.

Show Notes

*Notes from intro :

Siddhartha Mukherjee was a previous guest on episode #32 (December 2018)
Siddhartha is a cancer researcher and a practicing oncologist He’s an Assistant Professor of Medicine at Columbia University and a staff cancer physician at the Columbia University NYU Presbyterian Hospital
He also happens to be a luminary author; he’s written four books The Emperor of All Maladies The Laws of Medicine The Gene The Song of the Cell, an Exploration of Medicine and The New Human , his most recent book
In the first podcast with Sid , we mostly discussed The Emperor of All Maladies: the Biography of Cancer A book that won him the Pulitzer Prize
In this podcast, we primarily discuss his most recent book, The Song of the Cell
This is a book that Peter just devoured He wouldn’t have thought he could find a book about the history of the cell so interesting
In this episode we talk about everything from the evolutionary drive to go from single cell to multicell organisms, all the way up to cell therapy, gene therapy, and CRISPR
We talk a lot about Siddhartha’s writing process, given that he’s such a prolific writer
We talk about some very personal things, including his decision to open up about his own depression in his writing
He’s an Assistant Professor of Medicine at Columbia University and a staff cancer physician at the Columbia University NYU Presbyterian Hospital
The Emperor of All Maladies
The Laws of Medicine
The Gene
The Song of the Cell, an Exploration of Medicine and The New Human , his most recent book
A book that won him the Pulitzer Prize
He wouldn’t have thought he could find a book about the history of the cell so interesting

How the cell brings the genome to life, and how Sid’s recent book fits into his prior work to tell a story [2:30]

Give us a sense of where your most recent book fits into your prior work

The Song of the Cell is part of a trilogy and possibly a quartet that Siddharthais working on, broadly called “The Life Series”
The attempts of these books is to try to explain and understand how we understand life and how we’re manipulating life, living things (particularly humans)
The first book was The Emperor of all Maladies, the second, The Gene , and now The Song of the Cell
The best place to probably start is with The Gene The gene being the smallest unit of information As you end The Gene , you realize that genes which are encoded in the molecule DNA, are lifeless They don’t have any autonomous life A gene is just a molecule, it’s a chemical, and it’s the cell that brings it to life Without the cell, all of that code would be useless
The gene being the smallest unit of information
As you end The Gene , you realize that genes which are encoded in the molecule DNA, are lifeless They don’t have any autonomous life A gene is just a molecule, it’s a chemical, and it’s the cell that brings it to life Without the cell, all of that code would be useless
They don’t have any autonomous life
A gene is just a molecule, it’s a chemical, and it’s the cell that brings it to life
Without the cell, all of that code would be useless

“ I likened the human genome (or any genome) to a score of music, but a score is lifeless. There’s no music in a score, it’s just a code. You need a musician to bring it to life, and the cell is that musician. ”‒ Siddhartha Mukherjee

There’s no music in a score, it’s just a code
You need a musician to bring it to life, and the cell is that musician Hence the title of the book, the Song of the Cell
The second book, to some extent is The Song of the Cell , and then the third book, bizarrely enough, is the first book ( The Emperor of All Maladies ) It’s sort of like Star Wars, the prequel to the sequel to the prequel Where you learn about what happens when cells become average
Hence the title of the book, the Song of the Cell
It’s sort of like Star Wars, the prequel to the sequel to the prequel
Where you learn about what happens when cells become average

One way to read the series of books‒ start with The Gene , move on to The Song of the Cell , and finally end up with the dysfunctional average cell, and what happens to it when its genes go haywire ( The Emperor of All Maladies )

A completely different way would be to read them as they appeared They progressively go downwards and delve deeper and deeper into mysteries of that history
The first book was of course a history of cancer and cancer therapy.
What did we not understand about cancer? Obviously genes and genetics
What did we not understand about cancer in terms of its cell biology when the cancer genome atlas was completed?
And what do we understand now?
They progressively go downwards and delve deeper and deeper into mysteries of that history

If you read chronologically from the first to the third, you would get a different kind of story

In The Song of the Cell , that era of science had fewer tools and their discoveries are mind blowing

This might be tainted by a bit of recency bias because Peter read the books in chronological order, and he just finished reading The Song of the Cell (which he enjoyed immensely) He felt more surprised and in awe of the characters in this book than the previous books Peter notes, “ The characters of this story blew my mind even more because of the time and the era in which they had to do their science. There were fewer tools at their disposal. ”
The characters of that book are uncovering things that are very fundamental
If you were to do a historical comparison with the history of genetics, you would start with Gregor Mendel (being the pioneer here)
There is an enormous period of silence that follows Mendel (almost 40 years) in which basically nothing happens
Then his work is ultimately picked up by folks like Thomas Morgan and others
But for a long period of time, nothing happens and nothing is relevant
He felt more surprised and in awe of the characters in this book than the previous books
Peter notes, “ The characters of this story blew my mind even more because of the time and the era in which they had to do their science. There were fewer tools at their disposal. ”

What you see in this book is very different because you see a continuation of development

After the microscope is invented in the 17th century, you see a gradual blossoming of science
Ultimately ending up with someone like Rudolph Virchow , who can make really audacious statements that are missing in the history of genetics until much later The audacious statement that Virchow makes is every function that we carry out, regardless of its origin or regardless of what that function is, is a consequence of cellular physiology “ We, our cells and everything that we do is cellular, is a consequence of something happening in some cell. ” Other statements he says (which are equally audacious), “ Every illness is the consequence of some cell behaving incorrectly ” These statements are made in the mid to late 19th century, almost contemporaneous with Mendel
The audacious statement that Virchow makes is every function that we carry out, regardless of its origin or regardless of what that function is, is a consequence of cellular physiology
“ We, our cells and everything that we do is cellular, is a consequence of something happening in some cell. ”
Other statements he says (which are equally audacious), “ Every illness is the consequence of some cell behaving incorrectly ”
These statements are made in the mid to late 19th century, almost contemporaneous with Mendel

You have enormous sets of leaps in cell biology, which is why this book might feel that these characters are doing things while genetics is still plotting its way, trying to understand Mendel’s first very important paper; and there’s a remarkable 40 years of silence, whereas in cell biology, there isn’t that 40 years of silence

Peter thinks we take for granted the ingenuity that was necessary to even build the tool to permit their discoveries What the process is like to put together a microscope, to grind the glass and create the lens to give a window into this otherwise invisible/microscopic world
Siddhartha tried to make make one of Leeuwenhoek’s microscopes, and it was not an easy task; it was a disaster And Leeuwenhoek made 500 of them These are single lens microscopes, and they are about the size of half a sheet of paper The lens is smaller than the size of your eyeball There is a sense of the enormous amount of labor of love put into making this thing that’s mounted with tiny screws and tiny little apertures, so that when you look through your eye through the lens in a droplet of water, you can actually see these microscopic forms
What the process is like to put together a microscope, to grind the glass and create the lens to give a window into this otherwise invisible/microscopic world
And Leeuwenhoek made 500 of them
These are single lens microscopes, and they are about the size of half a sheet of paper
The lens is smaller than the size of your eyeball
There is a sense of the enormous amount of labor of love put into making this thing that’s mounted with tiny screws and tiny little apertures, so that when you look through your eye through the lens in a droplet of water, you can actually see these microscopic forms

There’s an enormous sense of wonder about how people even began to see these and how they found them and what the consequences of that finding were and are

How the germ theory of disease and an understanding of the cell fueled a big leap in medicine [9:45]

In Peter’s book (which Siddharthaha has read), he talks about this transition from medicine 1.0 to medicine 2.0 (and then the transition from 2.0 to 3.0) He talks about that first transition as two big events, but they were really transition of process 1 – The Scientific Revolution changed the way we thought The scientific method was introduced in the late 15th century This was a new way of thinking about observation and hypothesis All of the sudden, the idea of bad humors went away 2 – The Germ Theory of Disease was the big moment Once we understood microbial agents and that we had a treatment, we really leapfrogged into the era of modern medicine There has been no bigger reduction in human mortality, than the reduction of death that comes from infectious diseases
What Peter never thought of until he read The Song of the Cell, was that couldn’t have happened without this deep understanding of the cell
He talks about that first transition as two big events, but they were really transition of process
1 – The Scientific Revolution changed the way we thought The scientific method was introduced in the late 15th century This was a new way of thinking about observation and hypothesis All of the sudden, the idea of bad humors went away
2 – The Germ Theory of Disease was the big moment Once we understood microbial agents and that we had a treatment, we really leapfrogged into the era of modern medicine There has been no bigger reduction in human mortality, than the reduction of death that comes from infectious diseases
The scientific method was introduced in the late 15th century
This was a new way of thinking about observation and hypothesis
All of the sudden, the idea of bad humors went away
Once we understood microbial agents and that we had a treatment, we really leapfrogged into the era of modern medicine
There has been no bigger reduction in human mortality, than the reduction of death that comes from infectious diseases

“ This book describes how medicine went from effectively witchcraft, into where we are today ”‒ Peter Attia

Siddhartha agrees; think of any procedure, childbirth, any surgical procedure, anything that we do, and think of the effect of antibiotics on that procedure Think of how important it is that these antibiotics are now available and the lives saved Just childbirth alone, the capacity of saving lives through antibiotics, has been enormous and transformative
What’s astonishing in the piece that Siddhartha wrote about microbial biology and the discovery of microbes, is that microbes were imagined in the abstract, long before they were seen
What’s interesting is, people like Lister (the great surgeon who began to sterilize his instruments), folks like Semmelweis discovered that doctors were transmitting microbes
Think of how important it is that these antibiotics are now available and the lives saved
Just childbirth alone, the capacity of saving lives through antibiotics, has been enormous and transformative

The story of Semmelweis

Siddhartha writes about it in his book, and Peter writes about it in his book
It breaks Peter’s heart when someone dies without getting what they are due, and Semmelweis is the heartbreaking example of that
It’s also a remarkable story of this transition
Semmelweis was a junior obstetrician in Vienna
It’s important that he was so junior, and he made an incredibly important discovery
Semmelweis was delivering children, and there were two maternity wards (ward I and ward II)
This illustrates why it is important in medicine to listen to your patients
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? ” And it’s the one we forget the most
A bizarre aberration was going on‒ in ward I, the maternal mortality rates from childbirth were astronomically high; whereas in ward II, with the same people, the maternal mortality rates were much lower One in five women were dying in ward I
Semmelweis began to ask the question why ?
He looked at all sorts of variables; he was a classical epidemiologist
He found that ward I was run by doctors, and these doctors were running between autopsy rooms (doing autopsies) and then without cleaning their hands, examining patients and delivering babies
Ward II was run by nurses; nurses who were not doing autopsies or touching any dead material And there was no mortality
Semmelweis made the hypothesis that doctors were transferring (in his words), “ some material substance from the decaying, decomposing dead bodies that they had autopsied, into the bodies of the women that they were examining internally and thereby transmitting that material substance. And that material substance was the source of the putrefaction (or the infection) that these women were getting. ”
Semmelweis insisted that the doctors wash their hands with a diluted version of bleach, and he saw that suddenly now the mortality rate plummeted
Remember, he didn’t have a microscope; so this is all in the abstract
He made this argument that this material substance was responsible for what was then called Childbirth Fever (or maternal infections), and the transfer of the material substance could be removed by hand washing
In the abstract sense, he had basically founded the Germ Theory
It was not bad air, it was not bad humors, it was a material substance
And of course, if he had the capacity to look down the microscope, he would’ve found out that that material substance was in fact nothing else but germs
He is ridiculed, the last thing that the doctors want to do is to admit that they’ve been infecting other women
Semmelweis is ridiculed and he’s sent off to an insane asylum, and ultimately he dies impoverished and never vindicated
And it’s the one we forget the most
One in five women were dying in ward I
And there was no mortality

Advances in medicine

What really captivated Peter about the book is all that we take for granted in medicine is what really allowed this leapfrog, far more so than the genetic revolution
We thought once the human genome was coded, we would get an equal leapfrog forward, but this didn’t happen

What is the evolutionary drive for multicellular life? [17:15]

This is a question Peter had never contemplated until he read this book

Consider first, single cell organisms

Bacteria, protozoa, yeast, etc.
They’re extraordinarily successful
They live in virtually every environment you can think of Boiling water, thermal vents, inside volcanoes
Boiling water, thermal vents, inside volcanoes

“ The bizarre question you should ask is, ‘why we exist at all?’ ”‒ Siddhartha Mukherjee

We have trillions of cells, why do we exist? Why aren’t we all bacteria?
The initial idea in the ‘80s, was that there was a massive evolutionary leak from single cell organisms to multicellular organisms
What is surprising in evolutionary history is, that multicellularity evolved from single cell organisms, not once, but independently multiple times It used to be called a major transition It actually turns out to be a minor transition There was a great evolutionary drive towards becoming multicellular
You can ask the question then, if single cell organisms are so damn successful, why ever be a multicellular organism? The quick answer is, we don’t know But all the evidence suggests that it has to do with several possibilities The leading possibility is predation; it’s much harder for a predator to eat a multicellular organism for several reasons. It’s bigger It has defense systems It can move away through specialized apparati The other idea is about how multicellular organisms can access food and resources
It used to be called a major transition
It actually turns out to be a minor transition
There was a great evolutionary drive towards becoming multicellular
The quick answer is, we don’t know
But all the evidence suggests that it has to do with several possibilities
The leading possibility is predation; it’s much harder for a predator to eat a multicellular organism for several reasons. It’s bigger It has defense systems It can move away through specialized apparati
The other idea is about how multicellular organisms can access food and resources
It’s bigger
It has defense systems
It can move away through specialized apparati

Single cell organisms are still the champions. We are just a minor fixture in the world. If you took by weight all the single cell organisms in the world and their diversity, you would be shocked at how successful they still are.

Ratcliff’s experiments with yeast

William Ratcliff is a professor who studies this evolutionary transition from single cell to multicellular organisms
He did an extraordinary simple experiment with yeast , that he just thought about it over Christmas with his advisor
He said, “ Well, why don’t we just take some yeast and culture them, and we basically allow them to grow, and we just collect the sediment, and we allow that sediment to grow again in another cycle of evolution. ” Remember that yeast are single cell organisms, and anything multicellular is going to sink to the bottom of the flask This is sort of Darwin in a bottle He did this for 30-40 cycles and found that the yeast evolved
There are pictures in Siddhartha’s book of these multicellular yeast, these snowflake-like, multi-fingered, multicellular forms (really a new organism)
What is interesting is when they are left by themselves (no more recollection, no more sedimentation), they continue to propagate as multicellular yeast
Remember that yeast are single cell organisms, and anything multicellular is going to sink to the bottom of the flask
This is sort of Darwin in a bottle
He did this for 30-40 cycles and found that the yeast evolved

In other words, he created a new lifeform, which is multicellular

Even more interesting is when he looked at these multicellular yeast, they started to acquire specialized functions
You would imagine that one way that these multicellular yeast would reproduce, is that one cell could bud off and create a new multi-fingered, multicellular yeast But that’s not how they reproduce Instead, they use a specialized series of cells that sit in the middle of this snowflake , and commit a purposeful cellular death, such that this snowflake can break into two parts, two snowflakes and grow out new fingers
From an evolutionary standpoint, this organism learned how to create a specialized furrow in its middle where it can divide into two forms
Ratcliff has done many versions of this experiment (with algae and other organisms)
But that’s not how they reproduce
Instead, they use a specialized series of cells that sit in the middle of this snowflake , and commit a purposeful cellular death, such that this snowflake can break into two parts, two snowflakes and grow out new fingers

He finds there are even more specializations. These new “creatures” form little channels to deliver nutrients. They form pores, secondary structures… He created a new kind of life by doing nothing, just by allowing it to evolve naturally.

This involved just 30-40 cycles; maybe 60-90 days
You can imagine over the course of several billion years of history, the extraordinary amount of diversity and specialization that could happen in evolution that leads to people like you and me, having trillions of cells, very committed to doing one thing or another
Peter thinks about his boys who are 5 and 8, and are obsessed with dinosaurs; for them paleontologists are the most important people in the world
Peter wonders when he watches these recreations of what dinosaurs looked like, “ How did evolution allow something so large to be in existence so many millions of years ago? And are we basically seeing a correction now? ” Did the pendulum swing too far towards multicellularity where creatures can really defend themselves, get away, go after prey, but are too sensitive to a reduction in food or something like that Had it not been for volcanic eruptions and things like that, maybe we wouldn’t be here today and dinosaurs would be the sentient higher order creature
Siddhartha replies that this is a “ little bit outside my paygrade… but there are lots of theories ” We know that these life forms were very successful in their environment The problem was that they reached a maximal capacity of size and smaller mammal-like creatures became much more adaptable to the environment But there are a thousand theories about dinosaur extinction, including changes in the atmosphere, meteors and various other volcanoes and events, which you can read in most paleontology textbooks
When Peter was reading the part about the fitness of the cell, he wondered if there was something about their size that became their downfall, beyond the obvious external factors
There is an essay by Steven Jay Gould where he talks about a natural biophysical limitation on size That’s because the volume to surface area ratio of any creature reaches a place where it is no longer sustainable Because the surface area of a creature is no longer able to deliver the oxygen and the nutrients required for aerobic living
Did the pendulum swing too far towards multicellularity where creatures can really defend themselves, get away, go after prey, but are too sensitive to a reduction in food or something like that
Had it not been for volcanic eruptions and things like that, maybe we wouldn’t be here today and dinosaurs would be the sentient higher order creature
We know that these life forms were very successful in their environment
The problem was that they reached a maximal capacity of size and smaller mammal-like creatures became much more adaptable to the environment
But there are a thousand theories about dinosaur extinction, including changes in the atmosphere, meteors and various other volcanoes and events, which you can read in most paleontology textbooks
That’s because the volume to surface area ratio of any creature reaches a place where it is no longer sustainable
Because the surface area of a creature is no longer able to deliver the oxygen and the nutrients required for aerobic living

Four types of cell therapies, and the challenges of gene therapy [26:00]

Four types of cellular therapy

1 – A drug or substance used to change the behavior of a cell The simplest example is an antibiotic; it’s used to kill a microbial cell while sparing human cells
2 – Transfer of cells from one body to another without modification For example, a blood transfusion
3 – Use of a cell to synthesize something DNA is a lifeless molecule, but if you put it inside the right cell, in the right context, the cell will start making proteins out of DNA, and those proteins could be very useful An example is how insulin is made from cells Another example, Herceptin is an antibody made by cells and used to treat breast cancer
4 – Make a genetic modification in a cell and either transplant it or use if for a therapeutic reason For example, CAR T-cells are an example of genetically modifying T cells and putting them into a human
The simplest example is an antibiotic; it’s used to kill a microbial cell while sparing human cells
For example, a blood transfusion
DNA is a lifeless molecule, but if you put it inside the right cell, in the right context, the cell will start making proteins out of DNA, and those proteins could be very useful
An example is how insulin is made from cells
Another example, Herceptin is an antibody made by cells and used to treat breast cancer
For example, CAR T-cells are an example of genetically modifying T cells and putting them into a human

Siddhartha’s experiments on bone marrow transplants is an example of this fourth typology

Siddhartha has been doing a series of experiments on bone marrow transplants in which they genetically modify the bone marrow (using CRISPR and other techniques), and then transfer them into humans This is essentially creating genetically engineered cells
This is essentially creating genetically engineered cells

“ Gene therapy is really cell therapy ”‒ Siddhartha Mukherjee

People often talk about gene therapy, and Siddhartha always reminds them that gene therapy is really cell therapy
If you put the gene in the wrong cell in the wrong place or the wrong time, you get nothing/ disaster
Gene therapy is really a mechanism to put a gene inside a cell, and that would be the fourth typology
The book goes through elements of these four typologies, examples, and elements of these four typologies as medicines

The story of Jesse Gelsinger

Jesse Gelsinger (and 18-year-old in 1999) is one of the earliest example of gene therapy in a human
Jesse had genetic disease where he had a defect in an enzyme related to the processing of ammonia and ammonia-related substances
This work was done at the University of Pennsylvania
The idea was to create a virus that would go to Jesse’s liver and start making the correct version of the gene; that this would ameliorate his disease
They created a virus they thought would be harmless (a variant of an adenovirus), and they modified it to include the corrected version of the gene Jesse had a problem with
They infused that virus into Jesse’s body hoping it would infect cells and deliver it’s cargo (the corrected gene), and thereby correct Jesse’s disease
Peter clarifies‒ we don’t consider viruses in the same category as bacteria, yeast, and fungi
He asks, “ Are they not living things on their own? They basically contain DNA and RNA, but they’re sort of parasites in that they need us to replicate. ”
Siddhartha agrees, “ Viruses don’t meet the criteria of living things. ” They are essentially a strand/ multiple strands of RNA (or DNA) that have been packaged usually with an envelope and decorated with some proteins on top By themselves, they can’t reproduce, which is one of the reasons that they’re not considered living The only way they can reproduce is they go and attach themselves to cells, and use the reproduction apparatus present in the cell to make copies of themselves Once they’ve made copies of themselves, they butt out of the cell and then they go in and infect more cells and make more copies of themselves and so forth
In Jesse Gelsinger’s case, the idea was that this virus would infect his cells And because the virus was genetically modified, it would insert its genetic payload, (the normal gene) into Jesse’s liver cells The liver cells would now start making the protein that was defective, and this is gene therapy. In doing so, it would reverse his relatively mild disease
A rather terrible thing happened
Siddhartha has a very moving testimony from his father, which is in The Gene
In retrospect, we think that Jesse mounted a very vigorous immune response to the virus A virus is a foreign body, and you mount an immune response to it, especially if you for whatever reason, have been exposed to that virus before Adenovirus can cause the common cold; they are in circulation There is suspicion that Jesse had been exposed to the wild form of that virus before (perhaps through a common cold or something like that), and his immune system went berserk, because it was now recognizing not one virus particle, but millions of particles suddenly into his body
They are essentially a strand/ multiple strands of RNA (or DNA) that have been packaged usually with an envelope and decorated with some proteins on top
By themselves, they can’t reproduce, which is one of the reasons that they’re not considered living
The only way they can reproduce is they go and attach themselves to cells, and use the reproduction apparatus present in the cell to make copies of themselves
Once they’ve made copies of themselves, they butt out of the cell and then they go in and infect more cells and make more copies of themselves and so forth
And because the virus was genetically modified, it would insert its genetic payload, (the normal gene) into Jesse’s liver cells
The liver cells would now start making the protein that was defective, and this is gene therapy.
In doing so, it would reverse his relatively mild disease
A virus is a foreign body, and you mount an immune response to it, especially if you for whatever reason, have been exposed to that virus before
Adenovirus can cause the common cold; they are in circulation
There is suspicion that Jesse had been exposed to the wild form of that virus before (perhaps through a common cold or something like that), and his immune system went berserk, because it was now recognizing not one virus particle, but millions of particles suddenly into his body

Unfortunately, Jesse died from the consequences of this very hyperactive risk immune response raised against that virus and, the whole field of gene therapy was frozen for almost a decade as we slowly learned the cause of that death and how we could prevent it in other people

What is a safer place to consider using gene therapy?

There are safe harbors in the body; these are places that the immune system doesn’t usually reach easily For example, the retina The testes is another place, although we have not used that for gene therapy
There are also new drugs that can dampen down the immune response Think of the immune response as a dial What you can do is you can dial the immune response down so that the immune response doesn’t respond so briskly to the gene therapy
You can hide the virus; you can make a virus that your body has not seen before, that won’t raise a brisk immune response
You can do is you can give the gene therapy in small doses It’s called hyperfractionation Fractionation being small fractions so that the immune system doesn’t again go berserk seeing this massive bolus of a dose of virus
These strategies they’ve been very successful such that now, the number of deaths from this hyperactive immune response are much, much, much more controlled than in Jesse Gelsinger’s times (but the possibility of this remains)
For example, the retina
The testes is another place, although we have not used that for gene therapy
Think of the immune response as a dial
What you can do is you can dial the immune response down so that the immune response doesn’t respond so briskly to the gene therapy
It’s called hyperfractionation
Fractionation being small fractions so that the immune system doesn’t again go berserk seeing this massive bolus of a dose of virus

CAR T-cell therapy: promising gene therapy for cancer [36:30]

CAR T-cells are one of the great successes of cancer treatment, explain how gene therapy works in that regard

CAR T-cells are a very special example of gene therapy
What happens is you extract normal T cells from a human who has cancer, and you use gene therapy to weaponize the T cell so that they can attack cancer cells A T cell is part of the immune system; its job is to hunt out and kill foreign cells Cells that have been infected by viruses, or foreign cells that have somehow entered the body. A T cell is a foreign cell detector built into your body So now you take that T cell and weaponize it to recognize the cancer cells as foreign, you grow them in a Petri dish in the laboratory, and you re-inject them into the body
Siddhartha’s lab has done a lot of this work Siddhartha co-founded the startup Immuneel to reduce the cost of CAR T-cell therapy in India
The cost of doing this in the US is astronomical, almost $500,000 to $1 million per person
They are trying to reduce that cost 20-fold (or even 50-fold) in India using new technologies
They’ve treated 11-12 patients already and just released the data , and it looks very good
CAR T-cell therapy is used to treat blood cancers like lymphoma, leukemia, and myeloma
It has not been successful in treating solid tumors, for reasons that we’re still trying to understand
A T cell is part of the immune system; its job is to hunt out and kill foreign cells Cells that have been infected by viruses, or foreign cells that have somehow entered the body. A T cell is a foreign cell detector built into your body
So now you take that T cell and weaponize it to recognize the cancer cells as foreign, you grow them in a Petri dish in the laboratory, and you re-inject them into the body
Cells that have been infected by viruses, or foreign cells that have somehow entered the body.
A T cell is a foreign cell detector built into your body
Siddhartha co-founded the startup Immuneel to reduce the cost of CAR T-cell therapy in India

“ That’s what a CAR T-cell is. It’s a weaponized T-cell that goes and kills cancer cells in your body. ”‒ Siddhartha Mukherjee

Why is there a 20-50-fold reduction in cost doing this in India as opposed to the US?

Peter notes that cancer is full of marginal treatments that extend median survival by two months, at a cost of $100,000
Siddhartha explains that some of it is a structural problem in America
90% of drugs fail, and pharmaceutical companies make the argument that they’re trying to recoup the R&D costs of those failed drugs with the successful That’s a complicated and somewhat specious argument because you could ask, “ Why do these drugs fail in the first place? Is it because drugs always fail? Is it because you didn’t understand something about the human body before you therefore took this drug all the way to spend millions, perhaps even billions of dollars on the drug? ”
The second reason is that CAR T-cells are intrinsically expensive to make
The success rates of CAR T-cells are incredible, not just 1-2 month survival
Siddhartha’s book begins with the story of Emily Whitehead She was seven when she was treated with CAR T therapy Now she is 16-17, applying to college, completely cured
That’s a complicated and somewhat specious argument because you could ask, “ Why do these drugs fail in the first place? Is it because drugs always fail? Is it because you didn’t understand something about the human body before you therefore took this drug all the way to spend millions, perhaps even billions of dollars on the drug? ”
She was seven when she was treated with CAR T therapy
Now she is 16-17, applying to college, completely cured

“ We’ve seen people who’ve had terrible leukemia [and CAR T-cell therapy] essentially eradicate the leukemia forever and [they] become cured ”‒ Siddhartha Mukherjee

The problem is that CAR T cells are intrinsically hard to make The quality control that’s required is much, much greater than making aspirin or making any other tablet You have to grow T cells in an incredibly sterile environment (GMP facility) where you have to basically put on a hazmat suit to go in It has to be monitored because a single bacteria or a fungal infection will take that entire batch of T cells away
The quality control that’s required is much, much greater than making aspirin or making any other tablet
You have to grow T cells in an incredibly sterile environment (GMP facility) where you have to basically put on a hazmat suit to go in It has to be monitored because a single bacteria or a fungal infection will take that entire batch of T cells away
It has to be monitored because a single bacteria or a fungal infection will take that entire batch of T cells away

They reduce the cost several ways

1 – They make the virus in a much cheaper way (reduced the cost of the patent burden) They don’t have to recoup all that R&D cost
2 – They’ve changed the machinery used to harvest the cells
3 – Hospital treatment and therapy in India is much cheaper to begin with
They don’t have to recoup all that R&D cost

All of this comes to a 10-20-fold reduction in cost

The possibility of using gene therapy to treat germline mutations like sickle cell disease [41:45]

Are we in the realm of approaching success here?

A person with a germline mutation that results in pathology (like Jesse) is much harder to treat
Sickle cell is an amazing example because a single amino acid difference has such catastrophic consequences on the life of a person We know exactly what gene drives that A mutation in the hemoglobin gene ( Hb ) , the oxygen carrier in the blood Sickle cell is caused by a mutation in the HbA gene, known as HbS If you inherit two copies of the mutation, you get terrible disease In a low oxygen environment the red blood cells form sickles (shown in the figure below) and clog up small blood vessels all over the body (micro strokes) This causes terrible pain
We know exactly what gene drives that A mutation in the hemoglobin gene ( Hb ) , the oxygen carrier in the blood Sickle cell is caused by a mutation in the HbA gene, known as HbS
If you inherit two copies of the mutation, you get terrible disease
In a low oxygen environment the red blood cells form sickles (shown in the figure below) and clog up small blood vessels all over the body (micro strokes) This causes terrible pain
A mutation in the hemoglobin gene ( Hb ) , the oxygen carrier in the blood
Sickle cell is caused by a mutation in the HbA gene, known as HbS
This causes terrible pain

Figure 1. Altered blood shape in sickle cell disease clogs blood vessels. Image credit JAMA 2023

Fantastic new results in sickle cell anemia have been published in very major journals and will continue to get published (reviewed in Blood 2021 )
Two or three approaches have been tried to use gene therapy to fix the mutated gene (illustrated in the figure below)
1 – Gene therapy to introduce the normal version of hemoglobin ( HbA )
2 – Gene editing technology has been used to change both copies of the gene to make them normal Take a bone marrow sample (where blood cells are made), change the gene from the abnormal form to the normal form, then reinfuse that back into the patient This is the gene correction strategy
Take a bone marrow sample (where blood cells are made), change the gene from the abnormal form to the normal form, then reinfuse that back into the patient
This is the gene correction strategy

Figure 2. Gene therapy for sickle cell disease . (A) Antisickling globin expression as a gene-therapy strategy to prevent RBC sickling. (B) Gene-addition strategy to deliver antisickling genes. (C) Gene-editing approaches to induce HbF . Image credit: Blood 2021

3 – Another strategy involves fetal hemoglobin ( HbF ) The human fetus has a special kind of hemoglobin (different from adult hemoglobin) because the fetus has to extract oxygen from mom’s blood And mom’s blood, by the time it reaches the fetus, has already been depleted of oxygen because it’s gone through her body The fetus has a special form of hemoglobin that can even extract oxygen out of mom’s blood Another approach to sickle cell anemia is to forget about the sickle gene problem and reactivate/ express/ make fetal hemoglobin in an adult In that case, you don’t need to correct the gene, you leave the gene as it is You just make fetal hemoglobin, which is very, very avid as an oxygen delivery machine Now the cells don’t sickle anymore because they don’t have this problem in a low oxygen environment This approach has also been successful
The human fetus has a special kind of hemoglobin (different from adult hemoglobin) because the fetus has to extract oxygen from mom’s blood And mom’s blood, by the time it reaches the fetus, has already been depleted of oxygen because it’s gone through her body
The fetus has a special form of hemoglobin that can even extract oxygen out of mom’s blood
Another approach to sickle cell anemia is to forget about the sickle gene problem and reactivate/ express/ make fetal hemoglobin in an adult In that case, you don’t need to correct the gene, you leave the gene as it is You just make fetal hemoglobin, which is very, very avid as an oxygen delivery machine
Now the cells don’t sickle anymore because they don’t have this problem in a low oxygen environment
This approach has also been successful
And mom’s blood, by the time it reaches the fetus, has already been depleted of oxygen because it’s gone through her body
In that case, you don’t need to correct the gene, you leave the gene as it is
You just make fetal hemoglobin, which is very, very avid as an oxygen delivery machine

To summarize, you can either (1) give gene therapy to express a corrected version of the sickling gene (HbA), (2) use a second approach where gene editing technology is used to change the gene back to its normal form (HbS → HbA), or (3) reactivate expression of fetal hemoglobin (HbF) to correct the defect. All three are in trials, and all three have shown various measures of success.

“ My impression is that during our lifetime, we’ll see a cure, a permanent cure for sickle cell anemia ”‒ Siddhartha Mukherjee

The incredible revolution of gene editing with CRISPR [45:15]

Siddhartha remarks, “ The world of genetics was turned upside down in a very important way by the discoveries of Jennifer Doudna , Emmanuelle Charpentier and several others I should mention Feng Zhang and George Church . And there’s a history of this, which is in the book. ”
Imagine the human genome as a massive library If it was printed in normal text, it would contain 80,000 books
Imagine that you wanted to make a change in one word in that library You want to take book 61 on shelf 47 and make a change from verbal to herbal in that library This was a dream of scientists for a long time and no one could do it
And then Jennifer Doudna, Charpentier, assisted by Feng Zhang and other people figured out that there was a bacterial system that evolved millions of years ago that could make that precise change in one word in that entire library Either deleting that word (erasing it, the simplest change) or potentially changing the word to another word
If it was printed in normal text, it would contain 80,000 books
You want to take book 61 on shelf 47 and make a change from verbal to herbal in that library
This was a dream of scientists for a long time and no one could do it
Either deleting that word (erasing it, the simplest change) or potentially changing the word to another word

“ It’s an incredible genetic revolution. As we move forward into this new universe, we have the capacity to change the human genome in a deliberative and a processed manner. ”‒ Siddhartha Mukherjee

Consider the sickle cell anemia example discussed before, we can change that gene to the normal gene using the CRISPR gene-editing technology
We can change the abnormal cystic fibrosis gene to a normal gene (or the wildtype version) using this technology
This is exciting because we couldn’t change genes to new genes before, but now we have the capacity to do this
We can do this with embryonic stem cells, bone marrow cells, T cells CAR T-cells)

It’s a revolution, the depth and breadth of this is enormous

Explain using the library analogy how this system differs from the approach that was used 20 years ago in the case of Jesse Gelsinger that we described where an adenovirus was used?

Again, imagine the human genome as a massive library, 80,000 books printed on a page
The old technology that was used with Jesse Gelsinger is the technology in which I’m using metaphors and analogies here
We would insert a new page into that 80,000 page library
The librarian could come in this case, that immune response (the T-cell or the B-cell immune response) and say, “ Wait a second that’s not a page that belongs ,” and that’s what happened with Jesse Gelsinger and other people The librarian being the human body would come and say, “ Wait a second, you are inserting new pages into a library, that’s no good ,” and they would prevent that
Peter notes that it seems it was much harder to know where to put that page; if you wanted it to be between page 87 and 88, you might accidentally insert it somewhere else
Siddhartha agrees, you’re reading along and all of a sudden you find a new page that’s been taped in, the virus that’s carried in the new gene,and you say, “ Wait a second, that doesn’t belong there ” And that was where the technology sat for years and years until Jennifer Doudna , Charpentier and others discovered a method in which you would do just quite the opposite
With CRISPR, you can go into one page, in the right volume of the right book and change one word The first change was just deleting a word Then with more and more research, you could change the word You could change the word verbal to herbal by changing a single letter, and leave the rest of the library intact (for the most part) And if you were a very vigilant librarian, you would say, “ That’s okay, you haven’t put an extra page in Charles Dickens’ book. You’ve actually gone to the right book and changed the right word in the right space, in the right time from one to another .”
The librarian being the human body would come and say, “ Wait a second, you are inserting new pages into a library, that’s no good ,” and they would prevent that
And that was where the technology sat for years and years until Jennifer Doudna , Charpentier and others discovered a method in which you would do just quite the opposite
The first change was just deleting a word
Then with more and more research, you could change the word
You could change the word verbal to herbal by changing a single letter, and leave the rest of the library intact (for the most part)
And if you were a very vigilant librarian, you would say, “ That’s okay, you haven’t put an extra page in Charles Dickens’ book. You’ve actually gone to the right book and changed the right word in the right space, in the right time from one to another .”

CRISPR allows us to make extraordinarily precise changes in extraordinarily precise ways in a massive library, which would not be possible otherwise

Ethical questions around human gene editing [52:30]

JK and the CCR5 gene

All the details are in The Song of the Cell
A Chinese scientist who goes by JK He made a somewhat bizarre decision
The human gene CCR5 (the lack of it) makes cells resistant to HIV infection
He Jiankui decided that he was going to make a change in human embryos with gene editing technology (CRISPR), which would make the child of a couple in which the man was HIV positive and the woman was HIV negative He would make that change in the embryo so that they would be HIV resistant, and implant those altered embryos into the mom
This sounds great on paper, but the risk of these children to acquire HIV is basically zero, since they were produced by IVF The sperm doesn’t carry HIV This was not medically necessary
He would make that change in the embryo so that they would be HIV resistant, and implant those altered embryos into the mom
The sperm doesn’t carry HIV
This was not medically necessary

Siddhartha makes a very big distinction between disease and desire

Disease is fundamentally linked to 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
Now, in this case, there was no disease; the children had no risk of disease
The desire was an entirely scientific desire to create a genetically modified embryo That He Jiankui would be the first in human history to create a human embryo with genetically altered cells
That He Jiankui would be the first in human history to create a human embryo with genetically altered cells

Outcome of gene editing IVF

JK went ahead with this project and created two girls We don’t know their real names; they’ve been called Lulu and Nana
What he obtained was not exactly what he hoped for, which is not that precise erasure of verbal to herbal in a single book in the entire library of 80,000 books
What he obtained was a much cruder version of that
Scientists across the world were concerned about the duty of informed consent Did the parents even understand the language that we’re using? The risk of these children getting HIV was zero They had no disease, there was only this desire to create someone who was potentially resistant to HIV infection
We don’t know their real names; they’ve been called Lulu and Nana
Did the parents even understand the language that we’re using?
The risk of these children getting HIV was zero
They had no disease, there was only this desire to create someone who was potentially resistant to HIV infection

This is a very unusual situation‒ the desire to push the frontier of science and change human embryos where there is not disease

The scientific world became extraordinarily incensed about the idea that this scientist had crossed the boundary between disease and desire
If this had been some disease that the children had inherited, cystic fibrosis, sickle cell disease, Huntington’s disease, some terrible thing that they would encounter in their lifetime, the scientific community would’ve been much more sanguine about it

“ There’s probably no greater example of the relationship between science and philosophy ”‒ Peter Attia

Where does one draw the line?

This is why a doctoral degree is formally called a doctoral of philosophy
Peter notes, “ When you think about this question, it becomes kind of difficult ”
This topic is explored in Walter Isaacson’s biography of Jennifer Doudna ( The Code Breaker ) and in The Song of the Cell
Huntington’s disease is a great example in the sense that you have an acquired genetic mutation that is 100% penetrable It’s a devastating disease that shortens life and leads to immense suffering Would we find many philosophers of science who would say that it is wrong to alter the embryos of adults who have Huntington’s disease or carry that trait, that gene to prevent it from going to their offspring? If you play the thought experiment out, that would eliminate Huntington’s disease altogether because these are germline mutations
How does the scientific and philosophical community merge over questions of that nature?
And then eventually do we move that further to APOE4 , LPA , and other genes that are not as penetrant ?
Siddhartha discusses the example of how devastating APOE-ε 4 (AP4) can be for people who have combinations of AP4 that increase their risk for early Alzheimer’s disease The penetrance of this gene is not huge as it is for Huntington’s A gene with high penetrance means if you inherit the gene, the chances that you’ll have the disease is very high With lower penetrance genes, you might inherit some mutation in a gene, but you might not get the disease BRCA1 is a good example, you may inherit this gene but escape having breast cancer in your lifetime
The biomedical community would say that for diseases like Huntington’s disease, it’s probably worthwhile doing an intervention, whatever that intervention might be
But in this case for HIV, it is not warranted; it simply isn’t necessary
It’s a devastating disease that shortens life and leads to immense suffering
Would we find many philosophers of science who would say that it is wrong to alter the embryos of adults who have Huntington’s disease or carry that trait, that gene to prevent it from going to their offspring?
If you play the thought experiment out, that would eliminate Huntington’s disease altogether because these are germline mutations
The penetrance of this gene is not huge as it is for Huntington’s
A gene with high penetrance means if you inherit the gene, the chances that you’ll have the disease is very high
With lower penetrance genes, you might inherit some mutation in a gene, but you might not get the disease BRCA1 is a good example, you may inherit this gene but escape having breast cancer in your lifetime
BRCA1 is a good example, you may inherit this gene but escape having breast cancer in your lifetime

“ It moves towards desire without moving towards disease ”‒ Siddhartha Mukherjee

Ethical debate

Peter notes other examples of things clearly on the desire spectrum‒ enhancing intelligence or physical traits like strength, size, etc.
The area he finds most interesting is around mental health Autism and schizophrenia have an enormous genetic component On the surface it might seem like it would be great if fewer people were born with autism/ schizophrenia But it’s nowhere near that simple, is it?
There’s a Pandora’s box upon which we have no idea what we could lose as a society if we were to sort of “sterilize” some of these conditions
Autism and schizophrenia have an enormous genetic component
On the surface it might seem like it would be great if fewer people were born with autism/ schizophrenia But it’s nowhere near that simple, is it?
But it’s nowhere near that simple, is it?

The complex role of genetics in mental illness [1:01:30]

The last cellular territory are the cells of the brain

For Peter, the brain has the most complicated cells in the body
This is one area where it’s very difficult to appreciate a phenotype under a microscope or in a scanner
Part of it has to do with the complexity of these genes

What questions might society face around the use of this type of precision gene editing when it comes to genetic conditions of the brain?

Siddhartha agrees, “ The brain is the most complex of all organs, and it’s important to understand that complexity ”
When thinking about diseases, like autism and schizophrenia , there are (broadly speaking) two kinds of genes in the entire spectrum of genetics that have to do with mental diseases
1 – Siddhartha calls a shove gene ; shove, meaning it pushes you really hard Think about height; height has a strong genetic component Tall parents tend to produce tall children, and short parents tend to produce shorter children So, we know there’s a genetic component to it There are genes in the spectrum of controlling height that are very powerful shove genes They shove you in one direction or the other One example is Marfan syndrome , a genetic disorder caused by a single gene If you inherit copies of that gene, you will likely be extremely tall, and you might have other medical and other complications, but you’ll be tall for sure There’s a story that Abraham Lincoln may have inherited the Marfan gene Shove genes are relatively rare in the human population
2 – The more common variant is what Siddhartha calls nudge genes ; nudge versus shove Nudge genes move you little by little, by little, by little, by little towards increasing height There might be hundreds (or tens of hundreds) of genes that may increase your height little by little, by little, by little, by little until you get five feet 10 inches, five feet 11 inches, six feet, etc.
Now, transfer that same idea to mental health
There are certainly genes in the human genome that change your neuron physiology, the physiology of your nerves that are shove genes In other words, if you inherit them just like Marfan syndrome, you are much more likely to have mental illness (in whatever form it is) They are relatively rare, and they are inherited in families There’s a great book on this written recently about a family that has multiple kids with schizophrenia, etc. called Hidden Valley Road
Most mental illness is not a consequence of this shove phenomenon, but are consequences of “death by a thousand cuts”, small nudges that would push you towards depression, schizophrenia, autism, etc.
And in fact, in some cases we haven’t even found those genes yet, even though we know they exist
The capacity to change those genes is very limited because the examples that I gave you of gene editing, gene alteration technology, are limited to one gene, two genes, three genes
It’s very, very hard to find a way to change hundreds, potentially tens of hundreds of genes in the mental health spectrum
So, it’s not as if we can all of a sudden wake up one morning and say, “ I’m going to change your mental health or change the mental health of your embryo based on the understanding of our shove genes ,” because it just won’t happen
Think about height; height has a strong genetic component Tall parents tend to produce tall children, and short parents tend to produce shorter children So, we know there’s a genetic component to it
There are genes in the spectrum of controlling height that are very powerful shove genes They shove you in one direction or the other
One example is Marfan syndrome , a genetic disorder caused by a single gene If you inherit copies of that gene, you will likely be extremely tall, and you might have other medical and other complications, but you’ll be tall for sure There’s a story that Abraham Lincoln may have inherited the Marfan gene
Shove genes are relatively rare in the human population
Tall parents tend to produce tall children, and short parents tend to produce shorter children
So, we know there’s a genetic component to it
They shove you in one direction or the other
If you inherit copies of that gene, you will likely be extremely tall, and you might have other medical and other complications, but you’ll be tall for sure
There’s a story that Abraham Lincoln may have inherited the Marfan gene
Nudge genes move you little by little, by little, by little, by little towards increasing height
There might be hundreds (or tens of hundreds) of genes that may increase your height little by little, by little, by little, by little until you get five feet 10 inches, five feet 11 inches, six feet, etc.
In other words, if you inherit them just like Marfan syndrome, you are much more likely to have mental illness (in whatever form it is)
They are relatively rare, and they are inherited in families
There’s a great book on this written recently about a family that has multiple kids with schizophrenia, etc. called Hidden Valley Road

Two types of problems in science: the “eye in the sandstorm” problem and the “sand in the eye” problem [1:06:15]

The complexity issue around the brain

Peter remarks, “ You do a great job of it in the book describing the mystery. And you came up with a way to describe it that I thought was fantastic, which was…
You said there were two types of problems in science. There are the eye in the sandstorm problems versus the sand in the eye problems. And as the cellular biologists and neurobiologists were getting deeper and deeper into the brain, and it really seemed like they had figured out this thing, these axons, the movement of electricity, these action potentials. They were figuring this out, but they had a little piece of sand in their eye. ”

What was that piece of sand?

It’s a fanciful description, and it’s an important, philosophical distinction
The eye in the sandstorm problem is a problem in which you encounter something in medical sciences where the information just doesn’t fit It’s being in the sandstorm An example is when we made the transition in physics between Newtonian physics, and quantum mechanics, and Einsteinian understanding In other words, you reached a place, and all of a sudden, everything didn’t fit The bending of light, the presence of relativity, etc. So, you needed a completely new theory, a new paradigm, a total shift in paradigmatic thinking There’s sandstorms everywhere, and you can’t make sense of the real world That’s one kind of problem, and Siddhartha is interested in those problems
The sand in the eye problem is a different kind of problem; it is when everything fits except one fact
It’s very important to understand that both of those are really interesting because the sand in the eye problem says that our theory is almost right, but it’s not right because there’s a fact that won’t fit
It’s being in the sandstorm
An example is when we made the transition in physics between Newtonian physics, and quantum mechanics, and Einsteinian understanding
In other words, you reached a place, and all of a sudden, everything didn’t fit The bending of light, the presence of relativity, etc. So, you needed a completely new theory, a new paradigm, a total shift in paradigmatic thinking
There’s sandstorms everywhere, and you can’t make sense of the real world
That’s one kind of problem, and Siddhartha is interested in those problems
The bending of light, the presence of relativity, etc.
So, you needed a completely new theory, a new paradigm, a total shift in paradigmatic thinking

Understanding neural networks: an example of the “sand in the eye” problem being solved [1:08:45]

When people discovered neurons in the brain, they figured out basically by looking at anatomy that there was a space between neurons, that nerves weren’t just wires If you were an electrician fitting out an electrical situation in an apartment, what you wouldn’t do is put spaces between the wires so that all of a sudden, that space would become a communication between wires; you just hook the whole apartment up When people like Ramón y Cajal and other scientists figured out how to solve this problem, they understood all of a sudden, that nerves have spaces in between them (called a synapse )
If you were an electrician fitting out an electrical situation in an apartment, what you wouldn’t do is put spaces between the wires so that all of a sudden, that space would become a communication between wires; you just hook the whole apartment up
When people like Ramón y Cajal and other scientists figured out how to solve this problem, they understood all of a sudden, that nerves have spaces in between them (called a synapse )

The synapse turns out to be extraordinarily important for neuroscience

What happens between nerves is that an electrical conduction moves from one end of a nerve to the other, and then it changes from an electrical conduction to a chemical signal between one nerve to another, and that chemical signal resparks an electrical conduction So it’s going chemical, electrical, chemical, electrical, chemical, electrical This is important because what your nervous system is doing is in that transmission between electrical, chemical, electrical, chemical, is it’s putting weights, so that in the chemical transmission, an electrical impulse could come down a nerve
Let’s say there are 10 nerves (10 neurons/ nerve cells) that are impinging on one nerve cell You could assign a weight as to how much this one was transmitting versus another one And by assigning those weights/ calibrations, you could say one is louder than the other One is softer than the other One inhibits the other And it’s those combinations of inhibition, loudness, etc. that allow profound things like sentience, and conversation, and consciousness and so forth
This analogy explains how neural networks work There are weights put on how one layer of communication communicates with a second layer of communication In other words, some are louder than others, some are softer than others
Imagine discriminating a dog from a cat You could say that a very loud signal in that discrimination is if the animal happens to bark You know that for sure that’s not a cat A very soft signal could be the weight of the animal Some dogs are lighter than cats A very loud signal could be the way that the snout of an animal is fixed with the head of the animal Dogs have a particular snout, head combination Cats have a particular snout, head combination So, by adjusting the weights of these combinations, we think by analogy that this is how the brain can discriminate between dogs and cats We don’t know this for sure because this is an area of science that’s still in process
So it’s going chemical, electrical, chemical, electrical, chemical, electrical
This is important because what your nervous system is doing is in that transmission between electrical, chemical, electrical, chemical, is it’s putting weights, so that in the chemical transmission, an electrical impulse could come down a nerve
You could assign a weight as to how much this one was transmitting versus another one
And by assigning those weights/ calibrations, you could say one is louder than the other One is softer than the other One inhibits the other
And it’s those combinations of inhibition, loudness, etc. that allow profound things like sentience, and conversation, and consciousness and so forth
One is softer than the other
One inhibits the other
There are weights put on how one layer of communication communicates with a second layer of communication
In other words, some are louder than others, some are softer than others
You could say that a very loud signal in that discrimination is if the animal happens to bark You know that for sure that’s not a cat
A very soft signal could be the weight of the animal Some dogs are lighter than cats
A very loud signal could be the way that the snout of an animal is fixed with the head of the animal Dogs have a particular snout, head combination Cats have a particular snout, head combination
So, by adjusting the weights of these combinations, we think by analogy that this is how the brain can discriminate between dogs and cats
We don’t know this for sure because this is an area of science that’s still in process
You know that for sure that’s not a cat
Some dogs are lighter than cats
Dogs have a particular snout, head combination
Cats have a particular snout, head combination

Siddhartha’s takeaway‒

This classic example, in the 1950s of the idea of why on earth would you take an electrical signal, convert it to a chemical signal, and then convert it back to an electric signal?
The answer is because if it was just an electrical signal, we’d be a box of wires
And a box of wires without the weight between individual signals (between the wires) is a useless box Because we cannot understand how to construct a learning network between a box of wires Whereas we can understand how we can construct a learning network between electrical and chemical stimulations because we can modulate the strength of that chemical simulation such that we can really actually learn a process
Because we cannot understand how to construct a learning network between a box of wires
Whereas we can understand how we can construct a learning network between electrical and chemical stimulations because we can modulate the strength of that chemical simulation such that we can really actually learn a process

Another way Peter likes to explain it is using music

Think of the electrical signals that travel down the axon as digital It’s either completely on or completely off; there’s no modulation Imagine an orchestra where every instrument could only play at one maximum decibel level or not at all You would have no modulation of sound, and it would be a very awful sounding music
But if you could have analog adjustment of music, and now each of those instruments can go up and down, crescendo, decrescendo, and modulate Now we can make songs
It’s either completely on or completely off; there’s no modulation
Imagine an orchestra where every instrument could only play at one maximum decibel level or not at all
You would have no modulation of sound, and it would be a very awful sounding music
Now we can make songs

How did evolution figure this out?

Siddhartha thinks the reason is learning
In a purely electrical system there is no modulation By analogy, everything in music has the same volume, same tempo, same time That’s not music; that’s not the “song of the cell”
Our evolution converged on the idea that music has tempo, it has space, some pieces are softer, some pieces are louder And by altering this loudness, softness as we move along in our neurons, that we can produce not just a mechanical output of the score
By analogy, everything in music has the same volume, same tempo, same time That’s not music; that’s not the “song of the cell”
That’s not music; that’s not the “song of the cell”
And by altering this loudness, softness as we move along in our neurons, that we can produce not just a mechanical output of the score

We are not producing a mechanical output; rather, we’re producing a learned output, and that mature output has to do very much with modulation

In the mature output, some parts are louder, some parts are softer, some parts speed up in rhythm, some parts slow down in rhythm And that is ultimately the music of the cell, but also, the music of the brain
And that is ultimately the music of the cell, but also, the music of the brain

Importance of learning by doing: comparing the learning styles of a doctoral student to a medical student [1:16:30]

Peter notes, when Siddhartha went to Oxford to do his PhD as a Rhode scholar, he ended up in a lab where he learned immunology from his mentor Enzo
He would go on to Harvard Medical School and get a great medical education
But he was committed to this path of becoming a scientist first, a physician second

What is it that was bestowed on you from a learning perspective, as a doctoral student that we don’t really get in medical school?

It’s a very different kind of thinking process
Siddhartha likes to make medicines, medicines that are important for human life, hopefully for saving lives He talked about some of them in a prior podcast
Textbook knowledge in medicine and biology is important because it lays the groundwork and the foundations of what we know and what we understand
But textbook knowledge only gets you so far because when you come into the actual laboratory, you understand that there are things that are predictable, there are things that are not predictable
And then you get into these “eye in the sandstorm” and “sand in the eye problems”, which are very important
You learn to recognize failure
You learn to recognize how to troubleshoot your way out of failure
He talked about some of them in a prior podcast

None of this is in a textbook

Open a textbook of biology, any textbook of biochemistry, biology, and try to find me a section on troubleshooting
Troubleshooting your way out of failure is the most standard way that we think about medicine and biology
Nothing in a textbook will tell you about to select a patient for a clinical trial
A textbook won’t tell you how to manage a patient with complications for a clinical trial
You run an experiment which will set you up for a clinical trial There is no information in that textbook about how to troubleshoot, where and how to do that science that allows you to make it into human medicine What if for instance, you suddenly find that the medicine that you’re working with or you’re trying to create isn’t pure, that there’s a contamination? How do you remove that contamination? There is no method; you can’t find a textbook
What you do is you ask your peers who’ve done this before you
There is no information in that textbook about how to troubleshoot, where and how to do that science that allows you to make it into human medicine
What if for instance, you suddenly find that the medicine that you’re working with or you’re trying to create isn’t pure, that there’s a contamination? How do you remove that contamination? There is no method; you can’t find a textbook
How do you remove that contamination?
There is no method; you can’t find a textbook

There is a kind of learning that we do by doing, that we be by being, that we acquire by acquiring, that cannot be found in any book or textbook in the medical sciences, and there’s no way around it

“ I wanted to write about that process of learning by doing, learning by being, learning by experiencing ”‒ Siddhartha Mukherjee

Sid’s unique and brilliant style of writing [1:20:45]

Peter comments on what an amazing writer Siddhartha is; he calls it a gift but doesn’t want to suggest it doesn’t require an obscene amount of hard work
He says, “ I think you are hands-down the best writer who happens to write about anything that has to do with science in medicine ”

At what point in your education did you realize you had a brilliant way to write?

Writing is not an easy process for Sid; it’s a weird process He throws in everything He has a policy in which there’s nothing that’s outside of his box
Writing is a way for him to think and work through his thoughts
The analogies and metaphors of his writing are not really in service of writing but in service of making him think and understand why a certain phenomenon is related to another phenomenon
He draws from mythology, philosophy, conversations, interviews… everything goes into a book
Medical writing was about medicine; it wasn’t personal There was sharp distinction between memoir and case histories There was sharp distinctions between deep history and an interview or journalistic writing Siddhartha felt these distinctions are arbitrary
Siddhartha thought, “ Why not erase all of them and make a new kind of writing in medicine or in life? ”
The most important thing that people told Siddharthaabout medical writing was when people read writing about medicine, they want to enter your cosmos
People want to know what it’s like to be like you It’s absolutely intense exhilaration when a clinical trial is successful, absolute depths of depression and crisis when a clinical trial fails
He throws in everything
He has a policy in which there’s nothing that’s outside of his box
There was sharp distinction between memoir and case histories
There was sharp distinctions between deep history and an interview or journalistic writing
Siddhartha felt these distinctions are arbitrary
It’s absolutely intense exhilaration when a clinical trial is successful, absolute depths of depression and crisis when a clinical trial fails
Absolute anticipation, absolute apprehension, absolute admiration for people on whose shoulders he stands
He’s like you, he has terrible days, very good days, exhilarating days
He makes inventions; some of them work and some of them don’t
All of it is wonderful and terrifying at the same time

Siddhartha will combine memoir, journalistic writing, traveling writing, philosophy, mythology, everything. He’ll throw everything in there so that you understand what it’s like to be like him.

Falling as the leading cause of accidental death: a liability of multicellular existence [1:25:00]

Two things Siddhartha wrote about in different parts of the book are completely unconnected, but in Peter’s mind they were immediately connected
Peter thinks a lot about the end of life How we can delay and push of the end of life How quickly life can vanish in an older person when they fall
Siddhartha wrote very openly about his own depression (that kicked in a year after his father’s death, which resulted from a fall)
And near the very end of the book, he wrote about the end of Virchow’s life Peter was completely unaware that he ultimately died as a result of a fall and a broken femur
How we can delay and push of the end of life
How quickly life can vanish in an older person when they fall
Peter was completely unaware that he ultimately died as a result of a fall and a broken femur

Falls are the leading cause of accidental death

If a person over the age of 65 falls and breaks their femur, mortality is anywhere from 10-30% at 12 months (depending on the study)
When a lot of people are confronted with that fact, they simply can’t understand it, but Siddhartha does a very good job explaining it Peter couldn’t believe how Siddhartha tied it back to the cell It starts with the osteoclast , the osteoblast , and the matrix of the hip, and ultimately, it leads to organ failure That’s not a leap that’s easy to make; it’s not obvious
Peter couldn’t believe how Siddhartha tied it back to the cell
It starts with the osteoclast , the osteoblast , and the matrix of the hip, and ultimately, it leads to organ failure That’s not a leap that’s easy to make; it’s not obvious
That’s not a leap that’s easy to make; it’s not obvious

It’s obvious when you think about Virchow’s idea that the body is a citizenship

Imagine a citizenship in any capacity
All of a sudden, your Bureau of Transportation decides to take a leave for 20 days The trains in New York City stop running Therefore, people can’t go to work and the economy collapses The economy collapses, and all of a sudden, people who are dependent on small changes in their lifetimes, wage workers, collapse And then the entire system, the network of systems collapses, all because the Department of Transportation closed down for two days
That’s what happens in the human body
That’s the liability (in some ways) of multicellular existence There are many advantages of multicellular existence (discussed earlier)
One example of a liability‒ you depend on your pancreas for insulin Your brain doesn’t make insulin You depend on your brain for sentience and consciousness You depend on your muscles for movement Your brain can’t produce movement without muscles
There’s a citizenship that bodies develop and have developed with each other so that we, together, perform as organisms; and if you take away one piece of that (a broken bone), it pings into a capacity not to move The capacity not to move wastes your muscles Your wasted muscles then communicate with the rest of your body (via hormones)
The trains in New York City stop running
Therefore, people can’t go to work and the economy collapses
The economy collapses, and all of a sudden, people who are dependent on small changes in their lifetimes, wage workers, collapse
And then the entire system, the network of systems collapses, all because the Department of Transportation closed down for two days
There are many advantages of multicellular existence (discussed earlier)
Your brain doesn’t make insulin
You depend on your brain for sentience and consciousness
You depend on your muscles for movement
Your brain can’t produce movement without muscles
The capacity not to move wastes your muscles
Your wasted muscles then communicate with the rest of your body (via hormones)

Sid’s struggle with depression and his desire to change the stigma around mental illness [1:29:15]

How much did you weigh the pros and cons of writing about such personal matters as your own depression?

Peter adds, “ We o still live in a world where it’s not entirely clear to me why we view depression different from hypertension ”
It was a conscious choice for Siddhartha; he talked to his family about it
Depression can be what’s called an organic disorder A disorder in mood-regulating neurons in your brain Just like type 1 diabetes is an organic disorder, a disorder in the inability of pancreatic beta cells to secrete insulin
The reason these are viewed differently is that we associate a kind of victimhood to mental disorders, and that kind of victimhood is punitive It blames victims for being victims in a way We don’t say, “ Oh. You’re hypertensive because you have genetics or have behaviors, etc. that are related to your hypertension. ” But depression and mental disorders, grief, and perhaps even more complex disorders (schizophrenia), have a sense of blaming the victim (the person who’s experiencing the disorder)
This has to do with the idea that the brain is separate from the rest of the body; it’s a special organ
But on the other hand, it’s also an organ that has physiology, just like your pancreas has physiology, just like your heart has physiology
Siddhartha wanted to get away from is this idea of special victimhood and talk about the brain as a cellular cluster And thereby remove this or defend or even challenge this idea of victimhood and responsibility, because most people who experience severe clinical depression experience it as a consequence of environmental and emotional stimulation The grief of dying, the grief of their situation But there are neuronal or nerve cells and nerve cells circuits that push them in biochemical and chemical ways towards the state in which they cannot function And he wants to highlight that absence of function
A disorder in mood-regulating neurons in your brain
Just like type 1 diabetes is an organic disorder, a disorder in the inability of pancreatic beta cells to secrete insulin
It blames victims for being victims in a way
We don’t say, “ Oh. You’re hypertensive because you have genetics or have behaviors, etc. that are related to your hypertension. ”
But depression and mental disorders, grief, and perhaps even more complex disorders (schizophrenia), have a sense of blaming the victim (the person who’s experiencing the disorder)
And thereby remove this or defend or even challenge this idea of victimhood and responsibility, because most people who experience severe clinical depression experience it as a consequence of environmental and emotional stimulation The grief of dying, the grief of their situation
But there are neuronal or nerve cells and nerve cells circuits that push them in biochemical and chemical ways towards the state in which they cannot function
And he wants to highlight that absence of function
The grief of dying, the grief of their situation

If Virchow was alive today, he would say that absence of function (or that dysfunction) is not dissimilar to a person who has a failing heart or a failing liver because that function is a dysfunction of mood-regulating circuits and neurons in the brain, just as type 1 diabetes is a dysfunction of insulin-regulating cells in the pancreas

Siddhartha thinks that idea is important and radical in this book
Peter spoke to Karl Deisseroth about this Both agree that his book is excellent, Projections: A Story of Human Emotions
Karl was a classmate of Peter’s in medical school, and he talks about this idea that in psychiatry, we have not one biomarker or radiographic finding that lends itself to a diagnosis
In the example of a failing heart or failing liver, we have a menu of things to aid in the diagnosis
It’s much easier to make that diagnosis today than when William Osler had to make the diagnosis 125 years ago
The inside of our brain is still this black box, in some ways Peter can’t help but wonder where we will be in 20 years; he feels like there is enormous potential
Siddhartha agrees, biomarkers are helpful, but ultimately, it’s a clinical decision
He always tells people who haven’t been in clinical medicine, “ When you see depression, you know depression ”
This is what humans can see about other humans
There is a disproportionality or a disconnection between the level of grief that a person experiences and the level of grief that persists when a person is clinically depressed The ennui, the level of psychomotor inability to move
Even in the absence of biomarkers, there is a new age that is coming, and a respect for the autonomy of patients who experience neurological and psychiatric diseases
Deisseroth writes about them very carefully and very thoughtfully
Andrew Solomon has written about all of this
Both agree that his book is excellent, Projections: A Story of Human Emotions
Peter can’t help but wonder where we will be in 20 years; he feels like there is enormous potential
The ennui, the level of psychomotor inability to move

It’s very important because we could find therapies for these

Some of them may be related to alterations in diets, alterations in diets plus medicines, alterations in human physiology that could reset brain circuits Or electrical stimulation, as Helen Mayberg and others have been doing
To treat the problem as if it was a sort of an epiphenomenon is to minimize what the problem is
Or electrical stimulation, as Helen Mayberg and others have been doing

To be continued…

“ You have a wonderful way of explaining complicated ideas ”‒ Peter Attia

Peter remarks, “ Sid, there’s so much more I wanted to talk with you about ” The immune system The epigenetic phenomenon Cellular reprogramming and Yamanaka factors We only got through about half of what he wanted to talk about
Perhaps the single most important thing Peter wanted to talk about today was the future of science and the culture of anti-science that is propagating We couldn’t do that justice with a glib and short discussion
Once Siddhartha’s book tour is over, we will have to continue with part 2
The immune system
The epigenetic phenomenon
Cellular reprogramming and Yamanaka factors
We only got through about half of what he wanted to talk about
We couldn’t do that justice with a glib and short discussion

Selected Links / Related Material

Previous episode of The Drive with Sid : #32 – Siddhartha Mukherjee, M.D., Ph.D.: new frontiers in cancer therapy, medicine, and the writing process | Host Peter Attia, The Peter Attia Drive Podcast (December 10, 2018) | [0:45, 1:17:45]

Siddhartha’s books :

The Emperor of All Maladies: A Biography of Cancer by Siddhartha Mukherjee (November 2010) | [1:15]
The Laws of Medicine: Field Notes from an Uncertain Science by Siddhartha Mukherjee (October 2015) | [1:15]
The Gene: An Intimate History by Siddhartha Mukherjee (May 2016) | [1:15, 3:30, 32:45]
The Song of the Cell: An Exploration of Medicine and the New Human by Siddhartha Mukherjee (October 2022) | [1:15, 3:00, 53:15, 58:15]

Essay on the biophysical limitation of size : Size and Shape by Stephen Jay Gould | Reprinted in “ The Richness of Life: The Essential Stephen Jay Gould ” edited by Steven Rose (2006) | [25:15]

Siddartha’s company working on CAR T-cell therapy in India : Immuneel | [37:45]

Early results of CAR T-cell therapy in India : Immuneel IMAGINE Study Phase-II Varnimcabtagene autoleucel Early Results Press Release pdf (December 2022) | [38:00]

Review of gene therapy approaches to treat sickle cell disease : Gene therapy for sickle cell disease: moving from the bench to the bedside | Blood (A Abraham & J Tisdale 2021) | [42:30]

Walter Isaacson’s biography of Jennifer Doudna : The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race by Walter Isaacson (March 2021) | [58:15]

Book about a family that has multiple kids with schizophrenia : Hidden Valley Road: Inside the Mind of an American Family by Robert Kolker (April 2020) | [1:04:45]

Karl Deisseroth’s book about mental illness : Projections: A Story of Human Emotions by Karl Deisseroth (June 2021) | [1:33:30]

Andrew Solomon’s book about depression : The Noonday Demon: An Atlas Of Depression by Andrew Solomon (June 2001) | [1:36:00]

People Mentioned

Gregor Mendel (Austrian Monk and “the Father of Genetics”) [6:30]
Thomas Hunt Morgan (American geneticist, discovered chromosomes) [6:45]
Rudolph Virchow (German physician and “Father of modern pathology” [7:15]
Antonie van Leeuwenhoek (Dutch microbiologist pioneered the microscope, the “Father of Microbiology”) [9:00]
Joseph Lister (British surgeon and pioneer of antiseptic surgery) [12:15]
Ignaz Semmelweis (German physician and proponent of hand disinfection) [12:15]
William Ratcliff (Associate Professor of Biological Sciences at Georgia Tech) [20:00]
Steven Jay Gould (American paleontologist and evolutionary biologist) [25:15]
Jesse Gelsinger (first person to have died from gene therapy) [29:15]
Jennifer Doudna ( Professor of Chemistry at UC Berkeley, Nobel laureate ) [46:00]
Emmanuelle Charpentier ( Director of the Max Planck Unit for the Science of Pathogens, Nobel laureate ) [46:00]
Feng Zhang ( Professor of Neuroscience at MIT and member of the Broad Institute) [46:00]
George Church (“Father of genomics” Professor at both Harvard and MIT ) [45:15]
He Jiankui (JK) (Professor of Biology at the the Southern University of Science and Technology in Shenzhen, China; created first genetically edited human babies) [53:15]
Walter Isaacson (Professor of History at Tulane and author) [58:15]
Santiago Ramón y Cajal (Spanish pathologist, neuroscientist and Nobel laureate who characterized microscopic structure of the brain) [1:09:15]
Vincenzo Cerundolo (Enzo) (Professor of Immunology at Oxford) [1:16:45]
Karl Deisseroth (Professor of Bioengineering and Psychiatry and Behavioral Sciences at Stanford University) [1:33:15]
Andrew Solomon (Professor of Clinical Psychology at Columbia) [1:36:00]
Helen Mayberg (Neurologist at Mount Sinai, pioneered deep brain stimulation) [1:36:30]

Siddhartha Mukherjee was born in New Delhi, India. He holds a BS in biology from Stanford University, a PhD in immunology from Oxford University (where he was a Rhodes Scholar), and an MD from Harvard Medical School. He completed his internal medicine residency and an oncology fellowship at Massachusetts General Hospital. Dr. Mukherjee is an assistant professor of medicine at Columbia University Medical Center. He is a hematologist and oncologist who specializes in lymphoma, myeloma, and myelodysplastic syndrome at NewYork-Presbyterian / Columbia University Irving Medical Center.

He is the author of the Pulitzer Prize-winning book, The Emperor of All Maladies: A Biography of Cancer ; The Laws of Medicine: Field Notes from an Uncertain Science ; the New York Times bestseller, The Gene: An Intimate History ; and his most recent book was named a New York Times Notable Book of 2022, The Song of the Cell: An Exploration of Medicine and the New Human .

Dr. Mukherjee’s research focuses on the biology of blood development and malignant and premalignant diseases such as myelodysplasia (MDS) and acute myelogenous leukemia (AML). His goal is to develop novel drugs to treat these diseases. [ Columbia ]

Twitter: @DrSidMukherjee

Website: siddharthamukherjee.com

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