podcast Peter Attia 2023-08-28 topics

#268 ‒ Genetics: testing, therapy, editing, association with disease risk, autism, and more | Wendy Chung, M.D., Ph.D.

Audio

Show notes

Wendy Chung is a board-certified clinical and molecular geneticist with more than 25 years of experience in human genetic disease research. In this episode, Wendy delves deep into the world of genetics by first exploring the historical landscape of genetics prior to decoding the human genome, contrasting it with what we know today thanks to whole genome and exome sequencing. She provides an overview of genetic testing by differentiating between various genetic tests such as direct-to-consumer, clinical, whole genome sequencing, and more. Additionally, Wendy unravels the genetic underpinnings of conditions such as PKU, breast cancer, obesity, autism, and cardiovascular disease. Finally, Wendy goes in depth on the current state and exciting potential of gene therapy while also contemplating the economic implications and ethical nature of gene editing.

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We discuss:

Wendy’s interest in genetics and work as a physician-scientist [2:45];
The genetics of phenylketonuria (PKU), a rare inherited disorder [5:15];
The evolution of genetic research: from DNA structure to whole genome sequencing [18:30];
Insights and surprises that came out of the Human Genome Project [28:30];
Overview of various types of genetic tests: direct-to-consumer, clinical, whole genome sequencing, and more [34:00];
Whole genome sequencing [39:30];
Germline mutations and the implications for older parents [45:15];
Whole exome sequencing and the importance of read depth [50:30];
Genetic testing for breast cancer [54:00];
What information does direct-to-consumer testing provide (from companies like 23andMe and Ancestry.com)? [1:01:30];
The GUARDIAN study and newborn genetic screening [1:06:30];
Treating genetic disease with gene therapy [1:18:00];
How gene therapy works, and the tragic story of Jesse Gelsinger [1:22:00];
Use cases for gene therapy, gene addition vs. gene editing, CRISPR, and more [1:28:00];
Two distinct gene editing strategies for addressing Tay-Sachs and fragile X syndrome [1:37:00];
Exploring obesity as a polygenic disease: heritability, epigenetics, and more [1:41:15];
The genetics of autism [1:48:45];
The genetics of cardiovascular disease [2:01:45];
The financial costs and economic considerations of gene therapy [2:06:15];
The ethics of gene editing [2:12:00];
The future of clinical genetics [2:21:00]; and
More.

Show Notes

*Notes from intro :

Wendy Chung is a board certified, clinical and molecular geneticist and the new Chief of Pediatrics at Boston Children’s Hospital
Wendy earned her PhD in genetics from Rockefeller University and an MD from Cornell University Medical College
She completed her residency in pediatrics and her fellowship in molecular and clinical genetics at Columbia’s New York Presbyterian Hospital Where she then served as a Professor of Pediatrics and directed her research programs towards the genetics of obesity, diabetes, breast cancer, autism, and rare diseases
Wendy has received numerous awards for her research, as well as for her clinical and teaching contributions, including being elected to the National Academy of Medicine
In this conversation with Wendy, we focus on genetics from a variety of angles
We talk about what science and genetics looked like before we could decode the human genome, as well as what we know currently, when it comes to whole genome and exome sequencing This includes an understanding of the difference between clinical genetic testing and what’s available commercially
We also speak about genetics and newborn screening, as well as a project that Wendy is involved in called The GUARDIAN Study
We talk about genetics as it relates to a variety of conditions, including PKU , breast cancer, obesity, autism, and cardiovascular disease Some of you may have noticed on a diet soda can, it says, “ If you have PKU, don’t drink this ”
We ultimately talk about gene therapy, how it works, and what’s required to change a gene And, of course, the future and ethics of gene therapy
Where she then served as a Professor of Pediatrics and directed her research programs towards the genetics of obesity, diabetes, breast cancer, autism, and rare diseases
This includes an understanding of the difference between clinical genetic testing and what’s available commercially
Some of you may have noticed on a diet soda can, it says, “ If you have PKU, don’t drink this ”
And, of course, the future and ethics of gene therapy

Wendy’s interest in genetics and work as a physician-scientist [2:45]

Wendy is moving from New York to boston
She’s going to be the Chair of Pediatrics at Boston Children’s Hospital and will be at Harvard Medical School

You’re both an MD and a PhD, how do you balance your time between the lab and clinical practice?

They split about 20% clinical, 80% research, but truth be told, they’re really together
When she thinks about things, it starts with a patient and ends with a patient
It starts with a patient in terms of clinical seeing them
Many times the answers aren’t obvious, and so it becomes a research question
And at the end of the day, it has to go back to the patient
Within that split, it signifies how much we have to learn and why research is so important to improve clinical care

Wendy’s education

Did you do a combined MD-PhD or MSTP program?

You did your PhD first and then went to medical school

Wendy did a combined program between Cornell and Rockefeller Since Rockefeller doesn’t have a medical school, that is done at Cornell
She knew she wanted to be a physician scientist
Since Rockefeller doesn’t have a medical school, that is done at Cornell

What drew you to your current field of genetics? How would you describe to somebody what it is you do in the lab?

Wendy was fortunate enough, early in her career, to be exposed to the National Institutes of Health As an undergraduate, she was able to spend summers there
She was a biochemistry major as an undergrad and had the ability to work on phenylketonuria (PKU) (mostly in the laboratory)
She was able to spend time at NIH at the hospital and seeing patients, and realized this whole paradigm, which today is really how she does things Thinking about how these pieces fit together
As an undergraduate, she was able to spend summers there
Thinking about how these pieces fit together

“ I couldn’t really think about the science without thinking about the patients, and I couldn’t move forward and fill the gaps in our knowledge for patients unless I did the science. ”‒ Wendy Chung

She happened to be good at both, and so it was natural for her to do both
She was young and not so worried about the number of gray hairs by the time she finished
So she set out on this relatively long training path, but one that suited her extremely well

The genetics of phenylketonuria (PKU), a rare inherited disorder [5:15]

PKU is a good introduction to a genetic disease

Tell folks what it is and how frequently it occurs

PKU stands for phenylketonuria and it was how we started newborn screening
It was a paradigm in terms of patients and families really working together to improve care and being very much partners in that
As a biochemistry major in the late ‘80s, Wendy was interested in the biochemistry of PKU, but she realized that a lot of what she was doing was genetic sequencing to understand the genetic basis of this what we call a Mendelian or single gene condition
In this particular case, we did know the gene responsible for PKU
But there were so many other things that we were seeing that we didn’t yet know the genes for these underlying conditions
It was coincidental and fortuitous that the year she started her MD-PhD program was the year the Human Genome Project was announced
She had the foresight (or good luck) to be able to see that it was going to be a brand new future, when we would have that entire encyclopedia of information to be able to think about human disease differently And thinking about opportunities in the future and what one could do with the information when we had it
She really planned her career in thinking about what she’d be able to do 10 or 20 years after she started
She’s spent a lot of her time using that information and trying to apply it to health
And thinking about opportunities in the future and what one could do with the information when we had it

What is the clinical manifestation of PKU?

Phenylketonuria is a bittersweet condition, in the sense that it can be associated with intellectual disabilities, if not treated early Early detection allows treatment with a diet that is restricted in phenylalanine (one of the amino acids that we see in proteins)
Individuals with PKU can’t digest phenylalanine and get rid of the toxic byproducts
If we restrict that, we can prevent those toxic byproducts from building up in the body and essentially poisoning the brain
It’s tragic because Wendy has identified individuals who weren’t picked up through newborn screening For instance, she has picked up through some of her research studies, teenagers who had irreversible intellectual disabilities
But we can prevent those types of problems, if these children are identified as newborns
That is what our whole newborn screening program was originally predicated on: early diagnosis, early intervention, changing lives, improving lives And we do that extremely well for most individuals with PKU
Early detection allows treatment with a diet that is restricted in phenylalanine (one of the amino acids that we see in proteins)
For instance, she has picked up through some of her research studies, teenagers who had irreversible intellectual disabilities
And we do that extremely well for most individuals with PKU

Is PKU a dominant gene and is it fully penetrant or is there any variability in that?

It’s a recessive condition , meaning it takes two to tango, both your parents are carriers for that condition
Within this, there is a spectrum, so we have individuals that are what we call hyperphenylalaninemic: so they don’t technically have PKU, they’re not symptomatic, they wouldn’t have problems with intellectual disabilities, but it’s a spectrum of severity
Beyond a certain threshold, you have too much of the toxic buildup, and that’s when you end up with the problems in terms of brain function
But there are some individuals who have subclinical phenotypes, that is you could see it if you bothered to measure the amount of phenylalanine in their blood, but they have enough of the enzyme to be able to clear the toxic byproduct

That becomes one of the tricky things for us to do in screening newborns, is to decide where that threshold is, to adjudicate this and figure out who needs treatment

Is the screening that’s done on newborns a genetic screen where you’re looking for two copies of the gene?

The traditional method, in the very old days, was based on looking at bacteria and how they would grow on agar that was depleted of phenylalanine From a heel prick on a baby, you would use a little dried blood and spot that onto a bacterial lawn and see where the bacteria would grow This was how the screen was done in the late ‘60s, early ‘70s We’ve gotten more sophisticated in our ability to directly measure phenylalanine and we now do it with a process called tandem mass spectrometry This still uses that dried blood spot from a heel prick In a program recently started called GUARDIAN , there is an orthogonal way of being able to screen based on looking at the DNA So now there are two different data streams coming in to help with the adjudication of deciding who needs treatment and what is that threshold This helps improve the test parameters, both sensitivity and specificity, to allow them to identify with greater certainty the babies who need treatment
The traditional method, in the very old days, was based on looking at bacteria and how they would grow on agar that was depleted of phenylalanine From a heel prick on a baby, you would use a little dried blood and spot that onto a bacterial lawn and see where the bacteria would grow This was how the screen was done in the late ‘60s, early ‘70s
We’ve gotten more sophisticated in our ability to directly measure phenylalanine and we now do it with a process called tandem mass spectrometry This still uses that dried blood spot from a heel prick
In a program recently started called GUARDIAN , there is an orthogonal way of being able to screen based on looking at the DNA
So now there are two different data streams coming in to help with the adjudication of deciding who needs treatment and what is that threshold This helps improve the test parameters, both sensitivity and specificity, to allow them to identify with greater certainty the babies who need treatment
From a heel prick on a baby, you would use a little dried blood and spot that onto a bacterial lawn and see where the bacteria would grow
This was how the screen was done in the late ‘60s, early ‘70s
This still uses that dried blood spot from a heel prick
This helps improve the test parameters, both sensitivity and specificity, to allow them to identify with greater certainty the babies who need treatment
Peter’s takeaway ‒ the reason you don’t just rely on say a genome sequence at the moment is because that wouldn’t tell you about the phenotype fully
Even though you know what gene to look for The phenotype is just as important (maybe more) as the genotype as you make a clinical decision about dietary restriction
Even though you know what gene to look for
The phenotype is just as important (maybe more) as the genotype as you make a clinical decision about dietary restriction

Wendy agrees that’s very insightful, and it might be a subtle thing for some people so she’s going to repeat it

We are really good (not perfect) at reading out the DNA sequence
So being able to decide based on the DNA sequence alone of the relevant gene (phenylalanine hydroxylase) if you have disease, we’re not able to perfectly make that one-to-one correlation about whether or not you’ll be beyond the threshold of disease (in terms of phenylalanine levels)
The phenotype is the level of phenylalanine in the blood, and we have to have that phenotype before we get to the phenotype of intellectual disabilities And intellectual disabilities is what we’re trying to prevent
Phenotype alone is also imperfect ‒ depending on what you’ve eaten, your phenylalanine levels fluctuate during the course of the day
Phenylalanine levels are measured as a cross-sectional, one time, and you might happen to get a baby at just the wrong time or just a sort of higher level
And so, being able to have both of those data streams (genotype and phenotype) come in allow us to be even better in terms of the accuracy
And intellectual disabilities is what we’re trying to prevent

Is the amount of phenylalanine in a Diet Coke clinically significant?

If you look at a can of soda or anything with aspartame in it, it always presents this warning, “ If you have PKU, beware. ”
The absolute amount of phenylalanine in a minuscule amount of aspartame in Diet Coke or something seems really small

Are even milligrams of this amino acid problematic for those afflicted with PKU?

People with PKU have to be really careful
They have a very special diet No diet soda Nothing with aspartame It’s not a fun diet to be on, and many people don’t want to be on that diet for life (it’s not the tastiest)
In particular, when women become pregnant, not only are they influencing their own body, but that of the fetus developing inside They have to be quite careful with their diet
Because of that, from a labeling point of view, we want to make sure they’re aware of what’s in different food products Because they won’t feel the effect right away It’s not as if they’d get a headache or something We don’t want to see the effects on the developing fetus later on
No diet soda
Nothing with aspartame
It’s not a fun diet to be on, and many people don’t want to be on that diet for life (it’s not the tastiest)
They have to be quite careful with their diet
Because they won’t feel the effect right away It’s not as if they’d get a headache or something We don’t want to see the effects on the developing fetus later on
It’s not as if they’d get a headache or something
We don’t want to see the effects on the developing fetus later on

Amino acids show up in all sorts of places. Are there actual protein sources that are completely void of phenylalanine?

We don’t exclude 100% phenylalanine, so it’s a low-protein diet in general
We still need some protein, and you must have some essential amino acids for your body to be able to grow You need to make muscle, especially as a developing child, so we don’t completely restrict
It’s actually a titration
We make dietary interventions and we check, and then we go back and forth to be able to get it just right It’s a lifelong treatment in that way It becomes even more critical for young children, as both their brain is developing, their body is developing We have to get it just right It’s not trivial to do, but on the other hand, when we’re good about it, children grow up very healthy
You need to make muscle, especially as a developing child, so we don’t completely restrict
It’s a lifelong treatment in that way
It becomes even more critical for young children, as both their brain is developing, their body is developing We have to get it just right It’s not trivial to do, but on the other hand, when we’re good about it, children grow up very healthy
We have to get it just right
It’s not trivial to do, but on the other hand, when we’re good about it, children grow up very healthy

If you come off the diet later in life, will you still suffer cognitive changes or are you most sensitive to those during development (childhood and adolescence)?

You’re most sensitive during childhood when the brain is growing and when you’re making those synapses and connections and being able to develop all of the things you’re learning to do
Some people (adults in particular) will tell Wendy about differences that they have in terms of clarity of their thinking and other things, if they’re totally off the diet and not restricted whatsoever
But it is different in the sense that you don’t crash and burn instantaneously, it’s more subtle in terms of what you feel, how your body feels

Are there any benefits in having one copy of this gene [the disease variant that causes PKU]?

Peter notes that for some recessive conditions (such as sickle cell anemia ), having one copy of the disease gene (and therefore not having the full phenotype) poses an advantage and helps to explain the propagation of the gene

Is there any analogy to be made here?

Not that we know of
Wendy doesn’t think that we know everything, but it’s not so obvious in terms of the frequency of these mutations
Obviously, there are huge detriments to having two copies of this gene
There are historical reasons where we see PKU in certain parts of the world versus others

As far as we know, there is no selective advantage to the PKU gene variant

Is there an ethnic distribution of PKU?

There is, we tend to see PKU more frequently in Ireland Sub-Saharan Africa is an example that has to do with historical reasons where variants occurred, migration patterns of how people migrated around the world
We see PKU in all four corners of the world, everywhere
Newborn screening for PKU is pretty universal throughout the world
Sub-Saharan Africa is an example that has to do with historical reasons where variants occurred, migration patterns of how people migrated around the world

Just to paint the contours of it, in Ireland, what’s the frequency that a child is born with this?

Wendy would have to look this up but guesses it’s on the order of 1 in 5,000 or so [ GeneReviews states a prevalence of 1 in 4,500]
In the US is is a little bit less than that, maybe 1 in 10,000 Which is still a pretty common condition, relatively speaking
Which is still a pretty common condition, relatively speaking

In your career, do you think PKU will be a target of gene therapy?

This is something Wendy thinks about a lot
Inborn errors of metabolism are conditions like PKU, but also other things that have to do with the way the body digests/ processes/ metabolizes food
And some are easier targets for gene therapy
Many of these genes are expressed in the liver Think of the liver as the metabolic “brain” of the body or the metabolic “clearinghouse”
The liver is a relatively easy place for gene therapy to target
For certain conditions that are recessive conditions characterized by the loss of function, you have to add back the missing enzyme (or protein), but you probably don’t have to get it to 100%
Peter alluded to carriers for these conditions Individuals who have one copy of the gene that’s working fine but one copy of the gene that is not [it’s the recessive disease variant] Carriers tend to be fine, and this means for gene therapy, “ You don’t have to be perfect, you have to get some in there… (enough) but you don’t have to get 100%. ”
These types of conditions are interesting as gene therapy targets, given that the treatment is lifelong (that kind of stinks) Gene therapy could be transformational in terms of quality of life for many of these metabolic disorders
Think of the liver as the metabolic “brain” of the body or the metabolic “clearinghouse”
Individuals who have one copy of the gene that’s working fine but one copy of the gene that is not [it’s the recessive disease variant]
Carriers tend to be fine, and this means for gene therapy, “ You don’t have to be perfect, you have to get some in there… (enough) but you don’t have to get 100%. ”
Gene therapy could be transformational in terms of quality of life for many of these metabolic disorders

Wendy would not be surprised if within our lifetimes people will be trying genetic therapies for PKU

The evolution of genetic research: from DNA structure to whole genome sequencing [18:30]

How did you do genetic work during your PhD?

Wendy got her PhD in the early ‘90s about a decade before the human genome was sequenced
We obviously understood the structure of DNA and that DNA was a template that was used to make RNA, and that RNA was then used to make protein (the axiomatic principle of life)

Explain the differences between sequencing, protein gels, and what the state of science was a decade before the human genome was sequenced .

And also, if you can remember, speculate on what was believed to be the outcome of the human genome sequence and how that differed from what was actually found.

When Wendy first started her PhD, they didn’t have machines that would cycle between the three different temperatures needed for PCR PCR (polymerase chain reaction) is a molecular xerox machine we use to amplify DNA to then use it for sequencing and other things Automated thermocyclers are used to change the temperature for different stages of this amplification process Heat it up to denature the DNA The enzyme polymerase would work at a different temperature, so you’d have to bring the temperature down There were three different temperatures that you would go through for 30 cycles Imagine the cheapest labor as a graduate student: you’d have an ice bucket, a heating block, and a water bath to provide these three temperatures You’d essentially be a robot literally moving samples
The early days of DNA sequencing used radioactivity We’d have these gels and we’d be reading out these ladders of sequence It was all very manual and not very high throughput Wendy certainly did that, reading out the phenylalanine hydroxylase gene to be able to see all of this
PCR (polymerase chain reaction) is a molecular xerox machine we use to amplify DNA to then use it for sequencing and other things
Automated thermocyclers are used to change the temperature for different stages of this amplification process Heat it up to denature the DNA The enzyme polymerase would work at a different temperature, so you’d have to bring the temperature down There were three different temperatures that you would go through for 30 cycles
Imagine the cheapest labor as a graduate student: you’d have an ice bucket, a heating block, and a water bath to provide these three temperatures You’d essentially be a robot literally moving samples
Heat it up to denature the DNA
The enzyme polymerase would work at a different temperature, so you’d have to bring the temperature down
There were three different temperatures that you would go through for 30 cycles
You’d essentially be a robot literally moving samples
We’d have these gels and we’d be reading out these ladders of sequence
It was all very manual and not very high throughput
Wendy certainly did that, reading out the phenylalanine hydroxylase gene to be able to see all of this

Technological advances were necessary for the Human Genome Project

But if you think about scale and what was necessary to do this for three billion base pairs, there was no way that that could be scaled
Whole industries evolved in terms of being able to do this in a more automated way, and really the whole world organized itself around ways to do this massive project
In the early days, we had different chromosomes that were designed to different areas So Columbia used to be the chromosome 13 center of the universe, in terms of being in charge of that That meant that chromosomes are ordered by largest, so chromosome one is the largest chromosome So you’d have some groups that had bigger jobs than others, but we would spread these around, and different groups would come together from around the world for a chromosome 13 meeting, for instance, and try and compare notes
We would have things that we called yeast artificial chromosomes , in which we’d literally, under a microscope, dissect out these chromosomes and put these into these constructs, so that we could make more of the DNA and be able to go through and sequence these
There have been transformational technologies that have allowed us to go through in terms of higher throughput, greater processivity
So Columbia used to be the chromosome 13 center of the universe, in terms of being in charge of that
That meant that chromosomes are ordered by largest, so chromosome one is the largest chromosome
So you’d have some groups that had bigger jobs than others, but we would spread these around, and different groups would come together from around the world for a chromosome 13 meeting, for instance, and try and compare notes

But one of the things that the Human Genome Project did in the early days that was really important was data sharing

Data access, really being able to make the world come together by allowing large groups of people to work together
It wasn’t every person for themselves, it really was a scientific enterprise collectively, and that’s a fundamental principle in which many of us as genomicists believe very firmly in Data sharing, privacy, and protecting individual patients, individual participants But yet, be able to make data freely available as immediately as we can, so that we can all use it and get smarter together and learn from each other and be able to advance science as quickly as possible
Data sharing, privacy, and protecting individual patients, individual participants
But yet, be able to make data freely available as immediately as we can, so that we can all use it and get smarter together and learn from each other and be able to advance science as quickly as possible

The history of the structure of DNA

Peter remembers one of the most interesting books he read in medical school was Double Helix It’s a short but fascinating and gripping story of the discovery of the structure of DNA
Peter thinks that now we are so far removed from how much ingenuity was required to figure out that structure And how that laid the foundation for all that came
The structure was solved in 1953
In the early days, there were arguments about whether humans had 46 or 48 total chromosomes because it was hard to visualize them Eventually we were able to separate them by size and banding pattern and understand that there were 23 pairs of chromosomes
Credit for the structure of DNA is typically given to Watson and Crick , but really there were four people that played a pivotal role in this
It’s a short but fascinating and gripping story of the discovery of the structure of DNA
And how that laid the foundation for all that came
Eventually we were able to separate them by size and banding pattern and understand that there were 23 pairs of chromosomes

What was the breakthrough that allowed them to under the structure of this molecule [DNA]?

This is not Wendy’s speciality
They had to get a high enough resolution of the crystallography structure
It was quite technical and there were some unsung heroes in this story
It’s remarkable to look at the 2-D images that were captured and understand the mathematics and the picture to understand that this had to be a double helix
It’s interesting when you go back and look at some of the other proposed ideas Each one had a shortcoming Each one made sense, until you realized it wouldn’t project in this way or that way
Each one had a shortcoming
Each one made sense, until you realized it wouldn’t project in this way or that way

What was the first human gene identified?

How long after the structure of DNA?

More importantly, what were the methods used to identify a gene, long before we had sequencing?

There were biochemical things that were done
For example, with sickle cell disease we knew about proteins and used protein electrophoresis to be able to see that We understood this at the protein level well before we knew it at the DNA level
Other cases we knew based on enzymatic activity, and we could see biochemically in a test tube the reaction that was run
We knew about many of those things before we knew the exact DNA sequence or what genetic variants caused those conditions
We understood this at the protein level well before we knew it at the DNA level

When you were a graduate student, how much resolution did you have into what a gene looked like?

This was before the human genome was sequenced
It was around the time that Rudy Leibel was figuring out what leptin is
Wendy remarks, “ It was pretty painful at the time. ”
We would use these things called linkage maps to try and figure out what chromosome a condition was on Linkage analysis allowed you to get to the right neighborhood, the right zip code, eventually the right address
When we did this, we didn’t have great sign posts, to be able to even figure out where we were within this
We didn’t have things like structures of genes, references
As you were doing this, you were sequencing not just one person with a disease, but also you had to sequence “normal” people (or average people) for comparison We didn’t have that as something you could just look up online
At the time, we didn’t have the internet to be able to have investigators work together from around the world
It was much more sort of old school, passing papers back and forth, and meeting in various locations
Linkage analysis allowed you to get to the right neighborhood, the right zip code, eventually the right address
We didn’t have that as something you could just look up online

It was a lot slower, a lot more laborious

Peter mentioned Ruby Leibel, he did have this big, bold idea in terms of cloning a gene for obesity
And the first time he put in a grant putting out that idea, people thought it was totally ridiculous The idea that you could identify a gene solely based on its position within the genome (we called it positional cloning) Understanding and not requiring of the biology or physiology, but just purely based on genetics and genetic mapping People thought it was impossible to do, but subsequently, a whole generation of scientists found diseases that way If you can imagine that process was often a decades long process or longer This was not something you did very quickly
Wendy often tells people, “ The first gene that she cloned took eight years. The last gene she cloned took eight hours. ” So this is just absolutely astronomically different in terms of how we now find disease genes
Peter notes, “ The speed that you’re describing even exceeds Moore’s Law . It’s on a Moore’s Law trajectory with an enormous step-function when high-throughput sequencing came along (which we can probably get to later) .”
The idea that you could identify a gene solely based on its position within the genome (we called it positional cloning)
Understanding and not requiring of the biology or physiology, but just purely based on genetics and genetic mapping People thought it was impossible to do, but subsequently, a whole generation of scientists found diseases that way
If you can imagine that process was often a decades long process or longer This was not something you did very quickly
People thought it was impossible to do, but subsequently, a whole generation of scientists found diseases that way
This was not something you did very quickly
So this is just absolutely astronomically different in terms of how we now find disease genes

What was the first organism for which we had a whole genome sequence?

It was certainly a microorganism
Wendy doesn’t remember if it was E. coli , but it was definitely a very small organism [ Wikipedia ]
Yeast were another important part of our library
Being able to understand those small organisms is easier
When it comes to the human genome, even though the Human Genome Project has been finished, there are still things we have to discover Only recently have we been able to sequence telomere to telomere, including some of the cryptic portions of the chromosome that are hard to read through
The sequence of the human genome was first announced around the year 2000
Only recently have we been able to sequence telomere to telomere, including some of the cryptic portions of the chromosome that are hard to read through

Insights and surprises that came out of the Human Genome Project [28:30]

Based on the understanding of how many genes far simpler organisms had, what was the expectation of how many genes the human genome would have?

Some people thought it would have as many as 100,000 genes

Current estimates are about 20,000 genes

But the complexity at the level of an individual gene is probably more complicated than we appreciated
Our ability to have different versions of genes (what we call isoforms) The way genes are cut and pasted together Or how they’re utilized in different ways over time and space by different organs or cell type Any one gene could be made into a dozen or more different gene products
The way genes are cut and pasted together
Or how they’re utilized in different ways over time and space by different organs or cell type
Any one gene could be made into a dozen or more different gene products

And so, some of that complexity was not at the level of the individual gene, but how that gene is reused in slightly different ways

It was shocking the first time we appreciated that it was about 20,000 genes in the genome There were definitely people that were surprised by that
Peter adds, “ It seems like such a small number given the variation between individuals. ” Outside of identical twins, we have about eight billion people on this planet, all with distinct genomes
There were definitely people that were surprised by that
Outside of identical twins, we have about eight billion people on this planet, all with distinct genomes

And yet, how similar are we all, genetically?

We’re all 99.9% the same
Wendy adds, “ About 1 in 1,000 base pairs is what you and I probably differ by, on average .” Most genetic variants (differences that we have) are not meaningful Most of these variations don’t cause any differences in the way our bodies function
On the other had, something as subtle as 1 in 3 billion base pairs can be the difference between life and death The difference in the way the body or the brain functions
Most genetic variants (differences that we have) are not meaningful
Most of these variations don’t cause any differences in the way our bodies function
The difference in the way the body or the brain functions

So, small nucleotide differences can be profound depending on what genes and when those genes work

Peter’s takeaway ‒ the human genome has 3 billion base pairs, 20,000 genes, with 46 chromosomes providing the hierarchy of organization

Explain the difference between coding and noncoding portions of the gene

When you think about all of those A’s, T’s, G’s and C’s that you talked about, it’s a relatively small portion of that information that gets moved from the DNA to the protein The portions of the DNA that are made into the proteins are about 1.5% all of that DNA sequence (an easy round number)
For that other 98.5%, there’s a lot of it that we have no idea what it does There’s certain portions we do understand they’re very important for regulation, to know where and when and how much that gene is expressed There may be other things that are subtle in terms of being able to attract binding factors, transcription factors, other things that may modify the DNA (make biochemical changes to the DNA itself) which may affect gene expression There are repetitive sequences that probably don’t do anything positive for us but get carried along in the ride that people have called “ junk DNA ” We don’t know everything about this and there may even be disease causing variations in that space that we haven’t recognized yet
The portions of the DNA that are made into the proteins are about 1.5% all of that DNA sequence (an easy round number)
There’s certain portions we do understand they’re very important for regulation, to know where and when and how much that gene is expressed
There may be other things that are subtle in terms of being able to attract binding factors, transcription factors, other things that may modify the DNA (make biochemical changes to the DNA itself) which may affect gene expression
There are repetitive sequences that probably don’t do anything positive for us but get carried along in the ride that people have called “ junk DNA ”
We don’t know everything about this and there may even be disease causing variations in that space that we haven’t recognized yet

“ It’s a small minority [of the human genome] that actually encodes ultimately what we think of as most of what forms the body, physically forms the body in terms of proteins. ”‒ Wendy Chung

In 2000, when the Human Genome Project results were announced, what fraction of those 3 billion base pairs were identified?

Wendy estimates the answer to be around around 70% or so

Did that include all of the coding segments or was it not yet understood at that time what fraction of those were coding and non-coding?

The majority of the coding sequence was identified at that time
There were a few portions of the genome that were hard to read out for various reasons Or hard to map and put the pieces together
One of the things for the listener to realize is that there was a bit of a jigsaw puzzle When we did (and when we do) the sequencing in many cases were not sequencing telomere to telomere (or end-to-end along the chromosome) So it’s not as if we get one continuous strand of the DNA sequence that comes off the sequencers where we can just read through it In many cases, we have pieces of it and we have to informally put the pieces back together and put it back into the right order In some cases, that’s because we have overlap between those pieces and so we can see based on overlap, this is the first piece, that must be the second piece, that the third piece based on the overlaps And so we make these things called contigs (or contiguous sequences of DNA) and put the puzzle and the pieces together in that way
There are certain regions of the genome that are complicated called repetitive sequences And they may not be unique And it may be hard to even sequence through those regions So putting those pieces back together in the right order in some cases has been challenging to do
Sometimes you’ll hear some of us as geneticists say there’s “ dark matter ” or there’s some “ cryptic regions ” of the genome that we haven’t been able to really dig into, and that’s because of some of these complexities of the sequences there and our ability to sequence through them
Or hard to map and put the pieces together
When we did (and when we do) the sequencing in many cases were not sequencing telomere to telomere (or end-to-end along the chromosome)
So it’s not as if we get one continuous strand of the DNA sequence that comes off the sequencers where we can just read through it
In many cases, we have pieces of it and we have to informally put the pieces back together and put it back into the right order In some cases, that’s because we have overlap between those pieces and so we can see based on overlap, this is the first piece, that must be the second piece, that the third piece based on the overlaps And so we make these things called contigs (or contiguous sequences of DNA) and put the puzzle and the pieces together in that way
In some cases, that’s because we have overlap between those pieces and so we can see based on overlap, this is the first piece, that must be the second piece, that the third piece based on the overlaps
And so we make these things called contigs (or contiguous sequences of DNA) and put the puzzle and the pieces together in that way
And they may not be unique
And it may be hard to even sequence through those regions
So putting those pieces back together in the right order in some cases has been challenging to do

So even despite what you’re saying in terms of knowing the genes or even knowing portions of the sequences, we didn’t necessarily know that it was all part of one gene or that we had all the pieces or put it all together yet

As a result, some genes and some disease were easier to crack than others

Overview of various types of genetic tests: direct-to-consumer, clinical, whole genome sequencing, and more [34:00]

What’s the difference between someone who goes out and gets a whole genome sequence and someone that goes to one of the over-the-counter sequencing services like 23and Me?

What’s the difference in the analysis and what’s the difference in the information?

Wendy points out, “ This is an important question, and if people are listening, this is time to perk up and listen closely. ”

There’s a big difference and not all genetic testing is the same

Wendy is not being critical of any of the companies, but realize they’re trying to serve a different purpose
Using 23andMe as an example (or ancestry.com ) those are not medically targeted They’re not trying to answer a specific medical question of: Do you have an increased risk of breast cancer? Do you have an increased risk of heart attack? They’re really not getting at that level of detail
Ancestry.com is very good at being able to understand your heritage Literally where your family is from, where your ancestors are from It’s quite detailed at this point in terms of being able to say what part of the world your family comes from For example, if you were adopted and don’t know about your heritage or ancestry, it would be able to give you some of that. If you’re trying to find this out, you may identify some of your blood relatives, some people who you would know from a family reunion and some people you might not know for some reason Even people who are adopted can sometimes find their birth parents that way But this not for the intention of identifying information for a medical purpose
About these over-the-counter services, Wendy emphasizes, “ I just want to warn the listeners that if you get something back, or more importantly if you don’t get something back from those tests, it doesn’t mean an all clear for your health. It doesn’t mean that you’re free of cancer or won’t have any increased risk. ”
They’re not trying to answer a specific medical question of: Do you have an increased risk of breast cancer? Do you have an increased risk of heart attack?
They’re really not getting at that level of detail
Do you have an increased risk of breast cancer?
Do you have an increased risk of heart attack?
Literally where your family is from, where your ancestors are from
It’s quite detailed at this point in terms of being able to say what part of the world your family comes from
For example, if you were adopted and don’t know about your heritage or ancestry, it would be able to give you some of that.
If you’re trying to find this out, you may identify some of your blood relatives, some people who you would know from a family reunion and some people you might not know for some reason
Even people who are adopted can sometimes find their birth parents that way
But this not for the intention of identifying information for a medical purpose

There are other tests that are really designed for a medical purpose

Many listeners may have gotten a test for instance, if they were thinking about having children ( family planning ) and wanted to know if they were at increased risk of having a child with something like Tay-Sachs disease or cystic fibrosis One of those other recessive conditions that we alluded to This is not necessarily about abortion, but this is about being able to care for a child long-term and think about reproductive options
Another common use-case is for thinking about cancer risk
Some people may have a family history of cancer
People may be concerned due to their particular heritage (Jewish ancestry for instance) because they know there’s a higher chance of having a BRCA1 or BRCA2 mutation [which increases the risk of breast cancer] Some people will do a very targeted test to answer a very specific clinical question
It’s answering that question, it’s not necessarily giving a genetic “clean bill of health” for everything It’s focused
One of those other recessive conditions that we alluded to
This is not necessarily about abortion, but this is about being able to care for a child long-term and think about reproductive options
Some people will do a very targeted test to answer a very specific clinical question
It’s focused

The difference between a whole genome sequencing and exome sequencing [37:30]

Genomic includes all the genes It’s not focused on just a handful of genes It’s focused on the genes in the genome (those 20,000 genes)
You can look at the coding regions (discussed earlier) Looking at the regions of DNA that encodes protein sequence, we call in that aggregate an exome The littles pieces that code the genes are called exons , and all of them together in aggregate is called the exome
Other individuals are interested in knowing all 3 billion of their base pairs (their entire genetic sequence, and we call that a genome That will include everything, bot the coding and noncoding regions
Wendy thinks of a genome sequence as being in some ways THE genetic test; it’s all encompassing
One can blind yourself to look at very focused subsets of genes based on a clinical indication, or you can look at everything
Maybe you want to look at everything about your health or maybe you don’t know all of the genes for your particular symptoms and you have There are many conditions that are genetically heterogeneous (or have many different genes that can cause them), and so we want to be all encompassing in terms of looking at that
It’s not focused on just a handful of genes
It’s focused on the genes in the genome (those 20,000 genes)
Looking at the regions of DNA that encodes protein sequence, we call in that aggregate an exome
The littles pieces that code the genes are called exons , and all of them together in aggregate is called the exome
That will include everything, bot the coding and noncoding regions
There are many conditions that are genetically heterogeneous (or have many different genes that can cause them), and so we want to be all encompassing in terms of looking at that

Even though we can sequence all that data right now, we can’t interpret it all

Out of those 20,000 genes, we have now assigned functions with disease for about 7,000 That still means that for over 50% of those genes we don’t know of a gene-disease association
This happens to Wendy with fair frequency, “ Even when I think I know about an association of a gene with a disease, if we study it further we’ll realize that they don’t map just one-to-one. There may be more than one disease associated with a gene. And so there’s still things that we’re figuring out about what those genes do .”
That still means that for over 50% of those genes we don’t know of a gene-disease association

Whole genome sequencing [39:30]

Peter has had a whole genome sequence done

It used one or two tubes of blood, 10 cc at the most
It was sequenced at a university as part of a clinical trial

What did that university do with his blood to read the 3 billion base pairs that make up his whole genome?

Wendy is guessing they took the white blood cells in that tube of blood and extracted what we call the genomic DNA The DNA included in each nuclei of those white blood cells
Depending on how they did this, they may have captured out specific fragments and then read through all of that using what we call short read sequencing That short read sequencing was probably less than 100 nucleotides for each little fragment
As they did that, they then had to do that informatic computational step of putting all of those pieces together And in most cases, they were probably able to do that because they had a reference sequence (they knew what the average person looked like) and they put your sequence right on top of that And to the extent that those mapped uniquely, they could put that all together There may have been some of Peter’s sequence where they didn’t know where it fit, and that got put aside in an area that they didn’t even analyze
Whole genome sequencing is very technical, and we’re not perfect at doing this There are times when there is information put to the side that hasn’t been used
As they were able to read out the sequence and put the pieces together, depending on the purpose of the analysis they could say: Whether or not you have PKU by looking at the phenylalanine hydroxylase gene
As mentioned earlier, everyone has differences in sequence about every 1 in 1,000 base pairs
They can see a difference, then they have to do an interpretation
The DNA included in each nuclei of those white blood cells
That short read sequencing was probably less than 100 nucleotides for each little fragment
And in most cases, they were probably able to do that because they had a reference sequence (they knew what the average person looked like) and they put your sequence right on top of that
And to the extent that those mapped uniquely, they could put that all together
There may have been some of Peter’s sequence where they didn’t know where it fit, and that got put aside in an area that they didn’t even analyze
There are times when there is information put to the side that hasn’t been used
Whether or not you have PKU by looking at the phenylalanine hydroxylase gene

The interpretation is actually a lot more sophisticated than one might imagine because there are literally tens of thousands of genetic variants in your genome, and what they mean, and whether or not they do anything whatsoever is hard to know

“ Each of us has what people think of as mutations or genetic variants that are associated with disease and cause a problem .”‒ Wendy Chung

Some of these genetic variants are very, very powerful, and some that are kind of wimpy and they infer some very small risk
But in the aggregate, you put together a lot of these little wimpy genetic variants, and it may amount to something more substantial

Wendy’s conclusion: depending on when your genome was sequenced, when it was most recently interpreted, you might’ve gotten really profound powerful information in terms of taking care of yourself or you might’ve gotten the sort of, “ We don’t see much here… you go on your merry way. ”

For the average middle age person the outcome of whole genome sequencing is mostly, “ We don’t see much here .” Because you’ve survived, hopefully as a relatively healthy person to this point, and you’ve essentially made it through some of the most devastating things we can see in the genome
Because you’ve survived, hopefully as a relatively healthy person to this point, and you’ve essentially made it through some of the most devastating things we can see in the genome

One thing Peter learned from his whole genome sequence

Because this was part of a clinical trial, Peter learned that he was a mosaic for a certain gene
Everyone in his family was sequenced, and one of his children has a full copy of the gene (which they got from Peter), but he was a mosaic for it and didn’t have very much of it

Can you explain what that means?

This can come up in a couple of different ways
You would think that every cell in your body is exactly the same, but in fact, that’s not true Your listeners will realize this when we think of cancer
Our genomes are not stable over our life course from the point of conception to the point of death And when you think about every cell division, if you have to copy over 3 billion letters, we’re not perfect, and we have spellcheckers to try and catch these things, but our body doesn’t always catch them Over time, mutations can accumulate in the body (and of course as they accumulate) and this may lead to a variant cell growth, which is essentially what cancer is
Cancer is at the heart a genetic disease Oftentimes not from the genes you’re born with, but the changes that happen over your life course
In certain individuals, this will be true not just of your skin cells (for instance, if there’s too much UV damage to your skin in the summertime) but this can happen in your germline as well (the egg and the sperm) Mutations in the skin (non-germline cells) are somatic mutations
Mutations in the germline can be passed down to the next generation
You can have what we call a germline mosaic
A mosaic is just like a tile pattern where you have some color tiles one color and some other tiles another color They’re a different pattern because some cells have the mutation and some don’t
In the same way you can have what we call gonadal mosaics , meaning that the germline is affected
In some cases you can see that mosaicism in the blood as well
Your listeners will realize this when we think of cancer
And when you think about every cell division, if you have to copy over 3 billion letters, we’re not perfect, and we have spellcheckers to try and catch these things, but our body doesn’t always catch them
Over time, mutations can accumulate in the body (and of course as they accumulate) and this may lead to a variant cell growth, which is essentially what cancer is
Oftentimes not from the genes you’re born with, but the changes that happen over your life course
Mutations in the skin (non-germline cells) are somatic mutations
They’re a different pattern because some cells have the mutation and some don’t

So what you were talking about in terms of getting a blood sample, you might see that a certain fraction of the cells have those mutations in the blood, and then if you see them in the next generation as well, you’ll know that it was transmitted through the germline

Germline mutations and the implications for older parents [45:15]

An interesting factoid: the number of mutations in the gemline actually increases over the life course

If you think about the biological process for spermatogenesis with men, those sperm continue to divide over the life course And those mutations can continue to accumulate over the life course
In fact, some of the conditions that are associated with de novo mutations (or new mutations), we see the frequency of that being greater for parents who are older parents at the time of conception than for parents who are younger at the time of conception It’s not that it’s astronomically exponentially higher, it’s a linear process for those types of mutations But we do see those increasing over the life course
And those mutations can continue to accumulate over the life course
It’s not that it’s astronomically exponentially higher, it’s a linear process for those types of mutations
But we do see those increasing over the life course

Historically, we would assume that women are more susceptible to that via age. Why is that?

Peter notes that the rate of either aneuploidy or mutation seems to rise more sharply with women at an earlier age, starting in the mid- to late-30s

Is the egg more impacted by that than sperm?

Meiosis in the two sexes is different, and it is susceptible to different underlying biological processes
For women, if you look at the curve in terms of problems (aneuploidy or chromosome differences , namely Down syndrome is what many people think about), it increases with advanced maternal age Essentially, that has to do essentially with the stickiness of the chromosomes at meiosis and the ability to separate or not The curve that is associated with that is not a linear relationship with maternal age, but in the mid-30s it starts to increase more significantly There’s a whole medical way that we can follow women when they’re pregnant to try and pick up those particular chromosome issues
When it comes to DNA sequence differences (not whole chromosomes but single letters) we’re thinking about that process of being able to have the cell divide and replicate (copy over that information that happens every single cell division) There is a probability that DNA sequence differences [mutations] will occur That’s a linear relationship in ben based on the biology From a reproductive point of view, men may have children over a larger period of time We can see greater differences across men as they’re reproducing
Essentially, that has to do essentially with the stickiness of the chromosomes at meiosis and the ability to separate or not
The curve that is associated with that is not a linear relationship with maternal age, but in the mid-30s it starts to increase more significantly
There’s a whole medical way that we can follow women when they’re pregnant to try and pick up those particular chromosome issues
There is a probability that DNA sequence differences [mutations] will occur
That’s a linear relationship in ben based on the biology
From a reproductive point of view, men may have children over a larger period of time
We can see greater differences across men as they’re reproducing

Do you have a clear sense why you see more of these myotic differences with age?

What fundamental characteristic of aging is driving that?

Peter doesn’t want to anthropomorphize evolution, but is it like evolution saying, “ Well, I don’t care because I don’t want you to reproduce after a certain age.. Therefore, I’m not going to preserve the integrity of your genome beyond a certain age. ” This seems to be an explanation but not the reason
Wendy has not thought of the question quite that way
Throughout all of human history, the age at which people were reproducing and having children has skewed much younger than it is in terms of current society
Wendy thinks we have pushed the boundaries to a certain extent in terms of what the biology historically has been
She doesn’t know if we had a “use before date” in terms of ovaries and gonads, but she thinks this is just historically has been what’s happened
The fundamental biology for women has been proteins that are responsible in terms of meiosis and separating of the chromosomes If you remember when meiosis starts in females, it actually is starting way, way early in gestation, even during fetal life And so those proteins have to be working/ in intact before a fetus is even born and lasting all the way through until that pregnancy is conceived This is essentially when those gametes are finally dividing So that could be 30, 40 or more years for that process to have to work, and that’s kind of asking a lot when you think about the biology
For men , another interesting factoid is that for some of these mutations that arise during the process of gametogenesis , there are what we call “selfish” sperm mutations Certain mutations may give a selective advantage to those spermatocytes where they may have a reproductive division advantage And so we may see more of those in terms of the biology of what we see in the next generation because of the effect they have directly on the sperm
This seems to be an explanation but not the reason
If you remember when meiosis starts in females, it actually is starting way, way early in gestation, even during fetal life
And so those proteins have to be working/ in intact before a fetus is even born and lasting all the way through until that pregnancy is conceived This is essentially when those gametes are finally dividing
So that could be 30, 40 or more years for that process to have to work, and that’s kind of asking a lot when you think about the biology
This is essentially when those gametes are finally dividing
Certain mutations may give a selective advantage to those spermatocytes where they may have a reproductive division advantage
And so we may see more of those in terms of the biology of what we see in the next generation because of the effect they have directly on the sperm

Whole exome sequencing and the importance of read depth [50:30]

One step down from whole genome sequencing is whole exome sequencing

If one wanted the whole exome sequence, are they actually doing the whole genome sequence and just reporting out the exome? Or is it something technically different?

You have to read the fine print on your genetic test report or your clinical trial consent or whatever it is Wendy doesn’t know the answer without knowing that
It certainly was the case that a few years ago, it was so expensive to sequence a genome that we rarely did It was really just cost prohibitive
The exome was a really good shortcut because we didn’t know what a lot of the other information meant anyway, so it would’ve been just throwing it away
Increasingly, we have a better sense of what the non-coding regions do We have a better ability to interpret and recognize genetic variants
Wendy doesn’t know the answer without knowing that
It was really just cost prohibitive
We have a better ability to interpret and recognize genetic variants

As the sequencing costs have been coming down, there’s more of a shift to going to genomes rather than exomes, but truly most of what is medically used at this point is in the coding space

So even if you’re sequencing a genome, it’s still focused on the coding regions

On a research basis it’s very different

And of course, we have to do research before we can apply it clinically
A lot of the research now is understanding what all of those regions do and being able to eventually use that information clinically
Wendy thinks within the next decade we’re going to see a shift (and we may even shift from this) from what we call short read sequencing of these 100 base pair fragments, to things that are much longer in terms of accuracy, To be able to read through some of the areas that are more complex and probably that we’ve been missing out on before
To be able to read through some of the areas that are more complex and probably that we’ve been missing out on before

What’s the technical limitation for making that longer [than 100 base pairs]?

There is just lower and lower fidelity for each base pair that you do
So at some point you start getting errors within your readout

You don’t want to have too many errors because you can’t distinguish between what are true biology versus what are artifacts of what you’re doing in the laboratory

How are you correcting the errors?

If you’re getting even one error in one short read sequence, given that we only differ from each other by 1.5% of those base pairs For example, you wouldn’t be able to use this information in court How do we preserve the fidelity of this to make such bold claims as, “ Hey, we found this blood at the scene of the crime and we absolutely know positively it belongs to this individual? ”
Sequencing is not done just once
We have a term called read depth: it’s how many times we look at any one nucleotide in the genome, and we don’t look at each position just once Depending on how much we want to spend doing it we might look at the read depth of 30x, so we might look at every one position on average 30 times And if you see out of the 30 times 29 of 1 nucleotide, 1 of the other, you say, “ Oh, that one, the oddball there, that’s probably just a sequencing error. That’s an artifact of our method in the lab. The other 29 or the ones that we want to pay attention to .”
For example, in cancer, it becomes very important to know those somatic mutations that weren’t there from birth that They may be there in a small number of cells, but cells that can be very, very dangerous for cancer And so we may increase the read depth to be very, very high We may go up to 1,000x in terms of read depth to make sure we’ve got the accuracy to see something reproducibly even in 10% of cells But again, you need 10% of a large number to have the assurance that what you’re seeing is in fact representative of the underlying biology, not an artifact
For example, you wouldn’t be able to use this information in court
How do we preserve the fidelity of this to make such bold claims as, “ Hey, we found this blood at the scene of the crime and we absolutely know positively it belongs to this individual? ”
Depending on how much we want to spend doing it we might look at the read depth of 30x, so we might look at every one position on average 30 times And if you see out of the 30 times 29 of 1 nucleotide, 1 of the other, you say, “ Oh, that one, the oddball there, that’s probably just a sequencing error. That’s an artifact of our method in the lab. The other 29 or the ones that we want to pay attention to .”
And if you see out of the 30 times 29 of 1 nucleotide, 1 of the other, you say, “ Oh, that one, the oddball there, that’s probably just a sequencing error. That’s an artifact of our method in the lab. The other 29 or the ones that we want to pay attention to .”
They may be there in a small number of cells, but cells that can be very, very dangerous for cancer
And so we may increase the read depth to be very, very high We may go up to 1,000x in terms of read depth to make sure we’ve got the accuracy to see something reproducibly even in 10% of cells
But again, you need 10% of a large number to have the assurance that what you’re seeing is in fact representative of the underlying biology, not an artifact
We may go up to 1,000x in terms of read depth to make sure we’ve got the accuracy to see something reproducibly even in 10% of cells

Genetic testing for breast cancer [54:00]

BRCA1 and BRCA2 was mentioned earlier

When a person wants to be tested for breast cancer genetics, is the DNA still taken from white blood cells?

These days we do things lots of different ways
We’ve tried to make everything we do more accessible
We can do things from cheek swabs, from saliva samples, from blood samples
We try to make it less invasive and easier to do (even potentially from home)

When we do a breast cancer genetic screen, how many known genes are we looking for?

It’s your choice either as a doctor ordering the test or as a patient getting the test It’s a little bit a la carte
In some cases you know you have a family history of BRCA mutation and so we may know the exact address to go to It’s a very simple plus/ minus readout And we don’t have to do a whole genome sequence for that We just need to look at one gene and say yay/ nay for that particular variant
Certain variants are seen in certain communities
For example, if you happen to be Ashkenazi Jewish , there are three different spots in BRCA1 or 2 that account for the vast majority of all mutations in those two genes And if you know that, we can take a shortcut and for literally a small fraction of the cost of sequencing a genome, we look at those three spots We get yay/ nay, and you’ve got most of the information that you need
There’s some people who come in with a family history of breast cancer and they say, “ But I want to be careful, ” and so in that circumstance we may do a panel of 50 different genes 50 different genes that’ll cover most of the genes that we see for hereditary, not just breast cancer, but ovarian cancer, colon cancer, the most common cancers that we see that are driven by germline or inherited genetic factors
It’s a little bit a la carte
It’s a very simple plus/ minus readout
And we don’t have to do a whole genome sequence for that
We just need to look at one gene and say yay/ nay for that particular variant
And if you know that, we can take a shortcut and for literally a small fraction of the cost of sequencing a genome, we look at those three spots We get yay/ nay, and you’ve got most of the information that you need
We get yay/ nay, and you’ve got most of the information that you need
50 different genes that’ll cover most of the genes that we see for hereditary, not just breast cancer, but ovarian cancer, colon cancer, the most common cancers that we see that are driven by germline or inherited genetic factors

So for round numbers, 50 [genes] is a good number when you’re trying to be really comprehensive; if you said, “Just give me the focused breast cancer things” it might be more like 10

5% of cancer is accounted for by germline mutations, while 95% of cancer is accounted for by somatic mutations. Is that still accurate?

Wendy is going to modify that just a little bit for genes she’ll call monogenic highly penetrant Monogenic means single gene Highly penetrant means there’s a high probability that over the life course you’ll develop cancer if you have this particular genetic variant
So when you limit yourself to that, yes, about 5% of cancers are due to those powerful single genes, high probability of cancer
Now, on the other hand, over time we’ve realized that there are additional genes that I’ll call moderate risk genes Many of those genes may confer something like a two to threefold increased risk as opposed to something like a tenfold increased risk
So there’s another probably 5% or so that are due to those [moderate risk genes]
Then there’s this other thing that we call polygenic risk Poly meaning multiple and genetic means genes This refers to multiple genes The number of genes we often look at in those circumstances may be anywhere from 100 to hundreds, or even thousands of genetic variants All mathematically summed together to understand what the risk is associated with that package
Monogenic means single gene
Highly penetrant means there’s a high probability that over the life course you’ll develop cancer if you have this particular genetic variant
Many of those genes may confer something like a two to threefold increased risk as opposed to something like a tenfold increased risk
Poly meaning multiple and genetic means genes
This refers to multiple genes
The number of genes we often look at in those circumstances may be anywhere from 100 to hundreds, or even thousands of genetic variants All mathematically summed together to understand what the risk is associated with that package
All mathematically summed together to understand what the risk is associated with that package

“ All of us have genetic variants that go into that polygenic risk. ”‒ Wendy Chung

Part of the question is: along a distribution, are you at the high end of that risk curve or are you at the low end or at the average end?
And so within that, this is now something that is not clinically being utilized routinely, but we are on a research point of view trying to understand clinical implementation for now ‒ those polygenic risks for cancer
Peter assume this may amount to maybe 10% of cases, so you can say 20% of cancer has a genetic component And that’s broken down into these three categories: monogenic and highly penetrant, monogenic moderate risk, and polygenic
And that’s broken down into these three categories: monogenic and highly penetrant, monogenic moderate risk, and polygenic

Back to the woman who wants to do a deep dive on breast cancer, why is it that you don’t need to look directly at breast cells?

Four women in this woman’s family have died of breast cancer But we don’t know which genes it is because they’re deceased
But we don’t know which genes it is because they’re deceased

Why is it that we can infer that what we see in a cheek cell (an epithelial cell or in a monocyte in the blood) is also captured in mammary tissue?

Good question
The answer is, it’s probably not
What you’re doing with these samples is your getting at the germline Mostly what you were born with Inherited susceptibility
As we talked about, your genes are changing over your life course
Your cells are changing over your life course, and cancer doesn’t happen overnight You don’t go from a normal cell to a cancer cell overnight There’s a progression in terms of going through this
There are other ways that people have thought about that called a liquid biopsy [see more on episode #267 with Keith Flaherty ] It’s a slightly different test than what was discussed before
Liquid biopsies look for these somatic mutations, but when you’re looking for that “needle in a haystack”, if you’ve got a tumor that’s going to slough off some of that DNA into the circulation, you might be able to see some of that fragmented DNA floating around and you might be able to pick up some of those mutations that might be reflective of that mammary cell that’s either gone awry and is a cancer, but maybe not something that you’re detecting on mammography or something else
In some ways, this has been the holy grail of being able to do cancer screening
It’s not quite ready for prime time yet
Right now, people are thinking about liquid biopsies for recurrence of cancer How to monitor someone who had a previous cancer diagnosis
The other use-case people have thought about is someone who might be at high risk of cancer Someone who is identified for whatever reason (based on exposure or genetic profile)
But liquid biopsies are not ready yet for population screening, in terms of being able to pick up cancers at an earlier stage
Mostly what you were born with
Inherited susceptibility
You don’t go from a normal cell to a cancer cell overnight
There’s a progression in terms of going through this
It’s a slightly different test than what was discussed before
How to monitor someone who had a previous cancer diagnosis
Someone who is identified for whatever reason (based on exposure or genetic profile)

What information does direct-to-consumer testing provide (from companies like 23andMe and Ancestry.com)? [1:01:30]

Based on cost, these companies are obviously doing something far less than a whole genome sequence or even a whole exome sequence

What are they technically doing with the epithelial cell of your cheek (or the saliva) or the white blood cells that they get?

Wendy advises, “ Read the fine print of what you sign on the consent form. ”
It may change over time
She doesn’t represent any of those companies and doesn’t want to misspeak about what they are doing
In general, they’re not trying to: Detect cancer Not trying to read out the genome for the purpose of getting you medical information or “news you can use” to manage your own healthcare
They’re reading the genome in a way that Wendy calls more “recreational”
For example, with 23andMe you may find out something about: If you were to eat asparagus, what your urine might smell like What your earwax might be like If you’re lactose intolerant Things related to how the biology of your body works They are related to genetic variants
But they’re not telling you based on your earwax if you’re going to have major problems with hearing loss down the road or cancer risk or things like that
Detect cancer
Not trying to read out the genome for the purpose of getting you medical information or “news you can use” to manage your own healthcare
If you were to eat asparagus, what your urine might smell like
What your earwax might be like
If you’re lactose intolerant
Things related to how the biology of your body works They are related to genetic variants
They are related to genetic variants

But what are they doing technically?

This depends on the company
Oftentimes they’re reading out what we call single nucleotide polymorphisms (SNPs)
They’re not reading out the entirety of your genome
They’re selectively going in and asking, “ At this exact address, do you have an A or do you have G? At this other address here, do you have a C or do you have a G? ” And based on that, they may selectively look at those particular variants and say with your profile: I know that your family originally came from Egypt or wherever it is in terms of being able to look at ancestry I know this particular genetic variant may predispose you to be lactose intolerant That’s generally the type of thing they’re reporting out
And based on that, they may selectively look at those particular variants and say with your profile: I know that your family originally came from Egypt or wherever it is in terms of being able to look at ancestry I know this particular genetic variant may predispose you to be lactose intolerant
That’s generally the type of thing they’re reporting out
I know that your family originally came from Egypt or wherever it is in terms of being able to look at ancestry
I know this particular genetic variant may predispose you to be lactose intolerant

SNPs

Peter asks, “ If a gene differs by more than one nucleotide, a SNP is not of much use unless you sample two SNPs in the same gene? ”
This gets tricky because technically a SNP could be a genetic variant that has a big effect on a gene and from a medical point of view be very impactful
It’s not just that size matters, as some people would say “ location, location, location ” It’s like real estate It all matters which variant we’re talking about
It’s like real estate
It all matters which variant we’re talking about

In general, the variants these companies are looking at are not the ones that are medically impactful; they’re just the normal variants that are innocent bystanders but help us understand where our ancestors came from

Variants of APOE gene

Peter notes that they do comment on some important ones, such as the APOE gene
Isoforms were mentioned earlier as normal variants, and the APOE gene has three common isoforms that would all be considered normal variants The 4th isoform is not relatively common, but it is one variant comes with a much higher risk of neurodegenerative disease and 23andMe does read out that prediction
Peter reasons that if these variants differ by only one base pair, then there’s only one place they need to sample
In 10 years, Peter has seen several instances of a SNP read that does not match the more rigorous exome sequence
The 4th isoform is not relatively common, but it is one variant comes with a much higher risk of neurodegenerative disease and 23andMe does read out that prediction

Why do you think that’s the case? Does that surprise you

Wendy is not someone who has been asked to do quality control or anything like that for laboratories
She knows of things as simple as these are done in plates (oftentimes 12 x 8 plates), and if you flip the plate the other way, you can have sample switches And you’ve got a different person being read out for a different thing It can be something as simple as a logistic like that She has seen this lab error before There can be sample switches at multiple places
And you’ve got a different person being read out for a different thing
It can be something as simple as a logistic like that
She has seen this lab error before
There can be sample switches at multiple places

Wendy’s takeaway ‒ At the end of the day, if you are going to make a major healthcare decision, before you do something irreversible (such as having a mastectomy) and you are doing something from the recreational side, get a second opinion

The GUARDIAN study and newborn genetic screening [1:06:30]

Wendy has always been wanting to be able to get information that people could use to be able to maximize health and to just be the best person they could be
She started out in the space of PKU in 1996
For a decade, she has been studying a disease with colleagues called spinal muscular atrophy (SMA) This is a neurodegenerative condition and used to be the most common genetic cause of death for children less than two years of age
Starting in 2016, Wendy realized that we were just at the cusp of a treatment that potentially might slow down or stop the neurodegeneration
Yet tragically, if we didn’t identify babies before they started showing symptoms, it would be too late
We had this window of opportunity
They started a newborn screening program for SMA
Babies that were identified through that had the option (if they wanted to) of going to a clinical trial That ended up being quite synergistic in the sense that they did identify babies who would’ve been predicted to have the most severe type of SMA They got into early clinical trials right away and benefited
That helped in terms of the ultimate evidence that was necessary to show the efficacy of those treatments
And because we were able to show that we could do it technically and that people wanted it, SMA has been added to the recommended universal screening panel for babies across the United States
So now 4 million babies born each year in the United States are screened for SMA, and we have three FDA approved treatments including a one-and-done gene therapy
This got Wendy thinking on a larger scale
Since then, they did a newborn screening study for Duchenne muscular dystrophy (DMD) And actually just recently the FDA approved a treatment for DMD
Wendy is getting more impatient and doesn’t want to do these one by one
She started thinking about, “ How could we do these at scale for population health, but not just for one condition at a time, but how could we do it for dozens or hundreds or potentially even more conditions? ”
The GUARDIAN study stands for: G enomic U niform screening A gainst R are D iseases I n A ll N ewborns
This is a neurodegenerative condition and used to be the most common genetic cause of death for children less than two years of age
That ended up being quite synergistic in the sense that they did identify babies who would’ve been predicted to have the most severe type of SMA
They got into early clinical trials right away and benefited
And actually just recently the FDA approved a treatment for DMD

The idea behind that is to take that same newborn screening dried blood spot that we use already for PKU and sequence the genome

We don’t need to read out everything in the genome
We only read out the genes that we consent people to read
Wendy calls those genes, “ news we can use ” Information that has treatments immediately available
In planning this study for just over four years with families, we had many, many iterations about what they wanted us to screen for What should enable them to be the best parents and give their children the best chance at a healthy life
We also thought about this dynamic change in what we’d have treatments for The fact that the world is changing rapidly And we wanted the flexibility that if a new treatment became approved tomorrow, boom, we could instantly change the screen and be able to implement that We wouldn’t have to wait a decade to gather the evidence to do that We wanted to be nimble and flexible
Information that has treatments immediately available
What should enable them to be the best parents and give their children the best chance at a healthy life
The fact that the world is changing rapidly
And we wanted the flexibility that if a new treatment became approved tomorrow, boom, we could instantly change the screen and be able to implement that We wouldn’t have to wait a decade to gather the evidence to do that
We wanted to be nimble and flexible
We wouldn’t have to wait a decade to gather the evidence to do that

The reason for using the genome as the backbone is it gives us that infinite flexibility to be able to adapt and to be able to move the field forward

We’ve been doing the GUARDIAN study in New York City since September, 2022, and right now have screened just over 3000 babies
It has been remarkable to Wendy in terms of being able to see the broad support from our community in doing this
Most of the listeners probably realize the wonderful diversity we have in New York City, that is the people who participate It’s not just White folks It’s not just people who are from Ireland, earlier we were talking about Irish individuals and PKU It’s people from around the world We have about a quarter of people of European ancestry, of Latina ancestry, of Black ancestry, of Asian and other ancestry It’s representative of the world
It’s also geared to leave no baby behind because newborn screening is this one universal thing where everyone goes through the health system in the same way
And by making this free and being able to allow everyone to enter if they so choose, we can really see also what information people want and what they don’t want Within this one of the things that’s been refreshing to see that about 74% of parents that we approach and offer this to decide they want to do this When we did this for SMA, the number was 93%, and when we did this for Duchenne muscular dystrophy, it was 84% It’s not 100% of people who want any of these genetic screens, and that’s perfectly fine But it’s also not 10%
It’s not just White folks
It’s not just people who are from Ireland, earlier we were talking about Irish individuals and PKU
It’s people from around the world
We have about a quarter of people of European ancestry, of Latina ancestry, of Black ancestry, of Asian and other ancestry
It’s representative of the world
Within this one of the things that’s been refreshing to see that about 74% of parents that we approach and offer this to decide they want to do this
When we did this for SMA, the number was 93%, and when we did this for Duchenne muscular dystrophy, it was 84%
It’s not 100% of people who want any of these genetic screens, and that’s perfectly fine
But it’s also not 10%

“ The majority of parents are saying yes, if there’s something I can do to ensure that I have a healthier child, give it to me. Help me be a better parent. Why would I not want to do this? ”‒ Wendy Chung

Newborn screening

We realize that traditional newborn screening isn’t perfect Wendy never thought it was, nothing ever is
But we realize that adding this additional dimension helps us to do a better job And we’ve even done it for PKU within this study
For example, part of newborn screening identifies some children with severe combined immunodeficiency (SCID) , but a treatments is available including a bone marrow transplant This is a problem where you can have an overwhelming infection and die So because of that, we have, as part of newborn screening, a way to screen and identify some, but not all children that We’ve now added this genome sequencing to enrich and improve that In fact, we identified a baby that was missed by our traditional newborn screening for SCID And now there is the opportunity to intervene at an early stage when a bone marrow transplant will be most effective
There are numerous examples where we’ve identified disease Whether it’s Wilson’s disease, whether it’s severe combined immunodeficiency, whether it’s achondroplasia Other conditions that are treatable, that we just needed to identify those babies
Because Wendy has been practicing in New York City for 25 years, she knows how people navigate the system and how they get through, and we’ve been able to really get to many of the people who are usually unfortunately left behind These people may be immigrants, they don’t speak the language, they don’t have the same health insurance The individuals that we’re seeing come out positive for this are very, very different in terms of reflecting our community than the people who navigate the healthcare system and get in to see us
Wendy never thought it was, nothing ever is
And we’ve even done it for PKU within this study
This is a problem where you can have an overwhelming infection and die
So because of that, we have, as part of newborn screening, a way to screen and identify some, but not all children that
We’ve now added this genome sequencing to enrich and improve that
In fact, we identified a baby that was missed by our traditional newborn screening for SCID And now there is the opportunity to intervene at an early stage when a bone marrow transplant will be most effective
And now there is the opportunity to intervene at an early stage when a bone marrow transplant will be most effective
Whether it’s Wilson’s disease, whether it’s severe combined immunodeficiency, whether it’s achondroplasia
Other conditions that are treatable, that we just needed to identify those babies
These people may be immigrants, they don’t speak the language, they don’t have the same health insurance
The individuals that we’re seeing come out positive for this are very, very different in terms of reflecting our community than the people who navigate the healthcare system and get in to see us

Based on other studies that we’ve done, most of these children would’ve been diagnosed on average somewhere between 8-10 years of age, and we’re able to identify them literally a decade earlier, before a lot of damage has been done to their body

This is just the beginning
Having screened 3000 babies is great It demonstrates that we can do this It tells us what our community wants out of this It shows us some pitfalls in terms of how it’s hard to do and what we need to do, to do it better
Groups are working on therapies and there is now an opportunity for treatment
This is a powerful way of moving health equity forward at least for children for the next generation
It demonstrates that we can do this
It tells us what our community wants out of this
It shows us some pitfalls in terms of how it’s hard to do and what we need to do, to do it better

Is this something that’s done only at Columbia or is it a multicenter New York Hospital endeavor?

This is being done through the New York Presbyterian hospital system It’s not just Columbia, but it’s through this hospital network
Bases on the success of this, they are figuring out how to expand this more broadly
Integrating within the public health infrastructure is not trivial to do on this scale
For example, if we were to do this for every baby in New York state, we’d need to do it for about 210,000 babies a year
It’s not just Columbia, but it’s through this hospital network

This something that we’re gaining the experience to know what the pain points are and how to solve for them

Is this all funded by the NIH?

As you can imagine, this is not inexpensive to do
None of this is funded by the NIH

“ This ends up being about two orders of magnitude larger in costs than anything the NIH can fund. ”‒ Wendy Chung

It’s a challenge as you think about big, bold, new transformative ideas, how do we as a scientific community accomplish these?

They’ve done this by putting together many different stakeholders No one group could be able to take this on
And they’re not completely there with the funding
They need to demonstrate that they can do this with hopefully 100,000 babies They need this sample size to be able to see some of these rare conditions, and to know what the outcomes are, and to know that they can really screen for them
No one group could be able to take this on
They need this sample size to be able to see some of these rare conditions, and to know what the outcomes are, and to know that they can really screen for them

What is the actual cost of doing the sequence for each baby? To look at those 250-some odd conditions?

They started out with a round number of $1,000 per baby Thinking about generating the data, interpreting the data, getting it back to folks
The goal is to be able to do this and get it down by an order of magnitude ($100 per baby)
And in doing that, can we think about the economic impact, most importantly, the health impact for the baby?
We are doing the economic analysis to understand how we think about this as a society, how to be able to afford doing this
The good thing is sequencing costs are decreasing
More of this can be done in automated ways as we understand what normal variation is for people around the world And one of the critical factors is doing that around the world
Peter reacts, “ $1,000 is a fully loaded cost. That’s the interpretation, that’s the overhead, that’s the PI time and such. That sequencing cost must be significantly less than that given that Illumina could do a whole genome sequence for $1,000 now. Is that right? ”
Even over the course of this study, the sequencing costs have come down
The study began in September, 2022 (less than a year ago), but already the sequencing costs have come down Wendy expects they’ll continue to come down
So data generation certainly can be done for less than $1,000 now
But part of it is the interpretation and the study staff who explain the study to everyone, explain results It includes multiple pieces
Thinking about generating the data, interpreting the data, getting it back to folks
And one of the critical factors is doing that around the world
Wendy expects they’ll continue to come down
It includes multiple pieces

Treating genetic disease with gene therapy [1:18:00]

How many of these single gene, highly penetrant conditions that children are born with have FDA-approved gene therapies already?

At the outset of this discussion, you mentioned that SMA has a successful gene therapy

Not very many of them

The shining example is SMA (spinal muscular atrophy)
There are very few gene therapies that are now approved Examples include: Duchenne muscular dystrophy , hemophilia , and a few other conditions
Others have treatments available
One example that we’ve had through the GUARDIAN study, is a condition called Wilson Syndrome That ultimately leads to liver failure and need for liver transplant The treatment that we give children for this is zinc We can simply use zinc to outcompete copper and make sure that we don’t end up with a copper overload situation So it’s something that doesn’t require gene therapy, it doesn’t need anything that fancy Treatment is very well tolerated, pennies a day in terms of doing this, and we hope extremely effective
Examples include: Duchenne muscular dystrophy , hemophilia , and a few other conditions
That ultimately leads to liver failure and need for liver transplant
The treatment that we give children for this is zinc We can simply use zinc to outcompete copper and make sure that we don’t end up with a copper overload situation
So it’s something that doesn’t require gene therapy, it doesn’t need anything that fancy
Treatment is very well tolerated, pennies a day in terms of doing this, and we hope extremely effective
We can simply use zinc to outcompete copper and make sure that we don’t end up with a copper overload situation

“ Although gene therapy is wonderful, I want to underscore we don’t always need gene therapy as long as we have that early diagnosis. ”‒ Wendy Chung

If you could wave a magic wand, what would be the three diseases you would want to put high on the list of gene therapy targets?

What diseases that you see in the pediatric practice would be most amenable to gene therapy in terms of some aggregate score of the technical nature of doing the gene therapy and the lack of alternative therapies elsewhere, and the number of kids afflicted?

Great question; Wendy hasn’t ever thought it through in exactly that way
There are a lot of neurological conditions
In terms of places that we are woefully behind in terms of treatments, one shining example is Tay-Sachs disease Because there’s no treatment, the way many individuals have dealt with this is simply not having children or not having children together or going through other reproductive options Things like Tay-Sachs disease is just a terrible condition, and it has relatively high population prevalence and has really nothing available in terms of treatment today Those children are born healthy, normal children and die within the first few years of life with a degenerative course oftentimes associated with epilepsy
Fragile X is another similar condition, although we still need to understand treatability It is similar in terms of high frequency and really nothing in terms of treatability at this point Gene therapy for this is a little bit tricker From a technical point of view, it would take a different strategy
There is a large group of inborn errors that primarily affect the liver and cause liver disease Whether you’re talking about something like maple syrup urine disease or propionic acidemia We have good programs in place to identify those children, but our treatments are not as good as they should be
Because there’s no treatment, the way many individuals have dealt with this is simply not having children or not having children together or going through other reproductive options
Things like Tay-Sachs disease is just a terrible condition, and it has relatively high population prevalence and has really nothing available in terms of treatment today
Those children are born healthy, normal children and die within the first few years of life with a degenerative course oftentimes associated with epilepsy
It is similar in terms of high frequency and really nothing in terms of treatability at this point
Gene therapy for this is a little bit tricker From a technical point of view, it would take a different strategy
From a technical point of view, it would take a different strategy
Whether you’re talking about something like maple syrup urine disease or propionic acidemia
We have good programs in place to identify those children, but our treatments are not as good as they should be

How gene therapy works, and the tragic story of Jesse Gelsinger [1:22:00]

Peter recalls, “ Probably 23 years ago we had a tragedy in one of the most highly publicized examples of early gene therapy. The tragedy of course, really didn’t have to do directly with the gene therapy. It had to do with the vector that was used to deliver it. ”
The young man ( Jesse Gelsinger ) who received that gene had an inborn error of metabolism, a urea cycle defect called ornithine transcarbamylase deficiency
He was part of a clinical trial at the University of Pennsylvania in 1999
They used an adenovirus

Explain what that means

Contrast what was state of the art 25 years ago with what’s being done today

Adenoviruses cause the common cold, whether it’s adenovirus or adeno-associated virus
We often use that as the vector or the delivery vehicle to deliver genes
Within this, the viruses are manipulated, they’re engineered, so to speak, so that they’re not going to be contagious So even though you might get a cold or pass it along to someone, you’re not going to do that with gene therapy yet
There are problems with this because the common cold is common, and so people may have been infected with adenoviruses and their body may try and mount an immune response when it’s infected (as it would be with a cold) And that’s where a lot of the mischief comes in
Unfortunately, it hasn’t ended with Jesse and Jesse’s death There have been other deaths in the gene therapy space with others that have had a response to the vectors Oftentimes an immunological response to that
In Jesse Gelsinger case, the vector and the gene therapy was targeted at the liver
Sometimes there can be an overwhelming response from the liver, where the liver starts to fail, where there’s an immune response that goes on This has not been solved completely at this point
There have been other genetic therapies, other diseases, not just liver diseases, but where there have been similar responses
One of the things that we’ve learned from this is we have to be very careful with people with underlying liver disease when it comes to this, because a fragile liver can get tipped over, especially with adenovirus
We also have to be careful about who’s been exposed to those viruses Sometimes we do screens to be able to see who might have one of these responses
Ultimately and partly because of that, people have also been trying to figure out other delivery systems, other vehicles, other ways of being able to get those genes into cells that may not be as toxic or problematic
So even though you might get a cold or pass it along to someone, you’re not going to do that with gene therapy yet
And that’s where a lot of the mischief comes in
There have been other deaths in the gene therapy space with others that have had a response to the vectors Oftentimes an immunological response to that
Oftentimes an immunological response to that
This has not been solved completely at this point
Sometimes we do screens to be able to see who might have one of these responses

Why did Jesse have such a harsh response to gene therapy?

Adenovirus is very common, and Peter presumes that Jesse had already been exposed to some antigen related to this He already had memory B cells and memory T cells that were ready to mount a healthy immune response, should he be exposed to that adenovirus again
He already had memory B cells and memory T cells that were ready to mount a healthy immune response, should he be exposed to that adenovirus again

Was his response because of the dose of adenovirus that he received, or does it imply that he wouldn’ve had some catastrophic multisystem organ failure had he been exposed to that exact adenovirus as a cold and this was just a function of his underlying health?

It’s a very tricky situation
Peter is right, there is a dose response in terms of the immunological response So you don’t want to go too high on the dose because you don’t want to have too big a response
On the other hand, with these gene therapies, you often get one chance at this in terms of doing this Because once you’ve given the therapy, the body is going to mount an immune response to that and would neutralize that same therapy if you were to give that again
So the tricky thing about this is you don’t want to go too high and you don’t want to go too low If you underdose it, and if you don’t get enough in and that’s your one shot on goal, you’ve burned it
As it is with many clinical trials when you’re first in human, you don’t know
Oftentimes there is research in non-human primates in terms of trying to figure out as much as you can, but it’s still not a person And each person is unique
When you do the first person, you learn and you figure out from there whether you’re going to go higher or lower, but there is someone who’s going to be the first person
So you don’t want to go too high on the dose because you don’t want to have too big a response
Because once you’ve given the therapy, the body is going to mount an immune response to that and would neutralize that same therapy if you were to give that again
If you underdose it, and if you don’t get enough in and that’s your one shot on goal, you’ve burned it
And each person is unique

Is there no way to engineer the adenovirus to make it invisible to the immune system while still able to insert its DNA package into the cell?

There are certainly things that we do to try and do this better
For instance, one of the advantages with SMA is we’re dosing them at a week or two of life They haven’t had the common cold, they haven’t been exposed to these things They’ve got a fresh immune system, so the likelihood they’re going to have a response like this is much lower
So we haven’t been seeing those types of things with newborns that we’ve been treating with SMA
There are other vectors and other delivery vehicles that we use that are not viruses In terms of developing new technologies, things that may not pose the same problems With the experience we’ve had from the COVID vaccine, from mRNA vaccines and having delivery systems that were basically lipid nanoparticles to deliver nucleic acids to cells, we’ve learned a tremendous amount from millions of people who have been treated with that
They haven’t had the common cold, they haven’t been exposed to these things
They’ve got a fresh immune system, so the likelihood they’re going to have a response like this is much lower
In terms of developing new technologies, things that may not pose the same problems
With the experience we’ve had from the COVID vaccine, from mRNA vaccines and having delivery systems that were basically lipid nanoparticles to deliver nucleic acids to cells, we’ve learned a tremendous amount from millions of people who have been treated with that

Use cases for gene therapy, gene addition vs. gene editing, CRISPR, and more [1:28:00]

What is required to change a gene?

For example, if you wanted to use gene therapy to fix sickle cell anemia (a one amino acid change)

The 8th amino acid in hemoglobin beta , there are two different variations (1 amino acid difference), and one causes sickle cell disease
Peter points out, “ It’s not enough to do it in the red blood cells that are floating around in the bloodstream because they’re going to be trashed in the spleen a couple of months from now. You must change the DNA of the stem cells in the marrow, correct? ”
That’s exactly right You have to get those progenitor cells from which the future generations of red cells will be derived
It’s not hard to get the correct gene sequence, and we can put that into a virus
You have to get those progenitor cells from which the future generations of red cells will be derived

Why are viruses great vehicles?

A virus was designed by mother nature to infect ourselves, and it’s pretty good at being able to do that
The viruses discussed are often helpful for gene addition Where you have a protein product that isn’t working (loss of function) and you need it to be present You need to be able to deliver or add back that gene It may not be integrated into your genome, and there are some advantages if it’s not
The virus can bring a gene into cells
Many times that means bringing it into stem cells so they can have the longevity of continuing to populate the body over time
Where you have a protein product that isn’t working (loss of function) and you need it to be present
You need to be able to deliver or add back that gene It may not be integrated into your genome, and there are some advantages if it’s not
It may not be integrated into your genome, and there are some advantages if it’s not

Is it safe to say that the real challenge is that step, figuring out how to get that virus to selectively infect a progenitor stem cell within the bone marrow?

Is that why we don’t yet have genetic therapy for sickle cell anemia?

Sickle cell is interesting in that there are a couple different strategies people think of
One is gene editing ‒ fixing the gene where it is Not adding a gene but actually fixing the gene that’s present
Another strategy that people think about (for the aficionados who are thinking about that), there’s also fetal hemoglobin that’s made in utero Hemoglobin beta is the adult form of hemoglobin Fetal hemoglobin can substitute for adult hemoglobin quite efficiently It actually has a very tight binding of oxygen because the fetus needs to be able to get oxygen from the maternal blood One thing to do is turn up the amount of fetal hemoglobin expression and essentially be the in situ version of your gene therapy It’s just manipulating gene expression for a gene that’s already present
These different strategies are very technically different in terms of what we administer to people and what we’re changing in terms of gene therapy
Not adding a gene but actually fixing the gene that’s present
Hemoglobin beta is the adult form of hemoglobin
Fetal hemoglobin can substitute for adult hemoglobin quite efficiently It actually has a very tight binding of oxygen because the fetus needs to be able to get oxygen from the maternal blood
One thing to do is turn up the amount of fetal hemoglobin expression and essentially be the in situ version of your gene therapy It’s just manipulating gene expression for a gene that’s already present
It actually has a very tight binding of oxygen because the fetus needs to be able to get oxygen from the maternal blood
It’s just manipulating gene expression for a gene that’s already present

If you were to add a gene for a corrected version of beta hemoglobin, would you actually run into a problem now where you’re making too much hemoglobin and half of it is appropriate and half of it is sickle?

Is this the real reason why nobody’s interested in doing an addition therapy for sickle cell anemia?

That’s exactly right

We don’t use the gene addition strategy for sickle cell anemia because we’d have to dilute out (so to speak) so much of the hemoglobin with the sickling that physiologically we run into other problems

Would gene editing be the best solution for a situation like that?

From a simplistic way of thinking about this, you want to go in and in situ be able to correct the genetic variant

Single nucleotide variants are the easiest ones to edit

There’s just one single base pair that need to be flipped
It actually matters what that base pair is if you have to change an A to a G or a C to a T Believe it or not, there are different base editors that can do different types of nucleotide switches
But there are many mutations that are not just single nucleotides There may be multiple nucleotides, there may be multiple repeats
These are the complex things that we talked about with fragile X There may be entire chunks of chromosomes They get very complicated
Furthermore, when you think about population genetics, you may have a mutation distribution across a gene that may be quite heterogeneous
Believe it or not, there are different base editors that can do different types of nucleotide switches
There may be multiple nucleotides, there may be multiple repeats
There may be entire chunks of chromosomes
They get very complicated

In contrast, sickle cell disease is easy because you’re talking about the same position for everyone with sickle cell disease, a couple different nucleic acids, but it’s the same position essentially

Whereas other genetic conditions, it may be that almost everyone has a different mutation So you have lots of different things you need to edit and that may be easier or more difficult to do
So you have lots of different things you need to edit and that may be easier or more difficult to do

Nuances of gene editing and gene therapy [1:34:15]

Downsides of gene editing with CRISPR/Cas9

CRISPR/Cas9 is something that many will know because Nobel laureates were awarded for this amazing discovery Which was by the way, really good science with creative women who are thinking about other ways to use it
The discovery was not made with the intention of doing genetic engineering or genetic manipulations, but really smart people thinking about it
The CRISPR/Cas9 system makes changes to the genome using a double-stranded DNA break For this system to be able to make a correction, it has to cut both strands of the DNA Fundamentally, that leads to some instability as the cell repairs that process Earlier, Peter used the word fidelity, and it really is all about fidelity and potential off-target effects where you inadvertently introduce genetic changes other than the intended correction And sometimes those other genetic changes can cause mischief We call them off-target effects
Off-target effects refer to changes CRISPR/Cas9 may inadvertently cause to other genes that you weren’t even trying to target It can lead to problems of essentially promiscuity or inaccuracy or low fidelity, and Wendy points out, “ This is to me, in my opinion, the Achilles heel in terms of that particular system. ”
Which was by the way, really good science with creative women who are thinking about other ways to use it
For this system to be able to make a correction, it has to cut both strands of the DNA
Fundamentally, that leads to some instability as the cell repairs that process
Earlier, Peter used the word fidelity, and it really is all about fidelity and potential off-target effects where you inadvertently introduce genetic changes other than the intended correction And sometimes those other genetic changes can cause mischief We call them off-target effects
And sometimes those other genetic changes can cause mischief
We call them off-target effects
It can lead to problems of essentially promiscuity or inaccuracy or low fidelity, and Wendy points out, “ This is to me, in my opinion, the Achilles heel in terms of that particular system. ”

Prime editing is another gene editing strategy

Prime editing has the advantage of using a single-stranded DNA break It’s nick just one of the two strands of a chromosome The cellular machinery used for this repair is a much higher fidelity system So there are lower off target effects, lower error rates It tends to be a more robust system
This is still very, very early in terms of doing this
There are lots of other complexities in terms of the machinery to go in and make the changes
It’s nick just one of the two strands of a chromosome
The cellular machinery used for this repair is a much higher fidelity system
So there are lower off target effects, lower error rates
It tends to be a more robust system

Prime editing has strategies to be able to do just not single nucleotides, but also fix much more complex mutations

Best use and timing of gene therapy

You want to use gene therapy/ gene editing early enough before the damage is done to the body
It’s being able to get to the part of the body safely that you need to
It’s multiple pieces of the puzzle that have to all be solved simultaneously to get the whole package to work, and we’re not quite there yet
Wendy is optimistic that we are realizing that this may be one solution eventually when all the components are there that may be scalable to deal with many different types of genetic conditions

Two distinct gene editing strategies for addressing Tay-Sachs and fragile X syndrome [1:37:00]

Tay-Sachs is due to an enzyme that’s missing
It’s a recessive condition
This is a degenerative condition, and so you want to be able to get in early for all the reasons that we’ve talked about
You could do a gene addition The gene, the enzyme is missing so you can just pop it back in It doesn’t have to integrate, and that strategy would be a good strategy
The tough part as you’re thinking about the delivery system, is you need to get it into the brain
The gene, the enzyme is missing so you can just pop it back in
It doesn’t have to integrate, and that strategy would be a good strategy

What does that mean? Would you introduce an intranasal virus?

Where does this enzyme normally get made? In glial cells, in neurons?

There are multiple ways to access the brain
The blood-brain barrier makes it a protected space
Wendy doubts we’re going to be able to do it with intranasal , although there is some that you use the intranasal route
In some cases we do intrathecal For example, women who’ve had an epidural, this is basically the same way we access the space for an epidural
For anyone who’s thought about chemotherapy that we give for brain cancer, sometimes we actually have to administer it into the ventricle This sounds a little bit barbaric, but do injections through the skull
Wendy’s point is it’s not as simple as an intravenous infusion We can’t just give it peripherally and get it to the brain where we need it to go
For example, women who’ve had an epidural, this is basically the same way we access the space for an epidural
This sounds a little bit barbaric, but do injections through the skull
We can’t just give it peripherally and get it to the brain where we need it to go

Difficulties to overcome when targeting the brain

In some cases we need to get throughout the brain even into deep nuclei or different parts of the brain
For example, if you were to inject it and you had a high concentration on the left, but it didn’t get to the right, that would be a problem You need to be able to get even distribution
With Tay-Sachs, you probably don’t need to get to 100% of the protein or the enzyme that’s there Even 50% is enough And it’s possible you could get down to 20% and that would be just fine, and so that’s one strategy
You need to be able to get even distribution
Even 50% is enough
And it’s possible you could get down to 20% and that would be just fine, and so that’s one strategy

Treating Fragile X syndrome

Fragile X is a little bit more complicated
The actual mutation itself is what we call a trinucleotide repeat , a repeat that’s too big, and so we need to be able to make it smaller
It also has the same problems in terms of being in the brain
But it’s not just simply adding back some additional fragile X protein So we can’t just make it a gene addition strategy
We’ve got to really think about the gene editing to shrink the size of that repeat back down to the normal size
So we can’t just make it a gene addition strategy

What’s unknown

One of the things we don’t know until we do it in people is, “ What is that window of treatability? ”
Just to be provocative to let the listeners think about this: even if GUARDIAN worked perfectly and we could identify these babies within the first week of life, “ Is that early enough? ” Wendy hopes that for many conditions that will be It’s possible that we’ll need to go even earlier, and there are some people that have thought about in utero gene therapy/ genetic treatments For some conditions (not all of them) it might be necessary to treat during fetal development, to have the maximal effect Wendy is not saying we’re going there anytime soon, but just thinking through that
Wendy hopes that for many conditions that will be
It’s possible that we’ll need to go even earlier, and there are some people that have thought about in utero gene therapy/ genetic treatments For some conditions (not all of them) it might be necessary to treat during fetal development, to have the maximal effect Wendy is not saying we’re going there anytime soon, but just thinking through that
For some conditions (not all of them) it might be necessary to treat during fetal development, to have the maximal effect
Wendy is not saying we’re going there anytime soon, but just thinking through that

There may be imperfect solutions unless one gets to the right time and the right place, and, the right cell type even

Fragile X is a recessive condition. Presumably it can only impact women because you would need both copies of the X?

Fragile X is X-linked recessive , but what that means is that mostly males are affected Because they only have one X It’s much more unusual for a female to be affected, because they would need to have gotten the X from their father as well
Because they only have one X
It’s much more unusual for a female to be affected, because they would need to have gotten the X from their father as well

Exploring obesity as a polygenic disease: heritability, epigenetics, and more [1:41:15]

How much do we understand about the genetics of obesity and does genetic therapy play any role there?

We have ways of calculating heritability , and that gives us scientific insight into how genetic is a certain condition You can do this by looking at twins (identical twins and fraternal twins) and see how similar they are in terms of body mass index, adiposity
Obesity ends up being highly heritable It’s not the most heritable factor, but is highly heritable
To give it a round number, the heritability of obesity is somewhere around 50% (or 0.5)
Other conditions that are extremely heritable are closer to 1.0
For comparison, type-2 diabetes (non-insulin-dependent diabetes) is more heritable, there is a stronger genetic component Type-1 diabetes is less heritable; it’s a complex interaction of both the genetics that govern your immune system and what you’re exposed to
You can do this by looking at twins (identical twins and fraternal twins) and see how similar they are in terms of body mass index, adiposity
It’s not the most heritable factor, but is highly heritable
Type-1 diabetes is less heritable; it’s a complex interaction of both the genetics that govern your immune system and what you’re exposed to

On the other hand, there are environmental differences

You can look at what’s happened to the average body mass index of the average American over the last generation Our genes haven’t changed, but by most measures you can see that we’re more prosperous and in general, the average body mass index has increased
There have been some interesting studies looking at particular groups of Pima Native Americans They have genetically the same genes They come from the same original community, but they live in different environments One in which it’s more sort of a traditional environment in terms of the amount of access to calorically dense foods and the amount of physical energy that’s expended on a day-to-day basis And those same original groups, but in two different environments, you see much more obesity in the one group that has easy access to obesogenic foods versus the other that doesn’t
Our genes haven’t changed, but by most measures you can see that we’re more prosperous and in general, the average body mass index has increased
They have genetically the same genes
They come from the same original community, but they live in different environments One in which it’s more sort of a traditional environment in terms of the amount of access to calorically dense foods and the amount of physical energy that’s expended on a day-to-day basis
And those same original groups, but in two different environments, you see much more obesity in the one group that has easy access to obesogenic foods versus the other that doesn’t
One in which it’s more sort of a traditional environment in terms of the amount of access to calorically dense foods and the amount of physical energy that’s expended on a day-to-day basis

This strongly suggests that it’s not just the genes in terms of obesity

Genetics of leptin and the leptin receptor

This goes back to Rudy Leibel and his original work in terms of identifying leptin and the leptin receptor through positional cloning methods
Mutations in leptin and the leptin receptor do not account for the vast majority of obesity (they’re very rare) Wendy has had patients with these conditions, but that’s just because of the nature of her work, but it’s very rare and most people would not have seen this
Wendy has had patients with these conditions, but that’s just because of the nature of her work, but it’s very rare and most people would not have seen this

On the other hand, understanding the fundamental biology of how body rate is regulated and governed is critical in terms of understanding those two molecule

Wendy’s point is, “ I don’t know if it’s going to be for obesity, but it may be for other conditions (like myocardial infarctions or coronary artery disease) that knowing about the biology and the final common mechanism or the final common pathway through which the biology is regulated, one may have ways of either pharmacologically or some will say in terms of gene therapy being able to make permanent manipulations. ”

Statins as an example

In terms of treatment for hypercholesterolemia , there may be various different genetic mechanisms by which one has an increased risk for a heart attack
Yet statins seem to work for a lot of different people
Some have thought that rather than using statins as a medication, would there be a way of genetically making a manipulation? It’s a one-time therapy
Wendy is not saying that this is exactly where obesity treatment is going to be going, and she is excited (in a good way) that we certainly have better treatments for obesity now than we had five or 50 years ago
It’s a one-time therapy

Epigenetics adds another layer of complexity to understanding obesity [1:45:30]

Explain what the epigenome is and how it changes not just over a person’s life, but perhaps more importantly from one generation to the next

Peter wonders if epigenetics is playing a role in the propagation of obesity across generations

The bottom line is we don’t know
To break down the term epigenetics : epi means above, and then genetics the genes This refers to chemical modifications that happen to the genome, which are used to affect gene regulation
Some of those chemical modifications include methylation , and those are dynamic They can change over the life course, they can change by cell type, and they’re ways to be able to coordinate regulation of potentially groups of genes
They’re tricky to analyze from a methodological point of view Scientifically, they’re tricky because they do vary over the life course and they vary by cell type or tissue
For example, using a blood sample as a matter of trying to get the epigenetic profile for what’s going on in your brain or your pancreas doesn’t always work And it’s hard to even know whether or not it works because not as if we’re going in and doing pancreatic or brain biopsies on most people
You can do things in animal models, you can get some indirect evidence, but it’s hard to know for sure whether or not this is truly answering the question you’re trying to answer
This refers to chemical modifications that happen to the genome, which are used to affect gene regulation
They can change over the life course, they can change by cell type, and they’re ways to be able to coordinate regulation of potentially groups of genes
Scientifically, they’re tricky because they do vary over the life course and they vary by cell type or tissue
And it’s hard to even know whether or not it works because not as if we’re going in and doing pancreatic or brain biopsies on most people

Wendy’s conclusion, “There’s a lot of conjecture in the area of epigenetics and hard to know for sure exactly what that is.”

What we know from a mouse model of obesity (the agouti mouse)

Depending on how much folate you give that mouse, while the dam (the mother mouse) is carrying her pregnancy, her little mice, the amount of folate in her diet does affect the epigenetics
Folate is used for methylation of the DNA
You can see a readout in the agouti mouse, a change in coat color and obesity in these mice and their progeny
For transgenerational effects , we don’t entirely know the mechanism of how that might be occurring, whether it’s epigenetics or other things There are things that we can see, but these are complicated Wendy don’t feel like scientifically we have all the evidence to make definitive conclusions at this point But one wonders about what many different contributors could be She would have to guess that this is not going to be the major major, driver
There are things that we can see, but these are complicated
Wendy don’t feel like scientifically we have all the evidence to make definitive conclusions at this point
But one wonders about what many different contributors could be
She would have to guess that this is not going to be the major major, driver

The genetics of autism [1:48:45]

Autism is in the news all the time, it seems and certainly appears as though it’s increasing in frequency, and it’s unclear how much of that is due to an increase in diagnosis and recognition versus how much of that is triggered by other environmental factors
But there doesn’t seem to be much confusion around the fact that there’s a strong genetic component to it

Based on all of the twin studies, what is the heritability of autism?

Autism is a spectrum (as the name indicated); it’s not just one condition
It goes from severe, what some people will call profound autism and can be associated with intellectual disabilities to other individuals at the “milder end,” who are quite talented in many ways, yet have social challenges

So within that entire spectrum, if one includes everything within that, the heritability is estimated to be approximately 0.8, although some individuals will say in as high as 0.9

The point within that though is that it’s not 100% and in fact we do know of times over the life course in particular prenatal and early childhood that are important to the developing brain and where changes in exposure beyond the genes can play a role
As an example, prematurity is one of the more common exposures in terms of what happens to developing brain, and if you are born when you’re 26 weeks old, there is a much higher probability of autism than if you’re born at term at 40 weeks

There are other factors beyond just the genes that are involved, but clearly the other point that Wendy makes about heritability is one calculates heritability as a measure of the inherited genetic factors

One of the factors in autism is that there are de novo or new genetic variants that occur for the first time in the individual with autism, and those individuals aren’t captured in that measure of heritability because heritability is fundamentally trying to get transmitted genetic variants that are going from parent to child And those de novo genetic events are new in the child So there are genetic aspects not included in heritability
And those de novo genetic events are new in the child
So there are genetic aspects not included in heritability

What are the genes that seem to be responsible for autism?

This depends on who you ask and how you want to define this
Everyone would agree, there are at least 100 genes that have been identified with high confidence as being associated with autism Depending on how rigorous you want to be about this process, some people would say that we estimate that there are at least a 1000 genes , and we probably are about a third of the way there in terms of having some sense of those genes
Not surprisingly, those genes are genes that are expressed in the brain and they function in the brain
Many of those genes are especially active during intrauterine fetal development within the brain
Depending on how rigorous you want to be about this process, some people would say that we estimate that there are at least a 1000 genes , and we probably are about a third of the way there in terms of having some sense of those genes

What do they code for? How many of those genes would be genes in the exome versus the intron?

Most of the ones we recognize are in the coding sequence, but that’s a limitation of what we recognize
Statistically we realize that there is a signal in the noncoding space [of the genome]
But we have less evidence to implicate specific genes or specific genetic variants individually in the noncoding space because the effect size or how powerful they are is somewhat reduced compared to those coding sequences
The other issue is not just where in the genes, but what genes are involved

The genes that are involved fundamentally can be genes that function at the synapse ‒ the connections between brain cells and communicate between brain cells (that’s quite important)

They can be genes that are important in regulation of genes and gene networks, and many of them are transcription factors, histone modifiers

Some of those genes may be responsible for epigenetic changes
Often they have multiple downstream genes they affect
Instead of having a focused effect, they have more of a universal effect on brain function and cognition
These genes may not only be associated with autism but also intellectual disabilities, epilepsy, and they may be associated with more global effects on brain function

The SPARK study

Wendy runs a very large autism study called SPARK
Within SPARK they identified a teenage young man who actually has his autism as a responsible of undiagnosed PKU Even autism can be caused by full circle an inborn error of metabolism where there are toxic things that build up in the brain that then caused dysfunction of the brain Things that can diffuse to and have an effect on the function of the brain
Peter clarifies, “ Autism is a clinical diagnosis in the same way that familial hypercholesterolemia is a phenotypic diagnosis, it’s a diagnosis in the case of FH, where LDL cholesterol has to be above 190 milligrams per deciliter off treatment. And it’s incredibly heterogeneous in terms of the genes that are responsible. To my last count, I think there were more than 3,500 genes that could produce that phenotype of high LDL cholesterol. So autism is the same, right? The diagnosis is clinical, it’s a phenotypic defined disease, and maybe up to 1000 genes involved in that or 1000 different ways to get there or more, right? ”
Exactly right, it’s a DSM diagnosis in terms of clinical behavioral criteria
This gets confusing, but one can have a gene that’s identified as causal, but the diagnosis is still a behavioral diagnosis It’s simply a gene associated with that And as you said, not just one single gene (it doesn’t map one to one)
Even autism can be caused by full circle an inborn error of metabolism where there are toxic things that build up in the brain that then caused dysfunction of the brain Things that can diffuse to and have an effect on the function of the brain
Things that can diffuse to and have an effect on the function of the brain
It’s simply a gene associated with that
And as you said, not just one single gene (it doesn’t map one to one)

“ In fact, no one gene or genetic factor accounts for more than 1% of individuals who have that clinical diagnosis of autism. So incredibly heterogeneous. ”‒ Wendy Chung

What’s the approximate prevalence of autism today?

To give it a round number, 2% , but this number has fluctuated over time

Is this a function of greater awareness?

Wendy thinks it a function of several things
It doesn’t help that the definition has changed over time Literally the DSM diagnostic criteria have changed over time
Not surprisingly, the prevalence has changed over time
In a good way, there is greater recognition and diagnosis as Peter alluded to We’ve seen this in particular for underserved individuals that are more frequently diagnosed now Disparities are decreasing, and that’s a good thing
Literally the DSM diagnostic criteria have changed over time
We’ve seen this in particular for underserved individuals that are more frequently diagnosed now Disparities are decreasing, and that’s a good thing
Disparities are decreasing, and that’s a good thing

But there are also things that are changes in terms of society

Is this changing the biology, Wendy doesn’t know
There are possible contributing factors with that
There’s also a motivation to a certain extent in terms of the way our society works to be able to access resources So people that may not have been motivated to get a label per se, they may still have known it People may have thought it to themselves, but they didn’t necessarily seek a diagnosis or a label except that there were resources, educational resources, support resources that were important And we want to make sure those individuals get those resources
So people that may not have been motivated to get a label per se, they may still have known it
People may have thought it to themselves, but they didn’t necessarily seek a diagnosis or a label except that there were resources, educational resources, support resources that were important
And we want to make sure those individuals get those resources

What are some other, both neurologic and non-neurologic sequelae of autism or call it comorbid conditions with autism?

Wendy thinks this is a good way to phrase it
Comorbid conditions is one of the things that she thinks about
For example, some individuals will have epilepsy associated with their autism For some individuals, epilepsy will be recognized very early For some individuals that won’t come until the teenage years or adolescents, but that can be incredibly important
Within this, there are behavioral co-occurring diagnoses
For instance of anxiety is quite frequent
ADHD or attention issues are quite frequent
And some things we’re just beginning to understand
For example, most of what we know about autism is based on individuals below the age of 20 Those are the individuals who’ve been studied most
There is a whole lot we don’t know about adults with autism
Some conditions are associated with degenerative conditions, and when people are adults, there may be a particular subtype of autism that is neurodegenerative because the genes that are involved are responsible for maintenance Being able to sustain the brain and continue functioning And when they’re not functioning at some point, people start having things associated like Parkinsonism
Some subtypes of autism may be associated with increased risk of obesity
For some individuals, epilepsy will be recognized very early
For some individuals that won’t come until the teenage years or adolescents, but that can be incredibly important
Those are the individuals who’ve been studied most
Being able to sustain the brain and continue functioning
And when they’re not functioning at some point, people start having things associated like Parkinsonism

“ Believe it or not, some of these same genes may also predispose to obesity ”‒ Wendy Chung

Some of the medication we use to treat some of these behavioral conditions increase the metabolic effects and weight gain and diabetes associated with subtypes of autism
There may be more things that are under recognized and we have more gaps in our knowledge
They mentioned precision medicine earlier, but 2% is a large percentage of the population and there is heterogeneity

Everyone doesn’t need to have the same rules that they’re following or the same management guidelines, and how do we get greater specificity to not overburden people, but yet to be able to also allow them to achieve their full potential and lead their healthiest lives?

Most of what we know about autism is based on studying people who are up to but below typically 20 years old

Does that suggest that prior to about the year 2000 there was nobody really studying this?

1 many adults with autism were not diagnosed as having autism They may have had some of these challenges, but things have changed over time Having a label (a diagnosis) has changed with society
2 other individuals who were studied 20 years ago have not been followed longitudinally Although there have been some epidemiological studies like Framingham that have followed individuals over long periods of time, it’s hard to be able to do that People move, investigators lose funding, people die, lots of things that happen
Just knowing what someone looked like at 2 and that same person at 22, there are very few studies in terms of children, what that looks like
They may have had some of these challenges, but things have changed over time
Having a label (a diagnosis) has changed with society
Although there have been some epidemiological studies like Framingham that have followed individuals over long periods of time, it’s hard to be able to do that People move, investigators lose funding, people die, lots of things that happen
People move, investigators lose funding, people die, lots of things that happen

What is the heritability for other DSM conditions such as bipolar disorder?

Peter is shocked to hear that the heritability for autism is as high as 0.8-0.9
This is one of the highest heritability factors in terms of behavioral health or psychiatric conditions
Bipolar disorder and schizophrenia are certainly much lower, in the neighborhood of 0.5-0.6
Things like depression, major depression are lower still (maybe 0.3)

If the heritability is 0.8-0.9, does that imply that a person with autism will have an autistic child?

Wendy replies, “ That’s only half the equation, right? It takes two to tango in terms of making a child. So both individuals are contributing genetic factors as we’re thinking about this, and it’s the combination of those factors together within that combination. ”

You said 100-1,000 genes seem to be implicated in autism, even if we’re not talking about polygenic combination, some individuals with autism may only have one of those genes, correct?

Absolutely
Some of them may have only one gene that’s the predominant contributor in terms of this
Some will be more of that polygenic combination of factors

But a single gene individual has a 50% chance of passing that gene onto their offspring, and assuming it’s fully penetrant, they would have effectively a 40 to 50% chance of transmitting autism to their offspring?

That’s correct
For the types of genes that you mentioned, many of those individuals actually won’t go on to have their own families One of the factors within this is that those highly penetrant, single gene factors, many individuals, for instance if they’re not living independently, if they’re not verbal, they won’t pass those genes down
One of the factors within this is that those highly penetrant, single gene factors, many individuals, for instance if they’re not living independently, if they’re not verbal, they won’t pass those genes down

The genetics of cardiovascular disease [2:01:45]

Let’s pivot for a moment to cardiovascular disease and discuss the genetic perspective

FH (familial hypercholesterolemia)
Another is Lp(a) (attached to the LPA gene), roughly 1 in 10 people have an atherogenic condition genetically associated with elevated Lp(a) The most prevalent atherogenic condition Peter adds, “ That would be another great example of how gene addition therapy would be of no use because you’d want to be gene editing that. ”
The most prevalent atherogenic condition
Peter adds, “ That would be another great example of how gene addition therapy would be of no use because you’d want to be gene editing that. ”

How much of the rest of ASCVD appears to be heritable?

Beyond those two special cases of elevated Lp(a) and familial hypercholesterolemia

When we think about myocardial infarctions, hyperlipidemia, and that sort of cardiovascular health, there may be genetic factors that are numerous
But from a therapeutic point of view, we may not target all of those genetic contributors There may be final common biology
There may be final common biology

“ There may be final common biology, and so I think that’s a theme that I see most in terms of thinking about coronary artery disease, myocardial infarction, things like that. ”‒ Wendy Chung

Cardiomyopathies is one example

Cardiomyopathies affect on average about 1 in 500 individuals It’s not 1 in a million; it’s not 10% of the population; it’s somewhere in the middle
Wendy has been waiting to see the data come out, but we’ve known about many of those genes for a long time We’ve known about the mutations, we’ve known about frequency, we’ve known about natural history, and we’re waiting to see whether or not genetic therapies would be effective for those conditions
Therapy is not yet in people, but the early data in animal models are looking promising, in terms of being able to reverse this or prevent this
Wendy thinks the heart is a tricky organ to be fussing with, “ It always makes me a little bit nervous because electrical things can happen very suddenly and it can be quite dangerous. So that always makes me a little bit nervous to think about genetic therapies for the heart .”
This is a common condition that otherwise oftentimes we treat with transplant when the heart finally fails It’s be lovely if didn’t have to wait for hearts for transplant
It’s not 1 in a million; it’s not 10% of the population; it’s somewhere in the middle
We’ve known about the mutations, we’ve known about frequency, we’ve known about natural history, and we’re waiting to see whether or not genetic therapies would be effective for those conditions
It’s be lovely if didn’t have to wait for hearts for transplant

Back to ASCVD

It sounds to Peter like Wendy is saying that if genetic therapies and treatments are going to be deployed against conditions like FH, you would really do it more to mimic the drug than you would to try to correct the defect That makes a lot of sense in the case of FH because of the heterogeneity ‒ to have 5,000 different gene therapies for the 5,000 different genes that can be altered in the result of hyperlipidemia is a bad idea Whereas if you can simply knock out PCSK9 as a gene, you basically take care of everyone
That makes a lot of sense in the case of FH because of the heterogeneity ‒ to have 5,000 different gene therapies for the 5,000 different genes that can be altered in the result of hyperlipidemia is a bad idea
Whereas if you can simply knock out PCSK9 as a gene, you basically take care of everyone

Let’s talk about what that means technically

Presumably there are genetic therapies that are already in the works targeting PCSK9
PCSK9 inhibitors as a class of drug have been perhaps the most exciting drug class introduced in the last decade, and the results have lived up to the hype
Peter remembers reading the papers 15 years about when Helen Hobbs first made the discovery of individuals that were both hyper and hypofunctioning PCSK9 He thought, “ This is too good to be true. This will not pan out, ” and he was wrong
He thought, “ This is too good to be true. This will not pan out, ” and he was wrong

What does gene therapy to silence a gene but without creating some unintended consequence look like?

It’s going to start out with not just the average person who might have a higher risk
It’s going to start out at the extreme
We talked about Jesse Gelsinger, someone who’s going to be willing to be the first brave person and try this
Wendy won’t claim that she’s designed the clinical trial that goes with this, but it’s going to start at that extreme and there are going to be a lot of complexities

The financial costs and economic considerations of gene therapy [2:06:15]

Many listeners are thinking gene therapy is cost prohibitive right now

It’s not uncommon for current gene therapies to cost $3 million The range of genetic therapies currently cost between $1-3 million
We can’t afford to spend $3 million per person with the number of people who are at risk in the US population
To put this in perspective, Peter points out, “ It’s not uncommon to spend a million dollars on chemotherapy at the end of life for a year’s worth of life extension, and if you contrast that with a million dollar gene therapy in infancy that gives 80 or 90 years of life extension, it at least puts those two treatments in context. ” He’s not going to advocate one way or another
Wendy agrees
The range of genetic therapies currently cost between $1-3 million
He’s not going to advocate one way or another

Health economists have been trying to get at the cost of gene therapy in terms of the value

She’s not going to pit one against the other in terms of this, but you do have to think about it
There’s a lot of cost that goes into this if you do the economic analysis accurately Not just the healthcare system cost to the person, but the societal cost to the family, to the community
To say that it might be worthwhile in one case, you have to think about scaling
To throw a number out there, 10% of the US population has a rare genetic condition (they may or may not know it) This is true in terms of monogenic factors [single gene] that we’ve been talking about
If you now think about the percentage of the population that has obesity or type 2 diabetes or some of these other common conditions, that someday might be treated by these one-and-done types of things, then it becomes in terms of a society, what can we afford to do? What are the competing other healthcare costs or other societal costs in general that we have and how are we going to right size these?
Wendy is confident that as we have more ability to understand how to do this, there’s a lot of fixed cost, but the marginal cost is not nearly as high In terms of both what it takes to design the clinical trials, to do the manufacturing, to do the monitoring All of these things won’t scale linearly, and Wendy thinks we’ll have some cost realization that we can recoup
Not just the healthcare system cost to the person, but the societal cost to the family, to the community
This is true in terms of monogenic factors [single gene] that we’ve been talking about
What are the competing other healthcare costs or other societal costs in general that we have and how are we going to right size these?
In terms of both what it takes to design the clinical trials, to do the manufacturing, to do the monitoring
All of these things won’t scale linearly, and Wendy thinks we’ll have some cost realization that we can recoup

The big questions that we think about is how are we going to afford this and what are the key things that we need to do to enable doing this on scale? What are the competing alternatives?

With a medication you’re taking every day, if you can’t get to a good point in terms of MI risk or risk of heart health, stroke health, other things
All of these will be factored in
Eventually a health economist will price this out and figure out what a reasonable fee is to charge for such therapies

Thinking about the costs of gene therapy relative to gene sequencing, is gene therapy still in its infancy?

Absolutely
The Jesse Gelsinger case was more than 20 years ago, and we are still at our infancy in terms of being able to realize all the potential
Peter points out, “ In the year 2000, it cost $1 billion to sequence a human genome. Today it costs $1,000. So that’s a six log reduction in cost in part through Moore’s Law, in part through the step-function change of high throughput sequencing. We don’t need a six log reduction in the cost of gene therapy to make it readily available. ”

Do you think a two log reduction in the cost of gene therapy is feasible in the next two decades?

Yes
There are going to be certain catalytic transformative breakthroughs that will make and enable those changes that we’re talking about
Wendy goes back to what we did with the COVID vaccines It was incumbent upon everyone to be able to come up with solutions The solutions that allowed for the adaptability and even changing the vaccine on the fly were remarkable, at least from a scientific point of view
If you could think about the same way with delivering an mRNA vaccine and doing the same thing and realize that it’s different for genetic gene addition and doing it, but it’s not entirely different in terms of how to do this Wendy calls this “ rinse and repeat ,” But it’s being able to do this and having the infrastructure, the delivery system, the regulatory system, the manufacturing process, all of those things
Once you get this down, there are ways to scale this and to be able to do it repeatedly If the gene fits, if it’s a certain size, if there’s certain mutations
It was incumbent upon everyone to be able to come up with solutions
The solutions that allowed for the adaptability and even changing the vaccine on the fly were remarkable, at least from a scientific point of view
Wendy calls this “ rinse and repeat ,”
But it’s being able to do this and having the infrastructure, the delivery system, the regulatory system, the manufacturing process, all of those things
If the gene fits, if it’s a certain size, if there’s certain mutations

Wendy has hope that we’re going to see a step-function and it’s not going to be linear

The ethics of gene editing [2:12:00]

Last year Peter read Walter Isaacson’s biography of Jennifer Doudna and the story of the discovery of CRISPR A fantastic book that he can’t recommend highly enough
There was a fantastic discussion of the ethics of this and once you realize the power of gene editing, you very quickly start to pivot away from the discussion we are having today, which is a child is born with Tay-Sachs disease, this child is going to be dead in a couple of years and it’s a very ugly death There’s really nobody in their right mind that wouldn’t be in favor of a therapy there
If a woman is born with a BRCA mutation and she has a choice between a gene edit to fix it or a mastectomy to remove her breast, we’d probably prefer the former if for no other reason than it ends the gene there and her daughter won’t get it or her son won’t get it
A fantastic book that he can’t recommend highly enough
There’s really nobody in their right mind that wouldn’t be in favor of a therapy there

How can people think about the next layer of complexity [genes that confer disease susceptibility]?

For example, should we take a person who has an APOE4 isoform and turn that into an APOE3 or APOE2 isoform? Either would come with significant protection against neurodegenerative disease
Either would come with significant protection against neurodegenerative disease

This is slightly different because the penetrance and risk profile is different

Wendy points out, “ One thing I think we universally agree on (I hope) is that we’re not doing gene editing, gene manipulation to affect the next generation. ” We’re not looking for things that are transmissible in the germline We’re not trying to create superhuman where we’re trying to fiddle with the genes to either correct them or to be able to enhance them that is transmissible
We’re not looking for things that are transmissible in the germline
We’re not trying to create superhuman where we’re trying to fiddle with the genes to either correct them or to be able to enhance them that is transmissible

The consensus among the scientific community is that you would treat the body of the person that might be at risk or have those diseases, but you wouldn’t try and do manipulations that would be transmissible to the next generation

Peter realizes his argument for BRCA is only partially correct
Wendy continues, “ The other part of it is this tricky thing that you’re talking about, which is enhancement in terms of it’s not correcting something that’s problematic, it’s enhancing the body the way it is or trying to, in some sense, prevent a disease process. ”
Enhancement is a trigger word for, “ We shouldn’t go there. ”
Part of that is we’re not as smart as we think we are We can think that something’s not going to have off target effects, that it’s not going to disrupt a gene inadvertently
In the short term, what saves us is that the risk profile given the uncertainty in the long term is so high that there aren’t going to be either scientists or people who are going to go for things that are trivial in terms of enhancements
We can think that something’s not going to have off target effects, that it’s not going to disrupt a gene inadvertently

The APOE2, 3, 4 situation is one that people think about

The average listener here is more sophisticated about this
The average person walking down Broadway is not going to think about this in the same way They’re going to think about things that will be enhancements : being able to increase your earning potential, being able to be taller, more athletic, funnier
They’re going to think about things that will be enhancements : being able to increase your earning potential, being able to be taller, more athletic, funnier

Just to be an enhancement is a line that people are not crossing and this is really about disease and being able to make people healthier

There are certain medical industries that are not covered by insurance, that are not regulated
There are certain parts of the world that do things differently where people can go and seek certain things
Wendy hopes that there is a consensus scientifically about places we don’t go because otherwise there will be ways that people will find to do things

The story of the initial blowup around CRISPR, what took place in China, and how that brought the scientific community closer around this consensus

Wendy thought this circumstance in China was a little unusual
The CCR5 gene was manipulated to try and prevent children from getting infected with HIV This would not cure a disease or prevent a disease It was preventing transmission of infectious agent that those children were at increased risk for HIV But it wasn’t a foregone conclusion that they would be HIV positive
Peter points out that there was very little chance they would be infected because these children were born of IVF The sperm from the HIV positive father were washed The mother was HIV negative
This would not cure a disease or prevent a disease
It was preventing transmission of infectious agent that those children were at increased risk for HIV But it wasn’t a foregone conclusion that they would be HIV positive
But it wasn’t a foregone conclusion that they would be HIV positive
The sperm from the HIV positive father were washed
The mother was HIV negative

Wasn’t this a situation where it was almost entirely possible to prevent the transmission of HIV to the offspring?

This was Wendy’s point, “ I don’t think heroic measures needed to be made .” There were reasonable ways available that are very effective
Scientifically, it was an odd selection of a use-case
There were reasonable ways available that are very effective

The scientific community rallied around this line that had been crossed, that this was essentially a form of enhancement

It wasn’t something that was saving a life
It wasn’t something for which there were no other treatments or anything else

Wendy worries

The world is global and scientists are in all sorts of places, and it only takes one person to be able to do something that’s crossing a line
There is medical tourism in places
It is important for people to uphold certain ethical standards and for us to have those guiding principles so that people know where those lines are

Do you think it would’ve been different if the first use of CRISPR in humans was to do something that we could all agree on would be a great use-case?

Would the field be in a different place today?

It was 2018 that the Chinese scientist [ He Jiankui ] used CRISPR to edit the genome of human embryos
Peter asks, “ What would have been that perfect use-case? ” Sickle cell, Tay-Sachs? You could use gene editing to fix the gene and produce a phenotype that could have a normal life expectancy The technology would be the same, but a far better application
Wendy points out that most people in the field would take a different approach if you’re at the stage of an embryo with in vitro fertilization Rather than trying to dittle with the genes, you can simply do selection of an embryo that doesn’t have that genetic risk Therefore you’re not increasing the risk of something off target, and you’re still accomplishing what you set out to achieve
Some ethicists make the argument that if there were a very limited number of embryos and that were not possible to do, would that be a circumstance in which direct therapy for a very bad disease would be ethical (knowing that that would affect the germline)? In a situation where the couple had no other alternative in terms of having a biological child knowing that that would affect the germline This is different from what was discussed earlier If this were not a routine therapy in terms of the intention to do this in a universal way This is something that gets us close to the edge of thinking about the use-case
Sickle cell, Tay-Sachs?
You could use gene editing to fix the gene and produce a phenotype that could have a normal life expectancy The technology would be the same, but a far better application
The technology would be the same, but a far better application
Rather than trying to dittle with the genes, you can simply do selection of an embryo that doesn’t have that genetic risk Therefore you’re not increasing the risk of something off target, and you’re still accomplishing what you set out to achieve
Therefore you’re not increasing the risk of something off target, and you’re still accomplishing what you set out to achieve
In a situation where the couple had no other alternative in terms of having a biological child knowing that that would affect the germline
This is different from what was discussed earlier
If this were not a routine therapy in terms of the intention to do this in a universal way
This is something that gets us close to the edge of thinking about the use-case

The future of clinical genetics [2:21:00]

If you had a crystal ball and you could look into the future in 2040, and you’re looking back at a 40+ year career in this space that has probably seen more transformation than most fields in all of medicine. What would you not be surprised to see happening in 2040 in this field?

At this time, you’re probably coming to the end of your career, you’re thinking about retiring
Wendy would not be surprised that diagnosis is trivial She hopes that we’re getting to that point not just with the cost of sequencing decreasing, but with machine learning, artificial intelligence, the ability to ingest huge amounts of information (genomic information, clinical information, other information), and the diagnostic ability in medicine in general Not limited just to genetics and genomics, but is especially true in this field, diagnostics will be hopefully trivialized
She hopes that we’re getting to that point not just with the cost of sequencing decreasing, but with machine learning, artificial intelligence, the ability to ingest huge amounts of information (genomic information, clinical information, other information), and the diagnostic ability in medicine in general
Not limited just to genetics and genomics, but is especially true in this field, diagnostics will be hopefully trivialized

She hopes from an equity point of view that we’ll be more accessible to more people around the world just because of that cost barrier will decrease

Wendy is not sure about the therapeutic point of view and how much of that we will have realized within 20 years
She’s optimistic we will have gotten a lot of that done, but is not sure how much of it will penetrate parts of society in the US or globally
It’s very hard to predict timing Within some point in the next 100 years, we’ll get to this point Wendy is not sure if it’s the next 20 years or not, and what percentage of individuals we will have been able to serve
Within some point in the next 100 years, we’ll get to this point
Wendy is not sure if it’s the next 20 years or not, and what percentage of individuals we will have been able to serve

Gene therapy will progress in step-function; these transformative things are hard to predict, especially given that we got stuck for the last 20 years

We are gaining momentum, but it doesn’t take much in society and in science to get us stuck A word of caution ‒ Wendy hates to make things about COVID, but she would not have predicted societies response in the last 10 years and some of the trajectories we’ve had
A word of caution ‒ Wendy hates to make things about COVID, but she would not have predicted societies response in the last 10 years and some of the trajectories we’ve had

Selected Links / Related Material

The GUARDIAN Study : What is the GUARDIAN study? | The GUARDIAN Study (2021) | [9:30, 1:06:30, 1:09:00, 1:18:45]

Book recounting the discovery of the structure of DNA : Double Helix by James Watson (1998) [22:45]

SPARK autism study : SPARK: Understanding Autism (2023) | [1:53:45]

Biography of Jennifer Doudna and the discovery of CRISPR : The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race by Walter Isaacson (March 2021) | [2:12:00]

People Mentioned

Rudolph (Rudy) Leibel (Professor of Pediatrics at Columbia University, co-discovered leptin) [25:30, 1:43:45]
Helen Hobbs (Professor of Internal Medicine and Molecular Genetics at the University of Texas Southwestern Medical Center and PCSK9 expert) [2:05:30]
Jennifer Doudna (Nobel laureate and Professor of Chemistry at UC Berkeley) [2:12:00]
He Jiankui (Chinese scientist jailed for using CRISPR on human embryos) [2:19:15]

Wendy Chung earned her BA in biochemistry and economics at Cornell University. She then entered a MD-PhD program where she earned her PhD from Rockefeller University and her MD from Cornell University. She was a graduate student of Dr. Rudy Leibel. She completed an internship, residency, and fellowship at the Columbia University Medical School, New York-Presbyterian Hospital. Her residency focused on pediatrics, and her two fellowships focused on molecular genetics and clinical genetics. [ Wikipedia ]

Dr. Chung stayed at Columbia University Medical School as a Professor of Pediatrics. She was named the Kennedy Family Professor of Pediatrics (in Medicine). She served as the Chief of Clinical Genetics Division in the Department of Pediatrics, the Medical Director of Columbia’s Genetic Counseling Graduate Program, the Associate Director for Education at the Herbert Irving Comprehensive Cancer Center, and Co-Director of the Precision Medicine Resource within the Irving Institute for Clinical and Translational Research. In May of 2023, Dr. Chung accepted a position at Harvard Medical school, Boston Children’s hospital. [ Columbia ]

Recently Dr. Chung has been named Boston Children’s Hospital next Chief of the Department of Pediatrics. Harvard Medical School, Boston Children’s Hospital. She will also serve as the Mary Ellen Avery Professor at Harvard Medical School (HMS), and President of the Children’s Hospital Pediatric Associates. [ Boston Children’s Hospital ]

Dr. Chung’s research focuses on the genetic basis of a variety of human diseases such as obesity, type 2 diabetes, congenital heart disease, cardiomyopathies, arrhythmias, Long QT syndrome, pulmonary hypertension, endocrinopathies, congenital diaphragmatic hernias, cleft lip/cleft palate, seizures, intellectual disabilities, autism, inherited metabolic conditions, rare disorders, and breast and pancreatic cancer susceptibility. She also works on the implementation of genomic and precision medicine. Dr. Chung has identified over 50 new genetic conditions and has authored over 500 scientific papers.

Dr. Chung directs NIH funded research programs in human genetics of birth defects. She is the Principle Investigator of the GUARDIAN study . This is a research study that screens newborns for over 250 genetic conditions not currently included as part of standard newborn screening.

Dr. Chung is also the Principle Investigator of SPARK , a long-term autism research study. This is a study of over 100,000 people with autism and 175,000 of their family members. Over 100 genes have been linked to autism, and this study aims to better understand the genetic basis of this disease.

Dr. Chung has received numerous awards. She is a member of the National Academy of Medicine and American Association of Physicians. She was the recipient of the NY Academy of Medicine Medal for Distinguished Contributions in Biomedical Science, the Rare Impact Award from the National Organization of Rare Disorders, and the Presidential Award for Outstanding Teaching. Dr. Chung is rated one of New York Magazine’s best doctors and received the Castle Connolly Top Doctors’ award. [ GUARDIAN study ]

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