Transcriber: Zahra Panam Reviewer: Mujtaba Abdelwhab
It’s an old saying that prevention is better than cure. And this slide
Shows us a good example of that,
wouldn't you rather listen to a fire alarm than being stuck putting out
a raging fire? But this picture is about more than just that.
This is a reminder to us that prior knowledge is power
and it can even be life saving.
And that is no more true than in our health care system.
Where costs are skyrocketing, the system is overtaxed,
and curing disease is often more like putting out
a fire than really knowing what's going on.
Now, there are at least two ways for us out of this gloomy paradigm.
One of them is we can develop early health care warnings like a fire alarm
for our health care. And the second is we can better understand
the basic mechanisms of human disease.
Now, fortunately, there is at least one tool in our medical care toolkit that
can help us in this endeavor through better prevention
and better understanding of the nature of disease. And this, of course, is denying.
In fact, if everyone was able to get their genome sequenced
and was willing to share their health data with researchers,
we could make discoveries that would prevent and possibly cure all of
the diseases that cause our suffering.
Now not only that, we could potentially empower our physician colleagues to
become less firefighters and more of the kind of individuals who manage
and avert disease risk while speeding to new disease cures.
Now, understanding DNA is essential to this vision.
Dana, is that three billion long string of letters that you inherit from your
mother and from your father?
It's a molecule that occupies virtually every cell in your body,
and it's the molecule that can miraculously copy itself.
And if it did that job perfectly, we would not have a story here to tell.
But every now and again, about 100 times in each new person,
there’s an error in the copying and a wrong letter gets inserted.
We call that a mutation, and if the mutation occurs and a critical gene,
you can have a genetic disease.
So wouldn't it be perfect if you could take your whole genome sequence on
a computer disk into your doctor's office and have her read it
and tell you about any future health concerns that you might have or not?
This would be like you having a fire alarm for your health care.
Now, this was one of the parts of the vision for
the Human Genome Project and
the technologies we’ve developed since beginning almost 40 years ago
now together with our talented group here
in Houston at Baylor College of Medicine
and with thousands of collaborators
around the world,
we sequence the first human gene on.
we begin that project in 1990
and completed in 2003.
Since then, we’ve gone on to develop
the field of personalized genomics,
where we can actually look at complete individual DNA sequences
and study individuals health care trajectory.
So how does this mean we are doing in our general quest?
Well, let me tell you one story.
And now this is one story of many,
but it is one of the very first stories of its kind.
And this beautiful child is my grandma’s Molly. So she’s my sister’s granddaughter.
My niece's child, Molly, was born after a mother's fairly uneventful pregnancy,
and Molly's first few months of life were also just fine.
But at a certain time, she began to develop symptoms her parents saw of
weakness in her upper body and other developmental anomalies.
Now, Molly visited many doctors and had many tests,
but none of them could explain the source of her problems.
Molly had no relevant family history
and no apparent environmental encounters that really explained her malady that
there was just no explanation.
So when my sister and Molly's mother called me about 10 years ago,
it was a case of the universe offering us perfect timing.
We had just developed new methods that made DNA sequencing faster,
cheaper but still accurate enough for us to sequence entire families.
So what if we sequence Molly and her parents and look to see if there might be
a mutation that caused her disease?
Well, as you can probably guess, that's exactly what we did.
It was kind of a risky experiment and it took several months,
but we sequenced Molly, her parents,
and we found a mutation in a gene
for which we did not know very much about at the time.
We very quickly found three other families that had a similar story.
And together we had defined a new syndrome.
Now, Molly, then is one of the around one per cent of us that has
an important mutation that can affect her life long health care trajectory.
Now most people with such mutations are not
a severely affected that they end up as a child with a severe anomaly in
a doctor's office. But a very small fraction of one per cent is still
a very large number of people.
And so Molly and her family and the 300 or so other families we know with
the same syndrome now join
the thousands upon thousands of other individuals who have children with rare
genetic diseases for whom we know
the root cause of their problems thanks to DNA sequencing
and who are now seeking cures for those diseases.
Working with researchers like us. So this is the story in the children.
So how are we doing in adults? Why don't we just go out there and sequence adults?
Well, we could technically, but it would be very expensive.
It still costs more than a thousand around a thousand dollars to sequence
a human genome. And so to sequence everybody in aggregate would just be too
expensive. And there's another reason, though,
that we don't just rush out and sequence random adults.
Unlike the situation in Molly and her colleagues and friends.
Adult genetic diseases are more complicated,
adult genetic adult diseases tend to have contributions from environmental factors,
stochastic or chance factors.
And then there are often very many genes involved in each complex adult disorder.
In fact, we now know that if we really want to solve these adult genetic puzzles,
we need the genome sequences of literally millions of people.
Not only that, but we need very detailed health information on each one of them.
And so in turn, we have come to realize that
the best way to get this information is in the doctor's office.
After all, your doctor is used to taking detailed health notes about you,
and he's even used to preventative medicine, for example,
testing your cholesterol to see if you have heart disease
or were likely to develop heart disease.
So our dream is to fully integrate these genomic sequencing efforts into every
clinical encounter in a way that can allow
the individuals to share their health data with researchers in
a fashion that's protected their privacy is protected to allow those researchers
to develop these preventative disease fire alarm models,
as well as to advance our understanding of human genetic disease.
So this dream sounds pretty straightforward, but there's a catch.
The catch is that right now,
genomic sequencing is simply not useful enough in the clinic
for it to be very widely accepted.
And conversely, because genomic sequencing is not very widely accepted in
the clinic, we don't have the data from it to make it universally useful.
We call this the Catch 22 of genomic sequencing
and clinical genomic translation.
Now, if only we could sequence all these people and share their data,
we could revolutionize part of the health care problem.
So let me give you one brief vignette a thought experiment that illustrates
the power of this vision. And it's one that's very relevant to today.
From the beginning of the COVID pandemic,
it was clear that some individuals developed more severe disease than others,
but we did not know why. Imagine if we'd already had
the genomic sequence of millions of individuals in their health care records.
We were able to access those health care records,
and we could also know the COVID status and the disease outcome
for those individuals. We could have used a computer to do
the experiment very quickly to ascertain what were
the innate factors that gave rise to severe COVID disease.
Now those studies are ongoing and some have even been completed.
But the point is they have been retrospective
and they were very cumbersome to organize
and we want more frail human genetic disease studies.
So how can we get out of this catch?
Well, one thought is that we can look to individuals who already seek genetic
testing, people planning families who may have some knowledge of
a distant relative who have a gene.
It has a genetic disease, a likely to seek genomic sequencing in order to plan
their own child, their own their own reproductive future.
Altruist participate in scientific studies where they may have their genome
sequenced, and we know of at least a couple of large studies around
the world right now that aim to accrue the data from more than
a million people's sequences each,
and these are already contributing to our health knowledge.
But our problem is that not everybody is pregnant
and everybody wants to be adulterous, in fact,
not everybody can be an altruist because it can simply be too difficult
for them to do that logistically. So we thought long and hard about this problem.
How can we break out catch 22?
How can we get genomic sequencing into people's lives in
a way that both gives them something in return,
incentivizes them to participate in research
and doesn't disrupt their everyday lives?
Now, an important aspect of genetics helps us here.
I said a moment ago that many adult conditions have many genes that
contribute to them. But there are adult conditions which are driven by single
gene effects, just like in Mali.
But the situation is that those mutations in those individuals were never detected
in childhood. They persisted through to adulthood,
and now they're affecting adult health.
So maybe we could design a study where we could look for those kind of mutations,
and if we were successful,
then we would have a reason to do more genomic sequencing in the clinic.
We'd have a toehold, and we could begin to drive towards this vision of having
ubiquitous genomic sequencing in health.
Now we thought hard about which conditions to study.
We actually spent a lot of time thinking about cancer and
the complexities of DNA sequencing and DNA analysis there.
But in the end, we said it all settled on cardiovascular disease risk,
after all. Cardiovascular disease is the number one killer.
About one in four people die of that in the US.
Not only that, but genetic studies in adult cardiovascular health actually
quite advance relative to some other disease disciplines.
So we decided to study that condition.
Now it didn't make any sense to run out and try
and sequence everybody to determine their cardiovascular disease risk genes.
Nor did it make any sense to sequence people who were already in advanced
disease, perhaps in the in the in the hospital already.
They a fire alarm essentially had already gone off.
So we designed a study to target intermediate categories of individuals
and with our physician colleagues, we organized to enroll in a study.
People from all walks of life, bus drivers and bank tellers,
and people who for some reason were seeking out some kind of ideological
health care. They could be people with a mild heart attack,
but also people with just very mild chest symptoms over the course of a year.
We studied 700 people. We're actually trying to study a thousand,
but COVID got in the way, so we stopped the study,
then our physician colleagues consented and drew blood from these individuals
and we got their DNA sequence and then we returned
a genetic report to each one of them.
At the end of the study, we had made an amazing discovery,
a little more than 30 per cent of
the individuals had genetic data returned to them that affected their future
health care. This number of 30 per cent is actually an astounding number.
But even more surprising to us was that within the 700 participants,
nearly 10 per cent of them had a strong mutation of
the class that we saw in Mali.
That is, they were one of the one per cent or so of us with
a mutation that is guiding their health trajectory through their whole lives.
Some of these people had familial lipid disorders,
others malformations and some others connective tissue disorders,
but they were all in this class of being the one per cent. .
So our proof of concept had worked.
We now have the reason to recommend more of these tests in cardiovascular clinics.
We have the incentive for these individuals to participate in this kind
of research, and we now have
the motivation to move these tests over into other disease systems
as we march systematically towards this grand vision of having genome sequencing
in every clinical encounter.
So we have our fire alarm,
we have now the information we need to begin to develop these early warning
prevention systems. And even more importantly,
we now are in a situation where we can assist our physician colleagues in their
endeavor to become less like firefighters
and more like those who manage any overt disease risk.
So our clinical translation study has worked. We have broken the Catch 22.
Now what does this mean for everyone? What does this mean for you?
Well, what it means is now if you go into the clinic to see your doctor
for any condition that may really remotely be influenced by
a genetic factor, you really can legitimately justify you asking that
question Should I have my genome sequenced ? Thank you.