Articles, Blog

Genomics and Precision Medicine

February 29, 2020

in chief of a new patient center
magazine called genome which is aimed at educating and informing patients in the
area of precision medicine she also developed a genomic medicine course here
at extension that is part of the advanced bio sciences and health
professions programs so please join me in welcoming Dr Jeannette McCarthy
thanks karen thank you all for coming out this evening as Sharon said I have a
lot of different jobs right now but I actually very proud to be a berkeley
alone I did my PhD work here at UC Berkeley and had the immense honor of
working with professor mary claire king who as you may know is a world renowned
human geneticist so anyhow I spent most of my career doing research but about
four years ago I took a change in my career and decided to focus exclusively
on educating stakeholders in this exciting field of precision medicine so
precision medicine is basically using molecular information about an
individual to tailor their treatment and health care and this is not a new idea
the idea has been around for a long time goes by different names some of you may
know it as personalized medicine or individualized medicine but the term
precision medicine is really the one people are using now and it was
popularized earlier this year when President Obama mentioned it in his
State of the Union address in the context of the government’s precision
medicine initiative so it’s a really exciting time for the field of precision
medicine what I’d like to do this evening is tell you about some of the
exciting applications of precision medicine in the clinic today I also talk
about some of the hurdles that we face in practicing precision medicine then go
into some of the next generation but what’s on the horizon in in precision
medicine but before I do any of that i’m gonna back up a little bit and give you
a little primer on the human genome so DNA is basically what the human genome
is made of the human genome refers to all of the DNA in an individual and DNA
is a molecule its polymer of repeating units called nucleotide shown here and
each of those nucleotide pass on nitrogen base attached to it and these
coming four flavors and we appreciate them by their single letter codes eighty
CNG and so really when we’re talking about DNA we’re talking about a strand
of nucleotides and again they have either the letter G CT or a on them and
this molecule than actually does not occur as a single strand but is a
double-stranded molecule where these two strands join together in a very specific
fashion and this gives the DNA molecule its classic double helical shape that
were all used to so this is basically what DNA is when we talk about the
sequence of DNA we’re talking about the order and composition of these
nucleotides along a single strand of this molecule and here we have an
example of a DNA sequence that is thirty four nucleotides long to put this into
perspective the human genome consists of 3.2 billion nucleotides so it’s a very
large molecule but actually the DNA and the human genome is not one long
molecule not one long strand of DNA but rather it’s broken into 23 discrete
chunks that we called chromosomes these chromosomes are located in the nucleus
of every cell in your body that has nucleus which is most cells in your body
so every cell in your body has virtually the identical DNA and this is the
genetic code now chromosomes for those of you who are used to seeing them
appear as these condensed molecules of DNA where the DNA actually wraps around
proteins and condenses and you can actually see it under a microscope but
most of the time in the south when DNA is doing its job it’s fun while and and
when it on wines you reveal here stretches of nucleotides and some of these stretches are actually
genes what we call genes in these are the segments of DNA that code for
proteins so jeans are again very important because not only are they the
unit of heredity there passed down from generation to generation but they code
for every protein in your body and proteins play a vital role in every
biochemical process in your body there are estimated to be about 20,000
genes in the human genome with this represents less than 2% of all of your
DNA and the big question has been so what does the rest of that 98% of your
DNA do and the answer is we don’t really know we have some ideas we don’t even
know how much of the remainder of the DNA which by the way people have
referred to as junk DNA we really don’t know what it does but people have
estimated that anywhere between eight and eighty percent of that junk DNA is
actually doing something it has a function we just don’t know what it is
now and so we spend most of our time focusing on the portion of the DNA that
is the gene region or the gene regions and this is called the XO more the
coding region of your genome so DNA again provides the blueprint for the
production of proteins through this process of protein synthesis this is
where DNA is transcribed into an intermediate molecule called RNA which
is then translated into protein now if you think about it every cell in your
body has virtually identical DNA and when I see virtually it’s because there
are few exceptions a few important exceptions which I’ll talk about later
in the area of cancer but for the most part if you take a skin cell you take a
cell from your pancreas you take a cell from your I all of these cells have
identical DNA but they don’t have the same proteins because in fact it’s the
proteins the expression of these proteins that makes one cell different
from the rest so it’s important when you think about
DNA to recognize that no matter where you get it from your body it’s going to
be the same but the proteins are going to different now DNA is the unit of heredity passed
down from generation to generation and DNA is also present in every self every
cell in your body is dividing right near your cells are continually dividing to
make new cells it happens when a fetus is formed an embryo becomes a fetus and
rose to be a real human cell division is occurring all the time and in the
process of normal cell division and also when the sperm and egg are being formed
your DNA needs to replicate as cells replicate the DNA needs to replicate so
that your other cells all have the same DNA now DNA replication is happening all
the time it’s happening right now and during this process of DNA replication
sometimes mistakes are made and these mistakes we call mutations fortunately
you have enzymes in yourselves that correct these these mutations are these
mistakes but these enzymes are not always perfect and so once in a while a
change in your DNA sneaks through and you end up having what we call a
mutation know the term mutation tends to have a really bad connotation right when
you think a mutation you think of something bad and that’s why I prefer
the word variation because mutation as the naturally occurring thing the
mutations are bad the mutations in fact are good but it is
just a neutral phenomenon and therefore I prefer the term variation now
certainly there are contributing factors to mutations right we know about things
like UV radiation cigarette smoke X-rays these are all things that contribute to
higher mutation rates of cells there’s also another interesting thing that we
learned just in the last year too and that is the role of maternal age
advanced maternal age so as women you know we’ve spent our whole lives
thinking about the biological clock and how we have to have kids before a
certain age because of our increased risk of mutations that can damage the
child but in fact its advanced maternal age which is contributing to a lot of
the genetic variation it turns out that males are much more likely to contribute
these what we called single nucleotide variants to a genome and in fact I think
it’s with every increased year of paternal age there are approximately two
new mutations introduced into that sperm which then go into the person so I think
that’s just a fascinating fact and really interesting when you think about
it because first of all I was thinking maybe older males are contributing into
some of the diseases that we’re seeing now that have a genetic basis but then
on the other hand I was thinking well actually maybe it’s a good thing because
mutation is actually the foundation of evolution and maybe its advanced
maternal age is actually making the species of human species evolve faster
so I don’t know it could be good or could be bad but in any case the result
is whether whichever method we get to get to it we we have increased mutation
rates and we have mutations that persist in our genome so we have variation now a
lot have been learned about the human genome and variation in the human genome
through the human genome project and subsequent government projects what
we’ve seen over the past decade or so has been phenomenal growth in our
efficiency our ability to sequence the genomes as well as a drop in the cost
you can see when the first human genome was sequenced it costs about three
billion dollars today you can get your genome sequence for about a thousand now
just as a side note it may cost $1000 in laboratory reagents to get your genome
sequence but it cost several thousand more to actually have somebody interpret
it and tell you what it means it is possible to get your genome sequence
today and in fact there have been probably about 300,000 people in the
world today who had their whole genome sequence that’s a very small drop in the
bucket of the whole human population but there have been estimates that within
the next 10 to 15 years it will be routine a routine part of health care to have
your genome sequence so this is something that’s coming and what I’m
gonna show you in the next section is really where we’re actually taking
advantage of this technology in using human genome sequencing in the clinic
today but before I do that I’m going to continue on a little bit more with this
idea of human genetic variation there are different types of variations that
occurred in the human genome some of them involve large pieces of DNA others
involve small pieces of DNA but large variants include things like try soumise
Armada soumise these are conditions wherein tire chromosomes are either
found in excess so you have three copies were you should up to or there’s a dearth maybe you just have
one chromosome are you should have to and in any case these are very
deleterious there are in fact only a few human try some things that are viable
trisomy 21 is the most common one trisomy 21 has Down syndrome there’s
also trisomy 13 trisomy 18 and a few sex chromosome trisomy 10-10 means that are
actually viable all the rest are so deleterious and you just never see them
in the human population there are also large variance not quite as large as
whole chromosomes but conditions where we have what we call structural variants
where entire chunks of chromosomes for example here you’ve got this whole
section of a chromosome breaks off and you have another chromosome where
section breaks off and they basically swap places this is called a
translocation so it’s basically big chunks of DNA moving around the genome
so again these are very large variance as with the trisomy semana sony’s UK CDs
under a microscope and they’re quite rare they’re they’re often very
deleterious as you move to smaller variation they become more common in the
population and more common in an individual there are a type of variant
called copy number variants this is where you have a stretch of DNA and this can range from a few hundred
nuclear times to several thousand these sections are actually duplicated in
tandem so here you see a complete copy of this region just duplicated in tandem
right next door sometimes there are complete sections
that are deleted so these are think about me as a very large duplications or
deletions know when these happen they can be quite deleterious if they
happened to overlap a number of genes you could get some phenotype were some
disease that’s quite deleterious it’s estimated that each person has about 800
of these so you and your genome right now have probably about eight hundred of
these copy number variants the more common type of the most common type of
variation is actually a change in a single nucleotide so this is where a
single nucleotide is either swapped out for another one or perhaps it completely
deleted or its nucleotide is inserted where it shouldn’t be these are very common it’s estimated
that each person has about three to four million of these in their genome so the
real question though is you have all this variation it can’t all be bad if
you had that much damage to your genome and it was all bad you wouldn’t be alive
so not all variation is deleterious in fact most of the variation occurs in non
genic regions remember only two percent of your genome codes for jeans the rest
we don’t know what it does most of this variation is a Korean in nineteen
egregious and is thought to be of little consequence mutations that occur in
jeans though can but don’t have to have a big effect on the protein and on the
subsequent hope so for example there are types of mutations that affect the
protein in such a way as to truncate it so these tend to be quite deleterious if
you have a mutation in an important gene and it truncates that gene meaning it
truncates the resulting protein that can be bad news there are other types of
variance where you just simply have a change in the amino after the protein these may or may not be serious it
depends you have to take them on a case-by-case basis and then you have
variation that even though there’s a very short at the level of DNA seems to
have no effect on the resulting protein for various reasons so again not all
variation is deleterious but what we really want to know well first of all before we really want
to know that I want to tell you how much variation person has already mentioned
that every person in their genome has about three to four million of these
single nucleotide variants and about 800 of us copy number variants but in terms
of the single nucleotide variants only about 55,000 of these are in gene only
about twenty thousand of those are in what we call the coding region of the
gene that’s responsible for the protein about 10,000 of those are these non some
anonymous simple amino acid changes which may or may not be deleterious and
every person has about 100 what we call loss of function variants these are
variants that will essentially completely knock out that gene and knock
out that protein for that one chromosome so so given that you have two copies of
every gene it may not be so bad but in some cases it is ok but what we really
want to know about variation is it linked to disease do these variants
actually have any health consequences and the way that I like to think about
it in terms of what we know about the genetic basis of diseases there are some
variants that have very strong effects and these are typically very rare
variants that caused very rare diseases but if you have one of these variants
you have a very high likelihood of getting the disease we call these highly
penetrant barium and we typically study these in the context of a family because
they’re so rare in the general population and what you’ll see for a
very highly penetrant disease and variant is everybody who has the
mutation has the disease these disease here is denoted by a
colored in circle or square and you’ll see everybody who doesn’t have the
variant doesn’t have the disease so that is a completely penetrant variants you
have the variant you have the disease I don’t know how many examples there are
if any of variants that are 100% penetrant but there are a lot that are
highly penetrant in other words 80 to 95 96 percent chance that you’ll get
disease if you have this variant then there’s a whole bunch of variation in
our genome that seems to have a very minor effect on diseases reproducible
but minor effects these are typically variants that themselves are common in
the population and they are usually responsible for common diseases the ones
that you and I are most interested in diabetes heart disease schizophrenia
other ones that affect you especially later in life now in terms of
how predictable these variants are for Disease we we call them low penetrance
variance because in fact they don’t do a very good job of predicting disease in
this example here we have four people with the disease only two of them have a
mutation the other two don’t and you also see the mutation in people without
the disease now the mutation happens to be more common in the diseased
individuals 50% to be diseased people have it compared to what is about twenty
twenty twenty-five percent of the healthy people but again there is some
reproducible Association here it’s just not highly predictive ok enough of the
background I hope I didn’t bore you too much with that and hopefully you learned
something and I’ll give you a common vocabulary and help you understand some
of these applications of precision medicine in the clinic today precision medicine is really being used
today across the lifespan from preconception all the way through
adulthood and you know clearly we’ve been able to do some genetic testing in
adults but as you move to the left of the slide here you’re actually moving
more from a state where your diagnosing disease to
one where you can actually screen and predict disease so I’m gonna go through
and give you some examples of these different life life life cycle their
lifespans and and and show you where precision medicine is being used so the
first area is preconception carrier screen in some of you may have already
had experience with this I know when I was thinking about getting pregnant my husband and I were tested first
cystic fibrosis now cystic fibrosis is recessive disorder and other words you
need to have both copies of your gene mutated in order to get the disease if
you just have one copy you’re not going to get the disease but you are a carrier
and what happens when two carriers Mary well if you have a person who carries a
mutation in a gene and they marry another person who has a mutation in
that gene and they have children there’s a one in four chance that their child
will inherit both deleterious copies and therefore become affected by this
disease so many women and men before they have children undergo this carrier
testing to see if they actually carry one of these deleterious variant if
you’re European of European descent you may have been tested for cystic fibrosis
like I was if you’re african-american you may have been tested for sickle cell
anemia and if you’re gonna see jewish you may have been tested for tay-sachs
so I will these are examples of carrier testing that people have today but
what’s new since we’ve been sequencing the human genome and learning about the
genetic basis of not just a handful of these diseases but lots of them is there
are commercial test available now for over a hundred disorders so if you’re
planning on getting married and having children you can go to a company like Council
genomic sore good start genetics and you can get screened for these hundred
disorders as we move from preconception to prenatal diagnosis so prenatal
diagnosis as you’re already pregnant and what what has happened historically
is pregnant women at about 15 to 17 weeks gestation are offered what we call
a maternal serum screening test for chromosomal abnormalities like Down
syndrome but also for neural tube defects so very serious abnormalities so
these blood tests are screening tests and if you have a positive result you
would then undergo a very invasive procedure amniocentesis or chorionic
villus sampling in either case you basically get a needle stuck in and near
your fetus to get fetal cells to take out to be able to look under the
microscope and confirm a diagnosis this procedure is risky and very dangerous
and so it’s been really interesting in the last few yrs and especially with our
ability to sequence the human genome that were able to identify in the
maternal blood stream fetal DNA so it’s thought that beginning at around seven
weeks gestation the fetus which shares the bloodstream with the mother starts
to laugh off some of its cells the cells die they burst open and you have what’s
called cell-free fetal DNA floating around in the maternal blood stream it
comprises anywhere from two to ten percent of the maternal blood stream
that percent changes as a woman and get further on in her pregnancy but the fact
that it’s in the blood stream gives us an opportunity to now go instead of
through the abdomen into the actual fetus itself to go into the maternal
blood stream to get a sample of the fetal DNA to test for these chromosomal
abnormalities and that’s exactly what’s being done today there’s been a huge
shift in the practice of prenatal diagnosis there are four companies I
don’t think they’re all independent still but they simultaneously develop
this technology where they’re able to use non invasive testing to detect fetal
trisomy he’s such as trisomy 21 13 18 X it’s interesting though when you think
about how that’s these are very large chromosomal abnormalities can we bring this technology to detect
even smaller and smaller variations and that’s where we’re moving so smaller
than complete copies of chromosomes are these structural rearrangements or or
chunks of chromosomes that are either deleted or duplicated in there are
several diseases behind some of these these are also being tested for right
now but as we go forward in time it wouldn’t surprise me in the next 10
years for sure if we’re not able to use this technique to test for even single
base substitutions in maternal blood the next application of precision medicine
in the clinic is also really exciting and this is diagnostic sequencing for a
rare idiopathic diseases so rare diseases by definition affect about one
in two hundred thousand people in the us- of course they occur worldwide
that’s the statistics for the us- and although individually rare they’re quite
common collectively about one in 10 children born are thought to have these
rare diseases there about seven thousand of them have been described about 83 80
percent of these are thought to be genetic in origin and we know the
genetic basis for about half of those most of these disorders affect children
and they typically present as what we call a diagnostic dilemma or diagnostic
gotta see this is where a child goes to their doctor when they’re young one to
three years old they have some constellation of symptoms the doctor
doesn’t really know what it is he gives them a diagnosis which turned out to be
a misdiagnosis but they don’t know at the time they undergo treatment in the
meantime the disease progresses they go back to the doctor for more testing what
could it be there given another diagnosis more in effective treatment
disease progression around and around on average you know like 52 anywhere from five to 14 years that
these children are not getting a diagnosis for their disease these are
rare diseases some of them have named some of them don’t hear some examples of
some of these diseases which you probably never heard
of a sudden I’ve never known anybody with any one of these but again in
aggregate collectively they’re quite common now Nick volker with a little boy
who at two years old was very sick he had some problems with his intestine he
was not getting better at age four he only weighed 17 pounds and had undergone
surgery to remove part of his colon at six years old he had already undergone a
hundred and six 360 surgeries at that point he was in Wisconsin in Milwaukee
and he hooked up with Howard Jacobs at the Medical College of Wisconsin and
Howard suggested that maybe Nick should have his genome sequence now this
wouldn’t have happened 10 years ago but in 2010 this was a new technology it’s
worth a shot and Nick at his genome sequence they found a mutation in a gene
called XIAP this gene is responsible for a rare form of inflammatory bowel
disease the suggested treatment for this was a cord cord blood or bone marrow
transplant and when he underwent this therapy he was cured basically so this
is a picture of Nick later and you can see the big difference so this was the
first example of successful human genome sequencing to diagnose a rare idiopathic
disease in a child this is not an isolated incident since 2010 when Nick
Volcker’s the genome sequence we’ve seen a dramatic increase in the number of
rare diseases that have been diagnosed or the cause has been found using genome
sequencing here are the numbers in the bars and blues show you the use of
genome sequencing had we not had that technology the numbers would be less but
it’s just a tremendous confirmation that this technology is really powerful now
just because you have your genome sequence and you have a rare disease we’re gonna find the cause of it in fact
it’s only successful in about 25 to 30 percent of cases and Nicholas lucky
because we found the gene and there was also a treatment available but for many
kids even though we know we find the gene there still might not be a
treatment available nonetheless if you’re one of these
children one of the parents of these children undergoing these diagnostic
Odyssey’s you’re happy to have an answer either way so that’s a very exciting
application of precision medicine in the clinic so let’s move into adulthood now
after though we’re really dealing primarily with complex traits unless you
happen to have one of these rare genetic disorders that was missed in childhood
we’re talking about common complex diseases these are again the diseases that we are
worried about diabetes and cancer and heart disease and all kinds of things
which are due to a combination of genes and environment an example of a complex
diseases breast cancer but you couldn’t see any disease in the place when I tell
you about the basic genetic architecture of these complex diseases so typically
for these common diseases you have incidents that relatively high breast
cancer happens to be particularly high one in eight women or 12 percent will
develop breast cancer in their lifetime and for many of these complex diseases
family history is an important risk factor for breast cancer if you have one
first-degree relative with breast cancer your risk increases to fold so now
instead of having a 12 fold risk of disease it’s 24% so the more infected
relat affected relatives you have and the younger age of onset also increases
your risk now despite family history being an important risk factor for
breast cancer and for other complex diseases in the case of breast cancer
it’s thought that only about five to six five to ten percent of breast cancers
are indeed hereditary the rest are thought to be sporadic due to
environment due to other causes now what do we know about the genetic
basis of hereditary breast cancer well there are some forms of hereditary
breast cancer where there’s a single gene which is the
primary cause in that person the jeans bra kawana brackets to where
the first genes described for what we call hereditary breast and ovarian
cancer syndrome these are highly penetrant genes in
other words if you have a deleterious variants bad mutation in one of these
genes you have an eighty percent risk of having breast cancer by age 80 this is the testing that Angelina Jolie
underwent which which brought breast cancer screening into the headlights are
into the headlines so these are important genes for breast cancer we
also have examples of genes listed here that caused very rare familial cancer
syndromes for which breast cancer is one of the feature cancers these two are
what we call highly penetrant and in aggregate these make very good genetic
tests but then you have a bunch of common variants linked to breast cancer
that have very small effects they’re very low penetrance variants like I
described earlier so where are we at in terms of breast cancer genetic testing well a few years ago a woman could go
and get tested for brocco Nebraska two variants through myriad genetics because
they held the patent 401 and rocket to testing but a couple of years ago the
Supreme Court ruled that DNA was not patentable this opened up the door for
other companies to come in and offered genetic testing for these jeans but
simultaneously genome sequencing is really taking off and we’re discovering
the genetic basis for a lot more of these breast cancer genes and so now you
can go to any one of a number of places a dozen places at least and get a panel
of genes tested for to screen for breast cancer now it’s really interesting
because along with the doors opening up to these other testing companies has
really come a move to democratize breast cancer genetic testing in fact last year
earlier this year I think it was a company called Color genomics launched
a breast cancer test which instead of the usual price tag of like $2000 was
like $250 or something and so the idea here is that the should be accessible to
everybody and the prices are coming down and there’s also a move to do breast
cancer testing not only in women who have a strong family history but in any
women because in fact there have been studies that have shown that people with
these brocco one mutations about half of the time don’t even have a family
history so it’s very very interesting that we’re at a time when we can
actually do this type of testing moreover if a woman tested positive for
one of these variants there are things you can do about it now other types of breast cancer tests are
out there I don’t know if anybody has undergone 23 me genotyping can I see is
anybody done 23 me okay so has anybody here I can send it to everybody heard of
23 me for the most part so if you haven’t 23 me as genetic testing company
that was going direct to consumers to offer genetic testing for a wide variety
of disorders they were doing the carrier testing that I talked about earlier they
were doing some testing for high penetrance variance in jeans like broken
into a lot of what they were doing was for common complex diseases they were
looking at these low penetrance variance and when I talk about low penetrance
variants I’m talking about if you have this variant you have on average say a
one-point twofold increased or decreased risk of disease what does that mean well if if the
baseline risk of breast cancer in the population is 12% and I have one of
these variants that increases my risk 1.2 fold my risk is now 14.4% similarly
if I have a variant of that decreases my risk 1.2 fold I go from 12 percent to 10
percent risk for me that doesn’t really move the needle it’s not going to alter
any of my health care decision but the reality is that there are a
number of these variants out there and if you undergo testing 123 and me they
will test a number of these variants and in the case of breast cancer they looked
at seven different variants in my genome each of which increased or decreased my
risk very slightly I had three that elevated my risk a little in for that
decrease my risk a little bit now what happens if you have one that goes up in
one goes down what do you do with that information well nobody really knows them so they
just basically at all of that risk together and come up with the aggregate
measure and in my case they determine the baseline risk of breast cancer for
my age was 14% and now with all of my genetic risk combined there at 13% so
again these are not very useful clinically and but they are available or
they used to be available through companies like 23 me who by the way no
longer can offer that testing direct-to-consumer because the FDA has
been quite unhappy with their doing this in giving information that they might be
harmful to people ok so that was breast cancer as an
example of a complex disease but that same scenario is playing out across all
different complex diseases another interesting application of precision
medicine in the clinic is pharmacogenomics this is where we can
use information about a person’s genetic makeup to predict their response to a
drug so very quickly how drugs work well a person takes a drug and it’s absorbed
into the body and that drug may come in orally or inhaled or injection that drug
is distributed around the body through the circulatory system it hits the liver
where it is metabolized or transformed and then it’s a limit added now while the drug is in your body
it have to find the target so drugs act on targets targets are proteins they
might be receptor on the surface of the cell their their proteins in the body
that the drug then binds to and either turn turn supper turns down so it might
relate that somehow and its modulation of that drug target that leads to the
therapeutic effect of that drug oK so that’s basically how drugs work and with
that understanding you’ll start to understand how a person’s genetic makeup
can influence their response to a drug so how many of you when you take a drug
expect that’ll do more good than harm ok despite those commercials
direct-to-consumer advertising or drugs where at the end of the commercial long
list of adverse events is rattled off defense despite that you think that’s
never gonna happen to me but in fact adverse drug reactions are quite common
by definition there are unintended and their noxious while they’re individually
rare collectively the incidents is about two percent and that’s not even being
under estimate in the us- their leading cause of death in hospitalized patients
and cost them billions of dollars in added costs and these are not adverse
events for some random drug these are drugs that you and I take all the time right these are drugs nonsteroidal
anti-inflammatory drugs there antidepressants their penicillin there
are these different drugs that you take for which there are these written this
risk of an adverse event and it could happen to you would it be great if you
could actually genotype somebody in figure out if they were likely to
develop an adverse drug response well that’s exactly what we can do in some
cases an example here is a drug carbamazepine which is used to treat
epilepsy so carbamazepine binds to its target which is a sodium channel and it through this finding that it provides
the anticonvulsant effect but what also happens in some people is this
carbamazepine cross-react with some of your immune response proteins in this
case Hleb the subtype with 15:02 in people who have this genetic background
and they take carbamazepine they can have this life-threatening
hypersensitivity reaction which can lead to death people who have different Hleb genotypes
in other words are not star 1502 but some other type they can take this job drug knowing that they will not have one
of these adverse events so this is pretty amazing that were able to do this
we can’t predict this with a hundred percent certainty obviously but we are
able to do this for at least a handful of drugs now how many of you when you
take a drug actually think it’s going to work I spend my whole life thinking that
of course it’s gonna work why wouldn’t it work and so I was shocked to learn
that in fact no drugs working everybody and in fact many drugs don’t even work
and most people so the good news is if you take an analgesic a pain reliever
like Tylenol or something you have a pretty good chance of responding to it
about 80% of people respond to those if you take a cancer drug good luck because
only about one in four people respond so for me this was really shocking to
understand that what drugs don’t work and everybody and that there is in fact
a lot of interindividual variability in drug response so why is that well there are a number of factors that
contribute to that but of course genetics is also one of those one of
those things and in the topic of what I’m gonna show you next so variation
happens in many of those aspects of a drug enters your body it’s transported
through the circulatory system its metabolites excreted but one area that’s particularly important if
metabolism of drugs there’s a class of enzymes called the cytochrome p450 their
drug metabolizing enzymes these drugs are these jeans there there are actually
quite a number of them there is 226 239 239 teen and a whole bunch of others
they’re responsible for metabolizing large numbers of drugs 56 in particular
is known to metabolize over a hundred different drugs here are some examples 239 over 60 drugs 5319 over 50 drugs now
it was noted that the metabolism enzymes here with highly variable from person to
person and in fact vary by race so for example there are people who are poor
metabolizers and for example accounted for about 6 percent of a Caucasian
population and many fewer african-americans and asians there are
also people who are ultra rapid metabolizers and this happens to be more
common in African countries and less common in European populations so there
is this what we call phenotypic variability from person to person people are rapid metabolizers poor
metabolizers and so on and the basis of this
variation is indeed in part due to genetics and we can test for that now so
you can go and get a test and somebody can tell you are you poor ultra rapid or
normal metabolize ER for this enzyme this enzyme this enzyme and that can
tell you something about how you might respond to these drugs how does that
work well take an example of Cody in pain medication codeine happens to be what we call a
prodrug in other words codeine itself is not what’s active in your body it’s not
what provides that pain relief codeine is actually metabolized into an
active metabolite called morphine and that’s what gives you the pain relief
cuz morphine binds to your opioid receptors and it makes you feel good now
this process is controlled by this Sept 26
ensign so what happens in a person if they have a mutation in this gene that
makes them a poor metabolizers well poor metabolizers can convert coding through
its active metabolite and so you’re not getting enough of the drug so these
people are less likely to respond to this drug and should in fact be getting
a higher dose in order to have this drug beatification so there are a number of
examples I could go through many more with this scenario or related scenarios
where variation genetic variation in these drug metabolizing enzymes can help
you decide whether you should dosa patient higher and lower now another way
that genetics can play into drug metabolism or drug efficacy is when you
look at the drug target remember a drug enters your body goes through this
transformation and ultimately a binds to a drug target which is what its exerting
that’s it effect on but sometimes that target has
variation in it and in fact sometimes we’ve been able to exploit that
variation to develop drugs that are specific to people with a certain
variants in that target so a great example is in cystic fibrosis so cystic
fibrosis is a disease that caused by one of over a thousand different mutations
in a gene called CFTR this is a chloride channel with from the surface of the south and when
it’s functioning normally ions are transported into the in and out
of the cell through there that’s a healthy individual but there are
mutations that occurred in this gene which have deleterious effects the most
common mutation is a deletion of one base pair at amino
acid 58 which affects folding of this protein such that this channel doesn’t
even reach the surface of the cell there’s another mutation which causes
premature truncation or termination of that protein meaning that I chloride
channel is short you got a little channel there and then there are other
mutations such as this single amino acid change which affect the functioning of
this chloride channel in this case the gating of the channel now what’s really
interesting is how in the last couple of years pharmaceutical companies have work to
develop drugs that target specific mutations in the CFTR the first one was
this G 50 55 51 D amino acid change which affected getting here the drug
Iraq after was developed specifically to fix this defect this was really you know
a huge thing for a rare genetic disease like cystic fibrosis if you know anybody
who’s had this disease the fact that there’s never ever been a
treatment and this is the first and it’s a targeted treatment since then this
drug has been approved for nine other mutations that have similar effects and
just a couple weeks ago another drug was approved call door combi which is for
patients with the most common type of CIF mutation for this is all really
exciting this illustrates this concept of targeted treatments so looking at the
target of a drug scene if there is variation and really developing your
drug to specifically act on that mutation targeted treatments are really
big right now in the area of cancer so let me tell you a little bit about
cancer from a molecular standpoint cancer is a disease where south bypassed
cancer bypasses growth control in a self so you think about a cell cells are
dividing the proliferating and there are certain signals that tell
us so went to divide we call these growth factors and their other signals
in your body that tell a cell to stop dividing without enough those are called
growth inhibitors and these growth factors and growth inhibitors usually
act through receptors on the south and basically when everything’s working fine
you’ve got a really nice system of regulation here but what happens in
cancer is cancers are cells that have lost this ability to control the growth
and they’ve lost it because they’ve acquired mutations in the sum of the
machinery they’ve Rico acquired mutations perhaps in growth factors
growth inhibitors receptors may be some DNA repair enzymes and so once you get
these mutations what happens is the cells continue to divide and divide
uncontrollably as they continue to divide they acquire more mutations such
that by the time you look at a tumor itself and you look at that South that
cell is unrecognizable it has you know on average 30 to 60 new mutations and
they’re not just little single base changes their gross chromosomal
abnormalities these cells are very messed up so the cancer cell has divided
divided and and you get the tumor the tumor invades the normal tissue and
eventually apiece breaks off or metastasize and you find it in your
longer in your bone and and this is when most cancer eighty percent of cancers
are diagnosed since we have been able to sequence the human genome we’ve turned
our attention to sequencing two years now and what what have we found well we
find that again these tumor cells have a lot of different variations going on a
lot of mutations going on and it’s also interesting that the mutational burden
varies depending on the type of cancer if you look at cancers that occurred in
pediatric patients clio quickly Robusto my medal estimates things like that they
have on average a relatively low number variations in that to yourself as you
move to older individuals you have a higher mutational burden look at things
like lung cancer melanoma what are these have in common they have in common
environmental exposures right lung cancer cigarette smoking melanoma UV radiation
these types of cancers have an even higher mutational burden and then you get
colorectal cancer here it’s off the charts why is that cool rectal cancer is off
the charts because they’re the type of colorectal cancer called Lynch syndrome this is a an inherited form of cancer
where a person inherited mutations in the very machinery that supposed to
correct mutations that occur in your body so when your cells are dividing and
mutations are happening you have enzymes that correct those fees are defective
enzymes in these people get colon cancer at a very early age and their tumors are
full of mistakes so what’s really interesting now is that we understand
that mutations occur in these cancer cells if you look at a tumor a specific
answer you find all different kinds of variation but it’s really challenging to
figure out which of these mutations are bad in other words they’re the ones
driving the cancer versus which ones are just passengers they’re just mutations
that have occurred there they’re just they’re they’re not they don’t have
anything to do with the cancer a lot of work is going on to identify what are
the driver mutations and cancer and we’ve made huge amount of progress in
this area this is what breast cancers look like in terms of their driver
mutations this is a pie chart showing you if you were to sequence several
hundred breast cancer tumors 32 percent of them would have a mutation in this
gene like three CA another 32% would have a mutation and teepee 453 and then
you have other mutations that occur much less frequently but nonetheless these are thought to be some of the
driver mutations for breast cancer look at lung cancers what you see with
lung cancer lung cancer has a slightly different profile about 28% of lung
cancers have mutations in a gene called chaos but 52 p53 also shows up as it did
with breast cancer is about 22 percent of lung cancers have mutations in p53 so
it’s really interesting that you can take any camps are now and you can make
one of these pie charts and show what are the driver mutations that are
occurring in this type of cancer and it’s really interesting because you do
see some unique variance for those specific cancers but you also see some
some shared variance across those different cancers so why is this
important well if we can identify these driver
mutations and cancer that gives us an opportunity to develop targeted
treatments that work on those jeans or those proteins that are mutated the
poster child example of this is a breast cancer drug called Herceptin Herceptin
was developed to treat women whose tumors had overexpression of a protein
called her to this overexpression due to mutations in the DNA causes an excess
amount of this her to protein which contributes to the uncontrolled growth
that is cancer and Herceptin is a drug that actually blocks the action of this
her to protein preventing it from promoting cellular growth and therefore
causing the tumor to shrink so this is again the poster child example for a
targeted treatment in cancer but it’s not the only example over the last few
years there have been targeted treatments developed for a number of
different cancers here’s just a few examples of the drugs that have been
developed and their target genes let’s take a look at non-small cell lung
carcinoma so this is a disease which historically I guess has been relatively
homogeneous in terms of how we define it molecular pathological level but now
with genome sequencing we’re able to get much more clarity on what’s going on and
we recognize their different subtypes of non-small cell lung carcinoma based on
what aberrant proteins are are being expressed and what this has done has
really opened up an expanded our opportunities for treating this disease
because now with non-small cell lung carcinoma there are three drugs on the
market that target different genes so for example if you happen to have a
tumor that has an EGFR mutation there are two different drugs you could take
that target that variation similarly if you have a mutation in your out gene
there’s an fda-approved drug available and these are becoming standard of care
for these patients now what about all these other patients well what’s
interesting is that you can see for non-small lung carcinoma there are these
other genes that happen to be mutated and it just so happens for these that
there are fda-approved drugs available they just happened to be for a different
cancer so for example the be RAF gene is mutated in about 50% of melanoma
patient’s and there’s a drug available to treat that so now we see in non-small
lung cancer patient they have a beer after gene mutated the idea is well
let’s just tried that drugs that work time be wrapped in a press in melanoma
patient let’s try and this patient and see what happens and in some cases were were finding that
works so that’s really exciting and we call these sort of off-label uses of
drugs in these indications bill yet we have other markers or other genes are
mutated for which there are active clinical trials out there so there are a
lot of different drugs in the pipeline that are targeting these different types
of variation in cancer so it’s a really exciting time in the area of cancer in
precision medicine but I guess one thing I should say also is that none of these
drugs actually cure people there are rare instances where a patient will take
one of these drugs and have a complete remission for their disease in most
cases PSA’s what these drugs do is they extend
life but that’s a good step forward in the right direction ok so what are some of the main
applications of precision medicine in the clinic today but not all of these
are being implemented in the clinic your doctors might not even know about
many of these applications there are in fact several hurdles to practicing
precision medicine one of the biggest hurdles is actually cost I talked to an
online course which Sharon mention the massively open online course and genomic
and precision medicine and I surveyed on my students and I ask them which of the
following you perceive as a major barrier to obtaining genetic and genomic
information on your patience we were giving this towards health care
providers the number one response was costs in insurance coverage I was
certain that they would say lack of provider education and thank you for
offering this course for me because now I’m learning everything I will begin to
do this but instead it was costs and insurance coverage so that is a big
concern precision medicine is costly and insurance coverage is not what it should
be so this is a real real big issue one of
the problems I guess it’s not a problem that’s how we’ll just how things happen
is we practice what’s called evidence-based coverage so insurance
coverage depends on whether the drug or the genetic tests in this case has a
certain level of clinical validity in other words does this in the case of
genetic testing does this test really predict response to the drug or does it
really predict whether somebody’s gonna get this disease or not that’s clinical
validity clinical utility is okay yeah I predicts but does it save us money does
it lead to better health outcomes and all this and in those are important
questions the problem is it takes a lot of
research to get answers to these questions so here you have these
innovations in precision medicine and you have this big gulf and then you have
over here all of the studies need to be done in order to prove
clinical validity and utility and it’s just this huge gap that needs to be
filled now how is it filled well you have technology assessments that people
do you have professional guidelines that are put together but underlying all of
that is basic clinical research and those are studies that can be costly
time-consuming and one of the other problems we’re facing now is the fact
that we’re practicing precision medicine we no longer have a lung cancer patient
we have an out positive lung cancer patient so we’re slicing the spy into
smaller and smaller slivers in expecting to be able to generate all of this
evidence that yes that particular mutation if you tell somebody they’re
gonna respond to this drug so it’s a real conundrum that we phase gathering
the evidence to prove that these these tests and these new treatments are
actually effective and useful in order for insurance to cover one of the other
problems is that most private insurance companies look to Medicare for their
decision if Medicare proves that all approve it the problem with that is medicare is
designed really to focus on diagnostic procedures and diagnostic tools as
opposed to preventive tools moreover the Medicare population is serving people
who are over 65 years old so medicare might make some decisions that aren’t
necessarily online with some of the technologies and some of the uses of
precision medicine today one of the other hurdles is related to regulation
so very quickly the way that genetic and genomic testing is regulated there are
32 friend branches that that deal with this first is the Federal Trade
Commission FTC this is the the department that really looks at
advertising to make sure you’re not making false or misleading advertising
claims so if you have a website and it says or how do genetic testing on you
and tell you if you’re at risk for developing this disease or that disease
if you’re making false advertising claims they can come after you the FDA which you’re all familiar with
in terms of genetic testing is really only interested in regulating test kits
so these are the reagents the pieces and parts that go into making a diagnostic
test now the thing is most genetic and genomic testing that’s done is not
through a kid per se but rather in private laboratories using laboratory
developed tests and this is not regulated by the FDA but rather a
different organization the Senate the Centers for Medicare and Medicaid
Services and they really are interested in knowing is this a good laboratory are
the personnel trained do they have the right education are they doing proper
quality control they’re really concerned with the analytical validity of tests in
other words how good does this test actually measure what it says its
measuring now a couple of years ago the FDA which up until then had chose to not
regulate laboratory developed tests because it has the authority to do so it
just never did has taken an about-face and decided that they’re going to
regulate laboratory developed tests now and so this is a really big deal for the
industry as a whole right now because if you think about all of the different
applications I talked about and all the different laboratories and all the
different tests in all the different genes that this can always done really
overwhelmed a system that’s not prepared to do that so it’s currently gone a
little bit quiet over the FDA side right now as they try and figure out how
they’re actually gonna do this regulation but something to keep your
eyes on the other well there are a lot of other
hurdles and I’m not going to go through all of them but the last one that I
wanted to talk about relates to health care providers because you see health
care providers are the gatekeepers of precision medicine if your doctor
doesn’t know about any of this stuff they’re not gonna offer it to you and
and so when I think about health care providers with respect to precision
medicine I think of several characteristics first of all that their underwear
they’re just unaware of all of this technology they’re unaware of these new
tests it and you can imagine how difficult it is to keep up in such a
fast-paced filled another characteristic of healthcare providers is that they’re
skeptical and rightly so in some cases right they don’t know if these tests are
good or not they have a healthy skepticism towards them and finally
healthcare providers really lacked confidence in their ability to practice
precision medicine you know most of them probably never had a genetics course in
their life and then all of a sudden they’re expected to understand all of
this complicated science and they really have a lack of confidence in their own
understanding with and their ability to practice and and and nowhere to get
information so I think this is a big issue and one of the reasons that I
decided to get into education in the spaces to really trying to educate
healthcare providers as well as consumers in in this area so let me tell
you about a few things on the horizon that are really exciting one of these
things you’ll recall a time when I talked about non-invasive prenatal
testing it was taken advantage of the fact that a fetus sheds thousands of the
maternal blood stream of the same thing happens with numerous tumors showed DNA
into the host bloodstream in the form of cell-free DNA and were actually able to
detect that in the bloodstream and do a few interesting things with that first
of all we’re able to monitor recurrence and resistance to cancers by taking a
blood sample from a patient were also able to do some tumor
profiling so let’s determine whether this person has Alka mutation or be
reputation or whatever without taking an actual biopsy of that tumor but really
the Holy Grail will be when we can use it for primary diagnosis imagine a day
when you go to the doctor and you have a blood test and they can tell you whether
you have cancer or not and they can tell you early on so that you can actually
hopefully prevent it this seems pretty science-fiction pretty
sci-fi but in fact last year this story came out there was a woman who went to
undergo non-invasive prenatal testing when she was pregnant and the company
that did her testing came back with the report to her and said look you know
either your fetus is really messed up I mean it can’t even be viable it had so
many different genetic abnormalities that something else have to be going on
and it turns out that they were detecting abnormalities that occurred in
her tumor cells which were being shut off she had no idea she had cancer so
she was diagnosed with cancer because she did a blood test to detect
abnormalities in her finish her feed fetus so it’s not an isolated incident
this company actually reported at least 10 different cases of this so this shows
you that this technology is on the horizon and something that may even be
possible in your lifetime another super exciting area is the human microbiome so
how many of you have heard of the microbiome oK so it’s it’s out there
right basically our companion microbes that
occur everywhere in and on your body number human cells ten-to-one and these
include bacteria viruses fungi and we’re just beginning to map the landscape of
the human microbiome I actually had my gut microbiome analyzed and you can do
that to their couple of different places you can get this done I chose the American gov project because it seemed
like a good cause you can do a lot of research with this information and
basically if you get here your gut micro microbiome or any other
skin microbiome wherever analyze what they can tell you now is basically how
you compare to other people with respect to your most abundant species and so
here they they looked at the most abundant species that any person would
have in their gut and they looked at me and said oh you’ve sorry these colors
didn’t come out very well but basically here’s my level of Firmicutes as appears
I’ve got a lot of those and then you can compare it to other people now I made my
family go through this so you know my son has a lot more for me than I did my
daughter had about the same number and basically they allow you to compare it
to Michael Pollan’s microbiome so you’re not familiar with his work he does a lot
of nutritional consultation and stuff and thought you would think his God is
like pristine and sure enough he’s got a lot he’s got some things down here i
think is the cyanobacteria that none of us have ever really fun looking at this
will also tell you what your most abundant microbes are so not just
reporting on the ones that are most common and everybody but what are your
most common ones and then your most enriched ones so whereas something like
this I can’t even pronounce that is not very common in my god it’s significantly
enriched relative to the average person so of course when I got these results
back i’m looking all of these up on the internet really not finding much at all
although I did find something recently just when I was preparing the stock I
decided to look this one up cuz I’m 19 and reached for this one and it turns
out that they found bacteria in the gut of people who tended to tend to be leans
I’m like but actually one of the more important
things that if you if you read what’s important and I got my crime microbiome
its diversity and I am very psyched because I have 12 rare taxa whereas my
kids and my husband only had like two or three so I’m really excited about that
now of course the Holy Grail to all of this is trying to understand what your
micro bio ms doing with respect to disease and then how you can actually
alternate and there’s been a lot of research in this area there’s nothing
really huge to report it still primarily in the research area but there have been
links with different microbiome profiles and inflammatory bowel disease even
cardiovascular disease obesity and such and then you ask well so what can I do
about it well one thing you can do in this has been very effective in people
who have an infection and intestinal infection called C def which is very
hard to treat so basically they determined that this infection takes
hold because the gut microbiome is imbalanced in a certain way and the way
to treat it as by doing a fecal transplants and so it is exactly what it
sounds like and they transplant your microbiome with feces donor and are
curing patients that’s pretty yeah I’ve heard of people with ear infections are
some ear infection taking ear wax from the other ear and putting it in and
actually carrying it i mean it’s it’s really amazing so you know we’ve spent
so much time thinking about how do I kill all these bugs in my body but now
microbes are your friend and you really really wanna treat them treat them well
some of the other things that I’ve heard about their companies well there’s a pretty early stage
company now that’s using a different frequency technology because all of
those sequencing we do right now is that a very superficial level or not being down into the details of these
bugs were getting a superficial look at this company is starting to develop more
deep sequencing to characterize these microbes that a much finer level in
their ideas to then develop custom probiotics based on if you have a
deficiency now you don’t want just that over-the-counter probiotic that has just
10 species you’re gonna want this special mix which with tailored for your
specific deficiencies Dietary modulation we’re learning a lot about how diet can
actually change your micro bio and the importance of that and then there are
also people talking about creating synthetic microbes so this whole idea
that you can really engineer microbes in the lab to have benefit your health so
microbial is so so exciting the last mom up-and-coming thing that I
want to talk about isn’t a technology per se it’s more of a movement this is
that idea of participatory medicine this is where patients are actually taking up
arms and really taking control of their health now you might not see it everyday
and you might not be doing this yourself but you’ll see signs of its patients who
are beginning to connect with each other they’re beginning to collect their own
data they’re they’re sharing their health data and experiences and really
turning into advocates for their health one of the characteristics of a
participatory medicine is when patients start to become help data stewards so
how many of you have looked in your patient portal that your doctor offers
many many ok so it turns out that you’re ahead of the game because it only about
five percent of people I think look at their health data portals but the fact
that you can do that now is a big thing moral mer we’re not just looking at data
that was collected in a doctor’s office but we’re collecting regenerating our
own data if you have a Fitbit you know what I’m talking about here you can capture information about your exercise
there are other gadgets and widgets that you can use to track your diet and sleep
patterns there’s this whole industry of wearable technologies out there right
now where you can wear a center on you and you can actually do an EKG with
using your cell phone you put a sensor on you’ve got your cell phone and you
can look at your heart and see what your heart rhythm is you can measure oxygen
levels glucose levels blood pressure all of this with these wearable mobile
technologies this is a huge area that’s booming it’s
putting patients in charge of their own house and collecting data about their
health but then you know you got the issue of storage at but you’ve got
things like the new Apple is that Apple healthcare tour one of the apps that you
get on your iPhone now where you can actually begin to store some of this
information yourself but really what you want is to be able to take that
information and transmit at your doctor’s office so that it’s in your
medical record and it’s interesting I hear about all this health data
stewardship and personally I haven’t done any event really but I’m really
intrigued riot in fact I just came across the company the other day called
care seeing where you know how if you move around alot you got medical records
and all these different states and they’re not together that’s me and this
is a company that will actually get all of that to you and organize it and be
able to look at for example how is how is my weight changed over the years or
how have all these other measures change so it’s really an exciting time in terms
of a patient taking control of their health collecting their own data and and
of course we’re not just collecting it to keep ourselves we’re sharing it with
other people who sort of patients like me patients like me as a website which was
really started by a couple of brothers whose third brother developed I think
ALS Lou Gehrig’s disease and they wanted to find other patients like that so that
they could share best practices you know what did you do what treatment did you have did it work
for you so patients like me as a site where they they cover all kinds of
diseases you can go and find a community of people who have that disease and you
can share your experiences and and now just think about it if you’re a
pharmaceutical company one of your biggest challenges is developing drugs
than finding enough patients where you gonna find all these patients are gonna
have to comb doctors offices across the country to find a lot of patience will
now you’ve got a hub where you can actually find the number of patients
with your disease so I think it’s a win-win for everybody but patients are
willing to share so much information personal health information with
complete strangers on the site I think it’s really fun there are other disease
registries that have popped up more related to genomics now this one if you
have a certain genetic condition you can try and connect with other people who
have that genetic condition there is a genome Connect which is a new portal
that was started to allow people if they have their genome sequence to upload it
and have it somewhere safe and also be able to share it with whoever they want
so people are starting to connect as well and then you also see a lot of
patient advocacy on the rise this is particularly true in the rare disease
arena because think about it if you have a rare disease who you gonna talk to you
don’t know anybody else who has this rare disease and so you can go to this
organization for example global genes as one of them they teach patients and
their caregivers with rare diseases how to become advocates for their set for
themselves how do I raise awareness how do I find other people with the disease how do I fundraise how do I lobby for
this disease in washington and they have two day conferences where all of these
patients with rare diseases come together and learn how to become their
own advocate and really make changes so the last thing that I I wanted to
mention is how patients in terms of participatory medicine really lack good
sources of information about precision medicine and genomics
and that’s why I was really happy about a year and a half ago to be asked to be
editor-in-chief of the magazine genome which you have copies of the genome is
free quarterly publication that comes out in print and also is online this
magazine was written for a lay audience and the whole goal is to really bring
precision medicine to the people because really for you on this field to move
forward there’s sort of a push with physicians it’s like come and learn
learn about this but there’s also going to be a poll coming from patients right
and go to your doctor’s office then and talk to your doctor and say hey look I
read about this story about this test do you offer this and and they’re gonna
start to feel like there may be a little behind the times which is not our intent
because in fact about half of our subscription requests come from
physician so I hope you enjoy the magazine and those are three copies for
you all and if you’re interested in getting a free subscription their
instructions inside there but anyway that’s all I wanted to say I thank you
so much for your attention and I hope you enjoyed the structure I’m really interested in
the past I have
a friend who’s very sensitive to codeine and I tried to advise you know her
position about this the nature of the reaction that she gets
you know little goes a long way and that you mention that this was out there
right how would I advised my friend you know if she wanted to get that s taken
in and then have it as she could communicate or doctor and they could
have to adjust the dosage based on that yeah so you know I hear this all the
time patients wanting to access attacks like this and most of these tests you
have to go through your doctor to get it ordered there are very few places where
you can do direct consumer testing I would I mean I would press my physician
really if I wanted that test and there are places that you can get tested a
company called the sure our ex offers genetic testing for those three
metabolizing enzymes I talked about three positions in they just are not
aware that the they’re not even sure what stage this is in favor say think
it’s not really something that is useful right now those are some of the
responses I’ve gotten right so where where could I go to you know trying to
obtain the tester well previously 23 me offered genetic testing for for some of
these genes they didn’t do sit 2d six which is the one that metabolizes coding
cuz it’s a very complicated gene so you’re better off going someplace that
specializes in that you know you may want to contact some of the
companies that offer this task because they might be able to give you some
tools that you need to talk to your doctor with you you say that they are on
the market or you can purchase it and have it is part of pure oh yeah oh
that’s great yeah definitely relationship between and particularly
familiar with the research in that area so I can’t really comment on whether
those drug metabolizing enzyme variants are related to addiction or not I
wouldn’t I would have to bone up on that before I come into them that yes I’ve
had a lingering questions since the beginning of this genetic testing if I
were to take a sample from my lining of my mouth to mouth and Senate in take
five cents and send it to the same laboratory under different names in
different addresses or something like that what would be the degree of fidelity of
reproducibility and accuracy yeah that that’s a good question so we’re there
won’t be variation is due to differences in the DNA from the different times you
take that simple there might be differences in the amount of DNA you get
or the the integrity of the sample as it goes from your mouth to the laboratory
ok but assuming that they’re using a reliable technique and good quality
control measures you should be getting the same results from lab to the next
have you had experience in the country I’m sure to curious a number of years
ago there was big promotion to have full body to CT scans which proved to be in
many ways detrimental to people because they found some obscure little thing and
ended up having surgery they didn’t need and things like that so I just curious
what are the counter indications and studying all just the average person
going and having their genes tested yeah you know I know there’s a lot of
parallels to that right you go in and you have a full body scan and you learn
about all these things that could be wrong but you really don’t know if
they’re bad things are not and parallels exist in whole-genome sequencing so
that’s a healthy person I mean I’ve had my not my whole genome but my exon
sequence which is a smaller part of the genome just just the jeans and and I
found some stuff in there and so right then that the fear is that you’re gonna
find things number one to find things that sound like they should be bad but
they’re really not end and the truth is we don’t know if they’re bad or not and
and so it can provide can cause a lot of anxiety there are also people who get
tested for one thing but because they’re using genome whole-genome sequencing you
get these incidental findings and so that was a big issue that everybody was
grappling with a few years ago what do we do when we going in we want to test
somebody for mutations in the breast cancer genes but we’re sequence in them
and all we happen to find out you’ve got some other things going on so people
have been talking about this the American College of Medical genomics has
set a fifty six genes that they said okay if you happen to undergo sequencing
and you find a mutation in one of these days you have to report it because it’s
it’s an incidental finding and it could be something bad and they
need to know about it so I mean these are ethical issues that were grappling
with definitely as well as we go into this new area she said she had a
mutation in the bracket to gene which gave her an 80 percent chance of
developing breast cancer in her lifetime and also a significant maybe sixty
percent chance of developing ovarian cancer so a lot of a lot of women in
that position well your choices are increased
vigilance you can prophylactic drugs you can take like
tamoxifen I think and then there’s the radical you know prophylactic
mastectomies affected me so she chose the more radical procedure but a lot of
women do you think about if you have had your all of the South in your body of
the same DNA and then you have a few of these tumor cells floating around that
have some differences that’s one of the limitations right now as we can’t go out
and say oh this is a tumor cell in this is a normal cell instead the
applications today our applications where we’ve already biopsy the main
tumor we know what the main changes are in these are changes that are different
from the rest of the cells in the body and now we can track of those so we can
monitor recurrence by looking for something that we already know about so
there is no good way to like sort I talked to her from a normal cell right
now except for if we are to know something about what that tumor should
look like they mentioned the tumor you know there are some events that trigger
the tumor deform and these are based in your mutations that are occurred and and
deregulate the growth and so and so they keep replicating now every time they
replicate there’s a chance that more mutations will occur and what happens is
mutations tend to occur in some DNA repair machinery so they get more memory
patient’s right and so they’re just keep developing mutations basically I told
you earlier on about breast cancer about 10% is hereditary 90% sporadic
hundred-percent genetic in the sense that even if you have a hereditary
predisposition which kinda gives you a head start to be very got one bad
mutation and and you really it’s it’s the accumulation of mutations after that
that result in cancer even in the absence of that hereditary headstart
most cancer is somatic in nature in other words these mutations are just
popping up in the NE you know a pancreatic cell for example
gets a mutation and it happens to be in the wrong place in a gene and then that
so divides and divides and then another mutation happens and and then you start
this whole cascade event so only about 10 percent of cancers have you know
genetic kick-start this reddit Terry component but all cancers are genetic in
the sense that they’re due to mutations at the DNA level yeah so you have
basically a mutation in a driver jean is is going to for example produce a
protein that wouldn’t normally be produced or or turn on a protein that’s
normally not not turned on for example my question with more but more and more people
getting access to their genomes and with more and more information being shared
what what’s to stop like certainly insurance companies from who if they
would have access to your genomic information see potential markers for
serious diseases and it would cut and they would may increase rates or deny
coverage for certain people just because they have genetic markers that make them
more prone to disease and I even actually had the disease so there’s this
thing called Gina it’s the genetics information non-discrimination Act which
prevents health insurance providers from discriminating on a a person based on
their genetic predisposition so that applies to health insurance but that
doesn’t apply to life insurance in in these other types of insurance that are are not
deemed necessary for your health care so there is there’s legislation that
protects people hi my name’s Andrea them promote student and I found this really
interesting after just finishing genetics class at berkeley I have one
technical question and non-technical person so what are some differences
between the oncogenes and tumor suppressor gene when it comes to
metastasis I don’t know that there’s a difference with respect to metastasis because in fact we’re still trying to
understand what are the drivers of metastasis so we have a good
understanding of some of the genes both tumor suppressors and oncogenes involved
in the initiation of cancer and the progression of cancer but not
necessarily the metastasis P so you would have to basically compare the
tumor cells in the primary tumor with the tumor cells that have metastasized
and ask what are the order of the genetic changes what are the differences
between those include those be the drivers of metastasis but so far we
haven’t made a lot of progress in that area and the other question is one of
the take away from your presentation and he’s from my understanding is that with
all these innovative innovations and technologies very exciting things going
on in genomic medicine on the other hand we see on there is a lack of
understanding and knowledge in this area in both policymakers and the current
position so would just suggest a purely opinionated question to you what are
some of the things that current positions or future a future medical
students or future physicians can do to push this next step and do you think
that there should be more health care providers involved in policy-making and
even stepping to politics so I mean you’re recognized in the education gap
right the education gap for health care providers so fortunately a lot of
universities now are beginning to offer programs and precision medicine or
individual courses in precision medicine there are magazines like genome out
their healthcare providers can become educated in that area but you’re right
there are there other stakeholders their their people in government and law in
different aspects that touch on this field that need to be educated as well
so the real danger is many people get their news from like the new york times
or other publications and those are often incorrect and sometimes biased so
it’s really important to find good sources of information has a
specialization evolved for genomic in micro bio medicine among doctors and
physicians necessarily as you saw precision medicine is vast it
encompasses a lot of different specialties I would say for example
within cancer though you will see met on medical oncologists who with a specialty
now in tumor profiling maybe not a formal education but certainly there are
places where they’re trained in their docs to understand how to do this tumor
profiling and things like that and not not microbiome not yet but one day I
will bet I’m curious about epigenetics is that considered part of precision
medicine and how is it being used in the clinic so epigenetics refers to this
kind of chemical modification to DL so all of the variation that we talked
about so far where changes to the letters of the genetic code epigenetics
is a chemical modification that kinda lays on top of that so and it’s a means
of regulating whether that gene is expressed or not you know you can
measure genetic changes we found epigenetic changes associated with
cancer and other diseases but as far as I know it’s not really being used
clinically at all I just think they’re not as strong predictor of any diseases

1 Comment

  • Reply Donald Cummings December 14, 2018 at 8:01 pm

    Don't forget to establish a genomic data base for humans, "a specific data base for each nation" so we can search for "anomalies" that will lead us to "treatment-cures" for what ails us. The "treatment-cures" will guide us to the proper Caspr-9 etc. etc. for correction. This will lead us to discover other treatment systems that will increase healthy lifespans and lead us to a factorial reduction of the nation’s medical expenses.

  • Leave a Reply