January 29, 2025 • 25 mins
This week on Biotech Nation, Dr. Martin Borch Jensen and Dr. Francisco LePort from Gordian Biotechnology share a bold new approach to fighting diseases of aging before they take hold. Instead of testing one drug at a time, their technology allows scientists to test hundreds of potential treatments at once, making drug discovery faster and more precise. This could change how we treat conditions like arthritis, heart failure, and fatty liver disease.
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Episode Transcript
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Dr. Moira Gunn (00:11):
Working on what are usually considered the
diseases of old age when you'reyounger as they're developing.
Not only that, doctor MartinBorch Jensen and doctor
Francisco LePort from GordianBiotechnology tell us how
they've invented a way todevelop and test many cell
therapies all at once, all withan eye to making drug discovery
(00:36):
faster and drug approval morecertain. Doctor Borch Jensen and
doctor LePort, welcome to theprogram.
Dr. Martin Borch Jensen (00:43):
Thanks, Moira. Very
Dr. Francisco LePort (00:44):
good to be here.
Dr. Moira Gunn (00:45):
Now I'm actually going to start by quoting from
an opinion piece which you,doctor Borch Jensen, wrote with
UCSF professor, doctor NicolePolk, some 4 years ago in cell
and gene. You wrote, in reality,2 thirds of people aged 65 plus
have 2 or more diseases, whichshocked me, But putting a pin in
(01:09):
that, those diseases started inthese individuals when they were
much younger, before they were65. Where and how do these
diseases start?
Dr. Martin Borch Jensen (01:19):
Yeah. Obviously, we don't know
everything about every disease,but the way we can think about
this is that your body made outof lots of different cells, it
functions sort of as a society.All the cells are doing
different things in order topreserve all the functions, your
breathing, your movement, yourdigestion, and so forth. And
diseases basically occur whenthat system is challenged, which
(01:45):
can happen either through, let'ssay, an infection, you get the
flu, and so there's some outsideinvader and your body responds,
Or, as in the case of aging, thesystem of your body gets
increasingly confused,individual functions sort of,
get worse, and then your theability of your body to sort of
(02:05):
maintain this function whileyou're living your life drops.
And that's kind of the thingthat prefaces the things that we
call diseases.
Right? So you say, okay, I have,you know, Alzheimer's disease,
or I have heart problems. Thatis the symptom of your body's
reduced capacity to functionnormally, as happens through a
(02:26):
variety of biologicalmechanisms, that we call aging.
Dr. Moira Gunn (02:30):
And it all started a long time ago where
from one insult to another ormutation changes as cells are
replacing themselves, justlittle by little, eventually, it
becomes one of these conditions,if not more.
Dr. Martin Borch Jensen (02:45):
That's right. You have a complex
system, and so as individualthings fail here and there, it
seems fine for a while untilsuddenly things go downhill.
Dr. Moira Gunn (02:54):
So, what does that mean in terms of trying to
cure diseases?
Dr. Martin Borch Jensen (03:00):
Yeah. It makes it hard. Right? In the
case of, a virus, you can pointyour finger at, like, one exact
culprit. Here's the one thingthat's wrong, that's causing us
to be deceased.
But for these complex chronicdiseases that happen with age,
it's an interplay of differentfactors that goes wrong and then
causes disease. And so thatmeans in order to find out how
(03:25):
to treat the disease, we need tolook at the whole set of things
that change, and some of themchange for various reasons.
Imagine a busy office that's,about to have, you know, like a
meltdown. Not every conversationin that office is something
that's, you know, about to leadto a bunch of, buying whatever
(03:45):
subprime mortgages. Right?
So as a, you know, biologist,you go in and you can measure
all the things that happened,but you have to cut through and
find out what are the keythings. And usually the way
people do this is throughinterventions or putting
something into the system andchanging something, and then see
whether you get the result thatyou want.
Dr. Francisco LePort (04:05):
I think the interesting thing about
aging, as distinct from, many ofthe other, conditions that we're
going after is there isn't thisthis single kind of impact, this
single, you know, insult that'shappening to the body. In many
ways, you know, we areprogrammed to age. That is kind
of the the normal process, thathappens to all of us as humans.
(04:25):
And so there really is this bigweb to untangle, in terms of,
you know, what is it that'sgoing, quote, unquote, wrong as
we're aging, versus theseindividual pieces. And this
really makes it much, much morecomplex.
Dr. Moira Gunn (04:38):
Now let's get to what I'm gonna call better gene
targets, you know, which becomethe therapies. Today with gene
therapy, we tend to address 1 ora few candidate mutations. And
even with the highly vaunted AI,this is somewhat guesswork. And
then 1 or several candidates aretried on animals with a
(05:00):
similarity to humans, and, thenone and only one drug candidate
goes forward, is tested onhumans, a successive group of
humans, until we approve it'ssafe and effective. And this
isn't strange.
This is how we've been doingdrug development for a long
time. What's problematic withthis approach?
Dr. Francisco LePort (05:22):
Yeah. So even as you were describing it,
right, you can see that thereare many, many steps, in that
approach. And the reality isthat each of those steps is
extremely expensive andsuccessively more and more
expensive. So when you combinethat with this web that, that I
had mentioned before, you know,you look at the the number of
gene targets that you couldpotentially pick. There are over
(05:42):
20,000 genes, in the humangenome, so the space is very,
very large.
And if the, methodology that youhave, which is kind of what
we've had, you know,traditionally, is to kind of
pick a single one of thosetargets and then go after and
then kind of interrogate it, youknow, through 1,000,000 of
dollars of process andpreclinical study and eventually
(06:04):
clinical study, you know, it'sgonna take you a very long time
and a tremendous amount of moneyto get through 1,000 of those
targets. And I think that'sreally kind of the the issue.
Right? We're not very good atguessing what those initial
targets are. We've gone througha few of them for these age
related diseases that are verycomplex, and then we've met with
(06:24):
failure in the clinic.
And, I think, fundamentally, weneed a very different approach
to that.
Dr. Moira Gunn (06:29):
Well, here's where Gordian's approach is so
different, and I and I I kindawanna say to the listener, pay
attention now. This is what wecall in math, a stepwise
different approach. So this isvery important. What is
Gordian's approach?
Dr. Martin Borch Jensen (06:44):
So taking everything that we just
said, right, what you reallywould like to do is, to put a
lot of different interventions,a lot of potential medicines
into a system that has all thatcomplexity, cells talking to
each other, coordinating theirresponses, cells affected by
aging, and then be able to testall of the different potential
(07:09):
therapies at the same time,getting the answer that you
want, which is, does this workwhen you have all the complexity
included and all the barriers tothis medicine potentially
working for the disease. And sothat's the sort of technology
that we, invented early in thecompany's, life. The ability to
(07:30):
combine gene therapy withreading out states of different
cells and do these simultaneousexperiments, where we put many
therapies into the organ of ananimal that has often
spontaneously developed thisdisease that we're trying to
study and then test them allsimultaneously without them sort
(07:50):
of affecting each other and andgetting us a confused answer.
Dr. Moira Gunn (07:54):
Well, of course, I'm gonna ask you for a first
example here. And well beforethe age of 65, many people have
problems with their knees.Cartilage breaks down and you
took this example and decidedthat a horse's knee had a lot in
common with a human's knee andracehorses and working farm
(08:16):
horses, they have the sameproblem with their knees that
humans do. The cartilage breaksdown. Now tell us, what have you
done with these horses?
And let me get this straight.You're looking to rebuild
cartilage?
Dr. Francisco LePort (08:30):
I think it's a great, example and
actually points to one of thereal advantages of this, new
method. We are not only able toput, hundreds of different,
targets or thousands ofdifferent targets in some cases
into these animals. But becausewe can put so many, into these
individual animals, we can gointo these advanced animal
models of disease. So normally,people would go into mice, for
(08:52):
example, in osteoarthritis, andthey would, you know, if they
were to go into an an advancedanimal model such as horses,
they would do that only fortheir, you know, select very
last target because that's soexpensive. We can actually put,
hundreds of targets, intoindividual, horses right from
the very beginning of ourprocess, which is really neat.
Dr. Martin Borch Jensen (09:11):
As you were saying, do we want to
regenerate, the cartilage of thejoint? And when we go into these
complex models, the idea is thatwe can capture all the different
aspects of disease. Soosteoarthritis is, you know,
cartilage being worn away. Butwhat you want to treat is both
that and the pain that patientswith osteoarthritis are feeling,
(09:34):
which comes, in part frominflammation in that joint. And
so with our technology, what wecan do is go into this, system
that captures all of the biologyof the disease and then test
hundreds of targets that eachindividually might be effective
against some aspect of thebiology that's going wrong and
(09:55):
potentially in combination, ormaybe there is, one gene we find
that does everything you want tocomprehensively treat, this
disease and find treatments thatwill be really effective once we
go into people.
Dr. Moira Gunn (10:08):
So it's not just the I've a I'm a runner and I've
run 20 miles a day for 40 yearsthat creates this problem.
There's a breakdown in yourcells. There is for one reason
or another, either because inaging, they're just not as good
as they were. They've beenmutations, weakened mutations,
if you will, or some insult. Andso you're able to go in and say,
(10:31):
well, let's target and correctthis gene.
Let's target and correct thatgene. Let's target and correct
that gene. And then so you havea whole number of targets lined
up, gene corrections, that youcan put in. But then how long do
you leave it in the horse beforeyou take a look at what's in the
cartilage?
Dr. Martin Borch Jensen: Typically, let's say a month (10:52):
undefined
because, what we want to findout again is how do the
therapies, affect the tissuewith all of this stuff going on?
So we don't want to know, youknow, what happens immediately
when you take this medicine. Wewant to know what would the,
sort of biology of a patientlook like, after they've gotten
(11:13):
this treatment, right, in thelong term? So, yeah, 1 month,
let's say.
Dr. Moira Gunn (11:18):
I'm speaking with doctor Martin Borch Jensen
and doctor Francisco Laportefrom Gordian Biotechnology in
South San Francisco. DoctorBortch Jensen is the chief
scientific officer, and doctorLaporte is Gordian's CEO. Okay.
So now here's the $50,000,000question. You've put several 100
(11:40):
different
Dr. Francisco LePort (11:41):
More.
Dr. Moira Gunn (11:41):
Gene correcting, activities, if you will, into
this joint, and you say, oh,look. This looks better. The
genes look better. They lookyounger. They look they look
like they're all gonna function.
How do you know which of theseveral 100 gene correcting,
treatments you've put inactually worked?
Dr. Francisco LePort (12:03):
Yeah. So, for that, we use a technology
that's called single cellsequencing. So I'm sure everyone
has, heard about, DNAsequencing. Right? This got,
popular, in the 2000 as theprice started coming down with
the Human Genome Project and allof that.
So, at this point, there'stechnology out there that can
allow us to actually sequenceindividual cells. And we use
(12:25):
that to look at these individualcells that have gotten these
individual perturbations or genechanges in the, living horse.
So, we go in. We can identify,which cells got which, change,
which gene target change. Andthen using this single cell
sequencing technology, we canidentify what exactly did that
(12:46):
change about the cell.
It's kinda like looking at, youknow, the the code of a computer
program, and then getting asense of, well, what is the the
status of this, you know,computer? In this case, we can
get a status of what is the celldoing? What are the functions
that it's performing? How wellis it performing those
functions? Is it performing thefunctions that it would normally
(13:06):
be performing, in a healthyenvironment?
And all kinds of other, youknow, more complex or more
nuanced things. Right? Is it,serving the protective effects
that we want it to, in thisdiseased environment? So we get
this very, very rich, rich dataset by using this, single cell
sequencing technology.
Dr. Moira Gunn (13:23):
Well, you could certainly tell what's changed
positively. That's right. Buthow do you trace that back to
which of your several 100 genetargeting therapies that you
would you injected all at thesame time? Which ones worked?
Dr. Martin Borch Jensen (13:35):
The fact that we're using gene
therapies here to deliver thesegenetic payloads comes in really
handy sort of by design. So whenwe deliver a therapy that,
changes the expression of somegene, we also include this bar
code. It's called a barcode, youknow, in the in the industry,
but it's basically a sequencethat uniquely labels this
therapy. And so when we detectthat sequence in the cells that
(13:58):
we, are analyzing, then we knowwhich therapy was in there.
Dr. Moira Gunn (14:02):
You know, if you are a computer programmer,
you'll know that, sometimes youput in a series of things called
no ops, no operation. They justkinda fill it in, and the
computer thinks, oh, yeah. I'lljust go along. It just does it's
a instruction that does nothing.You can add such things in your
GCATs, which are the particularnucleotides that are your
(14:24):
programming your your DNA andthen you could you could say,
well, just put we'll put asequence that means nothing in
your body.
So that's enough variation thatyou can identify each one of
these separately.
Dr. Martin Borch Jensen (14:36):
Yeah. That's the basic idea.
Dr. Francisco LePort (14:38):
Yeah. That's right.
Dr. Moira Gunn (14:39):
You guys are pretty clever guys. I'll give
you that. I'll give you that.Okay. I have more questions.
Don't don't don't stop now.You're also working on heart
failure and fatty liver disease,NASH. Used to be called NASH.
What are you doing in each, andwhat animals are you working
(14:59):
with there?
Dr. Martin Borch Jensen (15:00):
So in each, disease, we really are
asking, well, which animals aresimilar to the patients? Which
in terms of their, the anatomyof the tissue, but also how they
get the disease. And so MASH isinteresting because, it happens
more with age, but diet alsoplays a big part. And so the way
(15:20):
that, many people including uswill, develop MASH models is
basically to give the animals,which for most people is mice.
In our case, we also use mice aswell as monkeys, which you can
imagine are more similar tohumans.
And we give them a diet thatthey actually quite like. The
(15:41):
technical term is a Westerndiet. It's high in sugar, high
in fat, and high in cholesterol.And then over time, and this is
the key part and the part where,you know, some companies are
impatient, but rightfully so,you want to run your studies
quickly. You don't want to feedthis diet over, let's say, more
than a year, but that's how itworks in the patients.
(16:03):
So we have, animals on thesewestern diets for a really long
period of time, and the monkeyshave been on it for more than a
year, at this point. And thengradually, your liver
experiences the same as thepatients, this accumulation of
fat and then eventually turns todisease.
Dr. Moira Gunn (16:20):
Uh-huh. So you're doing this in in monkeys
as well for the MASH, for thefatty liver disease?
Dr. Martin Borch Jensen (16:27):
That's right.
Dr. Moira Gunn (16:28):
Okay. What about heart failure? What are you
trying to do on heart failure?
Dr. Francisco LePort (16:33):
Yeah. So for heart failure, similarly, we
look at what are the best animalmodels that, we can go into
there. And, again, I think thisis the real to me, the neat part
about this technology and whatit enables is the ability to
really go into systems that areas close to human as possible,
depending on the particulardisease that we're going after.
So in heart failure, we arelooking at, actually 3 animals.
(16:57):
We've got mouse and rat modelsof heart failure and then, pigs.
Turns out that, pigs have heartsthat are actually quite similar,
to humans, in many aspects oftheir, physiology, and we use
those as well. And, in terms ofthe the mechanics of it, it's
actually very similar to what wedescribed with the horses, which
(17:18):
again, is a real advantage, thetechnology that's available. We
can really extend it to, anyanimal model of disease. It
doesn't require too muchfiddling with, in order to get
it to work, for these varioussystems.
Dr. Moira Gunn (17:31):
Now in those cases, are you looking to
restructure the heart or replacecells in the heart? What are you
looking for?
Dr. Martin Borch Jensen (17:39):
Not replace, more like reprogram.
And this is essentially what alldrugs do. You have this, machine
that is running differentprograms and they dysfunction.
And so
Dr. Moira Gunn (17:52):
Called your body.
Dr. Martin Borch Jensen (17:52):
Yeah. Exactly. Your body. But then,
you know, the subpart of yourbody, you can, call it the
engine if you want. Right?
The heart has to beat. Thecardiomyocytes, that's the
technical term for the cellsthat make up your heart, and
cause it to beat. Right? Theyhave to do a lot just to do that
simple job. They have tometabolize a lot of energy in
(18:13):
order to cause thesecontractions, and they have to
do that in a synchronizedmanner.
And so what we want is that thecardiomyocytes that have been
working for your whole life, tokeep your heart beating, are
behaving similarly to what theywere like without this,
accumulation of dysfunction,that caused the disease. And we
(18:33):
do that by going in and taking,as you said before, 1 or more
genes and just tweaking those,to tweak the whole system.
Dr. Moira Gunn (18:40):
Now in each of these cases, I'm assuming that
you're looking to create some,combination of cell targets that
that will be really great, andthen taking that through the
normal cycle of FDA approval,but with more confidence that
this combination treatment orparticular treatment will really
(19:03):
make a difference.
Dr. Francisco LePort (19:04):
That's exactly right. Yeah. We are
looking to identify, genetargets, whether it's a
combination, which I think thisalso really opens up, or, you
know, if we find that that, youknow, great single target that's
been hidden, you know, up untilnow, we are looking to identify
which of those, kind of best inclass that we can then create a
(19:25):
therapeutic for and take it intothe clinic. And, again, the the
nice thing about, the approachthat we've got here at Gordian
is we can look at that, youknow, 100 or thousands of genes
at a time. And so we can reallyexplore that very large space.
Right? I mentioned 20,000 genes.We can really take a big chunk
of that space and go and exploreall of that and really try to
(19:46):
find, you know, that needle inthe haystack, right, that really
best gene that's out there, andthen go and move that into
clinical trials, again, withthat increased confidence, as
you mentioned, as we go intohuman.
Dr. Martin Borch Jensen (19:57):
It's sort of like, we do a lot of
things that make life harder inthe short term. You know, we're
really picky about what is thesystem where we want an answer
to this test and, like, what isnot just something that could
work, but what is the best geneor combination of genes to
target upfront, because clinicaltrials usually fail. Even in,
(20:18):
you know, across all diseases,90% of them fail or more. And in
these diseases that are extrahard, it's, it's even greater.
So we wanna do everything we canto reduce the risk of failure,
at the clinical stage.
Dr. Moira Gunn (20:32):
Well, I can tell you the numbers. As you said,
90%. It's one out of 9 drugssucceed. On average, takes you
$1,000,000,000 to get throughthe whole process. 2,000,000,000
if you if you had to borrow themoney, get people to invest and
and pay them back.
I mean, we're tracking highstakes, for, only 1 out of 9
(20:53):
will succeed. So anything thatchanges that number that reduces
the, the the how many shots youhave to take on goal to get
there is is certainly welcomenews.
Dr. Francisco LePort (21:03):
That's right.
Dr. Moira Gunn (21:04):
Returning to the original part of our discussion
about how the diseases of thoseover 65 start much earlier.
Would you anticipate differenttreatments for different stages
of the disease?
Dr. Martin Borch Jensen: Potentially. I think, you know, (21:16):
undefined
as a scientist, I would say thedata will tell us, and that's
why we have different modelsthat are modeling different
aspects, different stages of thedisease, for example. But, with
what we know now, yeah, thereare changes that happen early in
the disease. Let's say, you getthis loop of inflammation that
(21:39):
keeps happening in the organ andit never turns off the way it's
supposed to when you have sortof an immune response. And
that's what later leads toscarring or dying cells in that
organ.
So depending on the stage, ofdisease, you might want
different treatments. And that'ssomething that we can examine
with, with our system.
Dr. Francisco LePort (21:58):
Yeah. And I'll I'll add to that, and just
say when we go into these largeanimal experiments, the the neat
thing about these large animals,as opposed to the kind of
genetically identical mice thatare typically used, these large
animals are genetically variedthe same way that humans are.
Right? All humans have differentgenes that look different,
(22:20):
different height, differentweight, different, you know,
whatever. And these diseasesimpact them differently.
And so we can actually exploresome of that variation, in
these, large animal experimentsand really get a better sense
for which of these targets thatwe're going after either will
have kind of a a targetedtherapeutic effect for this, you
know, level of disease or thistype of disease, it's called an
(22:42):
endotype, or, have a broadereffect, you know, that can
actually be useful for a largerpatient population.
Dr. Martin Borch Jensen (22:49):
And that's really important for the
trials. When you get really intothese, clinical trials, for age
related diseases, it quicklybecomes evident that this is a
huge factor, this heterogeneity,the differences between the
patients. You often seecompanies that, test a drug in
500 people. And it looks like,you know, statistically, you
(23:10):
have to sort of run the righttests and so forth. But it looks
like, you know, maybe 40 ofthose people actually had a
benefit from the drug.
All those people supposedly hadthe same disease. Right? They
all had osteoarthritis or heartfailure. But that's a label that
we put on to a diagnosis by adoctor. The biology is not
necessarily identical in everycase of this disease.
(23:31):
And so the ability to probe thatis something that, again,
hopefully will increase the rateof success in clinical trials if
you know what you're going in totarget and who might benefit.
Dr. Moira Gunn (23:43):
You know, there are so many diseases. You guys
have been working on this for awhile, and you've got 3
underway. Do you anticipateworking with with others to
bring them in, you know, so thatthere are more people or
organizations or companiesworking with you so that more
solutions can be found at thispoint?
Dr. Francisco LePort: Absolutely. I think, you know, (24:03):
undefined
even tackling one of thesediseases and producing a cure, I
think would be a real miracle,in terms of, improving, you
know, health span and lifespanand and all of that. And as you
said, you know, there are, youknow, dozens, that are really
the number one killers in thedeveloped world. So we would
(24:24):
love to work, and we do,collaborate with, other,
biotechs in the industry, pharmacompanies, and partners that can
really help us advance thesethings forward. Right?
We're still a relatively smallcompany, and our focus really
is, on identifying these noveltargets and, producing these
early stage drugs. And, we aredefinitely excited to get help
(24:47):
from the industry in pushingthese things through these very
large stage, clinical trials andeventually to commercialization.
Dr. Moira Gunn (24:53):
Well, I really appreciate you coming in. I hope
you come back and speak with meagain.
Dr. Francisco LePort: Absolutely. We had such a (24:57):
undefined
wonderful time. I reallyappreciate it. Thanks, Moira.
Thanks, Moira.
Dr. Moira Gunn (25:01):
Doctor Martin Borch Jensen is the chief
scientific officer of thebiotech firm, Gordian
Biotechnology. Doctor FranciscoLePort is Gordian's CEO. More
information is available atgordian.bio. That's gordian as
in Gordian not, gordian dot bio.
Working on what are usually considered the
diseases of old age when you'reyounger as they're developing.
Not only that, doctor MartinBorch Jensen and doctor
Francisco LePort from GordianBiotechnology tell us how
they've invented a way todevelop and test many cell
therapies all at once, all withan eye to making drug discovery
(00:36):
faster and drug approval morecertain. Doctor Borch Jensen and
doctor LePort, welcome to theprogram.
Dr. Martin Borch Jensen (00:43):
Thanks, Moira. Very
Dr. Francisco LePort (00:44):
good to be here.
Dr. Moira Gunn (00:45):
Now I'm actually going to start by quoting from
an opinion piece which you,doctor Borch Jensen, wrote with
UCSF professor, doctor NicolePolk, some 4 years ago in cell
and gene. You wrote, in reality,2 thirds of people aged 65 plus
have 2 or more diseases, whichshocked me, But putting a pin in
(01:09):
that, those diseases started inthese individuals when they were
much younger, before they were65. Where and how do these
diseases start?
Dr. Martin Borch Jensen (01:19):
Yeah. Obviously, we don't know
everything about every disease,but the way we can think about
this is that your body made outof lots of different cells, it
functions sort of as a society.All the cells are doing
different things in order topreserve all the functions, your
breathing, your movement, yourdigestion, and so forth. And
diseases basically occur whenthat system is challenged, which
(01:45):
can happen either through, let'ssay, an infection, you get the
flu, and so there's some outsideinvader and your body responds,
Or, as in the case of aging, thesystem of your body gets
increasingly confused,individual functions sort of,
get worse, and then your theability of your body to sort of
(02:05):
maintain this function whileyou're living your life drops.
And that's kind of the thingthat prefaces the things that we
call diseases.
Right? So you say, okay, I have,you know, Alzheimer's disease,
or I have heart problems. Thatis the symptom of your body's
reduced capacity to functionnormally, as happens through a
(02:26):
variety of biologicalmechanisms, that we call aging.
Dr. Moira Gunn (02:30):
And it all started a long time ago where
from one insult to another ormutation changes as cells are
replacing themselves, justlittle by little, eventually, it
becomes one of these conditions,if not more.
Dr. Martin Borch Jensen (02:45):
That's right. You have a complex
system, and so as individualthings fail here and there, it
seems fine for a while untilsuddenly things go downhill.
Dr. Moira Gunn (02:54):
So, what does that mean in terms of trying to
cure diseases?
Dr. Martin Borch Jensen (03:00):
Yeah. It makes it hard. Right? In the
case of, a virus, you can pointyour finger at, like, one exact
culprit. Here's the one thingthat's wrong, that's causing us
to be deceased.
But for these complex chronicdiseases that happen with age,
it's an interplay of differentfactors that goes wrong and then
causes disease. And so thatmeans in order to find out how
(03:25):
to treat the disease, we need tolook at the whole set of things
that change, and some of themchange for various reasons.
Imagine a busy office that's,about to have, you know, like a
meltdown. Not every conversationin that office is something
that's, you know, about to leadto a bunch of, buying whatever
(03:45):
subprime mortgages. Right?
So as a, you know, biologist,you go in and you can measure
all the things that happened,but you have to cut through and
find out what are the keythings. And usually the way
people do this is throughinterventions or putting
something into the system andchanging something, and then see
whether you get the result thatyou want.
Dr. Francisco LePort (04:05):
I think the interesting thing about
aging, as distinct from, many ofthe other, conditions that we're
going after is there isn't thisthis single kind of impact, this
single, you know, insult that'shappening to the body. In many
ways, you know, we areprogrammed to age. That is kind
of the the normal process, thathappens to all of us as humans.
(04:25):
And so there really is this bigweb to untangle, in terms of,
you know, what is it that'sgoing, quote, unquote, wrong as
we're aging, versus theseindividual pieces. And this
really makes it much, much morecomplex.
Dr. Moira Gunn (04:38):
Now let's get to what I'm gonna call better gene
targets, you know, which becomethe therapies. Today with gene
therapy, we tend to address 1 ora few candidate mutations. And
even with the highly vaunted AI,this is somewhat guesswork. And
then 1 or several candidates aretried on animals with a
(05:00):
similarity to humans, and, thenone and only one drug candidate
goes forward, is tested onhumans, a successive group of
humans, until we approve it'ssafe and effective. And this
isn't strange.
This is how we've been doingdrug development for a long
time. What's problematic withthis approach?
Dr. Francisco LePort (05:22):
Yeah. So even as you were describing it,
right, you can see that thereare many, many steps, in that
approach. And the reality isthat each of those steps is
extremely expensive andsuccessively more and more
expensive. So when you combinethat with this web that, that I
had mentioned before, you know,you look at the the number of
gene targets that you couldpotentially pick. There are over
(05:42):
20,000 genes, in the humangenome, so the space is very,
very large.
And if the, methodology that youhave, which is kind of what
we've had, you know,traditionally, is to kind of
pick a single one of thosetargets and then go after and
then kind of interrogate it, youknow, through 1,000,000 of
dollars of process andpreclinical study and eventually
(06:04):
clinical study, you know, it'sgonna take you a very long time
and a tremendous amount of moneyto get through 1,000 of those
targets. And I think that'sreally kind of the the issue.
Right? We're not very good atguessing what those initial
targets are. We've gone througha few of them for these age
related diseases that are verycomplex, and then we've met with
(06:24):
failure in the clinic.
And, I think, fundamentally, weneed a very different approach
to that.
Dr. Moira Gunn (06:29):
Well, here's where Gordian's approach is so
different, and I and I I kindawanna say to the listener, pay
attention now. This is what wecall in math, a stepwise
different approach. So this isvery important. What is
Gordian's approach?
Dr. Martin Borch Jensen (06:44):
So taking everything that we just
said, right, what you reallywould like to do is, to put a
lot of different interventions,a lot of potential medicines
into a system that has all thatcomplexity, cells talking to
each other, coordinating theirresponses, cells affected by
aging, and then be able to testall of the different potential
(07:09):
therapies at the same time,getting the answer that you
want, which is, does this workwhen you have all the complexity
included and all the barriers tothis medicine potentially
working for the disease. And sothat's the sort of technology
that we, invented early in thecompany's, life. The ability to
(07:30):
combine gene therapy withreading out states of different
cells and do these simultaneousexperiments, where we put many
therapies into the organ of ananimal that has often
spontaneously developed thisdisease that we're trying to
study and then test them allsimultaneously without them sort
(07:50):
of affecting each other and andgetting us a confused answer.
Dr. Moira Gunn (07:54):
Well, of course, I'm gonna ask you for a first
example here. And well beforethe age of 65, many people have
problems with their knees.Cartilage breaks down and you
took this example and decidedthat a horse's knee had a lot in
common with a human's knee andracehorses and working farm
(08:16):
horses, they have the sameproblem with their knees that
humans do. The cartilage breaksdown. Now tell us, what have you
done with these horses?
And let me get this straight.You're looking to rebuild
cartilage?
Dr. Francisco LePort (08:30):
I think it's a great, example and
actually points to one of thereal advantages of this, new
method. We are not only able toput, hundreds of different,
targets or thousands ofdifferent targets in some cases
into these animals. But becausewe can put so many, into these
individual animals, we can gointo these advanced animal
models of disease. So normally,people would go into mice, for
(08:52):
example, in osteoarthritis, andthey would, you know, if they
were to go into an an advancedanimal model such as horses,
they would do that only fortheir, you know, select very
last target because that's soexpensive. We can actually put,
hundreds of targets, intoindividual, horses right from
the very beginning of ourprocess, which is really neat.
Dr. Martin Borch Jensen (09:11):
As you were saying, do we want to
regenerate, the cartilage of thejoint? And when we go into these
complex models, the idea is thatwe can capture all the different
aspects of disease. Soosteoarthritis is, you know,
cartilage being worn away. Butwhat you want to treat is both
that and the pain that patientswith osteoarthritis are feeling,
(09:34):
which comes, in part frominflammation in that joint. And
so with our technology, what wecan do is go into this, system
that captures all of the biologyof the disease and then test
hundreds of targets that eachindividually might be effective
against some aspect of thebiology that's going wrong and
(09:55):
potentially in combination, ormaybe there is, one gene we find
that does everything you want tocomprehensively treat, this
disease and find treatments thatwill be really effective once we
go into people.
Dr. Moira Gunn (10:08):
So it's not just the I've a I'm a runner and I've
run 20 miles a day for 40 yearsthat creates this problem.
There's a breakdown in yourcells. There is for one reason
or another, either because inaging, they're just not as good
as they were. They've beenmutations, weakened mutations,
if you will, or some insult. Andso you're able to go in and say,
(10:31):
well, let's target and correctthis gene.
Let's target and correct thatgene. Let's target and correct
that gene. And then so you havea whole number of targets lined
up, gene corrections, that youcan put in. But then how long do
you leave it in the horse beforeyou take a look at what's in the
cartilage?
Dr. Martin Borch Jensen: Typically, let's say a month (10:52):
undefined
because, what we want to findout again is how do the
therapies, affect the tissuewith all of this stuff going on?
So we don't want to know, youknow, what happens immediately
when you take this medicine. Wewant to know what would the,
sort of biology of a patientlook like, after they've gotten
(11:13):
this treatment, right, in thelong term? So, yeah, 1 month,
let's say.
Dr. Moira Gunn (11:18):
I'm speaking with doctor Martin Borch Jensen
and doctor Francisco Laportefrom Gordian Biotechnology in
South San Francisco. DoctorBortch Jensen is the chief
scientific officer, and doctorLaporte is Gordian's CEO. Okay.
So now here's the $50,000,000question. You've put several 100
(11:40):
different
Dr. Francisco LePort (11:41):
More.
Dr. Moira Gunn (11:41):
Gene correcting, activities, if you will, into
this joint, and you say, oh,look. This looks better. The
genes look better. They lookyounger. They look they look
like they're all gonna function.
How do you know which of theseveral 100 gene correcting,
treatments you've put inactually worked?
Dr. Francisco LePort (12:03):
Yeah. So, for that, we use a technology
that's called single cellsequencing. So I'm sure everyone
has, heard about, DNAsequencing. Right? This got,
popular, in the 2000 as theprice started coming down with
the Human Genome Project and allof that.
So, at this point, there'stechnology out there that can
allow us to actually sequenceindividual cells. And we use
(12:25):
that to look at these individualcells that have gotten these
individual perturbations or genechanges in the, living horse.
So, we go in. We can identify,which cells got which, change,
which gene target change. Andthen using this single cell
sequencing technology, we canidentify what exactly did that
(12:46):
change about the cell.
It's kinda like looking at, youknow, the the code of a computer
program, and then getting asense of, well, what is the the
status of this, you know,computer? In this case, we can
get a status of what is the celldoing? What are the functions
that it's performing? How wellis it performing those
functions? Is it performing thefunctions that it would normally
(13:06):
be performing, in a healthyenvironment?
And all kinds of other, youknow, more complex or more
nuanced things. Right? Is it,serving the protective effects
that we want it to, in thisdiseased environment? So we get
this very, very rich, rich dataset by using this, single cell
sequencing technology.
Dr. Moira Gunn (13:23):
Well, you could certainly tell what's changed
positively. That's right. Buthow do you trace that back to
which of your several 100 genetargeting therapies that you
would you injected all at thesame time? Which ones worked?
Dr. Martin Borch Jensen (13:35):
The fact that we're using gene
therapies here to deliver thesegenetic payloads comes in really
handy sort of by design. So whenwe deliver a therapy that,
changes the expression of somegene, we also include this bar
code. It's called a barcode, youknow, in the in the industry,
but it's basically a sequencethat uniquely labels this
therapy. And so when we detectthat sequence in the cells that
(13:58):
we, are analyzing, then we knowwhich therapy was in there.
Dr. Moira Gunn (14:02):
You know, if you are a computer programmer,
you'll know that, sometimes youput in a series of things called
no ops, no operation. They justkinda fill it in, and the
computer thinks, oh, yeah. I'lljust go along. It just does it's
a instruction that does nothing.You can add such things in your
GCATs, which are the particularnucleotides that are your
(14:24):
programming your your DNA andthen you could you could say,
well, just put we'll put asequence that means nothing in
your body.
So that's enough variation thatyou can identify each one of
these separately.
Dr. Martin Borch Jensen (14:36):
Yeah. That's the basic idea.
Dr. Francisco LePort (14:38):
Yeah. That's right.
Dr. Moira Gunn (14:39):
You guys are pretty clever guys. I'll give
you that. I'll give you that.Okay. I have more questions.
Don't don't don't stop now.You're also working on heart
failure and fatty liver disease,NASH. Used to be called NASH.
What are you doing in each, andwhat animals are you working
(14:59):
with there?
Dr. Martin Borch Jensen (15:00):
So in each, disease, we really are
asking, well, which animals aresimilar to the patients? Which
in terms of their, the anatomyof the tissue, but also how they
get the disease. And so MASH isinteresting because, it happens
more with age, but diet alsoplays a big part. And so the way
(15:20):
that, many people including uswill, develop MASH models is
basically to give the animals,which for most people is mice.
In our case, we also use mice aswell as monkeys, which you can
imagine are more similar tohumans.
And we give them a diet thatthey actually quite like. The
(15:41):
technical term is a Westerndiet. It's high in sugar, high
in fat, and high in cholesterol.And then over time, and this is
the key part and the part where,you know, some companies are
impatient, but rightfully so,you want to run your studies
quickly. You don't want to feedthis diet over, let's say, more
than a year, but that's how itworks in the patients.
(16:03):
So we have, animals on thesewestern diets for a really long
period of time, and the monkeyshave been on it for more than a
year, at this point. And thengradually, your liver
experiences the same as thepatients, this accumulation of
fat and then eventually turns todisease.
Dr. Moira Gunn (16:20):
Uh-huh. So you're doing this in in monkeys
as well for the MASH, for thefatty liver disease?
Dr. Martin Borch Jensen (16:27):
That's right.
Dr. Moira Gunn (16:28):
Okay. What about heart failure? What are you
trying to do on heart failure?
Dr. Francisco LePort (16:33):
Yeah. So for heart failure, similarly, we
look at what are the best animalmodels that, we can go into
there. And, again, I think thisis the real to me, the neat part
about this technology and whatit enables is the ability to
really go into systems that areas close to human as possible,
depending on the particulardisease that we're going after.
So in heart failure, we arelooking at, actually 3 animals.
(16:57):
We've got mouse and rat modelsof heart failure and then, pigs.
Turns out that, pigs have heartsthat are actually quite similar,
to humans, in many aspects oftheir, physiology, and we use
those as well. And, in terms ofthe the mechanics of it, it's
actually very similar to what wedescribed with the horses, which
(17:18):
again, is a real advantage, thetechnology that's available. We
can really extend it to, anyanimal model of disease. It
doesn't require too muchfiddling with, in order to get
it to work, for these varioussystems.
Dr. Moira Gunn (17:31):
Now in those cases, are you looking to
restructure the heart or replacecells in the heart? What are you
looking for?
Dr. Martin Borch Jensen (17:39):
Not replace, more like reprogram.
And this is essentially what alldrugs do. You have this, machine
that is running differentprograms and they dysfunction.
And so
Dr. Moira Gunn (17:52):
Called your body.
Dr. Martin Borch Jensen (17:52):
Yeah. Exactly. Your body. But then,
you know, the subpart of yourbody, you can, call it the
engine if you want. Right?
The heart has to beat. Thecardiomyocytes, that's the
technical term for the cellsthat make up your heart, and
cause it to beat. Right? Theyhave to do a lot just to do that
simple job. They have tometabolize a lot of energy in
(18:13):
order to cause thesecontractions, and they have to
do that in a synchronizedmanner.
And so what we want is that thecardiomyocytes that have been
working for your whole life, tokeep your heart beating, are
behaving similarly to what theywere like without this,
accumulation of dysfunction,that caused the disease. And we
(18:33):
do that by going in and taking,as you said before, 1 or more
genes and just tweaking those,to tweak the whole system.
Dr. Moira Gunn (18:40):
Now in each of these cases, I'm assuming that
you're looking to create some,combination of cell targets that
that will be really great, andthen taking that through the
normal cycle of FDA approval,but with more confidence that
this combination treatment orparticular treatment will really
(19:03):
make a difference.
Dr. Francisco LePort (19:04):
That's exactly right. Yeah. We are
looking to identify, genetargets, whether it's a
combination, which I think thisalso really opens up, or, you
know, if we find that that, youknow, great single target that's
been hidden, you know, up untilnow, we are looking to identify
which of those, kind of best inclass that we can then create a
(19:25):
therapeutic for and take it intothe clinic. And, again, the the
nice thing about, the approachthat we've got here at Gordian
is we can look at that, youknow, 100 or thousands of genes
at a time. And so we can reallyexplore that very large space.
Right? I mentioned 20,000 genes.We can really take a big chunk
of that space and go and exploreall of that and really try to
(19:46):
find, you know, that needle inthe haystack, right, that really
best gene that's out there, andthen go and move that into
clinical trials, again, withthat increased confidence, as
you mentioned, as we go intohuman.
Dr. Martin Borch Jensen (19:57):
It's sort of like, we do a lot of
things that make life harder inthe short term. You know, we're
really picky about what is thesystem where we want an answer
to this test and, like, what isnot just something that could
work, but what is the best geneor combination of genes to
target upfront, because clinicaltrials usually fail. Even in,
(20:18):
you know, across all diseases,90% of them fail or more. And in
these diseases that are extrahard, it's, it's even greater.
So we wanna do everything we canto reduce the risk of failure,
at the clinical stage.
Dr. Moira Gunn (20:32):
Well, I can tell you the numbers. As you said,
90%. It's one out of 9 drugssucceed. On average, takes you
$1,000,000,000 to get throughthe whole process. 2,000,000,000
if you if you had to borrow themoney, get people to invest and
and pay them back.
I mean, we're tracking highstakes, for, only 1 out of 9
(20:53):
will succeed. So anything thatchanges that number that reduces
the, the the how many shots youhave to take on goal to get
there is is certainly welcomenews.
Dr. Francisco LePort (21:03):
That's right.
Dr. Moira Gunn (21:04):
Returning to the original part of our discussion
about how the diseases of thoseover 65 start much earlier.
Would you anticipate differenttreatments for different stages
of the disease?
Dr. Martin Borch Jensen: Potentially. I think, you know, (21:16):
undefined
as a scientist, I would say thedata will tell us, and that's
why we have different modelsthat are modeling different
aspects, different stages of thedisease, for example. But, with
what we know now, yeah, thereare changes that happen early in
the disease. Let's say, you getthis loop of inflammation that
(21:39):
keeps happening in the organ andit never turns off the way it's
supposed to when you have sortof an immune response. And
that's what later leads toscarring or dying cells in that
organ.
So depending on the stage, ofdisease, you might want
different treatments. And that'ssomething that we can examine
with, with our system.
Dr. Francisco LePort (21:58):
Yeah. And I'll I'll add to that, and just
say when we go into these largeanimal experiments, the the neat
thing about these large animals,as opposed to the kind of
genetically identical mice thatare typically used, these large
animals are genetically variedthe same way that humans are.
Right? All humans have differentgenes that look different,
(22:20):
different height, differentweight, different, you know,
whatever. And these diseasesimpact them differently.
And so we can actually exploresome of that variation, in
these, large animal experimentsand really get a better sense
for which of these targets thatwe're going after either will
have kind of a a targetedtherapeutic effect for this, you
know, level of disease or thistype of disease, it's called an
(22:42):
endotype, or, have a broadereffect, you know, that can
actually be useful for a largerpatient population.
Dr. Martin Borch Jensen (22:49):
And that's really important for the
trials. When you get really intothese, clinical trials, for age
related diseases, it quicklybecomes evident that this is a
huge factor, this heterogeneity,the differences between the
patients. You often seecompanies that, test a drug in
500 people. And it looks like,you know, statistically, you
(23:10):
have to sort of run the righttests and so forth. But it looks
like, you know, maybe 40 ofthose people actually had a
benefit from the drug.
All those people supposedly hadthe same disease. Right? They
all had osteoarthritis or heartfailure. But that's a label that
we put on to a diagnosis by adoctor. The biology is not
necessarily identical in everycase of this disease.
(23:31):
And so the ability to probe thatis something that, again,
hopefully will increase the rateof success in clinical trials if
you know what you're going in totarget and who might benefit.
Dr. Moira Gunn (23:43):
You know, there are so many diseases. You guys
have been working on this for awhile, and you've got 3
underway. Do you anticipateworking with with others to
bring them in, you know, so thatthere are more people or
organizations or companiesworking with you so that more
solutions can be found at thispoint?
Dr. Francisco LePort: Absolutely. I think, you know, (24:03):
undefined
even tackling one of thesediseases and producing a cure, I
think would be a real miracle,in terms of, improving, you
know, health span and lifespanand and all of that. And as you
said, you know, there are, youknow, dozens, that are really
the number one killers in thedeveloped world. So we would
(24:24):
love to work, and we do,collaborate with, other,
biotechs in the industry, pharmacompanies, and partners that can
really help us advance thesethings forward. Right?
We're still a relatively smallcompany, and our focus really
is, on identifying these noveltargets and, producing these
early stage drugs. And, we aredefinitely excited to get help
(24:47):
from the industry in pushingthese things through these very
large stage, clinical trials andeventually to commercialization.
Dr. Moira Gunn (24:53):
Well, I really appreciate you coming in. I hope
you come back and speak with meagain.
Dr. Francisco LePort: Absolutely. We had such a (24:57):
undefined
wonderful time. I reallyappreciate it. Thanks, Moira.
Thanks, Moira.
Dr. Moira Gunn (25:01):
Doctor Martin Borch Jensen is the chief
scientific officer of thebiotech firm, Gordian
Biotechnology. Doctor FranciscoLePort is Gordian's CEO. More
information is available atgordian.bio. That's gordian as
in Gordian not, gordian dot bio.
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