Greetings and welcome to EHA Unplugged, the official podcast
channel of the European Hematology Association, EHA.
Hello, I am Isabella Livera, a medical writer for EHA.
In this series, we are trying to explore the world of hematology
through conversations with leading experts in the field.
Today we are thrilled to have Professor Brian Huntley, Head of
the Department of Hematology at the University of Cambridge.
Professor Huntley is a renowned clinical research scientist and
consultant in hematology at Addenbrooke's Hospital, and he's
known for his groundbreaking work in leukemia stem cell
biology. Thank you for being with us
today. So to start off, we would like
to learn where your journey started.
What is your first memory of hematology?
Thanks for inviting me. It's very nice to be here.
My first memory of hematology was as an undergraduate.
You learn all about body systems, and I think even at
that time blood kind of fascinated me because of its
accessibility. You can take a tissue sample
from literally a blood test. Many of the sort of basic
biochemical principles were worked out in blood and blood
cells, and that kind of subliminally stayed with me and
was one of the reasons that I wanted to take it up as a
clinical specialty, this mix of science and clinical medicine.
And then I think it was one of the things that directed me
towards a sort of career in science.
Because you are a trained medical doctor and then you have
been doing research and translating that research always
to clinics. Yeah, I mean, it's a sort of
circular route. I, I, I wouldn't say that my
trajectory and my path was, was a classical one because I didn't
do much science until I, I had trained and, and specialized as
a hematologist. And then I decided I wanted to
try and do some medical science. So I did a PhD and then I've not
really looked back, but it, it certainly was the, the
application of science and the sort of basic mechanisms that
were much better studied in blood disorders and in other
disorders that made me decide to be a clinical hematologist.
And then when I was studying for my postgraduate hematology
exams, again, I wanted to explore the science more.
So that's why I decided to step back from clinical medicine and
to to pursue a PhD. And what led you to focus on
leukemia and stem cell biology? Yeah.
I mean, I think that as a practicing hematologist in the
UK, your, your practice is dominated by malignant
hematology. And to my mind, not only is it
the most common problem, it's the most intractable problem.
And it, and it continues. So this day, I mean, and I've
been a researcher in hematology for 25 years and I'm embarrassed
to say that we have improved the field, but we still have a great
deal of work to do. And the things that you remember
are probably more your failures rather than your successes.
And I study predominantly acute myeloid leukemia, which is a
very, very aggressive disease. And we still do very poorly in
terms of the numbers of patients that we cure.
However, we do cure a good number of of younger patients.
And so it was interesting, it was difficult and we weren't
really doing very well. So that was the reason for sort
of gravitating towards leukemia biology rather than studying
blood coagulation or or red blood cell disorders, which are
equally interesting. But in my practice, we're just
not as difficult problems and and I felt that that there was
more needed to be done in those than in other areas.
So your research has had several notable discoveries.
One of the significance findings was that the demonstration that
chronic and acute myeloid leukaemia may arise in separate
stem cell progenitor cells. Why is this important?
Well, I think it's, it's important to know how cancer
changes the normal behaviour of a tissue system.
And it's important to know where it comes from and how it
develops. And, and with that knowledge,
you can understand how you might be able to target it when it
develops as a full blown disease.
But also it, it, it provides the basis for working out how it
develops. And there's this concept of
earlier interception now where you can intervene earlier in
processes. And if you know the, the cell
that is giving rise to the, the problem and the cell that causes
relapses of disease, then it's easier to try and target that
that cell and to potentially eradicate the, the, the
leukemia. So we need to sort of understand
how the hierarchies of normal blood formation are aberrant
within leukemias, and that helps us to think about how we might
target leukemia stem cells for better eradication and what I
was talking about, which is trying to improve cure rates.
Another milestone in your career is that you describe what it's
the essential role for BET transcription and regulators in
AML RBT inhibitors, now a novel therapeutic approach, are they
being used? So the BET proteins are, are
transcriptional regulators and they're involved with various
stages of transcription and they're cancer cells are
addicted to them. So they are, they're, they're
obvious targets like a lot of these transcriptionally active
proteins, they are important for cancers.
But over a long period of time and as single targets, the the
inhibitors have been not particularly successful, but
they're now moving into combination studies and my hope
is that they will be much more successful there.
You have also done work looking at the sale of origin of
malignant lymphomas. What can you say about this?
We performed a study to look at one of the mutations that is
associated with a number of forms of lymphoma called Kreb
BP. Like the BET proteins, it's
again a transcriptional active protein and it has a number of
functions. What we found was that if you
lost the activity of this protein at different stages
within B cell development, that it had different consequences.
And we could show that malignant lymphoma was only developed when
it was lost earlier in lymphoid development rather than within
mature lymphoid cells. And I think this fits with some
of the data from human studies where it's suggested to be a
very early and possibly even an initiating event.
And again, it suggests that we should perhaps be thinking about
targeting these earlier events in these earlier cell
compartments. And, and, and that's what we're
studying further at the moment and we're looking into its
effects to modulate metabolism. So now you're looking how to
target earlier stages of differentiation.
In which way study? So we we've been looking at
studies to see how these diseases develop.
We do a lot of studies which look at early mutations in
leukaemias and lymphomas and how these diseases evolve and
important processes have to occur to fully transform cells.
And we've been doing a number of studies across a number of
diseases which are trying to identify targets for therapeutic
intervention and then possibly to think about ways that we
might intervene as early as possible.
If you look across the majority of cancers and the earlier that
you initiate treatment, often the better are the consequences.
And it's not a weird science to think that we might be able to
significantly delay the progression of earlier diseases
into more aggressive ones or possibly even think about
prevention of some of these hematologic malignancies.
And we're interested in that early biology and whether or not
you can identify targets that you can think about intervening
as soon as you know that there's there's an issue.
So for the moment you're trying to understand what happens
early, but there is not always then a drug or a treatment that
will come out of it. You're very interested in the
basic mechanism. The majority of the lab kind of
focuses on the mechanisms of why these things happen, why these
diseases develop, how they change through that evolutionary
process. But the, the, the, the way that
I have trained as a doctor first and a scientist second, I, I
think you always have that line of sight to the clinic.
You're always thinking about not just a mechanism, but a
potential target. We almost always try to make
comparisons between malignant tissues, whether those are
myeloid cells or lymphoid cells, and their normal counterpart.
You know, if we're looking at a leukemia stem cell, we're always
trying to compare the differences with a normal stem
cell and we're looking to, to find things that are specific to
the disease because they're much likely to be better targets.
You, you, you, you can't just target things that are required
for normal stem cell function or you'll just disable blood
formation completely. And that's not going to be any
better than the current chemotherapies that we use.
How does this research integrate with your clinical practice?
Yeah, in two ways. So, So first of all, my, my
clinical plaque practice is less than it used to be, given that
I've got a lot of administrative duties nowadays as well.
But it's always informed my clinical practice in terms of
trying to think of better ways to treat people, more clever
ways to treat people, thinking about better combinations for
them. But I think it works in the
opposite direction as well. And I come out of clinic
sometimes quite frustrated because I can't do things for
people. So it makes me committed and
motivated to get back to the lab and to try and work a little bit
harder. Or sometimes you identify a
problem from a clinical encounter and you think that's
very interesting. I wonder how that works.
And that might give you a research idea for, for a next
project or it will inform the way that you deal with a current
project. So I I like the the way that
they work together, but it does make your life quite busy.
Do you have any specific example of something that you discovered
in a pension that you wanted to understand and took back to the
lab? But there's lots of things.
I mean, the, the most obvious one would be our group are
becoming very interested in the development of resistance to to
therapies, particularly newer targeted therapies.
And that's always really bugged me about why these patients
develop resistance because often with leukemias, it's patients
don't die from the primary disease.
They die because the disease comes back and it comes back and
it's more resistant. So I think that has informed a
whole, you know, perhaps 1/3 of my lab work on resistance to
therapeutics and and that has come from the frustration of
seeing patients relapse continuously.
So you're a member of the European Hematology Association,
EHA, and you are a very active member.
You're in the executive board. How has EHA influenced your
career? I think in in quite a number of
ways, the first international conference I ever went to was
EHA in Barcelona in the last, the last Millennium.
The first conference that I actually gave an oral
presentation was EHA and during my PhD, and I was very lucky
when I came back from the, my postdoc in the States that EHA
gave me some money at a time when I was setting up my own
group. And that was hugely appreciated.
All of the other people that gave me money had, you know, I
had to follow a very rigorous, you can spend on this, you can
spend on that. EHA gave me the money and said,
you know, you do what you you think is best to further your
career. So that was both appreciated and
the freedom to do what I wanted with it, which which was
something a little bit more risky and that perhaps the
funding agencies in the UK wouldn't have allowed me to do.
So I sort of decided that I would, you know, try and pay Jay
back. I've sat in a lots of committees
and and, and various organizing committees for some of the
scientific meetings. But but it's it's great fun as
well. So I'm you you give, but you get
back. And I think it's a very
worthwhile organization or, you know, I probably wouldn't be
doing half the things that I do, but yeah.
So I I've kind of grown up with the HA.
I've been a member for yeah, more than 25 years it.
Has really been there for you during your whole career?
It has help you grow also being eha by the connections or.
I think it has, and it's given me a great kind of venue through
the Congress to present my science.
I've been lucky enough to give lots of presentations, so it's
helped my career. It's very sociable.
I mean, it's, it's always nice going to a nice European city in
the summer, meeting up with your friends.
Latterly, when I've been more heavily involved in the
organization, it's given me a lot of pride to, you know, to
have organised things. So yeah, it's been, yeah, very
enjoyable, but also rewarding. So you have so many different
activities because as a you are a clinician, although now a
little bit less, but during your life you have been very involved
with patients, also in research, I imagine in education and also
in all these societies, specifically EHA.
Which one of these activities do you enjoy the most?
And the science, definitely the science.
I like the variety. And you know, I get asked this
quite a lot by younger clinician scientists because it's quite
difficult to try and balance all of these variable parts of your
career. But I think it's it's good as
well because you don't get the chance to become stale and
you're moving from one thing to another.
And particularly with medicine and with science, they work on
completely different timescales. So in medicine you can see a
patient in clinic, see a patient on the ward, you can immediately
help them and, and you know, you get a lot of satisfaction for
that. In science project projects can
take years, literally years to read out.
With both of them. There are peaks and troughs, but
they work on different time scales.
And I think they, they, they dovetail quite nicely and they
feed off each other. I do a lot of administration as
well. And that can again be quite
harrowing. But again, it can give you
pleasure. And I always say that it's very
seldom that I'm having a bad day in the clinic, in the admin and
with the science, at least one of them is giving you some
pleasure. I can certainly work a lot
harder if I'm doing one thing, then another thing, then another
thing back to the first one. If I was doing the same thing
for 10 hours a day, then I think I'd find it both boring and
tiring. But if, if you have variety,
then I think it's it's interesting and it, it allows
you to, to sort of do a lot. So you enjoy very much changing
and the. Variety of not all the time, but
yeah, in, in general, you're not having a bad time with with
everything. There's always something that
you can get satisfaction from and something that you can feel
that you've done a good job on. So looking back at all this
work, what would you recommend to a young medical doctor that
is choosing their path now? I think you've got to do things
that that you're passionate about.
It's not easy and not suggesting it is easy to you, you really
have got to want to do it because it will be difficult at
times and you'll need to fall back on something that really
excites you or drives you and motivates you.
So I would always say sort of follow your passions.
You've got to be quite disciplined with your time.
Well, I do, I do far too many things.
And most people, they do research on one thing and they
do more and more. I do biz that and that and that.
But it's, you know, it's what what interests me.
So I always I've always done what I've found interesting.
So I. Think what you do is closer to
what I used to do because I was working reading stem cells and
for me it was how does this work?
Those basic questions of what is the sale of origin?
For me, it's always what I'm thinking of when I see all
these, you know, the new treatments or everything.
Where where does this? Come from, you know, the fact
that these things keep on coming back, you know, we're either not
getting to the root or they're just developing ways around it.
So yeah, it it it it both interests and annoys me in equal
measure. And now with all the tools to,
you know, sequence everything at the same time, and with AI to
compare this in a much more efficient way, are you advancing
quicker? I think we're advancing
knowledge quicker than therapy. And unfortunately the, the, the
advances in knowledge let us know how oversimplified we've
thought about the problems. 10 or 15 years ago, we thought of
tumors as much more sort of homogeneous entities.
Now we've got sort of cell biological hierarchies.
And even if you look at things that that are supposedly the
same type of cell, you look at the genetics in them, they're
slightly different. You look at the transcription
within them, they're definitely different.
You look at the proteins, they're even more different.
So we're sort of dealing with a much more complicated problem
than we had imagined. But you know, those advances
that we've made in terms of knowledge are really translating
greatly into new drugs. There's not that many of them
that are complete step changes. I I would say that things like
CAR T cells and immunotherapy, they, they really are a whole
new sort of modality and, and they are significantly changing
things, but they again are not curing everybody.
We're catching up, but the problem's becoming more
difficult as well because our knowledge is improving.
I'm very confident that we can significantly improve on how
well we're doing. And you know, what I was trying
to get through was that we now know about how long period these
diseases develop over and we we thought they kind of happened.
It was all kind of perfect storm, everything come together
and and all of a sudden, bingo, you've got cancer.
It's not like that at all. You know, with blood cancers,
some of these complicated ones can take 20, thirty, 40-50 years
and we can detect some of these pre malignant mutations at
earlier stages. And that gives us, I think and
the opportunity to think about intervening earlier.
Now the difficulty is that patients will go 25 of those 30
years without a diagnosis. They're not patients.
We don't really have a reason to look for these disorders, and
they're not common enough for us to be able to justify whole
scale screening projects for them.
So we're getting a better idea of the sort of Natural History
of these disorders, and we're also trying to work out how
related they are because you can have different mutations which
probably do different things to the same cell and from each
other. We don't know whether or not the
generate vulnerabilities within the cell and and then the aim
would be to try and work out what those vulnerabilities are
and can we come up with therapies that are safe enough
and non-toxic enough to think about giving them to people who
are not yet patients. And there are there are
significant ethical questions. There's questions about whether
they should know because we cannot tell them confidently
what will happen. We can tell them what might
happen. So we're at that stage where we
know a lot, but we're just trying to learn a little bit
more about how to predict what would happen, because not all of
these patients with one mutation will go on to develop a
significant disease. Knowledge is great, but it
brings responsibility with it. It's easy to describe things,
but it's difficult to tell what's going to happen
thereafter. So we're at a great stage, but
we need to know a lot more. We need to predict a lot better,
identify the patients that are really going to do badly.
So is it? Each patient will have a very a
unique cancer at the end of the day.
Even in relatively simple cancers like acute leukemias,
which have between 3:00 and 5:00 mutations, if you catalogue all
of the mutations within those patients and all of the other
abnormalities that are non genetic, it's it's not crazy to
say that almost every cancer is slightly different.
But we do know that some of them are very similar.
And we take advantage of that through personalized medicine
to, to, to treat the common single mutations, the common Co
occurring mutations. If you really look hard with the
magnifying glass, they, they will all be slightly different
and the genetic makeup of every patient will be different and
the genetic, their background genetic makeup will dictate how
they respond to therapies and, and their lifestyles will depend
on that and their premorbid condition will depend on that.
So there, there's a lot of heterogeneity that we need to
factor in, but this sort of takes us into the, the, the,
the, the area of personalized medicine because it's not just
personalized for the tumor, it's personalized for the way that
the patient will respond, what other medical conditions that
the patient might have. So there are tumour specific and
tumour nonspecific areas to personalized medicine.
I'm thinking about AI because there's a lot of talk about
synthetic patients. Yep.
So with AI to create patients based on what a typical patient
will be like with what we already know.
Yeah. But at the end of the day, the
point of a clinical trial is to see also the things that we
don't know. If we're going to be basing our
knowledge on something synthetic, we're taking out a
lot of complexity that we do not master.
I think that that AI can be applied to any number of
projects to improve our understanding and hematology
that we can discuss. But in terms of synthetic
patients, the, the, the area that they're most being
discussed is to form the control group because in standards,
randomised clinical trials, even if you have more patients that
go into the treatment arm, you always have standard of care or
a placebo. Now that means that, you know,
half of your patients or a third of your patients are actually
not getting anything that might improve them above what they,
they could get outside of the clinical trial.
And so the idea of synthetic patients is to really have a
standard to compare. So if you can generate that data
synthetically, then that means that more patients can be
treated. So I think that that is a a
possible area that that we can improve trial design.
But and there are not really any standards at the moment for what
constitutes a good synthetic and set of patients.
And if you get your control arm wrong, then you can't see
anything about the patients that are treated.
So, you know, you don't want to run a clinical trial that can
say nothing just because your control arm is very poor.
So I think it's an area of very active discussion and debate.
The other people that we need to bring into that conversation
very much of the regulators because clinical trials are
generally done to improve clinical practice, but they are
often done with new agents to get them regulatory potential to
be given as standard of care. And I think that again, it's
important that these trials which cost a lot of money and in
my opinion are always done too slow.
We've got to do them properly because and there are not enough
new medications coming in. So you think, yeah, the
synthetic patients will have a place in this control?
Area I think that they will do could be that there are some
controls, but they are in some way synthetically increased in
number to allow the statistical comparisons that are required.
But I think it needs to be done through a lot of discussion.
And I know that EHA is involved significantly in these
conversations with European Affairs and the, the, the health
data steering group. And you know, these are
discussions that are occurring with EMA, so the the the
regulators at the highest level. Thank you very much, Professor
Huntley, for being with us today, for sharing your
expertise with us, and thank you to all of you for listening.
And please tune in for our next chapters.
It's a pleasure. Thank you.