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Neal Young: Okay, thank you, Gene, for that kind introduction.
So what I'll do over the course of the next 50 to 55 minutes is to give you some information
on three discreet subjects, moving from the specific to the general. One is the recent
advances in our treatment of aplastic anemia, not a disease that I know that you will likely
see a patient or have to make treatment decisions, but a remarkable example of success in hematology
and medicine. And looking at the number of gray hands in the audience or bald heads in
the audience, I'm going to be able to tell you that a disease that most of you saw as
being uniformly and rapidly fatal in training is now one that is manageable in almost all
patients.
The second is to tell you about the new telomeropathies. That's a much more general and internal medicine
interest. There are patients that you undoubtedly have seen in your own clinics who have telomeropathies;
they're not rare, and they're hard to recognize because they involve multi-organs and can
be quite subtle. So you either will retrospectively or prospectively be able to make this diagnosis.
The third point is also of general interest, which is the relationship between telomere
attrition, which is a normal phenomenon, but also can be accelerated genetically or iatrogenically,
and cancer.
So I'm starting with aplastic anemia. It's a fantastic disease first described at the
end of the 19th century by this man, Paul Erhlich, in his younger days when he was a
docent at Charité Hospital in Berlin. Did an autopsy on a young woman who had died after
a catastrophic brief illness -- bleeding, clearly anemic, probably infected -- and when
he broke open her bone, he saw -- well, not this, he didn't have a confocal microscope,
but he saw instead of the plump juicy marrow of megaloblastic anemia, because pernicious
anemia at the end of the 19th century was common in Germany and fatal, instead of seeing
the rich bone marrow of B12 deficiency, he saw fat. And that was the basis of his case
report, probably not publishable in the New England Journal these days.
So this is the confocal image. I don't think I'm going to be able to get it to move for
a variety of reasons, but this picture shows you the marrow under the most modern techniques.
This is a marrow that is devoid of normal hematopoiesis; you'll see that more clearly
in a mouse model image in a moment. It's filled with fat, that's what shown in green, and
CD34, which is stained with red here, and which is the compartment of hematopoietic
progenitor in stem cells, is only staining the endophyllum; that's the vasculature that
you're seeing in red.
This is a patient with aplastic anemia; I'm going to return to her in the middle of my
talk. She's somewhat older than typical, but she's got most of the clinical manifestations.
She's presenting with anemia, she's pale, she's bleeding in multiple sites, so this
is very alarming to the patient, obviously, and to the emergency room physician or primary
health care provider. Hesh [spelled phonetically] petechiae ecchymosis, and shortly afterward,
became infected, so it can be a very dramatic presentation. Bone marrow is really an important
organ; if it is not functioning, if the blood counts are really low as in severe disease,
it's really uniformly fatal. These survival curves are from the '60s and '70s, when, for
example, Gene and I were in training, and patients with severe disease defined by blood
counts would be dead a year or a year and half after presentation, even with modern
blood transfusions.
This is a disease of young people, which makes it even more troubling to deal with, usually
young people who have been previously quite well. You see that the peak is in the late
teenage years, and early 20s and 30s. It's a disease also that has interesting environmental
connections; shown on the left is a clipping from a 1930s newspaper -- a 1920s newspaper
in New York, which made the association between benzene exposure and the leather factories
of northern New Jersey, and bone marrow failure that actually did not lead to any changes
in benzene use, despite great campaigning on the part of the Essex County Coroner. That's
not a problem in the United States anymore. It is a problem in countries like China, where
there are actually epidemics of benzene poisoning that's arising in industrial sectors.
On the right, though, is the more common phenomenon, which is idiosyncratic bone marrow failure
due to medical drug use. This also is a terrible occasion for the patient, who may be only
taking a thyrostatic or an antibiotic, and for the treating physician and, obviously,
the consulting hematologist. It also has a major impact on drug development, and this
clipping from the New York Times shows not only the stock share price but paralleling
that would be the number of people doing research in this company with only two dozen cases
of bone marrow failure aplastic anemia resulting from introduction of a new drug into the market.
This is a ward in the northern part of Vietnam in Hanoi, a picture I took some years ago.
Aplastic anemia is a very common disease in hematology services in East Asia and China,
Southeast Asia and India. This is the female service at that time; there were two or three
patients stacked to a bed, and a third to a half of the patients in the hematology service
had bone marrow failure, whereas most of you will not see a patient in a year, and even
a hematologist may only see one per year. We've done formal epidemiologic studies in
Southeast Asia, and the rate of the disease, the incidence of the disease, is two or three
times higher than it is in very similarly performed studies done in Europe and Israel,
and probably also in the United States.
This is a slide I took just recently on a trip to India, and shows the same thing. And
you can just note as the physician giving this talk -- he's shown in the upper left
-- noted that in this large hematology service, aplastic anemia is actually a more common
diagnosis than is acute myeloid leukemia in the Bengali area of India.
Now, in the historic period that Gene was alluding to my CV, we thought of aplastic
anemia really in isolation. It was one of these oddities separated from other hematological
diseases, other medical diseases. The focus was entirely on the etiology that came from
history, and the supposition was endless, I think, in retrospect, rather foolish, questioning
of the patient to possible exposures, none of which were relevant to what happened to
the patient afterward. They were usually sent home to die with minimal transfusions.
Now we have a modern, not final, but a modern view of aplastic anemia that looks something
like this. It's a very simple outline, which is that there are two major components, and
I'm going to tell you about a third, which is the genetics, but the major components
are the hematopoietic system, which is gone, but not completely in patients with aplasia,
and the immune system which is doing the killing of those hematic progenitor and stem cells.
So in the first phase, we do have some inciting event, but we don't worry about that; we think
that in almost all cases it disturbs the immune system. There are some ideas of how it might
do that. Leads to almost total destruction of the hematopoietic compartment because the
bone marrow, like a lot of other organs, is capable of pretty good function until almost
all the cells are gone. Then there's recovery, which can occur,
I think, rather uninterestingly as a result of transplant, more provocatively when we
give immunosuppressive drugs, from a biological point of view. And then what I want to stress
at the end of my talk is this late phenomenon of the development of leukemia or myelodysplastic
syndrome in a subset of patients, about 15 percent, who have responded, in some cases,
to anti-immune system therapy.
So this is an updated view of the Venn diagram in which we can now relate aplastic anemia
on one side to other immune-mediated diseases that affect a single organ, or, almost invariably,
T-cell mediated, and also to leukemia and myelodysplasia. This is adding the genetics,
and I'm going to talk a bit about that, especially as far as the inherited mutations are concerned
in the hematopoietic stem cells, as we go along.
So this is a dramatic case that we treated back in the 1980s, so we have a long follow-up.
A young man with hepatitis zero negative, non A, non B, non C; two or three months later,
very stereotypically, develops very severe pancytopenia, invariably fatal in these patients
according to the literature. Comes to the NIH from Colorado, is treated with just four
days of rather mild immunosuppressive called antithymocyte globulin, and six months of
cyclosporine; you see the dramatic rise in the blood counts, which were sustained and
have been sustained as he now has entered his 30s.
This is a summary of many trials of antithymocyte globulin, polyclonal preparation made from
horse serum of antibodies directed against thymus cells. You see that the NIH actually
has the largest, or among the largest, studies as a single center institution. I also think
the most careful studies since we're able to have long follow-up to do bone marrow cytogeneticism,
morphology, histochemistry without fiscal constraint. We have, at least up until recently,
the most detailed information on our patients as they enter and go through therapy. And
you see very consistent results: Between 60 percent and 70 percent of patients who have
a single round of this immunosuppressive therapy recover marrow function and blood.
So we're losing these nice images -- I don't know if I can go back and show you. This is
a mouse model, which you're not going to be able to see completely, but I'll just tell
you using words that when we take very small numbers of lymphocytes that are mismatched
either for them major or minor histocompatibility loci, and infuse those into a mouse that's
mismatched, we produce very specific bone marrow failure, and can demonstrate the potency
of small numbers of lymphocytes; they're far more effective than in the chemotherapy that
we can give in specifically destroying the bone marrow, and that's destruction as a result,
again, through using mouse models of CD8 cells as the effectors, type cytokines, and a major
bystander affect. In other words, once the destructor process begins, it affects all
the cells that are present, even if only a few are targeted at the outset, including
cells, at that point, that are matched either, for H2 or minor histocompatibility.
Now let me just tell you briefly about two major trials that were done across the street,
both of which have been very informative of treatment, and also give you an update on
where we are. The first is rather banal; we did a complicated study that was intended
actually to test a drug that's not shown here, which turned out to be a bust. These two studies
actually have told me that I don't really know how to do clinical research because I
keep getting results exactly the opposite of the ones we hypothesize. Rabbit antithymocyte
globulin is more potent than horse. When it came on the market in the United States, it
was likely, based on results, for example, in renal allograft rejection transplantation
in general, that rabbit would be better than horse because it was more effective, and we
did a study that incorporated a comparison of these two similarly named and similarly
labeled antithymocyte globulin. And the reason it ended up in the New England Journal as
opposed to some obscure hematology subspecialty venue is that the results were the opposite
of those predicted, which is that we saw the usual 60 to 70 percent response rate; in this
case I think it was 68 percent at six months with the horse ADG, that's a very good response
rate, meaning patients are transfusion independent, good neutrophil numbers, and about half of
that with the rabbit ATG.
The New England Journal insisted on some sort of mechanism. What I think they really meant
is that they wanted to see some biological difference between these two ATGs; they sound
the same. And the most likely difference, even though the rabbit ATG is far more potent,
as we expected, you see that in pink, is a very dramatic reduction in total lymphocyte
count with rabbit ATG compared to the more transient reduction with horse, is that unfortunately
the production is directed at CD4 cells and especially at T-regulatory cells. So T-regulatory
cells are simply gone in patients who get rabbit ATG for six months, whereas they recover
quickly to actually better than previous numbers in patients who receive horse. Now is that
absolute? No, we don't know that, but that's the strongest association that we were able
to observe with all lymphocyte subsets multiple cytokines and microarrays.
The long-term effects of this effective antithymocyte globulin therapy are obvious, and these are
the results of a long-term survival; of course, you see they go out for a decade or longer.
In patients who actually respond to that first round of immunosuppression, have virtually
90 percent, almost 100 percent, long-term survival, and that's been consistent for multiple
decades. We've also improved the treatment of patients who fail that first round of horse
ATG, and we now have results in terms of survival with -- in these failed patients that are
not dissimilar from what we saw at the outset when we were treating patients in toto at
the NIH back in the 1980s, so most of them will be alive five to 10 years later. And
the reasons for that are varied. They're, I think, mostly the credit of the pharmaceutical
industry, which has developed much more effective and easily administered antifungal drugs;
our aggressiveness in giving second courses of immunosuppression, which I'm not going
to go into detail; and also the ability to go to alternative donor transplantation in
patients who have failed; so multiple reasons.
So this is the sort of story overall, this great improvement in overall response rates.
Now what is the failure due to? I actually don't think it's due to a nonimmune pathophysiology
with perhaps rare instances, and, again, for the general assembly audience, we know that
we have patients with multiple sclerosis who can present with a single episode of opticneuropathy
or some other neurological syndrome; we call it multiple sclerosis, and they're fine. We
have other patients who have a progressive disease that kills them in just a few years.
We have patients with ulcerated colitis whose only symptoms may be a bloody diarrhea every
couple of years. We have patients who present with megacolon; we don't think of those is
having differences in their pathophysiology. We believe that that's simply a black box
in terms of the immune system and differences in the target organs. So I don't think it's
a question of the pathophysiology.
We don't understand our immunological therapy, as I've shown you. ATG, it's more potent,
should work better. Cytoxin should work better. Adding rapamycin, adding other drugs to cyclosporine
should work better; they don't. Horse ATG and cyclosporine remains the standard and
gives us the best results. And I think that the more likely explanation for why some patients
do not respond is that they don't have a stem cell reserve that's adequate. But that's something
we've felt hopeless concerning up until recently, and I wanted -- this is the simple diagram,
that if you don't have any stem cells, you've got nothing to work on when you remove the
immune effectors, and the desire, of course, would be to treat patients, shift the curve
to the right so that we're treating patients who have better blood counts and better stem
cells of the outset.
We know that stem cells are low in patients by indirect methods; this is a particular
type of bone marrow and peripheral blood assay for a very primitive progenitor cells. And
what I want you to appreciate is that there are very reduced numbers in all patients.
This is polymononuclear cell in the bone marrow; this is per volume of blood. These are severe
aplastics compared to normals. If you multiply this by the 3 or 4 percent, which is a number
of cells that are left in aplastic bone marrow, you've got 95 to 99 percent elimination of
the bone marrow stem and progenitor cells in patients with aplasia, so you're down at
the very bottom of the curve.
And we know the patients who either have good blood counts to begin with, or as shown here,
have a complete recovery after they're treated with antithymocyte globulin and cyclosporine
do better long term; they have better survival, and they have fewer long-term complications.
This is just one of many examples suggesting that the initial stem cell reservoir -- reserve
is -- dictates how patients do long term.
So we didn't know how to address this, and again, more or less accidentally, we were
able to discover what we think is the first effective stem cell stimulator that's available
in clinical practice, and it's this small molecule called eltrombopag, and the hematologists
in the audience will have that familiarity with this in the context idiopathic thrombocytopenic
purpura. It's licensed for use in patients with refractory ITP. And my colleague Cindy
Dunbar and I undertook a study really with the premise that we would avoid unnecessary
use of this expensive agent in patients with low platelet counts. That simply having a
drug that was thought to influence platelet counts didn't mean that you should use it
in a patient who's thrombocytopenic is a result of bone marrow failure because other growth
factors don't work very well in bone marrow. In EPO, patients with sky-high levels of erythropoietin,
given EPO doesn't do much; the same with neupogen G-CSF. And we knew from our own studies over
the course of several decades, and additionally the results from two papers, that TPO levels,
thrombopoietin levels, are really quite high in patients with a plastic anemia, so eltrombopag
should not work.
Now this also ended up in the New England Journal because the results were, again, counter
to our hypothesis and expectations. We took patients who had extremely refractory aplastic
anemia, who had failed immunosuppression, failed other growth factors, failed male hormones,
treated them with eltrombopag, and about half of them showed responses. That was totally
unexpected. And even more surprising was the quality of the responses. First, they were
either bi- or tri-lineage, not just in platelets, so that suggested a broad effect or a specific
affect on stem cells. Second, they were very robust. It wasn't the matter of the platelet
counts creeping up by 10,000 or 20,000. This shows your plate responses, some of them into
the normal range in the course of six months. Hemoglobin, even more impressive. These patients
who have responded are now receiving or undergoing phlebotomy to remove excess iron; I won't
show you the neutrophils, but they also comparably went up.
And third, the bone marrow is filled up. So when we look at six, nine, 12 months after
treatment, I'm showing you three pre and post pairs. You see the three of these four patients
actually have normal bone marrow cellulite, which we actually don't see when we treat
with immunosuppression. The patients get better; the bone marrow remains hypocellular.
So this really suggested that we had shifted the stem cell number to the right, and that
we now have more operating stem cells in these patients. We have a current trial that's combining,
which I think would be logical, combining upfront, in patients with aplastic anemia,
immunosuppression and eltrombopag. And I'll just you the sorts of results we're obtaining.
This is a young Navy petty officer who also had coincidentally eosinophillic fasciitis;
it's one of the rheumatologic syndromes associated with aplastic anemia. You see not only that
his bone marrow fills up when he's assayed in this instance at three months, but shown
on the right are CD34 cells which are also now visible, not excessively, but visible
in this patient.
These are the early results of the study, very high response rate to date at six months:
90 percent of the patients have responded, and the robustness of the responses is also
very striking. Patients' blood counts begin to go up in the first month; again, very atypical
for immunosuppression alone.
This is the CD34 number; you can ignore the scientific data, but in the early stages it
looks like we're getting really remarkable increases in CD34 cells in the bone marrow,
I think, shown here, 30 to 40 fold increases in CD34s. And these are the blood count increases;
again, you see this very striking slope to the curve, very rapid increases in reticulicytes,
platelets, and neutrophils.
Now there are problems with this type of therapy that will be obvious to many of you [unintelligible]
which is that we are stimulating stem cells but there's also the risk that we may be stimulating
abnormal cells, or, indeed, in the process of causing bone marrow cells to turn over,
lead to problems. So this is the big worry that we have is that we may elicit clonal
evolution, and I'll show you some data related to that as we finish.
I want to make a point in this slide also that the obvious question is why does eltrombopag
work when patients have very high levels of thrombopoietin? And I think this is a feature,
obviously hypothetical, a feature of the fact that it's a small molecule; it escapes binding
like plasma proteins such as thrombopoietin. There aren't other cells to compete with their
receptors; there's only a few stem cells left in the bone marrow of a patient with aplastic
anemia. And as a small molecule, we really can flood the hematopoietic niche with very
high concentrations, probably orders of magnitude greater than are achieved with thrombopoietin
and physiologic or even pathophysiologic circumstances.
Now I want to return to this patient I showed you early on who, 10 years after she was successfully
treated, saw her in the clinic every year, she's doing great; comes back again bleeding,
now with a very malignant-appearing bone marrow, blast that you can appreciate, abnormal cytogenetics,
and this is the problem of malignant or cloning evolution in patients with aplastic anemia,
which is shown in our large series. It occurs in about 12 to 15 percent of patients long
term, very troubling. It's really awful to have a patient like this come back after you've
had great success with them, think that their home free, and have them come back with a
virtually impossible-to-treat disease except for transplant.
So this is the problem of clonality, which was really raised by the great American hematologist
Bill Damaschke [spelled phonetically] in the mid-20th century. He put together aplastic
anemia, what we would now call myelodysplasia and leukemia, and hypothesized some relationships.
I and others have followed up on this problem, but we really have not understood where the
problem -- what the problem is. But the problem actually, I think, now has been has been solved
as to why these patients do go on to develop leukemia. And it has to do with a very fundamental
aspect of cell biology, which are the telomeres, the ends of the chromosome, and with the stability
of chromosomes in general; information that's so fundamental it's lead to a whole series
of Nobel prizes, and really dates back even prior discovery of DNA experiments that were
done in the 1940s and '50s by Muller and McClintock, and then the later discovery of DNA led to
this understanding that replication of DNA, the characteristics of replication of DNA
would lead to inevitable loss at the end of the chromosomes as a result of the requirement
to produce a fragment in the lagging strand. That that was not going to be feasible when
the DNA replication apparatus reached the termini; there would inevitably be loss as
Alexey Olovnikov called it, marginotomy, a problem with loss of the genetic information
that's transmitted from cell to cell with every replication.
So nature's solution to that problem, the end of replication problem, has been the telomere.
The telomere really is not that complicated a structure. It's DNA, it's hundreds to even
thousands of repeated hexaneucleatides, as shown here, with specific proteins that coat
these hexaneucleatides, and this provides many advantages to the cell. First of all,
it's nonsense material, so its loss doesn't impact on the transmission of genetic information.
Second, this complex forms a stable and recognized end to the chromosome that avoids it being
recognized as, for example, a DNA or chromosome fragment, or a DNA virus, or DNA that needs
to be repaired. And the third is it provides a platform, a template, for an active process
of repair with every mitosis, which is affected by this complex, the telomerase complex. So
there's the telomere, which is the end of the DNA, and telomerase, which is an enzymatic
complex that will add on hexaneucleatides at the end of every mitosis. It doesn't completely
repair the loss of telomeres but almost does, so it maintains telomere length and replicating
cells.
Now telomerase is made up of two major components which I'm going to talk of. One is the enzyme
itself, telomerase, encoded by a gene called TERT with a T at the end; the other is the
RNA template, so this is a gene that produces an RNA that is the template for the reverse
transcription to telomeres, and that's called TERC shown here. This is TERC, and this is
the product telomerase.
Now when cells get critically short telomeres, they are not able to continue to replicate.
So under those circumstances they either go to sleep, undergo senescence, or they undergo
apoptosis. For an organ, that's the appropriate response. If you've got a liver, and the liver
cells have been replicating and replicating and replicating, and it reaches the ends of
-- develops a critically-short telomere in one of the chromosomes, the cell just disappears
from the population, and that's a benign phenomenon as far as the liver is concerned. But if there's
suppression of the DNA damage or DNA response -- DNA repair responses, as, for example,
in artificial systems in which P53 is eliminated, those cells can continue to replicate, and
at that point, the chromosomes would become unstable, though short telomeres allow end-to-end
fusions, and nonreciprocal translocations, and other phenomenon that result in aneuploidy
and in frank malignancy.
So those of the two phenomena. Now if we just take cells, and put fibroblast, for example,
with them in the cell culture, we can't culture them indefinitely; that's the Hayflick phenomenon,
that's due to shortening of telomeres. It can be overcome by inducing or transfecting
with the telomere -- telomerase gene. But we haven't been very clear on what this actually
means in human beings until recently.
Now this is work from our own laboratory, but it's among many papers that have demonstrated
that short telomeres and defective telomerase underlie some patients with aplastic anemia
that's inherited presents either in the pediatric population as a rare syndrome called dyskeratosis
congenita, or, in adults, more subtly as aplastic anemia or other types of bone marrow failure.
This is our initial paper, and there's a number of points I want to make from the slide. These
are -- this is a description of the first mutations in telomerase in the terchin [spelled
phonetically]. That's the most important component of the enzyme complex, that's the enzyme itself,
and that's what regulated. So first I want you to appreciate, unfortunately, that this
is the pattern of telomere attrition in normals, and telomeres do get short as we age. Not
at our age, it's always people that are older than us up here, and most of the shortening
of telomeres occurs early on. So if you have teenage children, you can tell them they're
actually aging much faster than you are. And that has to do, of course, with the time;
kids are growing, their organs are growing, so there's a lot of replication going on.
The second point is that patients who have a telemeropathy, to the extent that we know,
almost always will have extremely short telomeres. It's the basis of a commercial blood test.
So, again, this is something that can be ordered, or you can send the patient over to our clinic,
we have a CLIO laboratory that does telomere length. And you see that whenever the mutations
were in these patients, they result in extremely short telomeres. This is really fun to work
with because this is not a gene with some funny combination of letters and numbers,
you're not really sure what the function is, and there's a yeast analog, blah blah blah,
and you think it's related to a 10 percent increase in Alzheimer's disease. We have an
in vivo assay, which is the telomere length, and we even can look at telomerase activity,
both transcription and protein in research laboratories.
Now I want to show you the spectrum of telomere disease as we see it in the clinic with some,
I think, dramatic cases. This is, again, a military officer, really a remarkable story.
He's airlifted out of Afghanistan because -- not because he has a blood problem, but
because he has tongue cancer, which is diagnosed while he's there. Comes back, he already has
metastatic disease shown here in this CT scan. Now I wish I could say that I was the physician
who made the diagnosis, but a very astute Army hematologist looked at his nails and
his skin, and said "Hmm, this looks like stuff that I heard about in medical school, this
is dyskeratosis congenital." So this patient we showed had a mutation in the DKC1 gene
which that protein product stabilizes the telomerase complex. Really critical, and that's
what we see in children with X-linked, very severe dyskeratosis congenita. So this is
the pediatrician's dream, this is the lead presentation of a clearly pediatric disease
presenting in adulthood. By the way, this patient's bone marrow disappeared when he
got a single round of chemotherapy, so he had underlying severe bone marrow failure
but it wasn't apparent at the time of diagnosis of his cancer.
Now this is the other end of the spectrum. Here's a patient who presented to our clinic
with a fairly modest history: a little bit of thrombocytopenia over the course of about
a decade, not terribly severe. He had big red cells, which is very typical; an elevated
MCV is a very good sign of bone marrow failure, and is often seen in these patients with telomerase.
He had hair that had grayed when he was in his early 20s; this is a very easy thing to
look for and to ask for in the clinic. It's a good icebreaker to ask a male or female
patient whether they've dyed their hair, and they always wonder why you're intruding, but,
in fact, this is a very typical history in the patient and in the family, not pathognomonic
but suggestive of a telomere problem. This guy took a picture of his hair after we identified
that he had extremely short telomeres and a mutation in TERC in our laboratory. So this
is a more typical presentation of a patient with a telomeropathy, and you can see why
this has been missed because these are fairly subtle hematologic manifestations. He also
had cryptic cirrhosis; I'm going to get to that in a moment.
This is a fantastic family that we studied; they live about an hour and half from NIH.
They're farming people, they're Mennonites, and the Mennonites and Amish are terrific
for genetic studies. It's familiar, of course, to those who are hearing -- listening in from
Johns Hopkins. This family is big; this picture was taken after lunch when half of them had
gone back to their tasks. They keep excellent genealogic records so we can trace them back
at least six generations. Everyone shown in green had a novel mutation of the telomerase
gene; those in white have wild-type telomerase. The patient that we saw had presented -- he's
a dairy farmer -- presented again with this story a very modest bone marrow problems,
a progressive thrombocytopenia and anemia, but had a striking family history; in retrospect,
although we didn't recognize at the time, he did indeed have gray hair, was easy to
make the diagnosis when we walked into the room and saw him. He had failed the previous
therapy given elsewhere. He was transplanted by my colleague Rick Childs, an excellent
example of the value of genetic testing because we had a choice of HLA-matched siblings, one
of whom was a young woman with macrocytosis who was HLA matched; she had the mutation.
That's a disaster; you don't want to actually transplant from somebody in the family, as
I'll show you in a moment, even if they have normal blood counts, and he's done quite well
with really minimal problems following transplant.
This is a problem in families, is that everyone who carries a mutation has a defect in hematopoiesis,
even if their blood counts are normal. These are a number of family members from another
family showing hypoplastic bone marrows, normal blood counts, but if you look at measures
of hematopoesis colony formation, CD34 cell number and so on, they are much decreased,
and the growth factors are elevated. So we think that patients can maintain normal blood
counts for a lifetime, and some other factor, immunologic presumably, is what overlays and
causes disease.
This is the same family showing a second manifestation; very important to remember of telomere disease,
which is cirrhosis, or liver failure. So four women in this family ultimately suffered fatal
liver failure, including a young woman who died just recently who had had a liver transplant
when she was 19 for liver failure; had done well for 20 years, and then finally succumbed.
I'm going to show you some of these patients, but I want to stress that this is something
we've not appreciated explicitly. I published a paper that was in one of the lesser of the
hematology journals several decades ago recognizing a relationship between cirrhosis and aplastic
anemia; no idea why. When we began to understand the telomere diseases, I remembered the patients
-- that's already a triumph, to remember the patient's name, I hadn't seen them in 20 years,
but we couldn't reach them, the doctor died, the phone number that we had didn't answer.
I finally got a phone call quite accidentally from Susan Lightman in our transfusion medical
department who said, "I have a young woman here who wants to donate to the National Marrow
Donor Program because of the terrible story in her family, and she says that you had seen
her brother and her father some years ago," which was the case. So the story was bad.
I saw the young man who had very modest thrombocytopenia. He progressed outside of our hands, and when
to transplant and died. His father also had aplastic anemia. He ended up with esophageal
varices due to severe cirrhosis, and bled to death from his gastrointestinal tract.
Terrible story.
So we saw this young woman, and actually, she had short telomeres, which was awful;
got a couple kids there, looks great, but she did not have a telomeropathy because her
genes was normal. So why is her telomere short? She inherited those from her father, so the
father's *** also had very short telomeres, and the mean telomere length was reduced.
But if you can repair your telomeres, work that Richard Hodus [spelled phonetically]
has done in the mouse and we've done in humans, it appears that if you can repair your telomeres,
even if you start with them being short, it doesn't lead to disease. So she was fine,
her kids were fine. She has a brother who was having problems with alcohol because he'd
had, obviously, this sense of being fated to have a terrible disease; he also ended
up having a normal telomeres -- I'm sorry, having telomerase genes, so he didn't need
to worry about that.
So we've also shown, it sounds like German group, that telomere -- telomerase gene mutations
occur rather frequently in patients with cirrhosis, independent of any prior history, family or
otherwise. So this may be actually the most common manifestation of the telomeropathies,
which is cirrhosis, often in the context of hepatitis infection, or steatosis with diabetes,
or with alcohol. So this is an underlying risk factor in about 5 to 8 percent of patients
as an our study and in the concurrent German study.
Now the third manifestation that you need to remember for the telomeropathies is pulmonary
fibrosis; this is recognized by others. This is one of the members of the Mennonite family.
She actually made the diagnosis of pulmonary disease at an NIH conference. She turned to
her husband and said, "I've been short of breath for the last month or two," and this
is her CT scan. And she actually died a couple of months later with a combination of pulmonary
fibrosis, cryptic cirrhosis, which was diagnosed on liver biopsy, and bone marrow failure.
This is the documentation of pulmonary fibrosis familial and telomerase mutations.
This is from our own hematology service. There's a very wide range of hematologic disease that's
associated with telomere gene mutations, from modern-day aplastic anemia, MDS, aplastic
anemia, and even leukemia. A few subtle points about the telomeropathies: Here's a family
where we could not identify a mutation in TERT or TERC, obviously not in DKC1, it was
a female patient, and it was only until we looked at the promoter region that we found
a mutation shown here in the CCAAT -- shown here -- in the CCAAT gene -- in the CCAAT
box of the promoter, very important binding site for transcription factors. This is actually
the first pathogenic mutation in this region ever described in humans, so that regulation
of the telomere repair complex is complex, including not only the promoter and other
regulatory regions for the genes but other genes that impact telomere activity.
This is a very unusual, very striking, and important example of telomere disease in the
clinic. A patient whose Galiseper [spelled phonetically] disease gets an umbilical cord
transplant, very prolonged period of engraftment, and donor cell leukemia a year and a half
later. This is a patient of our colleagues in the Cancer Institute, and the umbilical
cord blood that had infused into this patient had telomeres half of the length of normal.
So deficient product, for reasons that are not clear; all these balls represent the telomere
length in that infused umbilical cord blood in the patient after infusion of these cells,
and the patient ultimately succumbed to their donor leukemia.
And finally we can model this disease in inducible pluripotent stem cells as shown here, a paper
that's actually just appeared in JCI, and showing that, again, in IPS, you see this
reduction in telomere repair that occurs in vitro as it appears to occur also in vivo.
So this is the diagram to remember, that, first, this disease can manifest in three
organs. We think that telomere repair is the substrate on which environmental factors like
alcohol or hepatitis virus for liver, smoking for patients with pulmonary fibrosis, and
the anemia system for marrow failure. And a way of thinking about this keratosis congenita,
as it relates with a very highly penetrant set of genes, almost always resulting in disease
in the first decade of life associated with skin and mucosal membrane problems, and these
mutations occurring more subtly in the adult population.
Now I want to return to this patient to complete my talk with the link between telomere attrition
and cancer. So in this patient, there was a remarkable feature, which is that his father
had died in Baltimore many years ago with early onset mild dysplastic syndrome and acute
myeloid leukemia. Not only was he young when he presented with this in his 30s, but he
had an unusual course, which is that he died after a single round of chemotherapy, and
almost always we can get patients, even adult -- older patients, through one round of remission-inducing
chemotherapy. This patient died, never recovered his blood counts. So he also, we've learned
on testing of archival bone marrow, had the same mutation as did our patient, and that
led to a larger study by my colleague Rodrigo Calado, showing that, again, in between 5
and 10 percent of patients with new onset acute myeloid leukemia, this is non-APL, we
can find mutations in the telomerase gene complex. Again, germline mutations that are
the risk factor for the development of leukemia, and almost always associated with chromosome
abnormalities. That's not expected because about 50 percent of patients have normal chromosomes
when they present with AML.
When we looked at our patients with aplastic anemia and ask the question, is there a relationship
between telomere attrition and outcome, again we see this very strong link with short telomeres,
in this instance not related to genetic mutations, but simply to the pathophysiology of a aplastic
anemia, the requirement of limited numbers of stem cells to replicate in order to compensate
for stem cell loss and low blood counts. So this work published in JAMA a couple of years
ago now shows that the major risk factor for malignant clonal evolution, mainly monosomy
7, is having short telomeres even in the normal range, shown here. So patients with the lowest
quartile of telomeres, about five- to seven-fold higher rate of clonal evolution, and of evolution
to monosomy 7 than do those patients who have longer telomeres.
And we can see that in patients months to years before they manifest with chromosome
abnormalities. We take their bone marrows that we've stored out of the freezer, and
grow them with normal growth factors. Those patients with short telomeres, which you can
see here, it's just a slide of the chromosomes; you see that many of these -- let me see if
I can get that back -- many of these chromosomes are lacking a telomere. You should see nice
doubleheaded worms as we see on the left side with a longer telomeres. When we take those
cells out and culture them, we see abnormalities in the chromosomes. This is spectral karyotyping
of a variety of bone marrow, showing you chromosome rearrangements in their bone marrow occurring
ex-vivo years before they present.
This is more recent data showing that those patients who undergo clonal evolution have
extraordinarily accelerated telomerase attrition. So the normal telomere loss is on the order
of 40 to 60 nucleotides per year in a normal person, and that's also the loss that occurs
in patients with stable aplastic anemia. In those patients who progress, it's about five
to 10 times higher, so on the order of 400 versus 60 base pairs per year. That's an extraordinary
acceleration in telomere loss. Again, not because we think they have mutations, but
because limited numbers of stem cells are attempting to compensate for the total. And
we can also see that at the level of the individual chromosome, I'm just showing you this as an
example, this is a method that's called STLA, or single telomere length analysis; we're
looking here at the X and Y chromosomes. Here's a patient with stable disease, this is a southern
hybridization, and over the course of many months, you see this nice peak in telomere
length, no changes. Here's a patient who is undergoing telomere attrition, which we can
see in this individual chromosome, the telomeres get short. That telomere gets short over the
course of two years, and that is the typical pattern in patients who go to malignant transformation,
just showing you some summary slides here.
Now we've actually had the opportunity to do the -- or take advantage of the ability
to do the first, I think, direct comparison of genetics, genomics, and chromosome genomics,
as evidenced by this telomere attrition. So our patients are going on to severe pancytopenia,
MDS, and leukemia, and there are now about 60 candidate genes, some of which have just
recently, again, been described in patients with acute leukemia. So we looked in our patients
at those 50 are 60 candidates genes asking what are their mutations, and comparing that
with this telomere attrition that I've shown you which is a regular occurrence prior [spelled
phonetically].
So these are the genes, and this is an example of the data that we've obtained. So in two
of these patients, indeed we did detect mutations in two of the genes that have been implicated
in leukemia and MDS. One of them is DNMT3A, which is a gene that affects hematopoietic
cell differentiation versus self-renewal. But these were present in our patients for
years beforehand, and apparently stable. This is a patient who actually was successfully
treated with immunosuppression, as the DNMT3 large clone remained stable as she goes in
and out of remission; second patient shown here. But in six of our eight patients, there
were no mutations in any of the 60 candidate genes that have been implicated in MDS and
AML. And in a much larger series of 30 to 40 patients with aplastic anemia, again, we
see no mutations in DMNT3A or the other major mutations.
So at least the hypothesis for now is that this progression to chromosome instability,
which predisposes to leukemia, to severe pancytopenia, to MDS, occurs independent of selective mutations
in these candidate genes, and, as a result, not surprisingly, of this accelerated telomere
attrition due to limited stem cell number. And that, by the way, would appear to explain
why patients who have better stem cell numbers when they present to treatment do better long
term. In patients who can get a complete recovery, that's indirectly evidence of the fact that
they've got sufficient stem cells to avoid this rapid telomere attrition.
So this is just telomere lengths in those patients who have now under gone eltrombopag
therapy, and I think you can appreciate that in patients who have treatment-naive disease,
shown in red, they've got much longer telomeres in general than those patients who have refractor
disease, have who've been hanging around for two, three, four, five years before they get
eltrombopag. Now if we look at those patients who undergo clonal evolution when their bone
marrows are stimulated with eltrombopag, that's shown in red. Again, you'll appreciate that
they are, in general, at the lower portion of the telomere length, and indeed the patients
who are up here at the top tend to have rapid and successful reconstitution of their bone
marrows, shown here.
So this is a summary of the cancer story. Of course, genetic mutations, those are easy
to look at, but we also know that the major risk factor for virtually all cancers is aging,
and, as I've shown you, telomere attrition is just a normal phenomenon that occurs with
aging, and I think is likely to underlie all of those aneuploid cancers that we see in
other organs in addition to the bone marrow. And it isn't, in fact, in this middle group
of immune and inflammatory diseases, where there's been this link that we've been looking
at for well over 100 years between a state of chronic inflammation or immune destruction,
and the later development of cancer that I think telomere biology actually provides the
link. And there are many examples; everyone in a subspecialty can think of a disease like
ulcerative colitis and its predisposition to colon cancer; esophageal cancer following
on Barrett's esophagitis; graft-versus-host disease in late cancer; many links, and I
think that these are explicable by telomere biology.
All of which predicted well before any of us were born by this brilliant young guy,
Tyador Bophery [spelled phonetically], a very sad story. He published this fantastic monograph
just at the beginning of the First World War in German, and it really attracted far too
little attention. He died a little bit after the war, a very sad story. But he had really
a brilliant, brilliant book in terms of describing the importance of chromosomes and their instability.
Now I want to finish with the least one hopeful note: So can we do anything about this? So
this is one of our Mennonite patients holding up her handmade chart -- she had aplastic
anemia -- her handmade chart of her hematocrit when she was treated with a very old-fashioned
therapy for a plastic anemia, one we know works in a subset of patients, which are male
hormones. So here she got deca-durabolin; her hematocrit goes to normal, and actually
stays up on deca-durabolin for a decade.
So we've shown recently of that the mechanism of action for male hormones acting on the
bone marrow is almost certainly through telomerase. We've not really known what the mechanism
is, and I think that this is the most likely one. So this is just the effect of a variety
of sex hormones, male and female, on telomere activity, telomerase activity, in vitro, in
hematopoietic cells. You can also show the same thing in lymphocytes. And this is the
model based on many enzyme inhibition experiments. It is actually through the female sex hormone,
estradiol, and the binding site estrogen response elements that are present in the promoter
of the TERT gene, of that critical telomerase gene, that these hormones act and upregulate
telomerase. And maybe that's, in fact, why our telomeres are stable through much of our
adult life, is that we've got this sustenance as a result of sex hormone activity.
We can even model this in animals, so if we take TERC or TERT deficient animals, we can
avoid telomere length -- telomere attrition, as, for example, after transplant, the limiting
number of cells; you can see the difference in these mouse experiments between animals
treated with testosterone and those not. There's no telomerase that does not occur. Here's
animals that are exposed to repeated doses of total body radiation. Young animals, longer
telomeres; older animals, even more striking avoiding telomere attrition.
So finishing, we have a protocol that's up and running actually at NIH looking at long
course of Danazol in inpatients who has short telomeres, with or without telomerase gene
mutations. This just shows you the characteristics of the protocol, and this is the affect on
telomere length, which Danazol appears to stabilize, or actually allow elongation in
these patients with short telomeres, and leads to hematopoietic recovery in the majority.
When we select these patients based on telomere length, Danazol works.
That's it. So I want to thank, of course, the people who did all of the bench work and
clinical work, especially Rodrigo Calado, Phil Sheinberg, and others for putting this
all together, and thank you for your attention.
[applause]
Male Speaker: [unintelligible] other comments or questions
for Dr. Young?
Male Speaker: I have one [unintelligible]. The length of
the telomere comes down, and when does the chromosome become unstable, and why is it
unstable?
Neal Young: Yeah. So the answer to that actually not entirely
known. We don't know in humans. Certainly, in cell lines they are well-demarcated telomere
lengths that are not consistent with the cell continuing to replicate. And one of the problems
is that it's not the average telomere length; it's a single chromosome. Once that single
chromosome develops extremely short telomeres, the cell will stop replicating; it'll go to
sleep. It induces the appropriate responses for senescence apoptosis. So it's very dependent
on, in that particular cell, which chromosome was critically short.
Now the reasons for instability are not known in detail, but what occurs and what can easily
be seen in cell culture and in animal models, and I think we can see it in humans, is end-to-end
fusion. So without the full telomere, the chromosomes just stick to each other and are
dragged across the anaphase plate.
Male Speaker: Neal, thank you for a great talk, you got
my attention. I think this is cutting edge; eventually, we'll be ordering stem cell reserves
and telomeres on patients. But could you talk a little bit more just about anemia chronic
disease, at least that's what the clinicians call it, especially in inflammatory and autoimmune
diseases? Should we do any screening tests or be concerned?
Neal Young: Yes, and that's actually a very interesting
question. You know, I think if it's -- so let me give you the simpler -- you know, if
you've got the patient with liver disease and they're anemic, I wouldn't blow that off
their, you know, having some sort of -- I mean, in fact, there often are the big red
cells in that setting, aren't there? I wouldn't blow that off to just be a secondary effect
of the cirrhosis, which is what's been done since I was an intern. That may well be evidence
of an underlying telomeropathy.
I think the issue of chronic inflammatory disease or of chronic anemia is more complicated,
because what I've argued, and which I think is important in this general setting of inflammation,
is that there is a regenerative stress in an organ; liver, lung, we don't know, 73 different
cell types, who knows which of them is involved. Bone marrow is pretty easy: Stem cells are
just chugging it out, and their telomeres are getting short because there are too few
of them. But the other mechanism that has been postulated, for example, there's a very
strong link between short telomeres and atherosclerotic disease, cardiac outcomes and so on. Now is
that due to telomeres shortening occurring in endothelial cells? Possibly, but the hypothesis
has been that it's actually a reflection of reactive oxygen species. There's just more
damage to chromosome in general, and the telomere is part of the chromosome, so you're going
to see that being affected and be short. So telomeres may indeed be short in patients
with increased reactive oxygen species as part of a chronic inflammatory, or a tumor,
or some other underlying problem. It's really not been looked at; I mean, actually, it would
be interesting to see. And we've not looked -- and, you know, it's just hard to study
those patients because usually their anemia is not their major problem. But that would
be an easy thing for us to do.
Male Speaker: For our audience beyond the auditorium, could
you paraphrase the question?
Neal Young: Sure.
Male Speaker: What is the definition of normal length, actually?
Neal Young: Well it depends on the age, so -- and it also
depends on the assay. So the assay that we use is gene amplification -- sorry, the question
was the normal -- what's normal? And normal depends on how old you are and what the assay
is. So than normal for an umbilical cord blood, as you can see, is much larger -- much higher
than the normal for an elderly person in their 80s or 90s. But there's actually some -- you
know, there actually is overlap between older humans with their longer telomeres and some
children with relatively short telomeres, so it's not an either/or. So it's always age
adjusted, and it depends also on the assay. The gold standard or the standard is a southern
hybridization, but it's very cumbersome to do and not suitable for screening. We use
gene amplification, so it's a reverse PCR, and we have a range of kilo bases of telomere
length that we calculate for any particular age. There's a commercial assay that also
depends on fish, and flow, and they also have a range of normals, but it's always age dependent.
Male Speaker: The kilo bases is the length?
Neal Young: Yes.
Male Speaker: It's the unit of the length?
Neal Young: It's the length of the telomere.
Male Speaker: Have you ever had a chance to look at telomere
length in porphyria?
Neal Young: No. We haven't had a chance to look at telomere
length in porphyria.
Male Speaker: [unintelligible] removed essentially from
practice a couple decades again, with aplastic anemia, though it's apparently used quite
freely in other countries. Is there any relationship to that, or do you think [inaudible] --
Neal Young: Actually, that's really a brilliant question.
I mean, really -- sometimes you get a question that just makes you think -- sorry. So that's
a brilliant question because it has to do with chloramphenicol. So there's been -- you
know, chloramphenicol was related in the '60s and '70s to actually epidemics of aplastic
anemia supposedly occurring in the United States. So let me say first, I'm not sure
of that relationship, but then I'll assume that there is one. I'm not sure because the
epidemiology, really, is not very good, and it's unfortunately one of those examples of
somebody publishes one paper with a lot of, now in retrospect, defects in the methodology,
as, for example, the chloramphenicol being given after the aplastic anemia actually occurred,
but that wasn't looked at very carefully. I mean, that's kind of not like what would
be cause and effect.
So we don't actually know, and when you look a -- if you look either at East Asia, we saw
no relationship with chloramphenicol and aplastic anemia. It's freely available, it's still
widely used. If you look at countries like Sweden and others where they actually monitor
the amount of chloramphenicol that they imported, and also had rates of aplastic anemia, no
relationship between the chloramphenicol going up and coming down, so it's still a little
bit left up in the air.
The second point I want to make is it's often hard to make the distinction between cause
and effect. The story with the early graying in telomeres is pretty illustrative of that,
so there's a little literature about hair dye causing aplastic anemia. Now if, you know,
if you or your wife uses a hair dye, you know that it smells bad, and it looks like it should
cause all sorts of diseases.
[laughter]
So it seemed logical that hair dye could be a cause -- you know, you put it on your head,
scalp, it all gets absorbed, that it could cause bad things, but I don't think that's
a relationship at all. I think what we were detecting where those patients who were dying
their hair because it was gray early, and they had a fundamental genetic lesion that
they were a obscuring when they looked at their hair.
But the last point of your question, the part that I think is really interesting, is that
chloramphenicol does have a very regular effect on the bone marrow, and these were done -- actually,
I hesitate to even -- I hesitate, actually, to even describe them because they were probably
unethical, and you know we're not really supposed to talk about unethical studies, but since
having brought it up, I'll finish it. So there were studies done, let's say at an unnamed
institution, on terminally-ill cancer patients in which massive doses of chloramphenicol
were given to them in their terminal phases. And what happened in those patients, very
consistently, is that they developed a profound anemia. So you could speculate that what chloramphenicol
was doing was creating a tremendous regenerative stress on the bone marrow, and that it could,
in fact, be linked by that mechanism to bone marrow failure. But that's, again, speculative.
Male Speaker: It's quite a good antibiotic, and wouldn't
it be interesting to know if there are some people who are impervious to that.
Neal Young: Yeah, that was actually speculated on many
years ago because one of the questions, there's a famous hematologist whose name I'm blocking
but you may remember, at Wash U. who went down to Columbia, he had this relationship
with Columbia, and what he observed was that there seemed to be this outbreak of chloramphenicol-related
aplastic anemia, and then it went away. So you actually -- had you eliminated all those
susceptible in the population, then chloramphenicol could continue to be given.
Male Speaker: In studying elderly patients, and those studied
over the age of 100 who have relatively longer telomeres --
Neal Young: Yeah, well, how do we know they're longer?
That's the problem. So the studies that have been done -- and this is also a very critical
question -- there are some famous people, even those who have won the Nobel prize now,
who are promoting this idea of getting your telomeres measured, and then you'll see how
long you live because there are a lot of studies that have suggested some relationship with
longevity. I have pretty long telomeres, so you know, I don't have -- you know, I prefer
to believe that that were the case, but let me tell you what my reservations are, and
then I'll answer your question directly. The question has to do with the telomere length
and very old people, centenarians, for example.
So I think that the problem is really one of selective publication, that a lot of studies
that are negative or don't show relationship really just don't appear, and I'm, you know,
I'm really skeptical of this relationship, cause and effect, that telomeres actually
cause aging. And again, I mentioned that there's this overlap between kids with particularly
short but normal telomeres, and older people, 60s, 70s, and 80s, who had telomeres that
are particularly long, and actually are the same length as children. So it's kind of hard
to think that that's cause and effect when you've got that sort of overlap.
Your question, though, is really a hard one to answer because what is the right telomere
length for a person who's 90 years old? And what has been looked at are just the telomere
lengths per se, they are a certain number. They're obviously shorter than somebody who's
50 or 20, but what is striking is that they're in a very narrow range. But I think that that,
without getting into the complexities, that only reflects the fact that the homeostasis
of the hematopoietic system may lead to a regression to the mean. It's complicated,
but the idea would be that those hematopoietic stem cells with particularly short telomeres
get eliminated, and you now have a population that's actually very consistent in its telomere
length. That's what survived in the person that's 90 or 100. But there's no optimal length
because we don't know -- who do we compare it with? You'd have to be 100; that presumably
is the right telomere length for getting to be 100.
Male Speaker: So in cryptogenic cirrhosis, it's your hypothesis
that this turnover in liver cells that really drives it [spelled phonetically]?
Neal Young: Correct. Correct. And there are actually quite
good animal models of Dipono [spelled phonetically], and Lenhard Rudolph, and others that suggests
that that is, in fact, the mechanism for that, and for hepatocellular carcinoma.
Male Speaker: [unintelligible]
Neal Young: [affirmative] Yeah, the liver is quite regenerative.
Male Speaker: Is the change in life of telomeres over time
consistent, or does it alter?
Neal Young: No, it does change, and that may be important
as the rate of change, so as you saw, you know, the curve is sigmoid. So the rate of
change in childhood is much rapider than it is in most of our adult life, where telomeres
are relatively stable until we get whatever age I am, one year older.
[laughter]
Male Speaker: Yes?
Female Speaker: I recently read that nutrition and what you
eat can affect these changes --
Neal Young: Yes, and that's really -- that's the problem,
okay, so that is the sort of, I think, really not -- I'm trying to be tactful -- I think
that's the sort of information is very easy to --
Female Speaker: It's in scientific journal, so I --
Neal Young: No, of course, they're all scientific journals,
but, I mean, it's even hard to define what a scientific journal is. So the question has
to do with the relationship between nutrition, what you eat, and telomere length, so I don't
know how you actually do such a study. I mean, you know, I've shown you there's very little
telomere length that changes, so you go back and you ask, well, are they eating a lot of
red meat versus a lot of green vegetables, you look at the telomere length; I really
-- I just don't believe it. And I think it's a diversion from all the things that -- I
mean, when these sort of studies come out, and people are making money because they're
measuring telomere length, and, you know, you see something on the news, that's the
point at which you should become not just skeptical but somewhat cynical.
Male Speaker: It's the red wine.
Neal Young: Yeah, it's the red wine, why don't we see
Female Speaker: A doctor from the mountains printed something
aging [spelled phonetically] cancer, anti-cancer, I believe, from -- consisting of something
like that, and that [unintelligible] and they somehow are able to get all the cancer cells
and destroy them.
Neal Young: Maybe.
Female Speaker: [inaudible]
Male Speaker: I saw the associations of GI, inflammatory
reaction to cancer, but in the lung, it looked at pulmonary fibrosis, cigarette smoking;
why not cancer --
Neal Young: It does, well I can say it does but the GWASes
that have been done to show a link between short telomeres and -- between short telomeres,
and, more important, between SNPs in telomerase and other telomere-related genes in lung cancer.
So there -- it's not a relationship that holds true for all cancers, so this is where you
have to be -- where I have to be careful, so you can make these broad statements that
problems, either genetic or otherwise, always underlie cancer, and they have to do with
telomeres. So, for example, in breast cancer, the literature is all over the place. Some
GWASes are -- show in negative association, some show positive, but for lung cancer, the
relationship is pretty consistent that either SNPs or telomere length actually do relate
to susceptibility to lung cancer, so it's not different from liver.
Male Speaker: Well, it seems that our sample of one that
long telomeres are associated with excellent lectures [inaudible].
Neal Young: Thank you.
[applause]