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GG18CH02-Hirschhorn
ARI
3 August 2017
6:34
Kurt and Rochelle Hirschhorn

GG18CH02-Hirschhorn ARI 3 August 2017 6:34
Annual Review of Genomics and Human Genetics
A Conversation with Kurt

and Rochelle Hirschhorn
Kurt Hirschhorn,1 Rochelle Hirschhorn,2
Annu. Rev. Genom. Hum. Genet. 2017.18:31-44. Downloaded from www.annualreviews.org
and Joel N. Hirschhorn3,4

1
Icahn School of Medicine at Mount Sinai, New York, NY 10029;
email: kurt.hirschhorn@mssm.edu
2
Department of Medicine, New York University School of Medicine, New York, NY 10016;
email: hirscr01@med.nyu.edu
3
Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard,
Cambridge, Massachusetts 02142; email: joelh@broadinstitute.org
4
Division of Endocrinology and Center for Basic and Translational Obesity Research,
Boston Children’s Hospital, Boston, Massachusetts 02115
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First published as a Review in Advance on January lymphocytes, lysosomal storage disorders, Wolf-Hirschhorn syndrome,
26, 2017
mosaicism, adenosine deaminase deficiency, Pompe disease, somatic
The Annual Review of Genomics and Human Genetics reversion, genetic counseling
is online at genom.annualreviews.org
https://doi.org/10.1146/annurev-genom-080316- Abstract
090927
In this interview, Kurt and Rochelle Hirschhorn talk with their son, Joel,
Copyright c 2017 by Annual Reviews. about their research and collaborations, the early years of medical genetics,
All rights reserved
the development of genetic counseling, the challenges of being a woman in
science, and new challenges and directions for the study of human genetics.
31
Joel Hirschhorn: This is the second time I’ve had the pleasure of introducing my parents, Kurt and
Rochelle Hirschhorn, as I also did so when they received the 2013 McKusick Leadership Award
from the American Society of Human Genetics. Rochelle, my mother, was chief of the Division of
Medical Genetics at New York University for 24 years. She described the gene structure, genotype-
phenotype correlation, and pathophysiological mechanism for adenosine deaminase deficiency,
and through studies of somatic reversion and blood cell transfusions provided evidence that enzyme
replacement therapy would be effective in this disease. She also cloned the gene responsible for
Pompe disease, acid alpha-glucosidase.
Kurt, my father, began his career at NYU, but then founded one of the first Divisions of
Medical Genetics at Mount Sinai School of Medicine in 1968 and was the chairman of pediatrics
there for 18 years. He made important contributions in multiple areas: He and his colleagues were
responsible for describing the mixed lymphocyte reaction, which is the basis for HLA matching,
and he was also the first to describe partial deletion of chromosome 4p [4p−], also known as
Wolf-Hirschhorn syndrome.
Both of them are members of the National Academy of Medicine, and they have collectively
received numerous awards. They have been occasional scientific collaborators and, more generally,
have been a force in human genetics. They have also had multiple leadership roles and have been
a strong and sustained presence in the American Society of Human Genetics.
I’ll begin with Kurt. Were you interested in science as a child? How did you get interested in
science?
Kurt Hirschhorn: I was interested somewhat in medicine as a child because my uncle was a
physician. He was my favorite uncle, and I often talked to him about what he was doing. In high
school, I was a member of the science club, and we did a lot of things, especially with snakes.
J.H.: I know you were considering a number of different careers. How did you make the decision
to eventually go to medical school?
K.H.: I was undecided between being a musician—which I had been during high school and
college and so on—and possibly going into medicine. Music was actually the first thought. But
then I went into the army, and I was in the army in the last part of World War II. I sort of decided
that I could always do music for my and other people’s delight, but that I really wanted to try to
do something to help people. So I decided that medicine was probably the right thing for me.
J.H.: Rochelle, I’ll ask you the same thing. I know you were interested in a couple of different
things, and you had some experiences in early childhood and in high school that pointed you
toward science.
Rochelle Hirschhorn: I think I wanted to be a microbiologist. I don’t know where I got the idea
that there was such a thing as microbiology, but I liked it a lot. In high school, I had a phenomenal
teacher. He was really a PhD chemist, but he was teaching in high school, because in those days,
people didn’t have money and didn’t have jobs. He taught us with a college text. And I loved it. I
loved him, too.
I ended up taking what he had taught me in high school and using it to teach my fellow students
at Barnard College. I taught them not only chemistry, but also physics. Originally, I was going
to do economics, but I then decided that they didn’t know how to really do anything about the
economy, and maybe I’d do better as a doctor.
J.H.: Tell us a little bit about how you ended up in medical school and what it was like going from
Barnard to medical school.
32 Hirschhorn · Hirschhorn · Hirschhorn

R.H.: That’s a hard one to answer because it depended to a large extent on my husband, who
was not my husband at the time. I was interested in health before I met him. I worked in Hell’s
Kitchen, taking care of children and doing whatever needed to be done to get them healthy so they
could go to the country. It was in that era that one night I ended up at a hotel where everyone was
dancing. And the person I was dancing with was the man who would later become my husband. I
didn’t know—I was just dancing.
In those days, they were always pushing you to get married. I danced with him and spoke with
him and thought, “Now there is someone who has a brain.” I did! I thought, “That’s someone I
might marry.” I thought I’d never see him again, and I broke up with the person I was with, and I
got interested in medicine. I’m not going to tell you how we got together—I think his girlfriend
made the mistake of going away. And he went in his usual direct way and found out my phone
number and called me, and we were married five months later.
J.H.: So that was the beginning of partnership.
R.H.: Yes.
J.H.: At this point, Kurt, you were in medical school already. Did you start doing research in
medical school, or was it later?
K.H.: I started to do research primarily in my last year of medical school at an old hospital in
the middle of the East River called Goldwater Hospital, where I did a six-month experience in
research. I even got a paper out of it at the time. During my residency, I also continued doing some
research. And then I did a fellowship at NYU, initially in metabolic disease, and that’s what got me
into genetics, because I was assigned to do research in hyperlipidemias, like hypercholesterolemia
and so on. I saw a number of families who had abnormal lipid levels, cholesterol levels, and so on.
It was obvious that this was a genetic disease, and I knew nothing about genetics. So during the
fellowship, I took a master’s degree in Drosophila genetics with a man named Morris Harnly, who
had been one of Dobzhansky’s students and was teaching genetics at NYU.
That turned me on even more towards genetics, so I then did another fellowship in Sweden
at an institute for genetics that was originally called the State Institute for Racial Biology and
was later renamed the State Institute for Human Genetics. There I met a wonderful guy, Marco
Fraccaro, a geneticist from Italy who was also working in Sweden. He persuaded me not to become
a doctor out on the street, just seeing patients, but to become a full-time academic. That’s what
turned me on to doing academic genetics and staying in a research career in addition to doing
clinical work.
J.H.: That trip to Sweden was influential for both of you, right? You ended up working together
there, but Rochelle, you ended up not working with the person you thought you were going to
work with.
R.H.: I thought I had made arrangements to work with someone in endocrinology, which I had
done research in as a student, while Kurt did genetics. So I arrived there, and the person I had
made arrangements with wasn’t there—he was on a sabbatical in the United States. The head of
the institute offered to take me on. But you know how you can be sometimes when you’re young?
I didn’t think he knew enough endocrinology, so I went back to the Institute for Racial Biology,
and I also hooked onto Marco Fraccaro. Really, to cut short, I ended up also working with Marco.
J.H.: That was how the two of you ended up collaborating for the first time, right?
R.H.: Right.
www.annualreviews.org • A Conversation with Kurt and Rochelle Hirschhorn 33

K.H.: Her first paper was with Marco and me.

J.H.: Can you tell us a little bit about the early work in Sweden and how that changed the direction
of your careers?
K.H.: The work in Sweden was primarily for the purpose of learning what was hot in human
genetics. Then I decided to take my lipid experience further, by trying to figure out the percentage
of people who had abnormal lipids. So I made an arrangement with the medical school in Uppsala.
They allowed me to take blood from all their incoming students. I found a whole bunch of them,
and then we did additional studies with them and figured out what the incidence of hyperlipidemias
was among them. It was quite high, and together with Marco, the two of us wrote a paper about
that. It was her first paper, and my second paper—same thing.
J.H.: So early genetic epidemiology, then?

K.H.: Absolutely.
J.H.: In addition to the genetic epidemiology, you both ended up working on lymphocytes at
some point. How did that come to pass?
K.H.: It started actually even before, when I started looking at lymphocytes for a very good reason.
A gentleman named Hungerford in Philadelphia devised a method for allowing lymphocytes to
Figure 1
During their 1957 work at the State Institute for Racial Biology in Uppsala, Kurt and Rochelle’s research
was featured on the front page of Dagens Nyheter, Sweden’s daily newspaper. Also shown is Jan Book, the
director of the institute.

divide in culture so that one could look at the chromosomes from the peripheral blood. Until that
time, you always had to take a skin biopsy or a bone marrow biopsy to look at chromosomes. Now
we could just take blood and study them in lymphocytes.
When I looked at these lymphocytes under the microscope, they looked like cells that had
been described by a man named Gowans in England, called graft-versus-host cells. These were
the cells that grew when they tried to do a bone marrow graft. The recipient of the bone marrow
transplant developed cells that tried to get rid of the foreign cells, and these looked like graft-
versus-host cells. So then I decided to see what was really going on. I did some experiments taking
lymphocytes from people who were PPD [purified protein derivative, a skin test for tuberculosis]
positive—they had been exposed to tuberculosis at some point—and people who were negative,
put them into culture, and put PPD into the culture. For those that had been exposed to PPD and
to tuberculosis itself, the lymphocytes grew.
That led to a large number of experiments, including—again, almost by chance—mixing lym-

phocytes from two different people and showing that if they came from genetically different people,
they made each other’s lymphocytes grow. That was the beginning of the mixed lymphocyte cul-
ture, which was sort of the basis of understanding cellular immunology and led to a number of
different experiments, not just by me, but by a lot of other people.
J.H.: It sounds like you were on your way to learning cytogenetics, and on that road happened to
notice something that ended up being a happy major diversion.
K.H.: Absolutely. Then Rochelle became interested in that, and we did some joint experiments.
R.H.: When I was working with Marco, there was another paper from Philadelphia. They had
about ten different compounds that they had put in, including something called phytohemagglu-
tinin. I worked with Marco to decide which of these compounds were making the cells divide, and
we came up with phytohemagglutinin. Later, when I came to NYU, I actually wrote a paper with
one of my classmates showing that it was indeed phytohemagglutinin, and it was a tremendously
good way to make lymphocytes divide.
J.H.: So it was a real tool not just for cytogenetics, but for lymphocyte biology.
R.H.: Right.
J.H.: One of the unusual things about you is that you were occasional collaborators. Do you want
to talk a little bit about what that was like?
R.H.: We wanted to collaborate very much. But when we came back and I finished as an intern,
my chairperson, Lewis Thomas, said to me, “You cannot work with him. It’s nepotism.” So what
could I do? He said, “Go find someone else.” So I looked around for someone who I thought
might be as bright as I thought my husband was. And I did find someone, Gerald Weissmann, and
I proceeded to work with him also. But I had it in my mind, and I told the students who worked
with me later, “When you work here, what you do is, you do one experiment for yourself and one
for your boss. And then you can decide what you’re going to tell him.”
K.H.: The other interesting thing was that Gerry Weissmann’s lab was two floors above mine at
Bellevue Hospital. We walked back and forth, we discussed things with each other, we planned
experiments with each other. A number of those ended up as papers on which we were both
authors, and Gerry Weissmann was in it.
J.H.: So it became one big collaboration to some degree.

R.H.: I also had something: All of my experiments were done with a long, almost 24-hour incu-
bation. The reason for it was that I had two children at home. So all of the assays that I had were
overnight plus a few hours in the day. One time, I’m sitting there with my two youngest ones,
and I was pipetting at the end. I was a little late. And the door opens and who’s there but Lewis
Thomas, watching me.
J.H.: With Melanie and Lisa there.

R.H.: I was holding them under my arm.
J.H.: You ended up with your interests diverging a bit. In part maybe because of that early exposure,
Rochelle, you got interested in lysosomal biology.
R.H.: Yes, which Gerry was interested in. I didn’t work for a while because I had two children.
In those days, we didn’t have money to have anyone come in. I ended up with my pediatrician,
Dr. Shirley Stone, telling me I had to come and work for her at the Bellevue pediatrics clinic,
the well-baby clinic. And when I said, “I don’t know any of it,” she said, “You’re bringing up two
children! You should know!” So I did that for a while. And it was, I think, very worthwhile. But I
then moved on to arthritis and rheumatology. And that was, I think, due to Gerry’s influence as
well.
J.H.: At this point, Kurt, you were getting more and more into human genetics.
K.H.: And to some extent also immunology. The main thing was that I was always very actively
seeing patients. That was, to me, an important component of my life—especially when I moved to
Mount Sinai and suddenly became a pediatrician, having been trained as an internist. My thought
always was, why did I go to medical school rather than go for a PhD? I did it because I wanted to
help people, and therefore, I always continued to see patients as well.
J.H.: And you’ve continued that throughout your career.

K.H.: Absolutely. To this day.
R.H.: And he was a great help for me.

J.H.: In what way?
R.H.: Let’s see if I can explain this. [Pauses.] Well, go on ahead, we’ll come back to this.
J.H.: I actually want to go back a little bit. Very early on, Kurt, you had described the 4p−. Tell
us a little bit about that story and how that developed.
K.H.: When looking at chromosomes became easy, by doing it on lymphocytes, we started looking
for kids with no diagnosis, to see whether their difficulties both physical and mental were due to
a chromosome abnormality. Two of the early ones that I studied were with a couple of young
physicians who were doing electives with me, both of whom were classmates of Rochelle’s.
One of them was this child who had a variety of abnormalities, including severe intellectual
disability as well as a number of physical abnormalities. We looked at it, and it was the first case,
really, where we could demonstrate that missing a piece of a chromosome caused all of these
abnormalities. That was the 4p− Wolf-Hirschhorn syndrome. The other interesting one was a
child who was born with ambiguous genitalia. We found that this child was a mosaic of XY cells
and XO cells, and therefore had both male and female characteristics.
J.H.: Was that the first example of a mosaic individual?

K.H.: It was the first one, and the paper was published in the New England Journal of Medicine.
This was the start of looking at abnormalities in sexual differentiation, which also then led
to the discovery of other chromosome abnormalities in patients with abnormalities in genital
development.
R.H.: I’ll go back to how I also depended upon him. There I was, doing arthritis and rheumatism,
et cetera, but not seeing patients, really. It’s Thanksgiving, and I get a phone call. It’s my boss,
Saul Farber, and he says, “You’re the attending now for the next three months.” I almost went
through the roof. I said to Gerry Weissmann, “How am I going to be the attending?” He said,
“You’ve got to do it.” So I became the attending for three months. I went every afternoon, and I
spoke to everyone I knew who was an attending about every one of the cases I had seen. And that’s
how I became an attending. With Kurt’s help, with Gerry Weissmann’s help—I made all of them
teach me.
K.H.: The interesting aspect of that is that when I went to Mount Sinai into the Department of
Pediatrics, I was an internist. I was told by the chairman, Horace Hodes, that in six months I was
going to go on service in pediatrics and be an attending in pediatrics. So I did two things: I read
the pediatrics textbook, and I shadowed two of the senior pediatricians. So they taught me, really,
practical pediatrics. Then, ten years later, they thought I was a pediatrician, and they made me
chairman of pediatrics.
J.H.: And Rochelle, you ended up attending for many years as well.
Figure 2
The Hirschhorn family celebrates Kurt’s 1978 investiture as the Herbert H. Lehman Professor and chair of
pediatrics at Mount Sinai School of Medicine. From left: Helen (Kurt’s mother), Lisa, Kurt, Rochelle, Joel,
and Melanie.

R.H.: Basically until 1980, when I developed chronic fatigue syndrome.
J.H.: You ended up working on lysosomal storage disorders and adenosine deaminase deficiency
as two main areas of focus. I know the work on adenosine deaminase, in some ways, sprang out of
some work that you did on another trip to Europe. This was in 1971–1972 with Harry Harris.
R.H.: When I had gone to England before, I did not do any work. I was home with two small
children, and I had a marvelous time, but it was really on the second one that I was able to work.
I had been doing work at home in New York, and I had become interested in various things, and
Gerry Weissmann had done a sabbatical on lysosomes. So when I was working with him, some
of what I did was on lysosomes, and that was some of what I did when we went to England. I was
just interested in science—I didn’t know what exactly I was interested in. I tried out everything,
with all the people who were working there. I worked with someone called Dallas Swallow, and
that got me into lysosomes but also into another area, Pompe disease—not really Pompe disease,
but the whole area of alpha-glucosidase, which is still not finished.
I was also interested just in how cells and enzymes work. I used Harry’s techniques to look at
which enzymes were working, and one of them was adenosine deaminase. There had been some
work on that by a brilliant woman named Eloise Giblett, and I got into looking at it. I’m still in
it, in a way, in that we thought there was one adenosine deaminase gene called ADA1, and it now
seems that there is an additional gene, ADA2. What that gave you was immunodeficiencies, and
I was very interested in all of them. It used to be that if you had a child with this deficiency, you
had six months, and the child was gone. Now, you can treat it. First, we showed that you could fix
it by doing a transplant from one person to another.
J.H.: A blood cell.
R.H.: A blood cell and also sometimes a white cell. So it now is a treatable disease. Except now you
find that there’s really another form of adenosine deaminase called ADA2. What has been shown—
not by me, but by other people—is that it gives you early onset of neurologic abnormalities.
J.H.: Strokes.
R.H.: Yes. That needs to be looked at and treated. And that’s the most marvelous thing, that
you can open it up, you can find out where to go. Hopefully, even though it takes usually about
20–25 years, you can make it a disease that you can cure. I don’t think we’re following that up
enough, really.
J.H.: That must have been exciting for you to see—to go from this disease that was lethal, to having
provided some of the inspiration that this could be curable, to seeing it actually be treatable.
R.H.: Right. The same thing as for Pompe disease. Right now people are trying things. And it’s
very exciting. What I think was more exciting is what I fell over, which was self-cure.
J.H.: This is the somatic reversion, right?

R.H.: Right, somatic reversion. I had a patient I was collaborating with, and he died in about four
or five years. During that period, his parents had another child, and it turned out that that child
carried the adenosine deaminase deficiency. Except instead of dying, he was getting better! We’d
go over him with the person who was taking care of him, and he wasn’t dying, he was getting
better. We went and looked at all of his cells and his lymphocytes and saw that he had reverted
most of his lymphocytes to normal. So that was very exciting. And it turns out it’s not just for
adenosine deaminase. There are many disorders which, if you know how to look, you can find
reversion to normal. If I were still working in that area now, that’s what I’d go after.

J.H.: I remember that paper provided pretty good evidence that things like gene therapy would
be successful because you didn’t need to fix all of the cells. This child had fixed one of his cells,
and that was enough.
R.H.: Right.
J.H.: Kurt, you started one of the first Divisions of Medical Genetics. Can you talk a little bit
about what human genetics was like early in your career and how that’s changed over time?
K.H.: Human genetics really started at the beginning of the twentieth century, when Garrod in
England decided to study some diseases that seemed to be familial, and then wrote a book called
Inborn Errors of Metabolism in which he showed that these diseases are inherited. Of course, if you
look at history going way back, the Bible tells you that if a woman had two children who were
circumcised and died of hemorrhage, then she didn’t have to have circumcisions for her other
boys. This was the first understanding of an X-linked or sex-linked disease, which was hemophilia,
obviously. That’s what really started medical genetics, in a sense.
J.H.: So maybe there was a Babylonian Division of Medical Genetics, but then there was a gap.
K.H.: My idea of a Department or Division of Medical Genetics really started when I was still
at NYU. I came back from England excited about genetics after working with Harry Harris. At
the same time, my chairman, Charles Wilkinson, whom I had worked with on hyperlipidemias,
decided that this had a future. He went and applied to the NIH for a training program in medical
genetics, and he got it. So I came back and joined that program.
When, unfortunately, he died a couple of years after that, I took over that grant for a while.
My co-investigator in that was a man named Colin MacLeod, who was one of the people who
discovered that DNA is the genetic material. That was, of course, a very exciting business. So we
had a Division of Medical Genetics that was in its infancy at NYU. But because of that, I was
recruited to Mount Sinai when they formed a new medical school in 1966. The reason that they
wanted to recruit me was that several people—Horace Hodes, the chairman of pediatrics, and
Hans Popper, the chairman of pathology—decided that genetics was the future, and we needed
to do something with it in this new medical school. So they recruited me to start a Division of
Human Genetics. The logical place at that time, because most of the patients that were being
studied were kids, was to do it in the Department of Pediatrics, which is how that started.
It was a very exciting time, those ten years of running the division, and building it up, and
developing new techniques. But when I was named chairman of pediatrics, I wasn’t going to do
both. So I recruited Bob Desnick from Michigan and made him the chair of the Division of Medical
Genetics. That was a very successful collaboration, and then he recruited some more people, and
the end result of all of that occurred about two or three years ago, when Mount Sinai decided to
have an institute for human genetics and recruited Eric Schadt from California to run that.
When I left the division, I had about 50 people. When Bob eventually left the division, there
were over 100. Eric Schadt now has 250 people at the Icahn Institute and the Department of
Genetics and Genomic Sciences. So, like the discipline of genetics, it has grown by leaps and
bounds.
J.H.: There have been similar changes in the American Society of Human Genetics, at the annual
meeting. I know you both have been going to that meeting for a long time.
K.H.: A long, long time. My first time was 1956 in Storrs, Connecticut.
R.H.: And I was with him. That was the first time I saw a chromosome and really believed that
they existed.

K.H.: So, yes, we were there early. Now, of course, instead of the 28 people that were at the first
meeting that I attended, there are now over 5,000.
R.H.: I would like to talk about one of my students. I somehow or other got to run the teaching
of genetics, and one of the students was someone who had gotten a PhD at NYU in, I think,
microbiology. I was very impressed with him. I used to come on Saturday mornings, he’d make
coffee, and we’d talk. He basically taught me genetics from his point of view. He’s Jim Lupski.
We have been close for many, many, many years. I had two mentors—I had him [points to Kurt]
on one side, and I had Jim Lupski on the other side, along with a number of other people. I
became a member of the American Society of Human Genetics. It’s been a very exciting time, a
phenomenally exciting time.
J.H.: Tell us about something you found particularly exciting as you’ve watched this field grow
from 28 people in Connecticut to what it is today.

K.H.: Part of it is reflected by what I told you about the numbers just in our department at Mount
Sinai. That shows that there’s been enormous growth. But the science has grown unbelievably.
The question of what a gene is was barely understood when I started in genetics. A lot of people
at Cold Spring Harbor Laboratory and a few other places were trying to figure out what a gene
is and what it does. It has ended up with the ability to not only know that there’s a gene, but to
be able to sequence the DNA in that gene to find defects and explain them in a very real sense,
as opposed to the philosophical understanding that there must be something wrong in the gene.
That has led to phenomenal advances in diagnosis, in treatment, and in one of my favorite things
to do, genetic counseling, which I was one of the starting people in. It’s just been such an exciting
set of decades, with the growth of human genetics—of genetics in general, but from my point of
view, in human and medical genetics—that has just turned things upside down.
R.H.: And there are new techniques now that we didn’t even dream of, which have not yet reached
human use because everyone is being very careful about how they manipulate the DNA.
J.H.: Probably one of the things you’re referring to is CRISPR. Starting to get there, nothing
definite yet, but certainly pretty exciting.
K.H.: The other thing that I was very much involved with, that we were sort of the first group in
the United States to do, was prenatal diagnosis, which was the first way of predicting whether a
fetus would have Down syndrome or a genetic disease that was carried by other members of the
family. That caused an enormous difference in how couples looked upon their risks and what to
do about them.
J.H.: And Rochelle, you were involved in prenatal diagnosis for adenosine deaminase deficiencies,
right?
R.H.: Yes. And for Pompe disease also, which is very important.
J.H.: You mentioned genetic counseling. Can you tell us a little bit more about what your role
was in getting that started?
K.H.: Genetic counseling was started in the 1930s and 1940s, but it was very primitive. There
wasn’t enough information or technique to deal with it properly. But the concept was there. Shortly
after I came to Mount Sinai and started the Division of Medical Genetics, a woman named Melissa
Richter got in touch with me. She was starting a program at Sarah Lawrence College for a master’s
degree in genetic counseling, because it was obvious that there was a need for this. There were
many couples who had risks, but there were so few human geneticists that there weren’t enough

people to help them. So she came to me for advice, we decided how to do it, and I helped her start
the program.
Not long thereafter, we started a program at Mount Sinai, which has become very successful.
Clinically, perhaps the most important aspect of dealing with genetic problems in families is how
to counsel them. I and Lynn Godmilow, my first counseling student, together with two other
people, wrote a book on this subject, Counseling in Genetics. It became clear quite early that this
was one of the major advances in clinical genetics—the ability to predict what people’s risks were
and what their options were in dealing with it.
J.H.: One of the other areas that you both have been involved with is ethics in genetics, and I
know you both have some role in the Hastings Center. Do you want to talk about that a little?
K.H.: I was one of the founders of the Hastings Center, which dealt with ethical problems in
biology and science. A lot of the principles of genetic counseling also were developed there in a
couple of papers in Science, and I was a coauthor of those. We established a program at Mount
Sinai run by a philosopher named Rosamond Rhodes, who came from City University with a PhD
in ethics. We persuaded her to come to Mount Sinai, and that increased her interest in medical
ethics. We now have one of the leading Divisions of Medical Ethics in the country. The students
are very enthusiastic about it, and it makes them think differently about how to go about doing
medicine in an ethical fashion. It’s become a major topic in many medical schools.
J.H.: One other topic I wanted to touch on, particularly for you, Rochelle, was your role as a
woman in science and how a lot of people have looked at you as a role model. Tell us a little
bit about what your experiences were, how you think things have changed, and where you think
things are now.
R.H.: I think I was very lucky in that I was married, because to my classmates, I was their buddy.
They gave me a nickname. They never called me by my own name. And I have not told too many
people what that nickname was. So I had a very good experience with my classmates.
There was one thing that I wanted very much. There was this society that was founded by
Osler in, I think, 1905 or 1915, and I wanted to join. In 1985, no woman had ever been elected. I
liked my buddies, and they apparently liked me too. And so I was the first woman who was elected
to the society. I was on a sabbatical then, and I arrived late at the dinner that was there. When
I walked in, the man who was serving drinks, who was an African American, said to me, “There
aren’t many of you here!” And I said to him, “There aren’t many of you here, either!”
J.H.: Same issue.
R.H.: I really feel that I have not been treated equally, and I should have fought more for salary.
Because of all things, what you need is the money to make it easy for you. What I was told every
time was that I had a husband. And I would say to them, “Well, I may have a husband, but such
and such happened, and I need the money.” So they’d raise me that money. And then I would say,
“Well, my daughter just got a raise, and she’s making more money than I am.” So they’d tell me,
“Well, write a note, and we’ll see what we can do.” And they’d raise my salary to that. It sounds
like a joke! But the way I got my salary raised was by telling them the salaries of my children. I
don’t like to dwell on it.
K.H.: I think she did more than that. For example, the society where she was elected as the first
woman, one of the things she did right away—
R.H.: I told them, “You elect me and I’m going to bring in women.”

Figure 3
Rochelle is named as the New York University School of Medicine Master Scientist at the 2010 Dean’s
Honors Day. She is pictured with (left) Robert Grossman, dean of the New York University School of
Medicine, and (right) Kenneth Langone, president of the New York University Langone Medical Center.
K.H.: So they elected her for a few years as president of this society, and then she started bringing
in other women.
R.H.: They bring themselves in now. I don’t have to do it anymore. They come.
J.H.: So that’s changed.

R.H.: Yes. And there needs to be more change.
K.H.: The pay differential is still there.

R.H.: I think that’s very important.
J.H.: I just want to wrap up with a couple of things. First of all, what do you think is an important
challenge or new direction for human genetics?
R.H.: I think it’s how to make life better for people despite what they were given when they were
born.
J.H.: Translation into therapy.

R.H.: Translation into therapy, yes.
K.H.: Certainly the major thing right now is to develop methods not just of diagnosis—which
we’re pretty good at now, although not perfect—but also to translate all of that into easy and cheap
ways of treating these diseases. That’s the major thing to look forward to. I think the techniques
are not there. One of the main techniques that would make this possible is CRISPR/Cas9. But
there’s a problem with that, because changing people’s genes by using this technique in their
germline, which would cure them, would then do something that people are very leery of, which

is that these changes would be transmitted to their children whether they needed it or not. How
does one get around that, so as to help people who need it without putting others at risk? There
was recently a major conference dealing with that in which it was decided to hold back on using
this, especially on embryos and young children.
R.H.: But I think there’s another way to look at it too, which is manipulating the biochemistry to
cure a disease. That was done in the past, but it sounds too simple. “Oh, I’ll figure out what this
disease is, and if I give them A, B, or C, it will cure them.” You’ve got to think about it and you’ve
got to do something about it, and I think not enough is being done.
J.H.: You really have to know the biology, not just the genetic lesion.
R.H.: Right.
J.H.: It’s a very difficult challenge. It’s starting to happen. Cystic fibrosis, for example.
K.H.: The techniques are coming along. It’s their use that still is a little risky, when you don’t
know quite what you’re doing.
J.H.: If you don’t know the biology as well as you think you do.
R.H.: I also think that you have to change the way you write. People write, “Oh, this is CDE
disease”—but no one tells you, what is CDE? I think it has to be looked at more carefully. You
have apparently the same disease, and we know that there are five different DNA effects that will
give you what looks like the same disease. And we don’t look at it!
J.H.: Is there anything else that you wanted to talk about that I haven’t asked about?
Figure 4
Kurt and Rochelle receive the American Society of Human Genetics 2013 Victor A. McKusick Leadership
Award in Boston. Also shown is their son, Joel.

K.H.: The only thing I would say is that since I started in this business, which was back in the
1950s, the most exciting thing that has happened to me in my life is what has happened in medical
genetics, and the privilege I’ve had of being a part of that. That to me is the beauty of it.
J.H.: I agree—you talked me into it.

R.H.: I learned a lot from a nurse who was on the floor above me, and one of those things was
how to get into trouble. I think sometimes you should do that.
DISCLOSURE STATEMENT
The interviewer and interviewees are not aware of any affiliations, memberships, funding, or
financial holdings that might be perceived as affecting the objectivity of this article.

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Contents Volume 18, 2017
The Clinic Is My Laboratory: Life as a Clinical Geneticist

Judith G. Hall p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
A Conversation with Kurt and Rochelle Hirschhorn
Kurt Hirschhorn, Rochelle Hirschhorn, and Joel N. Hirschhorn p p p p p p p p p p p p p p p p p p p p p p p p p p p p31
Gene Regulatory Elements, Major Drivers of Human Disease

Sumantra Chatterjee and Nadav Ahituv p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p45
The Microbiome and Human Biology

Rob Knight, Chris Callewaert, Clarisse Marotz, Embriette R. Hyde,
Justine W. Debelius, Daniel McDonald, and Mitchell L. Sogin p p p p p p p p p p p p p p p p p p p p p p p p p65
Recent Advancements in DNA Damage–Transcription Crosstalk and
High-Resolution Mapping of DNA Breaks
Valerio Vitelli, Alessandro Galbiati, Fabio Iannelli, Fabio Pessina,
Sheetal Sharma, and Fabrizio d’Adda di Fagagna p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p87
Cognitive Dysfunctions in Intellectual Disabilities: The Contributions
of the Ras-MAPK and PI3K-AKT-mTOR Pathways
Sarah C. Borrie, Hilde Brems, Eric Legius, and Claudia Bagni p p p p p p p p p p p p p p p p p p p p p p p p p 115
Tailoring Medulloblastoma Treatment Through Genomics: Making a
Change, One Subgroup at a Time
Borja L. Holgado, Ana Guerreiro Stucklin, Livia Garzia, Craig Daniels,
and Michael D. Taylor p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 143
The Yin and Yang of Autism Genetics: How Rare De Novo and
Common Variations Affect Liability
Pauline Chaste, Kathryn Roeder, and Bernie Devlin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 167
Advances in Preimplantation Genetic Testing for Monogenic Disease
and Aneuploidy
Nathan R. Treff and Rebekah S. Zimmerman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 189
Application of Panel-Based Tests for Inherited Risk of Cancer
Payal D. Shah and Katherine L. Nathanson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 201
Gene and Variant Annotation for Mendelian Disorders in the Era of
Advanced Sequencing Technologies
Samya Chakravorty and Madhuri Hegde p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 229
GG18-TOC ARI 30 July 2017 13:15
Recent Advances in Mitochondrial Disease

Lyndsey Craven, Charlotte L. Alston, Robert W. Taylor, and Doug M. Turnbull p p p p p p 257
The Genetic Diversity of the Americas
Kaustubh Adhikari, Juan Camilo Chacón-Duque, Javier Mendoza-Revilla,
Macarena Fuentes-Guajardo, and Andrés Ruiz-Linares p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 277
On the Evolution of Lactase Persistence in Humans
Laure Ségurel and Céline Bon p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 297
A Robust Framework for Microbial Archaeology
Christina Warinner, Alexander Herbig, Allison Mann, James A. Fellows Yates,
Clemens L. Weiß, Hernán A. Burbano, Ludovic Orlando, and Johannes Krause p p p p 321
Participatory Genomic Research: Ethical Issues from the Bottom Up

to the Top Down
Heide Aungst, Jennifer R. Fishman, and Michelle L. McGowan p p p p p p p p p p p p p p p p p p p p p p p p p 357

Precisely Where Are We Going? Charting the New Terrain of
Precision Prevention
Karen M. Meagher, Michelle L. McGowan, Richard A. Settersten Jr.,
Jennifer R. Fishman, and Eric T. Juengst p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 369
Sharing Data to Build a Medical Information Commons:
From Bermuda to the Global Alliance
Robert Cook-Deegan, Rachel A. Ankeny, and Kathryn Maxson Jones p p p p p p p p p p p p p p p p p p p 389
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Annu. Rev. Genom. Hum. Genet. 2017.18:31-44. Downloaded from www.annualreviews.

Kurt and Rochelle Hirschhorn

Annual Review of Genomics and Human Genetics

A Conversation with Kurt

and Joel N. Hirschhorn3,4

Annu. Rev. Genom. Hum. Genet. 2017. 18:31–44 Keywords

32 Hirschhorn · Hirschhorn · Hirschhorn

J.H.: So that was the beginning of partnership.

www.annualreviews.org • A Conversation with Kurt and Rochelle Hirschhorn 33

K.H.: Her first paper was with Marco and me.

J.H.: So early genetic epidemiology, then?

some point. How did that come to pass?

34 Hirschhorn · Hirschhorn · Hirschhorn

That led to a large number of experiments, including—again, almost by chance—mixing lym-

J.H.: So it became one big collaboration to some degree.

www.annualreviews.org • A Conversation with Kurt and Rochelle Hirschhorn 35

J.H.: With Melanie and Lisa there.

J.H.: And you’ve continued that throughout your career.

R.H.: And he was a great help for me.

J.H.: Was that the first example of a mosaic individual?

36 Hirschhorn · Hirschhorn · Hirschhorn

www.annualreviews.org • A Conversation with Kurt and Rochelle Hirschhorn 37

R.H.: Basically until 1980, when I developed chronic fatigue syndrome.

J.H.: This is the somatic reversion, right?

38 Hirschhorn · Hirschhorn · Hirschhorn

www.annualreviews.org • A Conversation with Kurt and Rochelle Hirschhorn 39

from 28 people in Connecticut to what it is today.

40 Hirschhorn · Hirschhorn · Hirschhorn

J.H.: Same issue.

www.annualreviews.org • A Conversation with Kurt and Rochelle Hirschhorn 41

J.H.: So that’s changed.

K.H.: The pay differential is still there.

J.H.: Translation into therapy.

42 Hirschhorn · Hirschhorn · Hirschhorn

www.annualreviews.org • A Conversation with Kurt and Rochelle Hirschhorn 43

J.H.: I agree—you talked me into it.

44 Hirschhorn · Hirschhorn · Hirschhorn

New From Annual Reviews:

TABLE OF CONTENTS FOR VOLUME 1:

ANNUAL REVIEWS | CONNECT WITH OUR EXPERTS

The Clinic Is My Laboratory: Life as a Clinical Geneticist

Gene Regulatory Elements, Major Drivers of Human Disease

The Microbiome and Human Biology

Recent Advances in Mitochondrial Disease

Participatory Genomic Research: Ethical Issues from the Bottom Up

Heide Aungst, Jennifer R. Fishman, and Michelle L. McGowan p p p p p p p p p p p p p p p p p p p p p p p p p 357

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