Elaine Jaffe - Full Transcript

Elaine JaffeChief, Hematopathology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute

Interview location: National Institutes of Health, Bethesda, Maryland
Interview date: 28th November, 2007

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SA:  Elaine, let's start at the beginning – what sort of family did you come from and how did you get interested in science?

EJ:  My parents were immigrants to the United States.  They were both born in what's currently the Ukraine, near Kiev.  My mother came to the US when she was nine and my father when he was 16.

SA:  What brought them here?

EJ:  The pogroms in Russia. They were Jews living in Russia, and about the time of World War I there were these pogroms where the Cossacks came through – I don't know if you ever saw Fiddler on The Roof?  Okay, so there were these little villages called shtetls; they both lived in shtetls in the Ukraine, and the Cossacks would storm the village and kill and murder.  My mother described to me an episode when she and her mother and her baby sister hid in the woods while the Cossacks came through and destroyed the town.  

It wasn't a pleasant environment, so along with a lot of other people they emigrated to the United States.  This took a number of years in the case of my father's family.  My grandfather came over first with the eldest sister to establish a 'beachhead' and my father was left behind as a teenager as the man of the family.  He had six brothers and sisters -- actually seven; one died -- and so I think that forced him to grow up a lot.  He didn't talk about what he had experienced in Russia as much as my mother did; I think people deal with these things in different ways.

My grandfather came over before World War I and then during the war a lot of this immigration was interrupted, naturally.  So my father came over with the rest of the family after the war, and my mother came over about the same time.

SA:  And what did they do over here?

EJ:  Well my mother, as a nine year old, was placed in first grade and didn't know a word of English, but she rapidly progressed.  She had an uncle who was born here and he tutored here in English.  She actually wound up speaking, I would say, the King's English; she had no accent.  My father was 16 and I think he briefly attended high school, but it was really never clear to me how much schooling he had in this country.  It was something that he didn't like to talk about, but I think both of my parents were extremely intelligent.  My mother was an avid reader and very interested in the arts --not so much science, there was really no one in the family that was a scientist that I can think of.

Against the tide: choosing medicine in the pre-feminist era

SA:  And so when did you first get interested in science?

The science of living beings seemed more interesting than rocks and stones EJ:  As a little girl.  I loved astronomy -- I was a girl scout and I worked for my astronomy badge.  And then I became fascinated with geology; I collected rocks and I was always looking for fossils.  I was just very interested in the world around me.  Then in high school I took biology, and the science of living beings seemed more interesting than rocks and stones at that point.  I got more and more interested in biology and medicine and I just decided in high school, "I'm going to go to medical school".

SA:  Did you come from the sort of family that really encouraged education?  Really believed in excelling?

Most of the Ivy League institutions did not allow women EJ:  Yes, yes.  I had one sister who was six and a half years older than me and she went to Cornell, which at that time was a very selective university (still is).  In those days most of the Ivy League institutions did not allow women -- you couldn't go to Harvard or Yale or Princeton, they were 'all male' until probably the late '70s, early '80s.  There were what they called the Seven Sisters, which were very selective schools, comparable to the Ivy League, but they were ‘all women’.  The only co-ed schools in the Ivy League were the University of Pennsylvania and Cornell.  She went to Cornell and I sort of followed in her footsteps, so I went to Cornell as well.

SA:  And were you keen to go to a co-ed school…?

EJ:  Yes, I didn't want to go to an all-girls school.  Actually I was very shy as a teenager and not very social.  I didn't date and didn't do all the things that high school kids do, and in an all-girl environment the social life is very stilted -- you have all these arranged events, you know?  They'd have open houses, 'mixers', where you're sort of forced together, and you know…Agony!  I liked being with boys but in a more informal situation where I wasn't being judged on my social skills.  So I wanted a co-ed school.

When I went to Cornell I registered as a freshman as a pre-med, and I just thought, "This is what I want to do."  But it was relatively rare for women in those days – in my class at medical school there were only five women out of about 100.

SA:  Really?  Why was it not done for women to go into medicine?

In the '50s women didn't have careersEJ:  I don't know…I mean, we were just getting into the feminist revolution.  In the '50s a woman stayed home and raised children.  She could be educated, but women didn't have careers.  My husband is a lawyer (he went to law school about the same time I went to medical school) and I think there were only two women in his class at law school.

SA: So how did you manage to kick the trend?  How did you, as a shy young woman, decide that you weren't going to go the traditional route?

EJ:  I guess I knew I was a good student.  I thought, "Well, the one place I shine is in the classroom, and that's where I can prove my metal."  I enjoyed school.  And my parents were thrilled.  

My father was very much a self-made manMy father was very much a self-made man.  As I was saying, he really didn't have any education, and so at 16 he went to work in the diamond business as an apprentice.  He learnt the business and then at some point, maybe in his early 20s, he started his own business, and that expanded.  He bought and sold diamonds and then manufactured jewellery.  He started out in Brooklyn and then moved his business to the area where the diamond trade is in New York, on 47th Street, and it grew into a national concern where he sold all around the country.  In fact all his brothers and brothers-in-laws wound up working for him in the business.  He was a little bit of a dictator, if you will!  A very strong personality.  And actually I think he had more trouble with men than with women, so he was very encouraging for both of his daughters to excel in school.

SA:  Were you close to your father, or was he quite a hard task-master?

EJ:  Well, we would fight a lot!  But he wasn't a task master.  I think he adored me, but he didn't like you to disagree with him either, so if you had your own ideas…I mean, we would fight about things like politics and religion, not about whether I had to do the dishes! [laughs]  I don't know, our family was very vocal and so we would have these big family dinners, and everybody would be talking about the events of the day, and politics, so it became rather heated at times.

SA:  So did you get interested in feminism or did you just go your own way independently?

I didn't think I was being a revolutionary EJ:  I think I just went my own way.  I didn't think I was being a revolutionary or doing anything that was terribly novel; I just thought, "Well, this is what I want to do, and this is what I'm interested in, so why not?" You know, I never burned a bra!

SA:  So you went to medical school, and how was that?

EJ:  I loved medical school.  I went to Cornell Medical School, so I went from being a Cornell undergraduate to Cornell Medical School.  That's in New York City, and there were five women.  They put us all together in the dormitory and I had very close friendships.  I'm still close with some of my classmates today.

SA:  And did you see yourself basically as a physician?  How did you get into pathology?

Looking through the microscope I saw medicine come alive EJ:  I really became interested in pathology during my second year at medical school. We had a pathology course, and looking through the microscope I kind of saw medicine come alive.  I realised that by looking through the microscope, looking at tissues, you could really understand what was happening to the patient. Seeing patho-physiology unveiled beneath themicroscope really made medicine exciting to me -- I wanted to understand disease and what caused disease, and how these changes occurred in the patient.  

I had great mentorsAnd I had great mentors.  There were two residents at the time who had our small group for pathology, and one, Dan Alonso, went on to become a dean of the medical school and the other, Janet Mouradian, went on to become head of surgical pathology at Cornell, so they were obviously both talented people.  They were great teachers and made pathology very exciting and interesting.  It certainly was not a 'dead' science in any sense.  I felt I learnt most of my medicine by studying pathology -- it was kind of the basis for everything.

SA:  And had you known about it when you came into medicine?

I was just very squeamish: I didn't like hurting peopleEJ:  No I really had no idea what pathologists did until my second year.  And then when I started the clinical rotations I realised that I didn't like patient contact.  I was just very squeamish: I didn't like hurting people, so when I had to go draw blood I was terrible at it!  I think you have to divorce yourself from the patient in order to be effective -- you just have to go in there with that needle and stab them and pretend like it's an orange, and I had great trouble doing that!  I remember there was one older woman when I was a third year medical student and I would go on these blood rounds.  (In those days they didn't have blood-drawing technicians, the medical students did all of that, so at five thirty or six in the morning you made the rounds and drew the bloods for the day.)  Every time I would walk into this woman's room she would say, "Oh no, not you again!" [We both laugh].  So I realised that patient contact was not what turned me on, not what excited me, that I was really more interested in understanding the disease apart from the patient.

SA:  So was it a bit of a crisis to find that you were squeamish with patients, or had you already discovered there were other paths you could take in medicine?

I never had this Florence Nightingale fantasy of healing the sickEJ:  You know, I think what drew me to medicine was really interest in disease, in biology -- I never had this Florence Nightingale fantasy of healing the sick.  I mean I didn't go into medicine because I could help humanity; I went into it because I thought it was interesting to study.  So it was not at all a crisis for me to say, "Let somebody else do that, I'm going to stick with understanding disease".

SA:  So having decided you wanted to do pathology, what was then your path?

EJ:  Actually, during my fourth year at medical school my first child was born.  I'd got married after my second year.  My husband was a law student at Columbia Law School, which was across town from Cornell, so we met in New York City.  After he finished law school he accepted a clerkship with a Federal Judge in the Federal District Court in Philadelphia, so I applied for a transfer from Cornell to the University of Pennsylvania, and that was very easy – it wasn't problematic to transfer at that time.  That was during the Vietnam War.  He was a clerk for a judge and the judge said, "I will get you a deferment for your first year, but your second year of clerkship I'm not going to ask for a deferment.  If you get drafted you'll have to go." So he thought about enlisting as an officer in the navy, because if you enlisted and you became an officer you could have a more protected post.  But it was at least a four-year commitment and he wasn't very happy about that.  And in those days you could still get what was called a '3A deferment' by having a child, and so we decided I'd get pregnant! [We both laugh]  Actually I got pregnant right away.  

There was a lot of uncertainty at that time…Nobody wanted to go to war. Our president and our vice president [ie George W Bush and Dick Cheney] managed to avoid it.  I mean, you know?  At the time you got your draft number, and my husband got a very bad number, so he knew that if he didn't do something he was going to get drafted. It was either enlist and become an officer and disappear for four years, or have a child, so I had the child!  And it actually worked out pretty well.  My son Greg (he's the journalist) was born in September of my fourth year, and the fourth year medical school in the US is a relatively easy year. You've finished most of your required rotations, so it's mostly electives, and I could tailor my electives to be not too demanding, not so much night calls.  

They hadn't quite figured out what to do with these womenAlthough it's interesting, actually, to come back to the women's issue -- at Penn they didn't have a place for women medical students to sleep; they had a call room for men, but there was no room for the women there, so on one of my rotations they just sent me home at night.  I think today people would be horrified by that -- in a way it was depriving us of certain aspects of our education  although back then I must say I didn't mind all that much!  Somebody else just had to cover for you.  It was just one rotation, but it was just sort of emblematic of the times – that they hadn't quite figured out what to do with these women.

So that was the fourth year.  I toyed with the idea of doing a regular internship because it seemed like you weren't really a doctor unless you did a regular rotating internship.  Then my husband said, "You're not going to leave me at home with this baby?!" I really wanted to do pathology, so I applied for pathology residencies.  My husband's originally from Texas.  He was going to be finishing his clerkship and so he applied for jobs in Texas and Washington DC. We decided we'd rather go to Washington (or I would rather go to Washington) than go to Texas, so he accepted a job with a firm in Washington and I applied for pathology residencies in Washington and got a place at Georgetown.


Woman in a man’s world: The National Cancer Institute

I actually went there for one year and while I was there I heard that there was a programme at the NCI [National Cancer Institute], which sounded like a very interesting programme.  It gave you more opportunity for research and academic pursuits, and so after one year I applied to the programme at the NCI and transferred  to the residency here.  I completed my residency here and then stayed on and did a haematopathology fellowship.  I was actually only the second woman to do a residency here – the first was Deborah Powell and she's had a very amazing career.  She was right before me, she finished and then I started the next year.

SA:  So it was just a world of men?

EJ:  Yeah!  And actually for the first year the chairman of the department called me Debbie constantly because he confused me with Debbie Powell.

SA:  In the academic sphere did you get on easily enough in the male world, or did you find it difficult?

EJ:  No.  No, I think people were very fair, and open and supportive.

SA:  There wasn't a glass ceiling?

If there are glass ceilings they're subtleEJ:  No. Well, I think if there are glass ceilings they're subtle.  They still may exist.  I mean, if you look at the NIH -- this comes up every year, we have a Retreat, and they talk about how many women branch chiefs there are, how many women principal investigators there are -- and it's changed very very little over the past 25 years.

SA:  And do you understand that?

But more women drop off the tenure track circuitEJ:  I think part of it is a subtle glass ceiling -- perhaps discrimination and hesitancy to see women in a leadership role.  And the other explanation they always use is that women want more balanced careers.  I mean, if you look at the number of post docs that come in, there are probably more women than men, but more women drop off the tenure track circuit.  (The way it works at NIH is you come in as a post doc or a fellow, and in order to become a principal investigator you have to go on tenure track.  You have seven years to get tenure, and if you don't get tenure you're out.  But if you take another route, as a staff clinician or a staff scientist, you can have a permanent job but you'll never really have independent resources.)  

SA:  And d'you think there's something in that – that women choose a different path because it gives them more flexibility with families, or…?

EJ:   [She considers] I mean I think that's probably true.  But actually I think more men are cognisant of lifestyle choices today than they used to be.  Parenting is much more of a shared responsibility in today's generation than it was in my generation, where it was clear that if somebody had to take the kids to the paediatrician, or go to the school, that was my job.

SA:  And it really was, was it?

EJ:  Yeah.

The case of the missing pancreas

SA:  Going back to your time at Georgetown, what sort of training was it in pathology there?

EJ:  It was anatomic pathology, so we did autopsies, we did surgical path.  Anatomic pathology primarily.

SA:  And how was that, when you say you were squeamish with patients?

EJ:   I wasn't squeamish about autopsies, no.  It's the idea of the patients feeling pain, rather than blood or gooey stuff, if you follow me.  I mean, I didn't really look forward to doing an autopsy.  You'd walk in and you'd see this body in front of you and the first cut or so was kind of distasteful.  But then I'd get interested in it and I'd sort of lose myself – I'd just become engaged in what I was doing and all distaste for the blood and the smells and other unpleasant aspects of the autopsy disappeared.  

Somehow I had not found the pancreas I can remember one autopsy I did -- one of the first, so I was a very junior resident.  It was a very complicated case; this patient had unexplained hypoglycaemia, and was suspected of having a tumour producing insulin.  There was widespread metastatic disease, and so the autopsy was technically very difficult and I was there for hours.  I finally finished and later I was going over the organs with the faculty (the body is gone by now) and somehow I had not found the pancreas -- which was a rather important organ not to miss in this patient.  [Laughs]  

SA:  And what did they say to you?

EJ:  They said, "How could you not find the pancreas?!"  I felt absolutely awful.  I felt like I had failed, you know?  But I somehow got over it.  We still had evidence for this insulin-producing tumour, which was everywhere.  And you know, it may be that the pancreas was totally destroyed, probably very atrophic, and maybe replaced by tumour.  It wasn't as though there was a nice, beautiful pancreas just sitting there that I missed.  There may have been technical reasons why I had problems identifying it, but still I felt very badly about it.


A revolution in cancer therapy and immunology

SA:  When you joined the National Cancer Institute how did you decide what was most interesting to you and what you wanted to do in terms of research?

The world was really changingEJ:  I had no preconceived ideas before I came in.  I thought maybe renal pathology because it also seemed medically-orientated, but I started my rotations at a time when the world was really changing in terms of cancer therapy.  The first successful cancer therapies were being introduced.  [Vincent] DeVita had developed the MOPP chemotherapy regimen for Hodgkin's disease, and for the first time patients with this disease were being cured.  So there was a great deal of excitement about the possibility of a cure for LymphomaCancer originating in lymphoid tissue, a key component of the body’s immune system.  Cancers of lymphocytes (lymphomas) and other white cells in the blood (leukaemia) together account for about 6.5% of all cancers..

SA:  What was the management of these cancers before that?

EJ:  Well there was radiation, which was started by Vera Peters, actually – she was one of the pioneering radiotherapists in Toronto who introduced some of the early radiation therapy for Hodgkin's.  But that was only suitable for patients with localised disease.  For patients with advanced stage disease -- stage III or VI disease -- there was not much you could do.  

But now for the first time patients with Hodgkin's disease were being cured.  There was a great deal of excitement about therapeutic options and so there was a big programme in lymphomas at the NCI.  In addition it was the era when they first began curing children with acute lymphoblastic LeukaemiaCancer of the white blood cells, which are a vital component of the immune system (see also lymphoma)., so there were acute lymphoblastic leukaemia protocols in the paediatric oncology group and those patients were being cured and there were long-standing remissions.

SA:  So this was the beginning of chemotherapy, was it?

People were just starting to understand the normal immune systemEJ:  Right.  And at the same time people were just starting to understand the normal immune system, and to recognise that there were T cells and B cells, and that you could distinguish between these cells.  I'd have to go back and review the exact date, but it was in the '60s that the recognition of these various cell types happened.  

SA:  What had they known about the immune system before?

EJ:  Well, they knew about immunoglubulins [antibodies], and they knew that there were cells that made immunoglobulins.  Some of the very early experiments were done on chickens, where they would remove the bursa of Fabricius, and the chickens would have defective immune function -- they couldn't make immunoglobulins.  T cells got their name from the thymus, and they knew that if you were born without a thymus, for example, that you had defective function in certain components of the immune system, mainly cellular immunity.  And so those lymphocytes became known as T cells.  

SA:  Where is the bursa of Fabricius?

EJ:  It's off the GI [gastro-intestinal] tract -- humans don't have one.

SA:  So where do we make our B cells?

EJ:  We make our B cells in the bone marrow and, during fetal life, in the liver.  So during fetal life the liver is probably the bursa equivalent.

SA:  And are the T cells really the 'masters of the orchestra'?

EJ:  I'd say they both work very closely.  I mean, T cells regulate B cell function.  Both are important.

So, B cells came from 'bursa' and T cells came from 'thymus', but there was no way to identify those cells in tissues [ie you couldn't distinguish between them under the microscope].  About the same time they were showing that there were certain receptors that were expressed on the surface of lymphocytes, and T cells had what was called the 'sheep erythrocyte receptor', in which the lymphocyte could bind sheep red blood cell in the cold.  It really wasn't known what the structure of this receptor was.  We now know it's an AntigenAny foreign substance or organism that stimulates the body's immune system to produce antibodies and cells that react specifically with it. called CD2, but at the time it was just kind of phenomenological – it just happened.  And then it was shown that B cells had a receptor for 'complement', and so if you took a red cell and you coated it with AntibodyA protein produced by the body's immune system that recognises and attacks foreign substances. and complement, the B cells bound it.

SA:  What is complement ?

EJ:  Complement is a mediator in the blood that helps lyse [or bind] cells as part of an immune reaction. So if you want to destroy a cell, eliminated or destroy bacteria, you need complement to destroy it, to lyse it.

There was no way of identifying this in tissues But there was no way of identifying this in tissues [ie none of this detail could be seen down a microscope].  I started working with some immunologists – Ira Green, Michael Frank – and tried to apply these techniques [ie identifying the different receptors on the surfaces of the cells] to tissues.  We took frozen sections of lymph nodes and I took these sheep red blood cells…

SA:  Why sheep?

EJ:  Well that had been shown… Sheep red blood cell bound the T cell, so that was known already.  It was the only technique available for identifying T cells in those days; it was the one marker that you could show on T cells.  How somebody discovered it, I don't know.  What caused someone to put sheep red blood cells with lymphocytes and see that they stuck…?  Anyway, I took frozen sections of lymph nodes and spread sheep red blood cell on in the cold (because we knew this phenomenon required cold for the binding to occur) and then washed off the excess red blood cells and looked through a microscope.  And low and behold, in the T cell areas there were all these red cells stuck on.

SA:  So that was the only way you could find them -- by association, as opposed to being able to see them direct?

EJ:  Right.  I mean, if you looked through the microscope you wouldn't know what was a T cell and what was a B cell.  

The classification of these cancers was very primitiveAnd then we took red blood cells coated with AntibodyA protein produced by the body's immune system that recognises and attacks foreign substances. and complement (that was known as EAC), and showed that, low and behold, these stuck to what we thought were the B cell areas.  (We knew where normal B cells were in a normal node, and that this stuck to the B cell areas.)  So then we thought, "Well this is really exciting.  Maybe we can use this to understand lymphomas, and understand where lymphomas come from."  At the time nobody knew what the cells of origin were of LymphomaCancer originating in lymphoid tissue, a key component of the body’s immune system.  Cancers of lymphocytes (lymphomas) and other white cells in the blood (leukaemia) together account for about 6.5% of all cancers.s.  I mean the classification of these cancers was very primitive: there was lymphosarcoma, reticulum cell sarcoma, Hodgkin's disease…

Anyway, there was a type of lymphoma that at the time was called nodular lymphoma, because the cells formed these 'nodules'.  I knew that normal follicles had these complement receptors, so we thought, "Well, maybe we could prove that this lymphoma is derived from follicle centre cells, from follicular B cells".  And low and behold, we found that the red cells [coated with EAC] stuck to these B cells, proving that these were lymphocytes derived from the lymphoid follicles.  (The lymphoid follicle is sort of the main B cell compartment of the lymph node).

SA:  So that then became the focus of your research?

A pioneering discovery EJ:  Right.  The article on follicular lymphoma was published in 1974 -- it was actually the lead article in the New England Journal of Medicine and became a 'citation classic '.  Citation classics are articles that have been cited a certain number of times.  It was really, I would say, a pioneering discovery at the time.  

SA:  And was it just serendipitous that you were there at that point?

EJ:  Well, I mean, yeah, you know I was in the right place at the right time in that the immunologists were beginning to understand immunology and beginning to develop the tools to study lymphoid cells and there was more interest in knowledge about the lymphomas, and so it was just serendipitous to some extent…

SA:…but you were asking the right questions too?

EJ:  Yeah.

SA:  This technique – what is the technology called that you were using?

EJ:  It's no longer used because today we have much better techniques, but it was called the 'rosette technique', because we knew the lymphocytes formed these little 'rosettes'. We used this technique for a number of years and published a number of papers.  Then the next advance was the development of Monoclonal antibodyAn antibody produced in the laboratory from a single clone of cells, which is therefore a single, pure, homogeneous type of antibody that recognises only a single, specific antigen, or protein. , which were a discovery of Milstein, Kohler and Jerne, who received the Nobel Prize for that discovery.

SA:  Can you describe for the general reader what monoclonal antibodies are?

EJ:  Well, in the old days you would have an AntigenAny foreign substance or organism that stimulates the body's immune system to produce antibodies and cells that react specifically with it. , and you would isolate your antigen and then inoculate a rabbit with it, and the rabbit would make antibodies to that antigen, recognising it as a foreign substance.  Then you would take serum from the rabbit, from the blood, and you would purify the antigen and then use it to label whatever it was you were trying to identify.  But if the rabbit died you were out of luck – you had to start all over again.  And of course whatever you produced was of limited quantity, so you couldn't share it with everybody else in the world.  You had it, and you could maybe give it to a couple of other people, but it couldn't be universally employed by people who wanted to study that antigen.  

So Monoclonal antibodyAn antibody produced in the laboratory from a single clone of cells, which is therefore a single, pure, homogeneous type of antibody that recognises only a single, specific antigen, or protein. were a new technique in which you took that antigen and you inoculated a mouse with it.  Then you took the mouse spleen, and in that mouse spleen there were B cells making antibodies to that antigen.  And then you fused those B cells with a cell line -- a myeloma cell line, so a cell line derived from malignant plasma cells -- and this fusion was created in which, by screening, you could find some of the malignant plasma cells that were now making the AntibodyA protein produced by the body's immune system that recognises and attacks foreign substances. that you wanted.  And so you had a malignant cell line that was a permanent factory for that antibody.  As long as you kept those cells in culture, which you could do indefinitely, you could isolate the immunoglobulin product [the antibodies] of those plasma cells, and then you had a very pure and specific 'monoclonal' antibody that recognised exactly your epitope of interest.

Antigens are complexAnother difference [from the rabbit technique] is …Antigens are complex.  In other words, if you get exposed to bacteria or a virus, you're going to make multiple antibodies to that [infectious agent], because there are multiple AntigenAny foreign substance or organism that stimulates the body's immune system to produce antibodies and cells that react specifically with it. s exposed.  So when you make a rabbit antiserum, it's recognising all those different antigens; it's not recognising just one what we call 'epitope' (the antigen binding site.)  So in your body you have thousands and millions of B cells, and each one is recognising distinct epitopes.  With the monoclonal antibody you have a single B cell that's recognising a very particular epitope.  So not only do you have this permanent factory, but you also have great specificity.

The next step was that people began to apply these monoclonal antibodies to tissue sections, so they developed staining techniques.  (I can't claim any credit for inventing those techniques.)  The first monoclonal antibodies were applied to frozen sections, because everybody believed that in frozen sections the epitopes would be better preserved than in fixed material where it's been processed through formalin and then paraffin.  But it was discovered that, actually, a lot of these epitopes are preserved in formalin-fixed tissue, and the advantage of that is: 1) you don't need to keep frozen tissue around forever; 2) you have much better Morphology (1) The form and structure of an organism or part of an organism.  (2) The study of the form and structure of organisms. .  In other words, you can visualise the cells much better, because frozen sections distort the appearance of cells, so you have a harder time figuring out which cells are labelling.  Now there are more than 300 monoclonal antibodies that are directed against particular epitopes on lymphocytes and all the other cells of the immune system.


Cancers of the immune system

Receiving an honarary degree from University of BarcelonaSA:  So once you'd got these tools, what were you able to do to advance the understanding of lymphomas?

EJ:  Well, we quickly discovered that there were LymphomaCancer originating in lymphoid tissue, a key component of the body’s immune system.  Cancers of lymphocytes (lymphomas) and other white cells in the blood (leukaemia) together account for about 6.5% of all cancers.s derived from B cells and there were lymphomas derived from T cells, and that these were very different -- and that even within the B cell system there were different sub-compartments.  So there was a disease that had been known as lymphocytic lymphoma of intermediate differentiation, and this disease had that name because lymphomas that were derived from cells that looked like normal lymphocytes were called 'well-differentiated' – they looked like their normal counterpart.  And then there were lymphomas that didn't look very much like normal lymphocytes – the cells looked abnormal – and those were called 'poorly-differentiated'.  And then there was this group of lymphomas that were called 'intermediately differentiated' because they were sort of in between.  Nobody had any idea of what they were, and we actually showed that these lymphomas were composed…[she shows me a diagram].  So if this is a normal follicle, this part is called the germinal centre and this part is called the mantle, and we showed that the lymphocytes of this lymphoma that people called 'intermediate' were actually derived from lymphocytes of the mantle, or follicular lymphoid cuff.  

And what was remarkable was that in lymph nodes that were partially involved, the lymphocytes homed in on this area -- they selectively involved this compartment of the immune system.  So not only did these lymphocytes retain the markers of their normal counterparts, but they knew where to go – they went back to that component of the immune system.  So it began to emerge that lymphocytes of lymphomas, although they're malignant, in many instances they retain both the markers of their normal counterparts and also the other properties in terms of homing to certain components of the immune system.  I mean, that article up there [she indicates a framed picture on the wall], which was on the cover of Blood, showed that in follicular lymphoma the neoplastic cells [ie the cancerous cells] home in to the germinal centre.  So although they may circulate throughout the body, they know exactly where to go, and they go back to the germinal centre.  

So the focus of our work continued to be to try to understand how all the lymphomas related to the normal immune system, and what phenotypic and functional properties were retained.

SA:  And so what, in the end, made these cells malignant?  Just that they didn't know when to stop, basically?

BCL2 is a gene which immortalises cellsEJ:  Well, one, they're monoclonal, so it starts with a single cell and they continue to produce their progeny.  We now know that there are particular molecular abnormalities associated with many LymphomaCancer originating in lymphoid tissue, a key component of the body’s immune system.  Cancers of lymphocytes (lymphomas) and other white cells in the blood (leukaemia) together account for about 6.5% of all cancers.s – translocations that involve the genes.  Follicular lymphoma is characterised by a BCL2-JH translocation -- and actually I was co-author of the first paper that showed that.  JH refers to the joining region of the heavy chain gene, which is part of the immunoglobulin gene -- and making immunoglobulins is heart and soul of what a B cell does.  BCL2 is a gene which immortalises cells, it prevents apoptosis. In the germinal centre cells undergo apoptosis.  

So, let's say you are exposed to an AntigenAny foreign substance or organism that stimulates the body's immune system to produce antibodies and cells that react specifically with it. , what happens is that the germinal centre responds by making lots of B cells; the B cells that are making the right antibody --sort of the lock-and-key approach -- those cells are saved and they continue to proliferate and you have an immune response.  But the cells that are making the wrong AntibodyA protein produced by the body's immune system that recognises and attacks foreign substances. undergo apoptosis, they are killed off by the body.

SA: And the B cells making the right antibody go on living as long as the antigen is around?

That's the principle of vaccinationEJ:  Well, once you've made enough antibody you have 'memory' B cells that will stay there forever.  I mean that's the principle of vaccination.  With tetanus vaccination, for example, your B cells make antibodies, and those antibodies stay around for a very long time.  You can get a 'booster', and when you get a booster your memory B cells wake up and say, "Oh, I remember that antigen" and they start making more antibody.

So, in the germinal centre we want to select for those cells that are making the right antibody and get rid of those that are making the wrong antibody.  And what happens is that BCL2 prevents cell death, prevents apoptosis, and so it immortalises those B cells, and that leads to the lymphoma.

SA:  So when you started to look this closely at the picture did you discover that there were very many more variations in lymphomas than had been recognised?

“Lymphoma politics”: a confusion of classifications

EJ:  Right. So what started out originally as lymphosarcoma, reticulum cell SarcomaA type of cancer that forms in the connective or supportive tissues of the body such as muscle, bone and fatty tissue. Sarcomas account for less than 1% of cancers., Hodgkin's disease, now is probably more than 60 subtypes of lymphoma.  Actually, this is where some of the LymphomaCancer originating in lymphoid tissue, a key component of the body’s immune system.  Cancers of lymphocytes (lymphomas) and other white cells in the blood (leukaemia) together account for about 6.5% of all cancers. politics comes in, if you will.

SA:  Give me some of the lymphoma politics!

{audio}/mp3/Elaine Jaffe_clip2.mp3{/audio}

EJ:  Okay. Way back in about 1966, a pathologist by the name of Henry Rappaport published a classification of lymphomas called the "Rappaport Classification" and he described lymphomas according to how they looked under the microscope.  So they were nodular, or they were diffuse; they were big cells and little cells.  The big cells he called histiocytes because he thought they might be histiocytes, or scavenger cells.  This was a very primitive way to look at lymphomas, and it turned out to be wrong in a number of respects.  Then when these immunologic studies started to be done, some pathologists began to embrace them, as we did.  Karl Lennert in Germany, at the time, published what became known as the Kiel Classification of Lymphomas, (he worked in Kiel).  It became very political and there was sort of a proliferation of classifications.  Each expert wanted to have his own classification out there, so you had the Rappaport Classification; you had Lennert's; you had Dorfman; there was one from a British lymphoma investigation group; there was another one from the World Health Organization.

SA:  But were they all not just advances on each other?

EJ:  No, they were conflicting!  And it was a very confusing time for clinicians, because everybody was using a different classification scheme.  You know, how could you compare your patients treated with your chemotherapy regimen at your hospital with a study being done in France or Germany, where the classification was totally different? You were comparing apples and oranges.  So it was a very politicised time, and there was a lot of fragmentation in the pathology community, among haematopathologists.  

The political divisions of the past dissipatedAnd yet there were those of us who were all sort of talking the same language.  Actually, back in 1991, Peter Isaacson held a meeting of what he proposed to call the International LymphomaCancer originating in lymphoid tissue, a key component of the body’s immune system.  Cancers of lymphocytes (lymphomas) and other white cells in the blood (leukaemia) together account for about 6.5% of all cancers. Study Group, the ILSG.  He invited to that first meeting about 15 haematopathologists from around the world – all of the people that he sort of regarded as experts.  There were several of us from the US, Germany and France, and one person from Hong Kong, and he brought us together for three days.  A number of these people I had never met before -- we were all strangers to one another, and we realised that we all spoke the same language and were all seeing the same things, and the political divisions of the past kind of dissipated.  

The most highly-cited article in all of clinical medicineWe published a couple of consensus papers – one on mantle cell lymphoma.  This tumour had been called centrocytic lymphoma in the Kiel Classification, and it had been called intermediate lymphocytic lymphoma in the US. We all agreed that this was the same thing and it should be called mantle cell lymphoma, so we published a consensus piece on that.  And then, as we discussed lymphomas more and more, we realised there was pretty good consensus on most items, so in 1994 we published something called the Real Classification, which was the revised European and American lymphoma classification.  That was published in Blood, and actually became the most highly-cited article in all of clinical medicine over the next ten years.

SA:  My goodness!  So the clinicians were just desperate for some clarification of all of this?

EJ:  Right.  

SA:  And how important was this for therapy – was it then easier to see what therapies went with what condition?

They were mixing apples and orangesEJ:  Yes.  Actually in the US the classification that had been used before the Real Classification was something called the 'working formulation', which was an attempt to come up with some common language.  And unfortunately what it did was lump a lot of LymphomaCancer originating in lymphoid tissue, a key component of the body’s immune system.  Cancers of lymphocytes (lymphomas) and other white cells in the blood (leukaemia) together account for about 6.5% of all cancers.s together, so there were those that they called 'low-grade' and those that they called 'intermediate grade' and those that they called 'high grade', but you had a hodge podge in each one of these categories – mixtures of T and B cells.  And they would treat all the low grade lymphomas the same; they would treat all the intermediate lymphomas the same; and they would treat all the high grade lymphomas the same.  Trouble was that they were mixing apples and oranges.  But as soon as the Real Classification came along, they began to see that these are really distinct disease entities – and that was the whole premise of the Real Classification.  

'Real' was sort of tongue-in-cheek, because what we proposed that we were doing was identifying real diseases, not tumours grouped together because of arbitrary criteria such as cell size or growth pattern. We tried to define each disease by: 1) its Morphology (1) The form and structure of an organism or part of an organism.  (2) The study of the form and structure of organisms. ; 2) its clinical features; 3) its immuno-phenotype, using all of these Monoclonal antibodyAn antibody produced in the laboratory from a single clone of cells, which is therefore a single, pure, homogeneous type of antibody that recognises only a single, specific antigen, or protein. ; and 4) its molecular genetic basis, because we believe that probably each disease entity is a pure molecular entity.  

Now, for some lymphomas we still don't know the molecular PathogenesisThe origin of a disease, and the chain of events leading to that disease..  We do for follicular lymphoma and some others, but not for all of them.  (We do now for mantle cell lymphoma, for example.) So we were defining individual disease entities and the clinicians really embraced this -- particularly the more enlightened ones, I would say.  I mean there were some who resisted, who said, "Oh, you're making it too complicated…You've got 25 different lymphomas, and no one can ever remember that."  But I think the more astute ones realised that this really made sense, and so it very quickly became accepted and then it was adopted by the World Health Organization and became the WHO Classification.

SA:  Before that, it sounds as though treatment had been a bit of a hit and miss affair.  Have things changed significantly since you sorted out the classification?

We now know that they're totally different diseasesEJ:  I'd say there is much more of an attempt for disease-specific therapy today, and targeted therapy.  For example, mantle cell lymphoma was composed of relatively small cells and in some centres it might be treated like chronic lymphocytic LeukaemiaCancer of the white blood cells, which are a vital component of the immune system (see also lymphoma)..  We now know that they're totally different diseases, and there are totally different therapeutic approaches.

SA:  So was the outcome of treatment before pretty bad?

It's improved the clinical approach to lymphomasEJ:  Well it was harder to tell which lymphomas were responding and which weren't.  You couldn't sort out which patients were responding to your therapy and which weren't because they were all lumped together.  Once you began to segregate out these diseases you could say, "Oh, this therapy works for this lymphoma, but doesn't work for this one.  Now we have to work on finding a better therapy for this one."  I think it's improved the clinical approach to lymphomas because we have a better understanding of what works and what doesn't, rather than treating them all the same and hoping for the best.

Peter Isaacson, who started the ILSG, for example, he promoted -- I guess it was back in the late '70s, early '80s -- the concept of mucosa-associated lymphoma, or MALT lymphoma.  (The first paper relevant to this topic is 1979.)  He showed that Helicobacter pylori, which is a common infection of the stomach, promoted the development of MALT lymphoma, and that in some patients, if you just treated them with antibiotics, the lymphoma went away.  In other words, the lymphoma was responding to the Helicobacter, and if you took away the stimulus -- if what was driving the lymphoma went away -- then the lymphoma went away.  So this really dramatically altered how many patients with MALT lymphoma are treated.

SA:  But that was ages back?

EJ:  Yeah, yeah.  But MALT lymphoma was not recognised as a distinct entity until 1994 in the Real Classification.  At least it wasn't included in a classification – people talked about MALT lymphoma but it didn't officially exist.  The two main classifications in use prior to 1994 were the Kiel Classification in Europe and the Working Formulation in the US, and neither one had a category of MALT lymphoma.  So it was recognised and yet it wasn't formally identified.  And there wasn't anybody treating it with antibiotics.


How lymphomas arise

SA:  And what about the PathogenesisThe origin of a disease, and the chain of events leading to that disease. of these things --- do you know what starts them off?

EJ:  Well for a lot of the lymphomas that have translocations it's believed that…I mean, your B cells have a vast repertoire of immunoglobulins and that allows you to have this huge repertoire of AntibodyA protein produced by the body's immune system that recognises and attacks foreign substances. responses.  The way this takes place is that, during B cell development, you rearrange your immunoglobulin genes.  There are different components of the immunoglobulin genes -- there's the 'V' region which is the variable region, the 'D' for diversity, and the 'J' for joining.  All of these segments get assembled in the B cell, and there are enzymes at that stage of DifferentiationThe process whereby an unspecialized early embryonic cell acquires the features of a specialized cell such as a heart, liver, or muscle cell. that cut up the DNA stands for deoxyribonucleic acid.  This is the material inside the nucleus of the cells of living organisms that carries genetic information (see also RNA).  and allow you to reassemble all these segments in order to make the antibody that you want to make.  

These two little bits of DNA get together by mistakeWell that, it turns out, is a somewhat risky event, because while your DNA is getting cut up and reassembled sometimes it reassembles incorrectly.  It's believed, for example, that the BCL2-JH translocation of follicular LymphomaCancer originating in lymphoid tissue, a key component of the body’s immune system.  Cancers of lymphocytes (lymphomas) and other white cells in the blood (leukaemia) together account for about 6.5% of all cancers. occurs during this immunoglobulin gene rearrangement process, where a J segment from the immunoglobulin heavy chain gene joins up [she shows me a diagram].  So this gene is normally on chromosome 14, and this gene is normally on chromosome 18, and it's believed that in a pre-B cell, when this rearrangement is taking place, these two little bits of DNA get together by mistake, and join together.  And there's a 'promoter' that turns on the immunoglobulin gene, allowing you to keep on making immunoglobulin, and that promoter then turns on this gene, BCL2, which you don't want turned on.  BCL2, if you remember, stops apoptosis, so what happens is that your cells start to make lots and lots of BCL2, and instead of dying off when they should, they just live forever.

So it's thought that, for many of the B cell LymphomaCancer originating in lymphoid tissue, a key component of the body’s immune system.  Cancers of lymphocytes (lymphomas) and other white cells in the blood (leukaemia) together account for about 6.5% of all cancers.s, it's mistakes in immunoglobulin gene rearrangement that leads to them.  

SA:  So they're quite specific translocations – things that go wrong – are they, when you really study the genetics?

The clue to understanding cancer is understanding its molecular basisEJ:  Right.  I mean, cancer is a genetic disease, and really the clue to understanding cancer is understanding its molecular basis. And for B cell lymphomas the molecular basis often involves problems in this immunoglobulin gene rearrangement which leads to translocations.

SA:  So before that, before you had all these genetic tools and so on, pathologists could only go by the Morphology (1) The form and structure of an organism or part of an organism.  (2) The study of the form and structure of organisms. and appearance of things?

EJ:  Right.  But I mean the key to finding the molecular basis is to know what the disease is, and so the first step is for the pathologist to define the disease very precisely so that you have a homogenous group of cases.  If all the B cell lymphomas are lumped together and you're trying to understand what the cause is, you're going to have a much harder time studying it because every lymphoma's going to be a little bit different.  I mean the pathologists defined mantle cell lymphoma as an entity before we knew what the molecular PathogenesisThe origin of a disease, and the chain of events leading to that disease. was.  And we did it from tissue, from looking at it, from both astute observation and also applying some of these immuno-phenotypic tools.  And the same thing with follicular lymphoma -- you know, using my primitive rosette techniques, I defined follicular lymphoma as an entity, so we knew that it was a homogenous group of cases.  

The pathologist plays a very critical roleAnd so when Carlo Croce discovered this new translocation in the cell line and he wanted to understand, "Well, is that associated with a particular type of lymphoma?", we could give him very well characterised lymphomas, and he was able to find out very quickly that it was in the follicular lymphomas, but wasn't in these others.  So I think the pathologist plays a very critical role in elucidating the molecular pathogenesis of lymphomas.

Another example of that is a disease called anaplastic large cell LymphomaCancer originating in lymphoid tissue, a key component of the body’s immune system.  Cancers of lymphocytes (lymphomas) and other white cells in the blood (leukaemia) together account for about 6.5% of all cancers., which has sort of funny morphologic properties – cells have a rather bizarre appearance and they tend to invade the sinuses -- and that disease was first recognised morphologically.  Then it was discovered that those cells strongly expressed an AntigenAny foreign substance or organism that stimulates the body's immune system to produce antibodies and cells that react specifically with it. called CD30 and so that led to better definition.  Then people began to study cells and cell lines and a translocation was discovered, NPM-ALK (ALK stands for anaplastic lymphoma kinase), and it was discovered that that translocation is specifically associated with that lymphoma.  Then David Mason made an AntibodyA protein produced by the body's immune system that recognises and attacks foreign substances. to ALK, so now every pathologist in every hospital in the country, or the world, can stain tissue sections with ALK and quickly see which ones express that ALK kinase and which ones don't.  

So it's sort of a cyclical, or iterative, phenomenon, which starts out with the Morphology (1) The form and structure of an organism or part of an organism.  (2) The study of the form and structure of organisms. , and that's a little bit messy: some things fit and some things may not fit.  And then you have a marker CD30 and that allows you to define the disease a little bit better.  And then you work out the molecular PathogenesisThe origin of a disease, and the chain of events leading to that disease., and then you can make an AntibodyA protein produced by the body's immune system that recognises and attacks foreign substances. to something that's specifically associated with the cause of that lymphoma.  And then you go back and what you discover is that some things you thought were anaplastic large cell lymphoma are not.  There are other things with big funny cells, but they don't have ALK.  And there are some things that you never would have thought were part of anaplastic large cell lymphoma that are – so-called 'small cell variant', because it's composed of small little cells.  They don't really look like what you originally thought was the disease.  

It starts off with the pathologist seeing something distinctiveSo understanding the molecular pathogenesis ultimately leads to a much better disease definition.  But it starts off with the pathologist seeing something distinctive, and then it evolves and ultimately comes full circle to where you redefine the entity.

SA:  So where do you, as a pathologist, fit in to this circle?  

EJ:  Well, at the beginning and the end.  At the beginning in terms of describing some of these diseases, and then at the end in taking some of the new tools that are available and kind of going through the LymphomaCancer originating in lymphoid tissue, a key component of the body’s immune system.  Cancers of lymphocytes (lymphomas) and other white cells in the blood (leukaemia) together account for about 6.5% of all cancers.{s again and saying, "Yes, well this fits and this doesn't."

Once you understand the molecular Pathogenesis{end-link}The origin of a disease, and the chain of events leading to that disease. and you have the appropriate tools, you go back to study the lymphomas and you become much better at the H and E level (a standard tissue stain); you recognise something as anaplastic large cell lymphoma at the H and E{end-link}This is a standard tissue stain that all pathologists and labs use.  They stand for the chemicals hematoxylin (H), and eosin (E). level that you never would have picked up on before.  So while we often still rely on all the special techniques to be certain, you can pick up a case and look at it and say, "I think this is anaplastic large cell lymphoma," because of what you have learned by earlier cases.  And you know, there are a huge number of Monoclonal antibody{end-link}An antibody produced in the laboratory from a single clone of cells, which is therefore a single, pure, homogeneous type of antibody that recognises only a single, specific antigen, or protein. today, and you don't want to study every case with every one -- that wouldn't be practical either in terms of time or cost.  You have to be clever enough to know what to think about at the H and E level also.
As pathologists we see the disease more in its entiretyI mean, as pathologists we see the disease more in its entirety -- in terms not only of its morphologic features or its molecular Pathogenesis{end-link}The origin of a disease, and the chain of events leading to that disease., but its clinical features also, and this is very important.  For example, T cell lymphoma, by and large, is a very poor prognosis.  But there is one T cell lymphoma that has a good prognosis, and that  is anaplastic large cell lymphoma.  So that's a disease you don't want to miss, because making the right diagnosis is important for the prognosis and therapy of that patient.

Worldwide consultation

SA:  Okay, you were saying that as well as research you do service work – tell me about your service work.

EJ:  NIH still has a large clinical research programme in lymphomas, so there are patients being treated here at the NIH and we review all of their biopsies for diagnosis.  Then I also receive a lot of cases for consultation – about 2,000 a year from all over the US and the rest of the world.

SA:  And you say you've noticed distinct geographical differences in epidemiology?

There are close genetic linkages between Asians and Native Americans EJ:  Right, well of course I'm not the only one to make this observation, but I think there are striking epidemiologic differences among different Lymphoma{end-link}Cancer originating in lymphoid tissue, a key component of the body’s immune system.  Cancers of lymphocytes (lymphomas) and other white cells in the blood (leukaemia) together account for about 6.5% of all cancers. types in different parts of the world.  For example, there's one disease we call nasal NK/T cell lymphoma.  It's associated with Epstein Barr virus, and there are very clear risk factors for the development of this lymphoma that are genetic.  This cancer was first described in Asia -- it's quite common in Japan, in Taiwan.  And we were actually the first to show that in the western hemisphere it occurs mainly in individuals of Native American origin -- so you find the same lymphoma in Native Americans in Mexico, in Peru, in Central and South America.  Historically the Native American peoples of the western hemisphere are thought to have migrated across the Aleutian land bridge, or by water.  So in fact there are close genetic linkages between Asians and Native Americans in the western hemisphere, and here's a lymphoma that they are both at risk to develop that is very rare in Caucasians or blacks.

SA:  That's fascinating isn't it?  And are you seeing other things like that?

EJ:  I think that's one of the most striking examples.  I mean there's another lymphoma called enteropathy- associated lymphoma that occurs in patients with coeliac disease. Coeliac disease is a genetic disease in which you're sensitive to Antigen{end-title}Any foreign substance or organism that stimulates the body's immune system to produce antibodies and cells that react specifically with it. s in wheat, so you can't eat wheat products.  If you do eat wheat products you get diarrhoea, although patients sometimes have very subtle symptoms.  And it's associated with a certain genetic predisposition, and that's a disease of northern European Caucasians, so there's a high incidence of it in UK, Ireland, Sweden, Norway.  It would be rather rare in Italy.  And that lymphoma again is seen only in those patients that develop coeliac disease.


Eureka moments

SA:  You've watched this whole field of lymphoma develop from early stages to very sophisticated stages – what has been the most exciting moment in this whole evolution of understanding? Looking back across your career what have been the real…

EJ:  Eureka moments? [Laughs] Well, I think the most exciting for me was that very early stage.  I mean, I was a fellow so I was just out of my training...It was really the first time that people saw these cells in tissue sections and knew what they were.  I think that was a very exciting period, and it really opened the door…I mean it showed what the possibilities were.  That was certainly an exciting period.

There were no limits The next was after the introduction of Monoclonal antibodyAn antibody produced in the laboratory from a single clone of cells, which is therefore a single, pure, homogeneous type of antibody that recognises only a single, specific antigen, or protein. , because then we had a wealth of tools that were available – there were no limits to what you could dissect out and the various sub-populations that you could discover.  As I said, a T cell and a B cell look the same, so before that you wouldn't know what was what.  I mean people vaguely knew that germinal centres were areas that were occupied by B cells, and that T cells were in what was called the para-cortex.  But if you looked at a peripheral blood smear and you looked at a thousand lymphocytes you didn't know which ones were T cells and which ones were B cells.  You know, we had a rough idea -- from these accidents of nature where patients are born without a thymus or have a form of immunodeficiency in which they can't make B cells -- we knew which general compartments were involved.  But in fact it's much more functionally complex, and so you could never dissect things out at the single cell level.

SA:  So how exciting do you find this whole thing today?

I still look forward to coming to work every day! EJ:  Oh I still enjoy it; I still look forward to coming to work every day!  I almost regret when I have to leave at night because I know there are things that I've left undone, and then I can't wait to get up in the morning to come in.

What it takes to be a good pathologist

I think another exciting aspect of being a pathologist is educating young pathologists  -- sitting across the microscope from them and helping them develop their skills, and then also helping them develop their careers.  I have a number of former fellows that have gone on to very distinguished careers and are associate professors and full professors at various institutions.

SA:  What makes a good pathologist and how do you recognise it in a student?

EJ:  Well I think that you have to be born with a certain visual aptitude.  I can tell the first month when I sit down with a resident whether they have got it or not.  Unfortunately I feel there are some people who may choose pathology not really knowing what it is, or not having tried it, that are not well suited to it.  Actually a colleague of mine told me that one question she always asks residency applicants is about their hobbies, and if they like art or photography in particular she feels they are more likely to be good pathologists than if they have other orientations.  My husband and I both like art actually; we buy a lot of art.  The only problem we have right now is we've run out of walls!

You just have to have a memory for those images So you do have to be very visual and you have to have a visual memory.  I mean there are some people who will look down the microscope day after day after day and never get it.  They just can't capture those images.  You just have to have a memory for those images – that's what pathologists do, they keep visual images in their minds.

Actually, I enjoy educating not only pathologists but clinicians, and helping them understand pathology -- and basic scientists, because I think basic scientists will do a better job if they understand the diseases.  Last year I won the distinguished clinical teacher award, which is the award given to the best teacher for all of the NIH.

Overbearing bureaucracy

SA:  Something we haven't covered is the red tape governing pathology – are you knotted up with rules and regulations about tissues and tissue storage in the same way that they are in the UK?

The rules now are so  restrictive EJ:  I think what's happened is very unfortunate, because the rules now are so  restrictive that if you followed them to the letter it would really harm medical research.  I mean technically…Let's say you have a new AntibodyA protein produced by the body's immune system that recognises and attacks foreign substances. and you want to study a hundred LymphomaCancer originating in lymphoid tissue, a key component of the body’s immune system.  Cancers of lymphocytes (lymphomas) and other white cells in the blood (leukaemia) together account for about 6.5% of all cancers.s and try and figure out what it stains, you technically can't go back to those biopsies and stain them without the patients' consent – even though you are not doing anything to the patient.  Technically what you have to do is either get the patients' consent or take all those specimens and anonymise them so that you don't know who they belong to, and then study them.  But of course if you anonymise them and you want to correlate them with clinical features – say you have a new antibody and it becomes a very important prognostic market in terms of identifying patients that will and won't respond – you need the clinical outcome data.  So it's useless to do it in an anonymised fashion.

SA:  When were these restrictions imposed?

Patient advocacy groups have I think missed the markEJ:  I don't know, probably in the last 10-15 years or so they've gotten really restrictive.  Patient advocacy groups have I think missed the mark.  Yes certainly patients should be informed, and there should be full informed consent for any clinical protocol.  But patients somehow have this fear that you're going to be doing studies on their tissues, or that you're going to discover something that will, you know…

SA:  So it's patient advocacy that has pushed this agenda is it?

EJ:  Yeah.  The IRB, which is the Institutional Review Board, can give you certain exemptions.  So if you write a protocol and you explain what you're going to do, they can say, "This is really of no risk to the patient; okay you can go ahead."  But it's kind of cumbersome to do that.  I think it just slows down the whole process, and in a lot of ways impedes it.

SA:  So are you sanguine about it or do you feel you are being strangled as medical researchers?

I think we are being strangledEJ:  I think we are being strangled.  I think that it’s gone too far.  I mean, one of the concerns… Patients were concerned about genetic studies.  In cancers there are somatic mutations that are acquired when the cell becomes malignant, and there are germ line changes that you're born with, and patients don't want you to study germ line changes.  And I can understand that -- they’re afraid about discrimination.  Let's say they're discovered to carry a gene that leads to increased risk of cancer, well, they worry that they may not be able to get insurance.  So I think certain protections are necessary.  But I think it's gone too far – the stipulation that you can't do anything with the patients' tissues without their consent.


Family life

SA:  So what about family life?  How many kids do you have and how did you manage with raising a family and a high powered career?

EJ:  I've two children, two boys, the first was born when I was in medical school, and the second one when I was a resident.  I didn’t work as long a day when the children were little.  I always tried to be home to make the kids dinner and spend time with them -- the old thing about 'quality time'!  You know, I think my children never felt that they suffered.  I was there for them when I was home.  And actually my younger son married a physician.  He's a lawyer like his dad and married a doctor like his mum, so it was obviously not a lifestyle that he found difficult!  I felt I managed it okay.  

I knew that I wouldn't be happy if I were home, and I didn't think that if I were home I'd be a very good parent.  I was concerned about childcare, and I always had someone come either to the home or live in so that the childcare arrangements were relatively stable.  Actually there's a woman who came to work with me when my younger son was in third grade and she sort of still works for me part time.  She's just had her 80th birthday!  My children are still very close to her; everyone attended her 80th birthday.  She was a great role model for them because she was a very dynamic person, a very good athlete, she taught both my boys how to ski – something I never could have done.

SA:  And who were your role models?

My mother was a role model in many waysEJ:  Actually I think my mother was a role model in many ways.  I mean, my mother always worked in my father's business, so she went to work every day.  We lived in the suburbs and she went to work in the city -- my parents left every morning for work together and came home in the evening.  So while it wasn't a traditional career of today, she was very much a working mother.

SA:  And who else has been an inspiration in your life?  Whose shoulders do you feel you're standing on?

EJ:  Well, I don't know….I think we've all had a lot of mentors.  My first mentor in haematopathology was Costan Berard, he was head of haematopathology when I started my residency and fellowship.  Actually I was his first fellow, and he kind of opened the door for me to develop my own career, and initiated some of the collaborations with immunologists that led to our work, so he certainly made it all possible for me. I would say he was a very good mentor in that when some of the early results came out and they were exciting he insisted that I go and present them.  So if there was a meeting I was the one to go and present – he didn't ever try to take credit for my work. I think there are some mentors who wouldn't have done that.

SA:  And going back to the family life question, what are your main interests outside of work?

EJ:  I'll tell you a funny story.  Back in the '70s when career women were more novel, there was a lawyer in my husband's office by the name of Cynthia Milligan.  Her father had been Secretary of Agriculture (Clifford M Hardin) under Nixon and she was a good friend with Julie Nixon Eisenhower, who at that time was one of the editors of the Saturday Evening Post. I don't know if you remember that magazine? Anyway, they were doing an article on career women.  They selected me for this article, and they interviewed me.  

At that time I had two small children, I had a busy job, and they asked me what do I do in my spare time? -- and I didn't have any spare time!  I mean I did like to cook, I liked to always come home and cook for the kids -- maybe it was sort of like being in a laboratory! And so I said, "Well, I enjoy gourmet cooking."  My family thought that was a great riot, because I was not a gourmet by any stretch of the imagination!  But I was innovative in the kitchen; I liked different tastes and different foods, so I would make Indian food or Italian food or Chinese or Japanese, and my children would say, "Oh that's mum's Italian crap," or "that's mum's Indian crap…"! [We both laugh]

The NIH Clinical Center – a unique research hospital

SA:  Okay, going back to the pathology -- we've talked about your research and the developments in the field of Lymphoma{end-title}Cancer originating in lymphoid tissue, a key component of the body’s immune system.  Cancers of lymphocytes (lymphomas) and other white cells in the blood (leukaemia) together account for about 6.5% of all cancers.{end-texte}lymphoma, but can you tell me a little bit about what happens at this hospital?  I understand the NIH hospital is different from other hospitals.

EJ:  Okay, so the National Institutes of Health existed as a research institute from the 1930s, and in the late 1940s they decided that it would be good to have a more clinically-orientated programme so they built this hospital here.  It's called the Clinical Center, and it is exclusively a research hospital, so the only way you can get admitted is to be admitted to a research protocol.  There's no emergency room, and you can't call up and make an appointment.  Our pathology department actually does the pathology for all the institutes – so cancer, heart lung and blood, allergy, infectious disease, immunodeficiency diseases.  The pathologists in our department, we really have to be good at everything.

I focus mostly on haematopathology, but that also covers lymphoma, auto-immune disease, immunodeficiency disorders – today, for example, I signed out a very interesting node from a patient, a woman with HHV-8 -related multi-centric Castleman's disease, and Kaposi's sarcoma.  Actually there's a disease that was discovered here that I was involved in called auto-immune lymphoproliferative syndrome.  This is a disease of children. They present at a very young age with massive lymphadenopathy – just huge lymph nodes in the neck, great big spleen – and they have mutations in a gene called FAS.  FAS is another gene that is important in apoptosis and allows you to kill off your lymphocytes normally.  These children have mutations in FAS and so their lymphocytes don't die when they should, and they get these very huge lymph nodes.  And then they get auto-immune disease, because the lymphocytes that should be killed off that are making damaging antibodies are not killed off.  They have what's called haemolytic anaemia, where they're making antibodies against their own red blood cells.  And then sometimes later they're getting lymphomas.  The disease was actually discovered here.  It was first recognised by Stephen Straus in the early '90s, and now we have studied more than 150 families, mostly from the US but also from Europe, with this condition.  

So the families are brought in…I mean, what we're trying to do is understand disease 'penetrance' also.  If you screen the whole family, there will be some members who have the mutation but have minimal clinical effects of it, and others who have the mutation and have severe effects, so there seems to be difference penetrance.  Penetrance is the frequency with which a gene manifests its effects.  So high penetrance means that everybody who has the mutation gets the disease; low penetrance means that you happen to have the mutation but clinically you're normal.

SA:  And what are you discovering about this particular disease?

EJ:  Well we actually don't know what affects the penetrance.  We know that males tend to be affected more than females.  But whether there are hormonal influences, and how that works entirely, we don't know.

SA:  So you're also involved in translating what you're learning into clinical practice?

EJ:  Yes, we work closely with the clinicians and I would say they're great people to work with -- they're very interested in the pathology and trying to understand the pathology, particularly because there are always 'strange' patients.  We published on something called ‘grey zone’ LymphomaCancer originating in lymphoid tissue, a key component of the body’s immune system.  Cancers of lymphocytes (lymphomas) and other white cells in the blood (leukaemia) together account for about 6.5% of all cancers., where we saw overlap between Hodgkin's disease on the one hand, and another type of large B cell lymphoma on the other hand.  There were overlapping features, and in fact in some cases we saw both diseases in the same patient.  They might start with Hodgkin's but then relapse with this large B cell lymphoma, and yet originally these diseases were thought of as being totally independent entities.  

They're actually different manifestationsWell, more recently, using gene expression profiling studies (which again we've been involved in, not in terms of hands-on but collaborating with people), it was shown that certain Hodgkin's lymphomas and certain of these large B cell lymphomas have the same gene expression profile.  So they're actually different manifestations, if you will, of the same disease, and this has led to a very different understanding of what Hodgkin's is.  So I think this is a very closely cooperating team, with the clinicians, the pathologists, the molecular biologists, the immunologists.

Questions of motivation

SA:  So how would you define yourself – what is most important to your identity?  Is being a pathologists or a researcher most important to your sense of yourself?

I think of myself more as being a pathologist than a researcherEJ:  Being a pathologist.  I mean I think of myself more as being a pathologist than a researcher.  For me discovering a disease under the microscope is very exciting and when I sit down to sign out, I'm excited when I see a difficult case.  Yes it's going to take me more time, but maybe I'll learn something.  

Actually yesterday I had a case that was sort of novel.  There was a patient… But let me go back to the beginning.    A few years ago, I received a case in consultation, (and actually it was the patient who requested that his case be sent here).  He was a young man, a good athlete, ran marathons, and he had some gastro-intestinal symptoms.  So they did a biopsy of his stomach and intestine, and they told him he had an NK cell lymphoma, and that this was a very aggressive lymphoma.  He said, "I don't think that's possible.  I feel too well.  I want another opinion."  So they sent him to the University of Nebraska, and the people in Nebraska said, "You have a very aggressive lymphoma, you need a bone marrow transplant."  But he still wasn't happy, so he did some research and found my name and asked them to send the slides to me.  So I looked at them and I said, "Well, you know there are these funny NK cells here, but I'm not sure this is really lymphoma."  There were some things that just didn't fit, so I said, "I don't know exactly what's causing this, but I'm not certain it's malignant."

Then he went to another gastroenterologist who worked him up further.  Meanwhile he's emailing me every day; I'm in constant touch with him.  The gastroenterologist discovered that [the patient] made antibodies to gliadin (a gluten protein found in wheat), which is one of the things associated with coeliac disease, (although he didn't have coeliac disease, so this was still funny).  And so they changed his diet, took him off wheat products, and a lot of these lesions in his intestine went away.  That was about four or five years ago, he never had chemotherapy, and he continues well to this day.  

He actually was very interested, he was very proactive, he said, "I want the world to know about my condition.  I don't want anybody else to be told that they have LymphomaCancer originating in lymphoid tissue, a key component of the body’s immune system.  Cancers of lymphocytes (lymphomas) and other white cells in the blood (leukaemia) together account for about 6.5% of all cancers. when they don't."  I mean, he could have been killed with a bone marrow transplant.  We actually wrote a case report about this unusual proliferation, and this was published.  And then yesterday I'm signing out and we get a case that they think is an NK cell lymphoma, and I look at it and I say, "This looks exactly like that case of the young man."  

That's what pathologists do so well you keep things in your mindI mean I think that's  what pathologists do so well – you keep things in your mind.  I sort of have a knack, I can see someone that I knew 30 years ago and I recognise them just like that.  I think we have very good visual memory.  So I look at that slide and I say, "I know what that is…"!  People joke with me here because we'll be signing out, and I'll look at a slide and say, "Oh that looks just like Mrs. Jones from 1978," and I'll run into my office and grab a slide and come in with it.  There are just these cases that stick in your mind.

SA:  So was this a completely new entity?

EJ:  Yeah.  This was the first and only case.  Then there was a second and a third -- we are now up to six cases, and I'm sure there are more out there.

SA:  What are the important things going on here now, as far as you're concerned?  What are the big questions you're still asking yourself?

EJ:  Well, I mean the first major paper that I published was on follicular lymphoma, and it's a disease that I've always been interested in.  It's one of the most common lymphomas, it accounts for about 40-50% of all non-Hodgkin's lymphomas.  (Actually my father-in-law died of it.)  But it's a very interesting disease because I think it's at the borderline between benign and malignant.  In many ways these cells still function as normal B cells, but they're immortalised.  And it's known that patients with follicular lymphoma have disease that waxes and wanes, so it seems to be responsive in some ways to the normal immune system.  And in some recent studies that we did with Louis Staudt looking at gene expression profiling, it was shown that, if you look at genes associated with immune response, the immune response profile within the tumour is probably the best predictor of prognosis.  

In other words, it's not the tumour cells so much that are affecting outcome, but the normal cells and the normal host response.  So now we're trying to study that host response.  In biopsies we're isolating the cells, and then we're trying to study their proteins and cytokines and chemokines, which are products of lymphoid cells, to try and understand better this immune response.  

SA:  So the suggestion would be that you treat the immune response as a way of getting at it…?

EJ:  Right.  That maybe you can capitalise on this by either promoting the immune response, or enhancing the immune response.  Or at least doing that in concert with chemotherapy – it may not be enough to cure it altogether, but you may be able to affect outcome if you understand better the immune response and can capitalise on it.

Cancer in the family

SA:  You say your father-in-law died of this disease – have you had any other family members affected by cancer?

EJ:  Actually my nephew, who's a journalist and now writing a book on cancer, when he was 15 he developed Hodgkin's disease.  He had very advanced stage disease, and actually came and was treated here at the NCI -- he lived here for six weeks while he was getting radiation therapy and chemotherapy.  And he was cured.  He was 15 at the time; now he is past 40.  He was born the year Kennedy was shot, so you can do the math.

SA:  And was it a very poor prognosis when he got it?

EJ:  Well you know, it was among the most aggressive stages of Hodgkin's, so he fell into a not very good prognostic category, and I think he was lucky to be treated by very good doctors.  

SA:  Did you do the pathology?

EJ:  Yes.

SA:  And how did you feel about that, so close to home?

EJ:  It’s awkward; it's difficult.  Actually his mother died of cancer also.  She had something called carcinoid syndrome.  My sister…She was diagnosed when I was a second year medical student and it was a very slowly progressive disease, but difficult for her.  She lived more than 25 years with her cancer, but it was very debilitating and she was very much an invalid towards the end of her life.  I think because of those experiences my nephew became very interested in cancer and wrote a cover story for Fortune magazine on why we're losing the war on cancer and how to win it.  And now he's writing a book sort of questioning how we go about cancer research, and is the money well spent?  There are things I agree with and certain things I disagree with.

Cancer is not one disease; it's many diseasesI think we are making great progress -- certainly for many tumours that were once fatal, we're curing them…testicular cancer, many LymphomaCancer originating in lymphoid tissue, a key component of the body’s immune system.  Cancers of lymphocytes (lymphomas) and other white cells in the blood (leukaemia) together account for about 6.5% of all cancers. s.  I think the promise of a magic bullet is not realistic.  Cancer is not one disease; it's many diseases, and the hope is that we will be able to develop molecularly-targeted therapy.  While there's been some progress in that direction -- like with chronic myelogenous leukaemia, where your drugs target the BCR/ABL product -- eventually patients become resistant, and the identification of drugs that can do that for many other types of cancers is slow in coming.

SA:  So your intimate relationship with these kind of life-threatening diseases, what has it done to your philosophy of life – your thoughts about life and death issues?

EJ:  I think I tend not to focus on it.  I mean obviously it's hard when you have a family member who becomes seriously ill – it brings it close to home.  And you see certain people who are stricken by very bad diseases in the prime of life, so to speak, and it's difficult.  But I guess I don't focus on it in my day to day work.


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