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Miguel Reyes-Múgica - Full Transcript

Miguel Reyes-MúgicaChief of Pathology and Head of Laboratories, Children’s Hospital, Pittsburgh; Professor of Pathology, and Marjory J Harmer Chair in Pediatric Pathology, University of Pittsburgh, USA*

 * At the time of this interview, Miguel Reyes-Múgica was Director of the Program in Pediatric and Developmental Pathology at the Yale School of Medicine

Interview location: Paediatric hospital in New Haven, Connecticut
Interview date: 24th November, 2007


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SECTION 1

SA:  Tell me about your background and how you came to be in medicine – did you come from a medical family?

MR:  Yes, both my father and my mother were doctors.  My father has died, but he practiced medicine for about 20 years and then went into law school, and became a lawyer, but never quit practicing medicine.

SA:  Why did he become a lawyer?

I saw my first C-section (caesarean) when I was about 11MR:  He wanted to become a criminologist and he wanted to bring together the fields of pharmacology and law, in particular drug addiction.  My mother was a director of a hospital in a very small town in Mexico and I saw my first C-section (caesarean) when I was about 11.  I saw a few other procedures too, and I learnt how to examine patients with my father who used to go to home visits.  He would ask the mothers of little children that he was seeing if they didn’t mind if I would listen to their hearts or look into their ears – whatever he was looking at.  And mothers would say, “No, doctor, please go ahead.” From the age of about 11, 12, I started to go with him to visit homes, and palpate and ausculate and even help in some minor surgical procedures.  And when there were accidents in that small town, I would be attending some dressings and things of injured people, because there were not sufficient doctors and nurse and other people.

SA:  And was this because you showed a particular interest or aptitude or were your parents grooming you to become a doctor?

MR:  I really think it was a combination of the opportunity, the liking that I had for what they did, and the lack of resources around.  And I was also very close to them – particularly to my father.  He was more of a friend, a classmate at times.  My friends were closer to him than to many other people.

SA:  And could you talk to him about life and death issues – I mean was he a philosophical man?

MR:  Very much.  Yes, he was a well-read man and although not very religious we would speak about life, death and things.  And when he saw that I was going into medicine he helped me to discover my own path.  I thought I was going to go into internal medicine -- he was pretty much like an internist, although at that time there were no structured programmes of specialisation in Mexico.  So he was a generalist, but one of those very knowledgeable generalists who would take on any kind of case.  My mother was more surgically-oriented, so they would complement each other.

SA:  What was the name of the little town where the hospital was?

MR:  This was San Cristóbal de Las Casas in Chiapas, right where the Zapatista Revolution started in 1990.  My mother saw the whole thing develop there.  I grew up from 10-15 years of age in that small town, although I was born in Mexico City.

SA:  Your father died when?


MR:  He was relatively young, at 63.  That was 20 years ago.  I was a doctor; I was already a pathologist, very young, when he died.  Well, he saw me starting to climb the ladder of academic medicine in pathology in Mexico.

SA:  So when you went into medicine did you think you were going to follow the same sort of path as your dad – be someone who went out on home visits and that sort of thing -- or did you always want to be on the academic side?

MR:  No, I wanted to be a doctor like him and my mother.  I wanted to follow the attitude to help people, to attend sick people.  I wasn’t very much in contact with academic medicine, as I know it now.  And I never thought that I was going to be a pathologist. I never really knew what a pathologist did, or what was the trade of pathology in medicine.  I was familiar with the general idea of pathology very early because I started studying, but I wasn’t inclined to pathology.

A very unequal society

SA:  So going back to your childhood, with your father and mother working locally, what sort of social environment was it, and what sort of cases did you see, as a kid, in people’s homes?

MR:  Well, we certainly were a very privileged family in a small town where the social layers were very well demarcated.  There are many indigenous people around that town, and the relationship between the more Spanish-looking people and the indigenous natives has never been easy.  But my mother and father would see patients from all strata – from the highly developed and rich people, the well-off, to very poor people that could not pay.  Frequently, you know, the payments were in the form of a chicken, a bag of eggs, fruits or things like that.

SA: And what did that do to you politically?  Did you have a social conscience, was that how you were brought up?

It was not a very easy thing to see and to live withMR:  My father labeled me as a communist when I was about 11!  I had not read anything about communism, but I guess I had a little social conscience when I saw the differences in the standards of living in the different layers of the town where I was growing up -- seeing these people who could not pay, might even die because they couldn’t afford treatments.  It was not a very easy thing to see and to live with.

SA:  Did you follow a very clear path, or did you have a period of rebellion from your family background?


MR:  I was expelled from my high school for riding a horse and motorcycles inside the school, and rebelling.  This was a priest-run school, a Catholic school. I was about 15 and I wasn’t really very happy with the school, so I started doing things.  I was always a very good student except that year that I was expelled: I never attended classes; I failed four subjects; I started behaving as a typical teenager.  Finally I was thrown out and my father put me to work with my grandparents (his parents), who ran some butcheries in the local market.  So I had to drive (I started driving very young, at the age of 15)… I drove my grandmother to the slaughterhouse.  I used to go with my grandfather to buy cattle, and we would slaughter them. 

My first contact with cutting and looking at flesh was thereIt was a very primitive slaughter house.  It was not… Well you can imagine, not a very technically developed thing.  It was a matter of dealing with the cowboys there, and pulling an animal into the slaughterhouse with ropes and all kinds of force, tying the animal up, cutting the jugular vein, ex-sanguinating the animal, and then doing a complete “autopsy”.  (Maybe the word ‘necropsy’ or ‘postmortem exam’ would be more appropriate; ‘autopsy’ can be used only for human postmortem exams).  So my first contact with cutting and looking at flesh really was there.

SA:  You say ‘autopsy’, but surely butchery is a lot different?

MR:  Oh absolutely different.  But it was an animal -- it was muscle, it was viscera, it was handling a knife, it was knowing the different types of tissues from a macroscopic (a naked eye) perspective, and recognising when something is not exactly the way you expect it to be.  In retrospect I recognise that experience as a very important influence on my personal development in terms of pathology.  And I can tell you that when I cut an organ, not only in autopsy but also in surgical pathology (which is, by the way, what we do most of the time – we are not ‘death doctors’), the residents usually express some surprise to see the way I handle the knife, because I handle the knife differently.

SA:  Do you?


MR:  Yes!  [We laugh]

SA:  And you then have to tell them, “Well, I learnt on cattle”!


I am a very neat pathologistMR:  Yeah, exactly!  I tell them the story, and they are surprised because even though I am a paediatric pathologist and usually handle smaller organs, I use a longer knife, and I can cut very thin slices without injuring or cutting myself.  I can produce clean sections.  I work very neatly.  I don’t like blood.  I clean up after myself.  So I am a very neat pathologist when I am working in the lab with organs.

SA: So when you first started working in the butchery, and your father had put you there, was it a shock to you?

MR:  It was a big adventure, and I was never shocked.  I’m shocked now that I wasn’t shocked!  Because, looking back, it was really, you know, somewhat gruesome to see all this blood, and people get scared at those things.  But it came naturally to me and I blended in, maybe because I used to see my grandparents in the butchery when I visited them; it was part of my childhood.

SA:  And how did you graduate from the butchery – how did you not become a master butcher?!


MR:  Well I had to go back to school.  So my father and I made a deal and I left the small town and went back to where I was born and spent the first 10 years of my life -- to Mexico City, where I entered a military school.  Between a Catholic school and a military school there are significant differences and also significant similarities.  And I spent a year there, fighting my way out of little troubles every day.

SA:  You were a troublesome kid, were you?


MR:  Well I wasn’t at that time, but in a military school when you are a novel element, you are the target of a lot of abuse, and I have never tolerated abuse very well, so I fought with my fists frequently and learnt how to defend myself.  After a year I left that school and went to a more normal high school, and then I entered medical school.

SA:  So what was so singular about military school?

MR:  Discipline; I learnt discipline.  I learnt never to skip a day without a shower and be always clean and neat -- organized and disciplined, essentially.  It was a useful exercise in many ways.  For a youngster from a relatively privileged family, who had been expelled from school because he had been misbehaving but who was relatively intelligent and able, it was a good moment to realise that things can get really tough and if you want to make it you really need to discipline yourself.

SA:  So do you think your father knew what he was doing, sending you to that place?


MR:   Absolutely.  That’s what I needed.

SECTION 2

Training to be a doctor

SA: And so you got into medical school, and where were you heading?

I had to earn a living as wellMR:  Well things happened very fast in my life.  First I got married, aged 18.  That was not very well planned, I have to tell you, but I got married, and the same day that my first daughter was born I was accepted at medical school -- in the largest university on Earth, which is the National Autonomous University of Mexico.  The first day of class was very interesting, because I was the only one married with a child and the responsibility to feed a family.  I was very fortunate because I had four or five wonderful classmates, all of them very intelligent and very well-oriented, and I became part of this group that would get together to study.  I had much less time than they did because I had to earn a living as well.  So I used to work, the first year of my medical school, doing television.  I was the assistant to a producer of a TV programme on cultural matters.  I helped with interviewing people -- poets, writers, etc.  And I used to provide the bibliographical assistance, so I had to read a lot in addition to reading my medical school books.  It was fun, it was a lot of work, but you know, when you are young you can afford not to sleep a lot.

SA:  Did you find it interesting, or was it a huge strain doing all those things – being a young father, a medical student and also working?


MR:  I didn’t have much time to think about it.  I had to make some money.  My father gave me a place to live, but that was it.  I had a lot of support, but I had to make my own living and provide for my family and still study.  I didn’t feel it was that terrible, to be honest with you.  It was not that easy, but everyone has his own difficulties…

SA:  And you were still set on doing medicine, or did you sometimes think you might go into television instead?

That’s when I discovered histologyMR:  Well, television started to take second place pretty fast.  After the first year I realised I had to concentrate on medicine, so I looked for a position in the medical school as an assistant.  They opened a competition for people that had finished some first year courses to start teaching those courses to the following class.  So I took the competition and I won two places.  The competition was very tough because my class was tremendously big – you wouldn’t believe it, but it was about 5,000 students.  (When I tell you that the University of Mexico is the largest on Earth, I’m not exaggerating).  They selected the best 100 students and out of those six were selected to win positions to teach the course of histology – and that’s when I discovered histology, which is what we do.  Our pathology is based on histology to a large extent. 

Histology is the study of tissues, and usually it employs microscopes.  The first histologist was a Frenchman whose name was [Marie] Francois Bichat.  He never used a microscope but he described 20 different kinds of tissue just with his naked eye.  But then people started to use microscopes to define tissues…

SA:  So what year was Bichat?

Under the microscope, I discovered a different universe. The best way to learn something is to teach itMR:  In the 1700s, in France, so a very long time ago.  Before the use of microscopes became popular.  He never used a microscope.  But he was the ‘father of histology’, he described all these tissues.  When I discovered histology and I started looking under the microscope, I discovered a different universe.  And I started learning very fast, because I had to teach.  The best way to learn something is to teach it.

“The most important person in my academic life”

Those years were very, very important in my life, because I had such a need to make money, to move away from any distractions from medicine and to concentrate on my career, and I discovered that teaching something that was part of my own academic learning was the best combination possible.  So for several years I spent a lot of hours teaching histology.  In the mornings I would teach histology, and in the afternoons I would learn my own subjects in the medical school.  As an assistant teacher you had some privileges -- you could choose your schedule and you could put your name down for specific courses. 

Then I discovered several mentors, but one of them is the most important person in my academic life.  He is a pathologist, Dr Ruy Pérez-Tamayo, and you can see his picture there [he gestures to a row of framed photos on his shelf].  He was professor of pathology, and when I took that course in my second year of medical school I immediately knew that I was going to be a pathologist.  I wanted to be just like him, in many respects.

SA:  What was so special about him?

He has shaped the discipline of pathologyMR:  He’s still alive and he’s about 83.  He has shaped the discipline of pathology in Latin America, but also has made tremendous contributions to knowledge in certain areas of pathology in the world.  He was the professor at Harvard, at Yale, at Johns Hopkins, and at many other institutions, but he went back to Mexico and really developed a whole discipline of pathology – and modernised it.  He is still the most important pathologist that we have in the whole of Latin America.

SA:  You say that when you first looked down a microscope it was a different universe – what was the thrill?

I like to be challengedMR:  First it was the challenge.  Because the first time one of my lecturers told us, “Look at these cells on the screen” -- they used to project these slides, these kodachromes -- I couldn’t really understand all those little round things.  What were cells, what were nuclei?  I didn’t understand.  So it was a challenge, and I like to be challenged. There were a whole lot of things I didn’t know, and I wanted to know. 

Pathology is just ordinary life in abnormal conditionsThen I discovered that I had some ability to distinguish things under the microscope, and I liked that – the experience of recognising when you were looking at a piece of liver, or a piece of lung, or brain or whatever.  It was a very satisfying experience, and it gives you immediate gratification to be able to make the diagnosis of something under the microscope, be it normal as in histology, or abnormal as in pathology.  Pathology is just ordinary life in abnormal conditions, right?  So when you know your normal, you are able to recognise when something is not normal, therefore pathological.

SA:  Was there something more than just the intellectual challenge, was it a special world that you saw down there?

It is magnificently beautifulMR:  It was beautiful.  It is magnificently beautiful.  Images under the microscope are pretty; they are just very nice.  I still now can spend more time than I should just looking at something, normal or abnormal, under the microscope because of the beauty of it.

SA:  So Dr Pérez-Tamayo was your mentor at that time, and did he take you under his wing – were you a special student to him or did he treat everyone in the same way?

This was a completely different universe againMR:  Well, I took his course and he was aware of my presence relatively fast because I contributed opinions and questions and things.  Every year, at the end of the course, he used to select one student to go and visit his lab, and he invited me to go and work in his lab.  This was a completely different universe again.  Here it was not a matter of looking down the microscope, it was a matter of extracting proteins and doing all kind of these very strange things that scientists do in labs.  He worked in collagen, so I started having to learn how to extract collagen.  (Collagen is a protein, the most abundant protein in our bodies, and he was an expert on it).  So I started working with his group, extracting collagen and trying to identify an enzyme that would degrade collagen, to explore the biology of certain diseases such as liver cirrhosis and the like. 

I spent about a year and a half going to the lab and extracting collagen and learning with him and his wife, another mentor of mine, things that I never knew about – electrophoresis, protein extraction and things like that.

SA:  Were these fairly novel technologies at that stage?


MR:  At that stage it was the bread and butter …the equivalent of molecular biology nowadays.

SA:  So it was the precursor to the molecular biology techniques?


MR:  Right.

SA:  What sort of samples were you working on and what were you doing?

MR:  We would take pieces of skin -- could be human skin or animal skin.  We would degrade the skin or treat the skin with certain acids, and then we would put that into a concoction of sorts so that some proteins would be separated from others.  Subjecting that concoction to different temperatures or different acidities (ph) etc would produce different fluids that you would separate and, using membranes that are semi-permeable, you would divide things that contained more collagen or less collagen from other substrates.  Then you would centrifuge the samples in machines that spin them round at 80,000 rpm, and you would select the layer you would be interested in from the ultra-centrifugate, to reconstitute the collagen and run it through a gel that is charged with an electric field (that is electrophoresis), and you would separate the protein according to the ability to migrate. 

Never believe the first time you see somethingThe ability to migrate in that gel depends on the size of the molecule, the weight of the molecule, and that’s how you determine the weight of certain molecules.  So I learnt to do that kind of thing.  And in the process I learnt many other little lessons in science -- experimental design, and to be very sceptical, never to believe the first time you see something etc etc.

A special rapport with patients

SA:  So did you decide then that the academic side of things was beguiling to you rather than going into the patient-orientated field?

MR:  Well, yes, but I never gave up my intention of seeing patients, because as I mentioned, when I started with my father I discovered that I had some ability to relate to patients and to patients’ families, and I liked that experience.  Even now I sometimes go to the wards and examine patients myself when I have specific questions to answer. 

I never forget that behind everything that we do there is a patientBut pathology is not only research, it’s not only looking at microscopes and glass slides.  I never forget that behind everything that we do there is a patient, or group of patients.  So I am a doctor.  I consider myself a physician with a particular sub-speciality.  And even if you understand molecular issues, that doesn’t necessarily mean that you are removed from the medical perspective.  As a matter of fact, I think that if more physicians understood at the molecular level what they are doing we would be a lot better off.  But that’s not frequently the case.

SA:  This is a bit of a diversion, but in this country is it traditional and acceptable for the pathologist to have quite a bit of contact with patients and for patients to talk to the pathologist, or are you supposed to be at one remove -- the people who liaise with the clinicians?


MR:  Well, in the US pathologists interact with patients in certain situations.  Pathologists that are doing, for example, cytological analysis and fine-needle aspiration biopsies, they perform the procedures on the patients themselves.  I don’t do that kind of thing.  But when I suspect that a child has a particular syndrome, I will take my residents with me…

Let’s, for example, say that I see a tumour in a kidney, and in addition I see certain other things in the kidney that I think are related to a particular syndrome.  The syndrome that I’ll use as an example, because this has happened to me, is Beckwith-Wiedemann syndrome, described by Bruce Beckwith and Dr Wiedemann -- that’s Bruce Beckwith there, in the first picture [points at the row of framed photos on his bookshelf].  So when I feel that the patient may have Beckwith-Wiedemann syndrome, I will take my residents to the ward to see the patient and examine the patient.  Frequently that syndrome is missed because it doesn’t come to mind easily.  I have made the diagnosis of Beckwith-Wiedemann syndrome in both autopsy patients and living patients before it was suspected, and I like to do that.  So I go and I speak with the family or with the child, examine it.  And you know, it’s just fun to be in contact with patients.

Beckwith-Wiedemann syndrome is a relatively rare syndrome, but not as rare as we would think.  Bruce and I have had conversations about it and he tells me that sometimes he sees patients walking around that have never realised that they have the syndrome.  It’s a syndrome of over-growth, as you may know -- tissues tend to grow more than they should, for different reasons, and there are several genes that are involved.  But in the first 10 years of life it means that patients are predisposed to develop certain tumours, certain forms of cancer.  So it’s a ‘cancer disposition’ syndrome.  And the importance, in my practice, of detecting these early is that patients can be followed, and if a tumour is detected it can be treated before it spreads.  So that’s why, when I recognise in a one-year-old or two-year-old, something that looks like Beckwith-Wiedemann, I go and make the effort, and then the clinicians will be aware of the situation and will follow the patient for the next 10, 15 years until they have outgrown the syndrome.

SA:  Why is Bruce Beckwith up there on your shelf?


MR:  Because he’s my friend and I admire him.  He’s one of the best paediatric pathologists that we have ever had.  He’s now retired and he lives in a small town in Montana.  I am an editor-in-chief of a journal and he’s one of my best reviewers, part of my editorial board.  He helps me to review submissions to my journal, and we are in touch.

SA:  Isn’t Beckwith-Wiedemann one of those weird syndromes in which it matters whether the mutated gene is passed on from the mother or father?  And there’s another syndrome that is caused by the same mutated gene but from the other parents?

MR:  Yes.  This is called ‘imprinting’.  Genomic imprinting is a phenomenon that has to do with the fact that of the two copies that you have for each gene, normally one is silenced and the other one is active.  But in certain pathological situations, when the gene of the father is active and the gene of the mother is silenced, the clinical manifestations are different from when the gene of the mother is active and the gene of the father is silenced.  There are several other syndromes that are ‘reciprocal syndromes’, if you will, in terms of genetics, that are caused by genomic imprinting and have different clinical manifestations.

SA:  And are these only fairly recently understood?

MR:  We have begun to understand the biology of these conditions in the last 15 years.  But it takes a long time for a piece of information acquired in the basic science arena to make its way to the clinical arena.  To go back to the point I was telling you earlier, when you understand the molecular field of your practice you are much better prepared to serve.  And you have more fun!

SA:  That’s what you’ve found is it?

Intellectually it’s much more satisfyingMR:  Yes. Dr Pérez-Tamayo told me, “Listen, it doesn’t matter if you understand this disease or not, you will treat the patient the same.  But if you understand it you will have more fun, and that’s very important.”  And I believe that that’s true.  It is a thrill to understand, to really know every single piece of the chain that you are part of.  Okay, if you are just one piece of a large chain but you don’t understand the rest you may be very effective, but you are just like a machine, whereas if you understand all the pieces, intellectually it’s much more satisfying.

SECTION 3

SA:  Okay, so you went from working with Dr Pérez-Tamayo in his labs to what?  How did your career develop?

MR:  I continued my medical school studies.  I finished the four years of basic learning and then I did one year of practice, which is the internship, and then one year of social service, which is when you pay back to the society that has been generous enough to provide you with a free medical education – because my whole medical school cost me the equivalent of about $100.  That year I worked at the National Institute of Pediatrics, and I started doing the equivalent of the first year of a residency in pathology. 

And because I entered this huge hospital – it’s a 350-bed paediatric hospital in Mexico City, one of the largest in the whole of Latin America, and one of the busiest – I rapidly started to develop some knowledge about pathology, in particular paediatric pathology.  After my social service year I started my residence in pathology, and the director of the programme was again Dr Pérez-Tamayo, so I went back to him.  Then I moved from one hospital to another for a while, before I went to the General Hospital of Mexico, the largest in my country, where I finished my specialist training. 

The Mexican Earthquake of 1985

Then there was another significant event in my life, in all our lives: the big earthquake in Mexico City in 1985 where I lost… well, seven residents in my department were dead, including my roommate.  Together with other people, I pulled him from the rubble of the collapsed building.  Forty-nine residents just in my hospital were dead.  Many people died…

SA:  So where were you when it happened?

MR:  It happened at 7.19 am on the 19th September 1985.  I was kissing my son, my third child, and we both fell to the ground with the first shake.  But I was never very scared of earthquakes.  Mexico is an area with very high earthquakes activity, and my old memories were of seeing my father sitting on the bed looking at his watch and counting the number of seconds, and my mother praying.  I had had that experience many times and I was never very scared.  So, I got a little surprise that this one was very strong, but I was not scared. 

I was living with my three children -- I had separated from my wife, and I kept my children, I raised them.  So I asked the nanny to take my son to the kindergarten and I took my two daughters to school. (I used to drop them off around 7.30 am and then go to the hospital, which was very close.)  So I dropped them off at the school.  People were very scared, but there was no news yet of the magnitude.

SA:  And you couldn’t see the damage…?

There were 302 people killed in my hospital aloneMR:  I could see some people running along the streets and stuff.  But I didn’t see collapsed buildings.  Until I got to my hospital.  The residency building, the building where residents lived, was collapsed.  Then I began to realise the magnitude of the problem.  Two buildings within my hospital collapsed – one was the residency, the other was the gynaecology/obstetrics building where the nursery was.  There were 302 people killed in my hospital alone.  The official figures of people that died during that earthquake varied tremendously, between 8000 and 80,000.  Probably about 20,000 people died.  It was very bad…

I stayed there for about a week.  The army took over the hospital and the city in general, and we organised the groups to identify people pulled from the rubble, and tried to help all the injured people and stuff.  We would spend hours trying to remove rocks and all this material.  Fifty, 60 people would be working in an area, and someone would suddenly yell, “Hey, silence!” And you would hear someone asking for help.  So we would all concentrate on that area and we would pull that person out if we could.  There were people pulled out several days later still alive; babies still alive more than 10 days later, babies that were just born.  It was a terrifying experience.

SA:  What did it do to you emotionally and philosophically?

It changed my life in many waysMR:  Well, you know, looking back it had a very significant impact -- it changed my life in many ways.  First of all I am terrified of earthquakes now; I learned my lesson.  Secondly I switched my decisions.  I was going to be chief resident in the general hospital of Mexico that year.  But after the earthquake happened, there was talk about closing the hospital down because of the damage.  I switched and I took a job in the National Institute of Pediatrics, the institution where I did my social service in my first year of residency.  And instead of being a chief resident for one year, I began, in 1986, as a fully-fledged junior staff pathologist in a very big hospital.  So, it had a very significant impact on my life.

“The pathology of poverty”

SA:  What sort of cases were you seeing at the National Institute of Pediatrics – what was the disease profile of your hospital?

I was exposed to a massive amount of paediatric human pathologyMR:  It was a tertiary level centre with the ability to perform renal transplants and cardiac surgery and stuff.  But also we had a very large caseload of run-of-the-mill infections and the pathology of poverty – malnutrition, tremendously advanced cancers, all kinds of things.  It’s a hospital that covers the full spectrum of human pathology, from zero to 18 years of age.  I could see cancer, or I could see tremendously infected patients because they hadn’t eaten properly ever in their lives.  So I was exposed to a massive amount of paediatric human pathology in the four years that I spent there.

SA:  And could you see, just from looking at the pathology, what sort of social background people had come from?

Most of what I saw was pathology exacerbated by the lack of resourcesMR:  Oh yes.  Most of them were people that had no means; that were very sick, were coming from other parts of the country, because this was a referral centre.  And they were poor.  Some people were well-off, but they came to that hospital because it was the most advanced paediatric hospital in the country.  But most of what I saw was pathology that is exacerbated by the lack of resources.  People with advanced cancers, for example, were sent -- people that, had they been seen a year before, would never have presented with these tumours coming out of their heads, or invading their whole anatomy.

A lone parent

SA: And at the same time you were bringing up your small children.  How did you manage everything – your work and your learning and bringing up a little family?

MR:  Well, I had three children when I divorced.  My ex-wife had some personality difficulties, some psychological problems.  We decided to split and I kept my children.
I was a second-year resident when that divorce happened, so it was tough.  Usually I would take them to school in the morning and I would take an hour off to go and eat with them later.  It sounds okay, but in Mexico City it is a little tough because of the traffic -- to cross 10 kms takes you an hour.  Eating in Mexico is done around 2pm, and at 3.15pm I would run back to the hospital and continue my activities, and in the evening I would go back to the university to teach.  So it was crazy.  But I was committed to do it. 

I didn’t have that much time to be with [the children], so I had to spend what is now called ‘quality time’ with them.  And eating is an opportunity to exchange a lot of things, it’s a very important time of the day, and it’s a very educational experience for children.  So we used to eat between 2 and 3pm.  And that was every day.  Mexico and many other countries in Latin America have a schedule where people start working around 7am and they end working around 11 pm.  So it’s just normal life there; that’s how you do it.

SA:  And did you remain close to them?

MR:  Oh yes, I raised them.  And they lived with me until they all left.  They are now married and I have one granddaughter.  But then I had another marriage and another child, and that was another interesting experience.

SA:  In what way specifically?

MR:  When I divorced I met my second wife, who was a medical student.  We started dating, and it was a little tough because she came from a very conservative family that wanted to have her marrying someone that was not carrying a lot of baggage, and I had three children.  There were significant complications but she finally married me.  I was already a pathologist, and she was a medical student finishing her studies.  We lived together for four years in Mexico, and then we decided to try to come for one year to the United States.

SECTION 4

Leaving for the United States

He was a fantastic paediatric pathologist, a famous MexicanI went to speak with Dr Pérez-Tamayo and he said, “If you’re going to leave, go with the sharks.  Where do you want to go?”  I didn’t know, so he mentioned [Francisco] González-Crussí, who for me was a huge figure.  I mean, he had written the Armed Forces Institute of Pathology Atlas for Extra-Gonadal Teratomas.  He was a fantastic paediatric pathologist, a famous Mexican, and he had written Notes of an Anatomist that I had read.  So it was like…it couldn’t get better.  Dr Pérez-Tamayo wrote a letter to Dr González-Crussí.  A week later I got a phone call from Dr González-Crussí inviting me to go and visit him.  He said, “If Dr Pérez-Tamayo recommends you, you’re accepted!”

So I went to visit for two weeks and made an agreement with him to return with my family a year after.  My wife got her own mentor to help her.  Dr Pérez-Tamayo again tried to help me -- he loaned me $500 to pay for my ticket and we came to Chicago for one year only.

SA:  Your intention was to come and do some learning here and then go back home?

I had no licence, no credentialsMR:  Absolutely.  I never even took what they call the USMLE, the United States Medical License Examinations – I didn’t have a licence to practice pathology.  I was a research associate and I was doing research projects.  I wasn’t officially allowed to take part in any kind of medical procedure because I had no licence, no credentials.  I was just learning pathology on the side with Dr González-Crussí and his team. 

But then things got complicated with my ex-wife and it was very difficult. I sent my children on vacation to Mexico and they were kept there against their will and against my will.  Finally I recovered my children in a very complicated transaction that took all my little savings of a year in Chicago.  My wife was pregnant at that time, and we decided that it wasn’t possible to go on like that, so we decided to stay in the United States, and we cut our ties with Mexico at that moment. 

Dr González-Crussí told me, “Well, if you are able to take the USMLEs, get your credentials in time to be appointed fellow, I will keep the position for you.”  So I took step one on a Monday and step two on the Tuesday of the same week, and was fortunate enough to pass them.  And then a few months later I took FLEX [the Federation Licensing Examination] which was the equivalent of part three.  I got my licence just a week before the deadline and Dr González-Crussí gave me the fellowship, and I stayed as his fellow in paediatric pathology. 

I had enough experience for that post because I had been an attending pathologist (ie a consultant pathologist) in a high-volume hospital in Mexico City for four years and had completed my full residency in Mexico, which was very tough. And although it’s important to make sure that all physicians coming to this country are well trained, all the bureaucratic barriers that are in place are extremely unfair, and are often applied to people that could be completely qualified without having to waste resources, time and effort taking tests. 

When I did my fellowship with González-Crussí it was already my fourth year in Chicago, and at that time I saw an advertisement in the Journal of Pediatric Pathology, that Yale University was looking for a paediatric pathologist that was board-certified or board-eligible.  I wrote to them and said, “I’m not board-certified, nor am I board-eligible, but I will be eventually, and I want to do this.  If you’re interested please let me know.”  They invited me to come to give a seminar, to interview with a number of people.  They offered me the position, and I took it with the condition that I could become board-eligible after some time.  They could sponsor me; assure my eligibility before the boards.  And so I took my general board of pathology after three or four years and then my sub-speciality board in paediatric pathology the next year.  I was hired at Yale from the beginning as an assistant professor.  That was in 1994, and I have been here ever since. [In 2008 Reyes-Mugica moved to Pittsburgh, Pennsylvania.]

González-Crussí: “a fantastic pathologist”

SA:   Tell me about your time with Dr González-Crussí. You had started reading his essays before you met him, had you?

MR:  I have read every single book he has published up to date.

SA:  What appealed to you most about him and his work?

MR:  It’s very difficult to tell you…He is a vastly cultured man.  He speaks many languages.  But my first impression of him was that he is a fantastic pathologist.  Pathology is a difficult trade.  You need to be special in certain ways.  It’s like to do basketball you need to be tall.  Well, to be a good pathologist I think there has to be something in your brain that allows you to recognise shapes and to orient yourself in that visual, spacial field.  And he had a particular talent with that. But also massive medical information -- he knew everything, and I was very impressed with that.  And then I started reading his contributions to medical literature, and saw that he was able to jump from one topic to another, to another, in paediatric pathology, always as if he was the expert in that particular topic. And then I started re-reading his non-medical literature, or paramedical literature, like Notes of an Anatomist and others.

Also, when I was with him in Chicago the BBC of London came to visit him to do a documentary on his writings.  They wanted to film him in Mexico and to take the occasion of the ‘Day of the Dead’ [a festival of pre-Hispanic origin; families remember their dead, and the continuity of life] as a topic, because they saw something macabre about pathology, and they wanted to explore this with González-Crussí.  I really didn’t like too much that particular angle.  I don’t know why in England people get so much interested in this dark side of pathology, but at any rate they came, and Dr González-Crussí asked me to help with the crew. 

We took them to museums in Chicago, Mexican museums, and also I helped to coordinate their visit to Mexico, to my previous hospital, where an ex-classmate of Dr González-Crussí, another pathologist, was the director. They made a particular celebration of the Day of the Dead in that hospital and Dr González-Crussí went and they filmed him there.  It was a very interesting experience and Dr González-Crussí kept always his marvellous cultural stature and he was able to convey his own message and his reflections.

SA:  It’s interesting that you say that in Britain people are very preoccupied with the ghoulish side of pathology…


MR:  Yes.

SA:  I think that’s true, but I don’t think it’s just the ghoulish preoccupation.  It’s also a fascination with the people who are so familiar with death because everyone wonders what death is all about.  And they wonder whether you people learn something about death from exploring its physical manifestations that the rest of us don’t know about.  I think that’s what fascinates people, and González-Crussí does explore this theme in his writings, doesn’t he?

He sees things that we don’t.MR:  Yes, absolutely.  He has an essay called something like Life from inside out in which he tells you what it’s like to go into a body and look at it from inside out.  And yes, obviously he’s a very creative and imaginative guy who can look at the same things as you and I, but he sees things that we don’t.  Yes, this is a fascinating angle…

SECTION 5

“Things beyond our scientific understanding”

SA:  You yourself have a familiarity with disease and death – what philosophically does it suggest to you?  Okay, you have described the science, you have described the beauty of the field, but what effect does it have on you emotionally, philosophically? Are you someone who considers these things afterwards, or is it ‘just science’?

MR:  No.  I have thought a lot about it.  My influences again are González-Crussí, Pérez-Tamayo and others, but I have my own reflections, my own thoughts too. I’m not a religious person, so I have tried to look at the process of death from the most scientific angle.  But even there I recognise that there are certain things that are completely beyond our current scientific understanding.  And I have had my own personal little experiences -- I probably don’t make too much out of them, but others perhaps could. 

I was called to do an autopsy on a baby who had a disease that required very rapid intervention in order to make the diagnosis and to provide the genetic counseling to the family. The only option was to go immediately after her death into her heart and take some parts of her heart for examination.  This was a situation in which the clinician called me before the baby died.  He said, “Would you be available if she dies in the night?”  I said, “Sure, just call me.’  He called me and he said, “We are going to interrupt artificial life support in half an hour, okay?”  So I drove in the middle of the night, around 2 am, and they came with the baby a few minutes after she died. 

I felt at that moment as an Aztec prince. The experience was very chilling When I started opening her little body and I entered her heart…When you die, cells are still viable in many organs, and when you stimulate certain tissues that are contractile they can develop mechanical activity.  And what happened was that I was doing this with the head of the paediatric intensive care unit at my side, and when we got to the heart it started moving.  The baby was dead, but the heart was sort of beating…Not really, but in a disorganised fashion there was a beat.  I felt at that moment as an Aztec prince taking out the heart of a human sacrifice, if you will.  And I wondered at that moment, “What am I doing here, opening the heart of this little baby?”  Of course, that was just for a flash second, and I understood that what I was doing was very important.  I took the tissue that was needed.  It was analysed, the diagnosis was made, and the family now knows what type of disease they can carry, and has an understanding of what to do.  It was a very valuable autopsy.  But the experience was very chilling and macabre, if you will.

SA:  How did you manage to put that to rest afterwards?  I mean, you said the shock was just a fleeting thing, but has it been something that has lived with you?

This is a morgue, the place where death teaches or helps those that are still aliveMR:  It has.  It has.  So you wonder… See, in many autopsy rooms there is a statement in Latin that says something like, “This is a morgue, the place where death teaches or helps those that are still alive.”  And that’s exactly what came to my mind – the contribution this little baby, who was no older than two or three months, was making to her family and to humankind, if you will, by letting us, with her personal experience (and there is nothing more personal than death) understand a disease process that can protect not only her family but many others, was huge. 

So yes, I see autopsy as the most exhaustive, and final, medical exam that a doctor can provide for a patient.  I don’t see autopsy as something horrendous and macabre.  Yes, it’s not pleasant, I can tell you.  I don’t like it.  It’s just that I know how to do it fast, effectively, cleanly, and to get the most out of it. And in this particular anecdote that I’m telling you, that’s exactly what happened. We suffered through the experience of seeing something that was not pleasant, but we were able to establish an accurate diagnosis and help the family of this little kid, and probably many others.

SA:  But it was just too close to the event – was that what got through your professional defenses?

MR:  It was too different.  When you do an autopsy, usually the body has been in the refrigerator for several hours, it’s cold, and it has changed in colour and there are many familiar things. But with this little kid I saw something different.  She was completely dressed as a baby; she was pink and warm.  It is very difficult to open a body like that, and very different.  So that is what really first struck me as something completely wrong, if you will.  Not really, but something that I didn’t expect. 

“Fragemented” medicine: losing the big picture?

They lose track of what life is all aboutFrequently I have situations in which I come to see a case where the clinicians want to know what happened, and they have spent weeks -- sometimes months -- treating a patient with different types of complications.  They know all these parameters -- respiratory, cardiac and many others -- and they are following those and they see the curve of the progress up…down etc, and then finally, when the patient dies, they come to me and say, “What happened?  We don’t understand how this patient died.”  And my answer in several of those situations has been, “Well, I can’t understand how this patient lived.”  They lose track of what life is all about. 

Our practice of medicine nowadays is so fragmented, and such a terrible dissection into different specialities and little fields and tasks, that we as doctors lose track of the patient.  So they come and say to me, “No, no, but this patient was doing fine.  The blood pressure was this and that, the urine was this and that…”  But when I just show them the heart, the lungs, the whole thing…I mean you cannot recognise the human body. The baby weighs two or three times the normal weight because it has been inundated with fluids.  It has seven or eight catheters in different parts – in the heart, in peripheral veins, in the umbilicus, in the trachea and wherever.  It has been operated on three times…

What I am trying to say is that medicine is now a practice in which a lot of specialists lose track of [the big picture], and frequently it is only the pathologist that can try to bring all these little loose ends together.  I try to do that frequently. And I try to do that even at the biopsy cases, when I work not with dead patients but with living patients, and this is much more important for the patient himself or herself. 

There are situations in which specialists trust too much their results, and they are not sceptical enough, scientifically speaking. They make mistakes.  A memorable occasion was when a genetics counselor stormed into my office very upset because I had issued a report saying, ‘fetus without significant abnormalities’, after an autopsy was performed.  She said, “What do you mean?  We saw polydactily in the ultrasound – that’s why we interrupted the pregnancy.”  (Polydactily is more fingers than five). To interrupt a pregnancy on the basis of polydactily may or may not be justified, depending on a number of additional things I won’t go into.  But that’s not the issue. The issue is that I knew that this was going to happen, so when I performed the autopsy I put both hands on a glass slide -- they were so small that they could fit in this little space -- and you could see five fingers on each hand. So I didn’t open my mouth, I just took the slide and gave it to her as a response to her question.

SA:  And polydactily goes with other malformations, does it?


MR: Sometimes it does; sometimes it doesn’t.

SA:  But enough to warrant an abortion?

There is no more accurate and real examination than a pathological examMR:  In some situations, yes.  But the issue here was that in an ultrasound -- as much as they are very accurate and very advanced, and you can really trust a lot of the results -- you should never lose track of the fact that those are virtual images, and pathology has real images.  This is where things stop.  There is no more accurate and real examination than a pathological exam.

SA:  Okay, going back to where you said that medicine has now become so fragmented that you sometimes find yourself saying, “I don’t know how the child lived”, when you have done an autopsy – are you seeing too much technological effort to ward off death?  People know how to do so much that they can lose sight of the fact that this is a living being where quality of life is important and where there’s a need for a sort of unifying vision.  Is that what you’re talking about?



MR:  In a way.  Although I recognise the fact that if we do not apply our marvellous technology to these very sick babies and patients that are in need of that, we would not be making the progress that we have made.  In other words, there are voices that very strongly argue against the application of advanced technology to sustain life; against the application of advanced technology to treat certain conditions in childhood or adulthood.  I disagree with that because, as you know, our quality of life as humans is much better now than it was just 20 years ago.  And 50 or 80 or 100 years ago, when there were no antibiotics and no anaesthesia and things like that, if the doctors of the time had not applied all their efforts to pursuing a particular question we would never have got to this point.  So I think that, although the end does not justify the means, we should really have the curiosity and the will to apply this marvellous knowledge to new questions.  But we should do it in a respectful way.

“Tormented by bureaucracy”

Research is being interfered withThis brings me to another issue that I would like to address, which is research in medicine and the issue of human investigation committees -- approvals, disapprovals and the like.  I have been tormented by the bureaucracy of agencies that were created in an effort to avoid abuses and avoid fraud and avoid exposure of innocent patients to dangerous measures or invasive techniques without their knowledge.  And I have been tormented by these agencies because frequently -- most of the time -- our research projects don’t really expose patients to any harm.  Nevertheless there is a structure in place called the Human Investigation Committee -- IRB, they call it, Institutional Review Board -- that oversees the application of research projects on patients to extreme degrees of stringency, so that what is happening now is that research is being interfered with, obstructed by these approaches. 

Recently I read a paper written by a doctor in Chicago who, for many years, has been studying the formation of stones in the kidney, and for that he uses patients’ urine and he looks at the urine to determine the balance of different minerals.  Well, things have gotten so ridiculously obstructionist that he could not perform his studies on urine that was going to be discarded, because the IRB thought there may be complications had the information obtained in those samples been released and so on.  So, urine that was going to be discarded in the bathroom or the lab could not be used for analysis that this doctor has been carrying out. This is just an extreme example, but I spent three months trying to get approval for a very small project in paediatric pathology, and by the time I got the approval the fellow that was visiting from Spain to spend several months with me was almost done with his visit, and we couldn’t really get everything in place to perform the research. 

We have created a monsterThis is happening more and more.  We have created a monster in overseeing the activity of medical research, and I think we have forgotten what ‘good faith’ is.  Yes there is fraud in science as there is fraud everywhere, and there is corruption, and there are people who are ill-intentioned or disorientated.  But that’s very rare, it’s infrequent.  Most of us are good human beings that are trying to do the best we can to help.  And there has to be some un-common sense -- because there is no such thing as common sense -- in overseeing these activities.

SECTION 6

Neural crest disorders

SA:  People have expressed the same views and frustrations in Britain, and this seems to be a big theme in my interviews.  But tell me now a bit about your research, because from what I read, it seems a very interesting area.  What is your main interest in the research side of things?

MR:  Well, I have been interested in a particular group of disorders that involves the development of the neural crest.  The neural crests are transitory structures of the embryo that are the excess tips of the closing borders of the neural tube.  The neural tube gives rise to the brain and to the spinal cord.  But as the neural tube closes – because it first begins as a groove and then it becomes a tube that closes – the excess tissue that results from the closing remains there, and instead of disappearing it migrates, and it migrates to different parts of our bodies.  But the migration of these cells is a very complex process, and it goes to everywhere. 

The bowel has a brain of its ownNeural crest disorders are of different types.  There are neural crest diseases that are cancer-like, or cancer -- for example, neuroblastoma is one of the tumours that I have looked into the biology of.  There are neural crest disorders that are the result of an abnormal migration or survival of the cells, in the bowel for example.  The bowel has a brain of its own.  (Certain politicians only use that brain! [We both laugh].)  In order for the bowel to move… the peristaltic movement of the bowel is coordinated essentially by the brain in the gut.  And this nervous tissue, which has many millions of neurons inside, requires the migration of this neural crest, the invasion of this neural crest into the bowel and the proper development and survival of these elements in a coordinated fashion, so that the movements of your bowel take place.

SA:  But it is a whole lot of nerves, like a brain, is it?

MR:  It is a brain of its own.  Absolutely.  If you look at it under the microscope it looks like a little piece of brain sandwiched between layers of other tissue in the bowel.  Actually I can play a joke on someone by just taking a picture at a very high magnification of the bowel brain that is called the plexus -- there are several plexuses in the bowel -- and showing that to a pathologist.  And I can tell you that pathologist probably will not be able to tell if we are looking at a piece of brain in the head or a piece of brain in the gut.

SA:  That’s amazing!  And is there a lot of it?

Hirschprung disease

MR:  Yes.  It continues from the oesophagus all the way down to the exit.  And the proper development of that is necessary for our bowels to move.  There is this condition called Hirschprung disease that is a disorder in which babies in general – it’s a childhood disorder – are not able to move their bowel, become obstructed, or pseudo-obstructed, distended.  And they can explode, literally, with a colon that is like an anaconda – enormously distended.  Just imagine what it is like to not be able to move your bowel for five, six days.  There is no peristalsis, because there is an area that is lacking these neurons in the bowel.  The diagnosis of this disease is relatively challenging.  It requires a biopsy, and I have been interested in improving our diagnostic approaches to this disorder for some time. 

SA:  Is that a fairly recently understood disease?  Have you contributed to the understanding of this disease?


MR:  Well the disease was described in 1888.  It was poorly understood for the first 50 years and then it began to be unraveled by a surgeon at Boston’s Children’s Hospital.  For the first 50 years the surgery that was performed on these patients was the wrong type of surgery – they removed a normal piece of bowel and they left the abnormal piece of bowel inside because it looks deceptively normal.  But then we began to understand that, and the biology of this disease has been unraveled over the last 15 years.  There are several genes that are involved, and there are many more that will be discovered in the next few years. 

Absence of proof doesn’t mean proof of absenceI haven’t looked into the biology of this disease as much as in other disorders.  In this disorder in particular I have been more active in how to diagnose it rather than how to understand the genetic basis, because for paediatric pathologists this is a serious daily problem.  Frequently it comes to your table, a biopsy that says, “Please rule out Hirschprung disease.”  It is very difficult to make the diagnosis, because it is based on the absence of neurons, and absence of proof doesn’t mean proof of absence.  It’s very difficult to prove that there are no neurons there, so it’s a challenging situation.

SA:  So what have you done to try and improve the ability to diagnose this?


MR:  At least at Yale for the last 14 years we have established a protocol …This is not only to my credit, this is really part of a common effort by many paediatric pathologists.  But I have tried to push forward the idea of establishing a set protocol, very specific steps that require serial sectioning and a number of specific approaches to look into the glass slides.  And I have also tried to remove certain…what should I say?  Myths that have plagued the field.  Because as knowledge of this particular disorder has developed, people have followed different paths, and some of them are the wrong paths.

You know, a few years ago people started describing entities that many of us looking into these matters believe are just an exaggerated form of normal development, but people get diagnosed with entities such as intestinal neuronal dysplasia.  And they not only get that diagnosis, but they get operated on that basis, unnecessarily.  The criteria for the diagnosis of those entities have varied from one publication to another, but with the same authors.  So it’s quite problematic and controversial.  So what I am trying to do is join forces with other people to establish more of a consensus and a more reproducible opinion.  But my particular interest has been in the diagnosis.  And in this institution there was a need to establish a baseline.  And we have had, in 14 years, not one problem with that situation.  Before, it was quite a problematic entity to diagnose.

SA:  And is Hirschprung disease quite a common condition?

MR:  It is common.  It is about one in 5,000, depending on how you count it.  But it is quite common.  It is treated surgically now, although I expect that at some point other forms of treatment will be available, depending on the biology.  It is a very heterogeneous disorder.  There are at least seven or eight well recognised genes involved, and there are many more coming, and at some point genetic interventions probably will render some result.  But we are a little far from that now.

Giant naevi

SA:  And what other neural crest disorders are you interested in?

MR:  The thing that I am more interested in is a little more uncommon.  It’s called neurocutaneous melanosis, or neurocutaneous melanocytosis.  This is a disorder of neural crest cells that produce melanin, so-called melanocytes.  All the pigment in our skin, melanin, is produced by these cells, which come from the neural crest, with the exception of those that are in the eye, the choroids of the eye  – those are not from the neural crest.  But every other melanin pigment cell in our bodies – including those in the meninges, because we have pigmented cells in the meninges -- comes from the neural crest. 

As it turns out there are babies that are born with abnormalities in the population of melanocytes.  And they develop this condition, neurocutaneous melanocytosis, where they have extensive areas of their bodies covered by moles, naevi.  These very darkly pigmented areas can cover portions so extensive that they are sometimes called ‘bathing trunk naevi’, in which the whole body, or most of it is covered.  Or they look like Dalmatians -- hundreds, thousands, of little satellite lesions here and there.  And the problem with those situations is that not only is the skin abnormal, but the deeper tissues are also abnormal, and can develop malignant tumours inside those naevi -- they can develop melanomas. 

Frequently they develop abnormalities of the development of the brain and meninges.  They develop a nevus inside the brain, if you will, and the nevus can interfere with the development of other structures.  They have seizures, they have hydrocephalus (dilatation of the ventricles of the brain) and sometimes they die. The condition is relatively rare -- so much so that I can’t give you an exact figure.  One in 20,000 newborns will have a giant nevus, and some of those will suffer neurocutaneous melanocytosis. 

Working with family support group

But a little more than ten years ago, I came in contact with a developing group of parents that had recognised the need to create a more identified community of support to these patients.  They each had a child born with a giant nevus, and when they went to a doctor, frequently the doctors freaked out and said, “I’ve never seen this.  I don’t know what it is”. Or “It’s a melanoma; let’s take it out; let’s treat it like this…”  So there was very little knowledge, and parents created this group, a family support group.  All of them are either parents of children with these lesions, or they are patients, because many of these people have survived 20, 50, 60 years suffering with this situation, and they are ‘freaks’.

SA:  It looks awful, does it?

A tremendously distorting, disfiguring lesionMR:  It depends.  Sometimes you cannot see it, it’s just on your belly, or just on your legs and people can hide it.  But other times half of your face is black with a tremendously distorting, disfiguring lesion.  Or your whole face.  Or you have something on your forehead, or whatever.

SA:  But different from a Port Wine Stain?

MR:  It is different, although there are some similarities.  A Port Wine Stain is usually a lesion that involves abnormalities in the vascular development, haemangiomas and so forth.  These are tumours of melanocytes – relatively flat, although they can be bumpy, lumpy -- and they can kill.  I have done autopsies of these patients.

So that is the small area that I concentrate most of my research efforts.   I was doing that with my second wife -- she passed away five years ago -- she was a part of the group that started looking into these.  She had some training in dermatology and became part of the Yale genetics department, and we were looking into the biology of this some years ago.  I am now regrouping, and trying to push this to the next step.

SA:  And what are you discovering about this?


MR:  Well, first of all I am discovering that this is a much more frequently seen problem than we used to think.  People are now aware of this group and are coming forward more and saying, “I have one of those.  I was born with this naevus,” and they show you a 20 cm lesion on their back.  So that’s why I can’t give you the incidence, because we simply don’t know.

SA:  Lots of people don’t come to medical attention?

MR:  Right.  Or they go and the doctors don’t know what it is and they leave it alone.  Many patients survive despite the efforts of their doctors.  We are discovering that it’s a very complex disorder in terms of genetics, because we know of no twins for example that have this problem.  So, apparently, there is not an inherited basis.  It does not repeat in families.  There is nothing that the mother did during the pregnancy that would represent a particular risk for the fetus.  So we are first eliminating a number of things. 

We know that genes involved in familial melanoma – because there is such a thing as familial melanoma – are probably involved in this condition.  We are looking into that, and we sequenced the genes of familial melanoma from samples of these patients in a very preliminary study, but we didn’t find that particular problem.  We are sure that these are real clonal lesions -- and what I mean by clonal lesions is lesions that arise from a single cell that starts to reproduce and forms a clone -- because we have looked into a number of patients using a specific methodology that allows you to determine if proliferation is made of clonal or poly-clonal entities.  And at least in some patients this has been definitely clonal.

SA:  So literally it was one rogue cell that has…?

MR:  Apparently the defect begins very early and then it takes over.  But we are not sure.  It may be a more heterogeneous problem, but we still need to gather a lot more samples and make a very organised effort.  It takes a very long time, in particular because this is not something that involves millions of people, like, say, breast cancer or Alzheimer’s disease.  And when you don’t have such a massive number of patients it’s very difficult to gather the results, and get researchers interested.

The “shocking” first case

SA:  So what made you particularly interested in that -- especially when, as you say, it is so hard to get the numbers to make anything significant?

MR:  It’s very interesting that you ask that question.  When I was a pathologist in Mexico there was a baby that came to the department of oncology, and it immediately became the ‘patient of the month’, or ‘the patient of the year’ – everybody was talking about that patient.  It was a little baby that was born with something in the genital area that was completely impressive, ugly, and they couldn’t even say if this was a boy or a girl.  They didn’t know if this was a tumour that would kill the baby rapidly or what.  The head of dermatology made the suggestion that it could be a naevus, because he saw two other lesions, small lesions, in the leg and he said, “Well there are these things that could be satellite lesions, but…”
 
So they took a biopsy, and I got that biopsy.  What I saw was something very strange, and it reminded me of what is described in congenital naevi.  I made that case an index case for a presentation at an academic meeting, and I think I called it something like ‘pigmented schwannoma versus neurotised naevus’ or something like that, I don’t remember exactly.  But what I was trying to say was that this was a lesion that had features of a naevus, and at the same time features of nervous tissue.

SA:  Nervous tissue?

MR:  Yes.

SA:  From where?

MR:  From the neural crest.  That’s why it’s called the neural crest -- because melanocytes, in my opinion, are really modified neurons.  They are cells that become specialists in synthesising pigment, but they have these dendrites, these prolongations, they are like an octopus, literally.  They have cytoplasm that is the body of the octopus and they have all these ‘tentacles’ that carry the melanin, and they transfer the melanin to the other cells that they are surrounded by.  So these melanocytes come from structures that go through a phase that is really neuron-like.  And for me the case was not a real wonder – or it was a very fascinating representation of something that looks neural and at the same time looks melanocytic. 

I never stopped thinking about that caseI never stopped thinking about that case.  When I moved to Chicago and I told Dr González-Crussí about it, he said, in his classic reflective way, “Very interesting…I have never seen a case like that.”  Then a couple of months later he called me up for a frozen section analysis.  They were operating on a patient with a sort of melon-sized tumour in the perineal area that was surrounded by an area of hyper-pigmentation, like a naevus,  and I remember his voice on the phone, “Miguel, you remember the case you told me about from Mexico a few years ago?  I think we have something that is very similar.  Could you come up please?”  So I went up and sure enough it was identical under the microscope.  So we decided to publish those two patient cases together, in the oldest pathology journal, Virchow’s Archive – a famous German journal – in English.  But these things don’t move people very fast.  People had not seen such cases; they thought, “Well, it’s just a variation of naevi.”  And yes, it is some peculiar form of naevus.

SA:  But had people not made the connection between naevi and neurons?

MR:  Yes, they had.

SA:  But then why were they so surprised at what you were saying?


MR:  Because it’s very unusual to see these sort of melon-like… this grapefruit-sized thing in the perineum of a baby surrounded by a large congenital pigmented naevus area.  I have seen now at least three other patients, and they are extremely rare, they are very peculiar.  But I am sure there are many more that we don’t hear about.  And from that point on I was hooked into the biology of melanocytic development.  I’m not a melanoma researcher.  Melanoma is a big field.  But I think that looking into the development of these lesions we can uncover, or explore, certain things that may be useful to melanoma research.  Because cancer uses the same cell mechanisms for differentiation, cell population control, and migration or invasion, that the embryological tissues use.  An embryological cell will migrate, invade, survive or die, following the same mechanisms that the cancer cells will use, except that the cancer cell does not use them in a coordinated fashion. 

SA:  And tumour development is pathological and embryogenesis isn’t…

MR:  Exactly.  So, for some years I have taught Yale medical students about cancer invasion and cancer development using the model of neural crest development. And that’s how I have put the two things together.

SECTION 7

The development of paediatric pathology

SA:  Dr González-Crussí was telling me that paediatric pathology, as a specialism, is relatively new.  There was a time when people just thought that if a baby was born with all kinds of things wrong, it was too late -- there wasn’t much could be done.  And they thought that, once they were born, they were just mini-adults, but then gradually the began to find that they were completely different.  Were you aware of that, or did you enter the field when it was already becoming a really big specialisation?

MR:  Yes, I was aware.  I remember that when I came to Yale some of my colleagues were wondering, “Why do we need this guy here?  We can do essentially the paediatric cases.”  They were general pathologists with skills in many different fields.  This was a fantastic department at the time, and people were very well trained and experienced in many fields.



But paediatrics is really different from adult medicine, and paediatric pathology is completely different.  You look at a tissue under a microscope, and if it’s from a child that is one day of age it’s different from the tissue of a child one month of age, and that’s different from tissue of a one-year-old, and that’s different from the tissue of an 18-year-old. 

In paediatrics the key is development. When residents take a case to an adult pathologist, the questions the pathologist will ask when looking at a glass slide, of a tumour for example, are, “Where is the lesion?  How fast did it grow?  How big is it?”  The first question that a paediatric pathologist will ask is, “How old is the patient?”  Because it is not the same to be one month old or one year old.  Tissues are changing.  We don’t reach the normal number of alveoli until we are eight years of age, for example.  The kidneys keep on growing, the brain keeps on growing.  Things are in continuous growth. 

So yes, when I came to paediatric pathology I think that many people had started to recognise the need.  There had been paediatric pathologists, pioneers, but as a speciality it became more recognised around 25 years ago.
  And now, in this country, there is not only a society for paediatric pathology -- as there is one in the UK – but there are speciality boards.  You cannot be a paediatric pathologist without taking a board exam.  You have to be board–certified, sanctioned by the American Board of Pathology.  There is a fellowship training and so forth. 

And we have a journal that began as Pediatric Pathology, and now it’s called Pediatric and Developmental Pathology.  I am the editor-in-chief of that journal.  And when I look back I think, “How in Heaven did I come to be the editor-in-chief of that journal?”  My mentor, Dr González-Crussí, was an editor-in- chief and I have just followed in his footsteps quite by accident.  But I enjoy that a lot. And this journal is recognition of the existence of a very well established body of knowledge that we need to explore and we need to share with the rest of the world.

Questions of identity

SA:  Tell me, how important is your profession to you, on a personal level, and how big a part of your identity is being a pathologist?

I am a parent.  I am a fatherMR:  Well, pathology is a very important part of my life, but it’s not the only one -- and it’s probably not the most important one.  A friend of mine, another doctor who was with me in Chicago, told me something that has remained with me.  He told me, “You know, before I see you as a doctor, as a pathologist, I see you as a parent.”  And I think that is what defines me.  I am a parent.  I am a father.  I have four children and I have tried to do my best to help them grow in the best possible way…With many errors, many mistakes, and you know, challenges.  There are things I would probably do a little differently now.  But that is really what I think defines me: I am a father. 

Three of my four children live in this country, close to me.  My youngest lives with me, and the other two live in the area and we get together every other week.  We play pool around the table; we sit round the fire place; we drink a bottle of wine; we cook and have fun.  We speak about matters, we travel. 

My position here demands for me to travel a lot, and I have to confess that I always mix work with pleasure. Work has to be fun.  So every time I travel, no matter where I go, I will spend a day or two additional to my responsibilities visiting museums, getting to know the place. The most recent trip I did was to Turkey. We spent a few days at the European meeting of pathology, and then I took my daughter and my ‘significant other’, my woman (now my wife, as we recently married), to a place in Anatolia, in Kappadoccia.  We visited the underground cities; we visited the icons and the formations in Kappadoccia, and we learnt a lot about Turkey.  I’ve been with my daughter from Buenos Aires to Beijing, from Sao Paolo to Paris. And I like to think that that will shape her a bit more.

My three first children did not have… I didn’t have the means to travel that much with them.  But my contribution to them was to bring them to this country and keep their original culture alive.  All of them are perfectly fluent in Spanish and English; they have a strong knowledge of their original heritage, culturally speaking.  They go, they travel, they visit places, they have been around.  I think they like me -- and I like them very much.  So I think that’s what defines me.

SA:  That brings me to one final question: you didn’t go back to Mexico?

I still feel very MexicanMR:  I couldn’t.  The rupture with my ex-wife was so difficult that when my children were kept against my will and their will, and against the law, for a few days in Mexico, I realised I had to keep a distance, for their health and for their education.  So even though my original plan was to go to Mexico and become a pathologist there after some speciality training here, I couldn’t.  So, I remained here and tried to make the best of the experience.  But I have tried to give back to Mexico, and to the whole continent of Latin America and elsewhere, what I have taken.  I always have someone visiting.  I really do my best to provide opportunities for people to visit and learn with me.  I couldn’t go back to Mexico, but I still feel very Mexican. 

SA:  And do you feel accepted here, or do you feel like an immigrant?


To be an immigrant is a full-time jobMR:  Someone told me once that to be an immigrant is a full-time job.  You never relax completely. 

SA:  But are you an immigrant?  Is it a full time job for you?

MR:  Sometimes I am.  Sometimes I am.  The world is becoming such a difficult place to live in, no matter where you are.  But no, I blend. I feel accepted…I love this country.  And please, this is very important, I love a place where you can really do your best, in work and everything.  But I think you can do that in almost any place if you really want to. 

Borders are ridiculousI am not very nationalistic.  I think that borders are ridiculous; we should eliminate them.   I’m not very interested in keeping one flag or another.  So in that sense I’m not an immigrant.  As Bertrand Russell said, “I am a citizen of the world”.

ENDS
 

 
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