Nicholas Wright - Full Transcript

 WrightWarden of Barts and the London School of Medicine and Dentistry, and group leader at the London Research Institute, running the histopathology laboratory

Interview location:  The London Hospital
Interview date
:  8th October 2007


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SA:  Professor Wright, can you start by giving me a bit of the history of pathology -- when it started as a specialization – because I understand in the old days quite a few ordinary GPs used to do pathological studies?  Can you give me a historical perspective of it?

NW:  Yes, I think that before the Second World War, most hospitals had what was called a general pathologist.  And that general pathologist would perform postmortems; would do what's called clinical biochemistry (examining blood and urine); Haematology The branch of medical science concerned with the blood and blood-forming tissues;  haematopathology is concerned with diseases of. (that's looking  at the blood); and would also look at micro-organisms – bacteria -- and isolate and diagnose infectious diseases.  So they were very much generalists.

After the Second World War it became quite clear that nobody could actually do everything, so we had specialisations.  Very rapidly after World War II we got the evolution of what are now called histopathologists – they're the people who perform autopsies, analyse tissue sections, look at breast biopsies, look at things like cervical cytology.  And other people spun off into being specialist haematologists, microbiologists, clinical biochemists, virologists.  So now we have a cadre of people who specialise in each of these disciplines and give a very highly competent service without which the NHS just could not function.

SA:  Going back maybe a century, were ordinary doctors, I mean physicians, were they trained in this as well or was there still some special person who worked behind the scenes helping with diagnosis?

NW:  Oh I think 100 years ago certainly there were pathologists.  But again they were generalists in the main.  Pathology as a discipline probably evolved with individuals like Rudolph Virchow in the 1840s who really established the basis of pathology and disease.  But since then we've come an awful long way.

Virchow was very much a polymath.  He started off as a medical practitioner.  He became a pathologist.  He was the first person to recognise thrombosis, for example, and the fact that pieces of thrombus could break off and become what are called emboli – most people know about that now.  He analysed the cellular basis of pathology and really introduced the microscope into diagnosis.  He later became an anthropologist and politician.  However, all the best pathologists can make mistakes, because the Kaiser had a lesion in his larynx, which Virchow diagnosed as a benign condition.  In fact the poor Kaiser had cancer of the larynx and he died.  So even the best pathologists can make mistakes!

Even the best pathologists can make mistakes!SA: You've been called 'Doctors of death', and I think the general public thinks of you as doing postmortems most of the time.  But what proportion of your work is actually spent dealing with dead bodies and what proportion in dealing with specimens of people who are alive? 

NW:  Well I think most pathologists these days do very few autopsies.  For many, many reasons, the incidence of hospital autopsies – that's the postmortems done on patients who die in hospital – has been declining.  Methods of diagnosis have improved; there's been a natural tendency not to ask for postmortems; and certainly after the Alder Hey disaster -- or debacle, whichever way you look at it -- the willingness of hospitals to ask for autopsies, and also the willingness of relatives to give permission, has declined.  So there are very few autopsies done at the moment.  It's a very worrisome thing because it's a major teaching vehicle for both medical students and junior pathologists, and it's become a great worry for all people who are trying to educate medical students and pathologists. 

So, to answer your question, very little time.  The thing that most people like myself, who are histopathologists, do will be to diagnose diseases in living people
.  Let me give you a graphic example.  One of the worst things that can happen to you is to have a malignant condition of, say, a bone for example – so called osteosarcoma.  Now these often present in young people, who may have got a knock, or found a lump sticking out of their lower leg or something.  They go to the general practitioner and he or she will examine this.  And he probably doesn’t like the look of it and he'll send the patient for an X-ray.  Sometimes it has a characteristic appearance, sometimes it doesn't.  But what will happen is that the young person will be admitted to hospital and usually under general anaesthetic a biopsy is taken of the bump. 

Once that diagnosis has been made the die is castInterpretation of the appearances of that lesion is often not straight forward.  It's a very specialised and very difficult job.  And of course a great deal depends upon it, because if it is an osteosarcoma, although there are now modern techniques for preserving the limb, it usually means an amputation. This can be a traumatic and serious operation for a young person – losing a lower limb, for example. 

The decision about whether that lesion is benign or malignant is purely the pathologist's responsibility.  So he or she looks down the microscope and says, "Yes, this is malignant."  And once that diagnosis has been made the die is cast.  There is no way back.  You can't say a few days later, "I'm sorry, I made a mistake."  Or you can, but it doesn't go down very well.  So it's a very important role the pathologist plays in determining exactly what happens to you or anybody.  The histopathology service is really central to everything that surgeons and physicians do.


“A very ordinary family”

SA:  Tell me, what sort of family did you grow up in?  Were there lots of medics in your family?

NW:  No, not a single medic in my family.  In fact no one to my knowledge had ever been to university.  My father was by profession a sheet-metal worker.  He was badly injured in the war because he was working on Lancasters [bomber aircraft], so we had a bit of a hard childhood.  I won a scholarship to Bristol Grammar School from, I suppose, quite a poor home really. We were on supplementary benefit and all the rest of it.  My father was in hospital for a long time – three or four years – and then he came out and he went back to work again.  But he couldn't really work very well, and he was an invalid most of his life after that.

SA:  How many of you were there?

NW:  There was myself and my sister.  My sister became an actress, and I went off to  medical school.  My mother came from just an ordinary Bristol family.  Her father worked on the boats down Avonmouth, unloading enormous bags of corn and stuff – so we were just a very ordinary family.

SA:  I'm fascinated by the mobility of our generation of youngsters who did leave working class backgrounds behind.  Did your parents believe in education, were you encouraged?

NW:  Oh yes, very much so.  I mean it was always tacitly assumed I would go to university.  My parents didn't know what I was going to do – I think my mother wanted me to become an architect, because I was quite good at drawing.

Men against microbes

I started with the express wish to become a pathologistI entered medicine with the express wish to become a pathologist, which is very unusual.  It sounds rather poetic; it's not really!  But I read, as a 15 year old, a book called Men Against Death by Paul de Kruif.  This was really the history of the early bacteriologists, like Robert Koch who became my hero.  And when I went to see my careers master and said, "I want to become a pathologist" he said, "Well you have to read medicine."  When I applied to medical school, they said, "Why d'you want to do medicine?" and I said "I want to be a pathologist."  And they replied rather condescendingly, "What do you know about pathology?"  So I told them!  So I started with the express wish to become a pathologist.  I just changed from wanting to be a bacteriologist to being a histopathologist.  And I've never ever regretted it.

SA:  What was so fascinating about this book?  Tell me a little bit about the book and what it made you feel as a youngster.

NW:   Well it really was the fact that you had these conditions – like Rocky Mountain Spotted Fever, tuberculosis, leprosy, typhoid, cholera – which just seemed like black magic for the practitioners of those days.  They had no idea what was going on.  Then along came Louis Pasteur and Robert Koch and the early bacteriologists and isolated these organisms and put medicine on the first scientific basis it's had.  That golden era of bacteriology from, I suppose, 1880 till 1920, when most of the bacteria that cause diseases were discovered, was really extremely interesting.  For example, to look at diphtheria, isolate the organism Corynebacterium diphtheriae, develop an antitoxin, and actually go from isolating the organism to an antitoxin and then to an antibiotic – it's a real saga, and I think any young person reading that sort of thing now, it would really turn them on.  It's extremely exciting.

Now I think you can see the same thing happening in genetics.  We had these conditions which were a black box and now we're understanding the way they're working, and hopefully in the future we can actually correct those gene defects.  So the same thing’s happening.  It's a really romantic story, if you think about it. 

SA:  You say it was the bacteriologists who fired your imagination – how did you get into the branch of pathology you're doing?

NW:  When I got to know more about it, I got more interested in the effects the bacteria were having on the tissues rather than the bacteria themselves, and so then I got additional information – I was reading around this all before I went to medical school.  Then when we did pathology as undergraduates that was cemented.  So I just did my house jobs and then went straight into pathology. 

SA:  What about your teachers – did you have some inspiring teachers?

NW:  [There was] the person who taught me most of the pathology I know -- Dr. Alec Watson, who was Reader in Pathology in the University of Newcastle.   I spent many hours learning with him and I became extremely fond of him -- he taught me a great deal, and I really respect him a great deal among the people who are still alive.

SA:  What sort of character was he?

Those were the people who showed me that pathology was funNW:  He was a dry Scot, with a very acute sense of humour!  And I can remember some of his aphorisms even now, which I impart to my students.  For example, when I once said to him…We were trying to diagnose a lesion called a squamous CarcinomaA type of cancer that starts in epithelia, the tissues that line or cover most body organs.  At least 80% of cancers are carcinomas (see also sarcoma, leukaemia, lymphoma). – or I was trying to diagnose it – and I said, "But I can see prickles."  And he looked at me and he said, "I don't give a stuff for prickles."   I always remember that because you can see 'prickles' in all sorts of things!

After that there were a series of very colourful British pathologists who I admired and emulated.  Dennis Wright, for example, in Southampton; Dilwyn Williams in Cambridge, now retired.  Those were the people who were enthusiastic, vital, outgoing, colourful and showed me that pathology was fun. 

But I really taught myself how to do research, helped by a man called Adrian Morley who was a lecturer at the time.  I was taught the elements of pathology, the basics, by Alec Watson and passed my examinations – I got my MD and my PhD.  But it was soon quite clear that I was going to have to leave Newcastle to try to get my career into gear, because it was a bit of a backwater.  So then I went off to Oxford to a readership.

A clear vision

SA:  Having got your initial qualifications at Newcastle, how did you decide what path you were going to follow and how you were going to get there?

It was a very hard school I grew up inNW:  Early on I wanted to be a professor of pathology and run my own department – that was my ambition.  I had a very clear idea how a department should be run even then.  Not how the department in Newcastle was run; and not how the Oxford department was run, where the professor was the sort of dictator and kept all the power and money for himself.  I didn't want to do that – I wanted to really build the department up, and also try and produce people in my own image – people who would become professors and heads of the department.  That was my ambition -- to build a sort of family, or school of pathology, basically.

And so I got my basic qualifications, I got my MRCPath, and then I thought, "It's time to leave Newcastle because I'm not going to do very much here".  Then the readership came up at Oxford and I applied for that.  That meant us leaving Newcastle.  My in-laws [who lived in Newcastle] were quite old so it was quite a wrench for my wife.  But she's a game girl, and she very much liked Oxford.

That wasn't a particularly happy department.  It was a mixed department – it had NHS pathologists and it had the academics and they didn't get on particularly well.  They didn't like the professor, who was a bit of a prat, and I was caught in the middle of this.  I mean, he made extravagant claims for his research which he couldn't substantiate later on and which led to a very difficult position. I was only there for three years.

In those days if you wanted to become a professor you had to make a statement that you wanted to become a professor.  So I made a policy decision when I was 35 that the next chair that became available I'd apply for it.  I wouldn't get it, but it would be an indication of what I wanted to become in the academic hierarchy – head of department.  Of course the first job that came up was the Hammersmith job -- one of the senior chairs in the country. I thought, "This is ridiculous!  But anyway, I'll apply for it."  So I applied for it, went up to see them, went to see them again.  I didn't think I had a chance, because Dennis Wright, my namesake, was a very senior professor in Southampton, and I think they invited him to apply.  So I thought there was not much chance. Anyhow, I was interviewed and I got the job.  I was very surprised; I never dreamt in a month of Sundays that I'd get it!

The Hammersmith was a very difficult place, full of sharks – you know, very difficult people.  It's very, very competitive, and there's always only a limited amount of money in a medical school so all the professors were competing with each other.  So it was a very hard school I grew up in.  But you know, I turned the department around and at the last count I'd filled 11 or 12 chairs up and down the country with people who came from my department.  As I say, that's what I wanted to do.

Walter Bodmer was then the director of the Imperial Cancer Research Fund laboratory at Lincoln's Inn Fields, and he offered me a position there.  So I got myself seconded and I took all my research there. That was a very good thing, because it meant that when I eventually left the Hammersmith and came here [to Barts and the London] my lab could remain in the same place.


Stem cells: received wisdom takes a knock

SA:  So tell me about your research – you say you taught yourself how to do it, what did you start with and how did you find your path?

I was really interested in how tissues responded to insult and did repairNW:  Well I taught myself experimental design, basically.  I wrote these books with a colleague of mine [he reaches one off the bookshelf] – I was really interested in how tissues were put together and how they responded to insult and did repair.  So I became interested in the cell cycle and how cells divided, and that led naturally to stem cells.  I suppose stem cell biology -- I mean, that book's 1984 -- it's been my interest since the early 80s.

SA:  What was the state of knowledge at that time about stem cells?  What was known and what were you interested in teasing out?

NW:  I was interested in the gut basically, the gut and the skin.  There was very little known about what stem cells did – whether they were able to give rise to multiple lineages, or whether there was a stem cell for each lineage.

SA:  These are not the embryonic stem cells?

NW:  No, no, these are adult stem cells, tissue stem cells like you find in the brain, in the skin, in the gut, in the liver…

SA:  Can you explain that a bit further, because I think the non-medical person will be quite surprised to hear that there are stem cells everywhere.  So can you describe where they are and what their role is generally?

NW:  Yes.  Embryonic stem cells are found obviously in the embryo.  And you have to have a fertilised ovum, which is where all the ethical problems come in.  But when the human or animal is born, all the tissues contain cells which are stem cells.  They're cells which are able to give rise to all the cells in that tissue.  For example, the stem cells in the lungs are able to give rise to all the lung cells, and the stem cells in the gut give rise to all the gut cells etc.

SA:  And they're there for replenishing?

NW:  Yes, well many tissues turn over very rapidly – the bone marrow, the skin, the gut, are renewing very rapidly, so they have to have a reserve of cells to accomplish this, and the stem cell is the sort of ‘governor’. It produces cells and it sits in a thing called a ‘niche’.  It lives there all the time, and every time it divides, one daughter cell goes off to produce more cells to be replenished.  There are many of these niches in the skin and the gut.

SA:  What do they look like under the microscope?

This turned out to be wrongNW:  Just like ordinary cells.  But I mean it's only now that people are getting a handle on what they actually are -- what their markers are and how they behave, and working out ways in which you can study them in animals and man. Later it turned out that the idea that adult stem cells were fixed forever, giving rise to the same sort of cells always…This turned out to be wrong.  They have remarkable plasticity.  Bone marrow stem cells can give rise to skin cells; they can give rise to liver cells; they can give rise to lung cells.  My lab has done quite a lot of that work as well.

SA:  Yes, I understand that your lab was one of the ones that actually discovered this plasticity.  Tell me how that happened.  Were you looking for this or did it happen serendipitously?

NW:  Well there were some early suggestions in the late 90s that if you gave bone marrow transplants to animals then you eventually found cells in the liver that came from the donor.  So we had the happy idea that we could find that in humans too, because humans have liver transplants, they have bone marrow transplants.  So we got patients with bone marrow transplants and patients with liver transplants and we were able to identify the transplanted cells…We were able to follow exactly where they were going.  So we did that in the liver, in the kidney, in the gut in humans and …

SA:  But where had they come from, these cells?

NW:  They came from the bone marrow.  So if someone has a bone marrow transplant – for example, you want to replace the cells in the bone marrow because you have someone who's suffering from aplastic anaemia (their marrow's not producing enough blood cells), so you give them a bone marrow transplant.  You colonise all the marrow and you start producing blood cells again.  But the cells also go elsewhere – they go to the liver, they go to the kidney and they go to the gut.  In small numbers.  And the bone marrow cells become kidney cells or liver cells or skin cells as well…

SA:  This wasn't understood until you discovered it?

NW:  No, no.  Not until about the year 2000.  And we were the first to show that this occurred in humans.

SA:  And how exciting was it when you actually began to observe this?

It started an avalanche of thoughtNW:  Oh it was very exciting!  It was published in Nature – very exciting at the time.  Then people get a bit blasé about it, call it old hat.  But you know, there are more things being discovered now as a result of that.  American groups are now claiming that when you get tumours being produced in animals -- for example, in the stomach -- they really come from the bone marrow.  So it started an avalanche of thought.

SA:  So where is this story at now?  D'you think this is true?

NW:  Well it's a very interesting idea.  The experiment in question is…Helicobacter pylori is the organism that causes gastric and duodenal ulcers, and what these investigators did was to do a bone marrow transplant from male into female [this allowed them to track the transplanted cells because they carried the Y chromosome in their 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 then to infect the animal with Helicobacter pylori, and that gave rise to inflammation and then cancer.  And they found that the cancerous cells actually came from the bone marrow that they'd transplanted, which was very strange.

The Helicobacter infected the stomach and damaged the animal's own stomach cells and the cells in the bone marrow came in and took over and then produced a tumour.  So it's a very bizarre thing.  But there are things in humans that we're finding now, humans who've had kidney transplants -- they're developing tumours in the skin which actually come from the donor kidneys.  So the cells are apparently coming out from the kidney and grafting the skin and forming tumours.  We’ve had a go at this, but couldn’t confirm it – so it's all a bit up in the air at the moment.   But it’s clear that stem cells are a lot more plastic than we ever dreamed they would be.  And certainly a lot more than when I wrote that book!

SA:  So you're saying now that there seems to be a danger of passing cancer on with some interventions -- like transplants and so on – or stimulating cancer to arise?  Was any of this appreciated?

But this is something entirely novelNW:  No. Well, there's a condition called Kaposi's sarcoma which is quite common in AIDS patients, and sometimes when people have a kidney transplant from someone who's incubating Kaposi's sarcoma the recipient can get that.  But this is something entirely novel -- you give a kidney transplant; there are cells in the kidney which come out of the kidney and then engraft the skin.  And then these people with kidney transplants quite often get virus infections with human papilloma virus [HPV], and that then leads to skin cancers.  And what’s been claimed is that the skin tumours come from stem cells in the engrafted kidney.  It's very tantalising and very interesting.

SA:  Goodness!  And are there a lot of viruses that can do that?  Is Kaposi's caused by a virus?

NW:  Yes, herpes virus.

NW:  And is this phenomenon only observed with kidneys?

The challenge now is to understand the mechanicsNW:  No, you get the same thing with lung transplants.  Because in the kidneys and the lungs there are these things called mesenchymal stem cells – those are the stem cells which give rise to the connective tissues of the body, but they can also give rise to epithelial cells, and in this case that's what they're doing.

I'm not saying this happens in every case, but it has been reported. And the challenge now is to understand the mechanics of it – what makes it happen, basically.

Teasing out the mechanisms of repair

SA:  Is that what your lab is looking at?

NW:  Mm. We're trying to do that, yes.

SA:  So give me some of the excitement of the moment…When you first found this you hadn't anticipated it?

NW:  No. We thought that bone marrow stem cells give rise to bone marrow, gut stem cells give rise to the gut, kidney stem cells give rise to the kidney, etc etc.  We didn't know there was this ability to change tissues, basically.

SA:  And how much plasticity do you believe there is now?

The trick is to find out what triggers itNW:  Well I think there's a lot of plasticity potentially, but it doesn't happen very often.  The trick is to find out what triggers it and try and expand it, basically.  So I mean, if you give a bone marrow transplant to an animal and you damage the skin, about 14% of all the cells in the skin come from the bone marrow transplant.  In the kidney, if you damage it, it's about 7%.  So it's not a large number.  But there are animal models of liver disease where almost half the liver could be taken over by the bone marrow transplant.  It depends on the amount of damage you're able to produce.

SA:  This is an attempt to repair the damage, is it?  A sort of maintenance programme that goes a bit haywire?

It's pretty controversialNW:  Yes.  I mean, if you want to be teleological about it, there's a reserve of cells in the bone marrow which, when things are going wrong, can actually produce stem cells for other tissues.  That's the concept behind it.  It's pretty controversial, not everybody accepts this.  But there's a growing body of evidence suggesting that it's true.

SA:  So what do you have to do to convince people?

NW:  Well, it is widely accepted by a lot of people, but there are several leaders in the field who doubt it basically.  But you know, the number of papers coming out confirming our observations in the gut …30 or 40 groups are showing that what we did in the gut is true.  So I think it's highly likely to be true. 

SA:  How much hands on research do you do now and how much are you managing a team of people who are doing the microscope work?

NW:  Well a lot of this is molecular -- highly detailed micro-dissection and PCR SequencingThe process by which the exact arrangement of the units of information on a specific stretch of DNA, or a gene, are determined. -- and I don't do that.  I just come up with the ideas.  But I plan the experiments with clinical fellows, PhD students and post-docs, and help them analyse them.  And if there's any problem with the interpretation under the microscope then I will do that, because we're looking at diseased states – we're looking at gastric tumours, we're looking at colonic tumours, and I'm the one who has to say, "Well this is an adenoma; this is a CarcinomaA type of cancer that starts in epithelia, the tissues that line or cover most body organs.  At least 80% of cancers are carcinomas (see also sarcoma, leukaemia, lymphoma).".  So if you're a pathologist and you're running a basic science laboratory like I am you're in a very happy position, because the scientists depend on you to tell them what the tissue is.  And you have the medical background to say, "We should do this, because this is important clinically", or something, and that's the interesting thing about it. 

Without being medically qualified and having a pathological training, I don't think you can actually do a lot of the things which I've done in studying disease.  I mean, in the research institute where I work there are only two medically qualified people – one is a geneticist and I'm a pathologist, the rest are all pure scientists.  So we do pretty basic research, but my interest is pathology -- basically, how lesions develop in the gut with special reference to stem cells.  And it's a very happy position to be in, being a pathologist in a basic science institute, because you can do a lot of things that they can't do.

SA:  And you get a wider perspective, do you, because you're working with patients?

NW:  Oh absolutely.  You see we work on human tissues – so we get real human tissues from patients.  We do some animal work but mainly now it's humans.

SA:  One thing you haven't done is to give me any examples from your case book…

I've been turned on by diseaseNW:  Well I don't want to disappoint you, but I'm not that sort of pathologist!  I've never been turned on by individual cases, I've been turned on by disease.  The things that have made me think a great deal are the appearances you see with just ordinary cases -- when you're looking at a duodenal biopsy, when you're looking at an ileum biopsy in Crohn's disease, you see changes and you think, "What is going on there?"  When you're looking at a Barrett's oesophagus, you think, "Why is that how it is?"  They all look the same, these are all common diseases, right?  But for example, in Barrett's oesophagus and in the stomach, most of the common cancers don't develop actually straight from the ordinary epithelium.  The epithelium changes, and that change is called a metaplasia.  So the stomach epithelium changes into intestinal epithelium (it's called intestinal metaplasia), and the lining of the oesophagus becomes intestinal metaplasia too.  Now, trying to work out why that happens is the thing that really turns me on.  So it’s not individual cases, it's phenomena.  Looking at the stomach, "Why does this gastric Epithelium  The layer of cells covering most of the body's structures and organs, internal and external.  It includes the skin. suddenly change into intestinal epithelium?  And why is the intestinal epithelium more prone to get cancer?"  Those are the things.  It's really disease processes which turn me on, rather than cases.

You know, many pathologists will just say, "Right, intestinal metaplasia.  Next case."   But my way of thinking is, "Well yes, but why is it that?  How has it suddenly changed?  Why has this gastric stem cell suddenly changed into an intestinal stem cell?  And what are the stimuli for that?  What are the genetic changes?"

SA:  And what are you discovering?  Have you teased out any of the things that are stimulating a stem cell to make something in the wrong place?

That's the $64,000 questionNW:  No, that's the $64,000 question.  The change from one stem cell to another stem cell is the trans-differentiation event we want to try to understand.  And the phase we're at at the moment – we know how it happens, right? We know how the metaplastic cell colonises the gland and becomes an intestinal gland, and how that gland then spreads through the mucosa.  We know the names of the genes which are involved, but now we've got to find out what's happening to those genes to make the whole thing change.  It's a long process and I won't complete it by the time I retire.  But at least we'll get somewhere.

You see, many people are turned on by cases they've seen, individual cases, rare cases; I'm just turned on by processes. 

SA:  So that's a research brain!

NW:  Yeah, well I'll show you a picture; I'll print it off for you…How these mutant stem cells grow, when they get mutations how they grow. 


New molecular tools

SA:  Okay, so in your time as a pathologist, what have been the big technological advances that have allowed you to do this, to make these discoveries? 

NW:  Well obviously things like Immunohistochemistry A technique that uses antibodies labelled with fluorescent or pigmented dyes to identify, or indicate the presence of, specific proteins in tissues when looked at under the microscope..  When I went to Oxford in the mid 70s this technique was just being worked out by people there, David Mason and others.  Now that's routine.  In situ hybridisation A technique allowing scientists to identify particular DNA or RNA sequences while these sequences remain in their original location in the cell.; localisation of messenger RNAstands for ribonucleic acid.  RNA, like DNA, is found in every cell of every living thing on earth.  The relationship between the two, in summary, is that DNA makes RNA, and RNA makes proteins.  In other words, DNA is the director of the process of protein synthesis and RNA carries out the instructions. …The thing that has really made these advances possible is molecular biology.  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). technology -- recombinant DNA technology -- enables you to actually dissect out pieces of tissue using what's called a micro-dissection apparatus.  So you can dissect that whole "crypt" there [he's showing me the diagram he's printed out] and you can actually extract the DNA from it and look at the genes you're interested in from these tissues, these paraffin-embedded tissues.  And you can find the mutations in them.

 SA:  My goodness! So what is a crypt?

NW:  [He refers back to the diagram again and takes up his pencil] A crypt see these blind-ended little tubes in the wall of the epitehlium? 

SA:  What’s the purpose of them?

NW:  Well, it’s the way the gut is designed.  There are various theories about why you have crypts...So the stem cells are down here [pointing]...They’re probably designed to preserve the stem cells in the base of the crypt.

SA:  Which is where the stem cells live?

NW:  At the bottom of the crypt, yes.  [He continues to discuss the diagram he has drawn of the spread of mutated cells, which is the process he is interested in.]

SA:  So have you had to learn genetics?

This sort of stuff just wasn't dreamed ofNW:  Well yeah, you have to pick that up.  I mean this sort of stuff just wasn't dreamed of, not even when I wrote that book, you know?  Twenty-three years ago we never dreamed you could actually get ordinary tissue sections and extract 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 look at the molecular make up by techniques that we have now.  And in specific cells – you can dissect out individual cells. 

SA:  So you can find out where in tissues the tumour started?

NW:  In individual cells, yes we can.  Yes, absolutely.

SA:  Obviously it's very important to understand the mechanisms, but has this led yet to new treatments?

NW:  No.  I think one of the pleasures of working where I do is that no one is looking over my shoulder and saying, "Where's the clinical relevance of this?"  If my lab was in the medical school, or being funded by different people, they may say, "Well you know, how's this going to be translated into treatments?"  It won't be, but you can conceptualise quite easily.  If you could intervene here and stop that crypt from expanding, or intervene here and stop the rest of it going on down there, through understanding the process by which these crypts actually expand, you could stop these lesions growing.  Now that's a long way off, because we don't know the mechanism of the process which drives this yet.  But we will do.

SA:  So what motivates you?  Is it intellectual curiosity?

There should be room in the profession for people like meNW:  It's disease.  I've always been interested in disease.  I mean it's hard to put over.  You can say that disease does not exist outside humans, right? So you must therefore be interested in humans.  And I say, "No, I'm interested in the disease process itself."  This would not be a very good thing to say to a modern interviewing committee if you wanted to get into medical school, quite frankly, because they're looking for empathy, and for communications skills etc etc.  But I think there should be room in the profession for people like me, who is not interested in people as suffering patients, but in the disease processes that they suffer from -- as an intellectual exercise basically.  Because from that will come eventually an understanding of how these things can be prevented.  But until you understand the mechanisms you're not going to do that.  So, I'm not the sort of person who set out to heal suffering humanity – no, not at all.  Disease is what's always turned me on, basically, and how the tissues respond and how they try and heal themselves.


Fallout from Alder Hey

SA:  That leads very naturally to the question of the status of pathology at the moment.  When I spoke to you before it was soon after Alder Hey, there was huge fall out and people were very depressed, and saying that the difficulties of doing research were really profound then.  Where are you at now?  Have things settled down or got worse or what?

It's far more intrusive than they thought it would beNW:  Well, I think people are coming to terms with the Human Tissue Act basically, and it's far more intrusive than they thought it would be.  You see, it all went terribly wrong in England, because the Alder Hey and the Bristol things were about autopsy tissues, right?  I can understand the problems with that, but the English government said, "We're going to wrap all tissues up together."  Now, all my research is done on surgically-acquired tissues, and the Retained Organ Commission that investigated things post Alder Hey, post Bristol (this was Professor Margaret Brazier from Manchester), they never intended that their legislation should be applied to surgically-acquired tissues. 

But the government stupidly rolled them up into it.  So now surgically-acquired tissues are governed by the Act.  But not in Scotland, because Scotland said, "This is nonsense!"  Quite right, it's nonsense.  Now we have the bizarre position whereby surgically-acquired tissues in England are governed by the Act and you have to get all this permission and stuff, and in Scotland you don't have to do it.

SA:  So you mean if you've diagnosed a lump or something, you then have to chuck it in the bin?

NW:  No.  What you have to do is to make sure that the patient has said, "Yes, I don't mind having my tissues used for research", right?  And it's not entirely clear what that consent means.  Is it consent for this procedure or for a procedure you want to do in the future?  So it's very difficult and people are only coming to terms with this now.  But in Scotland, research and training for research are not scheduled purposes for tissues as they are down here.  We thought we'd got training for research out of the Act, but the Human Tissue Authority is interpreting it that if you're training for research it has to be on consented tissues.

SA:  Well how bad is this?

NW:  It's stupid!

SA:  But how much of a problem does it cause or have people got very good at asking for consent?

The legislative burden is just ridiculousNW:  Well, you know, the point is you can't use tissues unless they're consented, basically.  So up until the Act was passed -- all tissues [collected] before [then] are assumed to be consented.  But prospectively they have to be consented.  It's too early to know the impact of this, but the legislative burden… I mean, you have to keep records of all sections you've cut of these tissues used for scheduled purposes, which is just ridiculous.  You cut 50 sections, you have to make a note of [every one], and then you have to dispose of them properly because they're under the Act – you can't just chuck them away, they have to sort of be incinerated and a record kept.  Because it's a human tissue you see!

SA:  So it's a massive administrative burden.

We have to get this Act changedNW:  Yeah, absolutely.  And Lord Jenkin, who's been a real help to us in these things because he understands them, he was on this recent human fertilisation committee and he said the time was now ripe for the government to have another look at the Human Tissue Act, but they don't want to do it.  And what we want to do is get ourselves in the position that Scotland is in now.  If one was tempted to run for the presidency of the Royal College of Pathologists, that would be the platform…We have to get this Act changed.  I mean, you may make yourself extremely unpopular, because you'd be accused of scratching old sores.  But somebody has to do this, because it's just completely ridiculous.

I've written to Rosie Winterton [then Minister of State for health], but she said, "We're not doing this.  There's no chance of us changing the Act…"  So it would need a major effort by the Royal College or getting all the other presidents of the royal colleges together to say, "This is nonsense.  Scotland got it right; England got it wrong; what are you going to do about it?"  And make a big fuss about it.

The autopsy rate has gone right downSA:  From the point of view of the general public d'you think the fuss has died down -- calling you "doctors of death" and so on -- or do you think the stigmas is still strong?

NW:  Certainly the paediatric pathologists suffered.  A lot of them left the profession and there was quite a lot of fright among some other members of the profession. But it's gradually died down.  It's pretty clear that the Royal College of Pathologists didn't play a particularly good role at that time in terms of sticking up for the profession, so we got rolled over with the Human Tissue Act.

And there are precious few autopsies done these days.  Hospital autopsies are apparently unheard of, and most of them are forensic autopsies.  To get a fully consented autopsy, where you can do an old fashioned autopsy, is quite unusual.  And there are forms for children, and different forms for adolescents, and adults… I think in most places the autopsy rate has gone right down.

SA:  But has that put some sort of brake on medical advance?

NW:  Well, it's hard to say, you see.  Because the way in which autopsies have really contributed to medical advance is the recognition of new diseases.

SA:  Like new variant CJD?

NW:  Well, absolutely.  I mean new diseases are coming along all the time and unless these are recognised and the pathology worked out at autopsy we're not going to understand them.  So it's too early to know what the effect of this is, but it's likely to be severe.

SA:  What immediately strikes me is that there's been a lot of concern about the effects of climate change and globalisation -- mass movement of people, new diseases crossing boundaries and so on.  Is it going to be more difficult to recognise those if...

NW: ...if people are not having autopsies?  Yes, indeed.

SA:  Are you as turned on by pathology and this quest as you always were?

I can't imagine life without researchNW:  Oh yeah, I couldn't live without it.  I was talking to some American guys and they were saying that none of their deans were involved in research and how did I find time to do it?  And I said, "Well, I couldn't not do it!"  I can't imagine life without research, no.  When they make me close my lab I'll have to retire, basically!

SA:  Are you still full of ideas?

NW:  Oh yeah. Odd times, when you're shaving, or when you're listening to somebody talk, things suddenly strike you and you write them down.  Eventually they get done.

SA:  What about autopsies, do you still do them?

NW:  No.  I haven't done autopsy work for a long time.  Not since I was Professor of Pathology at Hammersmith -- I used to do occasional autopsies there.  But I've never really been an autopsy pathologist, I've been a surgical pathologist, so I actually diagnose conditions in living patients – that's what I've spent most of my life doing.  But I'm well trained in autopsy pathology.

Influences and interests

SA:  How did you get specially interested in GI pathology?

You're moulded by the environmentNW:  Well it really came from my research.  I became interested in the way in which gut cells renewed themselves and that naturally led, being a pathologist, to me asking, “Well, what happens in coeliac disease, and what happens in ulcerative colitis and stuff?”  And I saw a lot of coeliac disease and ulcerative colitis, so I naturally gravitated towards GI pathology.  But I was interested in skins too, so dermatopathology became one of my interests also.

I mean, when you're a young man you can't just suddenly start doing research by yourself.  You've got to pick up ideas from the people around you.  And in Newcastle, Adrian Morley, who I mentioned, he was interested in cell division in the prostate and I learnt a lot about measuring the rate of cell proliferation from him.  And a few other people in the department were interested in the same thing, so I naturally became interested in cell division and proliferation, and then in the gut.  So that was chance.  I learnt a lot from him and we wrote about 25 papers together.  Wherever you go as a young man – I was only 23 when I started pathology – you're moulded by the environment.

SA:  So who would you say have been your mentors?

NW:  They have not necessarily been pathologists.  I suppose the person who had a big effect on me was a man called Leonard Lamerton -- he was a biophysicist; he was Professor of Biophysics as applied to medicine at the Institute of Cancer Research.  He was interested in cell proliferation.  And I suppose the pathologist I admired for the research was  Dillwyn Williams.  He's still alive, he recently retired from his chair in Cambridge.  The way in which he worked out the cancer of the thyroid called medullary CarcinomaA type of cancer that starts in epithelia, the tissues that line or cover most body organs.  At least 80% of cancers are carcinomas (see also sarcoma, leukaemia, lymphoma).…He was working at the Hammersmith at the time with a man called [Iain] McIntyre, and Tony Pearse. Nobody knew much about medullary carcinoma but then McIntyre discovered the hormone called calcitonin, and, using very early Immunohistochemistry A technique that uses antibodies labelled with fluorescent or pigmented dyes to identify, or indicate the presence of, specific proteins in tissues when looked at under the microscope. methods, Tony Pearce identified it as a cell in the thyroid called the C cell.  Then Dillwyn Williams showed that the tumour in medullary carcinoma came from the C cell.  It was a lovely story, and I thought that was how research should be done.  He's been influential in my career, Dillwyn Williams.  I wouldn't necessarily want him to know about that because we've had our rows in the past, but I do admire him greatly! [Laughs]. 

SA:  What outside your medicine turns you on?

NW:  I like rugby football.  I’m a bit of a fanatic about rugby football.  I like cricket.  I played rugby and cricket as a younger man at a reasonably high level, so I like that very much.  I like reading.  I’ve got my grandchildren...

SA:  What grandkids have you got?

NW:  I’ve got three, and one on the way.  I’ve got a six-year old grandson called George who I get on very well with. 

SA:  And what children do you have of your own?

NW:  I’ve got a boy and a girl.    They’re in their mid to late thirties now.

SA:  And have either of them gone into medicine?

Failure was not an option!NW:  No, no, no.  My daughter said [medicine is] an awful lot of work for not a lot of money. Even in her choice of husband, she said she didn't want anyone who was going to be like me!  Because I think when you're a young academic making your way, you're not at home very much, so you do miss quite a lot of the kids’ upbringing.  You rely on your wife a great deal.  I probably see more of my grandchildren growing up than I did my own kids.  Because in your 20s it's a very critical point.

SA:  And were you quite a driven person?

NW:  Oh yeah.  I was determined to succeed.  Oh yes.  Failure was not an option!

SA:  Looking back across your life, what were you hoping to achieve?

NW:  I was hoping to produce the best department of pathology in the country, which I think I did at the Hammersmith.  I was hoping also to leave a cadre of individuals who would carry on the way I thought about pathology.   And I mean, there is a professor in Belfast, a professor in Liverpool, a professor in Birmingham, a professor in Nottingham, a professor in Hammersmith, a professor in Bristol – they’re all my boys, basically.

SA:  So are you disappointed that neither of your children wanted to go into medicine?

NW:  No, not really.  Not at all.  I think with children you’ve got to be very careful.  I think you should never try and live out your ambitions through your children.  They had to find out what they were interested in. 

SA:  Can you see yourself ever having done anything else?

NW:  Well, my wife often asks me that.  You know, "Would you do the same thing again?"  And I tell her I'd have done exactly the same thing again without any doubt at all.

SA:  How has your engagement throughout your working life with disease and death affected your attitude to living and dying? 

Disease doesn't happen to the doctors!NW:  Well, I suppose rather philosophically actually.  I think that once you're trained in medicine you never see other people the same way, there's no doubt about it. Doctors don't talk about this very often but before you've done medicine you accept other people just as other people, but when you’re a doctor you see them as potential patients – you never regard people the same way.  And then there's always this idea that I was taught: the patient is the one with the disease; disease doesn't happen to the doctors!

SA:  But at our age of life we've all had something -- what about your own mortality?  Is death still as much of a mystery?

NW:  Well, it's not a mystery.  It's more a feeling of resignation and acceptance.  Dying is a natural consequence of having lived, yes?  And you have to accept that.  There's nothing to be frightened of.  The only thing to be frightened of is the mode of dying, basically.  And knowing a lot about disease and disease processes, you just know a lot of the ways you can depart this mortal coil!  And you just hope it won't happen to you too soon.

SA:  What about religion?  Do you think religious belief is compatible with being a scientist?

Most doctors are pretty irreligiousNW:  Well I think atheism is as much an aberration as religious conviction, actually.  To have made the decision there are no supernatural forces at work is as ridiculous as saying that there are, because the evidence on either side is just not there.  And so I'm sort of healthily sceptical, slightly anti-clerical I suppose, because of the bad things that have happened through religion.  But I have an entirely open mind because I don't know the answer frankly – no one knows the answer.   You have to take refuge in a sort of healthy agnosticism really.  You see a lot of people die from a lot of diseases, and it doesn't actually encourage belief in a benevolent being looking after us.  So most doctors are pretty irreligious, I'd say.

SA:  Finally, is there anything else you’d particularly like to say about your life in pathology?

NW:  Well, I’m very glad I became a pathologist.  It's very difficult to explain to people why pathology is so interesting.  I mean it's quintessentially more satisfying than just diagnosing and treating patients.  Because you're making diagnoses, as a pathologist, in your professional life, and you're helping in the treatment of patients, but you also get far more opportunity to try and understand what's going on, what's actually producing the effects in the tissues. 

It's the easiest subject from which to design a research project.  For pathologists, every time they sit down in front of the microscope to do a load of surgical cases, with every slide they put beneath their microscope there is a problem to be solved, if only they can identify it.  It's there for you to ask the question -- and the techniques are there now for you to answer that question.  And so if you're interested in research at all, pathology's the ideal discipline to take up.


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