Kenneth Hillan - Full Transcript

Kenneth HillanVice President of Immunology, Tissue Growth and Repair, Clinical Development at Genentech, San Francisco

Interview location: Genentech, San Francisco
Interview date: Friday 16th November, 2007

 

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I'm Kenneth Hillan and I'm the vice president of immunology, tissue growth and repair, clinical development at Genentech, a biotechnology company in the western United States.

SA:  Ken, start off by telling me a bit about your background -- where did you grow up and did you come from a medical family?

KH:  I was born in Renfrew in the west of Scotland in 1961, born into a family that's absolutely non-medical.  My father always wanted me to be an accountant.  But actually I have two sisters, both of whom are nurses, so I guess the children went into the broader medical profession.  But there certainly were no aspirations on my parents' behalf for us to do that.

SA:  So when did you first get interested in the idea of a medical career?  Were you good at science at school?

Medicine was the only thing I'd ever thought about doingKH:   I was good at arithmetic, physics, chemistry, biology, so I guess those were my natural things.  I think I was always passionate about what could be done for patients. I was always intrigued by what doctors did.  I didn't have anyone in my family who was a doctor, but I always knew they were revered figures.  I'm sure that was part of the attraction from an early age.

Certainly it was pretty much the only thing I wanted to do.  The other thing I applied to do at university was pharmacy, but I was fortunate to get into medical school, and really medicine was the only thing I'd ever thought about doing.

SA:  You say you were motivated also by the idea of helping patients, but you've drifted into the side of medicine which is very un-patient-orientated, haven't you?

KF:  I would actually completely disagree with that.  One of the things that's really fun is that, potentially, you can have a much bigger impact on the lives of patients by bringing new medicines to specific diseases.

If you look at drugs like Herceptin or Avastin, really the impact you have on patients' lives -- and on physicians' ability to prescribe for patients with diseases that previously weren't treatable -- is pretty incredible.  You don't have the direct patient contact, so I think that is something you walk away from when you move into industry.   It's a very different perspective, but the benefits you can bring to patients are huge.

Paris and the world of transplant surgery

SA:  From studying medicine, how did you go into pathology?

The benefits you can bring to patients are hugeKH:  I studied medicine at Glasgow University.  I graduated in 1983.  I did my medical and surgical residences and had decided for some time that I wanted to be a surgeon.  My interest was actually in transplantation and immunology. First of all, after I did my residences, I had applied for a fellowship -- a French exchange fellowship organised through the Medical Research Council and INSERM, the French equivalent of the MRC  -- and was fortunate enough to go to the Hopital Saint-Antoine in Paris, and spend a year there in the largest GI [gastro intestinal] surgical unit in Europe.  I worked with a guy called Bernard Nordlinger who's a well-known surgeon in France.  And that was where I began to do my transplant research.

They were working on a programme of transplanting liver cells into different organs with the overall aim of encouraging those liver cells to grow and basically form a new liver. So, when you had liver failure, the potential was that you could augment liver function by transplanting these liver cells into the spleen, into the kidney...And I began to work on that research while I was there.  I was doing half time clinical (surgery) and half time research.  And in some ways it was that that actually brought me into pathology -- it was the liver interest research.

You could augment liver function by transplanting these liver cells into the spleen, into the kidneyI did that for a year, and it was terrific.  It really opened my eyes to the practice of medicine elsewhere, but also to research.  That was my first time of doing bench research.

When I went back to UK I did a year as a Cruden Fellow in Glasgow in the department of surgery, and continued my research on liver cell transplantation.  Then following that I'd applied for what we call the west of Scotland surgical rotation, and worked there doing my training in general surgery, but also with a special interest in transplants.  So I was part of the transplant team, in training, mainly doing kidney transplant actually, because at that time there were no liver transplant centres in Scotland.  (There subsequently was one in Edinburgh, but at that time it was all to do with kidney transplant.)

But I continued to do some work in the lab with liver cell transplantation, and I began to find things which were kind of interesting in terms of the pattern with which these cells grew.  Not being able to interpret Morphology (1) The form and structure of an organism or part of an organism.  (2) The study of the form and structure of organisms. , I had to go to people who were experts in the field, and right next door to where I was working was the department of pathology, at the Western Infirmary in Scotland.  I began to work with a guy called Alastair Burt who's now the chair of pathology in Newcastle, and I said, "Look I have these slides, have these cells, I don't quite know what to make of them."  And he introduced me to a whole new thing which became important from a biological perspective later, and that was the ability of cells to transform from one phenotype to another.  It's part of the concept of stem cells.  We began to do some research, and I got to know also Roddy MacSween who was the chair of pathology then, and his interest is also liver disease.  After working with them for a year I really became fascinated.  It opened my eyes to what pathology was.  I'd never thought of being a pathologist until then.

SA:  What had you thought pathology was up till then?


It opened my eyes to what pathology wasKH:  You know, like most medical students, I guess... There's an old joke which is: what's the difference between a physician, a surgeon and a pathologist?  A physician is someone who knows everything but is unable to do anything; a surgeon is someone who does everything but knows nothing; and a pathologist is someone who knows everything, does everything, but it's a day too late!

I think that was pretty much my vision, as a surgeon, of what a pathologist was.  Most of my encounters with pathology had been as an undergraduate medical student with these kind of old glass slides and microscopes that didn't really work.  It certainly didn't interest me at the time. And then, as you moved on, it was really on the autopsy service -- maybe some patient had died on the ward and you'd go down to see the autopsy.  So that was most of my exposure, and that didn't pull my chain!  It certainly didn't excite me.  It was on the research side of things that I began to get pretty excited, because I began to understand what morphological interpretation of things could bring in terms of knowledge.  So I was interested in that and then wanted to learn more about it. 

I began to understand what morphological interpretation of things could bring in terms of knowledgeTo cut a long story short, I hadn't quite finished my training in surgery, but I did my FRCS [Fellow of the Royal College of Surgeons] exams, and at the same time Roddy asked me if I was interested in coming to do pathology.  That was actually a big transition -- from being someone working day to day with patients, to moving into one of the lab-based specialties, into pathology.  But by that time I was hooked on pathology, and decided I definitely wanted to do that.  I wanted to develop an interest in all aspects of pathology, but specifically liver pathology.

And Glasgow was a terrific place to be, because, you know, Roddy was there in the department of the Western Infirmary in Scotland, Alastair was there, and one of the nice things is that they're a referral centre for liver biopsies from all across the world.  So you'd get people from Hong Kong, Australia, wherever.  Actually San Francisco was one of the places, and Linda Ferrell, who's the chair of pathology at UCSF [University of California, San Francisco] who'd spent some time in the department when they were setting up their liver transplant programme, she came across to Glasgow. 

And we would get biopsies from everywhere.  It's one of the nice things about pathology -- the camaraderie and the sharing of knowledge.  People will refer biopsies all over the place, and send them to someone like Roddy because he's able to help with the interpretation and diagnosis.  So it was a good place to learn about pathology training in general, but also specifically liver pathology.

SA:  It sounds as though pathology, as taught to medical students, often doesn't pull chains because, as you say, you get old machines that don't work properly and you're not really seeing what pathology is all about at that stage.  And you then suddenly did?

By that time I was hooked on pathologyKH:  Yeah, of course medical training has changed since I trained, but it's a very didactic specialty.  It was very much, "Here's a list of things you need to know, and here are the slides you need to be able to understand..."  You learnt about basic processes, but I think for a medical student who is really wanting to treat patients, wanting to be interacting with patients, that's really not very exciting.  You learned a lot, but really you wanted to be a surgeon or a physician, or a radiologist.  Very few people, I think, at that time wanted to be pathologists.

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SA:  Okay, and so then you suddenly decided you wanted to do pathology -- that was going to be your speciality.

KH:  That's right.  So I moved across into pathology, spent six years in the department of pathology in Glasgow, did my training, did my MRCPath, and also developed my interest in liver pathology.

During my time in Glasgow I also maintained an interest in research, and one of the nice things was that I was able to set up a lab that was supported by the people within the department.  We were able to get grants internally as well as external funding to help with that.  It was a great environment, actually, to learn some of the things that help people to be successful in the corporate world -- the ability to work with other people and share expertise.  I just found it a terrific environment to learn how to influence people to get things done, and that turned out to be very useful when I finally came into industry.

Amazing regenerative power of the liver

SA:  Okay, going back to what you were saying earlier about getting fascinated by the liver work -- I've interviewed one person who's doing research into regenerative medicine in London, Julia Pollok, but can you describe this kind of work to me as a lay person?  You were transplanting liver cells…?

KH:  That's right.  We would take whole livers (and we did this with animal experiments but also with human livers) and we would isolate the cells from the livers.  There are a number of different cell types within the liver, but the one we were most interested in is a kind of 'powerhouse' in terms of making proteins and detoxifying enzymes -- it is the hepatocyte.  So we would purify the hepatocytes (it was a technique I learnt when I was in France) and then we would transplant those cells into other organs.  We used mainly the spleen because that was an organ where we'd found that these hepatocytes would take, and where they would grow.

SA:  And they'd grow as liver cells, not spleen?

One of the remarkable things about the liver is its regenerative capacityKH:  That's right.  They'd grow as liver cells within the spleen.  One of the remarkable things about the liver is its so-called regenerative capacity.  It's one of the few organs where you can take out 70, 80, 90 percent of the liver, within a mouse or a rat, and within about 10 days that liver will be completely restored to normal.  And it grows back to its normal size and then it stops growing.  So there's this incredible homeostatic control mechanism around the size of the liver and the growth of the liver.  So one of the things we discovered was that if you transplanted cells into the spleen in an animal with an intact liver, they really didn't grow very much.  But when you then damaged the liver, by maybe removing some of the organ, all of a sudden the liver cells in the spleen began to grow as well.

SA:  But still in the spleen site?

KH:  Still in the spleen site.

SA:  So they wouldn't be functional?

KH:  So they would be functional, because the blood is still going through them, they're able to still filter things from the blood.  But it told you that there was some mechanism in the circulation which was able to control not just liver growth but also these liver cells that are in what we call an extra-hepatic site -- a non-liver site.  So there is some humoral  mechanism, there's something like a growth factor (and this was really my connection with Genentech, but I'll tell you about that later).

But the other thing that we found was that not only could you make them grow, but if you induced different types of liver disease [in the animal model], the transplanted liver cells would also show the same type of disease in the spleen.  So we weren't just seeing growth, we were also seeing that the intrinsic liver disease would modify the way these transplanted cells behaved.  Again telling us something about circulating factors that were controlling that process, and giving us some insights into the pathogenesisThe origin of a disease, and the chain of events leading to that disease. of the disease.

SA:  So they would get the disease, these new cells...?

It's that plasticity that's one of the things that is used to define a stem cellKH:  Yes, in certain types of disease, they would show the same phenotype.  For example, when you have what's called cholestatic liver disease you get this phenomenon where liver cells will transform into bowel duct epithelial cells.  And we would actually see then that same transformation occurring in the spleen.  So you would know that there was some factor, or something that was causing those cells to transform the phenotype to try and do a different job from the one that they were originally designed for.  And it's that plasticity of cells -- being able to change from one form to another -- that's one of the things that is used to define a stem cell.

SA:  That's amazing!  Was it only liver cells that you could do this with, or were there a lot of other things?

Performing at a social event – a barbecue and Blues lunch -- on Genentech campusKH:   There were other groups working on things like pancreatic islet cells, beta cells.  But livers, I think, are very particular because of this incredible regenerative capacity of the intrinsic organ.  That's a very unusual thing -- that these cells which are normally fully differentiated and almost never divide -- that suddenly, within about 24 hours of there being injury, almost every single one of them can be proliferating and can re-grow the liver within a matter of days in a rodent, and three months in a human.  So, that was the work.

SA:  Amazing!  So people with cirrhosis of the liver, they can mend the liver if they stop drinking, can they?

KH:  Well, cirrhosis is a disease which is basically characterised by liver cell damage, liver cell regeneration, formation of nodules, but the key thing is that you also get this scarring of the liver, this fibrosis.  And so the problem is, one of the things about a cirrhotic liver is that it's trying to regenerate, but it can't regenerate properly because it has the fibrosis which prevents it.  And in fact it's anecdotally known, alcoholics tend to have small livers and cirrhotic livers, and sometimes when they come into hospital and stop drinking, the liver is actually able to regenerate, but because it's regenerating within this cirrhotic confinement they can get portal hypertension [high pressure in the portal vein, the major blood vessel that carries blood to the liver], and those patients can actually end up bleeding to death when that happens.

So, because the liver is so damaged, you can never restore it to normal.  But the idea was, well, maybe we could put these cells -- isolated, without the fibrosis -- in a site other than the liver, and because they don't have fibrosis, those cells could grow and function more normally than the regular liver.  That was kind of the idea of the programme.

“Cell-based therapies are very challenging to implement”

SA:  And where did you get to with this?

KH:  You know, it's something that was never able to be translated into clinical practice.  One of the very challenging things is that liver cells in the spleen are likely to be killed very quickly by the host immune system.  Much more so than with a whole-organ transplant.  When you transplant across histocompatability barriers, they're rapidly rejected, and it's very hard to immuno-suppress that [with anti-rejection drugs].  This was a whole second piece of work I did, to try and get round that.  There are still people working on transplanting islets into the pancreas, or for diabetes into the kidney.  But though there are a few cases where that's been shown to help individual patients, it's never really been viable for broad application. 

Cell-based therapies are very challenging to implement in the clinicActually, one of the things you learn when you come into industry is that certain things can be done on a one-by-one patient basis, but if you really want to be able to impact all patients, something like cell transplantation is going to be extremely challenging.

SA:  And it's the immune system that's the big bug bear, is it?

KH:  Well it's the immune system; it's just handling the cells; it's finding ways of storing those cells for long periods of time prior to transplanting -- all of the challenges we still face today with stem cells.  I mean, as you know, there's a huge amount of interest, huge amount of investment in stem cell therapy, but very few stem cell therapies today.  And they face the same challenges.  Cell-based therapies are very challenging to implement in the clinic, other than on a one, two, three patient basis.

SA:  Going back to when you were doing  surgery, and you were most interested in transplants -- why particularly? And what were you doing?

I had to learn a lot about immunology and transplant in a very short space of timeKH:  At that time my research was in transplants, because I was transplanting cells.  I was faced with these challenges, and I guess necessity leads you to get interested in particular areas.  These cells were going to be rejected, and so I had to learn a lot about immunology and transplant in a very short space of time.  I was also in a transplant unit, so we were doing kidney transplants.  I was working with a team of people who know a lot about this, and I think you begin to build an expertise.  There was a lot of play off between my research and the clinical side: I could learn about the drugs they used in kidney transplants, and apply those into my experiments; and as you learn things from your experiments, you could potentially take those back into the clinic.

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Pathology training: “I learnt how little I knew as a surgeon about disease”  

SA:  How much time were you in the clinic and how much time doing research -- were you given your head?

KH:  It varied according to the training.  When I was in the Western, it was kind of one month on, one month off, when that was possible. But there's a year you do in your training where you go off to one of the smaller hospitals in the city, and that really was full time diagnostic surgical pathology.

SA:  And diagnostics meant what?  You were backing up the surgical teams, or what?


KH:  Well you were just working as part of the surgical team.  Basically, cases are coming through, you're doing the diagnosis, signing them out.  Also on the autopsy service, doing postmortem cases that would come through.  We'd split the diagnostic and the postmortem service so you'd have a month on autopsies and a month on surgical pathology.

SA:  And did you like the diagnosis and autopsy side of things?

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KH:  Yes very much.  And in fact one of the things I like most about the diagnostic aspect is that it's actually very challenging. The bits of tissue you get are all very different.  It's a very visual discipline, and so you have to be able to build pictures in your mind.  That's why the training takes a long time.

But one of the fun things is that because pathologists work together in terms of diagnosing cases, there's a terrific amount of mentorship in training.  That's one of the really nice things about the discipline, it's very one-on-one.  And people are always willing to help each other.  There are always interesting cases coming through that no one's ever seen before, and there's this camaraderie -- sitting round the multi-headed microscope together, some difficult diagnosis, somebody taking you through that and trying to figure out what the diagnosis might be, and how you'd guide the clinician who's treating the patient.

Breakthroughs and novel diseases

Who would ever have thought you could treat ulcers with antibiotics?One of the things I remember, when I went through training there were two particular diseases identified that were novel.  One was a Helicobacter infection in association with gastritis. You know, duodenal ulcers were common, but when I was at medical school nobody knew what the PathogenesisThe origin of a disease, and the chain of events leading to that disease. was.  Barry Marshall from Australia finally made the connection that it was an infectious organism that was involved, and it turned out that ulcers could be treated effectively with antibiotics.  Who would ever have thought you could treat ulcers with antibiotics?  It was while I was in training that all of a sudden everyone was looking at biopsies to identify these bacteria, because at that time they didn't have the other diagnostic tests. 

The second novel thing that happened during my pathology training was that it was the time of HIV and AIDS.  I guess I'd been exposed to this already because when I was a medical student I'd spent three months in Kenya.  That was in 1981, and at that time we'd seen a lot of what was known as Slim disease.  Nobody knew what it was.  The patients would come in and basically waste away and die, and nobody had any idea it was an infectious disease.  The patients would have TB and things, but it was really unclear what was going on -- that was at the Kenyatta Hospital in Nairobi.

Nobody had any idea it was an infectious diseaseThen when I came back (because obviously in pathology you're very plugged into all the new diseases) there began to be all these cases of pneumocystis pneumonia coming out of the United States.  And one of the things that was very interesting was seeing, as the years evolved, cases which had never been seen before -- whether it was pneumocytis, or an interesting viral infection -- and the immunodeficiency that went along with that, and then the HIV virus being identified.  Just being part of that whole period was, I think, pretty fascinating.

Actually in Glasgow there was relatively little HIV infection at that time.  One of the highest rates of HIV infection in Scotland was in Edinburgh, and that was because of differences in the practices in the drug user populations [between the two cities].  So Edinburgh had this rather high incidence, and Glasgow had almost none, because the drug user populations don't mix even though they're only 50 miles apart. That says a lot about Scotland and its culture!

But we'd get referrals of HIV cases, and cases where it was having an impact on the liver that would come from UCSF, from Linda Ferrell who was a very good friend of Roddy's.  I guess that was one of the fascinating things that evolved as I went through pathology.

SA:  So you were seeing brand new stuff?

Brand new stuff.  It wasn't even in the text booksKH:  Brand new stuff.  It wasn't even in the text books.  Or if it was, it was some tiny paragraph.  And all of a sudden it was becoming this huge problem, this huge disease.

SA:  What effect does HIV have on the liver?

KH:  Well it's really to do with the secondary infections that you see.  You can actually get Pneumocystis in the liver as well, though that's not usually what kills patients.  You'll see parasites in the liver that you would never have seen before, viral infections, viral inclusions.  It can have a multitude of different presentations in the liver, and the challenge was to be alert to the fact that when you saw something, not just to diagnose the infection, but to ask yourself also what was the reason for that patient getting that infection, and making the connection that it could be because of underlying HIV infection and immune-suppression.

SA:  So the biopsies didn't necessarily come with a history?

KH:  No, actually often they wouldn't.  It takes me back (but this is maybe a case you don't want to write up about), it reminds me of how differently people approached those diseases.  (I guess the same thing happened later with prion diseases.)  We had not had any cases of AIDS at the Western Infirmary in Glasgow.  Most of those cases went to Ruckhill Hospital, which was the infectious disease hospital, and there had been very few.  So we had really very little exposure to AIDS on the autopsy side.

And then the first case which came down to us was actually one of the consultants from the hospital.  It was a case that was all over the Daily Record, so it's well publicised.  He died of AIDS.  He was not known to be unwell, and he died, basically, overnight.  He came into the hospital very sick with pneumocystis, died, and then of course it hit the press that a consultant in the hospital was HIV positive and had been treating patients.

SA:  Were you involved in the autopsy and things?

KH:  I wasn't involved in the autopsy in that case.  But everyone knew about the case, and we all knew him as well, because he had taught all of us. So it was really hard when someone who has been your teacher, a colleague, dies, and then you see all the stuff being splashed across the press.  I think one of the things that was nice was that, being in the pathology group, people knew a lot about this disease and were able to handle it in a very professional way, despite all the media interest.

SA:  Okay, so other than that, what sort of things did you generally see as a young pathologist doing diagnosis?

I learnt how little I knew as a surgeon about diseaseKH:  I think you saw pretty much the full gambit.  I learned when I came into pathology… I'd been a surgeon, and I learnt how little I knew as a surgeon about disease.  Because pathology’s an incredible place for anyone in training to spend a year.  You just get exposure to all these different diseases from all across medicine.  It's just a great way to learn.

Down to basics: an autopsy with no mod cons

I do remember one of the things we always liked if we were on autopsy service.  We would cover the Western Infirmary, but we also covered the hospital in Oban, a town on the West coast of Scotland.  Maybe once every three months or so we would get sent up to Oban to do an autopsy, and it was great because, if you got up early enough in the morning, you could get up there, do the autopsy, put the organs into the various buckets and things (because you'd have to bring them back), and then you could go for a hill climb or something on the way back down to Glasgow.

We always went in pairs, and you liked it when you were on call and there was an autopsy to be done in Oban.  I remember myself and Annette Borland, one of my colleagues who's now in Sterling, were called up and it was a very well known bishop in Oban who had died.  It was actually the very first time I was up there, and one of the things about Oban is there's no electricity, and there's no technician to help you with doing the dissection, so you have to do everything yourself...

SA:  Why on earth was there no electricity?  You mean in the autopsy room?

The autopsy room was actually a chapelKH:  Yes, well the autopsy room was actually a chapel, so it was this very unusual place to go into.  I guess it was set up mainly for relatives to view the body, but it also served as a place where autopsies were done.  So you were literally going into this religious building, a chapel with an altar and things, and you had this body lying out which you had to do an autopsy on.  Obviously you don't do these things lightly, you're doing it for a purpose to try and get the diagnosis.  The bishop had died very suddenly, and the key question was: had he had a stroke?  If you're going to examine the brain that means you have to remove it, and I'd never removed a brain before. 

Robert McNeil, who was the technician at Glasgow, couldn't leave because of all the cases coming through the hospital, so we had to go up on our own.  So he taught us the day before how to remove the skull with a hand saw instead of the electric saw, because you don't get to use the electric saw in Oban.  And it's actually quite difficult.  You have to do it in such a way that you can take out the brain intact, and also so that when you put things back together again after the autopsy, the relatives can still view the body looking intact, because obviously that's very important.

He taught us how to remove the skull with a hand saw So we drove up early in the morning to Oban.  And it was just this very weird situation -- it was this bishop lying on an altar in this religious room, and we're having to cut this guy open!  We come to doing the brain and I get it all wrong... Now it's almost impossible to get the brain out, and finally it falls apart!

SA:  What, you cut the skull in the wrong place?

KH:  I cut the skull in the wrong place.  I didn't come down deep enough at the back...

SA:  Were you just too nervous?

KH:  I was very nervous! [We both laugh]  Because it really felt like you kinda shouldn't be doing this, but you knew you had to, it was your job.  Anyway, the brain came out in two bits!  David Graham, who was the professor of neuropathology, was going to pay special attention to this brain, and he really...He's a terrific guy, but he really didn't like it when people didn't do a good job of getting brains out.  And I came back with this slopped up brain in two pieces!  So, that was one of my interesting stories from going up to Oban.

SA: [We laugh] And did he give you a hard time when you came back with a bucket of bits?

Essentially the brain is like a mush, so it's very difficult to keep the shapeKH:  Well, I don't know if anyone has told you about the brain cuts, but when you take out the brain you actually don't touch it because it's very very soft, and if you just touch it at all you can almost make holes in it.  Essentially the brain is like a mush, so it's very difficult to keep the shape.  And if you're looking for infarct of the brain, or you're looking for, say, multiple sclerosis with inflammatory lesions, or old lesions, scars in the brain, it's very important that you maintain really good Morphology (1) The form and structure of an organism or part of an organism.  (2) The study of the form and structure of organisms. .  So we have this process where we "fix" the brains for three weeks, and they solidify, they become hard.  Then we have this very methodical way of cutting through the brain, in a specific plane, so you can look at all the areas you want to -- whether it's the brain of someone with Parkinson's disease, Alzheimer's disease, someone with a stroke.  Really it's a very careful procedure.  And to be able to do that you have to fix the brains. So the brain cut doesn't happen actually till three weeks after you've brought it back, so that you can really get a good diagnosis, and you can be absolutely certain about it.

SA:  And you say that in Oban you didn't have technicians or anything?  So you had to put the whole thing together again?

KH:  Well it couldn't be put back together again, it was put in a bucket.

SA:  No, I mean the bishop!


We had to put the bishop back together againKH:  Oh, the bishop! [We both laugh] Yes, we had to put the bishop back together again.  And the thing is that there were no lights in the place.  So you have to get up there early; you have to hope there's enough light when you get there, and then you kind of leave, nobody says goodbye or anything, so it's like you're creeping out with these buckets full of organs and things...It's a very unusual experience!

SA:  It sounds bizarre, it really does!

KH:  Well you know, that's part of a pathologist's job.  It's what we do. And it takes you into all sorts of interesting places.  I think when you start in pathology you don't necessarily realise what you will be doing.

Hazards of the profession

SA:  You were talking earlier about seeing new diseases like HIV and so on.  What about prion diseases, did you start to see that as well?

All of those autopsies were done with plastic instrumentsKH:  When you had cases that were suspected to be Creutzfeldt-Jakob disease, because no one was too sure about how that agent was transmitted, we were incredibly, incredibly careful about how we did the autopsies.  We would have very few people in the room.  And also, because it was known -- at least experimentally -- that you could pass on these prion diseases from surgical instruments even if you sterilised them, we actually had to make plastic instruments so that everything could be disposed of.  And so all of those autopsies were done with plastic instruments, which is very very difficult, and you really just had to be incredibly careful doing the autopsy. I was no specialist in that area.

As a pathologist you definitely expose yourself to risks -- especially to the potential for getting infectious diseases.  It's not uncommon...Oh dear, here I am doing an Edwina Currie!  It's well recognised that pathologists can catch infectious diseases from autopsies.  Hepatitis B is one of the commonest hazards because it's a very infectious agent.

I remember a specific case.  I worked with a lovely guy called Heffen Roberts, who was a chest pathologist from Wales and he ran the pathology at the Southern General. We had an autopsy case, myself and David Millan.  It was an old lady who'd died of double pneumonia on the wards. What was the cause of it?  We went down and we took out the lungs and we sliced them open, and it was just what we call consolidation -- solid lungs.  David and I were poring over this and we just couldn't figure out what was the cause, what was the likely agent.  Was it a bacterial infection?  Was it a viral pneumonia?  What was it?  And Heffen came in, this very experienced old guy, and he looked at it and said, "Oh boys, it's TB".

As a pathologist you definitely expose yourself to risksThis lady had tuberculous pneumonia, which is actually very unusual.  And you know, usually when you look down the microscope for the tubercle bacillus, you can spend like an hour trying to find one to make the diagnosis.  But our microscope was just full of them!  So there we were, in this room with TB everywhere!  So there are risks as a pathologist of catching diseases. 

SA:  And did you freak when you heard him say it was TB?

KH:  Yes, I certainly felt very nervous.  One of the things is, they always tell you, as a pathologist, that you should never be given the tuberculin test, because we're all exposed to a lot of TB and we can get a very bad reaction because we've got a very strong immune system against the tubercle.

Tuberculosis is one of the things that wasn't uncommon for pathologists to get in later life, particularly if they were diabetics or something, because they had been exposed to it so much as part of their job. 

There we were, in this room with TB everywhere!I actually caught the herpes simplex virus from an autopsy.  I had a case of a patient who had herpes simplex pneumonia.  I didn't know what it was before I did the autopsy, I just knew the patient had pneumonia, and when I was slicing the lung with the knife I cut my finger here -- you can still see. [He shows me the heel of his thumb.]  I sliced it with a knife and didn't think anything about it until about two weeks later, when I had a lot of pain at this site, and had little vesicles.  I went to see Liz McCruden, who was one of the virologists, and I said, "Kind of strange..."  I still hadn't had my autopsy case back, so I didn't yet know what the patient had died of.  And Liz said, "You know that looks like herpes."  She aspirated one of the vesicles and it turned out she was able to culture herpes simplex virus. 

I never had herpes simplex as an adult or an adolescent.  I had had blood taken because I'd worked as a researcher with the Medical Research Council, and it was stored, so they were able to go back to that and show that I hadn't been exposed to herpes simplex.  So I had definitely caught the infection from the autopsy, which turned out to be herpes simplex pneumonia.  I've had two recurrences since then, fortunately very minor, so that's fine.  But it's true, you can actually catch things from your autopsies!

SECTION 4

America beckons: taking a job with Big Pharma 

SA:  But autopsies were just a small part of your career as a pathologist, and you moved on from there?

I actually caught the herpes simplex virus from an autopsyKH:  Yes, that's right.  I was doing diagnostic surgical pathology. I developed an interest in liver disease, working very closely with Roddy.

There's a meeting called F.A.S.E.B, which is one of the American biological meetings -- you spend a week in Colorado, and I was lucky to have funding to go to that.  It was a week on the control of liver growth and liver regeneration.  We had had a collaboration with some people, actually at Genentech, on a factor called Hepatocyte Growth Factor, which had been identified in 1989.  It's very important for controlling liver growth.

SA:  And for telling the cells to stop growing when the organ had reached the right size?

KH:  No, it's not that control mechanism.  It drives the growth.  There are other mechanisms which stop the growth. 

So I had gone to this meeting.  It was November 1993 and the people at Genentech said would I like to come to give a seminar?  I said, "Sure, I'll come and give a seminar."   And then they said, "Would you like to come and spend two years as a post-doc?"  I had never thought about coming to do research, but I ended up deciding to do so in 1994, and my boss Roddy was not very happy.  He said something like, "You're a loss to British pathology."  I guess he's sort of right.  

It was actually one of the very first therapeutic antibodies for cancerThen I went back and I actually looked at a job at Guy’s and St. Thomas' with Sebastian Lucas, and jobs in Bristol and Sheffield.  The first job I interviewed for was with James Underwood in Sheffield, and I didn't get it.  I kind of decided at that point that I would stay and become a pathologist in research at Genentech, so I withdrew from the other two positions.

At that time the pathology department at Genentech was very very small. But I had come here and done some really fun research on liver growth and regeneration, and had learned a lot.  And then had become a little bit involved with a thing called HER2 testing...

SA:  Which is a breast cancer thing?

KH:  Which is a breast cancer test.  The drug which is sold in Europe by Roche, but actually was developed here at Genentech, is Herceptin.  So this company at that time was working on the development of Herceptin, and was very interested in identifying the women with breast cancer who would be most likely to benefit from the drug.  And actually it was a whole new thing at the time -- nobody had developed a diagnositic that went along with a therapeutic, but there were a lot of people working on it.

What they had to do was the human experimentI wasn't the main person working on it but I became involved, because I was a pathologist, both in understanding the expression of HER2 across human tumours, and then also in how to get this test approved by the FDA [the US Food and Drug Administration] at the same time as you got the therapeutic approved (I think it was 1999 that Herceptin was approved.)  So I actually began to realise that our knowledge of disease, our knowledge of a gene like HER2 -- and the fact that it is what's called an oncogene  (a gene that can, under certain conditions, transform a normal cell into a cancerous cell) that was amplified in a quarter or a third of women with breast cancer – was extremely useful.  And then I began to understanding that you could make an AntibodyA protein produced by the body's immune system that recognises and attacks foreign substances. that targeted it, and potentially that that could be a therapy.  At that time that hypothesis was unproven, because the drug had not yet been approved.

SA:  So the antibody was at first just a test to see if that was the kind of cancer a woman was suffering from?

KH:  Well initially people had just identified... They knew that HER2 was an oncogene, it would transform cells. And it was also something which was amplified in tumours and was over-expressed on the surface of the cell.  So Genentech made an antibody to that AntigenAny foreign substance or organism that stimulates the body's immune system to produce antibodies and cells that react specifically with it. (the over-expressed protein that was driving the tumour growth) on the cell surface.  It was actually one of the very first therapeutic antibodies for cancer. The first one was Rotuxin, an anti-CD20 antibody for LymphomaCancer originating in lymphoid tissue, a key component of the body’s immune system.  Cancers of lymphocytes (lymphomas) and other white cells in the blood (leukaemia) together account for about 6.5% of all cancers.; and then the second one was Herceptin, which is an anti-HER2 antibody, for women with breast cancer.

The tumour has to be characterised.  And it's characterised by the pathologistThe key thing was to make an AntibodyA protein produced by the body's immune system that recognises and attacks foreign substances. that targeted the cell surface receptor on the outside of the cell, and would potentially, we believed, kill those cells.  There had been some very nice work done in the lab of a guy called Mark Zukowski as well as others, showing that if you took breast cancer tissue from patients, or cell lines from patients' tumours, and grew them in mice, then if you had this anti-HER2 antibody, those cells which over-expressed HER2, those tumours, their growth was stopped by this particular antibody, whereas those that didn't over-express HER2 would continue to grow.  So it seemed like there was a target, and if you had a specific antibody, you could inhibit tumour growth.

Then what they had to do was the human experiment, in a woman with breast cancer.  And it's actually an interesting lesson, because HER2 is over-expressed in just about a quarter to a third of women with breast cancer.  (Women with HER2 amplification actually have a very aggressive type of breast cancer -- it's more aggressive than the non-HER2-amplified breast cancers.)  And it turned out that if we had run clinical trials in all women with breast cancer, not selected for just those patients with HER2 amplification, the trials would actually still be running today. It would have taken a huge number of patients and a huge number of years to see the treatment effect, because we're only actually treating a quarter of the patients. But because we were able to get a test, a lab-based test, and select out the patients, and treat only those who were relevant, we were able to see the effect quickly and to have that drug approved in 1999.

So, Herceptin is only indicated in women who have HER2 amplification -- or CRB2 over-expressed (often in the UK it's referred to as CRB2) -- but only when they have amplification of the gene or over-expression of the protein.

SA:  So the tumour has to be characterised?

You're redefining the role of the pathologistKH:  The tumour has to be characterised.  And it's characterised by the pathologist. 

So I was here while all those kinds of things were happening, and it was kind of fun… 

SA: Was it exciting?

KH:  Oh absolutely! You're redefining the role of the pathologist and helping to make decisions about treating patients. There's clearly evidence of benefit in those patients from Herceptin in the metastatic setting [ie when breast cancer has begun to spread]. 

What was really exciting though was a couple of years ago, the data that were presented at ASCO (American Society of Clinical Oncology).  It was subsequently published and it's now been approved.  This was the thing that was recently in the press, which was the use of Herceptin in the adjuvant setting.  That's women with early-stage breast cancer, but who would be eligible for what they call adjuvant therapy, which is therapy to try and prevent the recurrence of the breast cancer.  When those data were presented at ASCO they received a standing ovation. And George Sledge said, "Biology has spoken, and we should listen to it."  Because their treatment effect was incredible: what Herceptin was able to do for those women in terms of cutting down the recurrence and improving disease-free survival.

SA:  But if it works by attacking tumour cells that are active, how can it work in women who are in remission -- who don't have active tumours anymore?


Biology has spoken, and we should listen to itKH:  Well they have to have tiny little islands of tumour cells somewhere, but you just can't detect them clinically.  The AntibodyA protein produced by the body's immune system that recognises and attacks foreign substances. is potentially able to kill them.  It's able to switch off growth of those cells, and potentially it's also able, through [a process known as] antibody-dependent cellular cytotoxicity, to kill those cells.  It actually works through the same mechanism as it works in the metastatic setting. 

It seems that often with what we call biologics (these antibodies are often referred to as 'biologics') the earlier you treat, the bigger the effect you see. Not always, but often the case.  But your first clinical trials are always in patients with very end-stage disease, simply because they are the patients with the biggest unmet need, the patients for whom there are no therapy options -- that's where you start, because the first injunction is to 'do no harm' to patients.  But it's once you're able to move these therapies back into the earlier stages of cancer that you often see what they're really able to do.

SA:  Okay, you say this 'redefined' the role of the pathologist.  Up until then what had it been?

The earlier you treat, the bigger the effectKH:  Very much diagnostic surgical pathology.  The real role of a pathologist is to make the diagnosis, and to help the physician with treatment decisions for the patient.  For example, with things like colon cancer, or breast cancer, the pathologist plays a very important role in 'grading' and 'staging' of the tumour, and that can really help with the surgeon determining: does this patient need, say, radiotherapy?  Does this patient need chemotherapy?

You know, as pathologists we call people 'the lumpers' and 'the splitters'.  Some people split things out into multiple diagnoses.  But the key thing is to make sure that information is distilled in such a way that a physician treating a patient is able to make a decision about what to do. That's why pathology is actually very satisfying -- you potentially have a big impact.  So...

SA:  What I can't understand is how pathology has ever lost its footing.  Obviously the clinicians need you, and it's a kind of partnership.  How has pathology become so stigmatised?

We call people 'the lumpers' and 'the splitters'KH:  Yeah... When I was doing my medical training only a small number went into pathology and it was often the people who were top in their year, often quite academically-inclined people.  I think pathology was attractive to a certain type of person.

In terms of losing its footing, I guess it's relatively misunderstood as a discipline.  Patients have no interface, in general, with the pathologist, so I think it's hard for them to appreciate what the pathologist does.  Most people think of pathology as doing the autopsy, and actually that's very little of what we do.  I mean, forensic pathologists do a lot of autopsies, but for most pathologists it's a very small proportion.

I wasn't in the UK during [the Alder Hey controversy] but I know about it from friends.  I think there were some things [at that time] which were standard practice in pathology and which parents weren't necessarily aware of.  Like retaining brains, for example.  Every single brain that was taken out at autopsy was retained, but we didn't necessarily say, "By the way, the brain has been retained."  And when that patient was buried, the family didn't know that the brain wasn't there.  So there was a lack of communication, and I think that was one of the big gaps: the communication of what happened to a relative when they had an autopsy. 

And I do think there were some just bad things which shouldn't have happened.  People did some bad things that obviously hit the headlines, and that really doesn't do a lot for the reputation of pathology.

SA:  What about in this country, because it's obviously a very different scene?  For one thing, you've not got a 'national' health service.  Who does autopsies?  And what's the status of pathologists here?  What differences have you found coming to work here after UK?

The rate of autopsies in America is incredibly lowKH:  One thing is that the rate of autopsies in America is incredibly low.  That's partly to do with the fact that they cost money.  And things that cost money, if they're not absolutely necessary, they're not done. The education component is not necessarily seen as 'added value'. 

Certainly the pathology community here, which has the same practices as in the UK, hasn't gone through what the UK did with the organ scandal.  So I think the pathologist here is held in relatively high esteem.  Also, one of the reasons people go into pathology here is that you can actually make a lot of money as a private practicing pathologist. If you're a skin pathologist, for instance, you do extremely well here financially.

SECTION 5

A perfect time to join industry

It was just incredible funSA:  Talking about industry, how exciting has it been branching into this, and what extra opportunities have you had?  What's been the difference from if you'd stayed in research back home?

KH:  One of the things is that I began to 'join the dots' between things that pathologists can do that they generally weren't doing -- and that couldn't be done by these companies without pathology expertise.  So being part of that, and being able to connect those dots, was just really fun for me. 

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Also, I came into industry at a time in research when the whole of the Human Genome discovery project was going on, and we were a very active part of that.  We probably had more patents than anyone, at this company. 

When you cloned new genes, one of the important things was understanding where those genes were expressed in the body, in what cell types, and what happened when you had disease.  Being a pathologist, I was able to bring that expertise and help to build a department.  So we actually played a very important role at that time. Then as we've gone on to things like the cancer genome project --  understanding the genes that are mutated in cancer -- with all those tissues you're using, and all those different tumour types you're looking at, it's really important that you have pathology expertise.

So we were very lucky in having a very strong pathology department here when all of those things were going on.  We were able to do things that many other companies weren't able to do, just because we had the right expertise in place.  We had very good basic science and really good pathology
, so we were able to figure out the line between the biology and the pathology, the disease, and it was just incredible fun.  Also, being in a well-resourced environment where you could actually do those things, and still have collaborations with colleagues and friends back home -- like Phil Quirke and Alastair Burt and Linda Ferrell.  So, for example, with projects where we wanted to look at molecules and very specific diseases, we'd collaborate with those people.  Having that connection into the [wider] pathology community was terrific.

An “explosion” of information

Diseases like breast cancer are actually not just one diseaseNow, at Genentech, all of our programmes have what we call a diagnostic programme.  That means we want to have tests that allow us to match our drugs with the right indications in the right patients.  And again, I think, being a pathologist, you are able to help people understand that these diseases like breast cancer are actually not just one disease but are multiple diseases. We call them breast cancer because they occur in the breast, but there are the HER2 amplifiers, the ER-positive [oestrogen receptor positive] cases…  Helping people to understand that these heterogeneous diseases will all need targeted therapies, and being able to work with others to build a compelling rationale for why we should invest, not just in the therapy, but also in the means of selecting the patients….  Ultimately many of those tests for selecting patients will be used, we hope, by pathologists.

SA:  So has there been an absolute explosion in recent years in identifying different cancers -- you know, recognising that they're not just a single entity?

KH:  Yes, there's been a huge explosion in that, and also in the amount of information in data bases.  But the implication of the data isn’t absolutely clear.  A lot of work has been done by a guy called Guido Sauter, who invented what we call the ‘tissue micro-array’.  It's a way of looking at many thousands of tissues in one single slide.  He was able to use that technology to see how various genes were over-expressed in tumours (he could look at large numbers of human cases in a high-throughput way), and show whether or not that correlated with the clinical outcome of the patients.  In that way he was able to begin to tease out what might be the things that are important in driving disease -- helping us to say these EGRF-positive tumours are likely to be different from EGRF-negative tumours, for example. So we began to tease out, using clinical outcomes data and pathology, which were likely to be the important different types of tumours.

Pathologists are going to be hit with an explosion of new testsAnd in fact we also got insights.  As pathologists we'd often recognised that these tumours were different morphologically, as we'd looked at them under the microscope.  A kidney cancer could be papillary, or solid or clear cell.  And then we found, oh, the papillaries, they have the c-met mutation, and the clear cells, they have the VHL mutations.  So we began to recognise that different genetic mutations that we had recognised morphologically were driving these different tumour types.

So there's been a huge explosion, and part of the fun of being in pathology is matching back this kind of tumour with that gene mutation.  What needs to happen next takes a lot of time.  When you have a pathway that's driving a particular tumour, if you want to interfere with that pathway with a drug, for example, you have to do a full clinical development programme, and that takes seven to 10 years.   Pathologists are going to be hit with an explosion of new tests, and it's beginning. Erlotinib is an EGRF inhibitor, for example, and we're now beginning to test for specific mutations which cause resistance to that therapy.

I think you'll see, over the next five to 10 years, this whole thing exploding.  And poor pathologists will suddenly be faced with, "Wow, how do we manage all these tests?!  As well as making the diagnosis, now we have to go further so we can help with treatment decisions."

New opportunities for pathologists

SA:  And that is where, I suppose, you're in a unique position in industry – other pathologists may do research and so on, but they don't have the capacity to do the translational stuff.  Or it's not their role.

A lot of pathologists are beginning to collaborate with companiesKH:  Well I think actually more and more of them do now.  A lot of pathologists are beginning to collaborate with companies, and a lot of companies are beginning to build pathology departments.  So you're now seeing career opportunities, 10 years after I came into industry, beginning to open up.  I've seen people who I trained with moving into industry -- people are getting more and more involved in the translational aspects.

There's been a huge push – NIH [the National Institutes for Health], for example, in the US has designated 10 centres to be the first centres for really translational research, with very significant investments.  UCSF, UC Davis, Duke -- big centres.  And it's cross-functional collaboration, where the pathologist plays a key role in applying what we understand about diseases to the new medicines that are coming through.

New drugs in the pipeline

SA:  So what are the most exciting things in the pipeline at present in terms of new medicines that you're working on?

The pathologist plays a key role in applying what we understand about diseases to the new medicinesKH:  There are some things I can and some things I can't talk about!  We have a number of new molecular therapies approved, Glivac being a good example (from Novartis, not from Genentech).  But we have one drug that I'm particularly proud of because I worked a lot on it -- a drug called Avastin, based on a gene called VEGF that was cloned by Napoleone Ferrara here at Genetcech, and that is what we believe to be the most important factor driving angiogenesis, or the formation of new blood vessels.  The hypothesis was that if you could cut off the growth of these new blood vessels, you could starve the tumour.  And that proved to be true.  We made an AntibodyA protein produced by the body's immune system that recognises and attacks foreign substances. that neutralised it, we took it through clinical trials, and it's now approved throughout the world for four different tumour types -- colon, lung, kidney, and soon breast.

SA:  And how successful is it clinically?

KH:  It's been shown very widely to extend patients' lives.  It's the first time patients with metastatic lung cancer have been taken beyond a year of life, with therapy, from when their tumour was progressing.  They'd never broken through that year's barrier before.

Again with Avastin, we've got a lot of big programmes going on -- adjuvant programmes, moving that therapy into the earlier stages in the same way that we did with Herceptin.  Those trials just take a long, long time, and we're waiting anxiously for when we'll begin to get the data.

SA:  You said you were very involved with the Avastin story -- in what way?  Tell me about Avastin.  When did you begin to believe that you could cut off the blood supply to tumours?

If you could cut off the growth of blood vessels, you could starve the tumourKH:  It was really through the work of Napoleone Farrara.  VEGF was cloned in 1989, and then Napoleon and Jim Kim identified an AntibodyA protein produced by the body's immune system that recognises and attacks foreign substances. that neutralised the VEGF protein. Then they began to show in the early ‘90s -- 1993, I think, were the first publications, just before I came here, showing that the antibody could inhibit tumour growth.  Then after I came I worked a lot with Napoleon and his team, looking at the multiple different models where that would work.  We looked in particular for tumours that would be very sensitive, and those that wouldn't be sensitive, trying to understand the genetic drivers that might be causing the differences.  (Kidney cancer, for example, has a specific genetic mutation and seems to be very sensitive to this type of therapy.)  Then we began to go through all the translational aspects of taking that antibody from a mouse antibody and making it into a human antibody (I didn't do that, but other people here at Genentch did) then taking that human antibody, re-engineering it so it did what we thought it would do, and then starting a clinical development programme to take that molecule forward into the clinic.

At the same time we actually took that AntibodyA protein produced by the body's immune system that recognises and attacks foreign substances. and we did four different things to it to make it higher affinity.  We made it smaller, and we took away the Fc portion to make it into another drug called Lucentis that's used now to treat age-related macular degeneration, the commonest cause of blindness in elderly people.  Lucentis had just  remarkable clinical data in terms of restoring vision in those patients -- vision actually improved in a condition where it generally just continues to deteriorate.

SA:  So you can reverse the effects of age-related macular degeneration?

It's been shown very widely to extend patients' livesKH:  Reverse and improve vision.

SA:  And is it happening?  Are people using it?

KH:  Yes that drug was approved in 2006.  So from one discovery came two drugs.  Just being part of that, and working with a team that thinks through the diseases where that drug could be used, and then figuring out, “If it’s going to be used in the eye, what would you have to do differently?”

SA:  So what do you actually do now?  You've obviously crept really high in this organisation!  Do you still work at the bench, or are you an ideas man?

From one discovery came two drugsKH:  [Laughs].  I neither work at the bench nor do I have very many good ideas!  But I work with lots of people who have great ideas.  Actually I finally gave up my microscope four years ago.  Terrible for a pathologist to admit that, I know. 

SA:  What did you feel giving it up?!

KH:  It was a big decision to make.  I should say I still obviously interact with the pathologists here and I still see pathology and stuff.  But I moved, I guess, more into a role of managing and leading people.

SA:  And how do you feel about that?

KH:  A couple of things.  I really enjoy doing research and being at the bench.  But you begin to realise that in terms of your sphere of influence, you can probably help more patients by making new medicines.  So I could do fun research and really enjoy that, but I actually also enjoy working with people, working on teams, and helping people to think things through.  So I went into management and ended up being a vice president of the company.  And -- a really fun transition for me -- I currently head up all of the non-oncology clinical development programmes. We have two major clinical groups -- oncology, which has been my main area of interest while I've been at Genentech, and non-oncology, which does everything else from arthritis, asthma, blindness, etc. 

I finally gave up my microscope four years agoIn addition I head up what we call our ‘diagnostics piece’ for all of that area, so I still have wet-based labs and scientists in my organisation doing all kinds of work, from human genetics to bio-marker identification.  We have another group that translates those biomarkers within our clinical programmes into clinical practice, so, as we want to be able to select patients, we have a whole team of people who do that.  We also have what we call an exploratory clinical development group that tries to identify early on where drugs might work or not work, so we can make good decisions, and make those decisions early without huge investment.

I like thinking about how you would manage a portfolio, what's the best way to make trade-offs. I actually enjoy motivating people, working with them, helping to set priorities with them.

SECTION 6

The pleasures of pathology

SA:  But was it difficult, as you say, giving up your microscope?

You can probably help more patients by making new medicinesKH:  Yes, it was very very hard.  I still have all my pictures of histopathology images that I particularly enjoyed -- but I've just moved offices, so they're not yet on the wall.

One of the things I’ve always thought we should do, one of the ways to bring pathology to the public, would be to put on something like "the art of pathology" in one of the big museums in London, because it's a very very beautiful speciality, and the pictures are just very pretty.  And if you can take the pictures and actually explain the disease and what's going on, really tell the public, that would be a great story to tell.  Everything from multi-colour microscopy, through to just histological images, special stains, disease patterns --  I think the public would really enjoy it.  That would be a terrific PR exercise. 

SA: That would be tremendous!  You were saying earlier that you have to have good pattern recognition -- so there is an art, pathology is not purely a science?

It's a very very beautiful specialityKH:  It's a combination.  The histopathology diagnostic microscopy is definitely an art form, and it's being able to put together pictures in your mind -- even when you may just see one corner of a picture in your biopsy, you have to be able to put that into the whole picture of what's going on in the organ.  Being able to do that visually is one of the key things about histopathology.  But there's no doubt that it's very much based in science, and founded in strong science.  The discipline of pathology, the learning that goes on behind that, is all about the science.  I think it’s definitely matching the two.

By appreciating the patterns and the things that are changing in the tissues, and then bringing in additional scientific information, such as gene expression in the tissues, you can build both the artistic and the scientific picture that helps you to understand disease. Pathology is all about understanding disease and disease mechanisms.

SA:  You say it's very beautiful down the microscope, was there a thrill in using the microscope and looking at things?


Histopathology diagnostic microscopy is definitely an art formKH:  Oh yes.  Pathologists spend most their day looking down a microscope, and they enjoy it.  You never know what's going to come across your desk, and always, every single week of your life, you'll see something you've never seen before.  So it's just a fun discipline where you're never quite sure what is coming next.

SA:  What would you say have been the high points of your career?

KH:  There have been lots, but if I was really to say what the high points have been, I'd say it was always about the people.  Pathology's really a place where people look after each other, and one of the things I remember very fondly from when I was in Glasgow as a pathologist in training was just the camaraderie.  We had a woman in our department called Mary Catto, who's a very well known bone pathologist and soft tissue tumour pathologist.  When you were doing your month on service it was always very busy, and when you're young you're not as quick as you become when you get older and more experienced.  Every case was new, and you know, you’d be sitting there trying to report out your last cases, it would be six or seven o’clock in the evening, usually one or two other people around, and Mary would appear and she always had a cup of tea and a sandwich for you, or something to eat.  She was one of the best pathologists in the world in her field… It was just the fact that people cared a lot about the trainees, making sure we were well trained, well mentored.

Every single week of your life, you'll see something you've never seen beforeWhen we were coming up towards exams we’d take up a huge amount of people’s time in our training, because you have to see so much in such a short time.  Every single one of those people would give up their time willingly, to train and help us so that we could become the pathologists of the future.

So I think that in many ways the high point was the care and attention that people gave you.  Mary was really special.  Roddy McSween is another example -- again just somebody who’s able and willing to take you under their wing, to share their knowledge with you, and enjoy doing so.  And enjoy the time when you actually begin to challenge them -- show them things they hadn't thought about before.

It's incredible that people will spend so much time training you.  Pathology’s a discipline more than any other in medicine where you get training on the job every single day from someone else, basically.  They're helping you and showing you cases that they have.  They'd maybe come to you saying, "Look, I've got this referred case, what do you think of this?" 

Pathology's really a place where people look after each otherFrom a diagnostic perspective there were always trick cases that people would show you.  One of the ones that's very hard is telling the difference between fracture callous and osteosarcoma.  It becomes very obvious later and one of the nice things is the moment when you can tell the difference, but that's a very bad thing to get wrong -- you don't want to make a diagnosis of osteosarcoma if it's actually fracture callous, though they can look very similar.  You have to see a number of cases before you can see it's obviously different.  But until you get to that moment it's very hard, so having people keep throwing you cases until they know you'll never make a mistake between osteosarcoma and fracture callous is very important.

SA:  Okay, you've mentioned Roddy MacSween and Alastair Burt and people like that, I presume you see them as your mentors do you?

KH:  Alastair was my peer but just about two or three years ahead of me.  Roddy was obviously like a mentor for me because he was the head of department. I was one of the new breed of what they called molecular pathologists, and when I went through my training the ability to apply these new molecular techniques -- 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 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. techniques -- with tissues was just happening.  So I worked a lot with a guy called Phil Quirke who's at Leeds University, who's mainly known for his work on colorectal cancer, but also was one of those kind of molecular pathologists.

SECTION 7

The world of molecular pathology

SA:  And how would you define molecular pathology as opposed to other sorts?

KH:  Rather than looking at the cells and the patterns in tissues, it's drilling down that bit further and looking at the genes that are within those cells.  So you're kind of taking things down to the next level. You're looking at the 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. and 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). in the cell.  We talked earlier about HER2,  so looking not just for the tumour cell, but showing that that tumour cell had the HER2 gene amplification -- that would be the molecular piece of pathology.  And that was all very new at the time I came into pathology.

Anne Marie McNicol is an endocrine pathologist at the Royal Infirmary, and I spent a couple of months working in her lab to learn the techniques they had there so I could bring them back to the Western and apply them to our cases.

SA:  So this was brand new technology?

We went back to the historical samplesKH:  This was brand new. My interest was liver disease and I remember when I was working with Roddy, basically you had cases of Hepatitis A virus, and then there was hepatitis B virus, and there was so-called hepatitis D.  And then there were a whole bunch of cases that were known as ‘non A non B’ hepatitis, which were commonly seen post-transfusion, so transmitted often when you'd taken blood from an infected donor or from drug addicts, which was reasonably common in Glasgow.  In 1989 Michael Houghton, who actually was a scientist working at a company called Chiron just across the Bay over there, cloned this new virus, hepatitis C.  It was one of the big things in liver pathology, that this virus was cloned.  And one of the fun things was to figure out, with all these biopsies that we had stored away as ‘non A non B’, which of those cases were actually hepatitis C, and then to see what was the pattern of liver disease that characterised hepatitis C. 

SA:  So you did that, you went back to the historical samples did you?

There was a whole series of cases from the 60s that the cockroaches had eatenKH:  We went back to the historical samples.  Annette and I pulled out all the cases from the archives.  I don't know if you've been into a pathology department but often, in the bowels of the department, you have all these blocks of paraffin wax with tissues in them.  -- in Glasgow going back to the 1800s.  I mean it really starts that far back.  There were gaps in the war years when there weren't blocks, and there were gaps in the '60s. It turns out that paraffin wax is loved by cockroaches and there was a whole series of cases from the 60s that the cockroaches had eaten in Glasgow -- the paraffin wax and the tissue had all been eaten away.  But otherwise every single case is documented, archived, so we were able to go back and pull out all the ‘non A non B’ hepatitis cases that had been diagnosed, and then use molecular techniques -- working with people at the Medical Research Council, the Virology Institute, which is also in Glasgow -- to identify those cases that had this virus that had now been identified by Michael Houghton in Chiron.

We were able to apply techniques such as 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., and polymerase chain reaction which was an evolving science at that time.  PCR hadn't been invented in the early '80s, it was invented later.  So we were able to take those cases, those tiny slices of biopsies of liver disease, take a section, take out the nucleic acid, see if that virus was there, and then begin to piece the picture together.  Once you identified the cases, then you could look at the morphological pattern that characterised hepatitis C.

That was all new science, emerging scienceThat was a fun project, and that was all new science, emerging science, new molecular techniques we could apply in the tissues.  But the key thing was still having that archive of tissue stored away so that you could go back and look, and "Wow, yeah, we do know what these cases are!"  So moving forwards we were able to say, "Yes, this is typical of hepatitis C."  It changed the way we would report cases -- all of a sudden, as we got all these biopsies of patients, we could identify hepatitis C.

It's also interesting, I think, that if you go back into the archives you get to see just how different the patterns of disease were at different times.  If you look at the autopsy reports from before the days of antibiotics, people were dying of pneumonia, infectious diseases, it was completely different, it's infection after infection after infection, compared to what people die of today -- cardiovascular disease, strokes etc.  That’s just a fascinating insight into how things have changed in the country in terms of health. You can see this of course in graveyards -- look at the age of the people who were dying and it was often much younger than they are today.

SECTION 8

“Work hard, play hard” 

SA:  Okay, turning to more personal things, what do you do when you're not working in this fascinating field?  You said that when you went up to Oban you used to like hill walking on the way back...?

It changed the way we would report casesKH:  I still like hiking.  I have a place in West Marin.  The peninsular that we're on, this place called the Bay area, I guess, is a very intense concentration of people and industries and hi-tech and universities and things.  And yet if you just cross the Golden Gate Bridge you go into Marin County and much of it is protected land. It's really beautiful and you can hike and go places where you don't meet anyone, even though you've got millions of people living here.

So I enjoy doing hiking. And I'm a keen swimmer.  As a kid I used to swim.  I swam in my university team, and won, the first year I was there, the Scottish universities' championship for backstroke and various things.  In the Bay area, a lot of people swim.  There 's a school pool just down the road, a beautiful 50 metre outdoor pool where you can swim all year round.  A terrific team, lots of ex-Olympians, and I swim there four mornings a week.  I still compete.  I swam last year in the world masters.  There were 10,000 competitors who came and swam at Stanford, and there was a guy of 94 from Japan who smashed the world record for the 100 metres backstroke! 

Just a fascinating insight into how things have changed in the country in terms of healthHere it's a much more sort of outdoor lifestyle than in the UK.  It's partly due to the weather, of course, but also Californians are kind of the ultimate in terms of fitness consciousness.  So I enjoy that.

I also enjoy eating in good restaurants.  And I enjoy cooking.  I'm not the world's best cook, but I do enjoy cooking a great deal.  I'm a kind of Nigel Slater type of person.   I really like his recipes -- not too fussy, simple but very tasty, and reasonably easy to make.  He's the one of all those UK chefs I'd like to meet most; I'd like to have him cook a dinner for me.

I also enjoy science.  I still attend meetings and am still very involved in that.

SA:  And do you manage a reasonable balance between work and play?

KH:  We have a ‘work hard, play hard’ kind of mentality here.  One of the great things about working in this kind of place… When you work in the national health system there are always lots of reasons why things don't get done, and lots of barriers that are difficult to fix, and one of the nice things here is that we decide how things will be done.  We make the rules about how we do things, how we work together.  So it's fun, you can actually get things done. People who just like to point out problems all the time don't do so well here, whereas people who say, "Well here is the solution to that" do do well. It's a kind of 'can do' place.

We have a ‘work hard, play hard’ kind of mentality herePeople definitely respect the idea of taking time off.  The company was founded by a [couple of] guys called Herb Boyer and Bob Swanson.  Herb was a scientist and Bob was a finance guy. They founded this company based on what was called recombinant 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.  They figured out how to slice genes apart and put them back together again.  That was really the basis of what this company was formed on. 

SA:  That was brand new?


KH:  That was brand new. They were the first people to have done that and they had the IP [Intellectual Property, or patents] round it.  Herb said, when he first came here, “People work hard, play hard”, so he wanted to have a sabbatical programme.  We still have it -- every six years you can get a sabbatical to go and do whatever you want for a couple of months.  That's one of the core things about the company.

Every six years you can get a sabbaticalMy first sabbatical I did a round-the-world trip.  I started off in Europe and Greece, and then went down to Botswana and spent some time in the Okavango Delta, then went to South Africa, and then to Madagascar to see the lemurs.  The whole trip was based on NPR [National Public Radio].  There’d been a thing in the mornings of "calls of the wild" and they played the indri indri lemurs, which have this pretty amazing sound, so I went to Madagascar to see them.  And it's just an incredible thing -- you hear these calls from way in the treetops and it's magical.  I heard that one morning on NPR and decided I would need to go to hear them.  I did and it was fabulous. I then went to Hong Kong and Bali and Australia and New Zealand, did some hiking in New Zealand and then came back.

Lessons in living and dying

SA:  Okay, a final question...What does your pathology mean to you and what's your motivation for doing it now.

Pathology taught me an incredible amount in medicine that I would never have learnt in any other disciplineKH:  I don't do pathology now; I have people in my group who do it.  But yes, I am a pathologist.  Pathology taught me an incredible amount in medicine that I would never have learnt in any other discipline.  And it really opened my eyes to many different things.

Also, because the training is so broad, I came into this company having had a training that no one else had and could connect the dots between many different things.  Because of what I'd learnt in pathology, even if the diseases were in different organs, I knew the PathogenesisThe origin of a disease, and the chain of events leading to that disease. was similar, so if you had a therapy you were thinking of for this disease, you could also consider it for that.  It's a bit like the story of inhibiting angiogenesis in cancer – the thinking was, “Well what about age-related macular degeneration in the eye where there's also angiogenesis?”  So, very different diseases, but one of the pathogenic mechanisms they share is to do with the formation of new blood vessels.

SA:  So that's a question you raised is it?

KH:  I didn’t raise it, but it's an example of the kind of thing, where a pathologist, who has a very broad training, can actually raise those things. It's very fertile ground in a company like this. I would not be doing what I am doing today if I had not trained in pathology.  There's no question about that.

I like the fact that the journey you go on as a pathologist, you're never quite sure where it's going to end up.

SA:  And what has it taught you about the big issues of living and dying?

You should always treasure life, because you can never quite be sure when you're going to exitKH:  I was thinking about this as I was swimming this morning, because I knew we were meeting.  And I thought: you should always treasure life, because you can never quite be sure when you're going to exit.  And you can never quite be sure what you're going to die of, or what you're going to get sick with.

I was just thinking of some of the people I'd known.  Amina Behan, who was a pathologist at the Western, she died unfortunately of cancer.  Mary Catto still goes into the department every single day but unfortunately has Alzheimer's disease.  As I said, just a wonderful woman -- she never actually retired, she’s just kept on going into work and the people there have looked after her so she could go in every day.  Roddy actually -- and again this is known so I'm not breaking confidences – was for a long time very very sick when I was at the Western.  He had terrible shortness of breath and cough, and Roddy being Roddy just kept pushing himself; he wouldn't listen to anyone when you said, "I think there may be something wrong with you".  He turned out to have a very unusual condition known as BOOP, which is an organising pneumonia that’s very sensitive to steroids. He had the biopsy and the diagnosis and as soon as he got steroids he was better.  Hume Adams, who was a neuro-pathologist at the Southern, he fell into the River Clyde and ended up in intensive care with Weil's disease, which is leptospyrosis, an infectious disease.

You have a very intimate feeling and knowledge for diseaseSo I guess it teaches you a lot about life and about disease, and it just makes you value the health that you have.

SA:  Do you think that's any different from the rest of us who don't have your experiences?  Do you think it really does give a different sort of insight?

KH:  You have a very intimate feeling and knowledge for disease.  I guess I can't speak for all pathologists, but if you've ever done an autopsy and opened up an aorta on someone with terrible atheroma, it's just unbelievable that anyone could possible smoke when you see what goes on.  Even lung cancer...You could have prevented that by just not smoking.  I think it brings it home to you so it becomes very, very real.

SA:  And does it stay with you?

It's a very remarkable specialty, and it's just very poorly understoodKH:  Always.  Absolutely.  Maybe that's one of the things you can't convey -- that there are lots of autopsies you can still remember pieces of, that you can still feel and still see things.  And the gastric juices have an incredibly unusual smell.  There are just emotive things that you remember.  It lives with you forever, I think.

It's a very remarkable specialty, and it's just very poorly understood by people.  There's a lot that we could do through communication and through more interactivity to educate people, so that they would see the value that this specialty brings, because it makes a huge impact on patients' lives.

My training in pathology was the best six years plus... It was just an incredible opportunity that I almost stumbled upon through my research, and something that will always serve me well in life.

ENDS

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