James IronsideProfessor of Neuropathology, Edinburgh University

Interview location: His office at the Western General Hospital, Edinburgh
Interview date
: 3rd September, 2007.

 

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SECTION 1

SA:  James, if you'll start by telling me a bit about the background you came from -- how you chose medicine and how you chose pathology.

JI:  I came from a very ordinary working class Scottish background.  No one in the family had ever been to university before, and when I was at school my thoughts were initially to do science, because that is what I was good at.  I enjoyed chemistry in particular.  And then I discovered when I was in my final year in school that I actually hated organic chemistry – all these chicken wire sorts of diagrams! I couldn't stand it.  So I thought, okay I'll do something else that's vaguely scientific, and the idea of medicine came up.

SA:  Where did you grow up?

JI:  Well I was born in India, in Calcutta.  My father was working in the jute industry, he was from Dundee.  He and my mother went out to get married there and I and my sister were born there.  I came back when I was about five, though I still can remember living there. I remember being on the verandah outside our apartment, and there was this large population of monkeys in the trees that used to come in at any sign of food – they’d just swipe it and run away.  I remember going out as a little boy to see an elephant; and having a pet goose, and a drum, which was just a biscuit tin on a string.  A lot of unrelated snapshots really.

SA:  Does it have any bearing on your life now, having had your early life there? 

JI:  Has India had an influence?  I suppose the feeling that you’ve known something else, that’s the main thing; and the awareness that there are lives out there that are very different from what we have here.

I went to secondary school eventually in Dundee when my parents moved back home from India. I discovered that in order to do medicine I had to do biology.  At that time at school, for some obscure timetabling reasons, you couldn't do physics, chemistry and biology.  So I did a crash course in higher biology in a year, and got into medical school, in Dundee.  It's the only place I could get into at the time; I was turned down by Edinburgh!
It soon became clear to me that I was more interested in the mechanisms of disease, rather than in curing disease

So I started doing medicine and it was really very interesting.  But it soon became clear to me that I was more interested in the mechanisms of disease, rather than in curing disease or treating the patients.  And in Dundee you had the opportunity to do an intercalated degree.  This is now quite common but we're speaking over 20 years ago.  You could take a year out of the medical course and do this extra one year in an area that interested you, and I chose pathology because the course sounded specially interesting.  You did a bit of pathology, a bit of Haematology The branch of medical science concerned with the blood and blood-forming tissues;  haematopathology is concerned with diseases of haematology, a bit of genetics.  In fact I did a project in cytogenetics.  Those were the days when you got a student grant, and because I was on a full grant, I could afford to take that extra year, and I found that I was really very comfortable working in that environment. 
Being a pathologist was almost like being a detective

Being a pathologist was almost like being a detective – you're presented with a challenge:  here is a biopsy or here's someone who's died; this is what we think, but we don't know.  And you find out: can you make a diagnosis?  As a good detective you have to pick up as many clues from the story you're given, you have your list of suspects as to what they might be, and then you have to do tests to eliminate the various suspects, to end up with what is, hopefully, the truth.

The trainees now in pathology certainly don't have that kind of opportunity because there simply aren't the number of autopsies After that I went back to finish the medical course and enjoyed it, but knew then that I wasn't going to be a GP or anything like that.  So I did my house jobs and then applied for a job in pathology.  I got a post in Dundee actually, and I remember we spent a long time in the beginning being trained on how to perform an autopsy thoroughly.  In those days there were many hospital autopsies, very interesting cases, and we were given as much time as we needed to perfect those techniques.  That has stood me in good stead throughout my career.  The trainees now in pathology certainly don't have that kind of opportunity because there simply aren't the number of autopsies. 

SA:  So they don't do the bodies so much?

JI:  Well they do, but because there are fewer autopsies, and often many trainees, they don't have the time to learn.  The challenge for us is to come up with better and more efficient ways of teaching them, or trying to instil in them the skills they need over a more compressed timeframe.

SA:  But coming from the background you did, a family that wasn’t medical or anything like that, how did you find your way?  Were your family supportive?  Did you have the kind of support for further education that Scottish families are renowned for?  
    
JI:  That's right.  Well, my parents were supportive in a general way.  I didn't know anyone who was in medicine.  I mean I was very naïve at the time, looking back on it.  There was a careers advisor at school, but actually he was probably an alcoholic so he wasn't really very helpful!  So I went into medicine not really knowing what I was letting myself in for. I had no real idea of what it was about or what I wanted to do.  And I suppose one takes opportunities as they come along.  I always say to the trainees, “If you have a chance to do something you are interested in, then do it.  If you don’t like it, or it doesn’t work out, then fine.  But if you don’t try things you’ll never learn.”

Confronting death for the first time

SA:  When did you actually see your first dead body and what was your reaction?

You have to be able to step back or it's just impossibleJI:  The first time I saw that was when we were learning anatomy and we had to dissect the cadavers.  That to me was shocking at the time, because in biology we'd only ever done a dogfish, a worm, beetles and various things, but nothing much bigger than that and nothing recognisably human at all.  So that was…I mean it was difficult for everyone.  I remember some people fainting and things like that.  I didn't faint, but I began to see that, okay, the only way I can deal with this is just to detach myself from the personal perspective on this. “Alright, this is a person, but it's not someone I know,” and actually just to focus on the matter in hand.

you have to be able to step back or it's just impossibleAnd that's really what I do.  Over the years you're dealing with very difficult cases – particularly in cases of CJD (Creutzfeldt-Jakob disease) there are whole layers of difficulty apart from just the illness -- and you have to be able to step back or it's just impossible.

SA:  Was it something you had to learn, a technique to psyche yourself up, or what?  And has it become second nature now?

JI:  It has now… But yes, I think it is something I did have to learn.  We didn't actually discuss it apart from among ourselves, some of the students saying, "Oh God I hate doing this, I'll be really glad when we're finished."  I didn't hate doing it.  It was smelly and unpleasant, you know, fixed cadavers, but I felt that it was very important to be able to do this and to learn.  I think we all devised our own ways of handling it.  But there was never any discussion in classes.  It was just sort of: there you are, Monday morning, it happens to be dissection, in you go.  And that was it.  I think things are a bit different now but…

SA:  So there was never any attempt in those days to prepare young students for the fact that they were dealing with death and dying?  It was a science, you were being taught the science?

JI:  Yes, that's right.  You were there to learn anatomy, and that was it.

SA:  And how fascinating did you find bodies, when you'd learnt to distance yourself from the personal?

A body is a miracle of natureJI:  Well, of course in some respects a body is a miracle of nature, and if you approach it from that point of view then it is very interesting.  I must say, the anatomy cadavers I didn't find particularly pleasant, and when I subsequently saw an autopsy performed on someone who hadn't been embalmed or fixed, it was obviously much more real: everything is so much clearer; you can tell the difference between an artery and a vein, and a nerve and a tendon, which we found very difficult as students.  And the processes, the changes you see in the body, are much more vivid and much more apparent and so it's much more interesting.

As a diagnostic pathologist, most of one's time is spent dealing with biopsies, pieces of tissueOf course we do spend a lot of time doing autopsies, but also, as a diagnostic pathologist, most of one's time is spent dealing with biopsies, pieces of tissue.  Having said that, as neuropathologists -- people who specialise in diseases of the nervous system -- we do have a much larger involvement in autopsies.  Not just autopsies we do ourselves, but autopsies other people have done of someone who's died from, say, dementia, and they know that it's important to examine the brain but they don't have the skills to do that, and so the specimen is then sent to us here, as a super-regional centre.  Currently there are only three hospitals with neuropathologists in Scotland – Glasgow, Edinburgh and Aberdeen – and here in Edinburgh we provide the neuropathology service for Lothian and also Tayside. 

Choosing to work with brains

SA:  Having decided to do pathology, how did you find yourself doing neuropathology?  What was the path?

JI:  Well, that was due to a combination of local people and my own interests.  The pathology department of Dundee was a very good place to train at the time, because they had some very good diagnostic pathologists.  They had one person who was what we would call a 'morbid anatomist' who spent most of his time on autopsies and he taught very well.  That was Bill Guthrie, who died a few years ago.  There was also someone who had a great interest in neuropathology called John Anderson, and he had a research assistant, Beth Hubbard, and they were working on Alzheimer's disease – looking at what goes on in the brain with Alzheimer's, and asking how can we measure the atrophy, the shrinkage of the brain?  

I was particularly interested in the neuropathology, I just found it fascinatingHis other interest was at the opposite end of life, with neonatal neuropathology.  Brain injury is the commonest cause of death in premature babies and he was trying to understand what was going on and how it might be prevented.  I worked with all the consultants there, but I was particularly interested in the neuropathology, I just found it fascinating.  

The anatomy of the brain is one challenge – how it's all put together, how it works, and how you can see what's going on in different areas, and then how those can be interpreted as functional changes.  So for instance, if I see something in one part of the brain I can think, "Oh yes, this will cause X."  And then conversely, you have a case where the patient has X, Y, Z neurological dysfunction and you can think, "Well I must start by looking in these areas of the brain and then taking if from there."

So…interesting…That's when I decided that might be the area to train in.  But I couldn't continue doing that in Scotland, because there were no training posts in neuropathology in Scotland at that time.  So I looked further afield and got a job in Sheffield, at the Royal Hallamshire Hospital.  They had a neuropathologist there, Walter Timperley, who's retired, and he was a great character…He would be the one to tell you the colourful anecdotes!  He was regarded by some as the sort of Freddy Truman figure – a blunt Yorkshire man who called a spade a bloody spade and that sort of thing.

SA:  And was he quite a role model to you?

JI:  He was.  He was a different sort of role model to me from someone like John Anderson.  John Anderson was a very considered person; Walter was a much more spontaneous sort of person.  He was very good for me because he didn't do intensive supervision – I mean, he was there to support when necessary and he’s continued to give me great support over the years, but he allowed me to make my own mistakes.  Not patient-threatening mistakes, it must be said!  But learning, and encouraging me that if you want to do something, go for it and see how it works out.

SA:  So he gave you the courage to follow your interests?


JI:  Yes, that's right.  That was the time I was first given the opportunity to do some research as well, just to learn the trade, as it were, and to do some work on things like brain tumours, which I've continued to be interested in, and other diseases.  Walter was particularly interested in the problems in the brains of people with various haematological disorders – haemophiliacs and other things.

When I was in Sheffield another person who influenced me in a very different way was James Underwood.  James was appointed as the professor of pathology while I was there and he gave me an opportunity to do some research in his lab.  He was interested in particular in breast cancer.  He had a lab that was working on steroid hormone receptors in breast tissue – oestrogen, progesterone receptors – and at the time there was some interest in these receptors in certain types of brain tumours.  I thought it might be interesting to look at that, but I didn't know how I’d go about it because I needed funding.  James supported me and we got quite a few papers out of that research, and I was very pleased.  But he also let me go into the lab, work hands- on and learn by my mistakes.  It's very easy to say, "Well just go and do this and that."  But when you're actually doing the assay yourself it's really difficult.  It was a new experience for me but I really enjoyed it.

SA:  So you could have branched off into cancer then…?


In neuropathology it's important to know about diseases outside the brain that can affect the brainJI:  Well, in neuropathology it's important to know about diseases outside the brain that can affect the brain – particularly tumours that can arise in other tissues and then spread to the brain, and breast cancer is one of them unfortunately that does.  So it was important to learn about that.

But James presented a different picture.  He was someone who, it seemed to me, showed that you could have excellence in several areas. In research he was a highly regarded academic pathologist and went on to become President of the Royal College of Pathologists.  He was a very good diagnostic pathologist and had his areas of special interest and was able to continue with those even when he became head of the university department.  It's been very good to work with James.  And he’s now also a member of the Human Tissue Authority, so for the past few years I've been seeing a lot of him.  He's now retired from pathology, but is continuing with the HTA, fortunately, until we know what the future of that is going to be.

SA: That's a big issue we must come on to later.  But what research did you do in Sheffield and how did your path bring you here?


JI:  In Sheffield I did research mostly on brain tumours, because that's what we had a lot of in terms of specimens – a lot of clinical interest from the neurosurgeons. And we also had good collaboration with a number of biochemists who were interested in genetic and other changes in these tumours. So we had a multidisciplinary team working on brain tumours and we did some good stuff.

Thrown in at the deep end

I completed my training in pathology there, did my exams, and then I needed to find another job.  A post came up in Leeds, at the university, so I applied for that and got the job.  The professor of pathology in Leeds at the time was Colin Bird.  Now Colin Bird was Scottish and just in between my interview and my starting date, he left Leeds to come to Edinburgh.  So when I started in Leeds there was no professor in post and we had two years without one, which wasn't really ideal for the department.  I was working with one other neuropathologist, Tony Franks, at first, but he then decided he wanted a career change, so he left neuropathology and for a while I was left on my own. To be left on your own as a young consultant is really not good!  

SA:  So were you the only pathologist in Leeds?

JI:  Oh no, just neuropathology – there was a big pathology department and I made many friends there.  We had a very good neuropathology lab with excellent technicians.  And I had a trainee, Keith Robson, who fortunately was excellent and is now a consultant in Nottingham.  The two of us continued to teach each other, as it were.

SA:  So it was pretty scary stuff was it?

JI:  It was.  

SA:  Tell me about that period – were you really challenged, and up against the limits of your own skills?

JI:  Well yes we were.  Leeds is a bigger centre than Sheffield.  We had material from Leeds and also from Hull coming in.  They had a commitment to muscle disease in Leeds, which I hadn't seen a great amount of, so that was one area where I felt particularly pressed.

We were based in the Infirmary in Leeds, in St James's, and they had there the national centre for investigating a disorder called malignant hyperpyrexia.  This is a disease the genetic basis of which is now known, but it wasn't in the '80s.  Patients who experienced an adverse reaction to anaesthesia, where they have this accelerated temperature increase, were investigated because it was known to be associated with certain types of muscle disease.  So we had huge numbers of biopsies coming in from the hospital.  We also had a big paediatric neurology unit and huge numbers of biopsies from these babies with muscle diseases…Terrible.  

I was shocked, really shockedOne occasion I do remember, we received a muscle biopsy on one child, a neonate who was floppy and not breathing properly. We looked at this biopsy and I thought, “Well it looks like a case of a particular disease called body myopathy.” And as it turned out there was a family history of this disease, but a firm diagnosis had never been made.  So I did everything I could, including electron microscopy, made the diagnosis, told the clinicians, and I was shocked, really shocked, a couple of days afterwards when I asked about the case and was told, "Actually we switched the ventilator off".  I thought, "My God, this is serious."  I had discussed the case with other people and all the rest of it, but that really made a huge impact on me.

SA:  But why had they done that?  Because it was such a dire diagnosis?


Dealing with that sort of situation for the first time was really quite shockingJI:  It was a dire diagnosis.  It was a non-recoverable condition.  There had been a previous child who had died a few days after birth and obviously the clinicians had made a decision with the involvement of the parents, who felt that, in a way, history was repeating itself, and rather than go through weeks, or God knows how long, of prolonged ventilation with no improvement, this was probably for the best.  And one respects that, but for me dealing with that sort of situation for the first time was really quite shocking.

SA:  Recognising the implications of your diagnosis?


Diagnosis is not made in a vacuumJI:  Yes, that's right.  I think it's very important that we as pathologists remember that diagnosis is not made in a vacuum, or it's not something that exists only between you and the clinician. There's much wider impact, not just for the patient, but for the whole family.

SA:  So what did that teach you?  That you needed to have more time with the clinicians and discuss the implications?  Or do you see your job still as to give the information to the clinicians and they take it forward?

JI:  No, I think as a pathologist you have to be more aware -- and I wasn't at that time -- of the implications of your diagnosis. That matter has been addressed now, and most pathologists' work now is in multidisciplinary teams.  Each week here we have a meeting with the doctors dealing with patients with brain tumours, and we review every patient – we review the clinical features, the brain scans, the biopsy, the diagnosis -- “Is our diagnosis actually consistent with everything else?” -- and then the treatment is discussed, so we're much more aware of the implications.  And we have these meetings now not just for brain tumours but for other neurological diseases.  At that time in Leeds we did have these meetings for the brain tumours in children, but not for the non-tumours, although the non-tumours were equally significant in terms of diagnosis and prognosis in some cases.

SECTION 2

First exposure to CJD

SA:  What other stories can you remember from being at the sharp end when you were young and inexperienced?

JI:  Well, the other thing I inherited in Leeds when I moved there were two operating lists.  This came as a great surprise to me.  I wouldn't say I went into pathology to avoid doing the surgery, but I think one needs to be a certain type of person to be a good surgeon, and I'm not that type of person.  I've worked with surgeons all my life and I have a great admiration for them, but we're all different and we all have our place.  

But these lists were to do muscle and nerve biopsies on patients, and I had never really had any training in this.  I did get a bit of training from the surgeons, and I did these really very small procedures very slowly and with great care, trying to avoid any scars -- much to the frustration of the theatre nurses who just wanted to get on with things!

He turned out to have CJD and diedI do remember seeing one patient – and this is where a link with CJD comes in.  Patients came into the hospital the evening before I did the biopsies and I used to go and see them and explain to them and the relatives what was happening so everyone was aware.  This particular time I saw this one poor patient who looked really ill, and I thought, "There's something terribly wrong with him."  I suspected he actually had a brain disease rather than just a muscle disease, and in fact that was the case.  He turned out to have CJD and died, and I performed the autopsy later on, and that was more difficult because I had seen him when he was alive and spoken to his wife and other relatives.  That was one of my first exposures to CJD, and it was quite sort of dramatic, because he deteriorated very rapidly and died very quickly, as they sometimes do.

SA:  So you found it difficult to be brought out of the backrooms, and having to deal with the human side of things?


JI:  It wasn't so much difficult as different, and you needed a whole range of skills – communication skills particularly -- that I felt I hadn't used.  Obviously we did have communication skills courses years ago as students, but then you hadn't been doing it for real, and it's very different. And of course most of our communication skills are in communicating to other pathologists or to surgeons, or coroners, or whoever, about diagnosis.  I suppose working in England and being involved in some coroners' autopsies and inquests did allow me to speak to relatives – though under rather different circumstances of course: they had just suffered a bereavement.  Usually the coroner asks the relatives whether they have any questions they'd like to ask the pathologist who performed the autopsy.  So I had that interface.  But that was after the final event.

Speaking to relatives when someone is being investigated for what everyone realises is potentially a very serious illness, then it's a different sort of communication, and that I wasn't fully prepared for, I must say.  But I learned, and I try to be just as honest and straightforward as I can, you know?

SA:  So was that your first CJD case?


JI:  No, I'd seen cases of CJD in Sheffield, but I had never got to know more about a particular patient as I did that time in Leeds.  

I do remember looking down the microscope and seeing something just incredibleAnd then, I remember, I was asked to do an autopsy on another patient who had a family history of what was called spinocerebellar ataxia -- that is when the cerebellum, the hind brain, isn't working properly; there’s unsteadiness, inability to coordinate movement, and progression towards immobility and eventually death.  There was a strong family history of this but it had never been investigated.  So an autopsy was performed and I thought this was a very interesting case -- it would probably be one of these spinocerebellar ataxias, or SCAs as they're now called, which have a genetic basis.  And I do remember looking down the microscope and seeing something just incredible – because this brain was full of amyloid plaques, full of plaques.  I thought, "I've never seen anything like it before!"  It was everywhere, including the cerebellum.  

Then I dimly remembered, when I'd been reading about CJD recently, that there is this related disorder to CJD called GSS, or Gerstmann-Straussler-Scheinker syndrome  – a very, very rare inherited disease, usually affecting the cerebellum, but it looks different down the microscope from CJD.  Instead of spongy change, you have these amyloid plaques, and these plaques are composed of the prion protein.  I was on my own, as I said, and I thought, "Right, I really need another opinion on this".  So I sent it off to a colleague in London and he agreed with the diagnosis, and we performed some tests to show that these plaques, or aggregates, were in fact composed of the prion protein.  

There was such an interest in this case that I actually included it in a presentation to the British Neuropathological Society, and everyone agreed that this was a case of GSS, which made me feel very reassured.  That was the diagnosis then made to the family.  Now that family… I don't want to say anything more about that because they could potentially be identified, but that family was obviously advised of the diagnosis and received appropriate genetic counselling.

SA:  So you'd been expecting a completely different diagnosis till you looked down the microscope?

That shows the importance of actually performing an autopsy in patients like this with neurological diseases which are undiagnosedJI:  Yes, as had the neurologists.  They thought it was one of this group of SCAs, which are interesting – there are over 20 different genetic variants that we know about now.  But that's not what it was.  And, again, that shows the importance of actually performing an autopsy in patients like this with neurological diseases which are undiagnosed.  It makes a huge difference, particularly when a prion disease like that is diagnosed, because it does have wider implications in terms of health and safety and those sorts of things.

Keeping an open mind

SA:  From the point of view of diagnosis, when a case comes in and the picture that’s been built up leads you to expect something else, how easy is it to make a mistake, because you have preconceptions?  Obviously that time what you saw was really dramatic, but does one miss things because one doesn't have an open mind?

Just look at it with innocent eyes and formulate what you think, and then turn the form over and read the clinical historyJI:  I think that's always a possibility.  And there are various ways round it.  While I was being taught diagnostic pathology in Dundee one of the pathologists said, "One way to overcome this bias is to not look at the clinical details."  So you have a biopsy, you know it's a biopsy of, say, muscle or a lymph node or whatever, but just look at it with innocent eyes and formulate what you think, and then turn the form over and read the clinical history and put what you've seen into a context.  That's one way of doing it.  It can sometimes lead to some quite strange tensions: you read the clinical history and then you think, "Oh my God, I better look at this again!"  

Of course you can't do that with autopsies -- you need to know the clinical history in order to perform the autopsy, so you can examine the relevant pieces of tissue.  But there's a balance to be struck there.  You always have to go back and say, "Okay, let's look at this again; how sure can we be of the diagnosis?"  I've always felt that one of the challenges, and in many ways one of the joys, of diagnostic pathology is that every month, certainly, you see something you've never seen before.

SA:  Really?  You still do?


JI:  Yes.  Not a new disease, but a different manifestation of something, or some appearance you've read about in the books but you've never actually seen.  And there it is!  I think that's really what keeps the interest going, or one of the things that keeps the interest going.  I think the day I get tired of doing this is the day to go off and do something else.  I've not lost that over the years, and I hope I never do. 

It's about having an open mind and looking beyond the clinical expectationSo yeah, it's about having an open mind and looking beyond the clinical expectation.  And of course, with neurological diseases, because the central nervous system is such a complicated system, the opportunity for encountering new and different things is probably higher than in many other areas of pathology.  And despite advances in imaging and functional imaging and all the rest of it… And that's a whole new range of interests, because the neuroradiologists can produce these wonderful images, and they can see exactly where things are, but they're still not very good at saying exactly what they are!  "There's a lesion there; what is it?" 

In the diseases that affect the brain more diffusely and cause atrophy or shrinkage, of course, they can't differentiate Alzheimer's disease from something else.  In a way [neuropathologists and neuroradioloigsts] have grown closer together, but we still have our own distinct roles.  But I'm very comfortable with looking at images of the brain on scans because that's really what we do when we examine the brain at autopsy.

SECTION 3

Of mad cows and human disease

SA:  So staying with the CJD story, when did you start to specialise in prion diseases?

The CJD surveillance project was startingJI:  I was in Leeds for four years when a consultant post came up in Edinburgh, and I thought, “Let's go for it!”  By coincidence Colin Bird who’d interviewed me for the Leeds job was now professor in Edinburgh, so this was the second interview I'd had with him.  I'd prepared my answers to the various difficult questions – like the ‘golfing question’.  Colin’s a very keen golfer and it's just not my thing at all!  So I had to think, "How can I answer this without just dismissing it?"  I thought, "Well, I've handled it before, I'll just give the same answer again!"  Anyway, it worked.

I started here in 1990, and that, as it so happened, was the year the CJD surveillance project was starting.  My colleague, Bob Will, whose office is two doors along, was the physician responsible for the clinical part of that.

SA:  Was CJD becoming a problem at that point? This was before the new variant was discovered and BSE?


JI:  Yes.  Well, BSE had started in 1985/86.  It was interesting and rather worrying that all these cattle were dying of this prion disease.  And just before I left Leeds… Leeds was an interesting place to work for a whole range of reasons, not least that we had Richard Lacey a bacteriologist -- he was professor of bacteriology there, and he was a somewhat controversial figure given to stirring things up about listeria and salmonella and other sorts of things.  He was keeping a careful watch on the BSE situation, and just before I moved to Leeds, the first case of a similar disease in cats was identified – feline spongiform encephalopathy – and I can remember discussing that with him and his senior registrar, Stephen Dealler.  

SA:  What were their theories?


They had no idea what it might be other than that it was a very unusual infectious agentJI:  As specialists in infectious diseases they were interested in this, and their feeling was, "Well, cattle a few years ago, cats today, humans next year or sometime soon?” They had no idea what it might be other than that it was a very unusual infectious agent.  Of course the prion hypothesis was out there – it was 1983, I think, when Stanley Prusiner [who won the Nobel Prize for medicine in 1997] first proposed that, and it seemed very interesting, but kind of difficult to get your head round.

The prion hypothesis basically states that the infectious agent in CJD and other spongiform encepaholopathies (so-called because of the spongy appearance of the diseased brain) is a modified form of a protein that occurs naturally in the brain and in other tissues. This modified, or abnormal, protein accumulates in the brain, and this accumulation occurs by progressive conversion of the normal protein into the abnormal form.  

It's like a domino effect: once you have the first conversion from normal to abnormal then you get a sort of chain reaction building up as more and more normal protein is convertedIt's like a domino effect: once you have the first conversion from normal to abnormal then you get a sort of chain reaction building up as more and more normal protein is converted.  The abnormal protein is toxic and damages the brain and eventually causes death.  This is biologically heretical because all other types of transmissible disease rely on genetic material in order to spread, and there seems to be no need for this here.  

Just before I moved on from Leeds there was a meeting in London of the Medical Research Council where neuropathologists across the UK were asked to go and learn more about the CJD surveillance project and give it their support.  I moved here, and my colleague Jeanne Bell, who was the other neuropathologist -- I worked with her for 17 years and unfortunately she’s just retired -- she had decided she would support the project and give a neuropathology input.

SA:  At that stage the surveillance was just on the clinical side, was it, there wasn't pathology involved?


JI:  Not in 1990, it was just starting.  We had managed to get funding and the biggest challenge at that stage was finding space in the hospital where we could do the work -- everyone thought it was a genuinely interesting thing to do, but they didn't want it anywhere near them because of the perceived risk of “these prions floating down the corridors and jumping down your throat” or whatever!
It was sold to me as ‘a very rare but very interesting’ disease that probably wouldn't entail a great deal of extra work!
So after lots of negotiation with the hospital, we were offered the wonderful accommodation that you experienced before – with very few windows! We started with a small team, and appointed Linda McCardle who's now in charge of the labs here.  She was the first person to work in the labs then.  There was Bob, Linda, Jan MacKenzie, Jeanne Bell and myself.  Since then it's grown a lot, but at that time it was sold to me as ‘a very rare but very interesting’ disease that probably wouldn't entail a great deal of extra work!

There had been previous surveillance of CJD which Bob had been involved in, at Oxford when he was a trainee, so he had experience of doing this.  They’d been particularly interested then in looking at the risk factors for CJD, because the disease in the mid ‘80s had just emerged in recipients of human growth hormone, if you remember.  The question was whether any other groups treated in one way or another might also be inadvertently affected or predisposed to the disease.  So he had done work on that.

Multiple manifestations of CJD

SA:  So at that stage there was still no knowledge about how CJD got passed on, or how people got it?  Because there were the two forms of the disease, weren't there, the ‘sporadic’ and the ‘familial’ CJD?

JI:  That's right, and most of Bob's work was on sporadic CJD.  There's also the so-called iatrogenic CJD -- those cases are transmitted accidentally by medical procedures -- and the pituitary recipients are [of that category].  Then the very rare familial ones like the GSS case that I became involved in.  The incidence of those all lumped together was less than one per million people per year, so I was told there were 50 or 60 cases maximum per year in the UK. But like everything else, once you start looking for something you find more of it.  

Probably there was an under-ascertainment in the past, and also there was the unknown element of BSE -- we really had no idea what that would mean in terms of human disease.  So we began by exploring the parameters of what sporadic CJD was, clinically and pathologically, what it looked like.  We explored particularly the iatrogenic cases – human growth hormone-associated cases – because they were acquired not by ingestion but by injection, but there still might be some similarities there.  And also there was information then emerging on the genetics of the inherited cases.  In the early 1990s there were the first reports of a mutation in the prion gene associated with GSS.

So there was a lot happening and it was an exciting time, a lot of information to get your head round.  We began to try to put parameters round these things so that if something different came along we could say, "Well this looks different and it's outside our experience of sporadic CJD."  And indeed that's actually what happened.

SA:  But the iatrogenic ones, how different were these from what you'd already seen?


JI:  They were different.  The patients that developed CJD through growth hormone treatment did have a different type of illness.  It was a longer illness than sporadic CJD; it tended to present with a cerebellar syndrome, an ataxia (an unsteadiness), instead of this rapidly progressing dementia.  And the pathology of the brain was different – the cerebellum in the brain was targeted particularly severely.  And we were interested also in the question: how does it get to the brain?  If it's injected into the body then how does it get there?  Does it go through the blood?  Does it go along the nerves?  Or does it get there some other way?  We tried to address these questions by looking where possible at these other tissues as well as the brain.

The search for risk factors

It's important, you know, that pathologists should think outside the box and think outside the brainIt's important, you know, that pathologists should think outside the box and think outside the brain.  We know from studies of scrapie in sheep that the spleen can be involved.  Was the spleen involved in these growth hormone cases? It seems the answer is ‘no’ for some reason, so our best working idea is that it travels along nerves into the spinal column and then up to the brain.  We thought, “That's worth exploring, and then we can compare that with sporadic CJD where that doesn't seem to happen…”

SA:  Really?


JI:  Yes, well, sporadic CJD, we don't know what the cause of it is, and one theory is that it arises de novo from a spontaneous event in the brain analogous to cancer developing de novo.  But most cancers develop due to some environmental or genetic trigger or a combination of factors, so there's a big ongoing study here on sporadic CJD to look at risk factors.  We know more about genetic susceptibility, and Hester Ward, who's our epidemiologist here has done a lot of work on looking at potential risk factors for sporadic CJD.  One thing we really need in order to do that is big numbers – and the only way to get big numbers is to collaborate with colleagues in Europe.  So there's a big European surveillance project using comparable methodology in an ever expanding number of countries.  That has involved interacting with pathologists in other countries and it's been very interesting.

SA:  When you as a specialist see sporadic CJD, does the pathology look roughly the same in most cases, or is there quite a range of manifestations?

JI:  There's quite a range of pathology -- and that was known, actually, even going back to the descriptions of the '60s.  There were different subtypes of sporadic CJD.  There's the type which is associated with blindness, for example, the so-called Heidenhien's variant of CJD.  There's the type associated with unsteadiness rather than dementia initially, which is the so-called Brownell-Oppenheimer variant of CJD.  And there’s the classical one, which is rapidly progressive dementia.  In both clinical and pathological terms those are different, and what we've been interested to find out is what the basis of those differences is, and it's clearly partly genetic.  

There's one variable area in the prion gene which has what we call a polymorphism – a variable part – and that polymorphism affects both susceptibility to the disease and the clinical and pathological features of the disease. The other thing that affects those is the type of prion protein that accumulates in the brain.  We were very fortunate in taking on Dr Mark Head, who is what I call a ‘proper scientist’.  He's a cell biologist who's worked with us now for about nine years and he has been studying the prion protein in the brain and other tissues in both variant and other sporadic CJD.  And that's been a major step forward. 

The value of archives

Pathology is expanding its boundariesSo pathology is expanding its boundaries.  As a pathologist I've always seen myself as having a foot in two camps, really.  One is the sort of cell biology camp -- I'm quite happy to speak about cells, molecules, genes -- and the other is the clinical camp.  The huge advances in science, and the molecular biology revolution, have allowed us as pathologists to use tissues and cells in ways that no one could ever have dreamed of till relatively recently.  We can go back in our archives – and this is why it's important to have an archive and to keep blocks of tissue -- to look at genetic events in cancers, in Alzheimer's disease, in a whole range of things.  The field has opened up to an extraordinary degree – it's just fascinating.  The challenges are correspondingly much biggerBut the challenges are correspondingly much bigger.  In some ways the old days were nice when you could say, "Well, it's this", and that was the end of it.  Now it's not like that, but it's much more interesting.

SA:  So tell me about some time when there has been a big advance and you've thought, "We really need to go back to some historic samples"?  When have you used your library most and what have you been able to find in historical samples?

JI:  Well, we use it the whole time really.  But I guess the best example is when we were involved in the identification of variant CJD.  We had cases of this strange form of prion disease occurring in young adults that had a particular type of pathology with lots of these amyloid plaques in the brain.  Now these plaques were different from the ones we see in GSS, and we knew by then that these patients didn't have the genetic mutation associated with GSS.  So we knew that whatever it was wasn't an inherited disease.  So then we had to say, “Okay, what does CJD look like in 20- and 30-year-olds?” because most patients are 60 to70 years old.

SA:  This was the first time you'd really started to see youngsters, was it?


What are the chances of this happening by random association?  There's something very different going on hereJI:  Yes, yes, that's right.  And, um, the reality of the situation really dawned on me when one day – I can remember this quite clearly – I had to perform two autopsies on the same day in Edinburgh on patients with suspected CJD, although it was a strange illness.  One of them was young, in their twenties, and one of them was rather older, in the late forties.  And I thought, “Well, the older one might be sporadic CJD, but the younger one could be this new…” whatever we were calling it at the time.  But in fact both had the same pathology in the brain, and I thought, “What are the chances of this happening by random association?  There's something very different going on here.”

SA:  So this was completely new stuff you were seeing?

So we took great trouble to go back through all the archivesJI:  Yes, yes, absolutely.  So we took great trouble to go back through all the archives, -- not just our own archives here, but in the literature also, to identify reports of CJD in young people in the UK, and overseas.  We consulted Paul Brown who's a very senior figure in the field in the US to see if he knew of any cases, and we tried to trace the pathology of these cases.  I think one case came from Poland…

Talk about detective work, it was really intense!You know, talk about detective work, it was really intense!  And we felt the pressure was on, for a whole range of reasons.  If you're going to claim that you've found a new disease that's related to BSE, that's no small claim and you want to make sure you've got it as right as you possibly can.  I think people didn't actually appreciate how much effort we had gone to, and some would even say, "Oh it's ridiculous to go to all this trouble."  But I really didn't feel that was the case, and Bob was in complete agreement.  

So we got these cases from the archives; we compared them in every possible way we could, and it was clear they were different.  They looked like sporadic CJD but in young people, so we were faced with the conclusion that whatever this was we were seeing, it was something that hadn't apparently been seen before. And to back that up we decided to do another project called the National Retrospective Review.  

This was a multicentre study funded by the Department of Health.  It was an archive search with neuropathologists, and it was asking the questions: number one, do you have any cases of what look to be variant CJD that actually occurred before 1995 and were then called something else, like sporadic CJD or Alzheimer's disease or something else?.  Do you have other cases of CJD that might have been misdiagnosed, or not identified as such?  Because we now knew a lot more about the different manifestations of CJD, and we asked people to look at funny diseases – unknown ataxias, diseases with psychiatric features, because variant CJD begins with a psychiatric condition before the hard neurological signs emerge.  

That work took yearsThat work took years and, reassuringly, it found that there weren't any cases of variant CJD, though we did find there were cases of sporadic CJD which probably hadn't been identified as such, but not very many. This work allowed us as pathologists to go through the archives and to re-examine the disease and to categorise it [in the light of our current knowledge].  That put us all in a much stronger place than we were before.  Okay, it's not rocket science, it's not discovering a new molecule, but it's actually very important to do that.  So that's a good example of using the archive in a very constructive way to address an issue which was a real public health concern.

SECTION 4

New variant CJD discovered

SA:  Take me to the moment when you actually looked down the microscope and saw something different. I mean you mentioned that time in Leeds…how fascinating was it as a scientist?  What did you see?  And how much did bells ring?

JI:  Well in Leeds the GSS case I saw – this is a very rare disease, I'd never seen it before, but I knew that I'd seen pictures of something like it in books, so that was my starting point for the diagnosis.  Most of us as histopathologists have good visual recognition – ‘pattern recognition’ as it's called – and I think because of that, a lot of us are interested in art, actually.  But that's another interesting thing that we can maybe explore later.  Anyway, with the GSS case I knew I'd seen pictures of something like this before; I just had to access my memory to see what it was, and which book it was in.  

I knew that we hadn't seen anything like this beforeBut with variant CJD here in Edinburgh, this was something that hadn't been described before, and of course you need to make sure of that.  We were using techniques that weren't available in the past – techniques to demonstrate prion protein, genetic analysis, all the rest of it – and so there was a concern that, “Well, is this just an artefact of technology?  Is this just a result of using these new methods that haven't been used extensively yet?”  People think, you know, you're looking down the microscope and the bulb lights up and you think, "Yes, this is it!”  And actually in a way it did.  Jeanne and I knew that we hadn't seen anything like this before.  But it did take a long time to make sure.

SA:  Tell me about the first case you saw…

That was the time I really thought we had something newJI:  Well the first case of variant CJD was a difficult one…There were two cases in England; we'd reviewed them and thought they were very strange, and they were reported as letters in The Lancet as “unusual cases of CJD in young patients”.  But that wasn't enough to make it a ‘new disease’.  I suppose [what convinced me] was the day that I did the two autopsies myself – I knew that we'd studied everything, taken everything we could at autopsy to allow us to identify this, gathered all the necessary information.  And the two cases, although they were in patients of different ages -- one young, one middle-aged -- were so similar in terms of their brain pathology you could line them up side by side and really not be able to say which was which, they were so similar. The brain pathology was also very different from any case of sporadic CJD that we had seen, or that had ever been reported. That was the time I really thought we had something new…

SA:  What did it look like?

JI:  It looked like…Well, in some ways it looked like a combination between what we call GSS, which is the one with the amyloid plaques, and sporadic CJD, which tends to have a lot of spongy change, because it had both.  And the most striking thing to me was using 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. to demonstrate the abnormal prion protein in the brain, because you saw this pattern of deposition which was totally unlike anything we'd ever seen before, and which, when I showed it to Bob, he said, "Oh it looks like a Christmas tree"! [Laughs] I said, "Yes, Bob…"  He's a clinician, that's absolutely fine!  But he had an understanding of what it was, and over a short period of time we had a series of 12 cases that were published and that looked all very similar, not only in terms of the brain pathology, but in their clinical features and genetic background.  And I think that by then there was really little doubt that it was something different.  

But in order to convince both myself and eventually others, we employed other techniques.  I thought, "Well, how can I get hard information on this?"  So one of our strategies -- we'd been using it for many years -- was to employ computer-based image analysis.  We'd got funding and we had a computer scientist working with us in order to do this, so rather than just taking my word for it -- "Well, you know, it's got Christmas trees on these stains!" -- they could actually count and measure the severity of the spongy change.  They could measure the amount of amyloid; they could count the number of plaques; we could measure other changes that were going on in the brain.  

And on the day that Bob and I were summoned to the SEAC (Spongiform Encephalopathy Advisory Committee) meeting on 8th March, I was able to show them not just a visual depiction of what it looked like, but actually some hard data saying: "Here are the measurable differences between these cases and sporadic CJD, and these cases and growth hormone-induced CJD."  

Using this hard evidence has enhanced the status of pathologyAnd that I think helped change this idea that, you know, "Pathology is an art; medicine is an art generally; you look down the microscope and you form a very subjective impression based on how you're feeling at the time."  Maybe that is true some days, or was true in the past, but now we have so much more hard evidence.  And I think it's using this hard evidence has enhanced the status of pathology

New tools

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Fashions change in the science of pathology.  When I was training, it was all molecular genetics -- you had to get your bit of 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 your 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 then your protein.  But now we're in what's called the  'post-genomic era', and we know that, actually, it's not just having an altered gene [that's important], but it's having the gene actually produce something, a protein, that's actually in the cell and that you can detect.  And I think one area that's used this particularly is neuropathology, in looking at degenerative diseases of the brain.  All these diseases – Alzheimer's disease, Parkinson's disease, motor neurone disease, Huntington's disease, CJD, the list goes on and on – they are all associated with accumulations of abnormal proteins in the brain, sometimes it's outside the cell as in CJD, sometimes it's in the cell like Parkinson's, sometimes it's even in the nucleus of the cell like Huntington's disease.  But we can now use these tools and study the disease in far greater detail.  

Also, knowing so much more about human diseases, we can actually be a little bit more critical about some of the animal models and other models that are used.  There was a famous paper published a few years ago with the title "Does my mouse have Alzheimer's disease?" and the answer was: "No!"  Just because it's got one of the genetic changes that could be associated with Alzheimer's and it's churning out a lot of this abnormal protein doesn't make it Alzheimer's disease. I think we've learnt a lot through models of cell culture and various animal models, but I think the human is where these diseases are at, and the challenge of understanding these diseases in humans still remains.

The importance of patterns

SA:  I'm interested in what you were saying earlier about pathologists having to have good pattern recognition and that this seems to be associated with an appreciation also of art.  Tell me more about that, because it seems to me that on one level you're very reserved about letting the excitement of pathology run away with you -- you have to pin down the science as opposed to relying on the art of pathology.

To function effectively as a pathologist you need to have 'the eye’JI:  Yes, that's right.  I guess to function effectively as a pathologist you need to have 'the eye’, you know?  You need to have a good pair of eyes down a microscope, and if you don't have that – and not everyone does – then it's just not going to work for you, and this is one of the things we have to look for in trainees.  If you have that sort of visual, pattern-based, whatever you want to call it, method of analysis then you can use that not just looking down a microscope but in lots of other things as well.  

As pathologists we tend to be obsessed with classifications and sub-classifications of things, and I think you can do too much of that…your excitement of what you're looking at can be overtaken by the need to pin it down.  Going round, for example, the Picasso Exhibition that's in Edinburgh just now, which is great, you can find yourself thinking, "Oh yes, that's drawn in his early blue period…" or "When does late blue become early rose period?" And actually does it matter?  When you're looking at something like that, it's what the message and what the emotion of the image is actually all about, what it's saying to you, that's important.  With pathology what the image is saying to you may be important, but what it means for the patient is actually something else, so we have to try and temper that.

SA:  Really?  So they are different, are they?  You're using the same ‘eye’, and you still are getting very visual messages, but you have to say to yourself, "I can't read this like a painting; I can't let my imagination go; I have now to pin it down to the science" do you?

JI:  I think you have to pin it down to the science.  I suppose I've never thought about whether there might be a relationship to people who are art historians or things like that, whether they use a similar sort of approach -- that if you're learning in detail about the different types of painting and different periods of painting by the one artist you need to be able to step back from the pure appreciation – "that's a wonderful Titian, or Picasso, or Rembrandt, or whatever" -- because actually what you're interested to know is how dense the brush strokes are, or something like that.  Then it becomes a different thing altogether, and how you can switch between one or the other, I don't know. I'd rather not be an art historian and just let the impact of the image hit me.

SA:  And do you love art?

JI:   Oh yes, absolutely!  

SA:  And what kind of things?

JI:  I just go for things generally.  I did like particularly Italian Renaissance, but now I'm into modern.  The sort of in-between I'm not so keen on – the sort of romantic, neo-Raphaelite is not my thing.  The same with music as well.  Music's my main hobby, I guess.

SA:  Do you play?

JI:  I play the piano, but I also sing.  I sing in the Scottish Chamber Orchestra chorus, and we've had great fun doing a concert in the Edinburgh Festival this year.  And we're about to start rehearsals again for the next season.  I find that's a good way of relaxing -- having to concentrate hard on music takes your mind off everything else.  It's also nice when you're meeting people who have similar interests from very different walks of life.

SECTION 5

Ritualistic endocannibalism and ‘kuru’

SA:  Going back to the CJD story, how much did you already know about other transmissible spongiform encephalopathies?  About what had happened in Papua New Guinea for instance…?

JI:  Oh ‘kuru’, yeah, absolutely.  That was really very important.  Kuru and what could be learned from it was something that we'd focussed on in the unit.

SA:  What exactly is 'kuru'?

JI:  Kuru was an unusual neurological disease that was a common cause of death in a tribe called the Fore in the highlands of Papua New Guinea. The disease was transmitted within the tribe by the practice of ritualistic endocannibalism, when members of the tribe ate the bodies of the deceased as a sign of respect. The cause of kuru was initially unknown, but when the neuropathological similarities between kuru and scrapie, a common prion disease in sheep, were recognised, kuru was transmitted experimentally and shown to be a transmissible spongiform encephalopathy, or prion disease.

Kuru was acquired by ingestion of infected brain tissue and we had the opportunity to study cases of kuru pathology through collaboration with colleagues in the University of Melbourne.  Colin Masters, who's the professor of pathology there, worked with Carleton Gajdusek in the past -- Gajdusek was the one who identified kuru first, and received a Nobel Prize for this -- and they had some tissues in the University of Melbourne.  One of the neuropathologists there, Catriona Maclean, came to Edinburgh with kuru material and we did some comparative studies.  

I'm ashamed to say I thought kuru would be as different from everything else as variant CJD is.  But actually it's more like sporadic CJD than anything else.  And that's presumably where it originated from – there must have been a case of sporadic CJD in the tribe and it got passed on because they practiced this ritual endocannibalism.  People have questioned whether it's ethically or morally okay to say that that happened, but having spoken to people who were there at the time, they are in no doubt that's what happened, so you're not making a moral judgement to say so; it's just a statement of fact.  

What kuru has taught us is that you can have a long incubation period -- of 40 and 50 years -- for these diseasesKuru is not yet extinct, although it is almost extinct.  In fact there's a meeting in London at the Royal Society of Medicine in October that's to celebrate what seems to be the end of kuru.  But what kuru has taught us is that you can have a long incubation period -- of 40 and 50 years -- for these diseases following oral exposure.  Clearly there are parallels with variant CJD and implications for other things.  The other thing that kuru has taught us is the influence of genetic variability, and that certain genotypes are associated with long incubation periods. That's why in variant CJD --  although fortunately the numbers of cases are declining -- the question is, "Are these simply in the group with the shortest incubation periods?  And will other waves emerge later, as they have with kuru?"  And we don't know; we're just waiting to see.

SECTION 6

Negotiating the legal minefield

SA:  Okay, so tell me about your work with the Human Tissue Authority.  Because from talking to people, I can't get a sense of whether the new laws since Alder Hey are a sort of sop to the public, and pathologists didn't fight their corner hard enough, or they are a measured response to the modern issues.

It was a dark hour for pathologyJI:  Right, well, it's a complex subject, and there's no doubt, I feel…What happened in Alder Hey was terrible.  It opened up the whole question of autopsies -- retention of tissues and organs, how much relatives knew, how much relatives had been consulted -- and had some terrible messages for all concerned.  It was a dark hour for pathology, no doubt about it.  Not helped, I must say, by the media.  You were made to feel that not only had you examined a baby that had died from cot death or something, you'd actually gone out and killed it beforehand.  Just terrible!  And also I think that we were not best supported by the minister of health at the time, Alan Milburn. A more measured response would have been better He just opted to go ‘belly up’ and do anything to satisfy the various pressure groups that had emerged from the media, and I think a more measured response would have been better.  Some of the first attempts at the legislation were just completely unworkable.  And through pressure from a whole range of groups, the legislation was changed in the UK.  It's still not perfect, but it's better than it was.

SA:  But I mean did pathologists really fight their corner quite strongly?

JI:  We did absolutely.  James Underwood was involved with this, and I think he did very well.  

There are things in the Scottish legislation that are better for everyone than the UK legislation So what we have in the UK, we've actually got two sets of legislation. There's the UK legislation and there's the Scottish Human Tissue Act, and there are differences between the two.  I was involved in discussions with the Scottish Executive.  My colleague Jeanne Bell also was involved in this, and due to her input particularly I think, there are things in the Scottish legislation that are better for everyone than the UK legislation.  Most people in the UK seem to agree.  

So the Scottish legislation doesn't cover tissue from living patients, it only covers tissue from deceased patients.  And it allows retention of blocks of tissue and slides as part of the medical record automatically, for the archive, either from consent autopsy or from clinico-legal autopsy.  We feel this is particularly important, especially over issues of sudden infant death – we don't know what the cause is, and we need to be able to do research. It's what Jeanne is doing, and she felt she wouldn't be able to continue doing it if it suddenly wasn't possible [to keep some material].

SA:  And you couldn't have done what you did with the CJD archive?

Suddenly there's going to be no archiveJI:  No, absolutely not.  And so we have this paradox that the value of the archive is demonstrable, not just for CJD but for a whole range of other things, but that suddenly there's going to be no archive.  That seemed to me not very sensible.  So my main motivation for joining the Human Tissue Authority was to try and make the implementation of the legislation as good as it could be for both the profession and indeed the public – because there were many members of the public who were not happy at the outcome.

SA:  Well nearly everyone would feel that way if they realised the implications, wouldn't they?


JI:  I think that's right, and more are now aware of it.  Anyway, I [applied to join the HTA] and I had to say "I'm someone who performs autopsies; I'm someone who removes brains.  I haven't done this either without the consent of the relatives or the instruction of a medico-legal authority, but I think it needs to be done and that there is a lot of valuable information that can be gained from the practice, both in terms of diagnosis and for research."  

It was the implications on research that I was particularly concerned about, and I was relieved when the Authority -- you know, you had to go through the NHS appointments commission, which you can imagine is not the most streamlined of systems – appointed me.  I had no idea who else had applied, and I met James Underwood there and I thought, "Thank goodness, this is someone I know who is sensible!"  And in fact the members of the Authority are great – a whole range of backgrounds.

Devising codes of practice

SA:  And what's your task?

We've had to devise codes of practiceJI:  To implement the legislation, that's basically what we have to do.  We've had to devise codes of practice for autopsies, retention of tissues, storage, consent -- that was the first thing we had to do -- and take it from there, covering the whole remit of the legislation.

SA:  Okay, so the legislation is just the rules and you then have to find ways of practicing them?  

The magnitude of the task came as some surprise to all of us!JI:  Yes, such things as who may give consent, and who should ask for consent and how should it be done and recorded?  The Human Tissue Act of course covers tissue from the living; it covers transplantation of tissues and organs from living patients (there was a complex interaction with European legislation on this).  So that's really what we've been doing.  And we've been doing it by engaging the various professional groups – College of Pathologists among others, the MRC, the Wellcome Trust -- in trying to get codes of practice that are workable. It's been a lot of very, very hard work.  I think the magnitude of the task came as some surprise to all of us!  But we're up and running, and licences are now being issued.  Of course things haven't always gone smoothly, but by and large it's been reasonably successful.

SA:  Licences for what?

JI:  Licences are required for performing an autopsy.  If you're storing tissues from deceased people you need a licence; if you're storing tissue for what's called a 'scheduled' purpose -- research, teaching and training and other things -- that needs a licence; storing tissue from living patients for a scheduled purposes requires a licence as well.  So we had to devise a licensing framework – how were we going to do that? And how could we set up a system where people could apply for licences? How many licences were we going to issue?

“Not a moral watchdog”

SA:  And how would you manage, with your system, to screen out people like Van Velzen?

JI:  Well, that’s a very difficult thing.  I think the way to do it is to have somebody in the administration who is the licence-holder, and then you’ve got a designated individual who is managerially responsible for that activity.  And by having those two, it kind of gives the idea that the game keeper isn’t the poacher and vice versa – there’s more than one person involved per institution in looking at the activities going on there.  

The other way is by inspection. The applications are filled in online, so we had to set up all that technology too.  It’s really a compliance audit, and people are asked questions about how they’re currently performing against the standards that the act requires.  On the basis of that they’re assessed, and if they’re deemed to be high risk they are inspected pretty quickly, and either a licence can be refused, or more likely given with qualifications – that you have several months or a year to get this sorted out.  

[The licensing process] had to start with premises where tissues for human purposes were to be stored -- things like bone marrow for transplantation, corneas for transplantation -- because it involves treatment of living patients, and that’s the highest risk of all, in a way.  Then the other sectors: the autopsy sector, research, and eventually things like public display.  Public display has been an interesting one:  what’s acceptable to show in public?  How would we deal with Professor Von Hagens if he comes and does one of his displays?

SA:  Yes, indeed, would he have to be licensed?  Because I went to see his Body Worlds exhibition in London and it was absolutely wonderful – I thought it was thrilling.  And you don’t have to go and see it if you’re going to be squeamish…

JI:  No indeed – and we’ve had a lot of debates about that.  In our training we have explored various scenarios, and that was a good one!  [Laughs]

SA:  What sort of scenario….?

JI:  Well, for example, he comes and says he wants to put on his show here; he applies for a licence; and provided he can show that he has consent from either the individual or the relatives to use the body for this purpose, then he’d be given a licence.  That’s how it would work.  And he says he does have this consent.

The HTA is not there as a moral watchdogWhat we can’t use as criteria for licence are things like decency and public taste as it were – that’s not for us to decide.  I think the local authority also has to say that something can be shown in their area.  So in terms of the licensing it’s actually quite straightforward – the HTA is not there as a moral watchdog, or anything like that.  And as you say, people don’t have to go and see it.

SA:  But they did in their hundreds of thousands!


JI:  Indeed, indeed.  And in principle I’m not against that sort of thing.  But it’s a complex area.  This is one of the areas that we’ve been involved in that I guess I really wasn’t focussed on initially.  I was thinking in terms of autopsies: the need for some sort of archive research, and are we spoiling things for the future?

“It’s a nightmare”

SA:  And how do you feel about that?  The sort of status of pathology at the moment, and the environment in which you’re able to do your work?

JI:  I think, fortunately, in my experience at least, the worst is over.  And I think perhaps in Scotland things haven’t been as bad as they were in England, because we didn’t have quite the number of coroners’ cases and all the rest of it.  

I’m very uneasy particularly about the medico-legal cases in England, where you’re not allowed to retain anything from a medico-legal autopsy without the consent of the relatives.  Of course, many of them do give consent, and of course in the CJD cases there’s a great wish and anxiety… In fact some relatives have felt thwarted that their wishes haven’t been taken as seriously as they deserve.  

But then we go into difficult areas, like deaths in children. Now unfortunately some children are murdered, but you know if that is the case, the people involved would never be likely to give consent to retain tissues or anything that could be used in evidence in the future.  In Scotland we actually have had convictions on the basis of evidence from material in the archive from many years ago, and that seems to me the glaring anomaly between what’s going on in Scotland and what's going on in the rest of the UK.

SA:  So in Scotland you can retain material from a coroner’s inquest?

JI:  Well it’s the procurator fiscal, but yes, it’s the same principle.  But in England you can’t without the express consent of the relatives and this is causing problems.

SA:  Massive problems I should imagine!

It’s a nightmare!JI:  Yes, it is.  And often there are communication problems.  The scenario we’re actually discussing just now is: the pathologist has done the autopsy; the inquest has been held, but the relatives’ wishes have not yet been communicated to the pathologist; time is going on, so what does he do?  Does he hold on to the material and risk prosecution, or does he dispose of it and risk the relatives saying, “Well, we didn’t want you to do that!” you know?  And whose job is it to find out what the relatives want done?  Is it the coroner’s?  Is it the coroner’s officers?  Is it the pathologist?  It’s a nightmare!  

So that needs to be reviewed.  I know there are on-going debates with the Ministry of Justice, and hopefully some sense will be injected into the proceedings.  But that’s a difficult one.

The need for greater clarity

SA:  So do you find this a big diversion from what you’re trained to do and what you want to do?  Having to wade through all this and make sure the red tape isn’t too tangled…

There are things about the current legislation that need to be changedJI:  Yes…[hesitantly].  It certainly is involving – all of us in the Authority have other jobs.  One’s a transplant surgeon, another is a pathologist, and there are many lay members -- from whom I’ve learnt a lot, it must be said.  So we’re all there as sounding boards or advisors for the Executive, which are the people working full-time.  But we can all see there are things about the current legislation that need to be changed, ranging from: what is relevant material? It’s defined as anything that contains [human] cells, apart from hair and nails, so we have the debate about, well, what about urine, faeces, plasma, serum? They all contain cells!  You know, it’s just causing endless problems. So we need more clarity on that sort of thing.

The whole question of whether tissue from the living should come under this legislation or not, I think, is a good one.  It doesn’t in Scotland; it does in England.   And there are some advantages, I think, in the English legislation.  The sort of standards set for collection and storage of tissues for use in research helps.  It’s helped sort of raise standards in terms of specimen storage, traceability, documentation, all that sort of thing – I think that’s improved, and we don’t have that in Scotland now. So there’s debate going on here about that.

On Thursday we have a public meeting of the HTA in London and that’s where some of these things are going to be discussed.  It’s interesting to have the public meetings just to get feedback.

Learning from lay members

SA:  Yes, you say that the lay members in the HTA have taught you a lot – what has it done to you as a pathologist having to go through this, because to a certain extent it was probably a moment of evolution – health care has been democratised by the internet and things, the public wants to know more, so maybe this was the cracking of an old mould.  Do you think that’s true, and what has it taught you?

JI:  Not so much cracking of an old mould… The public interface doesn’t worry me in that I’m happy to explain to people what we’re doing and why we’re doing it, and how we’re doing it – and also to explain the limitations of what we’re doing.  And that’s largely through involvement with support groups for the CJD network.  

Involvement with the lay members has taught me just how strongly the public feels about this and also how supportive many of them actually are of pathologists.  Not all of them obviously, but many have been.  Their feeling is that people need to be asked, and they actually want to be asked what their wishes are, or what their relative’s wishes were.  And if you don’t ask them, that’s not good.

We’ve really come at the situation we’re in now from two very different directions, but at first I was apprehensive, thinking that there might be preconceived ideas against pathologists. But that’s not the case at all.

SA:  So you’ve been quite encouraged by that, have you?


I’ve learnt a lot from the lay members and the focus groupsJI:  Yes, yes, very.  And I’ve learnt a lot from the lay members and the focus groups.  The way the Authority works is that we have focus groups dealing with various things, but there are lay members on all of these groups and they’ve been really helpful in bringing us back to common sense.

SECTION 7

“I deal with death every day”

SA:  What has your long experience of looking death in the face, dealing with death, done to your own outlook, your philosophy of life?  Has it coloured things, or is it ‘science’ and separate?

JI:  I think for a long time it was just separate.  When you’re young you don’t think about death.  When you get older and you become more involved by death, either in the family or whatever, then it becomes more real.  Yes, I deal with death every day at work, but I don’t think of that in personal terms.  Illness, maybe more…You know, when you start off as a young pathologist you see all these people getting these terrible tumours and things, but they’re all older than you.  Then as you get older you realise not only are they the same age but they’re actually younger than you!  And how do you deal with that?  

There’s also this feeling that you’ve got to keep busy; if you keep on the move then it won’t get you!  But that’s not true, and we’ve seen colleagues who’ve developed terrible diseases and have died.  I think that I try not to become too introspective about things like that.  I suppose I’m more concerned about my own family history and what risk factors I might have inherited in terms of blood pressure, cholesterol and whatever.

SA:  So there is an awareness, is there?

JI:  Oh yes, yes, definitely.  But you can’t wake up every morning and worry about every little pimple and think, "Oh my God, it’s a melanoma!"  I think there’s a tendency in medical circles to go one of two ways: you either ignore everything, which is also not good; or you think every cough and sneeze you’ve got is the beginning of legionnaires disease, or something.  You’ve got to find a middle way.

SA:  And is death itself as mysterious to you as to those of us who haven’t seen much of it?  Is it still, "My goodness, what is it all about?"  Or are you very much more at ease with mortality?

JI:  I think that’s the case. I’ve seen death, I’ve seen hundreds of dead people, and that doesn’t worry me.  Dying is an inevitability and it’s not something I’m afraid of at all, no, no.  However, the process by which you get there is a concern.  I think that, like many other people, I’d rather go quickly and cleanly rather than through a slow prolonged agonising illness.  And certainly having seen individuals with something like Alzheimer’s… I mean, CJD is a terrible disease, but at least it’s relatively short.  But Alzheimer’s disease is a slow burnout, decline, and all the burdens that places on families, carers, finances… I hope that doesn’t happen.

SA:  So you’re very aware of the poignancy of illness?

I’m very aware of human frailtyJI:  Yes, yes.  I’m very aware of human frailty.  And certainly, if you hear of an illness in someone you know – a colleague or a friend – then obviously your brain fast tracks to the whole gamut of the illness.  Not just where they are, but where they’ll be at the end.  There is a tendency to see other people’s illnesses in terms of sections in a book, rather than what it means for them.  And I suppose that’s inevitable given your professional background, but it’s best to try not to do that.  Similarly with yourself, but I’ve been lucky – I’ve had no serious illnesses in my life.

SA:  On a philosophical level, has it affected your view of religion?


Other things bring you to think of the meaning of life and death.  Music is one of themJI:  No, I wouldn’t say it’s affected that sort of thing at all.  I think one’s beliefs – such beliefs as I have – are based on other things.  And other things bring you to think of the meaning of life and death.  Music is one of them, one of the main things for me.

SA:  Really?  That has more influence on your feelings about the meaning of life than your job does?


This is the sound of lifeJI:  Yes, it does actually.  For the past few weeks the Festival has had on a series of concerts in Greyfriars Church at 6pm -- mostly early music concerts, unaccompanied vocal music covering several centuries.  And difficult as it has been to get myself up to Greyfriars for 6 o'clock after a working day – I’ve been coming in early and doing what I can, rushing off and getting frustrated because of traffic jams and car parking issues.  But to go into Greyfriars and stand in the churchyard near all these graves, queuing, and then getting in, sitting down and just listening, with this wonderful acoustic, has meant more to me than seeing any number of dead bodies.  Just actually to listen to the sound of it, and to think, "This is the sound of life."  That’s been quite wonderful.

SA:  What other things are similarly important in your life?  Are you a reader?

JI: I do read, but I don’t read as much as I want to.  I kind of feel a bit guilty if I’m reading a book -- I feel I ought to be reading The Lancet or the BMJ.  You get these things every week or every month and you feel you ought to be taken up with them.  I guess what I read on holiday is biographies of interesting people often from the past.  I’ve read a few recently about the enigma that was Shakespeare – who was he and what he did…Who wrote all these plays?  Was it him alone, or a combination of people, or other people we don’t know about?  So that’s been interesting. 

Mentors

SA:  So who, in your career, have been your mentors?  Your heroes?

JI:  Well my mentors – John Anderson, the neuropathologist in Dundee is one. The geneticist I worked with in Dundee, Michael Faed, who’s also retired, he’s another.  James Underwood is one of the major ones.  I tried to explain that to him when he was knighted -- I wrote this little letter congratulating him. Then Walter Timperley who trained me in Sheffield is another.  Walter always used to say, “If you’re not sure, think again tomorrow.”  So if you’ve got a really difficult case, although there’s always an anxiety to get a result out quickly, it’s actually in everyone’s best interest that you don’t rush it, and that you give it another day to think over, or to ask someone else to have a look at it.  

And there’s another colleague of mine who’s also retired from neuropathology, he’s in Glasgow, David Graham, who I always felt was a sort of role model.  He and I are not close friends, but he’s a man of great integrity, high professional standing, and I had a lot of admiration for him.  And my colleague Jeanne Bell, who’s just retired from the NHS.  She is a remarkable woman in many ways, and I really feel lucky that I’ve worked with her for 17 years.  What we’ve managed to do over these 17 years between us is, I think, something to be proud of actually.  I’m not being arrogant about this, but I feel we’ve given neuropathology in Edinburgh a presence.  I think we’ve both made, separately and together, a meaningful contribution to our subject.

Continuing questions

SA:  So what are your big research questions at the moment?  What are you working on and what are the teasing things?

JI:  We’re interested still in CJD -- in terms of variant CJD, how many people are out there who are infected that we don’t know about?  That’s still a big question.  And what can we do about this?  The Department of Health in the UK have got a very large project going on to address this, but they’re contemplating another one which, interestingly, is based on collecting tissue from autopsies and trying to see whether the tissue they collect, perhaps a bit of spleen, is infected by prions.  In order to do that, because of the Human Tissue Act, they’re going to have to get consent from relatives.  And since most autopsies now are done through the medical legal system, how are they going to get consent?  That question will occupy us for a while.

There’s the HTA, where is it going?  How can we try and shape improvements or refinements in the legislation?  And then there’s the everyday thing of keeping up to date with diagnostic pathology and making sure that my brain tumour diagnostics are as accurate as possible.

SA:  So tell me, where do you fit into the team here at the Western General Hospital?  How often do you get stuff you have to look at?  

JI:  My contract is officially 50% NHS, 50% university.  So half the time I spend in my office in the building across there in the department of pathology, delivering an NHS diagnostic service, which means looking at biopsies of brain, muscle, nerve, CSF samples.  It means looking at brains of patients that have died and have had an autopsy.  Either I do it myself or the autopsy has been done elsewhere and the brain has then been referred for an expert opinion.  This covers everything from premature babies, or fetuses even, to the extreme of age.  And getting on top of all that is a huge challenge.

Working in an NHS department in a hospital that’s financially challenged, shall we say, is no mean feat.  For the other half of the time, my research here is studying cases of suspected CJD, doing research, collaborating with colleagues not just in the UK but in Europe and overseas.  

SA:  Do you get samples sent to you from overseas?


JI: Yes, we do.  In fact we’re probably – or at least we’ve been inspected to become -- a European Reference Centre for CJD.  We get cases from all over – most recently, off the top of my head, Czech Republic, Iceland, Portugal.

SA:  And from Africa?


In Africa the spectre of HIV disease and malaria and other things is enormousJI:  Occasionally.  I’m glad you mentioned Africa.  I’m actually going to Cape Town at the end of this month.  At the University of Cape Town they’ve managed to get a little lab which they’re calling the CJD Lab – it’s not just for CJD cases, it’s for neurological diseases generally – and they’re trying to develop their expertise, and we’ve helped them by giving them all our protocols and things.  I’m going over to the official opening, and to try to enthuse them. There are so many questions that we need to ask, and of course in Africa the spectre of HIV disease and malaria and other things is enormous. We have – at least my colleague Jan has -- done a lot of work on HIV in Edinburgh, so I hope to take some of that also with me to encourage them.  Because there’s a lot we just don’t know about these diseases in Africa.  And if this can be the start of something, that would be good.

SA:  Do you expect, when you go to Cape Town, that you’re going to see dramatically different pathology once you start looking – mainly because of the massive burden of HIV?

JI:  … And other tropical diseases.  Yes, I think so.  There’s no doubt about it.  I’ve had some referral cases from there, and yeah, I think we’re going to learn a lot.  And of course with globalisation we have more people in the UK who have come from overseas, so it’s a two-way street.  But of course the challenges in Africa are enormous.  So this is a welcome development, and the people there want to have expertise, they want to develop their skills.  They don’t want to be seen as only being able to do the basics, the bare minimum.

The continuing puzzle of prions

SA:  James, when I spoke to you a few years ago for the BBC programme, you said you were probably sitting on the fence a bit about the prion hypothesis.  Where are you now with that?

JI:  [Laughs].  I’m still pretty firmly on the fence, I’m afraid.

They still don’t know what protein X isThere’s no doubt that the prion protein is key to all these diseases, but whether it’s the only thing that’s important, we don’t know.  Prusiner himself says that there could well be other things and has postulated the existence of another thing which they call ‘protein X’.  Sounds like something out of Star Wars!  But they still don’t know what protein X is, and until we have a better idea about what other things might be involved, I like to keep an open mind.  Obviously it’s not a conventional virus, it’s nothing like that; it’s something very, very different.  But whether it’s just the protein, or protein-plus is how I would see it…?

SA:  What’s the missing thing as far as you’re concerned?  Is it the trigger – the thing that starts the prion protein misfolding?


How can a misfolded protein encode so many different strains or types of disease?JI:  No, the protein folding I’m quite happy with.  The normal form of the prion protein is present in all of us in many tissues – for example, lung, heart, muscle and brain -- but in CJD and other prion diseases, this protein becomes misfolded.  It changes its shape and structure, and the misfolded protein is associated with infectivity.  According to the prion hypothesis it is, in fact, the infectious agent. Proteins misfold in a whole range of diseases.  That’s not the problem.  There are two things: one is the transmissibility.  It’s the only protein-misfolding disease that is transmissible.  And the second thing is: how can a misfolded protein encode so many different strains or types of disease?  BSE, for example, retains its fundamental biological properties on transmission to mice, cattle, cats, antelopes, sheep, humans…

SA:  So it remains BSE in these different species?

JI:  Yes it does.  And how can a protein be replicated -- bearing in mind in all these different species you’ve got slightly different amino acid sequences in your gene, but yet, if you do what we call a strain-typing study and look at the biological properties, they are retained.  How can it do that on its own without something else just to give it a bit of a steer?  We don’t know.  I don’t understand that, and I’m not alone.  Until we know a little bit more about that… I think there might be something else as well as the prion.  

The idea is to develop a cell culture system that we can grow prions inThat’s one of the things that drives our interest onwards.  We’ve now started a cell culture facility downstairs in our new lab. Mark is working on that, and who knows?  We’re collaborating with the people in the university from the Centre for Regenerative Medicine, which is very exciting -- working on stem cells with them.  The idea is to develop a cell culture system that we can grow prions in.  We’re using stem cells to try and grow them and differentiate them so that they can support a prion infection.  And once we can do that we can start looking at what the prions are doing to these cells, how the cell is reacting to it,  We can try to stop it, try to block it, try to find out what else is in involved.  That would be really interesting.

The Centre for Regenerative Medicine is a big umbrella and we’re working with one particular group of that who are interested in neural stem cells.

SA:  So what exactly are you trying to do?


JI:  We’re taking stem cells and trying to grow them and differentiate them towards neurons, basically.  That’s easy, some would say.  But to try to get them then to support a prion infection, in the dish…Now you can do that for certain types of prions, but it’s not really been done successfully for human ones, and it’s the human ones that we’re interested in. The project has only just been funded by the Chief Scientist’s Office, and we’ve got a new PhD student starting this month, so…

SA:  Are you excited about it?


JI:  Yeah, I am.  I’m very excited about it.  But Mark, my colleague, is most involved with that.  But even if you’re not hands on, you can watch and observe and advise, or throw a few suggestions in, and that’s what I’ll be doing.

Convincing the World Health Organization

SA:  One last question, about your work with the World Health Organization – do you have to go over to WHO quite frequently?

JI:  Yes, I’ve been to Geneva a few times, and that’s very interesting.  One time particularly I remember is going there just after variant CJD was announced, when Bob and I were summoned to this big meeting in WHO and basically asked to account for why we thought this was a new disease.  You know, all these experts from all over the world were there, sitting in judgement on you.  And I thought, "If we can handle this we can handle just about anything!"

SA:  Really?  It was quite a challenging meeting was it?  


JI:  Yes, it was quite challenging indeed.  It was a very large meeting – they were invited representatives, experts in CJD from other countries, experts in infectious diseases, neurologists, neuropathologists, WHO representatives.  It was in that big circular room where they have their big meetings, and it was quite a tall order!   

SA:  How did they take it?

JI:  I think we won them round in the end.  It was a slide presentation. Also we had to account for how we’d done the research.  I think having the publication in the Lancet was fine, but it didn’t go into all this stuff I’ve told you, of searching through cases and contacting people in Poland and the States and asking them to review new cases and going through everything -- you couldn’t convey all that in a publication, but you could tell people about it and you could show them exactly what you did.  

SA:  And they really needed to know all that, did they?

JI:  Yes, yes, and I can appreciate it.  

SA:  Did you enjoy it?

It became a global matterJI:  In the end, yes.  I was quite apprehensive about it before hand, but on the other hand I thought, “Well, all you can do is give it your best shot.”  And having been grilled fairly extensively in the UK by SEAC and others I had a forewarning of what might be asked, and could try to offset that by giving the information in advance and trying to show the hard data from the computer-based analysis.  To show that this is not just my aesthetic eye saying “this looks different from that”, but actually there are measurable differences, and that is hard evidence.

SA:  And that really put variant CJD on the map, did it?

JI:  Yes, that did really.  The whole thing took off, it became a global matter actually then.

ENDS