Julia Polak - Full Transcript

Julia Polak Director of the Tissue Engineering and Regenerative Medicine Centre at Imperial College, London

Interview location: Her flat in Chelsea Harbour, London 
Interview date
: 25th July 2007


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SA:  Let’s begin with a bit about your early life, where you grew up, what sort of family you had, what your folks did…

JP:  I was born in Argentina.  My parents were Argentinian, but my grandparents were immigrants from Eastern Europe.  And then during medical school I met my future husband – we were sort of teenagers, and we married young.  We wanted to come [to UK] for one year for training in a better place than Argentina.  And when we came the situation in Argentina deteriorated a lot – it was the time of all the 'disappeared' people and the 'mothers in the plaza', you know? 

My husband's brother, my brother-in-law, was taken away in front of his father.  He is one of the 'disappeared'.  It was the mid-70s; he had two little daughters, one aged one month and one a year.  Now they are grown up -- one is a doctor and one is a lawyer -- and they never knew their father.  His mother was one of the women going around the plaza.  So the situation became quite difficult for us to go back.  But it was a combination of factors – we became more and more established here, we loved our work, the people liked us, and Argentina wasn't very appealing, so we stayed.

SA:  What was your childhood like?  Was it a happy childhood?

JP:  It was very happy. A middle-class family.  My dad was a lawyer, and my mum was a writer. I had two brothers, but one died suddenly at the age of 32.  But I was already here, because I have spent most of my life here.  We came in 1967.

SA:    When did you decide to do medicine, and why?

JP:  In my household, my family, it [would have been] a horror if I didn't do something as a profession!  It was not a choice.

SA:  Really?  Who was the driving force?

JP:  Both of my parents.

SA:  So education was hugely important?

Doing well academically was expectedJP:  Oh, that was the only thing, yes.  Doing well academically was expected.  I was born into that environment, and so I didn't even think about it.  There was no choice.    I did want to be an actress actually, but I was so bad! [Laughs] I was in lots of plays.  But then I thought, “I better do something more serious.”  My dad perhaps would have liked me to be a lawyer.  But my brother is a lawyer, so that's fine.

SA:  When you say you did acting, from what sort of age?

JP:  Nine, 10, and continuing as a teenager, amateur theatre.  I was tormenting my family rehearsing my plays in front of them.  They were fed up!

SA:  So at what stage did you pick on medicine and was it an obvious choice, or were there other things that interested you?

JP:  I had a famous uncle, Moises Polak, who was a pathologist.  He was very famous in Europe too, a neuropathologist who trained with some famous people in Spain -- Rio Ortega and Cajal, they were his mentors. He was around in my life a bit, but really I don't know how I went into medicine… [Laughs]

SA:  And are you a natural student?  Did you find medicine easy?

JP:  I was one of the top students, yes.  It was easy for me.  I seem to have a good memory.  I didn't do a lot of work, though.  I was studying together with my husband, and he worked harder than me, but he got lower marks.  But then he remembers much more.  Mine was just absorbing for the exam.

SA:  He's a pathologist too, is he?

JP:  No, he's a haematologist [Daniel Catovsky].  Well sort of pathologist, because pathology in the broadest sense includes not only histopathology; it includes chemical pathology and Haematology The branch of medical science concerned with the blood and blood-forming tissues;  haematopathology is concerned with diseases of. where they look at films and slides and sections and all that.

Attracted to research

SA:  And what interested you in doing pathology rather than any other specialisation?

JP:  I think it was because of the research angle.  I was interested more in understanding the mechanisms of disease than curing patients -- the mechanisms and the science.

SA:  And you practiced a while as a pathologist in Argentina?

We were very unconventional pathologists! JP:  Yes, not for long, but I got the equivalent of a diploma in pathology there.  Then in 1967 we came here, only for a year and then we intended to go back to Argentina.  But of course we never went back.  I came here to train with a famous histochemist– a person who understands the chemistry of the cells – who was creating reagents to light up the cells.  I got a scholarship to work with him at the Hammersmith Hospital.  Although we were within the department of pathology we didn't do conventional work – we were very unconventional pathologists!

SA:  Who was he?

JP:  Professor Everson Pearse.  He's written many of the books on histochemistry.  He's dead now.

SA:  So what was unconventional about the way you worked with Professor Pearse?

JP:  Well he was unconventional, and I followed him.  He wasn't in the group that was doing the postmortems and the routine diagnosis.  If you are working with the Pathological Society, you will be coming across that kind of work, the hard core pathology, much more than with me.  I'm an oddball!

SA:  That doesn't matter – what I’m trying to do is give some insight into the kind of people who go into pathology and what their working lives are like.

JP:  I think the public misunderstands what are pathologists.  First they think they are coroners, or people who find out [what happened] when someone got shot or something, like on the telly.  Well that is pathology too, but pathology is a broad term, extremely broad, including haematologists, as I told you, who look at the films, chemical pathologists who do the analysis of the urine and the blood and things, and histopathologists who do diagnosis.  When they take a lump from you, histopathologists cut it into salami slices and look down the microscope and say, “Yes, you have cancer, or “No, you don't have cancer,” and things like that.   I did all of that in Argentina.

SA:  And how interesting did you find the job of pathology at the beginning?

JP:  All that was very interesting.  But then I thought I wanted to understand why a disease occurred.  And I was doing quite a bit of research while I was a student.  Because I started doing pathology before I qualified.

SA:  What were the things that most stimulated your imagination when you were doing routine pathology?  What were the things you felt most that you wanted to understand in more depth?

The why of diseases was what interested meJP:  Well merely the diseases…If you get an ulcer, why?  The why of diseases was what interested me.  Nowadays the hard core pathologists do a lot of mechanistic research.  In the early days it was more routine, but now they're doing some very good research.

“A hand clasped my hand!”

SA:  What was your first experience of death? Was it when you first came to do postmortems, or had you experienced death before that?

JP:  No, it was more or less when I started pathology.  As a student I was very, very junior, and I had to clean the pieces for the museum -- they don't do that anymore because of 'health and safety' -- and there were bits in formalin that I had to take out and in.  I remember I had to come in very early one morning to the postmortem room, it was a very cold morning, and when I reached into the bucket a hand clasped my hand! [We laugh]

SA:   And how did you react to that?

JP:  With disgust; I ran out of the room!

SA:  But you psyched yourself up and went back in?

I'm not the reflective sortJP:  Oh, it wasn't a crisis.  I'm not that kind of person.  I remember after my transplant, people said, “You'll need psychotherapy, some support...”  But I'm not that kind; I'm not the reflective sort.

SA:  Was it the disease mechanisms that most fascinated you even in your early days as a pathologist, or were you very aware at that point of the patient and the patient's family?

JP:  No, no.  I was more into the science.  I mean, to such a degree that when they took my diseased lungs for research purposes at the Hammersmith, people asked “How could you look at your diseased lungs?” But you don't think: that was part of me.  You look at the science behind it.


The story of her heart and lung transplant

SA:  So tell me about your operation.  What were the symptoms and how did you come to realise you needed a transplant?

I was in heart failure and it was terminalJP:  It's a long story…I probably had the disease all my life, but nobody knew. I was becoming more and more breathless, I couldn't breathe, and people said, "It's asthma."  But I had a very rare disease called pulmonary hypertension – high blood pressure in the lungs – where the incidence is one in a million.  It was only diagnosed when I collapsed at the Hammersmith.  I was in heart failure and it was terminal.  But until then no one considered it. 

SA:  How long had you been noticing that you were breathless?

JP:  All my life.  I had probably had it all my life, although it was probably a very mild form until it suddenly deteriorated.  Because I had my three children, and I was flying all over the place, giving lectures all over the world, while pregnant or not pregnant... I mean, you know!  But it wasn't comfortable.  And then at the end I couldn't walk, obviously.

SA:  Did you ever suspect that's it might be pulmonary hypertension?  Or did you accept that it might be just asthma?

JP:  No. Neither of those.  I didn't suspect pulmonary hypertension and I thought it was something more than asthma, but I couldn't tell.

SA:  But you'd been studying pulmonary hypertension, hadn't you?  Why did it not occur to you?

JP:  I suppose I thought, “It doesn't happen to me.”  I don't know.  I can't tell.  It could be denial...  I'm not a very good psychologist! 

SA:  So what exactly happened?

JP:  Well, I collapsed.  It was in April 1995, and my transplant was on 17th July 1995.  I was born in 1939, so I was 56.  When they got me to hospital they were shocked, obviously, because they went out of my room to talk.  I suppose they were discussing how to break the news -- I couldn't understand why they'd gone outside.  And then when they said, “You have pulmonary hypertension.”  I demanded, “But why?”  I was so angry I wanted to hit someone. They said, “We don't know why.  But we have to move you to the ward.”  I said, “No, no, I'm going home, get my clothes.”  They said, “No you're not, you're staying.” 

Then they called [my husband] Danny and told him to bring me some clothes.  He was shocked and didn't understand at first, and then they told him, “She's seriously ill.”  They put me on a drip and oxygen and all that.  Then an expert from the Hammersmith, Celia Oakley, was flown over – she was on holiday in Greece, she's retired now – and she made a diagnosis.  That was in April, early May. They started treating me with something, but it didn't do any good. I was terminal, so I was deteriorating even faster, and then I was admitted again.

SA:  Were you in hospital all the time or had you gone home?

JP:  I was in hospital only for two weeks at first.  They sent me home but I collapsed there again so I went back.  And then at a certain point Sir Magdi Yacoub, the famous transplant surgeon, appeared.  I was carrying out research projects with him, and I said, “Why are you here?”  "It's a social visit," he said! [Laughs]

SA:  So they were keeping you in the dark?

JP:  Actually they were in the dark.  I mean they were so shocked and astonished… they just couldn't believe anything.

SA:  And they thought you were going to die?

JP:  Oh yes.  I mean, when they put the possibility of a transplant, we didn't want to accept it, because Danny knows a lot about bone marrow transplant.  Remember, this is 13 years ago; it's not the same as today.  But they didn't do so well in the early days, heart and lung transplants.  It was only when one of my colleagues at the Hammersmith... I was in the bed, Danny was by my bedside, and [my colleague] walked in.  He had nothing to do with my case, but he knew we were resisting making a decision, and he said, "Look, she's dying", in front of me.  He said, "Okay, she may die during the transplant or soon after.  But it's the only chance she has."  It was shock therapy, and at that moment we accepted, because we didn't have any choice.

SA:  And how did you feel, knowing how serious the disease was, and being given a death sentence like that?  You say you're not a reflective person, but how did you take the news? 

JP:  Actually, I was too ill.  I was too busy trying to get better and I couldn't think very well.  But then sitting in the hospital...They told me I had to wait for a suitable donor organ, and then nobody contacted me again.  I was in intensive care, and of course they can't contact you until they have a suitable organ. The waiting was very, very hard.  I was also wasting away, because I couldn't eat.  It was horrendous. 

Then they said, "If you fit oxygen in your house (which was a job because it was a house on several floors), you can go home on a Saturday and come back on Sunday.  You can go for a little rest."  So I went.  It was a big palaver with the oxygen, these big machines.  I couldn't walk so they had to get me up the stairs with a wheel chair, and all the oxygen, blah blah.  That was a Saturday. And then Monday, at 2 o’clock in the morning the telephone rang.  Everybody was so fast asleep that no one else heard it and I had to drag myself over to the phone. I picked it up and someone said, "You have to come immediately, we have some organs." 

The dash to Harefield Hospital

SA:  Goodness! So you thought it was just to be a weekend break at home and then it would be back to the IT unit?

JP:  I had left all my things at the Hammersmith.  Everything was there, because I was there for months.  All the cards and the flowers and the books, and my nightie, and my shoes, blah blah blah.  And my makeup – anything you can think of was there, but I never went back.  I went to Harefield. 

I was used to going to Harefield because I worked with Sir Magdi every week, so I knew the way.  Danny was driving and he didn't have a clue; it was the middle of the night.  My son Sebastian was in the car, too, and they were both terrified.  I was saying, "Turn right, turn left, go straight", and when we got there, I wasn't thinking, I told them, "Park here."  It was the parking space I was allowed to use when I came to see Magdi, but that wasn't the right place, because I couldn't walk, and in fact there was a wheelchair waiting for me at the main entrance.

They asked me for authorisation to donate my heartWe must have arrived at about three or four in the morning.  Poor lady that was in the same room as me, she must have been disturbed by all that was going on! Then they asked me for authorisation to donate my heart, and I signed very happily.  But I don't remember any of this -- my family confirms that I signed the consent form for my operation and for them to use my heart, which was okay.  So my heart went to somebody else. 

SA:  So your heart is in someone else?

JP:  Was.  He passed away.

But to go back to our arrival.  I was too frightened and too sick, so finally a stretcher comes to take me, and that was horrendous.  I was saying goodbye to the family, and I really thought it was goodbye forever.  Danny saw another stretcher being carried in at the same time, and he saw that I had consented to give my heart.  Then when I was in the ITU after my operation, Danny said, "Don't say anything, but I think this is the family of the person that came in at the same time as you.  I think he might have your heart."  They might have said the same thing to each other, because later when we were walking in the ward, after we'd both recovered, the man said, "You saved my life; I got your heart."  So there he was.  But he passed away very fast – about two or three months afterwards.

SA:  What has your experience with this disease done to your practice of medicine and how you do pathology?  What impact has it had on your life?

New life; new direction

It has completely changed my life and my work! JP:  It has changed completely!  I went into tissue engineering and stem cell research – creating lungs to overcome the lack of donor organs. Yes, it has completely changed my life and my work!  [When I got back to work after the operation] I thought I had to do something that relates to what happened to me, and I wanted to study more of the pulmonary hypertension.  But then the new field started: tissue engineering and regenerative medicine, stem cells.  You could say that I would have gone into that field anyway, because I always liked to be into the exciting new areas.  Or you could say it was the influence of the transplant.  Take your pick: there is no evidence either way!

SA:  Going back to your operation itself – did they offer to show you your own organs or what?

JP:  No, no, not at that point.  Because we were working together, the Hammersmith and Harefield teams, we had a bleep system to let us know when there were organs to collect from Harefield for our research labs in Hammersmith.  One day one of my colleagues received a call and was asked to come and collect a specimen of pulmonary hypertension.  And they all knew that I was waiting for a transplant, so he asked, "Is that Julia Polak?" and they said "Yes."  So he went with someone else to collect the organs and then to dissect them.  I was asleep, so I didn't see the organs myself till much later.  Did my colleagues find it difficult working with my organs?  Some did, but apparently some not.  But I don't know because I wasn't there. 

She presents her own pathology

But afterwards I did see them, yes, very interesting, they were lovely in terms of pathology.  I presented them.  There is a case report; I think it's written in the British Medical Journal: ‘The pathologist as patient’. I think you can find the reference.

SA:  Tell me about the presentation – where was it and to whom?

JP:   That was at the Hammersmith Hospital.  They have a famous thing there called the 'staff rounds'.  They present three cases where a clinician presents a clinical picture, and if it's [a surgical case] a surgeon will present how he did it, and then a pathologist comes and presents what he or she found, either in postmortem, if the patient died, or from the surgery.  It's a regular event, but this was an anniversary of some sort.  I was at home recovering and they said, "Can you suggest someone?"   I said, "You can present my case if you like," and they said, "Oh! Would you mind if we did that?" 


It was a large lecture theatre, for about 1,000 people.  But some people couldn't get in; they had to be outside; they were all crying, it was…you know!  [Laughs] I think they sent a note round which said that I was very susceptible to infection, because it was still very early days.  I didn't know that that note was sent round, but I thought, "Funny, why don't people come and greet me?"  Now I understand in retrospect…

SA:  They'd been told not to kiss you?

JP:  Not to come near; not to come near.  They were all going… [she mimics them all waving at her from their seats].

SA: [Laughing] Waving at you!

JP:  My brother came from Argentina with his wife; Daniel was there; friends were there.  Everybody was crying!  Because for most people it was the first time they saw me after the transplant and you know, it doesn't happen often, a colleague with a transplant!  Of course I'm not very big, so I was just standing there looking small.  And the clinician who'd made the diagnosis of my disease presented; then Magdi Yacoub presented the operation he did; then I presented the pathology – my own lungs.  Everyone was [she gasps]!  And then it was published.

SA:  Did you yourself feel emotional at the time?

JP:  Well no, I was busy trying to remain strong, because I was still quite wobbly, and I was busy trying to concentrate on what I had to present. I felt strange that people were doing that [waving] and they were all crying. [We both laugh]  And apparently I said -- you had to conclude as a pathologist -- and I said, "This pair of disgusting lungs!" 

I couldn't imagine how I had managed to breathe through those lungsIt was an extreme case of pulmonary hypertension – no chance of medication.  Nothing.  I would not have responded.  It was probably the worst case I have seen.  I couldn't imagine how I had managed to breathe through those lungs.

Living with a transplant

SA:  But people offered you all kinds of support did they, after the operation?

JP:  Well they do after a transplant anyway, they offer, but I didn't take it.  But I did have nightmares at some point.  For a while I would get up in the night saying I couldn't breathe.  I could breathe actually.  But in the end obviously I worked [my fears] out myself.

SA:  You now have the reputation for being one of the longest-lived heart and lung transplants.  What are the everyday challenges to survival?  Why do most people not survive so long with this operation?

For statistics you need numbersJP:  The statistics for survival go as far as five years, and then no more statistics.  I don't know if everyone has gone by then, but for statistics you need numbers, so there are obviously too few who do survive longer than that for them to show up in the statistics.

SA:  What are the big risks?

JP:  You can die during the operation because at certain points you are not alive.  They take your heart and lungs and they put you in an artificial heart and lung machine and you can die then.  You can die when they put the organs back and they don't ‘take’.  You need to get the organs pumping, the new heart, which has just been connected up to your own blood vessels.  And then you can die – which I nearly did – because they put you in this artificial heart and lung machine so all your blood clotting is altered.  I was bleeding like mad from my drains, and Sir Magdi came and said, "She needs fresh blood."

But I was dying!Fresh blood means 'not from the blood bank', so they had to bring the soldiers from the barracks near to Harefield.  They didn't have time to test for HIV or anything else – but I was dying! They tested for matching, and that's all.  But my lungs didn't match, the tissue didn’t match.  Magdi Yacoub explained to Danny, but at a certain point you have to decide, “Do we match, or do we take the chance?” You might find the perfect match if you wait, but it might be too late.  I mean, you know?

SA:  What do you have to do now to stay healthy?

JP:  I have to take drugs to suppress the immune system [to prevent rejection of my new organs].  Are they difficult to take?  Not to take, they are very easy, except that I have to take loads in the morning and loads in the evening.  But the consequences are not nice.  You can develop malignant tumours.  You can develop very serious infections, and some people die from what is called chronic rejection.  Tomorrow is my 'annual' actually – my MOT!  I have to have an MOT every six months.

SA:  And do you get frissons of fear before you go?

This is uncharted territoryJP:  Oh yeah, I'm completely neurotic, I hate it.  Every time I do the lung function test I hate it.  And my lung function is declining – it's difficult to tell if it's age or just the lungs.  But this is uncharted territory and you just hope…Nobody knows…

SA:  But how do you feel in yourself?

JP:  I feel fine.  I do gym every day; I do yoga once a week -- which I hate, it's so painful!  I work all the time.  I never stop on anything.  But you don't know what's next, and nobody can tell you because they don't know either.

SA:  So do you feel vulnerable because your immune system is suppressed?

JP:  Oh yes, very vulnerable.  I can get skin cancer, I get lung infections.  The drugs don't give you side effects like heartburn or anything like that, it's the consequences.  It's not a good idea to go in aeroplanes [because of the germs circulating in the air], but I go.  But we go first class, which has a bit more distance between people.  And there is a rule that people don't come and see me at home or in the office if they have any kind of infection.  Washing hands is very important too.  I make sure that when people come to see me they are not unwell.  And the children, they know to stay away if they are not feeling well, even mildly unwell.


At the forefront of research

SA:  So tell me a bit more about your pathology career – your road to where you are now.  You started doing the regular work – cutting up bodies and that sort of thing – and then how soon was it that you moved into research?

We discovered what is called the ‘gut endocrine system’JP:  Well I was always interested in the academic side.  And when I came here the professor gave me a research project to try to discover if there are cells in the gut that produce hormones.  Because they thought hormones were just produced in the glands, like the thyroid.  But we discovered what is called the ‘gut endocrine system’ – it became famous. 

SA:  Tell me about this research.

JP:  I was very young -- I think I was 28 or something -- I was doing some initial research.  I was developing the technique of immunocytochemistry, and my mentor was Professor Pearse, who’s now passed away.  He said that he'd managed to get some antibodies to a hormone that is in the pancreas, and would I go and collect them from the Middlesex Hospital.  So I went, and I met this young doctor there who gave me these antibodies, and he said, "Why don't you try it in the gut?  I think you might find it also in the gut."  And I tested, working Saturdays and Sundays in the lab and all that, and I finally succeeded, I found it there… [outside of] the pancreas.  That's how we started -- he's Professor Steve Bloom, and we started a great collaboration of many, many years on the gut hormones.

Then we found them in the nerves, as neurotransmitters, too.  This was the gut-brain axis which was a big field – everybody was talking about it.  And then we asked the question, "Wait a minute, why would it be gut and brain only?" A German professor had described, in the lung for instance, there were possibly... he called them 'paracrine', like endocrine, cells.  So we looked and we became well known, with papers in Nature and all that…Wherever we were looking we were finding a diffuse neuro-endocrine system. 

I ended up on a stretcherAnd then when we found this diffuse neuro-endocrine system, we said, "What will happen in disease?"  So we were looking at diseases of the gut, and we published a number of papers. Then we said, "If the gut has the same embryological origin as the lung, let's try the lung. What will happen in [diseases of] the lung]?"  I contacted somebody I'd never met before; we met and we established a fantastic relationship.  He was Sir Magdi Yacoub, and we started doing the research.  He was giving me the lungs of the explants and I was staining them (doing immunocytochemistry).  They were all from people who needed transplants…And then I ended up on a stretcher being his patient, and donating my own lungs for research! [We laugh]

SA:  At that stage, before you started all this, it wasn't understood that the endocrine system was as diffuse as this?

JP:  No, no.

SA:  Where was it thought to be located?

It was an unknown fieldJP:  In the pancreas, and in the thyroid, the pituitary -- what we call 'the glands'.  My professor, my mentor, he was interested in that.  But then, with Steve Bloom, he said, "Wait a minute; it seems that they may be in the gut, because there is some action, so let's see what cell [is involved]."  So that's how we started – it's always the localisation story.  But of course in those days the localisation was a challenge, because it was an unknown field, which I developed.  Nobody believed the immunocytochemistry at the beginning.  They said it was an unwanted artefact.

SA:  Really?

JP.  Oh yeah.

SA:  For how long?

JP:  Oh a year or two or more.  But you know, when you find something new, the people think it's an artefact.  But then it was proven and nobody objects; now it's a routine technique.

SA:  But what sort of diseases was all this relevant to?

JP:  In the gut we looked at diseases like coeliac disease, Crohn's disease, and we published  a number of papers: Crohn's because they have bad nerves; coeliac because they have bad cells.  And then the lung, we were looking at anything that came out of the explants – they were cystics, and then there were fibrotic lungs, and pulmonary hypertension lungs, and things like this.

SA:  And you were looking for the hormone systems?

JP:  We were looking for the neurotransmitters or the cells which are in the airway Epithelium  The layer of cells covering most of the body's structures and organs, internal and external.  It includes the skin. – you know, in the pipes, in the lining of the pipes – to see whether there were alterations.  But I didn't make it, because then I ended up with a transplant as a patient, and then I started with regenerative medicine.

Validating a new technique

SA:  How challenging was all this to discover?  What were the frustrations along the way?

To demonstrate that this was a robust technique was hardJP:  It was impossible…very, very hard.  It's easy to talk in retrospect…The frustration was mostly because people didn't believe in the idea [of immunocytochemistry]… Well they did, because I had all my papers accepted and I became well known.  But to demonstrate that this was a robust technique was hard.  And actually to reach the point where the technique was robust was hard.  But I wasn't scared of working hard!

SA:  So did you have to fight to get this recognised or to get funded?

JP:  Well yes, the funding, as always was hard.  But you don't fight.  You just show very sensibly and with facts.  There are no emotions involved in that.

SA:  So when you’re involved in that sort or research, what is your working day like?  Do you disappear into a lab and just work at the bench all day long?

JP:  That's what it was like in the early days.  And then the more you progress, the more you allow the younger people to do that work.  Now I have the status of an elder statesman!  I can advise them and direct them.  They need to develop their own careers.

The story of nitric oxide

[After the work on the gut endocrine system] I went into another area.  I started to work on nitric oxide, which is a product of exhaust fumes and which exists in our bodies.  I was looking at the enzyme that produces that, and it was a novel field. 

SA:  What exactly is nitric oxide?  And what are the implications of finding it in our bodies?

JP:  As I say, nitric oxide is a gas that's found in the exhaust fumes of cars. There were pharmacologists working -- in particular in the States and some at Glaxo Wellcome -- who noticed that, in vitro, if they put a [certain] compound in with a blood vessel, [the blood vessel] dilated.  And [so it was suggested] that nitric oxide was a gas that in fact we produce inside our bodies – it's not only cars that produce it.  This was very much a chemistry, a pharmacology study. 

Then they discovered that this gas is produced by an enzyme -- the enzyme produced this substance that causes vasodilation.  So the question was, “Where is this enzyme located?”  This is where I come into the story, because nobody knew where the enzyme was, and I had a reputation with this technique of immunocytochemistry, which I described to you already.  They were asking, "If [the effect we're seeing] is happening in the blood vessels, is the enzyme present in the blood vessels?"

SA:  You mentioned immunocytochemistry before, but you didn't describe it…

JP:  Well I can tell you now what it is.  Bodies produce proteins, and you are able to raise antibodies to these proteins in a rabbit.  The antibodies that you've raised against a particular protein, you can tag them with a colour, and then when you put them in the tissue you are studying, it shows up fluorescent red, or whatever colour…

SA:  So the AntibodyA protein produced by the body's immune system that recognises and attacks foreign substances. will find the protein and stick to it?

JP:  Yes, because the AntigenAny foreign substance or organism that stimulates the body's immune system to produce antibodies and cells that react specifically with it. and the antibodies are like this [she clasps her hands together].  They fit like this, so when you wash [the tissue] the antibody will go everywhere, but it won't wash [away from the proteins it's stuck to].  And because it's a colour, you can see it.  In fact I made my name discovering that hormones are secreted in the gut by this technique.  But this technique now is used in departments of pathology all over the world routinely.

SA:  Is this the same as 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.?

JP:  The same thing, yes.

SA:  Okay, because lots of people have mentioned it.  So that's your discovery?

JP:  I didn't discover the actual technique, but I discovered a way of applying it to tissues and pathology.  I have books on that, and I became well known.

SA:  So what was it being used for before you applied it to pathology?

JP:  Research, mostly research, and very little.

SA:  So you applied it to tissues?

JP: It was used also in tissues but very little, and it was very early days.  I made it more robust.

SA:  Okay, so you get the dyed AntigenAny foreign substance or organism that stimulates the body's immune system to produce antibodies and cells that react specifically with it. , you put it into the substance and you wash it, and the stuff that doesn't attach to a protein will wash away? 

JP:  Exactly.

SA:  And the stuff that does attach will show you where the protein is?

JP:  So the protein, which is an enzyme in the case of nitric oxide, was in the tissues.  We raised antibodies in rabbits to this protein, which was purified and extracted by chemists, and characterised by pharmacologists, etc etc.  And then we tagged the antibodies, put them in there [with the tissue samples], washed, and the only thing we could pick up was that the enzyme was in the blood vessels. This explained how this exhaust fume substance, which we produce endogenously, produced vasodilation. 

Then it was discovered that there were three different types of this enzyme.  Others are involved in inflammation and other things. You know, it became a big subject, and a Nobel Prize was given [in 1982, for physiology and medicine] to the discoverer, who has now passed away, Sir John Vane.

So, I was in the field, at the forefront.  I couldn't be in the field when they discovered  [the endogenous nitric oxide] because I'm not a pharmacologist or a chemist, so I had to come in when the question arose about where it is produced.  Exactly the same as when we discovered the hormones being secreted in the pancreas -- I can't come in until they are discovered, but then the people need me to say where it is being produced; to explain…

SA:  So you were working on blood vessels?

JP:  No, I work on all tissues. We [also] found the protein in inflammatory cells when it was another but similar type of enzyme, a sub-type that has to do with inflammation.  We found it in blood vessels; we found it in neurons in the nervous system.  We published numerous papers etc.

SA:  And what was it doing? You say it was a vasodilator …?

JP:  In the blood vessels it's a vasodilator.  In the macrophages, which are inflammatory cells, it has another function, and in the neurons, in the nervous system, it's a neurotransmitter.  So it has different functions, different sub-classes of enzymes, all under the big heading of nitric oxide.

SA:  And were people staggered that this little molecule could be doing so many things?

It led to the Nobel PrizeJP:  It was a very big field.  Amazing!  And of course, it led to the Nobel Prize. I seem to have staggered on topics which are at the frontiers.  Because I got involved in the gut hormone field which was very big, and then the nitric oxide, and then the stem cells, or tissue engineering. 

SA:  But nitric oxide, what tissues in the body is it in?

JP:  In the blood vessels, the brain… it's everywhere practically, playing different roles.

SA:  And what applications have come from this discovery?

JP:  Ah, have you heard of Viagra?  Well that's nitric oxide, because it's a vasodilator, it dilates the blood vessels.

SA:  And have they tried it for other things?

JP:  They tried it for angina.  In fact they tried it on me when they did the first study, before my transplant.  They did AngiographyA special form of X-ray examination that shows the blood flow in  arteries and veins. and they tried to give nitric oxide to see whether my blood vessels would dilate.  But of course I was so advanced that my tissue was already very 'remodelled'… So nothing worked, actually.

SA:  But in exhaust fumes it's supposed to be a fairly dangerous substance, isn't it?

This substance can be very dangerousJP:  Yes, this substance is not so marvellous, it can be very dangerous.  In the inflammatory response it can be cytotoxic -- it can kill cells.  As a neurotransmitter it's fine.  It plays a multitude of roles.  [How it works] depends on the quantity, where it is located and what kind of enzyme subtype.


Stem cells and regeneration

SA:  So, okay, after your transplant you left your work on pulmonary hypertension and changed course completely?

JP:  I changed completely.  Well, it's all geared to saving human lives, and it's all geared to the diseased state, and the technology is the same, but the projects are different.

SA:  You were a pioneer in the tissue engineering field too, and you started the multidisciplinary research centre for this at Imperial College in London.  How would you describe your work to a non-medical person?  How would you describe what tissue regeneration is?

JP:  We all have the capacity to regenerate [due to the presence of stem cells in every tissue].  Otherwise you would cut your skin and you'd die by bleeding, but you do heal.  A baby will not easily leave a scar because it has much greater capacity to regenerate identical skin.  The older we get, the more we get these horrible scars and marks all over the place, but we do regenerate.  If we would regenerate really well we wouldn't get ill.  A lamprey or a frog, you cut a leg off and it regenerates very well.  So [the question is] what have we lost?  Or what have we gained as an inhibitor [of that process]?  And what can we learn to get humans to repair like that?

[Say] you get ‘smoker's lung’, which is a very common disease called COPD (chronic obstructive pulmonary disease): the airway Epithelium  The layer of cells covering most of the body's structures and organs, internal and external.  It includes the skin. is all destroyed because you killed it with the nicotine, then the air sacks become enlarged, which is emphysema.  Maybe if we are able to encourage the lungs to regenerate, or we can ameliorate the condition, or stop it at that level…

There are three ways in which you could help the body to regenerate itself: either by giving the [patient] a new lung, if you do it in vitro...

SA:  You mean grow it in vitro?

JP:  Yes.  That's not going to happen by yesterday, but there are steps in the right direction.  There are clinical trials on the bladder that was produced ex vivo, a whole organ, a whole bladder.  Such an organ has been put into children and it is still functioning eight years later.  It's not a perfect bladder – they didn't do the ureters and they didn't do the urethras -- but still, it improved the condition of the children.

SA:  And starting with the child's own stem cells?  So it's a match to the person themselves?

JP:  Yes, correct.  But one day maybe the famous, or infamous, embryonic stem cells, which are very ‘plastic’ and can become anything, could be used, if we can overcome the immunological problems because they don't belong to the patient, and ethical and moral concerns etc.  Umbilical cord stem cells are also becoming quite famous – Richard Branson is starting [an umbilican cord stem cell] bank -- so there are several kinds of stem cells that could be useful.

The idea is: either you can have an ex vivo organ; or you could grow cells and then give them to a patient [ie start the process of growing a new organ and then hope it will continue by itself inside the patient]; or kick the patient in the backside and say, "Mobilise your stem cells", and those stem cells migrate to the injured site.

SA:  And how do you do that?

JP:  You need to create drugs that will mobilise your own stem cells.  It's early days, but it's done in Haematology The branch of medical science concerned with the blood and blood-forming tissues;  haematopathology is concerned with diseases of., and probably will be done more widely in the future.  So these are the three big approaches, and people are working all over the world on different strategies. 

This is very nice research, and I can sell you any lies you like about how marvellous it is, but [the fact is] it only produces this amount [she indicates with her fingers a minute quantity of material].  That won't cure the whole population!  So that's the biggest challenge now -- we need to have robust ways of mass producing identical cells for particular diseases.  They have to be mass produced like cars.

SA:  So what is the material that you've got only minute quantities of so far?

My God there are hurdles!JP:  Well, they are cells that you grow, either from the patient you are treating, or embryonic stem cells, or umbilical cord stem cells.  Richard Branson is collecting the umbilical cord cells, and that's good but there won't be enough.  We need to learn how to expand stem cells in such a way that there won’t be changes in the cells.  You know, you introduce artificial changes and God knows what the cells might be doing.  So all that needs to be overcome.  I don't need to tell you all this -- I could say it's all marvellous and it's going well.  Yes, that's so, in a glass-half-full kind of way.  We are certainly making steps in the right direction, but my God there are hurdles!

SA:  So what are the main hurdles, and what have been some of the stumbling blocks along the way?

You need mass production, industrial-scale productionJP:  Well, there is the blocking of the embryonic stem cells in research.  Then with cells from a patient, they are older cells and they may all carry the same genetic defects, so they are not marvellous.  Umbilical cord cells, as I said, are ideal, but there are not enough of them.  So if you want to cure smoker's lung, which is very common, what do you do?  You need mass production, industrial-scale production, of things for clinical application.  Nobody knows how to do it.  That's a challenge!

SA:  So at the moment have you got proof of principle that you can regenerate a lung?

JP:  No.  We discovered… Take my transplant, for instance, this lung belonged to another person, okay?  I don't want to test it while I'm alive, but suppose I die, then my lungs can be stained and they can be checked to see whether these lungs are being repopulated by my own cells.  We did demonstrate and published that donor lungs can be repopulated by the patient's own cells.  So there is an attempt [by the body] to regenerate even a foreign lung when the lung is damaged.  So obviously there is the release of something in these damaged lungs that attracts the cells to regenerate.  Fine.

SA:  And you will leave your lungs to medical science, will you?

JP:  Yeah, I will…And we are now working with experimental animals on a model of emphysema.  We will put umbilical cord stem cells, which are expanding, and see what happens.  If these cells a) do not produce any unwanted effect, and b) lung function improves, then we can consider going to a larger animal model and then man.  So you see, the timelines of the conventional pathologist are totally different from those of research.  A pathologist wants to save life now; they are aware of all the things that can be done, and they can suggest a course of action and see the result.  But I might not see any of my research [come to fruition] in my lifetime. 


Science and commerce

The other thing that is important is not to lose sight of the fact that many important discoveries are made in this country, like Monoclonal antibodyAn antibody produced in the laboratory from a single clone of cells, which is therefore a single, pure, homogeneous type of antibody that recognises only a single, specific antigen, or protein. , but they are commercialised everywhere else.  This country didn't make any penny from the discovery [of monoclonal antibodies], which is typical!  That could happen to our discoveries [in this field], so we have had to make sure that we protect our discoveries.

SA:  So you've started a company?

JP:  Yes.  I have two different things – one is my charity and one is a company.  The company is going reasonably well, but it's early days.  We started a company with [bio-engineer] Larry Hench – he's the one who produces the man-made materials, and I'm the one who works on the cells.  And then we thought we needed to protect [our intellectual property], and we started a company about two or three years ago, with commercial people. 

The new CEO now is a person who reads the Financial Times, while I'm reading Science, or Nature.  He's very intelligent on the science but he doesn't understand in depth – he understands the potential, and he talks to me about the finance.  I haven't a clue what he's talking about most of the time – share options, etc etc!  But it's crazy that this country shouldn't benefit from its discoveries, absolutely crazy.  So we started the company to protect our discoveries for this country.

In real life, you want to save livesOur company is fully integrated with all these discoveries at Imperial, and I am the chairman of the scientific advisory board.  At the beginning we didn't have that.  So we got a management group who are financiers, and they understand business.  And then I run the science.  And that's fascinating, because the science moves from the test tube to something that could become reality.  Doing research and writing papers about your discoveries is beautiful and you become famous.  But in real life, you want to save lives…And to protect your discoveries, and make money to bring it back to the research.

But first shall I tell you how I came to know Larry and why we're working together?

SA:  Yes, yes.

JP:  It was the identical same question [as with the nitric oxide story].  People come to me after they find something to ask where it is [in the body], the localisation.  So Larry was working with ‘bio-glass’, a man-made material, and he noticed, first in rats and then in man, that you give this powder [she rubs her hands as if grinding something] and there is bone regeneration.  And he said, “Why?  How?” 

He moved, as a professor, from the University of Florida to Imperial College -- at that time the Hammersmith Hospital where I worked wasn't part of Imperial, but it became part of Imperial a year or two later.  He heard that there was a 'famous' woman in UK that can localise products… He was looking for somebody who would help him to explain the phenomenon, why this powder induces bone growth.  So he came to me, and I told him, "It's easy, I can help you."

SA:  Where was he putting this powder?

JP:  Locally, wherever.  It was mostly maxilo-facial repair he was working on.  His bio-glass hasn't been proven to be as effective – hasn't been shown, but it doesn't mean that it isn't effective -- in soft tissue.  So it's mostly bone. 

SA:  So you first met him when he came in to see you…?

JP:  He came in to see me and he said "Hello", and I said "Hello", and looked at him.  He said, "I'm an engineer," as though he wanted to repair a television!  And then we started an amazing collaboration.  He said, "I would like to know whether you can help me to understand the mechanism by which there is bone repair."  And I said, "Well, we need to use the cells and try to identify what the effect is at the microscopic level in these cells."

We found that this bio-glass material that he produces attracts cells, and the cells attach.  And then we found that they proliferate – the cells grow -- and also differentiate into bone.  The material attracts stem cells from the bone marrow that is there in the bone, and then they attach there and they proliferate, then they differentiate, and that was the mechanistic explanation of Larry's finding.

SA:  And do you know why -- what it is in the substance that attracts the cells?

JP:  Yes, yes.  This substance releases ions and the ions attract cells, like local stem cells.  It's called 'bio-active' because it's not inert -- it doesn't just sit there and hold the cells and hope the body will do the rest; it tells the cells to do something about it.  So it's an interaction between the cells and the material.  And that's how we started the whole story.

First we started with adult bone, and we looked at the femur and hip replacements.  We were taking the cells from there and looking at his bio-glass.  And then suddenly I said to Larry, "I think we need to use younger cells."  It was already known that Martin Evans had discovered something called 'embryonic stem cells', but they were from the mouse.  We started working with mouse, and then suddenly came the discovery that the same cells could be found in the human, and then we continued with that.  That's how the story evolved.

Creating three-dimensional environments

SA:  And so what are your big questions at the moment?

We need to learn how we can culture in three dimensionsJP:  Right, the biggest challenge we have at the moment… There is lots of research being done all over the place on cultured cells two-dimensionally in a Petri dish.  But we are three dimensional, therefore we need to learn how we can culture in three dimensions, because the cells talk to each other and talk to the surrounding tissue.  Also, if we want to apply this to translational work, to cure patients, we need to have identical batches of identical sets of cells [to do clinical trials] -- we can't give to you one group and then say, "Sorry we've run out, we'll give another thing to another person." If we do a trial it has to be totally uniform, GMP (Good Manufacturing Practice), identical.  And that's a challenge.  It's happening, but…

The best example of a bioreactor is the wombThis is another strong collaboration with engineers, because we need to grow the cells in what is called a 'bio-reactor'.  The best example of a bioreactor is the womb.  If you think about growing a baby inside our wombs, and how it happens from one cell... they get signals from us [the mothers], which decide what happens -- sugar levels, and things.  The development of the baby is controlled by all these natural signals in the three-dimensional environment: a bioreactor. 

We need to grow the cells like this, and have signals, and be able to check, for instance, that the levels of nutrients are enough.  People can't do that at the moment, so that's what the challenge is.  Not mine alone, but the rest of the world as well.  But that's what is happening.  We are more interested of course, because I'm a pathologist, on translational research – how we can apply [this research] to cure diseases.

Clinical applications

SA:  Which diseases?  Reading some of the literature there are a lot of things being mentioned – Alzheimer’s, Parkinson's, Cystic Fibrosis…those sorts of things.  What are the applications that you see coming along?

JP:  Broad, like diabetes, Parkinson's and others… There are a lot of people doing heart trials with bone marrow.  And the bottom line is – this is very controversial – but the bottom line is that there are about six, seven, 10 trials all over the world and nobody has died in any of them, so thumbs up!  Is it effective?  Very small: 30%, and nobody knows whether the effect will last.

SA:  What have they been doing?

In a nutshell, there are no comparable trialsJP:  What they do is they get the bone marrow stem cells from the patient, and sometimes they treat it, and sometimes they put it in just like Campbell's Soup [ie they don't do anything to it, just use it with all its component cells like a jumbled soup].  It depends.  They put it either in the coronary artery when they are doing a procedure for a stent or AngiographyA special form of X-ray examination that shows the blood flow in  arteries and veins. or whatever.  Sometimes they put it in a special device in the myocardium, and a bit of the muscle of the heart, and sometimes they put it in the pericardium.  So there are different ways of using it.  But in a nutshell, there are no comparable trials.  One group is trying this; the other group is trying another thing. The bottom line is, if they find an effect it's a small effect, and nobody knows how long it will last.  And nobody knows exactly what [is effective] -- which cell is effective, or is it the Campbell's Soup?  Nobody knows.  But to sum up: nobody has died, and some people have found a short-term effect in  30% of cases. 

When not to stick to the rules!

Well if you think, in heart transplantation, the first patient – the famous one in South Africa – he lasted 18 days.  Now they last forever!  So you have to start from somewhere.  If heart and lung transplant would have been suggested now it wouldn't be allowed with all the regulations!  You know – to put an organ from another person…"How d'you know it hasn't got a virus?  How d'you know …?" 

One of the first patients of heart and lung transplant, a friend of mine was working as junior doctor in San Francisco and the patient died; she started doing mouth-to-mouth resuscitation, and the senior doctor came in and said, "You can't do that!  How about if you give him an infection!"  The patient was dead… I mean, you know!

With me it was the same.  I started bleeding like mad -- though I didn't know because I was unconscious -- and Daniel was going bananas, and my family, you know.  The doctor said, "That's it; we're losing her."  And Sir Magdi Yacoub walks in and says, "Fresh blood."  It wasn't tested -- it was tested for matching, that's all, but they didn't test for viruses.  But I was dying!  And the blood banks said, "How can he do a thing like that?!"

SA:  So are you finding that your research is quite restricted by all the new rules?

JP:  The problem is I sit in a lot of committees related to these things, so I hear all the time … In growing cells, probably we are restricted in doing GMP because there are a lot of clinical regulations.  But we are not there yet.  I'm trying to develop ways to grow the cells in a robust and identical manner at the moment in a three dimensional configuration.  Then we start with some initial clinical trials.

SA:  But do you think this is the future of medicine?

JP:  I think regenerative medicine – in my unbiased opinion! -- will rewrite the books of medicine.  Of course!  I mean that's where we should be going. 


Balancing work and family

SA:  Tell me about your family. You obviously have an extraordinarily busy life and yet you've brought up three kids. How did you manage it?

JP:  I have a good husband.  And the nanny was amazing, because she stayed until I had to tell her, "The children can be looked after by their girl friends now!"  I had the same one nanny all along.

SA:  Did she live with you?

JP:  No, even better, she left at 6 o'clock.  When we came back, she left.  She was amazing and we're still in touch.
SA:  And your husband you say is very supportive – has there ever been tension at home about who does what?

JP:  No, it has all happened naturally.  He takes care of the stupid car, which I hate, and he better not interfere with my cooking!  I'm good at the internet and computing, and he does the phone calls.  But it's not something you decide; [it just happens naturally].

SA:  Are you a workaholic?

JP:  Now we are officially retired, both of us.  But my daughter was here – she's a barrister – and when we said, "Give us another date, we're too busy," she said "You're always too busy," so…

SA:  I can remember [one-time Israeli Prime Minister] Golda Meier saying in an interview once that if you're a mother with a high flying career as well as children you can never really reconcile the two; you just have to come to terms with the fact that you will always have a guilt complex.  Do you agree?

At Buckingham Palace to receive her DBE in 2003JP:  Oh yes!  Completely horrible!  My son reminded us… Now he denies this story, but he was such a difficult person when he was a teenager! [Said with an indulgent smile].  He said, "I'm writing a play to say goodbye to school, will you come?"  We said, "Yes of course!"  We were so proud, the great genius writing a play, acting in it and staging it and blah blah blah.  Somebody warned us, "I don't think you should come."  And we said, "What d'you mean?  Of course we'll come – all the family!"  We were in the front row, and everyone was saying, “Oh the genius, Michael Catovsky...”

The story was of a disturbed child who is disturbed because his parents are academics and flying all over the place.  And he commits suicide in the middle of the stage because his parents forgot his birthday... We never forgot his birthday!  All the children were pointing at us, and we said, "We'll never talk to him again!  We're going to get out every single photo album with pictures of him blowing out candles at his birthday."  And then we couldn't find the damn albums! [We laugh]

SA:  So you were you shocked?

JP:  Completely!  And everybody looking at us – it was embarrassing!  And you know I don't think he remembers.  I think he's expelled it from his consciousness.  Because then he phoned me about a year later and said, "Can you come to a play?"  And I said, "You're joking!  I'm not coming to any play of yours!"
SA:  And what about the others?  Did they give you a hard time?

JP:  The middle one was wonderful.  And the daughter, the eldest one, she was different.  She appeared with pink hair.  And one day she appeared with a motorbike she'd bought that occupied the whole garage, but she never touched it again!

SA:  How did you deal with things like that?

JP:  It's hard dealing with teenagers; I could have killed them all! [Laughs]  They're lovely now, absolutely wonderful.  No problems.

SA:  And what about your Argentinian heritage?  You say your grandparents came from Eastern Europe -- under what circumstances?

JP:  You know, a lot of people emigrated at the turn of the century from Russia and Poland and all that – conditions were not nice there, and I think it was just chance where they ended up. We grew up thinking of ourselves completely as Argentinian.  But now we have been here much longer than we were in Argentina and the children are more English than Argentinian. We go back but after two or three days I think we've had enough.  I'm in touch with my brother daily.

SA:  How did your family fare during the dictatorships?

I think he died of a broken heartJP:  It was very hard.  Daniel has a brother, and I think when he was taken away it virtually killed his father – he died eight or nine years later, but I think he died of a broken heart.  It was very, very hard, you know.  He was taken away in front of his father in his printing shop. They said, "If he has done nothing he will come back."  He had done nothing, but he never came back.  They most probably threw him in the Atlantic; they never recovered the body.  Unbelievable; unbelievable.

SA:  What about your own family?

JP:  They were fine. They were very sympathetic [to the dissidents] but [the political situation] didn't affect them directly.  But they advised us to stay here.

SA:  Culturally, as Latin Americans, how did you find working with the people here in the UK?

JP:  The [academic] level is fantastic.  Everything is so civilised here, and the culture – I mean we're spoilt.  It's amazing.

Support for women in science

SA:  Julia, tell me about your charity, the Julia Polak Trust.

JP:  Well, I was in hospital quite sick after my transplant and I was trying to collect money for the Harefield.  Sir Magdi said, "No, set up your own charity, for your own research."  So we started collecting and we supported a lot of research students, and all that.  Now Imperial College wants to establish a prize for young women called the Julia Prize, and we are collecting that money to help give the young women a chance. 

SA:  Have you felt as a woman in science that there are barriers – have you experienced barriers yourself?

JP:  I am very thick-skinned, so I didn't.  But lots of people say there are barriers.  I'm very well aware that we need some TLC for women; we need to discriminate in favour of them.  I do strongly believe we really need to nurture women, because they lack confidence, and nobody helps them really to gain confidence.  So giving this prize will help.

SA:  What have been some of the most exciting times in your life as a researcher?  And also some of the worst times?

JP:  Discovering that there were hormones in the gut.  And discovering that this stuff that is in exhaust fumes and in Viagra is localised in the body. And then creating the regenerative medicine centre at the Imperial was very exciting.  Creating the business was very exciting – and the charity.  Those have been really big moments. 

People always ask me to name a date that is most memorable, and Daniel and the children and I will always say, “17th July 1995”, because that was the day of the transplant. But of course the biggest moments were when the children were born.  Those were the biggest moments in life -- getting married and when the children were born. 


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