Professor Stephen Angyal, carbohydrate chemist

Professor Stephen Angyal

Professor Stephen Angyal is a carbohydrate chemist whose research has
shed light on many aspects of carbohydrate chemistry. Born in Hungary, he received a PhD from the University of Science (Budapest) and worked as a research chemist in the pharmaceutical industry prior to arriving in Australia. He was employed as a research chemist in both Sydney and Melbourne
before being appointed as a junior lecturer at the University of Sydney. It
was there that he began his lifelong investigation into the chemistry of inositols. He moved to the University of New South Wales (then the New South Wales University of Technology) in 1953 and remained there for the rest of his working life. He was appointed Professor of Chemistry and also served the University as Dean of Science. He was awarded the University's first Doctor of Science in 1964.


Interviewed by Mr David Salt in 2004.

Contents


Gaining an unexpected interest in chemistry

You were born in Budapest at the beginning of the First World War, a very turbulent time in world history. Do you have any memories of your early childhood?

I remember very little. I know we moved about because of the war, when my father was an army medical officer who would be placed in different positions. And when we returned to Budapest we had to move out again because of the Romanian occupation. Then came the Communists, but I remember little of them. I have not much memory of my very young days until I got to school and started having lessons.

Would you say your father was a role model to you?

Yes, very much so. I have very good memories of my father. He was a medical doctor with a private practice, but he also gave lectures at the university. He was very intelligent and very kind, and obviously a good doctor. Patients thought a lot of him and used to say that he cured them when he talked to them, even before they took the medicine. He was a wonderful man who was very nice to me and helped me in many ways. He talked to me a lot, and we went for walks during which he would tell me stories of what he had read, before giving me the books to read for myself. I had a very close connection to him.

Did he want you to become a doctor also?

Yes, but to spend all my life with sick people just didn't appeal to me. I don't know what attracted me to science instead. I had a classical education – lots of Latin and Greek – with very little science, and my schoolteachers in science were quite uninspiring. At first I was attracted to mathematics, which seemed interesting, but after one year of mathematics I decided this logical solving of problems that I couldn't really see was too difficult. I was also taking chemistry and physics, so I thought I would continue with chemistry. But I had no role model for chemistry, nobody to particularly inspire me to do it.

Was the science education at university any more inspiring than at school?

No, it wasn't. It was a four-year course, essentially designed for high school teachers. You didn't really get going in chemistry until the PhD, but even then my supervisor was not very inspiring – even though he had once worked with Emil Fischer, who was the famous carbohydrate chemist. (He got carbohydrate chemistry going, and was the one who first determined the structure of the sugars.)

The PhD was very much of a routine job: my supervisor told me exactly what to do. But then we got a compound we didn't expect, and that's where it became interesting. Nevertheless, when I finished the work and had found out what this unknown compound was, I said that I was not going to work with carbohydrates any more – there were no more problems, they had all been done. Nowadays we perceive many more problems in carbohydrate chemistry than ever before!

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The fundamental importance of research

When you finished your course, your first job was at Chinoin Pharmaceutical Works, as a research chemist.

Yes. Industry wasn't very strong in Hungary, so just to get a job was a great thing. This was a big company, and is still the biggest pharmaceutical company in Hungary. The owner, Dr Emil Wolf, thought that research and business were closely connected in the pharmaceutical industry. I once heard him say, 'Business is not very good. Let's engage a few more research chemists' – exactly the opposite to what many pharmaceutical companies are doing. It was a question of always developing and testing new drugs, changing the way the drugs are used, and he spent most of his time in the laboratory. Unless he had to go to his office, for example to sign something, he was so much in the laboratory that every morning a barber came and shaved him there. I learned from him that research is the most important thing.

Wouldn't it be good if more of our chief executives were practising researchers who spent more time in the laboratory than in the boardroom?

Yes. Also, we had some really first-class chemists who could easily have been university professors but preferred to work in the industry. I liked my job there.

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A lucky change of location

You decided to emigrate to Australia but before you could leave, the Second World War broke out and you were called up. How did you make it to Australia?

It was sheer luck. I had obtained a permit to go to Australia, just in case. We knew that with Hitler about, things might not be so good. Actually, when the war broke out, we all said, 'Fine, it's over now. England and France have decided to stand up. Why worry about Hitler?' But they didn't, of course. I realised that if I stayed, then I would be left to fight on Hitler's side, or go to Russia or something like that. Anyway, after my year's compulsory military training I had finished up as a reserve officer, and therefore as soon as the war broke out I was called in to the army. I said, 'Well, that's that. I'm stuck now.' Fortunately, Hungary managed to keep out of the war. (I've been very lucky in many of these things.) And as soon as they sent us home, a month later, I packed and went. I had the permit already in my pocket, so quite legally – no problem – I left Hungary and went to Australia in 1940.

But even in that you were very lucky, because you came across on the last Italian ship that actually got to Australia.

That's right, the Lloyd Triestino Viminale. After that Mussolini joined Hitler and no more Italian boats arrived in Australia.

Why did you choose Australia?

The main reason was that the waiting list to get to America was very, very long, but I had a cousin who was either more pessimistic or saw further ahead than I, and he had gone to Australia a couple of years earlier and set up business. He could fix up things like accommodation and money and all that for me. In central Europe in those days we didn't know much about Australia, but – let's be quite frank about it – it was as far as I could go!

My first impressions of Australia were that it was wonderful: the climate and the sea and the way people moved about, the freedom and all that. I recall the boat stopped at Perth and then Adelaide and in Melbourne, everywhere. Adelaide was very hot, something like 110°F. I didn't mind that at all, it was such a lovely place. I liked this country very much. The only thing, it was hard to get a job. There weren't any jobs in chemistry, particularly not for a recently arrived foreigner.

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Dipping into the Australian pharmaceutical industry

You ended up in Sydney. How did you manage to get work?

I met a Hungarian called Andrew Ungar, who came out with licences from foreign companies to market their things. On the way he thought maybe one ought also to make some pharmaceuticals which were not made in Australia yet. I talked to him, and then since I had free time I joined him. He set up a small laboratory in a garage, and I went there and did a little bit of work. Ultimately we formed a company, Andrews Laboratories, in which I invested £100. I was doing freelancing work – analysis and advice and information for pharmaceuticals – but there wasn't much pharmaceutical industry here at all in those days.

It was mainly a matter of getting known by people. I went regularly to lectures and so on at Sydney University, so I knew everybody there. I even went to the technical college, where there was a strong chemistry department. So I just familiarised myself with what was going on.

Very shortly you moved down to Melbourne to take up a job as a research chemist for the Nicholas company. How did you get that job?

That was a very interesting story. At the university I often talked to Dr Lions, who was one of the strong organic chemists, and he mentioned that the university was doing pharmaceutical work so that if we were cut off from overseas supplies we could make our own essential pharmaceuticals. In that process he made a new drug called sulfathiazole – those were the days when the sulfanilamides came in, mainly marketed as sulfapyridine, and this was a modification of it – but it happened that in Chinoin I had also made sulfathiazole. So I told him that.

A few days later, a newspaper article reported that the university was helping the pharmaceutical industry, and mentioned that Dr Lions had made a compound sulfathiazole, a new drug. 'And by the way,' it continued, 'curiously enough a recent arrival from Hungary, a Dr Angyal, has also made sulfathiazole.' The next day I had a phone call from the general manager of Nicholas, 'Do you know how to make sulfathiazole?' When I replied, 'Of course I know how to make sulfathiazole,' he said, 'Well, come down to Melbourne and we may discuss a job.' And that's how I got the job: out of the blue. It was a really good job, too – £10 a week – but sulfathiazole was never mentioned again in the five years I spent there.

I think you worked on the synthesis of a whole series of vitamins, to figure out how they could be produced on a commercial scale.

Yes. The management of Nicholas knew absolutely nothing about pharmaceuticals or chemistry, and I was only a research chemist. Although the company started with old Nicholas making aspirin, by that stage they weren't making any chemicals. Even the aspirin that they marketed was made by Monsanto. But since the company marketed shark liver oil for the vitamin A content, they said, 'Well, it is just as well if we produce vitamin B, C, D and so on,' and they put me onto vitamin B. After about six months on this, they said, 'Forget it. It's too complicated. Let's make vitamin C.' Then they found that CSIRO was already making vitamin C. So we made vitamin D. And then we went to vitamin K. None of them were ever marketed, so it was really a waste of time. But I learned a lot of chemistry doing that.

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Diving into academic research

In 1946 you moved back to Sydney to take up a job, at quite a pay cut, as a junior lecturer at the University of Sydney. Why was it important to you to take up a university position?

To put it simply, the research potential in Nicholas was very low. I couldn't choose my own research problems, and I was always diverted by the time I started moving. University was the only place with a future for research.

That is if research was what you wanted. Many people choose to go into industrial processes, where you can make a lot of money.

I wasn't so interested in money. I wanted to do some interesting work, something inspiring that would keep me really going. At Nicholas I was just hanging about, and it didn't get better, it got worse.

And Sydney was a place you wanted to be?

Well, I liked Sydney better than Melbourne. From the first nine months I spent in Sydney – much of it at Bondi beach, because I didn't have a job – I thought Sydney was a lovely place. So it was a good opportunity to come back. But really it was just that there was a lectureship vacant and advertised.

There weren't so many universities then, only one in each state, and a lectureship vacancy was quite rare, but there were only two applicants. (The other one was a foreigner too.) The reason was very simple. Today, 30 people apply if a university lecturer job is advertised. But in those days Australian universities didn't grant PhDs, and when their students finished and wanted to do research they all went off to England or some other countries. During the war they couldn't do that, so afterwards a stream of young chemists – all those who would apply for lectureships – went off overseas. That was extremely lucky for me.

You worked at Sydney University for five years. What was important for you about being there?

First of all, I got a firm basis in university life – I lectured a lot – and also I could do the research I was interested in, and I started developing first one line and then another. Of course, I had lost a lot of years. Usually academic researchers started at 22 or 23, but because of the war and emigration I was 32 when I really got going in research. But I wanted to get going, and this was an opportunity.

During that time, I think, you realised carbohydrate chemistry was still an open field – the big problems really hadn't been solved – and started working on inositols.

Yes. That was the first subject I picked. It was readily available and there was only one person in the world who was working seriously on it. The inositol group of compounds are related to carbohydrates. During my industrial work, when I worked with vitamins, for some odd reason it was believed that one of the inositols was part of the vitamin B group. It isn't, but it is very widespread in nature, and as I looked at it I saw that little was known about its chemistry. I thought, 'When I get into a position where I can do research of my own, I will look at these inositols.'

Eventually, much later, they turned out to be very important compounds. After I retired, it was found that one inositol derivative is an essential part of the human nervous system. All the basic work I did, building up the knowledge of the field, was essential then to understanding the chemistry of inositols.

Moving beyond the back waters

You put together your knowledge of inositols in the next phase of your career, at the University of New South Wales. But before that, in 1952, you took a year of study leave in Cambridge. That was a pivotal time for your career, wasn't it?

Well, the main significance was in meeting many chemists. Australia is at the end of the world and travelling still took three weeks on the boat. I knew very few of the world's leading chemists, but in that year I met many of them, particularly those in the fields I was interested in – sugar and inositols – in England. Then I was lucky enough to get a Carnegie grant to America, for two months travelling; and from Cambridge I travelled in Europe. So I met all the people of interest in my field and all the really famous chemists. I was no longer isolated at the end of the road, but part of the international community. I kept in contact, and I sent students to those people and they sent some students to work with me.

Another important thing I went to the first Carbohydrate Symposium, in Birmingham. They continued regularly, every two years. I have been involved in the organisation right from the beginning and ultimately I organised one in Sydney – another continuing active connection. If you work in isolation you get stuck, or you do something that somebody else is already doing. You have to keep in touch and know who does what, and what is happening where, and that I got during that year.

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A career advancement

While you were in Cambridge you were offered the next big phase of your career, an associate professorship at the University of New South Wales – known then as the New South Wales University of Technology.

It wasn't an actual offer; there was a job advertised and I applied for it. That was a very big step forward, because in those days lecturers had no way of being promoted to senior lecturer until there was a vacancy. If you were a lecturer, you just had to wait. (Now you can be promoted to associate and even professor.) I went straight to associate professor.

Wasn't this university regarded as the 'new kid on the block'?

Yes. Not many people were interested in the job, because the university wasn't regarded very highly. Most people said, 'We have got a university. What do we need a second one for?' It was called a university of technology because it focused on nothing else but science and engineering. And chemistry was about the strongest of all the schools. The departments were taken over from the technical college, where chemistry was very well developed. I kept in touch with them, so I knew what was going on there and that they were good people. I thought there was really good potential in the job.

Indeed, the university was nicknamed the University of Chemistry, wasn't it? I suppose it suited your background and your outlook that science needed to have an application and to be relevant to the wider world.

Yes. And obviously the people who knew about it regarded it as a promising institution, because at the same time another associate professorship was advertised in inorganic chemistry, and that was given to Ronald Nyholm, who became Sir Ronald and a very famous chemist and finished up as professor in London. So the good people did go there. It is now the second major university in Sydney.

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Advancing knowledge: via inositols to carbohydrate chemistry again

This was really where your research on inositols took off. What was special about this group of compounds? What did you do with them?

They are closely related to sugars – the sugars are ring compounds, with six-membered rings, and so are the inositols – but in many aspects they differ from them. They are well known in nature, but not all of them. One is widely spread in nature. There are nine possible inositols, depending on the shape of the molecule, but two of them were still unknown and we were the first to make them so you had the complete group.

When you have got all the possible compounds and all the different variations, you can study which physical, physiological and chemical reactions differ just because of the shape. This seemed a neglected area – a natural product, an interesting compound but not studied sufficiently – and I thought, 'Let's go.' That was in the early '50s.

As soon as we started going we found some reactions which are applicable to sugars, and then we found a very interesting reaction which allowed us to measure the energy of various sugars. And once we had that, we applied it to sugars and so I branched off to carbohydrates. But I kept on developing inositol chemistry, publishing about 50 papers on it. So later, when inositols became biologically important, we had all the chemistry on a firm basis.

You had started getting into the new field of conformational analysis. Would you say this was the key to understanding the inositols?

It was. It is about studying the shapes of the molecules. We knew the structure of the molecule, nicely written down on paper, but that didn't indicate the shape, yet it turns out that how the compound reacts depends on its shape. Other molecules have to approach it, it has to fit against other molecules. The theory became so important that several books were written on it – I wrote the carbohydrate part in one of them – and the two people who introduced it won Nobel Prizes.. But now there are no separate books because it has become an essential part of organic chemistry.

I realised that the inositols are ideal compounds for studying the shape and then purely by chance I discovered a reaction which was relevant to carbohydrates. Previously we hadn't understood why compounds react the way they do. Even more important than the shape is the energy contained in each of these compounds. And that is what I approached now: I could for the first time really define the energies of the different shapes, which then explained why they take up the shape that they do. Applying that unexpected reaction to carbohydrates solved one of the problems in carbohydrate chemistry, and that is when I got back suddenly to carbohydrate chemistry. Ever since, I have found there are still plenty of problems.

What is it like, being the father of the research in this group of compounds, important ingredients of our nervous system?

It is very interesting, because at first when you start talking about it people say, 'Oh, what's this all about?' and then it turns out to be quite important.

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Personal and institutional leadership

In 1960 you were appointed as the Professor of Organic Chemistry at the University of New South Wales, one of the highest offices at the university. You never really sought high positions in managerial authority, but in 1970 you were appointed the Dean of Science, having previously been the head of school. So you were one of the main authority figures guiding the university.

Actually, by then the university was pretty well settled. Professor Baxter had built it up in a marvellous fashion, very quickly, against quite a bit of opposition from academics who thought it was all too quick. But by the time I became Dean, we were not putting up many more new activities; it was mainly a question of consolidating – and teaching the students, who were coming in increasing numbers.

There were lots of changes, because originally we had colleges in Newcastle and Wollongong, and then at Broken Hill. I regularly visited Broken Hill – most interesting – and I went to a graduation ceremony there which had more officials present than graduating students. Professor Baxter's idea was that the university should have colleges all over New South Wales, but fortunately that didn't come about. It would have been very cumbersome to operate.

By 1970 it was fairly smooth going and all those difficulties we have now at the university, getting so serious, weren't in sight yet. As Dean I had mainly routine jobs to face, rather than very difficult problems.

You must have been popular, because I think that although you had intended to be Dean for only a couple of years, you were talked into staying on for 10 years.

Well, the Vice-Chancellor, Rupert Myers, and I knew each other quite well; we have always been good friends and we see things very much in the same way. And somehow I must have appeared to be the most suitable man for the job.

What contribution has the University of New South Wales made to Australia and the international scene in science?

A very great contribution, in various fields. For example, its electrical engineering people are in the lead in utilisation of solar energy, and the school of optometry has been very active – it is the only one in New South Wales, and maybe in Australia. We started a school of business administration, which was frowned upon in those days but now most universities have such a thing. That school is now shared with Sydney University, which came along to ask to become part of it. And the same applies to many, many other fields.

Of course, we had things which looked interesting and didn't get anywhere. We had a school of nuclear engineering in the days when it was thought that Australia might be going to have a nuclear industry, but that has gone out. We had a school of traffic engineering, but we no longer need a separate school for that. We had the first school of food technology, which was very important but is not quite so important now. So we are willing to vary things.

We had aeronautical engineering; that too is now not so important, but the main engineering schools are still very important. And in the Faculty of Arts, a new school of music – which was never planned for – came about simply because we had Roger Covell and he built it up. It is doing a wonderful job.

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Behind every successful man...

Helga, your wife, was also a prominent player at the University of New South Wales. She was your longest and most productive collaborator, wasn't she?

Yes, and still is.

I think you met and married her in Melbourne.

Yes. I met her in 1941, and in early '42 we married. That was very, very lucky. Having just come to a foreign country and with an uncertain future, the last thing I ever thought about was getting married. But once we started going together, well, that was that. I said, 'It's the best thing I can do,' and got married.

What role, then, did Helga play at the University of New South Wales?

When we started there, the university was rather small. Everybody on the staff knew everybody; all the wives knew each other. Then later the wife of Rupert Myers, the Vice-Chancellor, set up a group so that the wives could help their husbands overcome the severe financial problems. Whatever we wanted to do, we found, 'We can't. The government doesn't give money for that.' We weren't at a stage yet where industry supported us very much, so these women got together to raise money. At first they had dinners. Then they had productions, and a concert, and an exhibition and all kinds of other things, even lecture courses – all for money. Their biggest venture has been the book fair every two years, and now every year. Ultimately they raised a couple of million dollars for purposes for which money could not readily be raised otherwise.

Helga was also very active in the social angle, bringing newcomers' wives in, inviting them to come and join us and so on. About a dozen of the wives left over from those days still meet regularly every month, and they still give some help to the university.

Then Helga was involved in the music school, which set up the Australia Ensemble – undoubtedly Australia's best chamber music group. She had a lot to do with developing that ensemble and was in its advisory committee, a kind of a governing body, for about 25 years.

A prodigious organiser of scientific conferences

You have actively pursued connections with the international scientific community to make sure that Australia is part of the network, arranging to bring some of the world's best chemists on visits and promoting a free flow of ideas between Australia and the rest of the world. You have also been – with the help of your wife Helga – a prodigious organiser of scientific conferences.

Well, the conferences are important as a method of communication and contact. In the early days there were separate groups working in science here and there and not contacting each other much, and you read in the literature what they did. The literature is so big now that it is impossible to keep up with it all, and it is more and more important actually to meet those people, to hear what they are talking about and discuss problems. There is a lot of international collaboration, which in those days was very difficult but now is very easy. Somebody flies here, or sends you an email, so you can have a lot of international cooperation. Whereas in 1952, the year I spent in Europe, there was only one chemical conference, now even in Australia there are at least two every week.

I was very much at the beginning of Australia's contribution. You have got all these trees and plants containing chemicals which are not found anywhere else, and in the 1950s, '60s and '70s most Australian chemists worked on these things. I was on the organising committee which arranged the first international symposium on natural products, in Sydney, and these conferences have been held every two years since then.

I have already mentioned my involvement in the organising committees of the carbohydrate symposia, the first of which was held in Birmingham. Ultimately I organised one in Sydney and I found it very interesting, because there is a need to pick the right speakers, to guide them to give the right kind of talks, and then to try to bring the right people here, to keep them in contact with each other – the publications, abstracts and all that, and the way it is organised are all important. And usually you come back from these conferences with ideas. That's the point of it: you get new ideas by listening to what those people have to say.

Many scientists, while acknowledging that the conferences are valuable, would do anything to get out of actually organising them. Not many are prepared to put their hand up and say, 'Yes, I will help organise them.' To have done so many of them, you and Helga must really enjoy the organising work.

I enjoyed it, but it is a hell of a lot of work. Helga helped me very much with the big one we had in Sydney. I had a team of people with me and we thought that with a bit of work we would get it going, but it was continuous hard work for about six months. It was worth while doing it, but it was a full-time job and I couldn't have done it until I retired.

Helga also used to help with the ladies' programs, which were very important so that the ladies would enjoy seeing the country and learning about it all, and would more or less talk their husbands into going to the conferences.

But it is completely different now: there are so many of them and they are so large that it is mainly done by professional conference organisers. The International Carbohydrate Symposium we had two years ago was in Cairns, mainly in the hands of commercial organisers. We told them what to do, but the details – the bookings and the finances, the printing and all that – were done by commercial people. It is getting too big now to be handled by amateurs, as we were.

But good amateurs, I think. This is not just about exchanging scientific ideas; it is about building relationships and forming friendships.

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The Andrews Lectures

Tell us about the Andrews Lectures.

This started purely by coincidence, as so many of these things do. When we had the natural products symposium here in Australia I thought it would be a good opportunity to get one of the speakers who were coming to stay on for a couple of months as a visiting professor. But although I asked several, none of them could come for long enough. Ultimately, Professor Ewart Jones, from Oxford University, said he could come for three weeks and give a lecture course. That was successful and I said, 'Well, why not do it again?' The next visiting lecturer was picked in an amusing way. We had here a famous American, Carl Djerassi, who had developed the contraceptive pill. He was a very enterprising fellow, and when I asked him what he thought about the idea of having regular visiting lecturers he said, 'It's a wonderful idea, provided I be the next one.' So I agreed.

The lecture series evolved, and I found it very interesting. Again organising it was a lot of work for me: selecting the lecturers, arranging the travelling, getting the money, organising the program. Since my retirement, the University Chemical Society does this. It has been highly successful and we have really brought out good people, including four Nobel Prize winners. Amongst them all – some have died by now – there is quite a record of chemistry. And it is still going; we will have the next one this year.

Nowadays there are quite a few such lectures; most of the universities have something similar. But this was the first one. Probably we still bring the best people out, because it has got the name and reputation now. If you show any potential Andrews Lecturers the list of past lecturers, they say, 'Oh, wow.' They regard it highly.

I think the name Andrews Lectures had something to do with the first project you were involved with when you came to Australia.

Yes. I had to raise money for the original lecture – not a lot of money, about $500, whereas nowadays we need about $5,000 each time – and since Andrew Ungar and I have remained friends and he had the money, I asked him. And when I thought about a name I felt that Angyal Lecture would not be very good, nor would Ungar Lecture, so we decided to name it after his firm, Andrews Laboratories.

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The vital importance of chance findings

Stephen, when you started out, your training was more in the area of industrial research – training on the job, almost – but you have spent most of your career in academic research. Would you like to make any observations on the difference between industrial and academic research?

There is a very basic difference. Industrial researchers have to produce results according to the aims of the company for which they are working. The company has to make money. If it sets out, say, to develop a drug, that means your job is to develop it. You can't branch off to anywhere else. In university research you can take advantage of any chance developments – and these are very important in science: you do something and something else turns up. You need the prepared mind, as Pasteur said, to pick up the chance when something unexpected turns up, to say, 'Look, that's interesting. It's even more important than what I am doing,' and to branch off to that. You can do that at the university.

That means you can't plan your career in advance. You may get a university job and say, 'I'm going to do this in 20 years' time,' but really you have got no idea what you are going to do in 20 years' time. And that varies tremendously from one researcher to another. Recently I have been reading several books on the life of important scientists, mainly chemists, including quite a few Nobel Prize winners. I recall clearly that one American said, 'I have been changing the direction of my research every 10 years. I can't hold on to the same thing. Something else turns up' – and he got the Nobel Prize. Yet Merrifield, for example, worked on peptides all his career, from beginning to end, and he got the Nobel Prize too. So we can't prescribe it, but it is very important to look out for the quite unexpected things that might turn up.

So an ingredient of important academic research is always to have the capacity to follow up on a chance discovery?

Yes, very much so. It may not always work everywhere. A chance discovery may be made by a student who does not recognise it; in such a case the supervisor needs to recognise that this is something unexpected, something that can be explored. I would say most of the really important things in science, most of the important methods we have now in chemistry, have been discovered and developed by chance. People didn't set out to do this. Nuclear magnetic resonance, which is absolutely basic to organic chemistry now, started with people doing something in physics, not at all related to chemistry. When I came back in 1958 from my second study leave, during which I worked in America, I wrote a report (which I still keep) saying, 'I've come across nuclear magnetic resonance. This may have some interesting uses, but it is so expensive' – $10,000 – 'it is not worth us buying it.' We couldn't do without it now!

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'If I started again I would become a biochemist': the changing world of science

You have seen a lot of change, both in the world around you and in the way science is done. What are some of the changes you have witnessed in the practice of science?

There are a lot of differences. One is instrumentation. We have now got instruments, such as nuclear magnetic resonance, whereby we can determine the structure of a molecule in a day. In the 1940s, to determine the structure of such a very important compound as cholesterol took five or six years of work by five or six large teams. You could do it in a few days now. That means you can study compounds which are so complicated that nobody would ever have thought of studying their structure then. I am talking about the really important things in the body, such as the proteins and DNA. We just didn't have the methods for handling them in those days.

Also, calculations have now been evolved whereby we can work out the best structure of the compound. A compound will take up what is energetically the best structure. We can work out the energies of different structures so we can probably determine the compound's structure purely by calculation, even without experimental work. We have got facilities like X-ray crystallography – one can determine the structure of a pretty complicated compound just by doing an X-ray picture – and computers with which we can calculate from those X-ray data the structure of the compound. Without computers we could never have done those calculations.

This has made a tremendous difference to carbohydrate chemistry. The carbohydrates in the body are very complex substances. There are several different sugars attached to each other, and they can be attached in different ways. You can take two ordinary sugars and connect them in 20 different ways. With three, you have got about 300 different ways. In these compounds occurring in the body, there are six, seven, eight, nine or 10 sugars, arranged in different ways: there are millions of possibilities.

To approach these structures 30 or 40 years ago was hopeless. To build them up was even more hopeless, whereas now carbohydrate chemistry is all about building up these complex sugars. We can figure out what we want to build up and we can develop methods to do it. What we do now is first of all to make the ones which occur in various parts of nature – in bacteria, in the body, in plants – and then to modify them slightly.

The modification may have two effects: to enhance the function of the molecule or to oppose it. If it opposes it, that will stop organisms from using it. If it enhances it, the result will be better than the natural compound and we can use it. And now we can synthesise those. Even 20 years ago I would have said that it is so complex that we would need a huge team just to make one compound; now you need a few people to make several compounds, because the methods have improved so much.

You have recognised and shed light on many of the big problems in carbohydrate chemistry through conformational analysis and an understanding of the energies of the different configurations and the way they work together. Is carbohydrate chemistry still a wide open field today, when people are starting to look at how these things actually work in our body and how to make small modifications to change the functionality?

Very much so. The interesting thing is that 30 or 40 years ago most of the carbohydrate papers were in the two journals about carbohydrates – seldom was there one in the general chemical journals – whereas now you find carbohydrate papers in every chemical journal. It was a fairly isolated area but now it is at the centre of organic chemistry. The Journal of Carbohydrate Chemistry is getting bigger and bigger all the time, with lots of work published there.

Is it a case of the more we learn, the more we discover there is to learn?

Yes. Now it is really what happens to these carbohydrates in the body. You look at different plants and different animals, at the endless variation of different carbohydrates here, there and everywhere. If I started again I would become a biochemist. In those days we still needed to know more fundamental chemistry; now we have got that. Now it is the application in biological systems, which the biochemist does. And even the biochemist doesn't do it alone but works with a bacteriologist, a physiologist and a few other people.

Perhaps another thing that has changed about science, then, is that it is harder to do science by yourself: your knowledge is part of a team approach, and you need skills from different areas.

Yes.

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Details and explanations: forming the knowledge base

You have written hundreds of important scientific papers, but you say that 'The Composition and Conformation of Sugars in Solution', published in 1965, was one of your most successful papers. Why was it special?

The reason, I think, is that it was a summary of much work we had done with inositols, which of course many people didn't know applied to carbohydrates. Many carbohydrate problems were solved with the knowledge we gained from inositols. It was well known that when dissolved in water, most sugars will turn into several compounds. What wasn't very well known until later was how much of each compound is formed from each sugar – and why it is, wasn't known at all. The knowledge we gained from the inositols explained this. We applied it to sugars, and then you could predict that this sugar would give so much of one compound and that would give so much of the other. And that is very basic knowledge of the sugars.

In this article I just summarised the results, very clearly. They were already all available – nothing new in it – but this was a summary, easily read by chemists and giving the whole story.

So this was really a synthesis of a lot of your work and why it was important?

Not only mine, no. It was a summary, all together, of recent work in carbohydrates, and how recent work shaped our outlook on carbohydrates.

That paper was complimented for its lucid style and the ease with which it could be read. Has communicating your science been important to you?

It is important. Some scientific papers are very hard to read, and people read them only if they have to. But this was meant to be a popular one, to be read by everybody. There weren't any very difficult concepts in it, but we gave a general idea of what is going on and why.

You started academic research comparatively late, you are largely self-educated and you claim that you have little imagination, in that you have not generated fantastic new inventions. What is it about your approach to science, then, that has allowed you to make such a monumental contribution?

Maybe two things: looking into details, looking at problems and saying, 'Well, this is not really solved. We do not quite understand that,' and also picking up things which have been mentioned here or there without anybody ever following them up. I developed things which were undeveloped and I figured out the details and – most important – the explanation of many things. There were lots of facts known and stated but the connection wasn't established. We didn't know why these things might have happened. So my contribution has been in rounding out and firming up the knowledge, forming a base on which others then can build. That applies particularly with carbohydrates, where I published several reviews, mostly on the conformation and the composition. If anybody now wants to look at conformation and composition, they look at my reviews. I summarised it and rounded it out.

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Complexity and opportunity: science yesterday, today and tomorrow

If you could choose, would you enter science today, having access to a lot of sophisticated technology but being required to specialise in a very small field and often to be a small part of a larger team, or in the days when a person had a greater overview of the entire field and could choose the direction in which to travel?

I think it used to be easy, in a way. It was more interesting too, when you could see the whole field and all the possibilities, and it didn't depend so much on other people. But the way the world develops, it is different now. You do need the instrumental people and the theoretical people, and ideally you need to work in a team.

Science is so tremendously large now that you can't see the whole thing; you can't see the large parts of it. In a team, the biochemist looks at this, the physiologist looks at that and the X-ray person looks at something else, and together they present the knowledge. It would be very difficult for a single person to have a proper outlook over the whole field. I am afraid the position is getting more and more complex.

Yet it is wonderful, because the insights that they bring in this multidisciplinary type approach are astounding, compared with what could have been achieved only 10 or 20 years ago.

Oh yes, the opportunities are wonderful. The very basic operations of life we don't understand at all, even now. I mean, an egg starts going. What governs which part of the egg will be what? When the human being starts with a sperm, what determines that there will be eyes and ears and what colour the eyes will be and the hair? It is all written down in the basic molecules, and we are not even beginning to understand that. It is fascinating, but there is a lot more to learn about it.

Are we actually on the cusp of making some major breakthroughs, or are all the major breakthroughs behind us? Are we just making incremental improvements on what we already know?

It is both. There are incremental improvements but there are still major breakthroughs coming. We don't understand the very basic way that life develops. When a bird comes out of the egg, there is nothing left in the shell. All the white and all the yellow has become some part of the bird. How that process is governed, we don't understand.

I am sure that many of the discoveries made in future years will actually be based on the information and the understanding that you have given us through your life.

Well, not only I, but the people who worked out the basic chemistry. It's all chemistry, but what governs the reactions during the growth process, I don't know. There is a tremendous amount of information in DNA. Whether you have black hair or white hair or no hair is all in the DNA, but how that is governed we are only just beginning to understand.

Thank you very much, Stephen, for sharing with us your insights and memories of your life.

It was a pleasure.

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© 2017 Australian Academy of Science

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