The Life Scientific: AP De Silva

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1:03Hello. As little as 30 years ago, if you'd ended up critically ill in intensive care and needed a detailed analysis of your blood to decide the next course of treatment, chances are doctors would have had to wait a day or more for results to come back from a lab, time that could have meant the difference between life and death. But that wait has been transformed down to less than a minute thanks to the research of my guest today. Professor Amilra Prasanna de Silva, or AP de Silva, as he likes to be known, is a pioneer in the fields of photochemistry and molecular computing. Born in Sri Lanka, AP studied at both University of Colombo and then at Queen's University Belfast, where he's still based today as Emeritus Professor of Chemistry.

1:46In the 1980s, he developed a molecular photosensor. Yes, this will be explained. That's led to a range of small, portable blood analysers that have saved thousands of lives around the world. His achievements have won him many awards, including a prestigious Royal Society of Chemistry, Blue Plaque. But he insists it's a career that's been shaped and dictated by serendipity, along with the kindness and passion of others. AP De Silva, welcome to The Life Scientific. It's a privilege to be here. Now, Now, AP, we hear a lot about molecular engineering these days, not least from guests on this programme.

2:23What is it about manipulating matter down at the molecular scale that you find so fascinating? I suppose the story starts for me regarding what engineers do. Engineers typically take components or parts or modules, as they like to call it, and then they put them together in known rules, previous science and previous knowledge, And then the parts come together to give a whole, which is more than the sum of the parts. So in the same kind of way, we can take molecules and then stitch molecules together to give something super compared to what you had before. And again, preserve many of the old properties and then have new emergent properties, which can be predicted.

3:12And that was something me and my friends in the lab, we fell into. about 40 years ago. It's a long time, isn't it? I also mentioned in the introduction that you've pioneered the use of optical sensors in medicine. So before we get into the details of how they work, tell me, AP, how does it feel to have had a hand in helping to successfully support treatment for so many critically ill patients around the world? I'm seriously, seriously humbled. But at the same Sometimes the big feeling I have is what you kind of mentioned in the intro, which is the kindness and the help of others. So there was lots of bits of serendipity falling into place.

3:52And maybe at a time like this, I must advertise Sri Lanka where I'm from, because that's where serendipity comes from as a word. Serendip is an old name for Sri Lanka, which translates as Golden Island in the Indian epics. so every time serendipity happens it's not only to scientists when I cross the road and a bus does not hit me that is a happy accident and that word comes from Sri Lanka what a lovely way to look at the world I guess and I also feel that's Sri Lanka's biggest gift to the world not cinnamon, not tea, not tourism this one word of hope serendipity, wonderful so let me take you back then AP Da Silva to Sri Lanka and your origins.

4:39You were born in 1952 in Colombo into a very poor family. What do you remember of your early childhood? We were materially very poor. There was no electricity, no running water. And we lived in the middle of the city of Colombo. It was like a little Jurassic Park stuck in the middle of Colombo. And so we were very deprived in many ways. But my mother insisted that I went to a particular private mission school, which her family had some contact with in the past. But they charged school fees, and we couldn't afford it. But she worked and worked and somehow kept me in school. And then also, she kept feeding me material.

5:19My father tried his best too. But there was one incident my mother did, which really, I think, changed my direction. There was a bookshop close to our house, which were the agent for Encyclopedia Britannica. And they were a posh shop. But they had an encyclopedia, a single volume on science and technology. I would put my nose against the glass and we are never going to afford that. And then guess what? We had a monsoonal downpour and there was floods in the shop and they had a flood-damaged sale. And this encyclopedia, with half of it drenched in water, was offered at a knockdown price and my mother brought it for me.

5:57And it was about inventions in science and technology. And here we are discussing that now. So you developed an interest in science from an early age. But I think in Sri Lanka, as in many countries and cultures to this day, there was a heavy emphasis on what subjects one was encouraged to pursue. If you're bright and you're good at science, you should go on to do engineering or medicine. So how did you come to choose chemistry? Serendipity again. I thought you might say that. You're going to hear this word a few times. You are very right, Jim, because I was lucky to meet one particular teacher and I would like to mention his name because generations of Sri Lankans were taught by him called Errol Fernando.

6:37And this man changed my course of action. He showed me and many other generations of Sri Lankans that chemistry is where we transform matter. And then when you transform matter, it will involve everything, what's inside of us and what's around us. and that message was hard to look away from. So you went on to study for a degree in chemistry at Colombo University. You completed your BSc in 1975 and you were keen to continue your study. So tell me, how did the move to Belfast come about? A dear friend of mine, still a dear friend, who's a fine musician and a fine chemist too, was in the British Council Library and he picked up a magazine there and he saw an advertisement from the Queen's University of Belfast, Department of Chemistry at the time, looking for students to visit with full scholarship to study for their PhD.

7:36And of course, Belfast was in trouble then, so nobody would come to do chemistry research. So they were desperate to take on students from anywhere, provided they had a decent recommendation. As you mentioned, at that time, the troubles were escalating in Belfast. Were you concerned? We all, I suppose, had a bit of a concern because at that time, Sri Lanka didn't know what troubles are. And God alone knows what we were going to get in a little while later. This was before it all kicked off in Sri Lanka, of course. And we were given that kindness and care. So the bombs and bullets didn't get in the way at all.

8:14And your PhD was in organic photochemistry. So I guess that means the study of chemical processes taking place inside living organisms, but which are also initiated by light. What exactly were you working on? You are very right. But there are also cases where sometimes we study outside influences on the body. And my supervisor at the time took me under his wing because he was the resident photochemistry person. And he had an interest in persistent pollutants, halo carbons or halogen carbon bonds and molecules which contain those bonds. So those used to be really persistent pollutants. Like, for example, some of them to be used as flame retardants, like in curtains and carpets and things.

9:02And these, once they get into the environment, they used to stay and then they get concentrated up the food chain. And so because of that, people around the world were trying to address this problem. And they thought, well, sunlight falls on these materials. Then will the light energy break these things down? So Jim, my teacher, he asked me to study that. Of course, I must admit, we did not solve the full problem at the end. But it gave me a chance to show how it can be done, developed like the details how carbon halogen bonds are broken, and basically earn my stripes. Right. So you get your PhD.

9:43You are now a fully-fledged photochemist. After your PhD in Belfast, though, you went back to Sri Lanka. I gather duty-bound to look after your ailing grandmother who'd played such a big role in your formative years. There was duty, yes, because I was the eldest grandchild. So there was that. But there was love, too, because she had looked after me. She literally fed me. When I went back, of course, I have to pay the bills. So I went across to the university. We are a small place. Even now, University of Columbia is a small place and I still have contact. But at that time, I just went to them and said, can I have a job, please, please?

10:20But I can't come early in the morning because I have a caring task to do. And they were very kind to me. And I haven't forgotten that. So these were again kindnesses. They said, OK, you can come and we'll put your lectures and classes a little late in the day. And then I would work a bit into the evening. So you were teaching, but also able to do some research. And I guess this is where you began to formulate your ideas of photosensors. What I realized fairly quickly was I couldn't really do photochemistry because chemistry would involve transforming molecule A into molecule B. But then I have to find out what molecule B is.

10:57So I need quite a palette of equipment to do that. And I didn't have that. So I turned to the physics side of it, not the heavy physics that you would do now, Jim, but it was at least to measure the light that comes from molecules. So I would take old drug molecules like old anti-malarial drugs, for example, and then shine light on them like quinine, for example, the famous example. And then light will come off it like in tonic water. And then I can measure that amount of blue light that comes off. So by capturing and measuring the light that comes off, that tells you something about the molecule that's given it off.

11:37Not only about the molecule that's giving it off, but the environment of that molecule. So this is a little bit of like all our photosensors have a little bit of James Bond about them, which is to go into inaccessible places, like a small volume, like inside yourself or outside, and then gather information. Remember, M can't go there because she's too old. So she sends off Mr. Testosterone. You go and you find out our photosensors are nice and small. They're very biocompatible. So we could send them to places where humans can't go. I also gather it was an insight into your grandmother's treatment for high blood pressure.

12:18That proved to be a big turning point in your research. So we had the help of a general practice doctor. So, for example, my granny had these pressure issues and a congestive condition. So when she breathes out, you can nearly feel the water in the lungs. So he said this medication is going to pull out some sodium from her body and her kidneys are going to work a little harder. So when one sodium leaves the body, a whole pile of water molecules goes with it. And he said, now her congestion will ease. And it did. And so that was the time when I realized this sodium fellow is an atom, but it can make my grandmother better again.

13:02So what you realized was you needed a way of measuring how much sodium there is. Yes. Now, usually, you know, when we think about tests for sodium in school chemistry classes, it's the famous flame test, isn't it? And what color it is, the flame burns. That tells you what elements you're looking at. I'm glad you mentioned it because this is the way sodium used to be measured in blood in hospitals quite a way back. So you needed, you want to develop a test for sodium that didn't involve flames. No fires. This idea of yours was based on what's called photo induced electron transfer or PET, which in fact is a process that happens all the time in nature, doesn't it?

13:45You are very right. Photoelectron transfer is what runs photosynthesis. And the starting point of that in the case of photosynthesis is one molecule within the green leaf will send out an electron. and the same electron is then picked up by another molecule close by and this is driven by the light energy which is absorbed by one of those molecules.

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15:18So you were developing an idea, AP, based on fluorescent PET. The idea was to design a light emitting sensory system that tells you, in this case, how much sodium there is. How do you go about doing that? Yeah. So it's like, remember, right at the very start, we talked about how we can take entire molecules and then shave a little bit off so that it becomes sticky. And then stick molecules together to get this hole that is bigger than the sum of its part and give this emergent properties. so what we do here is as you know in the east arranged marriages are still quite the rage and so here we'll be arranging a marriage between two components whose properties are well understood so one we would take a fluorescent dye so the property of a fluorescent dye is the molecules in there must absorb or swallow light from the outside and then spit the light back out again and of course some of the energy is lost inside from the hard physics in there and so different color comes out.

16:25So we can choose these molecules and then shave off a little corner for stickiness and look for something else to marry it off to. Now who's this other partner that we are shopping for? So it's like looking up the matrimonial column in a Sri Lankan newspaper and so what we go for are receptor molecules. And receptor molecules mean what they say. They receive other atoms and molecules. So we take the simpler receptors of chemistry, shave off a bit, take a fluorescent dye, shave off a bit, stick them together so that they are modular in behavior. So then we could plan what color is going to go in, what color is going to come out, and maybe More importantly, what target the molecule is going to catch and in what kind of concentrations.

17:13In the case of someone like your grandmother then, who would have needed accurate measurements of the amount of sodium in her body, how would this fluorescent receptor system work? Correct. So if the sodium is absent, let's say at the start, we have a hijack situation. The moment we shine light at the fluorescent dye, the fluorescent dye gets charged up like a battery, and then it lives for a moment with this newfound wealth. And the receptor says, I have an electron which I would like to fire across into you, the fluorescent dye. So the electron moves house. As you kindly said, this PET stood for photo induced electron transfer.

17:57So we are transferring an electron. It's moving house. And it jumps across into the fluorescent dye because we've just charged up the fluorescent dye like a battery. It says, I have money to burn. And so I've got all this light that I want to spit out again. Exactly. So before the light can be combined and sent out again, which is where the hard physics of the matter energy conversion comes in. in that time the receptor says you give me about half that energy you have and I'll pull this electron out like a farmer pulls potatoes out of the ground and then take the electron across the transfer and push it into the ground like a farmer would plant new potatoes and you need energy for both those which is paid for by that light energy supplied so there's no light to come out so the fluorescent dye had these great plans to send out light at gym but it's given up half its energy Essentially all can be taken away So you are looking in the dark And you see nothing So we have primed our marriage system To give out light someday And some days when My granny's blood with the high levels Of sodium are present The sodium swarm around the receptor And the receptor says Okay, okay, I'll let you in And one sodium gets in And here's the magical thing Sodium that exists in the body Is missing an electron It's sodium plus.

19:22Positive ions. Exactly. So sodium has a plus charge on it. And this electron, which was planning to get away, has a negative charge on it. Even Tina Turner says opposites attract. And so the electron, which had plans to move over to transfer, is held back by the sodium. Right. So the electron transfer collapses and the fluorescent dices. Now I can live the way. I can keep all my light energy. And I can fire it all at Jim Al-Khalili. Wonderful. I love all these metaphors. So the receptor captures a sodium ion that stops the electron from transferring over. The fluorescent molecule then doesn't have to give up any of its energy.

20:05It can shine. So if there's sodium present, it switches on and it fluoresces. And the more sodium you have in the blood of my granny say, more and more of these arranged marriage molecules receptors will get blocked. So the more intense the light is. AP, you published this work in 1985, and it has since become a much-cited paper. At what point did you realise the idea could work for other salts and minerals, not just sodium? Almost straight away, I must say, in all humility, we were naturally interested then in potassium or calcium and so on. Of course, those took time, because again, in Sri Lanka, it wasn't quite easy to convert them into practical products.

20:47But the thinking process was there. The following year, 1986, your grandmother sadly passed away and you came back to Belfast to take up a new lectureship. Now, with better lab facilities, you were able to develop your ideas further. Then came yet another one of those serendipitous moments. A large commercial company came knocking on your door. Yes. So what happened is Roche at the time, with their huge multinational ability, they had started to develop a point of care blood analyzer because they had realized that waiting for results, as you kindly pointed out in your intro, waiting for a result to come from the big clinical lab takes time.

21:27but when they took the device it was launched they take it to the major hospitals they had said this is very nice we know you are Rosh all very nice but we would love to have some salts like sodium and potassium and calcium and things so they had to come back with their product and think again and they looked around the world for someone who could help them out and they came over to Belfast in the middle of the war in these lovely Armani suits which I'd never seen before. They came over. They were so desperate then. And then they challenged me. Look, we have this important problem. You claim you have this engineering design, which is predictive.

22:10Now, come on, do it for us. So this is then to make a portable sensor that can measure the amount of sodium and other elements in blood. And you've brought the vital part of that product with you into the studio today. Like it's a little piece of plastic, about three centimeters long. And in this little plastic chip, we have a little channel inside this plastic chip. And then the blood goes down this tube channel, really. And then along the tube channel, there are six little stations on this. And these six stations will be optical sensors, fluorescent PET sensors, as we discussed, for different targets.

22:52So, for example, sodium, potassium and calcium being measured by this one little chip in less than a minute. And thanks to the commercial clout of Roche, this device has gone global. Now, the success of your fluorescent sensor research allowed you to connect chemistry with computer science. Because you found that those on-off fluorescent sensors might be a bit like the binary zeros and ones in a computer's logic circuit. As you very rightly summarized, zeros and ones in voltages and zeros and ones in light. What's the difference? Whether or not a fluorescent molecule gives off light. Or not. Or whether a sodium comes in or not.

23:38And that was again the connection with the body. So a normal information technology is very much based on silicon. and God bless, it works very well and transforms society for us. But there are many similarities and some differences, of course, between these two worlds of silicon and that of carbon. And I contend that carbon has been ignored for too long. Well, I know that in a computer circuit, there are thousands of these logic gates, basically switches combined together in a complicated way so that different combinations of input signals go through to turn into different combinations of outputs.

24:15That's how a computer works. These molecular systems are, of course, thousands of times smaller than any computer microprocessor. They've been described as being able to boldly go where no silicon chip has gone before. What kind of applications can you see for them? Molecules always have this ability to be really small, but maybe the more important thing that molecules have is they are biocompatible because molecules are us. So we are then able to use that James Bond analogy again. We are able to go where scientists can't go. When our early papers came out, engineers were not at that time prepared to look at it.

24:57Now it's different. Now it's different. It's a complicated concept to someone who's not familiar with it. And picture a network of these molecular logic gates inside a cell that are therefore picking up coincidences. Yes. Like two chemical signals coming in. If they happen together, you get a signal coming out. And that signal says, look, if these two things happen together, that might be indication of a malfunction or something. So, for example, one where they use this for is fluorescence guided tumour surgery. As you know, if I have a solid tumour, then the surgeon will need all the blessings from me when he or she is going to cut out the tumour.

25:36But when they do that, they are always concerned. Have I resected everything? Now they are beginning to use some target inside the cancer cell. Like, for example, the acidity of many solid tumors is higher than normal cells. So you could get acid or a proton to be an input and look for a fluorescent signal. But the more parameters that you can locate from a tumour cell, so there are certain enzymes which are produced inside the cancer cell. So now there are these logic gates which are enabling clear definition of the boundary of a tumour. It's only in animal trials so far. If it goes further up, then hopefully a few lives will get saved there too.

26:27Has anything like this broken out into everyday use yet? So we hope there will be adventurous institutions who will take a look at the literature where there are animal trials for fluorescence guided surgery being improved. And then maybe serendipity will strike again. Well, AP, among the many awards you've received, like your Lifetime Achievement Award from Queen's University of Belfast, was the award of a prestigious blue plaque from the Royal Society of Chemistry that was unveiled at the university last year. How did that make you feel? The first feeling I would say was, I'm glad I'm not dead.

27:07Because as you know, blue plaques are normally given to dead people. So this would have been something beyond imagination. Like many of the things that happened to me all along have been outside my imagination. And I gather it was a wonderful occasion. You had friends coming over from far, far afield. Because it was then a chance to say thank you to all the people who have been kind to me. So it was a wonderful occasion just to get people to see each other again. Wonderful. Well, you're 73 now, AP. So how are you spending your retirement? But you didn't say I look 17, huh? Well, I was going to say, you know, you said, thankfully, you're still alive.

27:44You're still alive. You're a long way, hopefully, for many more years to come. Yeah, hopefully there's a bit more to go. Yeah, you're right. I mean, retirement, because I did feel at the time, 70 was a nice round number. And even the research had come around nice closed circles. And the youngsters who have now gone on to do research from our lab, some will carry forward these stories and they're captains of industry. So I'm very happy with how the next generation is going, besides the people around the world who've taken up these ideas. So I'm fairly sure these things will live on after me. So I think it was a nice time to step off and then also keep in touch with the chemistry.