Chiral objects, like left and right hands, cannot be superimposed on its mirror image. Find other ‘chiral’ objects in this game.
The Nobel Prize in Chemistry 2024
The Nobel Prize in Chemistry 2023
Nobel Prize lessons – Chemistry prize 2023
Moungi Bawendi, Louis Brus and Aleksey Yekimov are awarded the 2023 chemistry prize for the discovery and development of nanotechnology’s smallest components – quantum dots. Quantum dots are nanoparticles that are so small that their size determines their properties, including the colour of light they emit. These luminous attributes are now utilised in making television and display screens. They can also be used to guide surgeons in tasks such as removing tumours from the body.
This is a ready to use Nobel Prize lesson on the 2023 Nobel Prize in Chemistry. The lesson is designed to take 45 minutes and includes a slideshow with a speaker’s manuscript, a video and a student assignment.
1. Show the slideshow (15 min)
Show the slides, using the speaker’s manuscript.
Speaker’s Manuscript (PDF 220 Kb)
2. Show the interview (5 min)
3. Student assignment (15 min)
Let the students work with the assignment.
Student assignment (PDF 350 Kb)
4. Conclusion (10 min)
Summarise the work with the assignment and capture any questions from the students.
Links for further information
Press release for the 2023 Nobel Prize in Chemistry
Popular information for the 2023 Nobel Prize in Chemistry
A Swedish version of the lesson is available at nobelprizemuseum.se
More about the Nobel Prize and its founder in the lesson “Alfred Nobel and the Nobel Prize”
The Nobel Prize in Chemistry 2022
Transcript from an interview with the 2005 chemistry laureates
Interview with the 2005 Nobel Laureates in Chemistry Robert H. Grubbs and Richard R. Schrock, by Joanna Rose, science writer, 6 December 2005, during the Nobel Week in Stockholm, Sweden.
Dr Grubbs and Dr Schrock, my congratulations to the Nobel Prize and welcome to this interview and to Stockholm.
Richard Schrock: Thank you.
Two months have gone since you got the message from Stockholm, what happened during this time, Dr Grubbs?
Robert Grubbs: It seems like it’s been a very long time, many things have happened with many interviews and many events. The other fun thing has been many people who I’ve lost track with over the years have gotten back in touch with me, and so we’ve re-established a lot of friendships which we’ve lost over the years.
And the message caught you in New Zealand actually?
Robert Grubbs: New Zealand, yes.
In the middle of the night?
Robert Grubbs: Yes, late in the evening I was …
Richard Schrock: 12:30 or something, right?
Robert Grubbs: Yes, it was 10:30 at night.
Richard Schrock: 10:30 at night?
Robert Grubbs: Yes, so there were the crazy time changes, so yes. I was there on a fellowship teaching a course, so I came back from a trip and then the call came and I taught my course the next morning, so we finished up.
I see. Maybe it was worse in the States, you got that call in the morning?
Richard Schrock: 5:30.
5:30, well that’s …
Richard Schrock: I was up having breakfast, coffee, I usually get up at 5 or 5:30.
I see, and go to work that early? Before all your students come?
Richard Schrock: No, I don’t go to work, I catch up on e-mails and do some work on a paper or whatever, and then go in after the traffic at 9 or 9:30.
And what happened after this call? The first one?
Richard Schrock: After the call a lot of things happened, people started turning up with cameras and my neighbour came over and the telephone started ringing and finally I had to take it off the hook because it was ringing constantly, as soon as I would put it down it would ring. Many people were having their automatic diallers dial my phone number.
Could you pursue your work after that?
Robert Grubbs: Yes, it changed a bit but not much. I did return back to California and started teaching a course there and I’ve kept my research group going and written papers and so life goes on. It just adds a few extra things.
I see, so now you are back on the track, the life is like normal.
Robert Grubbs: Well, not totally normal, no, no.
Richard Schrock: Ah, I wouldn’t say normal.
Robert Grubbs: Not normal but…! But yes.
How did you become involved in science if you go back?
Robert Grubbs: For me it was probably goes back to a teacher in junior high, middle school, who was an outstanding teacher and who started challenging me and getting me interested in science, and so it continued from there. It took many different variations along the way until I arrived at chemistry, but it was still always a science emphasis.
And you dr Schrock?
Richard Schrock: I’ve always been curious about things and interested in making things and I still work a lot with my hands in wood working and so on. When I was maybe eight years old, my second oldest brother Ted gave me what we call the proverbial chemistry set and so that got me interested in chemistry. I decided to channel my efforts in that direction and never really changed, I kept with chemistry more or less.
Some dangerous thing to get, the chemistry set, to put it in the hands of a child.
Richard Schrock: Back then they were pretty good things, yes, a lot of stuff in it.
No accidents?
Richard Schrock: I wouldn’t say no actually, but I have all my fingers and toes.
Robert Grubbs: That’s why it keeps you in chemistry is the explosions, the accidents.
Are you the kind of nerds that do just nothing but science?
Robert Grubbs: I don’t know about that, we do many things. I know Dick has many hobbies as do I, other than chemistry.
Yes like?
Robert Grubbs: It changes over the years. From early days I was active in sports and then rock climbing and more recently just walking as I’ve gotten older. And also wood working and building and construction, so I’ve done all those things too.
Did you do walking in New Zealand?
Robert Grubbs: I did walking yes, that was a part of the reason I went to New Zealand, was to walk, I didn’t walk as much I’d like but it was still very good.
Because of the message or …?
Robert Grubbs: Partially, and because also the weather was very snowy and wet. So we had one really good walk in the snow which for a southern Californian boy is an interesting thing.
I see. And what do you do besides science?
Richard Schrock: I used to play sports, not seriously, just casually, and I still do physical exercise but I do wood working, my father was a carpenter and so I have a big wood working shop in my basement, it gets bigger and bigger as my sons leave and so on. I love to cook, I like to listen to music, I don’t play any instrument but I like to take pictures again and, you know, quite a few things, I would say my most serious hobby is wood working.
Maybe you can tell us more about the discovery? I know that Dr Chauvin made the discovery first and very early, and then it took like two decades almost until you came with a new idea.
Richard Schrock: Maybe you’d better tell that one, Robert.
Robert Grubbs: That was pretty early on yes.
Richard Schrock: He was involved in a lot of the early stage.
Robert Grubbs: I was involved in it earlier.
Richard Schrock: Quite crowded there for a while.
Robert Grubbs: Yes, so it was a … I mean the reaction was discovered in the 1960’s as an accident, and the real question was … I learned about in when I was a post doc in 1967, -68, -69 time frame. The reaction was quite new, and no-one had any idea how it happened, and so that was what really attracted me to it was trying to understand how this crazy reaction happened. We started doing some experiments and then there were a lot of different mechanisms proposed to how the reaction takes place and we were trying to sort those out, and Chauvin proposed the mechanism which was consistent with some data, and so we were involved in developing some of the mechanistic studies, labelling studies which demonstrated that his mechanism was probably the right one, along with Katz and a few other people. Then that really set the definition for what the catalyst needed to be, and then we started working for years, Fred Tebbe, who you worked with made some catalysts that worked, not very well, but we started using those as model studies and then Dick developed some catalysts that were really outstanding catalysts, and they did a lot of things, and we started working with those. Then we were lucky to find another different direction to go in with different kinds of metals and ended up making another catalyst which now has been moving along very rapidly. But there really wasn’t a discovery, it’s been a situation of changes and additions and …
Slow work.
Robert Grubbs: Slow work and finding something and then pointing it in a new direction and then following that direction until something changes and then you go in the next direction.
And you never give up.
Robert Grubbs: You shouldn’t give up, no, still working hard. Still lots of problems to solve.
On the same reaction?
Robert Grubbs: The same reaction, still lots of problems to solve, yes.
And do you remember how you got the idea? It was also the slow work…
Richard Schrock: In my case I was at DuPont, so for three years, from 1972-75, about the time that Bob and Chauvin and others were investigating the mechanism. I discovered a kind of compound that had this new ligand in it, this new linkage that was part of the Chauvin mechanism, although at that time I don’t think I really knew about the Chauvin paper because that wasn’t known for some time, I think exactly who was first …
Was it in French or …
Robert Grubbs: It was in French yes.
Is this the obstacle? That it was in French?
Robert Grubbs: It was in French and it wasn’t …
Richard Schrock: What journal was it in?
Robert Grubbs: It was in a polymer journal which …
Richard Schrock: Polymer, right.
Robert Grubbs: … a lot of people didn’t read, so it was some time before …
Richard Schrock: See, we’re basically organometallic chemists, he’s an organic chemist, not an inorganic chemist, and Chauvin is a polymer chemist, so he published in French, polymer …
Specialisation.
Richard Schrock: … journals that we didn’t read every day.
Robert Grubbs: A lot of people didn’t read it, in fact someone else sort of rediscovered what he discovered later, but anyway.
Richard Schrock: I was at DuPont and I was doing tantalum chemistry which is one of the metals right next door to the ones that work well, or that first worked well, molybdenum and tungsten, and it turned out that I made a type of compound that was different, it had this required linkage in it. I thought maybe it’s possible that this one would have something to do with this crazy new reaction, and so it took about I guess 1980 was the year that I started to put it all together I would say, so that’s about six years later, after I moved to MIT in 1975. But tantalum, it works out, is not what I call a classical catalyst, it’s not something that makes this thing easily, you have to work at it very hard, but molybdenum and tungsten we found out what was the right combination and then we could make, again by designing, something that’s stable and will do the reaction very rapidly and do everything that Chauvin said it should do, make these intermediates and we could get structures of them and so on. And then we could continue to refine the catalysts and move ahead. There is another part of this chemistry that was not actually mentioned, usually, in the Nobel Prize statements and that is there is a triple bond version called alkyne metathesis which is very closely related, and we discovered that similar compounds will actually, could be made that would do that reaction.
Robert Grubbs: What year did you come to Caltech?
Richard Schrock: -86.
Robert Grubbs: -86, okay.
Richard Schrock: We published one paper …
Robert Grubbs: One paper together yes, in ‘86, on tantalum.
Richard Schrock: No, it was tungsten. The first tungsten catalyst.
Robert Grubbs: Okay, that’s right.
Richard Schrock: I would say was the modern one, they say 1990, but actually it was 1986, was the one that I actually brought to Caltech and we made some polymers and we proved that it did what it’s supposed to do, and so that was the one and only paper that we published together.
Did you start to work together then? Or you knew each other before?
Robert Grubbs: We knew each other long before.
Richard Schrock: We knew each other since the early 1970s I would say.
Robert Grubbs: Early -70’s, yes.
Because you work in the same field?
Robert Grubbs: The same field, work in the same field, go to the same meetings. I remember the first basketball game we played together. I still have a scar I think from that game.
At the conference or…?
Robert Grubbs: It was a conference, that’s right yes.
So this is what you do at conferences?
Robert Grubbs: Yes, we decided we should never do that again.
Richard Schrock: So Bob did do a lot of further studies with these and similar molybdenum catalysts. I made more variations probably, since I’m an inorganic chemist, so I work more with making and designing catalysts and Bob with applying that chemistry to make polymers, and then really set his sights on organic chemistry. He was the first to really see the possibilities, since he’s an organic chemist, that one could influence organic chemistry powerfully.
But you worked in the industry?
Richard Schrock: Just for three years.
For three years.
Richard Schrock: Yes, from 1975, so for 30 years I’ve been at MIT.
What is the relation between applied science and fundamental science? Can you comment on that?
Robert Grubbs: I think they naturally sort of flow together, at least for me it’s been. We started out doing very fundamental work, we still do very fundamental work, but you also have to keep an eye for where it might be useful and then point it in that direction. Then once you get it going in the right direction there’s lots of people who will take that then and use it to make things and do the applied stuff. I try to do the fundamental and then point people in the direction that the applied stuff can happen and then there’s all kinds of wonderful people around who takes that and does nice things with it.
Richard Schrock: And the main idea is to control these catalysts and what they do and then you control it by making different catalysts and you know everything about them in a fundamental way, and then you can apply that knowledge to making a polymer of a certain type or doing a certain type of organic reaction. Then you can apply what you know with these catalysts, but it all begins with fundamentals.
Yes, but in the 1970’s there were lots of research laboratories in the industry, it’s not so many nowadays.
Robert Grubbs: It’s getting much harder.
Richard Schrock: They’re almost gone, I would say there’s nothing even close to what DuPont was, for example.
No.
Robert Grubbs: I mean DuPont was an amazing place.
In what way?
Robert Grubbs: It was like an academic laboratory.
Richard Schrock: Fundamental research.
Robert Grubbs: For fundamental research and that’s all gone. In fact there’s almost no real fundamental industrial labs any more. In one sense that’s okay because the universities are there to do the fundamental work. I think the problem now is the transition work, it’s that in the past, if you did fundamental work there was then someone in the company who had the understanding of the fundamental work and could do the transition part which then got it to the applied edge. That part seems to be missing now, and so we’re working really hard to try to come up with ways so that one can go from an academic laboratory and then get through this missing piece to the industrial part. And what’s happening now is that small companies are starting to fill in that gap.
And they are started by academics?
Robert Grubbs: In many cases by academics yes.
Richard Schrock: Like him for example.
Yes. That’s another sort of job, I would say.
Robert Grubbs: It’s another sort of job but if you do it right it’s a very fun job and not so difficult, if you find the right people to do that transition work.
So you work with a company and in academia?
Robert Grubbs: Yes. My job is in academia, but part of getting the technology, the fundamental stuff, we’ve developed two applications which after all one loves to see your stuff used and done. It was essential to build up this middle part and the only way to do that is to be involved in starting a company that is involved in that transition work. I tried doing it lots of other ways but it’s the only real way that I found to do it now. Dick’s also involved in the company too.
Richard Schrock: Yes, but not to such an extent. But they’re trying to get all of metathesis under their roof, I would say, and push it, which is good. And they will try to apply this reaction for pharmaceutical companies or for whoever wants to use it because it’s so universal in the sense that you can go in many directions. It’s a fundamental reaction, you can do many different things with it, and many companies might see some reaction that they could do in fact, and then they would license for example the possibility to do that from this company.
Robert Grubbs: But you need someone there who, as I say, that middle piece is missing, I mean for example DuPont used to do a lot of the fundamental work but they also could do the transition into the very applied stuff. But that’s all missing now. So I think that’s going to be the next generation of the way the technology develops.
There is also a question on going another way. How do you get information about what are the problems in the industry to solve in academia?
Robert Grubbs: Yes, that’s hard, but you don’t have to do that. What I’m finding now is that if you generally go around and you talk about the fundamentals, you talk about the places where the chemistry can be applied. The places where industrial chemists find applications always astounds me, you know, it becomes important and commercially viable, not for some fundamental chemical reason but for some small business reason which I have no idea about. It’s just been really fascinating to watch this happen, and there’s no way you can predict it or even think about it, and so you just put the science out there and get it to the point where people can understand it and use it and then they just find amazing applications.
There is one point on the road there that when science needs to become not so open as it’s used, we need to get patents and then you have to be secret about …
Richard Schrock: This is tricky and a question I often get is how is the chemistry used? What is being done with it exactly? Bob knows more than I do, but I don’t know because of this fact, and even people at materia may not know what exactly their catalyst’s being used for because naturally they want to keep it quiet…
It’s the company’s secrets.
Richard Schrock: Companies do not want you to know too much.
Robert Grubbs: Yes, and I know a lot I can’t talk about, but on the other hand I mean a lot of it is still getting to be known and the information does get out. At the academic side there was a change about seven or eight years ago which changed the way one could work. In the days before then you had to have a patent written and out before you could publish, and then the US patent office, and I think It’s now going around the world, is a thing called the provisional patent. This allows you then to basically claim an area without having a formal patent written, and then you have up to a year to write the formal patent, so that gives you a, as an academic that’s really been liberating in terms of how one can do patenting as well as publication, because in the end what we have to do is publish.
Yes. There are some other changes in science that maybe are more bothering, about how the public view science today compared with even ten years ago.
Richard Schrock: That’s hard.
Robert Grubbs: Yes, I’ll let you take that.
Richard Schrock: I think the public is as, the general public, it depends on the country I would say, but it’s lost the faith in science that we once had. After World War II and Sputnik of course, that created a stage for science and people looked to science to solve many problems, and now they’ve become maybe a little jaded as we would say, a little too accustomed to what progress we’ve made and they no longer have maybe the confidence in science, I think, that we had at that time for sure.
Robert Grubbs: Sputnik was the one that for, that was what changed the life in the US in terms of science, and at least in my generation, I was in high school when Sputnik went up and I remember precisely that, and it really paved the way for me to go into science and go through science, so that was important, but that’s getting harder and harder. I think as Dick said there’s a lot of faith being lost, there’s no at least in the US attitudes that are very non-scientific that are becoming prevalent, that are being supported at levels which make it difficult for science in many ways.
Who’s to blame for that? If you blame anything. Is it school systems?
Robert Grubbs: I don’t know, it’s really been frightening the last few years to watch the change happen.
Can you see it with your students? People who come to the universities?
Robert Grubbs: I don’t, not in our students, I mean we’re both at institutes of technology which have probably the two highest standards for admission in the US and so our students come in interested in science, wanting to do science, and so for our students that we work with everyday it’s not an issue. It’s outside of that group you see it.
Richard Schrock: And you see it through the funding agencies and the money they get which has, fortunately this year I think increased, but there have been some difficult years, and well, the government statements, our government and any government has positions, and sometimes they are not, shall we say, scientifically what we would like them to be. And that’s something that is very visible and it’s very distressing to see things said that are just not true or certainly debatable at best.
Robert Grubbs: The other thing is when we started out there was a great emphasis on doing fundamental science and over the last number of years … it’s not a bad thing but it’s a different thing, which is that even at the agencies that support fundamental work one has to say where this can be used, the applied end, and see it, and if we’d been starting out that way we’d have never started our work because there was no way in the world one could have imagined where this would go, it was just a fascinating reaction to look at.
Richard Schrock: And now you have to say how is this going to benefit mankind before you even know basically what you are going to discover or develop. We know now what this reaction has done but you cannot predict the future, and to say where it’s going to actually benefit mankind at a point where it’s fundamental research is impossible really.
Robert Grubbs: I mean after 35 years now working on this reaction I still get shocked very often about new thing it can do and new directions it would go in, so it’s a … I hope it stays for a few more years.
It’s fantastic, yes, and it’s just started with a happy end I would say, even if it’s not the end yet.
Robert Grubbs: Not the end yet no, I keep saying I have a few more years before I retire so I’ve got a lot more things to do.
Yes, I look forward to seeing what happens. Thank you very much.
Richard Schrock: We’re both young, we’re both young.
Thank you for the interview, and I hope you have a great time in Stockholm now.
Robert Grubbs: Thank you, thanks.
Richard Schrock: I’m sure we will.
Robert Grubbs: I’m sure we will yes.
Richard Schrock: Thank you.
Did you find any typos in this text? We would appreciate your assistance in identifying any errors and to let us know. Thank you for taking the time to report the errors by sending us an e-mail.
The Nobel Prize in Chemistry 2021
Play a game!
Nobel Prize Lessons – Chemistry Prize 2020
Teacher’s Guide
This is a teacher’s guide for a Nobel Prize lesson – a complete lesson on the 2020 Nobel Prize in Chemistry, which is awarded for the discovery of one of gene technology’s sharpest tools: the CRISPR/Cas9 genetic scissors. The lesson is planned to take about 45 minutes.
Teacher’s Guide (PDF 60K)
A Swedish version of the lesson is available at nobelprizemuseum.se
A revolutionary tool for gene technology
The 2020 Nobel Prize in Chemistry is awarded for the discovery of the genetic scissors, a tool for rewriting the code of life. Researchers can use these scissors to change the DNA of living organisms, which is a great benefit to basic research about how genes work. The technology can also be used in plant breeding, for example, and can lead to innovative medical treatments.
1. Warm-up (5 min)
Ask your students the following questions.
- What is the Nobel Prize?
- Why is it called the Nobel Prize?
- Are you familiar with any Nobel Laureate?
2. Show the video about Alfred Nobel and the Nobel Prize (5 min)
3. Slideshow (15 min)
Show the slides, using the speaker’s manuscript.
Slideshow (PDF 2 MB)
Speaker’s Manuscript (PDF 300 Kb)
4. Show the interview with an expert in the field (5 min)
5. Student worksheet (10-15 min)
Let your students work individually with the questions and then discuss their answers with a classmate.
Student Worksheet (PDF 50 Kb)
6. Conclusion (5 min)
Summarise what you and the class have understood, and what you have not understood. You can work with the latter on another occasion.
Links for further information
Press release for the 2020 Nobel Prize in Chemistry
Popular information for the 2019 Nobel Prize in Chemistry
Nobel Prize lessons – Chemistry prize 2021
Teacher’s guide
A Swedish version of the lesson is available at nobelprizemuseum.se
This is a step-by-step timetable for the Nobel Prize lesson – a ready to use lesson on the 2021 Nobel Prize in Chemistry. The lesson is designed to take 45 minutes.
A new tool in the chemist’s toolbox
The 2021 chemistry laureates have studied how chemical reactions work and how they can be accelerated. Working independently of each other, they have developed a method that is cheaper, more efficient and more sustainable than previous methods. This method is called asymmetric organocatalysis.
Teacher’s Guide (PDF 30Kb)
1. Warm-up (5 min)
Ask your students the following questions.
- What is the Nobel Prize?
- Why is it called the Nobel Prize?
- Are you familiar with any Nobel Prize laureate?
2. Show the video about Alfred Nobel and the Nobel Prize (5 min)
3. Slideshow (15 min)
Show the slides, using the speaker’s manuscript.
Slideshow (PDF 2,3 MB)
Speaker’s Manuscript (PDF 300 Kb)
4. Show the interview with an expert in the field (2 min)
5. Student worksheet (10-15 min)
Let your students work individually with the questions and then discuss their answers with a classmate.
Student Worksheet (PDF 150 Kb)
6. Conclusion (5 min)
Summarise what you and the class have understood, and what you have not understood. You can work with the latter on another occasion.
Links for further information
Press release for the 2021 Nobel Prize in Chemistry
Popular information for the 2021 Nobel Prize in Chemistry
How many chemistry laureates can you match?
Can you pair the portrait of the Nobel Prize laureate in chemistry with the image representing the Nobel Prize awarded discovery? Drag the images from the left to the right to pair, and press check to see your result.
Don’t recognise the laureates? Keep scrolling down for some extra help below the game.
Featured chemistry laureates
Marie Curie, née Skłodowska
The Nobel Prize in Chemistry 1911in recognition of her services to the advancement of chemistry by the discovery of the elements radium and polonium, by the isolation of radium and the study of the nature and compounds of this remarkable element.
The Nobel Prize in Physics 1903
in recognition of the extraordinary services they have rendered by their joint researches on the radiation phenomena discovered by Professor Henri Becquerel.
Melvin Calvin
The Nobel Prize in Chemistry 1961for his research on the carbon dioxide assimilation in plants.
Emmanuelle Charpentier
The Nobel Prize in Chemistry 2020for the development of a method for genome editing.
Want to try another game?
Match physics laureates
Match chemistry laureates
Match medicine laureates
Match literature laureates
Match peace laureates
Match economic sciences laureates
Match awarded women with their discoveries
Match female literature laureates
Image credits
Battery: Kilimanjaro ru, CC BY-SA 4.0 <https://creativecommons.org/licenses/by-sa/4.0>, via Wikimedia Commons. Genetic scissors: © Johan Jarnestad/The Royal Swedish Academy of Sciences. Quasicrystals: J.W. Evans, The Ames Laboratory, US Department of Energy, Public domain, via Wikimedia Commons. Buckyball: Mstroeck, CC BY-SA 3.0 <https://creativecommons.org/licenses/by-sa/3.0>, via Wikimedia Commons.
Transcript from an interview with the 2012 chemistry laureates
Robert J. Lefkowitz (left) and Brian K. Kobilka (right) met with Nobelprize.org’s interviewer Adam Smith (middle) on 6 December 2012.
Copyright © Nobel Media AB 2012
Photo: Niklas Elmehed
Interview with the 2012 Nobel Laureates in Chemistry Robert J. Lefkowitz and Brian K. Kobilka, on 6 December 2012. The interviewer is Nobelprize.org’s Adam Smith.
Robert Lefkowitz and Brian Kobilka, welcome to Stockholm, indeed a snowy, wintry, beautiful Stockholm. It could look more inviting, but very different from North Carolina and the bay area this time of the year.
Robert J. Lefkowitz: Indeed. We only get snow maybe once every three or four years. It has been kind of a treat!
You are here for Nobel Week, the culmination of two months of fairly frenzied activity I imagine since the calls came. How have those last two months been? How have you found it?
Brian Kobilka: A bit overwhelming. It would have been a busy two months had this not happened, but it has been an extraordinarily busy time.
I am sure. How about you?
Robert J. Lefkowitz: I had been warned. As soon as this happened, I spoke with several colleagues, Harold Varmus and Joe Goldstein, old friends and colleagues and they warned me about just how intense it was. But I must say it was, as Brian said, I found it a bit overwhelming right up to our arrival here. It is something that nothing, I think, prepares you for.
I suppose not. And you had the added ownness of being the first Nobel Laureate from Duke University?
Robert J. Lefkowitz: Yes, indeed. This caused quite a bit of ruckus, that it was the first, and they likened it to when we won our first NCAA basketball championship under the very famous coach K, coach Krzyzewski. I think one of the most exciting things that happened to me, during this period of time was that I was honoured at Cameron Indoor Stadium, which is the basketball stadium, by coach K and the basketball team that presented me with a jersey with a number one on it and my name. Which seemed to impress my children perhaps even a bit more than the Nobel Prize itself.
It is nice that intellectual pursuits and athletic pursuits have reached the level.
Robert J. Lefkowitz: Indeed.
It is hard to count Nobel Laureates from institutions because you never know where the people are associated. I have heard Stanford themselves say that you are number 27.
Brian Kobilka: That is probably right, yes. It is not quite as big of a deal there.
I am sure it is still a very big deal. One thing that often is said, is whether it gets you a parking space on campus?
Brian Kobilka: I am afraid not.
Not yet. If you win two prizes.
Robert J. Lefkowitz: How about your own bathroom, do you get that?
Brian Kobilka: No, no.
Robert J. Lefkowitz: Me neither.
Anyway, you have been awarded for your work in the field of G protein coupled receptors, GPCRs. These are the gateways to the cell together with ion channels. It is commonly said that 50% of medicines acts through G protein coupled receptors. It is hard to imagine really that forty years ago when you started to work in the field, the concept of the receptor itself was still not all that widely accepted. It was still some doubt as to whether they existed.
Robert J. Lefkowitz: Yes, there was a great deal of scepticism about this and in fact in my Nobel Lecture on Saturday I am going to review some of this. Frankly, I could give the whole lecture on that topic, but I will not. But remarkably the scepticism we shared even by some of the giants of the pharmacology field, such as Raymond Ahlquist. He was a very famous American pharmacologist who won the very distinguished Lasker prize for first putting forth the idea that there could be two types of receptor for adrenalin which he called alpha and beta receptors, that was in 1948. That was based on some classical pharmacological work that he had done. But as late as 1973, which is when I was just beginning some of this work, he published an article basically saying that it was essentially arrogant of people to even think that these things really existed. For him they were just sort of an idea, a way of organizing thinking. But he did not really … there was not really a concept that these was specific molecules if you will. They were just viewed as some very unclear nebulous pattern of forces on the surface of cells, that could somehow allow them to interact.
That is interesting! Because the first half of the 20th century was really the golden age of neurotransmitter research. This slew of neurotransmitters was discovered, and their functions were to some extent understood, yet nobody knew how they operated.
Robert J. Lefkowitz: This is correct, and in fact the earliest ideas about receptors came from a British pharmacologist named J. N. Langley. More than hundred years ago he wrote about the idea that there must be something, that we now know as a receptor. But interestingly, forty years later, his student Henry Dale – talking about neurotransmitters – he won the Nobel Prize, I am not sure what year, for his work on cholinergic neurotransmission and in the mid-forties he wrote an article mocking his mentor Langley for saying that there was such a thing as receptors. He said: It does not really teach us anything to say, the receptors, there is of course something about cells that allows them to interact with molecules. But giving it a name just does not really make any sense.
So why did you choose that field for your own research when you started research?
Robert J. Lefkowitz: I had been at the NIH for a fellowship in 1968 to 1970 and this was the golden age of second messenger signalling. Earl Sutherland had recently won the Nobel Prize for his discovery of cyclic AMP which is a molecule generated on the inner surface of the cell membrane when what we now know GPCRs are activated. My mentors there Jesse Roth and Ira Pastan thought it might be possible to label the receptors because they felt they existed. They were what would be called molecular endocrinologists and they thought it would be possible to label them with radioactively labelled materials. I was assigned the project of trying to label a receptor for ACTH, Adrenocorticotropic hormone, which works through a G-protein couple receptor and I spent my two years there radioactively labelling ACTH and showing that I could bind it to some sites on the plasma membrane of a tumour which was responsive to ACTH, so it was an ACTH responsive cancer that I passed in nude mice. We were successful in doing that. The work did not really go any further than just developing these radioligands, but really, the idea caught fire in my imagination!
It gave you an inkling that you could …
Robert J. Lefkowitz: Do this, right. Further on in my carrier I was a cardiology fellow a couple of years later and I really wanted to pick up this theme, but I wanted something more cardiovascularly related and the adrenergic receptor seemed to fit the bill more so than ACTH, so that is why I turned to the adrenergic receptors in the early seventies.
I would just like to pause there. One thing that defines you both, you are both cardiologists.
Brian Kobilka: I had the intention of becoming a cardiologist.
Robert J. Lefkowitz: What are you talking about, you did the fellowship?!
Brian Kobilka: Yes, so then I started out in Bob’s lab and that was pretty much, with the exception of the intensive care unit, the only thing that I really did to complete my cardiology fellowship, which I did not complete.
But you started out with the intention of becoming a medical doctor? And then you transitioned to research. I was going to ask you both, what sort of flipped you away from medicine onto the bench?
Brian Kobilka: I think I had the intention of, at the time I was in training in internal medicine in St Louis, of being an academic physician. Which meant that I would continue seeing patients and I would find some line of research. At the time I was really very interested in intensive care medicine and I believe there were not intensive care medicine fellowships at the time. It was either cardiology or pneumology and so I decided to go into cardiology. I learned that … I was also really interested in research, although I cannot at the time say I was really interested in adrenergic receptors. I was interested in the concept of using adrenaline in other compounds like that in intensive care unit. And Duke hade a fantastic research program for cardiology fellows. You could go to Duke, you could spend at least a year and a half doing research and you could do it up front, which was really attractive to me after spending three years taking care of patients and really wanting to try out research. I do not know how many places I applied to, but I was very happy to be accepted into Duke and very happy that Bob chose to let me in his lab.
We will come to your lab environment soon. When was the last time you saw a patient?
Brian Kobilka: Actually, I continued to see patients while I was a fellow, primarily moonlighting and weekends, and I am not sure, but I think I can say this now since the statute of limitations is up, but when I moved to Stanford my wife Tong Sun started medical school, so our children were old enough to go to school. She started in medical school in Stanford, so we had a very large mortgage in tuition, and I continued to moonlight for quite a few years in emergency rooms.
Maybe you are still moonlighting, maybe we should not talk about this … How about you, Bob, you had wanted to be a doctor?
Robert J. Lefkowitz: I very much wanted to be a physician, and had harboured that goal, I would say from the time I was eight or ten years old. Like Brian, I learned last week, a very similar experience, I was inspired by my family physician, who made house calls, and I decided that is it, that’s what I want to do, and I thought about nothing else in terms of a goal, right through grade school, high school and college. I would say that Brian, for what I know, who actually showed an interest in research earlier than I, because as I understand Brian had a mentor experience in college, and I think even won an award for his research thesis at Yale, if I am not mistaken. I had absolutely no research experience until I went to the NIH in 1968. In fact, in medical school we had a couple of opportunities to do two month’s electives in research – I never took one – I had no interest in it, I wanted only the clinical electives, so called sub-internships.
But in the late 60s, the Vietnam war was raging and many of us were opposed to that war on multiple grounds, there was a drift, physicians were drifted. You had to go in after two years of training which many of us did not want to do, so there were few options, they were very competitive to get, that would get you out of going to Vietnam. One was to join the United States public health service as a commissioned officer and be assigned to the NIH for two years. Very very competitive to get such positions, but I had a strong academic record, and I was able to get that, and it seemed like a good thing to do, because like Brian, I pictured myself someday as an academic physician and I vaguely had it in my head that academic physicians did some research. So, I figured, well, I get my research papers and I go. And that is where I got started in research.
Now there is a very interesting and timely piece in, I guess, last week’s issue of Science, by Mike Brown and Joe Goldstein, in which they review basically the history of that year, and remarkably it turns out between 1964 and 1972, I think is the slice they took, I became the ninth Nobel Laureate to have trained. I actually went through the list. Six of us came between 1967-70 and when I say came, I do not mean there were a hundred of us each year – in a year there might have been eight or ten or twelve – so it was a remarkably high success rate.
And they are going in that article to regret the loss of that kind of training environment.
Robert J. Lefkowitz: Exactly. It was a remarkable environment. They tried to dissect what it was about it that made it so remarkable. I think they do a pretty good job, but there are some things that cannot be fully understood. Obviously, they got the best talent coming in, because we were so competitive to get the positions and there were some wonderful mentors there, but … maybe something else, that is harder to define.
Anyway, avoiding the draft in fact led you to your research career somehow.
Robert J. Lefkowitz: Exactly, right. It was not what I had imagined at all, and I certainly did not have a smooth start, things went very poorly at first.
When did you give up on patients?
Robert J. Lefkowitz: I actually made teaching rounds for 30 years at Duke. I would do one rotation a year, six weeks, from age 30 to age 60, at my 60th birthday, for a variety of reasons, I hang up my stethoscope.
At Duke, you pursued this difficult task of purifying the β-adrenergic receptor, it took 15 years to purify and clone, that is quite an undertaking. Did you have, as you were on that path, the goal of that purification so that you were always looking that far ahead?
Robert J. Lefkowitz: Definitely. That was a goal for many, many years. Something interesting that … at least it is my view of things now, and maybe it is revisionist history, but when I look back on that period, my sense is that it almost never occurred to me we would fail. I always believed we would be successful. When I look back on it now, it was kind of crazy, but that is my sense of it now. I always assumed it would all work, I did not know when or how long it would take, but sooner or later we would get there. It never occurred to me that maybe it would not work at all and it would be a total dead end.
Along the way you have to be generating enough material that keeps it all moving.
Robert J. Lefkowitz: Moving, right. Exactly, and I think Brian had similar experiences these last 15 years with his crystallography, or I do not know, maybe you did entertain the idea that it would not work at all? Or did you always think someday I will get there?
Brian Kobilka: I think I always thought some day I will get there.
Robert J. Lefkowitz: I think that kind of optimism, what did you call it once?
Brian Kobilka: Henrik, a colleague of mine from Bob’s lab calls it ‘irrational optimism’.
Robert J. Lefkowitz: Irrational optimism, yes, sometimes that’s … I think it’s a good leadership, quality, because it is sort of infectious, I think, in terms of the troops, the folks in the lab, if they think the boss has any doubt we’re going to get there, that doesn’t foster the kind of attitude that you want.
Let’s talk about the lab a bit because you have had an immensely productive lab, both in the sense of papers and discoveries, but also in the sense of people. You have had more than 200 people? You must have got a research environment going which people want to join. What was the secret of it?
Robert J. Lefkowitz: That’s a very good question. I think there probably are a number of elements. One of course is the old business of success breeds success, if a program is successful then people want to come because there is high visibility research going on. As to why we were so successful, I mean there is a lot of mystical stuff, like I’m a great judge of talent, that’s how Brian came to my laboratory. I say that and we both laugh because when he came to interview as I recall, I was out of town.
Brian Kobilka: Right there, yes.
Robert J. Lefkowitz: I wasn’t there, and I think he even made a second visit, and I was also not there. But in any case, as I wasn’t there, so obviously I’m a good judge of talent, and I took him anyway, sight unseen. I think one of the things about working in a lab is to have good esprit de corps, which can’t be 100%, there is always going to be some odd balls or some oil and water mixtures of people just doesn’t get along, but I think in general we had good chemistry of people in the laboratory. I think I always brought to the endeavor a real sense of enthusiasm for what we are doing. Enthusiasm is something that you can’t fake, you can’t fool people. I remember at my 60th birthday party that Brian was at and many of the fellows came to, they were giving various talks about what they remembered. I remember one postdoc from that era, a wonderful guy named Rick Serione, who is now a professor of … has a name chair, in chemistry actually, at Cornell, was saying that one of the things that kept him going is that he always sensed from me that his project, which was a reconstitution of the receptor after it was purified, was the most important project in the lab, and he liked that, until one day he talked to some other guy and he said: No, I felt my project was the most important. It turned out that everybody thought their project was the most, and I guess somehow I transmitted that, because probably I believed it, including Brian’s, which really was the most important project in the lab.
With Bob sitting here maybe it is not the right place to ask you, or maybe it is the right place, does that rhyme with your experiences of Bob’s lab?
Brian Kobilka: I would say yes. He was always very enthusiastic and encouraging, and you felt that you could try anything. I don’t actually remember there being any kind of limit on even what we could spend to try something that was completely sometimes crazy.
Robert J. Lefkowitz: I think one of the things I taught Brian was how to go into debt in the laboratory, and he has been very god at that, the reason he is I am sure he could tell you about. The folks in the lab probably didn’t even know it, bur on several occasions when things really got hot, and we were making progress on a project, I would just overspend, I would just not care about the budget, we would just do what we needed to do. I was called on the carpet on several occasions, both by the chairman in medicine, named Jim Weingarten, and also by the head of the Howard Hughes medical institute. The administrator of the Hughes institute, a guy named Kenny Wright, he was a good old Southern boy, and I remember on two occasions they sent him down specifically, as he put it, to ‘slap me on the wrist and take me up behind the woodshed’ because I had totally overspent my budget and he was there to sort of arrange things in. On the other hand, we were doing good work and he was kind to give me a wink, but he brought the message anyway.
I know that you have a very large number of people coming from all over the world to help you celebrate here, you’ve got this get-together of 50+ people …
Robert J. Lefkowitz: Yes, at the moment, it is up to 55 with a few family members.
I suppose that speaks to the social aspect of all this, that it’s not just productive and supportive but you are also becoming friends, lasting relationships. I’d like to talk a little bit about that.
Robert J. Lefkowitz: Yes, and I think Brian will have a lot to say about this as well. I think both of us have tended to view our laboratories as a second family, I mean you really get close to this people, and they really are … as a mentor they are like your kids, and like your kids when they leave the nest doesn’t mean you’re finished with them, it goes on for a lifetime. Then I think some of the relationships amongst the trainees that they make within the laboratory, people who are in the lab at the same time I think become colleagues and friends for life and it’s a very, very special bond. In my own laboratory probably, if there was a peak period when things were rolling, it was really the eighties and into the early nineties, many of the people who were in my lab at that time are acknowledged leaders in our field and are good friends and colleagues of Brian. I think it speaks to the way they feel to not just about me but about Brian, that they are all coming here at their own expense and unable to get into the ceremonies, but just to be here with us I think speaks to that family aspects of things.
In a way that is at odds with how science might be often perceived by the public. We have got the image of the lone scientist coming up with ideas and pursuing their goals and indeed that’s in some way supported by the Nobel Prize which selects individuals for the prize. Yet of course it is a very social affair. And in your case even a family affair, because you and your wife were together in the lab.
Brian Kobilka: It’s true. There’s no conscious decision that it is going to be that way, but it seems that at least part of my success is finding people that both I enjoy working with and are willing to engage in very challenging projects. My wife in particular I would say particularly during the past decade where some of the projects in the lab were too risky for graduate students and post doctor fellows, she would be enrolling up her sleeves next to me and working on these projects and also helping out fellows and graduate students with really difficult projects to make it at least more feasible for them to engage in these high-risk projects.
When you pick people to join your lab, what do you look for? People you can get on with foremost?
Brian Kobilka: It’s very important that not only I get along with them, that they get along with other people in the lab, it’s really important to have chemistry in the lab. I would say that the lab has been most successful when people work together on again, very challenging projects, sharing ideas, sharing reagents, really take teaming on projects – I think that’s really key to having a productive and enjoyable experience.
Robert J. Lefkowitz: I think something that is very important both to Brian and myself is the mentoring of the young people. People often ask me, because I have been successful in training so many people, ‘What are the keys to mentorship?’ It’s like everything else, there’s not one right way to do it, just like there’s not one right way to do science. I think many people consider both Brian and myself for good mentors but our personalities couldn’t be more different, so obviously we can’t possibly mentor people in the same way, and yet we both seem to wind up doing a fairly good job of it. I think a lot of this is just a matter of are you willing to invest yourself in people and really care about them and care about their careers and success. And challenge them! To put things in front of them which they really have to reach to get to. If you can give somebody the experience of working right at their potential, really doing something which tests them and extends their limits and let them feel what it is like to succeed at that level – then you have done it, because then they know what it feels like, they know what they are capable of and they are willing to challenge themselves in the future.
You have to know them pretty well to know what to challenge them with?
Robert J. Lefkowitz: Exactly. For me personally getting to know people, getting in their head, because you challenge different people in different ways, it takes different kinds of things. The whole issue of how much to direct people, it’s a delicate balance, you can direct them too much, they may be successful in the short term, but they never gain the confidence that they can really do it by themselves. Or you can direct them too little, and they just drift and become unfocused etc. So the question is to provide enough direction but not too much direction. Of course, there’s nobody who can tell you what that is, you just have to figure that out individually.
But it must be a lovely feeling when you see that it works and the person thrive.
Robert J. Lefkowitz: Absolutely. I’m aware of some very very distinguished scientists who, in the course of long careers have not trained that many successful people and you say: ‘Why is that?’. And at least in a couple of cases I’m thinking about I think I know the answer. I think it is because they so closely directed their trainees while they were there that they really did not really have a chance to develop their own independent thinking and confidence to really do things on their own.
One other aspect of this, and then we move on, by generating 200+ people from the lab I suppose you are also generating, it’s a bit of a nasty thing to say, 200 competitors, you are seeding a lot of people who are interested in the same stuff.
Robert J. Lefkowitz: Absolutely, in a sense it is true. Then it becomes a matter of … Competition is in the eye of the beholder. Brian, when he left my laboratory, continued along, doing things that I might have worked on, sometimes I did work on, but I guess it’s like your kids, I can’t imagine ever feeling competitive with one of my kids even if they were doing exactly what I was doing – it just does not work that way. I think that’s the familial aspect to it – how could any of them compete with me, they are like my kids.
And you have been in a pretty competitive place for the last fifteen years going for this crystal structure, because there were other big groups heading down the same road, but in this case there’s not the familial bonds, they are just the groups out there.
Brian Kobilka: Yes, and I have to say that even among some of my competitors there’s been a great deal of collegiality and collaboration as well, I would say, particularly with Gebhard Schertler who was one of the earlier structural people in GPCRs, in fact he generated the first structure, he was a … we call it two-dimensional crystals, it was a low-resolution structure, it was really our first view of what GPCR looked like. He has always been a great colleague, he in fact took us to the beamline when we got our first crystals which weren’t good enough to get a structure but they were small and too small to actually study in a conventional synchrotron. Gebhard was really interested in developing microfocus micron beam crystallography and he had worked with scientists at the ESRF on the first really high quality microfocus beam, sometimes called mini-beams. He took my pretty lousy crystals and brought me to his synchrotron, we went to ESRF, Tung Sun would join me in the trip. He really taught me how to start collecting data from very small crystals. We’ve been friends and competitors, in some respects.
Robert J. Lefkowitz: Brian makes a really good point. I have found, in my career, that competition per se doesn’t necessarily – I’m talking about outside the family now – competition per se doesn’t necessarily mean difficulties. I have had direct competitors who I have had lovely personal relationships with, and I have had others which were not so pleasant. So it is not the competition per se, it is more a matter of the personalities.
I suppose so. In some ways it is there to keep you at the top of your game.
Robert J. Lefkowitz: You know that the competition does drive a lot of science. I think all of us are inherently somewhat competitive.
If we just return to the lab. You came into the lab and were involved in other stages of this β–adrenergic purification and cloning experiment where the structure of the β–adrenergic receptor was revealed. That acted in a phrase that seems very appropriate, as the Rosetta stone unleashing lots of other G-protein coupled receptor structures and revealing that there was this super family. I have often heard people say that in retrospect of course there was a super family, it was obvious, but was it obvious as you went into it?
Robert J. Lefkowitz: Not in the least. When we were cloning, we had first been successful in getting what we knew to be valid clones for the receptor. It’s not like today, it’s amazing to think back. How many nucleotides were there in the open reading frame … a couple of thousand?
Brian Kobilka: Yes, 1,500.
Robert J. Lefkowitz: And how long did it take between us and Merck to sequence that piece of DNA?
Brian Kobilka: I don’t remember.
Robert J. Lefkowitz: That wasn’t a day or two, was it?
Brian Kobilka: No, wasn’t a day or two.
Robert J. Lefkowitz: It was probably a matter of weeks.
Brian Kobilka: Probably between 100 and 200 base pairs.
Robert J. Lefkowitz: While we were sequencing it, word began to get around on campus, I don’t know if you know this story… Word got around the campus: we had it. OK. And I don’t remember who, but somebody … We had part of the sequence, I don’t know how many base pairs, and we knew we had the right thing because we already could see some of the five peptides that we knew were in there from our sequencing of pure protein. And a colleague said: ‘What does it look like?’ And I remember distinctly saying to him ‘It doesn’t look like anything, why should it look like anything, this is the first one’. So that shows you the extent to which we were not expecting what we eventually found which was the homology with rhodopsin. This even now, the functional analogies between rhodopsin and transducin and the /- – -/ with the βreceptor, the G protein, those functional analogies were clear, and I think by then it was probably clear that transducin and Gs were members of a family. Nonetheless, nobody was expecting the βreceptor and rhodopsin to look alike, it was only later, after the full sequence emerged that these homologies became clear. But in the early going I thought we were describing the very first … they were so generous.
Was it with great pleasure that you realized that you were suddenly opening up this super family, or was it in fact a sense of oh, other people knew this already, other people could have tweaked this?
Robert J. Lefkowitz: Shortly after we reported our clone, about four months later, Elliott Ross, Dallas, reported on another, the β1–adrenergic receptor, from a turkey, and it looked very similar. Then /- – -/ Anouma, a little bit later, reported on two muscarinic receptors. Very quickly, within a year or less, we had those, and then we, Brian, cloned the α2–adrenergic receptor again, within about a year based on protein sequence that we had. Very quickly it was filling out that there was this family. I think in the moment we cloned the β2 I think it was a Heureka moment, but I don’t think any of us … and we /- – -/ right enough for a paper maybe they are all going to look like this, but I don’t think any of us really conceived just how large and diverse this family was going to be. And certainly of course the olfactory receptors which came four, five years later doubled the number of receptors right on the spot. It’s like all discoveries – many discoveries – you don’t fully appreciate the significance in the moment, it becomes clearer and clearer and clearer over the years.
Your lab continued to discover things about the structure and function of GPCRs, or mass, so to speak, there were lots of discoveries pouring out. Meanwhile you then moved away, went to Stanford and began this quest. What you eventually produced was the high-resolution structure of a GCPR with ligand and G protein attached, there was the whole kit and kaboodle. I remember in 2004 you commented, in an article that we asked you to write, you thought you might be a year or two away from the structure and I guess the high-resolution structures. It seemed to take longer than you thought it might. It must have been difficult.
Brian Kobilka: Yes, it was difficult. In 2004 I think we were starting to get crystals so I felt that … I am not sure I said that we would get it, I said somebody would get it. There were of course a lot of rumours.
Robert J. Lefkowitz: You were telling me, I remember, there was a rumour that so and so had it. You were quite nervous about it.
Brian Kobilka: There were some really detailed rumours which I don’t know how they ever originated but … I knew that we had succeeded, and other individuals were telling me that they had crystals, I think it was the logical assumption that it would happen sooner or … but it took much longer than I thought.
It was a good sign at that point that you were thinking about it harder than other people, at least as hard as anybody else was, because the question I think we asked was ‘When will the structure come and what needs to be done in order to get there?’ We asked 20 people to answer that and they wrote back this much. You wrote about this much, so you obviously had a lot of thoughts.
Brian Kobilka: I had been working on this project for a long time, not just crystallography but trying to understand the protein using other approaches, particularly by biochemical and biophysical approaches, these were much lower resolutions. Particularly fluorescence spectroscopy really told us a lot about the protein, how it behaved, and I think in many respects that experience, with these different approaches, told us a lot about what we probably needed to do to overcome the obstacles we were having with getting the high-quality crystals, ultimately informed us about the different approaches that ultimately succeeded.
One other thing that struck me at the time, this was an article that was written for one of the Nature journals, that you said this in, you were very giving with your suggestions, you seemed to be revealing quite a lot about the way you were thinking in the answers you gave, and again, it speaks to the idea of being a collaborative person rather than a secretive person.
Brian Kobilka: I hope that’s true. Of course, I wanted to be the first and I probably wasn’t completely revealing …
Robert J. Lefkowitz: It is interesting when I think back at the situation Brian found himself in, I guess about 2006 or -07, when it was clear the field was converging on a crystal structure and there were several players and nobody knew who would get there first, but let’s go back in time to 1985-86. As a very young fellow he was actually put in a very similar position because we were in direct competition with probably several, but we knew about one. Early on, they were ahead of us, but then, because of a bunch of circumstances, we leaped from the whole thing, it happened very fast for us when it finally happened. But it was a similar kind of deal with a lot of pressure, intense competition – who is going to get there first? He basically had had that experience once before, at the very beginning of his career, and now here he was 25 years later, in the same position. And he and I talked, I tried to advise him as best I could, I wasn’t involved in the science of course, an older head, just as I was to tell people that the key to Brian’s success is that whenever it gets important decisions to make, he discusses them with me – and then does the opposite, and this has led to a great deal of success on his part.
Everybody needs a sounding board; you obviously have an appetite for these high-pressure situations. We don’t have very long left, but I would like to just touch very briefly on the medical aspects. As I said in the beginning, about 50% of medicines acts through GCPRs, but there are a lot of off target effects and side effects. Would you like to say how the work that you do has impacted, or will impact, the development in medicines?
Robert J. Lefkowitz: I think that in particular the recent work that both Brian and I have been doing – totally different kinds of work – each in their own way has implications for potentially developing more specific medications, by which we mean medications which have less side effects. If you look back over the history of pharmacology at least during the 40 years that I have been involved, there have been several advances that have helped us to … by “us” I mean others, I mean the drug /- – -/, the tailor GPCR targeted drugs with less side effects. The first development was the elucidation of previously unknown receptor sub-types. The cloning revolution changed everything. When I started my career I think there were three adrenergic receptors and then early on, I guess around the time in the early med-seventies a fourth was discovered. By the time we got done with our cloning we had eight and then a ninth was added. There was one dopamine receptor, it went to five; there was one muscarinic, it went to five; there were one or two or three or – I forget – tone receptors that went to 15. With the advent of these greater and greater receptor subtype you could get more and more specific actions because you didn’t have to get the off-target effects from a different subtype. But now I think there may be even other ways in which we can get greater specificity.
One of the things I’ve worked on during the past decade has been the fact that in addition to signaling to the inside of cells through G-proteins the receptors can also signal through a different molecule called β-arrestin. This is a molecule that we discovered about more than 20 years ago as a key part of the mechanism which turns the receptors off, it turns them off with respective G-protein signaling but at the same time, we’ve only come to appreciate recently, serves as an alternate signaling mechanism. Now it turns out that you can design drugs which will activate signaling either through the G-protein or the /- – -/ through the same receptor. For some drugs it turns out that the desired effect through that drug actually is being mediated through G-proteins, but some of the side effects are being mediated through β-arrestin signaling or vice versa. If you had a drug which can target one or the other mechanism you may be able to get a few side effects, in fact there are several examples of such compounds which are now on early phase clinical trials. So that may be an example of how my work in recent years may have implications for getting even more specific drugs with less side effects than we’ve had.
And as for the crystal structure?
Brian Kobilka: I think there are two ways that we might facilitate the development of more selective drugs. One is as we learn more and more about the binding pockets particularly how related receptors are so similar to each other in terms of /- – -/ assets from the binding pocket. We’re discovering that just outside of the binding pocket there’s greater diversity that could be sampled and in some drugs do sample this, for example it’s a structure that we recently obtained that hasn’t been published yet, it’s a drug called /- – -/ which is used to treat asthma. It’s extraordinarily selective for the β2 over the β1 and it is partly because it extends out of the, what we call /- – -/ pocket into more of the /- – -/ surface samples between β1 and β2. I think that’s an opportunity for the structures will give us an opportunity to actually design drugs that might be more selective. The other is to take advantage of unconventional binding pockets. First of all there are also allosteric binding pockets that are for example the most clinic receptors are well-known. There may be other druggable surfaces on the receptor including surfaces on the inside of the receptor that we might explore, that will also have greater structural differences from even close related receptors, say for β1 and β2. Those are a couple of opportunities to develop more selective drugs.
So for the first time it is really possible to use the structure to do structure aided drug design?
Brian Kobilka: Yes, and I think a colleague of ours, Brian Shoichet, has really been at the fore front of using computational /- – -/ and shown, as he likes to say, that GCPRs is really great binding pockets for /- – -/ screening.
Just to wind up, something that happened on that day in October when you got the call was that you were both converted into chemists, because you were awarded the Nobel Prize in Chemistry. I guess if you’re doing crystallography that is fine, but in your case, I imagine it was a bit of a surprise to be awarded the Chemistry Prize.
Robert J. Lefkowitz: It was indeed a big surprise and in fact I was telling somebody recently that I only succeeded in telling two of my five children personally about the prize because of Facebook, it spreads very rapidly, but one of my sons had learnt about this almost immediately on Facebook. He lives in New York and he called his sister, out in California, so it is 3 o’clock in the morning her time, all excited he says “Dad won the Nobel Prize” – this was Wednesday morning – and she merely says “No, he didn’t”. She says “You’re mistaken”. “No no, I just heard, he won.” She said “No no, you heard the prize was announced on Monday, in Medicine, and he didn’t get it. He said “No, he got it in Chemistry.” “Chemistry? What’s that all about?” It is interesting. In my career I published hundreds and hundreds of papers, but the single publication vehicle in which I’ve published the overwhelming majority of my work is The Journal of Biological Chemistry, it’s the single journal by far, there’s not even a closed section. In that sense, if there is a term that could be applied to my work I guess it is biochemistry or biological chemistry, which is a branch of chemistry. We have had some fun with the fact that we are now chemists.
I was going to ask the last question, does it matter how it is labelled, does it matter whether it is chemistry or biochemistry?
Robert J. Lefkowitz: I think in a sense not. I think what it shows is just how the interface between chemistry and biology and medicine … I have been called a lot of things in my time, not all pleasant, but I can handle chemist. Over the years, people have always gone: Well Bob, you’ll win the Nobel Prize someday. It was nice to hear although it didn’t seem to be happening, but if it happened, I always assumed it would be in medicine and not in chemistry. I think I have Brian to thank for that.
Brian Kobilka: I think I might even take a little at it to like in being awarded the chemistry prize. I think medicine and physiology are wonderful as well, but I’ve sort of been a chemist and want to be for the years.
It was a great pleasure to speak to you both. Thank you very much indeed. It just remains for me to wish you a wonderful Nobel Week in Stockholm.
Did you find any typos in this text? We would appreciate your assistance in identifying any errors and to let us know. Thank you for taking the time to report the errors by sending us an e-mail.