Enrico Gratton

Zierler:

This is David Zierler, oral historian for the American Institute of Physics. It is September 30th, 2020. I'm so glad to be here with Professor Enrico Gratton. Enrico, thank you so much for joining me today.

Gratton:

OK. Pleasure is mine.

Zierler:

OK. So, to start, please tell me your title and institutional affiliation.

Gratton:

Well, I am a professor of Biomedical Engineering at the University of California, Irvine.

Zierler:

And are there any other appointments that you have in terms of laboratories that you run or collaborations that you're in?

Gratton:

Yes. I have a joint appointment with the biology department, with physics, and I collaborate with people in almost every department at UCI. And I spent most of my life in Urbana, Illinois, where I was there for 32 years, and where I met Kandice Tanner among the other things, and many other people, of course. And then I retired from Illinois, and I moved to California because all my family at that time was in California. Now they have left, but anyway, in these years it was one of the reasons to move, not because I didn't like Urbana.

Zierler:

Well, Enrico, let's take it all the way back to the beginning, to Italy. First, let's start with your parents. Tell me a little bit about them and where they are from.

Gratton:

OK. So my father, Livio Gratton, he was a physicist, too, in astrophysics, and he was one of the few people who were students of Enrico Fermi.

Zierler:

Uh-huh.

Gratton:

It was because of my father affiliation with Enrico Fermi I believe, my name is , Enrico...

Zierler:

Oh, yeah? You're named after Fermi?

Gratton:

Yeah. Yes, I am. So my father had a big numerous family. That's my older brother were named after of the grandparents [?], I was the first one who was out of the list. I was the fourth in the family. My two oldest brothers were physicists and they spent most of their time in South America, in Argentina, where also my father spent many year of his life. And then I am a physicist too and then two other in my family are physicists. So I would say that it's a family of physicists.

Zierler:

The family business is physics.

Gratton:

Yeah.

Zierler:

Where are your parents from, Enrico?

Gratton:

Well, my father was from Trieste, born in Trieste, so in North Italy where the name comes, Gratton. And it's a common name in that part of the region. And my father started his schooling with the Austrian system, Austria was in charge of that part of Italy then, and then they lost that part of Italy during World War I.

And then, after World War II, my father moved to Argentina because it was one of the most advanced countries and many people were leaving Europe, and many people didn’t want to come to United States because of the McCarthyism and many other things involving the atomic bomb. And so many physicists went to work in South America. And then, at that time, astronomy was very advanced in Argentina. As it is today with the large optical telescope in Chile and Argentina was also advanced in astrophysics, and my father was in astrophysics.

And then, in 1961, my father returned to Italy. He got a professorship at the University of Bologna in Italy first and then moved to Rome, where we lived. So I went to the University in Rome and then, from there, well, I moved. I had a postdoctorate with Gregorio Weber in Urbana, Illinois. And then they offered me a position in Physics, where I spent most of my life. My name is associated with the Laboratory for Fluorescence Dynamics, which is a grant from NIH which started in 1986. Well, I applied in 1985 and started in 1986, and they still award me this grant until today. The grant will finish in 2021 because the NIH put the limit maximum of 15 years after I moved to California . And, fortunately, they reset the clock when I moved to California.

Zierler:

[laugh]

Gratton:

So we get 15 years of the grant at UCI. And now there is a possibility to reapply for the grant. It's a different kind of grant. It's to maintain a user facility, to maintain collaborations and other things, so it's not for research anymore. So they believe that research at some point is finished. I don't believe so, but, anyway, this is their opinion. And so I applied for continuation of collaborative work, and I don't know if I will get it or not. But if I will get that, it will be for another five years. So if I get it, it will be a total at least of 40 years of the same grant, which is very, very unusual, I believe.

Zierler:

[laugh] Enrico, where did you grow up? Did you grow up in Italy?

Gratton:

Well, I was born in Italy, and when I was 2 years old, my family moved to Argentina.

Zierler:

Yeah.

Gratton:

So I was in Argentina until 1961, so for 12 years, approximately. So I did go to elementary school and part of the high school in Argentina.

Zierler:

And what was your first language, was it Italian or Spanish?

Gratton:

Well, in the family, we would talk in Italian, whatever is Italian because you only talk with the family using always the same words. But my mother language is Spanish, so when I started school, I learned to read and write in Spanish, and I still do. After many years I have many people from South America in my lab and I maintain my collaboration with South America very much, so I have many of the student postdocs and the people in the lab from South America. In the lab I will speak English, of course, Spanish, and Italian.

Zierler:

And what kind of school did you go to growing up in Argentina?

Gratton:

Well, the elementary school and then I went to the middle school and then started the high school.

Zierler:

These were public schools or private schools?

Gratton:

No, only public schools. Argentina had a very good system of schools in education, and still has. It is a country where education is free. It's free for everybody, so you can go to any public school and it's free, which is a very unusual thing. I think it's one of the few countries in the world where that happens, but that gives a chance to everybody. So you see, still, even if it's free, it's a very good system. And people learn physics or biology, and they have really very, very high-level people.

Zierler:

When you were growing up did you visit Italy? Did you have family in Italy that your family would visit?

Gratton:

Yes, but I would never visit them. My father was going back and forth as a scientist, but I never went back to Europe. So when I arrived to Europe, it was a shock in some ways to see a different country coming from Argentina, at that time, You have to think that Argentina was a rich country. They then, during the military junta, they went down, down in essentially power and they sold most of their resources to the foreigner, and then Argentina had become the country that it is now.

So it's a very nice country, the terrorism or whatever is very, very low. You can travel everywhere free. You can rent a car and travel everywhere you want. It's not dangerous from that point of view at all, at least if you know the language. But, yes, Italy has no comparison with the science which is done in the United States or the science which is done in Europe. But it has a very, very good education system.

Zierler:

And do you feel, Enrico, that you developed an interest in science on your own or, just being in your family, physics was something that was just very natural to you?

Gratton:

Well, yes and no. So my father never wanted for us to talk about physics. He never talked about physics during lunch or dinner or when we were together. I don't know exactly the reason for that, but he believed that there were many other things that were very interesting, like archeology, geology, history, literature, and many other subjects, and he would prefer to talk about those subjects rather than talk about physics. So I never talked physics with my brothers or sisters.

Zierler:

When did you become interested in physics on your own?

Gratton:

Well, essentially, I started in Italy, I was 15, 16 years old and my father bought for me or I bought, I don't remember exactly, a series of books that had to do with biophysics. Those years—we're talking about the '60s—when people were discovering the genetic code, so were very interesting. I remember I was going to a lab with a professor, and it was a very important professor in biophysics in Italy, and he would say, "Well, I can't believe in the planet there is only one genetic code. Why it has to be that one?" And so those were the years where people were looking for a variant of the genetic code, and we know now that that does not exist. Actually, we don't have a clear explanation for that, but we know that this is the case. And so this is one thing.

Another book I remember very important in my career and in my knowledge is a book that was entitled Aging, Cancer, and Immunology, which today I wish I still had that book because it has become such an important subject. So, at that time—I'm talking about the '60s—people knew that aging, immunology, and cancer were in some way related, and you can find those relations and you can find it today probably. The only case in which you can really cure cancer is through immunology and through a reaction of our immune system. And immunology is very important for many other things. So my information started there.

And then I did a thesis in Italy at the University of Rome, and it was about the status of the DNA molecule, condensation, chromosomes, and all these started to become very important later on. And then I learned a lot of electronics, a lot of optics, which were very substantial for my development as a scientist.

Zierler:

Who was your graduate advisor at the University of Rome?

Gratton:

Well, he's dead now, and it was Professor Mario Ageno. And during the '68 uprising in Europe, as in the United States, there were really—let us say a revolution in the universities, and then most of the Red Brigade's movement, which probably you are aware of, were people in the physics department in the University of Rome is where they started. And so we had many meetings with the Red Brigades, with people in the Red Brigades. I was never associated with the Red Brigades, but many of my friends were killed because they were part of the Red Brigades. By definition it's terrorism, and those were students in physics like me. But I was away in some way. I never got involved, I never wanted to be involved in politics, and that remains still today. I don't want to be involved in anything that has to do with politics, but I saw my frimds die. And most of my friends died because the police killed them.

Zierler:

Enrico, why did you want to go to Italy for your education? Why not stay in Argentina?

Gratton:

Well, that is a good question. So, in my family, we are 11 and I am number 4, so the first three brothers remained in Argentina, also because they have girlfriends and so on. So I was the first one which was, let's say, not really with the root of that kind, at least, of a girl or whatever that will have some power on mw, I believe. But I was the first one who really embraced Italy in a full way and moved to Italy. But my brothers, my older brothers, some returned to Italy but then they went back to Argentina. We always considered—I still consider Argentina to be part of my country.

Zierler:

And what did you do after your dissertation? What was your postdoctoral research?

Gratton:

Well, I started to work in a company which was a very strange company because it was a company where you can do research. And it was a part of the Italian oil company and so they have essentially an incredible amount of money. The money was never a problem. And so they were able to pay people to have them in an adjunct position, so we have a corridor that I remember in the building where every door had the name of a Nobel prize winner. They would spend a few weeks a year at the lab.. Everything was paid by the oil and the sheiks and they enjoyed. So they were coming to Italy and talking with us, and that certainly influenced me a lot.

Zierler:

What was the work you were doing?

Gratton:

We were talking about a new field actually which is protein dynamics, which now is a very big field. And so the idea was that a protein or an enzyme was able to correlate—fluctuations from the surrounding. So the important question was what happens in the water surrounding a protein, and that the enzyme was getting some sort of energy. So it was like an enzyme was a machine to do correlations. This is where I started.

And so I remember that then there were reasons to leave Italy or to leave the company, and the reasons were related to an oil crisis, so there was the first oil crisis of the Suez Canal. And then they decided that what we were doing on enzymes was not important anymore and we have to work on the energy. And, at that time, still they were building nuclear power plants in different parts in Italy and Europe, of course, in all Europe, and they wanted for me to work on nuclear reactors. And then, that is the reason I decided to go to Urbana. You say, well, what does nuclear power have to do with Urbana? Nothing.

Zierler:

[laugh]

Gratton:

But I remember I submitted a proposal at that time, in which I said through photochemistry you can done by infrared at low temperature and you could excite some particular vibration of the uranium-238 which is different than 235, and by this change set up a chemical reaction. A chemical reaction that would enhance one isotope and purify the system like they are doing today, when they use a centrifuge because it's cheaper, but that is another alternative way.

And so I looked in their directory and that there was a professor, Gregorio Weber, who was a famous professor, one of the few people working in protein dynamics. And then I wrote to him, actually, invited him in Italy, and then I talked to him, I said, "Can I come to be a postdoc with you?" And he said, "Yes." And that settled it.

So I went to Urbana and I was assigned to a project which then, more or less, it was for all my life. I've worked in one way or the other in this project, which is to build an instrument to be able to see the fluctuation in proteins. And then, of course, I was involved in that, and in companies and other things. I was involved in that all my life.

But when I started with NIH, I left everything, I left the company. I left everything because I didn't want to have any conflict of interest. I remember, I was receiving grants for review and people were asking to buy my instruments, so that's clearly a conflict. And I said, I don't want to have that. And so I give the company to somebody else who is still running the company, and it was a very good idea. So I have no—any sort of interest in the company.

Zierler:

Your first appointment at Urbana-Champaign was in the biochemistry department.

Gratton:

Yes, as a postdoc. And then, during that time, I knew people in physics, because I was a physicist, and I felt that it was their work in protein dynamics, too, and then other people, too, Peter Debrunner and d Hans Frauenfelder. And I was going there. They invited me for giving talks and giving other lectures, and then, after I give a talk there, they simply said, "Do you want to have an assistant professor position in physics?" I said, "Oh, maybe." So I didn't apply. It was just an interview was based on the talk I gave.

And, at that time, having people working in this area probably was very, very rare. But, at that time, two of the Nobel Prizes winners were given a course in biophysics in the physics department. And, of course, I went to their lectures and become friends with them and they wrote letter to support my application. So I was very luck, let us say. But I didn't apply to it never, so I was simply invited to get this position.

Zierler:

Now, did you create the Laboratory for Fluorescence Dynamics, or that was—

Gratton:

Yes.

Zierler:

—before you?

Gratton:

No, no, no. There was nothing before me in physics about microscopy. I was the one bringing fluorescence and bringing instrumentation and so on. I had several studies and at that time I needed, so biophysics today, a wet lab. A wet lab means a lab where you have water, where you can prepare your samples. And I was talking with the head of the department of what I needed because they invited me to have an assistant professor position, but they never discussed about the startup I needed. And then I said, "I need a wet lab." And then they said, "What is a wet lab?" I said, "A wet lab is a place where you have water, you prepare your sample." And then the guy looked at me and said, "Physicists don't play with water." [laugh]

Zierler:

[laugh]

Gratton:

And he didn't pay for anything, so I had to have a grant just to have a wet lab. So, anyway, well, different times. Today, of course, when we talk with the young people coming in, everybody knows what they need as a starting lab.

Zierler:

Now, did NIH, did they support the LFD from the beginning?

Gratton:

Yes. Yes. So I had a grant with NIH to work on protein compressibility and other things, but that then expired. Then I applied for the LFD resource. A friend of mine who was working actually at that time in ’85 with the green fluorescent protein, without knowing what it was, but I was able to help him. and so he came in my lab and we did the measurement with that strange protein, which nobody knew what the color was coming from.

And then this person becomes an important person, at NIH, he had some sort of council position and he said, "Why don't you apply for this new kind of grant?" At that time, this type of grant was new, which it's called the P41 Resource. And I applied and I got the funding. Today you would write the specific aim and write all the things you wanted to do. I just make a list of 1 to 11, I remember—still I have a copy of the grant—1 to 11, and this is what I will do, and I did it. And the comments of the people were, if you are able to do those things, better you get the money. And actually, at that time, I already had done all of it.

Zierler:

When did you first meet William Mantulin?

Gratton:

Bill Mantulin was a student with Gregorio Weber when I was a postdoc with Gregorio Weber, so I met him in his lab, and then he went to Texas for a postdoc. And then I needed somebody who will be the co-director. And then I called him, because he was working in fluorescence with Gregorio Weber, and I knew that he was not in the position to continue in Texas. So he moved to Illinois and started to work with me, and certainly has been an extremely important person, both for me and for my career.

Zierler:

Enrico, what were some of the original research questions that you were asking that you saw the LFD laboratory as necessary to answer those questions?

Gratton:

Well, I told you when I went to work with Gregorio Weber, the idea was to work on protein dynamics. But then, in Gregorio's lab, I learned that there is dynamics in cells, dynamics in membranes, dynamics in interaction, so the idea, which is the basic idea we developed at that time, was to build a FLIM instrument. FLIM means a fluorescent lifetime imaging microscopy. So I went from solution measurements to a microscope that will be able to do image but on the large field, And the large field was supposed to be a cell, so looking at the different parts of the cell, how the different parts of the cell interact with each other and so on.

And that was something so new and so unbelievable for that time. So today you can buy a FLIM microscope, but at that time it was new. And then, after that, we learned how to do STED microscopy, how to do many other things. So it was really the first thing that I submitted. They were the seed of all the things that I developed for many, many years.

Zierler:

Were there any specific clinical or therapeutic research programs that were motivating you?

Gratton:

Yes. But it was not me—I am not a medical doctor, OK. But I was collaborating with people who needed a measurement on organs, kidney and so on, and I am still collaborating with those people. And one person in particular was Dr. Moshe Levi, who now is a dean of research at Georgetown University. But he was also a bioengineer, so he had the language. He knew what was possible to do. And then he did his career on the basis of this collaboration. I did my career on the basis of this collaboration. It was a very important subject, and still we continue. We continue to work together.

So the kidney was a particularly important thing, not because it was important or, better than the brain or whatever, but simply because he was an expert. And, of course, there are a lot of diseases of the kidney, including diabetic, fibrosis and other things, that we could use fluorescence as a diagnostic tool to see if a person has this kind of disease or not. And today it is still very valuable.

Zierler:

How much teaching did you do when you were running the lab? Did you have expectations to teach undergraduate classes?

Gratton:

Oh, I was teaching undergraduates. So I was teaching physics 101, 102 at UIUC. But at that time, I have to repeat the same lecture three times because I have more than 1000 students in those classes. Fine, I said, I don't know, that's not bad looking in retrospect, it didn't make any difference, actually. I taught courses like electronics, optics that actually help me a lot in my career. Teaching is a very good thing. And then, teaching was giving me access to students and so on, so I had really the best students.

Zierler:

And any graduate students you had, they would have been working at LFD?

Gratton:

Yeah. Yes. And, at that time, to be a graduate student, you will get fully paid, so you don't have to pay out of your grant. So I will have, like, seven, eight, nine students in parallel, so all of them simultaneously. And certainly there was work for everyone.

Zierler:

Enrico, what were some of your most significant patents when you were at Urbana-Champaign?

Gratton:

Well, the major patent is the patent to do FLIM, which took a lot of time to be recognized and was given only—which is valued in Europe, in various countries—it was given in 2018, although I applied for the patent more than 20 years before. But it was recognized only in 2018, which, in some ways, was a big favor because a patent lasts 17 years, so otherwise if we had been [?] recognized immediately I would have no chance—well, not—to start a company. I don't have interest in that. But it took a lot of time.

And then, another patent we had which actually has a lot of influence in diseases in kidney and so on is a patent to measure bacteria in blood. Sepsis, as you know, is a disease which, apart now from COVID-19, kills more people than any other disease, more than cancer, more than anything else. And since there is no cure, but if you know very much in advance, you know the kind of bacteria, you can try to kill it with antibiotics and other things. When you realize that the disease is in advanced state, it's too late. So current methods—of course exist, you can get a drop of blood and do petri dish culture and see if there are bacteria or not in that blood, but it takes four or five days to grow the bacteria colonies and the patient is dead after a few days. So we were interested in something that can be done that it almost instantaneously, and instantaneous means 20 minutes. And that is a patent which is also valid in all countries. And it's all through the University of Illinois because I was working at the time at the University of Illinois.

All my patents are patents through the University of Illinois up to 2005. For three years—you have to, if you have an invention—after I move out, still will belong to University of Illinois. So that's the standard contract. But then I continued to have patents and so maybe now I have 24, 25 different patents. Most of them are about devices and methods in fluorescence spectroscopy, a kind of fluorescence and. diagnostic.

Zierler:

Given how long NIH has supported your work, I wonder if you've ever had opportunity to collaborate with NIH personnel? In other words, have people from Bethesda, have they come out to Illinois or later on California?

Gratton:

Yes.

Zierler:

Have you worked with them directly?

Gratton:

Yes, of course, NIH is the parent institute and I always got the money from NIH NIGMS, which is general medicine. But cancer or diabetes or infectious diseases are other institute. And so, yes, I still have today people coming from different institutes, not so much NIH GMS but there's nothing that prevents people from being part or needed the technologies developed at the LFD. So we have unique instrumentation, so if they need that instrumentation, they are coming, and we are working with them.

Zierler:

And what is unique about your instrumentation that would compel them to come all the way to you?

Gratton:

Well, all our microscopes, which is 17, 18 different microscope at the LFDs, can do FLIM, and that is unique. So there are a few microscopes that can do FLIM in the country. We have 17, 18 just in the one lab, so if one isn't working for what the person needs to do, we go to the next one. And so the LFD it's really—we view that to be a tremendous asset. And, at some point, that will finish, and I have not found yet a person who is willing to continue it because it's a lot of work, maintaining a resource is a lot of work. But if you're funding is stable, it gives you a more research time. But now I think they're making a rule that is not stable anymore, so you can have one of those resources for 15 years maximum.

Zierler:

Enrico, I'm curious of your decision to retire from Illinois and start up a new in California; what were your decisions on doing that?

Gratton:

As I said it was family because, at that point, when I have three kids and all of them were in California, and then that was my attraction. So I said, what am I doing in Illinois if I can be in California? So I come for a sabbatical in California, I talk with people, and they said, oh, yes, it would be easy to have you here. It was easy, and so I moved, and I was able to move the entire lab. Because if you buy all your equipment on grants and the grant moves, you can bring all the equipment with you. So we packed everything in trucks, make a caravan like the ancient people would do

Zierler:

[laugh]

Gratton:

—and we moved from Illinois to California. Lots of people moved, too.

Zierler:

So you never would've made the move without your equipment, that was part of the deal?

Gratton:

Yeah. Well, it was part of the deal. In Illinois they said they didn't want even to spend the money for me to have a wet lab, so at the end, I was able to bring everything with me.

Zierler:

Enrico, did you take the opportunity in setting up the new lab to look for new equipment?

Gratton:

Yes, very much. Because, for example, some kind of microscopy like STED, light sheet microscopy and so on were developed at the time when I moved the lab. And so we had a chance to start new technologies, a new thing, which today is very much used. And with cameras for nanosecond FLIM resolution. I think I'm the only one in the United States having it yet. It's really unique. It's the kind of thing—if you want to do a measurement, you need those things, you have to come to my lab.

Zierler:

[laugh]

Gratton:

Which was pretty nice. Coming to California is very nice, and today it's 85 degrees, 89 outside, actually, at this moment, so it's sunny and beautiful in South California. In the North they have fires and smoke.

Zierler:

Right. On that point, Enrico, I wonder if you can talk a little bit about some of the technological advances in the instrumentation that have really helped to advance your research over the course of your career?

Gratton:

Well, first of all, as I said, one of my original interests was two do research in dynamics’ in cells , and that was something that maybe we were the first to focus on this area. And now they do, but it's not really the same thing. So fluctuation Spectroscopy started in physics in Cornell and was developed in the '70s. But then it was a dead field, so only a few people like me were continuing to work. And as soon as we developed a microscope where we can see single molecules to do fluctuations, we immediately realized that we can do images of fluctuations. And I think we are still among the few labs that can do that.

And so between 2005 and 2010 I had the only lab that was developing those things. And now we know things have been disseminated into other places, but still it's the same technique that I worked out. There are labs in Singapore and China and other people have developed something in this area, but still the basic idea comes from my lab.

Zierler:

What were the origins for Globals Software?

Gratton:

Well, that was different. So the Globals Software was a software used to analyze the decay at every pixel of an image of a complex system. And that was developed in parallel by my lab UIUC which is—we called it Globals, and by Joe Beechem, who was a postdoc with me. He is now the head of the NanoString, by the way, which is a big company. And so he developed all the time domain methods and I developed all the frequency-domain part. We were working really day by day and comparing the results.

And so all these thing has to do with frequency domain, which in images is much easier than anything else that was available in my lab. So one of the big advances was done using the phasor method, which is just a method. The phasor method for electrical circuits was known more than 100 years ago, way before I was born. But the use in spectroscopy images is very recent. And still some people believe that there is no advantage of using it. Of course, they miss the point, but fine, OK.

Zierler:

When you came out to California, Enrico, what were some opportunities that you had for new collaborations?

Gratton:

Well, biology is very strong in South California in general, with San Diego, Irvine, UCLA, and that was lacking in Illinois. It was lacking at least for me very much in Urbana. So now Urbana has available much more biology, but at that time, in 2004 and 2005, biologists were leaving the place and going to other places because there was really not critical mass. Now it's different. Other universities, maybe in Chicago or in Madison, Wisconsin, and other places where you have a critical mass and they have become very important. But in Urbana I was very isolated, so there was not medical school, so you need really like a hospital to have a clinical center. But clinical medical biological center, and that was lacking at that time. Now they have a medical school, but the medical school wasn't existent at that time.

Zierler:

When did you meet Michelle Digman?

Gratton:

Michelle Digman was working with a professor in the University of Illinois at Chicago. It's also part of the University of Illinois’ at Chicago campus. And then she came to work on some of the techniques of fluctuation, and then she worked for two to three years to finish her PhD thesis. And then, at that time, I needed a person, so she asked me, "Do you have a position of postdoc?" I said, "Yes, I do. Do you want to start tomorrow?"

Zierler:

[laugh]

Gratton:

And that was the way—and then, of course, she brought in a kind of knowledge which was lacking in my lab, which is cell works —how to have cell cultures, cell transfection . At that point, I was ready to apply to the fluctuation methods to biological systems, but I didn't have the proper knowledge in the lab; outside yes, but not in the lab. And she brought that stuff in, and we published just many, many papers together. And now she's an associate professor. She got tenure and is an associate professor here in Irvine. She has her own collaboration, her own stuff.

Zierler:

Your appointment is in the department of biomedical engineering, and so I'm curious—

Gratton:

Yes.

Zierler:

—what new opportunities either for teaching or collaboration that this new kind of department has offered you?

Gratton:

Well, first of all, I am also adjunct position with other departments, and mainly in biological science, which is just in front of us, the building just in front. And I have, with some people, have collaboration with very high-level scientists, another grant with them which is a was a P50 grant, to work for five years on using fluctuation technologies for problems in biology. And now that grant has finished, too, because that had a limit, but now he has a new one which is a U54 grant. And we continue to collaborate.

The recent problem that they have, as you know, probably, gene expression or protein expression in single cells, itself is a very, very important problem, if you believe that everything can be reduced to gene expression. But it's not easy to do. And on tissue, on real tissue, not on cells, single cell is OK, but on real tissue you will need different technologies. You don't have an absolute expression in every cell of a tissue. So I say, well, why don't you use FLIM, because FLIM will delete all to the cellular background. And so we have been collaborating with that, and, yes, we have a new technique and this seems to work.

Because today if you want many genes to get an answer and you have to do many measurements on the same cell. And then you have a problem of how to maintain the image to be measured. How do you know that it's the same site or not? But we do it with only one pass, so it's only one wash and that seems to work. And that is again, coming from a different technology in a field which is crowded because everybody is working in the genomic field. It's not just washing and imaging; it's just using the spectroscopy in a way that is not used today.

Zierler:

Enrico, I'm curious if you've ever worked with pharmaceutical companies in drug development?

Gratton:

Well, I did some work, for example, when I was in Illinois with Johnson & Johnson and othesr—but the work was really boring, boring things. So I remember once they invited for a seminar at Johnson & Johnson, and after the seminar, they said, "Do you want to work on this project?" I said, "No." They said, "We would pay you a lot." I say, "No." I worked for many years with Abbott out in Chicago and continue to work. But I think that they are really very, very boring things. Essentially, it's too boring for me. There's nothing new. So you bring to the market—of course, they do that and do it very well, and they become billionaires and so on, but it's nothing new. There are no intellectual discoveries. Everybody can do that.

Zierler:

I'm curious—there's so many different scientists that are working on this issue from so many different backgrounds—I'm curious if your research at all is relevant for therapies or vaccines related to coronavirus?

Gratton:

Well, yes and no. In general, I have some people from UCI Irvine came to me and said, "Can you do those measurements, because we don't know how to do it." Which is essentially a slide where you have all the antibodies that will bind and then, following the binding pattern, you will end up to know if this person or this drop of blood or sputum, whatever, will have the antibodies, the appropriate antibody.

And really, in one hour I showed them how to do—I just used a phone as a camera and it worked. And then they were absolutely amazed to see that they have been blocked for a lot of time because they didn't know that just using a simple phone you can do it, have enough sensitivity to do it. And then we got a grant for that and they went to a company here in Irvine who is developing this method. I don't know, but I'm not—it's very boring work. I don't know. It's something that I would not like to do anymore, that sort of thing.

Zierler:

So, Enrico, just to bring our conversation right up to the present day, what is some of the research that you've been involved with in recent years?

Gratton:

Well, for example, one thing I told to you is about gene expression and protein expression. But the gene expression, the genes, you don't know really what the genes do because of the way the gene and the proteins would get modified. And even if a protein is expressed, you don't know if that is—would have any effect or not.

So fluorescence has a possibility to look at other things, for example, how things will go in the nucleus or not, how the membrane will become more fluid or less, and how a cell will interact with other cells. So you have fluorescence markers than can do—you can observe all those things. So, in some way, instead of doing single cells, we are doing single cell but in a tissue, which gives you all the interaction and gives you, in some way, the result of the gene expression, the result of the expression, the result of—I suppose to look to one particular protein or one particular thing and then trying to figure out what the cell is doing.

If you see metabolic genes activated, of course, you have to express those genes, otherwise the metabolism will not change. But you can measure it directly yourself to see if a cell is metabolically active or not. And, of course, to be metabolically active you need to have the genes. But you can do that cell in the context, for example, of a tumor. But you cannot do it with genomics or other techniques that are used today.

So it, in some way, is to measure multiparameter; we say multiparameter, I mean hundreds of thousands different parameters, but in that tissue. And go almost the opposite of the single cell where you measure the tissue, but single cell in the tissue, which is different. And that cell, of course, has to express all the genes. But you are not interested in measuring them. You want to see the result of that. And that is the field in order to measure a thousand parameters at a time you need the technology.

And fluorescence can, in principle, have this power, but you need to know how to use, and there's no instrument, for example, today that can measure a thousand parameters. So we are building one, and maybe we will build two or three, and having collaboration and working with people for which that information is absolutely needed. But, you see, it's something nonexistent, so that is challenging because you don't know where you will end up. So it's a very different thing than working in a company that wants to test its target for drug or whatever is working or not. This is very diagnostic, and you can measure it in a simple way using instruments we ar developing now.

Zierler:

Enrico, I'd like to ask, for the last part of our conversation, some broad questions over the course of your career. First, what is understood in your field now that, when you were even a graduate student, really was not understood?

Gratton:

Well, clearly, as I said, I started when the DNA genetic code was known and now that is understood very well. If you look at the data, work on ribosomes, some other things occur, but still you need to understand very simple processes of how molecules will get into the nucleus, how they interact with the DNA, activate the gene, and that is not known other that on brad terms. Even the simple question of—so we know that the molecules will have to pass through nuclear pore complexes, but how they do? It is a motor, is not a motor? They clearly cannot go by diffusion because they are too large to go by diffusion.

But even such an elementary process which every eukaryotic cell has, is not known. And then, of course, interaction of the cell with viruses, which that is very, very important, is not known also. Well, we know that a virus will penetrate the cell and then make a thousand copies of itself but e we don’t know how that occurs. How it can activate all the mechanisms of gene expression and how to use the system that the cell has, or bacteria has that duplicates themselves at that speed without control. And today you know that essentially the entire world is in lockdown or whatever because we don't know how those things happen.

Zierler:

It does raise the question, given all of the advances and the technology and the understanding, what do you think it is going to take in order to move ahead with these very fundamental mysteries that we still don't understand?

Gratton:

Well, you need programs. And, for example, the HIV program which uses experiments, which uses a lot of billions of dollars every year, clearly was important to understand retroviruses and how the virus get in the cells—but essentially the disease is still there. And, yes, you know drugs can control the disease and so on, and but there is no way to fix it yet. And maybe someday we will need to fix it.

But AIDS is not the only virus that is important. But the COVID is having an influence in every country, and much more than anything else, as you know. But no money was used for the understanding of its function. In regard to money, for example, in the United States, most of the money went to companies, but not necessarily they will produce the basic knowledge to understand the process. Maybe they will figure it out, how to do a vaccine or something to protect the population, but from there to understand what is happening and to be able to get the next virus, because there will be a next virus, immediately, this is not known. And money goes to the company instead of going to research.

So, of course, you need the companies because university will not be able to do a product. That's of course. But not all the money to the company and nothing to the university. That's wrong.

Zierler:

Enrico, over the course of your career, from a cellular perspective, what have you learned about why people get sick?

Gratton:

Well, one cell maybe will not do very much, but one cell that goes bad and produce cancer that is an issue, why a cell will initiate cancer? Why a cell produce any of the genetic diseases? So it, in general has to do with the interaction of the cell with the rest of the surrounding. In that understanding is what very few methods that can do.

So just image in that tumor and figure it out. Well, that part is different than the other; why is it different? And I don't think there is enough knowledge of that. And there is not enough knowledge because people cannot measure enough parameters in a tissue. As I was saying before, if we can give to people a method to measure a hundred different things or a thousand, maybe they will start to have tools to understand why that cell behaves in that way and the other not. And then how that cell interacts with the immune cells and how the immune cell gets control or they don't get the control.

And so that kind of disease—of course, are well understood, but that kind of disease is what is making the life of the entire world population—we don't have it yet, but it clearly affects many, many, many, many billions of people. It's not a few people. And still, you spent the money on other things, in destroying the planet, for example, but without really spending in what is the health of people.

Zierler:

Would you say that your motivations, as far as they have therapeutic or clinical value, are more oriented towards elongating life or improving life?

Gratton:

Well, So if you can, let us say, cheat a tumor because you know how to activate the immune system to take care of—so it will go in every part of the body, well, not necessarily that will improve the life of a person, but certainly the person will not die or will not be so—just to know that you have a tumor it destroys the career or the life of a family of a person, then knowing that, yes, OK, you get it and you can fix it, that would change dramatically. But the disease is affecting everyone and today we are afraid of the COVID because simply we don't know how to control, actually. We know how to control but we don't want to control because it has enormous consequence on others, but that's another story.

Zierler:

When you say that immunotherapy is the only true cure for cancer, does that apply to all cancers or are there specific cancers you're thinking of?

Gratton:

Today have been applied with a lot of success to blood cancer, because blood is easy to get and cells are easy to control. But that has fixed the problem in many diseases that where absolutely deadly 20 years ago, today are not deadly anymore. That makes a difference for a lot of people, for a lot of kids, a lot of families.

So going back to what you asked, why you were interested in that, well, I was reading books at that time, people had some ideas, but the ideas were correlations. Yes, there is a correlation between aging, cancer, immunology, and other things, but today we start to understand what this correlation is coming from. And I said, well, I believe that in some cancers, so one when I was—even 20 years ago, 10 years ago, you have a skin cancer, it was deadly, but today it's not as deadly anymore. So you can control and you can fix many of those cancers. Not every one, but many can be fixed. But I think that that's an enormous success. So until we get everything understood it would be maybe many more years, but if we don't work, we will not get very far.

Zierler:

Enrico, in all of your decades studying human sickness, what have you learned about environmental factors and lifestyle choices that contribute to sickness?

Gratton:

Well, for example, what can help human sicknesses is—well, clearly, exercise helps you a lot. And exercise promotes the immune system, so if you do exercise and then you measure the cell of the immune system after you have done the exercise, you find a completely different pattern from the people who do exercise and people who don't. Well, that really tells you that the way you conduct your life changes dramatically your chances if the immune system is in good condition and you can fight diseases much better than in any other ways. Much better than with drugs, and that's much cheaper in some way. But, of course, that doesn't apply to everyone, but it applies to a large part of the population anyway.

Zierler:

I wonder if, at some point, you see disease as a method of evolution to control population?

Gratton:

Well, I'm not so sure I understand your question completely, but, clearly, people who have some disease will do everything to get rid of the disease.

Zierler:

Of course.

Gratton:

So, yes, it controls the population so if that is what you meant, yes, it's even today, but that was true over the centuries of civilization or the priests or whatever was always the most important person because he knew how to deal at least with some diseases. Not with everything, but with some diseases. And so the religion has an effect because the priest is the person who has the knowledge how to fix some people, Yes, indeed, he has enormous control. So if this is what you have in mind, absolutely, yes.

Zierler:

I guess what I'm asking is, disease is a part of life, so there's no such thing as a goal to cure all disease; that's not possible?

Gratton:

Not yet.

Zierler:

Not yet?

Gratton:

Not yet.

Zierler:

What do you have in mind to say, "not yet"? When might that be the reality?

Gratton:

Well, it's simply a question to see the progress, to see—if you plot the progress over 10 years, you see that there is a slope. We don't know if it will bend and will saturate, but still there is a slope. As you note, the average age of people—like me, I'm 75. I do everything. And if I look in my previous generation, people are not able to do and continue to be active. And then you say, why is that? Well, because I'm lucky. That's obvious at the beginning, but it's in some way also the lifestyle. I still run every morning at my age, but I was running faster when I was younger. But, still, I have not decreased that because I feel that that is good for me.

Of course, maybe for other people are unable to run, but that does not really change the average. Clearly, the life of the entire planet, except of some countries, the life length has increased very much. People at 80 years of age are—I will not say young because they're not young,___ but they can live by themselves very well.

Zierler:

Enrico, there's very much excitement over the possibility of quantum computing over the next five or ten years. I wonder if you've thought about when we might get to that point, what that exponential growth in computational power, what that might mean for the kind of research that you've been involved in?

Gratton:

Very much. So at the end the artificial intelligence methods used today are basic because the moment you can have the disease and the normal people and they'll say, which parameters are different? It's very difficult to see by eye [?]. You can see a person and measure the fever [?], yes, but it's very difficult to see by the eye, but the artificial intelligence method tells you the analysis of many parameters].

Now, if you need quantum computing, I am not so sure that you will need something like that for clinics, but certainly that will help do research. OK. We'll have more of the methods of AI that they are doing now, because of the method of neuronal network will benefit form faster and larger computers. But it was impossible to use some of the methods of AI. But tomorrow they could become possible. So, yes, absolutely, it's a necessary expansion, and the United States is lagging behind a lot because there is no industry yet using it.

Zierler:

I want to ask you, Enrico, for my last two questions, first a very broad question retrospective over the course of your career. Would you say—are you most proud of your contributions in basic science, in other words just simply discovering, or are you most proud of the way that your contributions in basic science have advanced human health?

Gratton:

Well, I'd say the second one. It's obvious. You are very proud when you go home and you say, oh, wow, I invented something new. But until you disseminate that, you make it available to others, you have done only a part of it. I don't know. It is certainly the dissemination which today is controlled by capital, so even if you have a good idea, that doesn't mean that you can apply it because you can tell it to a company and they will say, well, we have a different instrument that is making a lot of money; why we should change?

So it takes years, it takes many, many years—or taking new countries. You go in China and then those things are immediately accepted because they don't have the same control that we have here in the United States. But that's a different kind of thing, but certainly I'm much more proud when I look at people in, in Argentina, or in Chile, or in China, Thailand, wherever using the principle I developed. And I'm not jealous at all. That's very good. I would say that that is very important.

Zierler:

Enrico, you come from a physics background from your family and from your own training, and so I'd like to ask, as you primarily work in a biological field, what are some of the most important theories or concepts from physics that inform your research, they inform the way you see the world, inform the way you set up your research and the kinds of questions you ask?

Gratton:

Well, I will respond very personally to that. So I am a physicist but very, very, very early, at 17, 18, I learned to program. And then, probably that has been the single thing that makes my career different. So I never developed anything, but I am able to simulate or have a computer doing the experiment, and then I understand how it works because simply your brain cannot do everything, but for the computer is much easier.

And so I would say that that—I developed a virtual environment, everything that was working essentially inside the computer, and I remembered many ideas of how to do experiments, you program your computer when you get the answer you know how to do it. And that sort of knowledge which comes from physics but also comes from mathematics. It's not only the physics, it's really the preparation that you have in mathematics. You know how to do the method, and how to do the programming.

So I can tell you—to finish this thing and episode with my father—so I was a student. I was working with the convolution of Gaussians on spectroscopy, which in the '60s was something unique. And I remember we were in the same desk, but my father was in one side and I was sitting in the other. And I said, "Daddy, I have to tell you something that I learned how to do. I can resolve 3 gaussin a component in this Univac computer and it takes three hours." My father looked at me and said, "I do 16,000 components in less than a second." [laugh]

Zierler:

[laugh] Yeah.

Gratton:

And he was right because he used a different method and so whatever was taking for me three hours, he was because I was wrong. So I will never forget that I was so proud of what I did but it was just conventional it was not an invention

Zierler:

Yeah.

Gratton:

—and he said, "I do 16,000 in a second."

Zierler:

That stayed with you.

Gratton:

Yeah. OK. So that maybe is a single case. yes. My father had a lot of influence but just saying the sentences or...

Zierler:

Well, Enrico, for my last question, I want to ask you to look ahead. What are the things that you're most excited about, both personally, in terms of what you want to accomplish for the remainder of your career, and beyond your career in your field, what do you see as some of the most promising advances in the research and the technology that will continue answering the questions that have motivated you over the course of your career?

Gratton:

Clearly, the questions have changed very much, but the technology has also changed. But I continue to have postdocs and students working with me, and that is the best thing I can continue, simply to teach. I don't know, sometimes some students don't need a lot of teaching. They know better. But in some way to help them in starting their career. And I still do that every single day. It's mentoring, and until I can do that, I think that that would be still the best thing I can do.

Zierler:

Well, Enrico, on behalf of everybody, your success is everyone's success, so I want to wish you a lot of luck as you continue in your career.

Gratton:

Yeah. And important is to be healthy.

Zierler:

That's right. Always. Enrico, it's such a pleasure to spend this time with you. Thank you so much.

Gratton:

OK.