An interview with Carlos Bustamante

What inspired you to become a scientist? 

As a child I already had a passion for Medicine, and was led in this direction by my parents because my father was a medical doctor, and already at a young age I was convinced I would follow on my father’s footsteps. When I was 11 or 12 years old, the space race between the USA and the USSR was going on, and like many other children, I became passionate about rockets and aeronautics. In some way, I was also very interested in Chemistry and research, because as a young boy, I came across the biography of Santiago Ramon y Cajal in my father’s library. He was a Spanish scientist who is the father of neuroscience. I found it fascinating that he developed a staining method to label neurons, which allowed him to observe the structure of neurons and develop theories on these cells, including those on electrical connections between them, and its relevance to the nervous system. This inspired me to develop a staining method too using my own Chemistry set. By trial and error, I managed to develop a method to see the nuclei of onion cells. From then on, I became interested in this type of work. As a young man, when I was 15 years old, I asked my father if I could use one of the rooms of the house to build my own lab. I had an uncle who was a Chemist and he helped me equip the lab. My father gave me a microscope too, and with this microscope I started doing experiments, first with Paramecium spp. -a protozoan, and all this led me to develop an ever-increasing interest in science. I eventually entered medical school, but after 3 years in I realized that my true passion was scientific research. I quit medical school and completed a BSc in Biology and a MSc in Biochemistry. Then I moved to the USA to do my PhD.

You have a career-long involvement in Biophysics and microscopy. Can you tell us a bit about what inspired you to choose this path?  

Perhaps I can tell you an anecdote, which also helps to illustrate that my transition from Medicine to science wasn’t sudden. It was a progressive and very slow process. I had my own lab in my parent’s house, where I was culturing Paramecia. I must have been 15 years old, and I was looking at Paramecia through the microscope one summer, and since I had few coverslips and few slides, I had to wash them to be able to reuse them. Once, after washing the glass, I put a drop of my Paramecium culture, and these ciliated protozoans began bursting one after another. This caught my attention, and I wondered whether this was a spontaneous phenomenon. I was intrigued, because if it was a spontaneous phenomenon it would have happened in my culture flasks, and at that rate all paramecia would be already dead. So, I figured that it had to be something happening from the point at which I put them on the slide/coverslip. I remember at this point my mother called me for lunch. As I went downstairs to have lunch, I was still thinking about what the cause for the cell’s explosion could be. I thought that perhaps I hadn’t properly washed away the soap I used to clean my coverslips and slides. So when I finished lunch, I decided to test my hypothesis. I used one perfectly clean slide and coverslip and one in which I placed a tiny drop of soap, and then looked down the microscope. In the clean coverslip I could see my Paramecia moving around as usual, but in the one with the added soap everything had exploded. When my father came back home from work, I told him that I had done a “very important discovery”, and he asked me what my great discovery was. I told him my observation and said to him “I think the cell membrane must be made of lipids, which are soluble in soap!”. At this point my father told me that he thought this was a good moment to get myself a good Cell Biology book. He invited me to join him to downtown Lima to buy a book on Cell Biology. That same afternoon, I bought a copy of the celebrated Cell Biology book by De Robertis, Nowisky and Saez, and on the bus back home, I opened the chapter on cell membrane and realized that, of course, the fact that cell membrane is made of lipids had been known for over 30 years. I was somehow disappointed that my great discovery wasn’t novel at all, but on the other hand I was excited that I had reached the right conclusions through my experiments. This was a huge event for me, one that motivated me to pursue a scientific career, which I did by quitting medicine. After my undergraduate and MSc degrees, I came to the USA to do my PhD. Originally I wanted to focus on theoretical biophysics, because at that point it was my intention to go back to Peru, and I thought that being a theorist rather than an experimentalist, would make my return easier. When I finished my PhD in Berkeley, however, the war with the Maoist guerrilla group Shining Path had just begun in Peru, and if there was something that wasn’t needed at all at that moment in the country was a theoretical biophysicist. So I had to make a living and forge my own path in the USA. I finished my PhD, and applied to join the lab of another PI at the University of California in San Diego as a postdoc. While I was waiting for the PI to get news about the renewal of his grant, my PhD advisor, Professor Ignacio Tinoco Jr. told me that while I waited, I could stay in his lab to build an instrument to measure the phenomenon that my theoretical work had predicted. I found it an interesting proposition, and I dedicated myself to this while waiting for an answer from the other lab. We built the instrument, and published our work in Nature. By the time this was finished, I no longer wanted to do a postdoc. I felt ready to go ahead and have my own lab. I had done both theory and experiments, including instrument building, and therefore I applied to several open positions and was offered a faculty position in the Chemistry Department of the University of New Mexico. That’s where my independent scientific career began. 

Can you tell us a bit about what you have found uniquely positive about becoming a researcher in Peru, from your education years?

I was lucky to belong to a family that encouraged learning and a respect for knowledge and scientific research. The fact that my father was a medical doctor meant, among many other things, that through him I had access to specialized scientific journals, and all this had a major influence in my career, because the idea of people doing science for a living, was something very natural to me. At home, in my lab, I designed an experiment with semi-permeable membranes to measure the molecular weight of starch. I prepared a starch solution in an apparatus in which one could measure the level of water and in this way I could calculate the osmotic pressure of the solution relative to that of water, and from this value obtain the molecular weight of starch. This type of experiments, for me were very natural: it was like playing but in a serious way. It reflected my interest for science and my faith in that through an adequate experimental design, one could obtain useful information that otherwise you could not get. 

Can you tell us a bit about your day-to-day work as a group leader at Berkeley? 

In my lab I have a huge range of expertise – from undergraduate students to graduate students and very experienced postdocs. The group is divided into sub-groups. One focuses on transcription, another one on translation, another one on protein folding and unfolding, as well as on molecular machines that unfold proteins in the cell (unfoldases for their English translation). We study unfoldases using single molecule methods. One of the events that allowed me to develop my scientific career in the USA is that my lab did the first experiment on single molecule force spectroscopy. At taht time, we came up with the idea of grabbing a single DNA molecule from both ends and pull it to measure how much force was necessary to stretch it, in other words to characterize its elastic properties. This experiment, which we eventually published in Science, in 1992, opened up the idea that it was possible to mechanically manipulate molecules and to develop methods that allowed for the analytical measurements of these manipulations. In other words, not just applying an electric field and seeing how the molecule moves in response (experiments that we also had been doing), but systematically applying a specific amount of force and seeing how and by how much the molecules deform under this force. This field opened up many possibilities to study molecular motors, protein folding and unfolding, as well as cell mechanics. It was a whole new field of research, and the first experiments were done in New Mexico. I have often been asked if I wonder whether starting in New Mexico instead of a top Ivy League school played a negative role for my career. What I think is that in life we don’t have the possibility of doing “control experiments”. We make certain decisions and one can only speculate on what would have happened if one had chosen a different path. The idea of making these experiments, which were crucial for my career, was easier to carry out in New Mexico. From the third year as an independent investigator, I was promoted to tenure, and in the 5th year I was promoted to full professor. In this context, I had the impression that I could run more risks i.e. explore riskier ideas and do experiments that no one had thought about before. Not having this security, can be a big problem for scientific progress. There is this tension in Science between secured knowledge and the advent of new ideas that could be right or wrong. This tension influences the mind of all scientists, for we are supposed to push the boundary of knowledge but we do so while resting on previous ideas that makes us somewhat conservative. After having started the experiments on single molecule force spectroscopy, as the field is now called, I was very careful not to write grants to NIH that directly described these experiments. I proposed to do other experiments and on the side I piggybacked the single molecule ones, for fear that they would not be accepted and funded. Only once we had published 8 papers in the field of single molecule experiments, after 4 years of work, I dared to propose this approach in an NIH grant. At that point there was already enough evidence that we could do the work, and that what I was proposing could indeed be done so I had a good chance that my grant would be funded. In New Mexico, I was pretty much isolated (rather than being one more member of a huge Chemistry Department), and already had tenure, so I could do what I wanted. Perhaps in a top Ivy League University I would not have had this certainty and security, and would have maybe thought twice before embarking on risky projects. But I’ll never know. One never knows what will happen or what would have been different if one had taken a different decision. In this sense, beginning my career in New Mexico was the best choice, and something very positive for my career. 

You also lead a lab in parallel in Peru? How is your experience coordinating both?

In 2002 I was invited to Lima for the first time, to give a talk at the Latin American course of Physics which was taking place in a resort in the outskirts of the Peruvian capital. I had left Peru in 1975, and in 27 years I had never been invited to give a talk. I was convinced that no one in Peru knew I even existed. I had been in New Mexico for 8 years, and after that in Oregon at the Institute of Molecular Biology for 7 years, and in 1998, I had gone back to Berkeley. In 2002 I had been in Berkeley for 4 years already when I got the invitation to give a talk in Peru. I thought that if I didn’t accept the invitation I would never be invited again, or would have to wait another 27 years. So I thought this was really a wonderful opportunity to go. They wanted me to be in charge of the Biophysics part of the course. While I was there, a group of professors approached me and asked me if I could help them to promote science in Peru. As a result, in the ensuing years, I organized several international courses with Peruvian and foreign scientists in Lima: one on Advanced Biophysics, one on Cell Biology, one on Metallurgy, one on genetic markers in American camelids (a subject of great important in Peru), and so on. As a result of this experience, I realized that the courses were not going to have the impact that I was really looking for. One can organize courses everywhere. So, speaking with a friend of mine, Marcos Milla, who is also a Peruvian Biochemist, we came up with the idea of founding a twin lab in Peru. I spoke to many Universities in Lima, to propose this idea: I would train a person from Peru in California, who would later go back to Peru and establish a lab that would be a twin to my lab in Berkeley. This is what I did, and one of the Universities – Universidad Peruana Cayetano Heredia, accepted my proposal the very same day I spoke to them. As a result, they sent a scientist, Dr. Daniel Guerra, to my lab as a postdoc and in 2009 he went back to Peru where we founded the lab of single molecule studies in Lima. While I thought it was a great idea, I’m a bit disappointed that the idea hasn’t been replicated by other Peruvian scientists working abroad. In part because there is no mechanism of financing this pursuit. I was able to do it because I am part of the Howard Hughes Medical Institute, which gives me a lot of economic flexibility, which allowed me to collaborate in this process. If the idea were to be appreciated in Peru, the funding agencies in Peru could organize a project called Twin Labs, to promote knowledge exchange and capacity building, making the most out of the knowledge and skills of Peruvian scientists abroad too. Peruvians, like many Latin Americans, “mourn” and complain about the brain drain in our countries. This is the official sad song. But there are alternatives. Let’s us imagine and pretend for a second that 40 years ago, Peru decided, as a strategic measure, to send Peruvian young scientists abroad to do their PhDs, and then have them position themselves in the best Universities in USA and Europe as part of a “premeditated strategy” that would later allow for knowledge exchange, knowledge transfer, and the creation of twin labs all across Peru, with a plethora of disciplines and skills. There’s no difference between both scenarios: the imagined one, and the one existing today, namely, many Peruvians scientists living abroad do not return to Peru, and this is fine. But between the two scenarios there is a fundamental narrative change: with the second we chose to make the most of it, instead of playing the sad violins and lament the loss of talent. So, I think we should support those Peruvians abroad to help build the country’s scientific capacity, and turn a “defeat” (i.e. brain drain) into a victory. It’s so obvious and simple, and I thought it would be an idea that would be picked up by both, funding organizations, and other Peruvians abroad. Sadly, neither of those things has yet happened. But I don’t lose hope, we must keep hope alive. 

Did you have many opportunities to interact with other Latin American groups, outside of Peru?      

Yes, especially because my lab is a magnet for Latin American students. I’ve had Brazilian, Argentine, Chilean, Colombian, and Peruvian students, among others. Many of the undergraduate and MSc students in the twin lab in Peru have later gone on to do their PhDs in Berkeley – many have graduated and others are still doing their PhDs. That’s actually another reason why I think twin labs are a good idea: they open channels that allow young students in Latin America to go abroad with a strong academic network of support. This is not specific to Peruvians- my feeling is we must support one another in Latin America. I am a firm believer in the Patria Grande. There are important differences in scientific development among countries in Latin America, but I firmly believe that people who have gone abroad and decided to stay abroad for whatever reason A, B or C, can still contribute to the development of science and technology in their countries. Right now, this potential is being wasted. I think the most important asset in Science is the human resource. Money is important, but the human resources – the scientists with the capacity to invent, create and research, are the most valuable capital. Currently our countries are exporting talent, when, in reality, what we actually need is for that talent to find its way back to Latin America. An analogy would be that Argentina, which is a producer of meat and wheat, would export all its meat and all its wheat abroad, and there’s nothing left for the Argentines. And then they buy meat and wheat from the USA or other countries. This makes no sense. Becoming exporters of human talent is the worse scenario for a country. If our countries don’t have a strategy to recover this talent, by offering attractive jobs for young scientists to return, or the chance to contribute through twin labs, then this talent is really lost. 

Who are your scientific role models (both Peruvian and foreign)?

That’s a difficult question! I think that in the first place, I’d have to do it by disciplines. But I must say that my most important role models are to be found among the physicists, not among biologists, chemists or biophysicists. I greatly admire Enrico Fermi, who was capable of doing both theoretical physics and experimental science. Albert Einstein, Niels Bohr, Heisenberg and Dirac, and everyone who worked on quantum theory is also in my list. In Biology I greatly admire Santiago Ramon y Cajal – he is probably the most renowned Hispanic scientist in this field. I also greatly admire Francis Crick, whom I think was an extraordinary physicist and biophysicist who figured out early on, how to use his physics training to do biological research, and did that in an era where Physics hadn’t formally entered the field of Biology. He used his preparation and education to advance ideas in structural biology. I admire his work a lot. I’ve focused on the very top, what you could call the historical figures. But there are many scientists I admire who are my contemporaries and my co-workers. 

Are there any historical events in Peru that you feel have impacted the research landscape of the country to this day?

Absolutely. First of all, early in the 1800s, there was a student who was finishing his degree in Medicine, Daniel Alcides Carrión – he was studying the disease of the Peruvian wart, at a time when it wasn’t known whether it was caused by an infectious agent or how it was transmitted. In Europe, around this time, Louis Pasteur had founded the field of Microbiology. Carrión, in order to demonstrate that Peruvian wart was caused by an infectious agent, took a purulent secretion from a patient and inoculated himself with it. He became infected and he died from the infection, but in the process demonstrated that indeed, it is an infectious agent that causes this disease (now known as Carrión’s disease). He became the hero of Peruvian medicine – he sacrificed himself to demonstrate that this infectious agent was responsible for the disease. There were other microscopists and pathologists at the beginning of the 20^th century, specifically Alberto Barton, who discovered a bacterium – Bartonella bacilliformis (after his own name) as the causing agent of Peruvian wart. And then, we have great scientists who have specialized in Altitude Medicine – there’s Carlos Monge, who described for the first time, the clinical syndrome of chronic mountain sickness or altitude sickness. In Peru, we have a large population who live above 3500 m above sea level. When tourists go to the Peruvian mountains, usually people get the acute version of altitude sickness, also known as “soroche”. What Monge described was different: people who had been born and had always lived at high altitude (around 3000 – 4000 m) that suddenly lost adaptation to altitude and began showing manifestations that resulted in death if the person wasn’t immediately taken to sea level. Until Carlos Monge carried out his studies, this phenomenon had not been recognized. He demonstrated that this was a new pathology – now known as Monge’s illness, or chronic mountain sickness. An afflicted person can never return to high altitude. Anyone of us, without this illness, can arrive to high altitudes and has the capacity to adapt. The body begins to adapt in a matter of hours by raising the concentration of phosphodiglycerate in blood, which decreases the affinity of hemoglobin for oxygen so that when red blood cells go from the lungs to the tissues, hemoglobin more easily releases its bound oxygen to the tissues. The other is the increased production of erythropoietin. But people with Monge’s illness become permanently dis-adapted, so they have to return to sea level immediately.  

Have you faced any challenges as a foreigner if you have worked outside Peru?

In general I’ve felt that the USA has welcomed me with open arms. I’ve rarely ever felt treated as if I was in my current academic position for the wrong reasons. I feel that this is one of the great things about this country. It’s a nation of immigrants – no one has a greater right over others to be in this country just by precedence. Some people forget this, and the politicians play a lot with this idea, without realizing that what allows the USA to have a unique dynamic range when it comes to all human activities and talent, is precisely the influx of people with a vast range of skillsets. While trying to succeed, these people, from all backgrounds, make the country succeed too. It’s common sense, but some people with different priorities forget this. Unfortunately, as my father used to say, common sense is the least common of all senses. 

What is your favourite type of microscopy and why?

I don’t think I have a favourite type of microscopy. I think that my favourite type of microscopy is yet to be invented, namely, a microscope that works in water, with the resolution of an electron microscope. The different microscopes that currently exist fill in gaps, but each with their own limitations. Optical microscopes are compatible with liquid, but are resolution limited. Super-resolution cannot yet compete with EM. Then we have EM which allows us to see atoms, for instance with cryo-EM, but it’s incompatible with liquid. So these limitations are huge. Ideally, it would be great to see molecules moving and working in real time. This is my dream – this is a field where we can push the boundaries of science and knowledge.

What is the most extraordinary thing you have seen by microscopy? An eureka moment for you?

The most impressive moment happened when I was moving from Berkeley (in my PhD years) to New Mexico (as a young PI). There was a symposium at Cold Spring Harbor in 1981, and a professor in Berkeley went to this symposium – he then came back to Berkeley and gave a talk about what was discussed in CSH. He said there was a group of Japanese scientists who had stained DNA molecules with an intercalator – ethidium bromide, which fluoresces more strongly when it intercalates with DNA, generating contrast. They had placed these DNA molecules in a coverslip and had managed to see them under an optical microscope. This was an eureka moment for me because an analogy is looking at the night sky and seeing the Orion Constellation. We can see where it’s located against the dark background of the night sky. Not that you can resolve the individual stars, but you can see all three of them moving in the night sky together. That was a Eureka moment for me and I thought to myself “why this did not occur to me before?”. The next year, I was leaving to Berkeley, and around this time, the book with that article arrived to the chemistry library in Berkeley. I photocopied this paper and since I was moving, I placed the photocopies in my car’s trunk. It traveled from Berkeley to Albuquerque together with me and my brother in law. My wife, who was 9 months pregnant, traveled by plane together with my brother in law’s wife, and my 2 year old daughter. So the paper was in my car’s trunk for 3 years before I could take another look. Every time I would open the trunk I would see it, but I had so many things to do setting up my new home and my new lab, that I had to keep ignoring it for a while. In 1984, the department of Chemistry nominated me for the Searle Award, and surprisingly, I got it. I had then enough money to buy a microscope. I had two postdocs, and I asked one of them, Dr. Tim Houseal, to repeat the experiment of the Japanese team. Then I asked whether we could do this, without sticking the DNA molecules to the glass – I wanted them to be freely moving, so that we could apply pressure or electric fields to make them move. We then studied how molecules move within a gel, while undergoing electrophoresis. We mixed DNA with gel, placed the gel between a slide and a coverslip, and then applied electric fields, so we could see DNA molecules slithering towards the positive electrode (since DNA is negatively charged). This observation allowed me to study DNA dynamics during electrophoresis, but as we saw the molecules slithering around, expanding and contracting, it also gave me the idea of mechanically grab and pull these molecules to characterize their elastic properties. This was the beginning of everything that came up later in my career.  

What is an important piece of advice you would give to future Peruvian scientists? and especially those specializing as microscopists?

With regards to being a scientist, I think the only thing you should never worry about is whether you will be able to live in Peru or not, or if as a scientist you will be able to earn a living. When you want to be a scientist, this passion is unavoidable. Whoever feels interest towards science cannot get rid of this curiosity. Don’t worry about the rest. It will be taken care sooner or later. I’d say, pursue your passion and your gut feeling. Don’t stop and think of the cost, because everything worth anything, has a high cost. My other suggestion is to keep an open mind. Being a scientist represents a dichotomy. What we know and learn allows us to look into the future, but what we know also represents an anchor in the past: for example, when I was a student of Analytical Chemistry in Peru, our teacher told us that the signal was proportional to the number of molecules in the cuvette or the assay. If you think about a mol of any molecule (Avogadro’s number, i.e. 10²³ molecules), if you go on to focus on a single molecule, you diminish the number of molecules by a magnitude order of 23. Your signal will diminish by this amount, and you won’t have anything to see anymore. When we started to think about pulling a single DNA molecule, this idea was deeply embedded in my brain and gave me many doubts about being able to measure anything after dilution by 23 orders of magnitude. However, as it turned out, designing this type of experiment, the instrument to perform measurements also has to become microscopic so you don’t lose 23 orders of magnitude in the signal: the sensitivity of your instrument as it gets small enough to do the measurement increases by several orders of magnitude so you can actually do the experiment. So it’s important to know things, but keep a reasonable amount of doubt on what you know. This knowledge otherwise can become a hindrance and an obstacle to give the next step. Regarding microscopy, I’d say, microscopes are the most marvelous instruments ever invented perhaps only comparable to the telescope. Both are instruments that allow us to see beyond what the human eye allows us to see. It’s interesting to think that the microscope allowed Marcello Malphigi, who was a Professor in Bologna, to become the father of microscopic anatomy in the 17^th century. He was doing his experiments around the same time that Galileo was doing his experiments visualizing the Moons of Jupiter. They were both laying the ground for the parallel revolutions that took place in Biology and in Physics. In both cases, the catalysts of these revolutions were the microscope and the telescope. 

Where do you see the future of science and microscopy heading over the next decade in Peru, and how do you hope to be part of this future? 

The future of microscopy is linked to the future of science, so perhaps the best way to answer this question is to talk about the future of science in Peru. I see the future of science in Peru a bit uncertain, because the efforts to establish a governmental policy for research, and the development of science and technology, depends to a great extent on the economic and political stability of the country. Peru is famous for its economic stability – the Peruvian “Sol” (the name of the currency) is the most stable in the sub-continent, together with the American dollar. This is an interesting phenomenon. The reason for this is likely that, unlike other Latin American nations, many years ago in Peru the economic and governmental policies became separate. So, neither the president nor the legislative power has authority over the monetary policies of the country. This is restricted to the Central Bank, and the decision is left to a group of financial technologists with great expertise. Sadly, policies governing research and development depend on the political actors. And at present, Peru is one of the most politically unstable countries in the continent, so we have this situation in which the future of science depends upon institutions that are fickle and volatile. So I’m skeptical about the future of science and microscopy in Peru. 

Beyond science, what do you think makes Peru a special place to visit? 

While a subjective question, it has elements of objectivity! I hope I don’t offend anyone by saying that there are countries that due to unknown historical reasons have a major historical weight that transcends time. An example is Greece – no one can deny that Greece is the origin of western civilization. Another example in the East is China- no one can deny that the Chinese Empire is the origin of many cultures in the East. And no one can deny that both Mexico in the North, and Peru in the South are the equivalent in the Americas. That’s where the major civilizations of the New World developed. In this sense, they were the point of attraction of European countries. When the Spanish “discovered” the Americas, they came about a significant contrast: the Antilles had an established population, but it was in contrast to what they found once they arrived in Veracruz, in the coast of Mexico. The Aztec Empire had achieved major advances: scientific, architectonic, cultural, etc. The same happened to Pizarro who upon reaching Peru, discovered the Inca Empire. The Spanish decided to create, in both countries, the biggest metropolis: Mexico City in the North, and Lima in the South. Nowadays Peruvians and Mexicans are the historical inheritors of the Inca and Aztec achievements, and of the Viceroyalties of New Castile (in Peru) and of New Spain (in Mexico) In addition, Peru is a country that due to its geographical location has major biological diversity: coast, mountains, the trans-Andean valleys, and the jungle – the Amazonas river is born in Peru and runs for 500 km before reaching Brazil. So we have an enormous biodiversity, both in fauna and flora, and due to our history, we have an enormous cultural diversity. This cultural diversity of Peru is obvious, for instance, through its gastronomy. If we think about it, gastronomy is not the result of some Peruvian or Mexican suddenly coming up with a recipe in March of 2023. Our gastronomy has 50 centuries of history that included its fortunate fusion with Spain’s own creations. Culture cannot be bought – it takes time to develop. 

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