Under the Microscope

I grew up in Peru. As a kid, I read a biography of Santiago Ramon y Cajal, a neuroscientist who won the 1906 Nobel Prize for the theory of the neuron. I was amazed that a Spanish scientist who was living in this little town had made it so big, and I started dreaming about becoming a scientist.

When I was 15, I had an experience that sealed my fate. I was looking at paramecia through an old microscope my father had given me. I didn't have many coverslips and slides, so I would wash them and recycle them. One day as I looked at the paramecia culture under the microscope, they start bursting and breaking. I was shocked. I knew that this couldn't be happening in my culture, or everything would be dead. Something was happening the moment I put it on the slide. I used soap to clean the glass, and it occurred to me that maybe I didn't rinse it so well. So I did some experiments and saw that everything was dead in the slide I'd prepared with the soap, but everything was fine in the clean slide. It was an incredible moment in my life. I thought, why would the soap break the membrane, unless the membrane is made out of fat?

I told my Dad, I think I made a very big, important discovery. I think the cell membrane is made out of lipids. He listened carefully and then took me to buy a cell biology text. I opened the book to the cells and membrane section, and sure enough at that time they already had a model with lipids. It was a big disappointment—I had made my discovery 30 years late. But deep inside, I felt really good. I felt like I was a scientist.

My father was a very well-known physician in Lima and at one point became the President of the National Academy of Medicine, and he expected me to become a physician like him. My professor Melgar in Lima convinced me that I had to have the courage to tell my parents that I didn't want to study medicine but science. They were very supportive. I studied biology and biochemistry in Peru, and in 1975 I came to the U.S. as a Fulbright Fellow to get my Ph.D. At Berkeley, I met Ignacio (Nacho) Tinoco, who became my mentor in the Ph.D. program in Biophysics.

I decided to be a theorist, because I wanted to return to Peru, and it is easier to do research with a pen and a piece of paper as, I thought, this way I didn't have to build a lab upon my return. And so I did my thesis on the theory of new light scattering phenomenon. Afterwards, Nacho told me, why don't you build a machine to measure the effect that your theory predicts? And so I did, and it was the first measurement that was ever made of this effect. We published it in Nature.

In 1981, I was hired at the University of New Mexico, in Albuquerque, and I went back to microscopy. Looking at single molecules of DNA moving through a gel, I noticed how elastic these molecules were. I felt like I could almost grab one like a piece of string. I collaborated with Steven Smith to find out if we could pull a single molecule of DNA. It was an experiment done out of curiosity, almost blindly. We were exerting femtonewton and piconewton forces on micro-sized objects.

That was a moment of innovation, because everybody knows that the magnitude of the signal is proportional to the number of molecules, and if you go down 20 orders of magnitudes from 10²⁰ molecules to 1, the signal should essentially disappear, but it didn't, because your instrument also becomes smaller and smaller and ever more sensitive. By the time I moved to the Institute of Molecular Biology, in Eugene, OR, in 1991, we had quite a bit of data. In 1992, we published the complete account in Science.

From that point onward, I was catching up with the discoveries, and everything moved very fast. I became a Howard Hughes Medical Institute investigator in 1994. I had to give up my HHMI fellowship when I moved to Berkeley in 1998, but in 2000 I got it back.

Single molecule manipulation methods are here to stay and remain the main focus of my lab. But I also have a small effort underway to build a cell from the bottom up using mitochondria. We want to reverse endosymbiosis and make the mitochondria independent.

Science is most gratifying in that instant when you figure out something through your reason, your experiments, and you realize that it's something that nobody else knows. To do that you need faith—faith in the scientific method and in the scientific act. Nature is not malicious, it is willing to give up its secrets.

A true scientist is working at the very limit of his own knowledge, and therefore half of the time he is feeling incompetent. Our job is to feel incompetent 50% of the time, by pushing the boundary. When we are feeling completely comfortable and competent, we are not doing our job.

I have a wonderful family. At times I know that they would have rather had me at home on Saturday or Sunday rather than in the lab, but they've showed me a lot of love and understanding.

I go to Peru three or four times every year. I am trying to help Peru to rebuild the scientific infrastructure, which was greatly destroyed during the civil war with Shining Path in the 1980s. I talk to authorities to convince them that they should give more money to science. They are beginning to listen.