I was born in Colmenar Viejo, then a small town 20 miles north of Madrid. My parents, who grew up in post-civil war Spain and did not have a chance to finish even secondary school, were obsessed with giving my brother and me a college education and made any sacrifice needed to make it possible. High school was a glorious time. I loved learning, whether history, literature, science, or philosophy. Importantly, my math, biology, and physics teachers were amazing women, each with a passion for their jobs, who have been my role models till today (there were no women faculty in the department where I carried out my studies at the Universidad Autónoma de Madrid). I decided to study physics. I always loved how mathematical formulation can explain and predict natural phenomena, and the great communicator Carl Sagan also influenced that decision. From then on, I grabbed the opportunities that came my way.
I changed my scientific direction to biophysics when I met the director of the UK Synchrotron X-ray source SRS, Joan Bordas, at a summer course in Santander. Joan, a physicist who had moved into biology, was inspirational. After his talk, I asked to join his lab and a few months later (and an accelerated English course), I moved to England. There, I studied tubulin polymerization when exposed to anti-mitotic drugs using time-resolved small angle X-ray scattering. I also started to use cryo-electron microscopy (cryo-EM), then a budding technology practiced by few. When my boyfriend (now husband) and I were considering moving to Berkeley, I was able to interview with Robert Glaeser, the father of cryo-EM. I was intimidated, but Bob was incredibly kind and helpful, as he has been for many years as my colleague and mentor at Berkeley. When I mentioned my work on tubulin, he walked me right to the office of Kenneth Downing. It was like winning the lottery. Ken was an expert in electron crystallography, a modality of cryo-EM that uses 2D crystals. Tubulin can form a 2D polymer in the presence of zinc that is both similar and distinct from the microtubule, the natural assembly of tubulin in cells. We stabilized those with Taxol, a major anti-cancer agent, and, after overcoming major technical hurdles, obtained the first structure of this critical cellular component. This success helped me land a faculty position at UC Berkeley. In my own lab I have continued to study microtubules till today.
Once at UC Berkeley, my scientific horizons quickly expanded. I was introduced to transcription by my colleague and long-time collaborator, Robert Tjian, an international leader in this field. I decided to use electron microscopy to visualize the large human transcription factor TFIID. The size, scarcity, and flexibility of this complex, which is required to determine where transcription starts and then to assemble the transcription pre-initiation complex (PIC), made structural characterization daunting. For years, our painstaking progress had to push the limits of what cryo-EM allowed at the time, but we ultimately were able to describe the structure of TFIID and its molecular acrobatics to bind DNA and subsequently assemble the PIC. This work, started by posdocs Frank Andel and Patricia Grob, culminated with the work of three sequential graduate students: Michael Cianfrocco, Robert Louder, and Avinash Patel, all of them fearless. In parallel, we worked building up the human PIC, one step at a time in order to facilitate interpretation of our limited-resolution structures obtained before new detector and software technology revolutionized cryo-EM. This extremely challenging task, which had to be done with miniscule amounts of sample, was carried out by a truly brilliant postdoc, Yuan He. Once better technology became available, he pushed the resolution and visualized the human PIC in three sequential steps through transcription initiation. Postdoc Basil Greber later obtained an atomic model of the multifunctional component TFIIH by itself and was able to describe the conformational changes that it undergoes as it joins the rest of the PIC to open the DNA. These studies built on the heroic work of lab manager Jie Fang, who purified samples of these human complexes over the years. It was a privilege working with them and all those that have come to my lab, made their own scientific contributions, and made my professional life so enjoyable and adventurous. Many of this group of amazing scientists are now running very successful labs of their own. I am immensely thankful for all their efforts, intelligence and drive. I also would like to thank the National Institutes of Health and the Howard Medical Institute for funding our research and allowing us to take risks. And thanks to all those that lighted the path before us. Science is a large community effort. Within it, we continue to visualize complex and flexible molecular players in gene regulation.
12 November 2023 Hong Kong
