In the movies that play in his mind, José Rodríguez sees antibodies latch onto receptors and stop cancer cells from feeding on iron. He sees an infectious protein fragment grip its neighbors to form the flat sheets that clutter the brains of people with Parkinson’s disease. Atom by atom, his imaginary animations crystallize as he creates minuscule maps of some of the most elusive biological structures ever studied.

A biophysicist at the University of California, Los Angeles (UCLA), Rodríguez is a pioneer of a new molecular imaging technique called MicroED – short for “micro-electron diffraction.” The method uses beams of electrons, rather than more damaging X-rays, to reveal the precise locations of atoms within exceptionally small crystals. Scientists are now using MicroED to peer more deeply into disease-causing molecules than they ever could before. A team at HHMI’s Janelia Research Campus is working with Rodríguez to develop and refine the low-cost approach, which promises to make molecular mapping more accessible to research groups worldwide.

An obsession for imaging, and a devotion to access – together, these two themes define Rodríguez’s approach to science. As an undergraduate at UCLA, he wondered, “Why can’t we just have movies of proteins moving around?” He loved learning why it’s so hard to visualize tiny things, and has bridged academic chasms to work with physicists, biochemists, biomedical researchers, and computer scientists to devise solutions. He is equally passionate about removing barriers for students whose roads into research may be as long as his own path was, from central Mexico. “I believe anyone can do fantastic science, wherever they come from,” he says. “It’s my duty to help them achieve that.”

The eldest of five siblings, Rodríguez was born in 1985 to young parents in a rural town near Aguascalientes, about 500 kilometers northwest of Mexico City. Most adult men in the village worked elsewhere to support their families. Both of his grandfathers were braceros, contracted laborers in a program that brought hundreds of thousands of Mexicans to the U.S. during World War II and for two decades afterward. His father was a migrant worker, too, on farms and in construction in northern California. When José was a toddler, his parents received U.S. green cards in an amnesty deal for migrants, but he had to stay in Mexico with his grandmother.

At age 4, he finally joined his parents and baby sister Maria in Los Angeles. At the time, many elementary classrooms in California were segregated by language, and José spoke mostly Spanish until 3rd grade. “He passed everything very easily, and he always wanted to do experiments,” recalls his mother, Jacinta Rodríguez, who insisted that José start learning with his English-speaking classmates. When a statewide measure compelled all immigrants to be taught in English as José entered 5th grade, he was well on the way to catching up with his peers.

In high school, his aptitude for mathematics emerged. He started at UCLA in fall 2003, and quickly made an impression. “I noticed early on that this guy was special,” says Argentinian biochemist Gustavo Helguera, a frequent visitor to UCLA and current collaborator with Rodríguez. “When he was 19, he was doing math analyses that the PhDs couldn’t do.”

A UCLA program for science students from underprivileged backgrounds offered mentoring and lab experience to Rodríguez and a small group of peers. He switched his major from math to biophysics and then spent the summer after his sophomore year doing research at Yale University in HHMI’s EXROP, Exceptional Research Opportunities Program. He studied a key protein in chicken cells that helps regulate antibodies, and became fascinated by the actions of proteins within cells and on their surfaces. Back at UCLA, he joined the lab of Cuban immunologist Manuel Penichet, who was interested in how cancer cells sop up the iron they need to grow. Rodríguez examined a particular antibody that jams the entry point for iron – a potential anti-cancer strategy published in The Journal of Controlled Release in his senior year, with Rodríguez as first author.

He spent much of his spare time as an undergraduate learning how to create images of proteins, with guidance from Chinese physicist Jianwei (John) Miao at UCLA. Miao taught Rodríguez how to see proteins in 3-D using X-ray diffraction, and Rodríguez became enamored of Miao’s prowess with cameras that could take half a million images each second. Rodríguez picked it all up quickly, Miao recalls. “José was so outstanding,” he says. “He broke that culture barrier. Nature doesn’t give some problems to physicists, some to chemists, and some to biologists. For many problems, we need them all.”

When Rodríguez was a senior, HHMI invited its former EXROP students to apply for a Gilliam Fellowship, an award of full graduate-school funding for applicants from groups underrepresented in the sciences. His work in multiple labs helped Rodríguez earn one of the five fellowships given in 2007 – a boost that convinced him he could turn his passions into a career. He was admitted to the Massachusetts Institute of Technology, Stanford University, and UCLA, but he chose to stay in Los Angeles to continue the collaborations he loved.

Rodríguez earned his PhD in Penichet’s lab, where he continued exploring strategies to gum up the workings of cancer cells. Along the way, during a meeting of Gilliam Fellows at HHMI headquarters, he learned that a Harvard University group working on the viruses that cause hemorrhagic fever in South and Central America had zeroed in on the same antibody he was studying. In a quirk of cellular mechanics, that antibody not only attached to the iron-ferrying receptor in cancer cells, starving them of iron, but also blocked the entire family of hemorrhagic fever viruses from entering and infecting cells. The dual role amazed Helguera, who was employed by Penichet’s group at the time.

The UCLA and Harvard teams joined forces to reveal the antibody’s actions in a 2012 paper in The Journal of Virology. Since then, Helguera has tried to move the work closer to clinical trials, as Argentine hemorrhagic fever is one of the world’s most virulent strains. He has had little help from his government, but Rodríguez provides support and materials from afar to keep the project going. “It’s a real opportunity to make a difference in the lives of a lot of people,” he says.

Rodríguez’s current passion, MicroED, blossomed during his postdoctoral research under HHMI Investigator David Eisenberg, a structural biologist at UCLA. Eisenberg studies the protein snarls in neurodegenerative disorders such as Alzheimer’s, including the malformed proteins called amyloids, which clump together to cause brain-wasting diseases and may even trigger type 2 diabetes. To see how these proteins interact, and to try to design drugs to keep them from going rogue, scientists must know their shapes down to the atom. To learn this, they typically grow crystals from large numbers of the proteins and then expose them to narrow beams of X-rays. The resulting diffraction pattern – created by deflections as the X-rays scatter through the crystals – encodes information about the position of each atom.

But some proteins form “invisible crystals” that are orders of magnitude smaller, says Eisenberg – too tiny for X-rays to see. “There are many examples of projects that have stalled for decades because of these vanishingly small crystals,” says Tamir Gonen, a structural biologist at Janelia.

That problem inspired Gonen, and starting in 2012 he led a team at Janelia that showed the power of MicroED to illuminate such crystals. Beams of electrons interact with the atoms so strongly that a crystal need be only 20 to 50 molecules thick to produce a clear diffraction pattern, thousands of times finer than the dimensions needed for conventional X-ray crystallography. Gonen used MicroED to reproduce the known structures of several proteins to show that the method worked. Still, many biologists doubted whether MicroED was good enough to unveil completely new structures.

Then, Rodríguez joined the collaboration and brought some of Eisenberg’s invisible crystals. One of these was the core section of a protein called alpha-synuclein, which clumps into harmful brain deposits seen in Parkinson’s disease. That segment, just 11 amino acids long, may spur the clumps to form. MicroED revealed the stacked, sheet-like structure of the segments as they linked tightly together, with a sharp resolution of just 1.4 Ångströms – smaller than the width of a single bond between two carbon atoms. The team’s landmark paper, with Rodríguez as first author, appeared in Nature in 2015. “At that point, the remaining skepticism in the community tended to disappear,” says Eisenberg.

One of those early skeptics was structural biologist Yifan Cheng, an HHMI investigator at the University of California, San Francisco. The method looked so tenuous, Cheng admits, that he would have denied funding to a MicroED proposal as a grant reviewer. “But when the first results came in, I was so stunned,” Cheng says. “They have produced results that cannot be obtained in any other way. Now I’m a big fan.”

The team has gone on to sharpen its resolution to 1.0 Ångström. For researchers who imagine designing a drug to stop proteins from hooking up in harmful ways, that fine vision is essential, Rodríguez says. “There are cases where even a single-atom difference can lead to a profound change in the behavior of the molecule,” he notes. “We have to look in close detail at every single atom.” He and his colleagues are now honing the technique and the computer analysis that determines the atomic coordinates.

MicroED has caught on in a big way: HHMI workshops on the method are the most oversubscribed meetings in Janelia’s history, Gonen says. This thrills Rodríguez, who wants to open new imaging windows for teams that don’t have access to huge particle accelerators for X-ray crystallography.

“Taking pictures of molecules can be transformative,” he says. “Releasing these tools in a way that is friendly for others to use will make the biggest impact.”

In his lab at UCLA, Rodríguez fosters that same egalitarian spirit. He sits with the team at their workstations, arrayed in the open style of a startup tech company, and amuses them by talking to molecules and diffraction patterns on his screen. “His enthusiasm is super-motivating,” says graduate student Callie Glynn. “He has the knowledge of a principal investigator and the approachability of a fellow grad student.”

Rodríguez aims to give real responsibilities to undergraduates and even high school students, recognizing that a faculty member’s attention can be catalytic. Evelyn Hernandez, a junior studying biochemistry and systems biology, is a first-generation college student whose parents emigrated from Mexico. Her role is growing crystals from small portions of infectious proteins, and she happily geeks out about the challenges. She already knows a PhD is in her future. “Having a PI with a similar background as mine is really cool,” she says. “It makes me feel, ‘Oh, I really do belong here.’”

When he thinks about his own trajectory, Rodríguez recalls no attempts by others to steer him away from science. “I was not the smartest person in all of my classes,” he says, “but I had support. I began to realize there were a lot of very capable people who were not exposed to opportunities in the same way. We should not have a preconception of who will be good at something, especially science.” His most lasting personal impact of the Gilliam Fellowship is his determination to “pay it forward” through meaningful experiences for his students. “That’s the only way we can reach some critical mass,” he says.

Rodríguez knows there is one eyebrow-raising aspect of his academic life: he has spent all of it at UCLA. After 13 years as an undergraduate, graduate student, and postdoctoral researcher there, he applied to a faculty position in UCLA’s Department of Chemistry and Biochemistry – and nowhere else. “He had great confidence,” says Eisenberg, chuckling.

Rodríguez would be honored to emulate the career of Eisenberg, who like Rodríguez joined UCLA’s faculty at age 31; he is now in his 48th year there. That may be enough time for Rodríguez to make his mental movies come alive. “Right now, we’re isolating molecules and seeing what they look like,” he says. But that’s far removed from his goal of watching them jostle, join, and jumble inside living cells. “It will be a lot of fun to get there,” he says, “not just for me but for everyone going on this journey.” ■

Story by Robert Irion
Photography by Marc Olivier Le Blanc