On a cold night in March 2000, a team of molecular biologists held their breath as they opened a dataset 30 years in the making. The group, led by the eternally restless and now exhausted Venki Ramakrishnan, had spent the previous 48 hours racing against time borrowed at Argonne National Lab’s synchrotron, the Advanced Photon Source, bouncing x-ray beams off a frozen cell. The data they had collected would eventually reveal the complete structure and function of one of the two parts of the half-a-million-atom ribosome, the molecular machinery in every cell that translates mRNA into the proteins from which life emerges. Usually composed and humble, that night Ramakrishnan leaped from his chair, dancing as he shouted, “We’re going to be famous!” Nine years later, Ramakrishnan and two other molecular biologists were awarded the 2009 Nobel Prize in Chemistry for solving the process that produced proteins out of genetic information.
In the decades that followed, Ramakrishnan received a dizzying assortment of accolades, wrote a book called Gene Machine that chronicled molecular biology’s race to solve the ribosome’s deepest mysteries, and served as the President of the Royal Society, the world’s oldest scientific institution. He is currently founding a company, RNAvate, to use mRNA for therapeutics. He is also turning his gaze from reductionist, sub-cellular-level research to broader, systems-level questions. Ramakrishnan joined SFI’s Fractal Faculty last year and is working on a new book about how and why we age and die. “You only have one life to live,” he says. “Why not do the thing that actually matters most?”
Ramakrishnan found what mattered most to him early in his career. He left India for the United States in the late ‘70s at the age of 19 to get a Ph.D. in physics from Ohio University. But at age 23, recently married and with a doctoral degree in hand, he realized that he didn’t want to be a physicist at all. Many of the big questions in physics had already been answered, and he couldn’t see where the field — or his role in it — was going. But biology was in a revolution. It was “where the greatest advancements in 21st-century science could be made,” he says. So Ramakrishnan packed up his physics career and moved with his wife and two young children to the Pacific coast to go to grad school again — this time in biology — at UC San Diego. He began by taking undergraduate courses along with pre-med students. From the outside, his decision may have seemed rash, but Ramakrishnan says, “My life has been guided by pragmatism.” Two years later, Ramakrishnan decided he’d learned enough biology and began a postdoc at Yale with Peter Moore where he used neutron scattering to see where pieces of the small subunit of the ribosome were located.
The biological revolution that inspired Ramakrishnan’s research began in the early 1950s with James Watson and Francis Crick’s discovery of DNA’s double-helix structure where the instructions for an entire organism are packed into chains of nucleotides. But DNA is an inert code that can’t run without a cell, and a multistep process, to read it. The genetic information in DNA is first copied to a molecular messenger, mRNA, which in turn is read by a large molecular machine — the ribosome — to make fully functional proteins. Using the most advanced imaging techniques of the day, the ribosome was a mysterious black box of life made up of two non-distinct blobs. Could we ever see what the ribosome looked like and figure out how it worked?
This question intrigued Ramakrishnan and he pursued the problem over two decades at Brookhaven National Laboratory and the University of Utah. By 1999, technology had evolved to the point that a few teams were racing to solve the ribosome riddle. Ramakrishnan, then a full professor at the University of Utah, had a plan that could win the race. He would grow thousands of ribosomes into crystals, soak them in special atoms that scattered x-rays differently, deep freeze the entire batch to near liquid-nitrogen temperatures, then blast them one by one with x-ray beams that would produce the data from which he could construct an atomic model of the ribosome’s full structure. But he had no idea how long it would take. Others had been working on the problem for 15 years. Britain’s MRC Laboratory of Molecular Biology, the storied lab where Crick and Watson uncovered the structure of DNA, has a tradition of supporting scientists for long periods while they work on difficult but important problems. The caveat was that they could only pay about half the salary he was making at the University of Utah. Ramakrishnan didn’t hesitate. “OK, maybe that decision was a bit romantic,” he says. But it ultimately led to the discovery that had him dancing on a cold winter night inside an x-ray lab. Every step in the moonshot plan that had required moving his family five times and laboring in relative obscurity for three decades — it had all worked. The image his data produced looked like a rat’s nest of rainbow confetti. To the few who could interpret, Ramakrishnan’s was the first clear image that showed where mRNA entered the ribosome and where the proteins that birthed life emerged. “It felt like discovering an entire new continent,” he says.
Ramakrishnan has spent his career as a reductionist scientist, viewing the world through the highly focused lens of cellular biology. “SFI represents almost the polar opposite of my career,” he says. “I reduce big systems into a molecule. Here, they study everything from the point of view of the system: how do all the big players interact?” But in a different sense, joining the Santa Fe Institute is an ideological homecoming for Ramakrishnan. His uniquely clear cellular perspective will help researchers grapple with ideas about why life exists and the mechanism of death. Ramakrishnan’s contribution to SFI will again ask that he step out of his comfort zone. He’s glad for the opportunity. He likes to call it pragmatism.