Venkatraman “Venki” Ramakrishnan’s story is the stuff of fiction. He went from an eager undergraduate student in India to a self-described “failed physicist” to a major player in the race to uncover one of biology’s biggest mysteries—the structure of the ribosome, the most important molecule that nobody’s heard of that earned him a Nobel Prize in chemistry in 2009.
The opportunity to research the ribosome drew Ramakrishnan to the University of Utah in the late ‘90s. The ancient molecule brings him back as a Nobel laureate to discuss his “Adventures in the Ribosome” at the College of Science’s Frontiers of Science Lecture Series on Sept. 26, at the Natural History Museum of Utah. The evening should be enthralling—his popular memoir Gene Machine reads like a thriller that navigates inspired collaborations, friendly rivalries, and cutthroat competition behind scientific discoveries and international accolades.
“Why did my career work out? I didn’t go to any famous schools for my undergrad or graduate school, and I was sort of an outsider most of my life. I think there’s some sort of general lessons there,” Ramakrishnan said. “One of them is if you find things don’t work out, you have to be open to change.”
Ramakrishnan has never been afraid of change. He earned a PhD in theoretical physics at the University of Ohio, but immediately realized that developing theories and mathematical calculations wasn’t for him. The field of biology grabbed his attention.
“Every issue of Scientific American when I was a grad student was full of big breakthroughs in biology. That was a time when the first sequences of DNA were being reported, Ramakrishnan said. “Biology was going through this huge revolution, and it hasn’t stopped.”
He studied biology for two years at the University of California San Diego before beginning his postdoctoral work at Yale University, where he became enthralled with the ribosome, a molecular machine made of protein and RNA. The molecule DNA holds genetic information with instructions that build all life on Earth, but the blueprint is useless without something to read and carry out the instructions. Enter the ribosome, which translates the genetic information encoded in DNA into thousands of proteins that that carry out all functions necessary for life.
“I like to say that everything in the cell was either made by the ribosome or were made by enzymes that were themselves made by the ribosome. So, really you can think of it as the mother or grandmother of everything in the cell,” said Ramakrishnan. “Ribosomes are incredibly essential to understanding life. And it’s also hugely complex.”
Ribosomes consist of two separate units, known as the small and large subunits. Since its discovery in the 1950s, scientists had searched for the answer to ribosome structures like the holy grail. Famous scientists had been working for decades on large subunit, so Ramakrishnan decided to focus on the ignored smaller subunit, known as 30S. During his postdoc at Yale, he met Wes Sundquist, a University of Utah biologist on sabbatical with whom he shared a lab bench. They maintained contact and eventually, Sunquist convinced Ramakrishnan and his wife to move to the University of Utah. Then the doubts kicked in.
“I accepted the job,” he recalled, “but a week later, I panicked at the thought of having to be totally reliant on external funding once my start-up had run out.” He called up Dana Carroll, who was chairman of the Department of Biochemistry at the time. “I said I was sorry, but I couldn’t come after all.”
Though disappointed, Carroll kept the position open, allowing Ramakrishnan time to ruminate on the offer. “[A]fter some agonizing, I decided to put aside my fears about funding and move to Utah.”
Upon his arrival at the U in 1995, the Department of Biochemistry was a small but dynamic entity that had a relatively young but decidedly ambitious faculty working on answers to the big questions. Along with Carroll and Sundquist, he soon fell in with the “charismatic crystallographer” Chris Hill. Beyond his immediate colleagues, John Atkins, Brenda Bass, Jim McCloskey and biologist Ray Gesteland, now professor emeritus of the School of Biological Sciences, were pushing forward knowledge of the ribosome and RNA.
“The department lived up to every promise it had made,” said Ramakrishna, “and within a few months, I had settled in and got my lab running.”
Ramakrishnan’s lab was soon joined by a technician Adrian Hahn and postdoctoral researcher Bob Dutnall, and the team focused on solving ribosomal protein structures of the smaller subunit that they believed was being ignored by other labs.
“[German scientists] had been working on [the structure of the larger subunit] for 15 years when I arrived in Utah. And a couple of meetings that I went to right around that time, ’95 and ’96, made me and some other people in the ribosome field feel that that group had stalled, and the field could use new ideas, new insight, new approaches, and maybe some competition.”
At a conference in Sweden in 1997, he realized that the groups that had previously focused on the larger subunit had turned their attention to the one he was working on. The race was on truly on.
After doing foundational work at the U, Ramakrishnan moved to the United Kingdom in 1999 where he has been a group leader at the MRC Laboratory of Molecular Biology (LMB) at Cambridge University. Using a technology known as x-ray crystallography, Ramakrishnan and other researchers were able to collaborate to map the atomic structure of the 30S ribosomal subunit and its complexes with ligands and antibiotics, leading to insights into how the ribosome “reads” the genetic code. It was a watershed moment.
“Before that, you had no idea how all these players came together in three dimensions. And of course, biology doesn’t happen in two dimensions, it happens in three dimensions. So does all of life,” he said. “To understand how all these molecules could come together to interact, why they interacted the way they did, I think that the structure opened up those possibilities.”
Ramakrishnan will expound on his adventures in the ribosome on Tuesday, Sept. 26 at the Natural History Museum of Utah. The event is free and open to the public; however, seating is limited. More information about this event can be found at here.
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