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A Nobel laureate recounts the story of his quest to discover the structure of a key molecular machine

Gene Machine: The Race to Decipher the Secrets of the Ribosome

Venki Ramakrishnan
Basic Books
2018
288 pp.
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By the late 1970s, the structure of DNA had already been “solved,” and the genetic code already “cracked,” leading many to conclude that there was little left to learn in this arena. However, the quest to understand the process by which the ribosome converts genetic information into proteins was still in its infancy. In Gene Machine, Venki Ramakrishnan provides a frank behind-the-scenes account of the 30-year race to solve the structure of the ribosome that earned him a share of the Nobel Prize in chemistry in 2009.

The first chapters of Gene Machine cover Ramakrishnan’s early career as a researcher, revealing how he serendipitously stumbled onto ribosomes as a research topic. He had wanted to study membrane proteins in Don Engelman’s laboratory at Yale, but there was no vacancy when he inquired. A position was available, however, in the neighboring laboratory of Peter Moore. Moore, incidentally, worked closely with the late Thomas Steitz, who would become Ramakrishnan’s biggest competitor, illustrating the interconnectedness—or, as he describes it, the “inbred” nature—of science.

Ramakrishnan would go on to attain high-resolution structures of the small ribosomal subunit and subsequently the entire 70S ribosome, providing fundamental insights into the process of translation and shedding light on the mechanism of action exploited by antibiotics.

Despite the ribosome’s complicated architecture, it was evident by the early 1980s that obtaining three-dimensional crystals of ribosomal particles was feasible. Here in his retelling, Ramakrishnan reveals a little-known story about Hasko Paradies, a German pediatrician who claimed to have crystallized ribosomes in 1974. Leading crystallographers questioned Paradies’s findings, and he soon “disappeared from the world of biological structures.” But, as Ramakrishnan notes, “Often, just being told something is possible…spurs people to try things.” A number of crystallographers reported that Paradies’s spurious findings encouraged them to continue their own research.

The colorful characters that were involved in the race to crystallize the ribosome provide a richness to the narrative. Ramakrishnan was the “dark horse”—someone who “came out of nowhere and surprised everyone,” according to biophysicist Joachim Frank—and his postdoc, Brian Wimberly, was “Ferrari Boy” (a nickname bestowed on him after Ramakrishnan likened Wimberly’s excitement over a set of electron density maps to “giving a teenager the keys to a Ferrari”).

The text is also full of comical anecdotes. In telling the story of how Pat Unwin and Carlos Taddei obtained two-dimensional protein crystals from lizard oocytes in 1977—the first demonstration that ribosomes were indeed crystallizable—Ramakrishnan reveals how Taddei set off the fire alarms with his cigars and how the pair’s lizards escaped and were seen scampering around the grounds of the Medical Research Council Laboratory of Molecular Biology for years afterward.

As mentioned earlier, among Ramakrishnan’s main competitors was Thomas Steitz, a talented Yale crystallographer, who was renowned for his directness and—as Rama-krishnan observes—a slightly Amish appearance due to his chin-strap beard (on page 897 of this issue, Ramakrishnan and Richard Henderson reflect on Steitz’s legacy). Others included the Israeli crystallographer Ada Yonath, who led a large team split between the Weizmann Institute in Israel and the Max Planck Institutes in Berlin and Hamburg, and the “Sage of Santa Cruz,” biochemist Harry Noller, an RNA expert with “the demeanor of a mellow, pot-smoking California hippie.”

Ramakrishnan, Steitz, and Yonath would share the Nobel Prize in chemistry in 2009 for their work on the ribosome. Although Noller would go on to receive the $3 million Breakthrough Prize in 2016, the Nobel committee’s decision was not without controversy. (Another presumed contender for the 2009 award, Joachim Frank, received the Nobel Prize in chemistry in 2017.)

Ramakrishnan includes some insightful thoughts on the topic of prizes and the politics of recognition. In addition to arguing that limiting the Nobel Prize to only three people is inappropriate, he also identifies some common ailments associated with it, including “pre-Nobelitis,” a condition in which frustration sets in each year when one does not receive the Nobel Prize, and “post-Nobelitis,” an affliction to which many Nobel laureates succumb, which compels them to pontificate on topics in which they are not specialists.

Gene Machine is not an unbiased historical account but rather a memoir that documents a momentous endeavor in scientific history. In the end, however, Ramakrishnan’s personal reflections add color and humanity to the story

About the author

The reviewer is at the Institute for Biochemistry and Molecular Biology, University of Hamburg, 20146 Hamburg, Germany.