Mention the word DNA, and virtually everyone nods in understanding.
They know or think they know what DNA does. It is the molecule that carries our genes and defines who we are. But mention the word ribosome, and even most scientists will give you a blank stare. Yet life needs the ribosome. The ribosome is the machine that translates the DNA code into the proteins that are essential for life. Virtually every molecule made in every living cell was made either by the ribosome or by enzymes that were themselves made by the ribosome.
In my book, Gene Machine, I describe not only the quest to understand the ribosome, but also the human side of science: the competition and rivalry, the often quirky personalities, as well as the blunders and dead ends along the road to success. The result is a frank look at what scientists are like and how science actually progresses.
It is also the story of how a relative outsider like me suddenly found himself in a high-stakes race for the structure of the ribosome.
After the mid–20th century identification of DNA’s structure, many labs worldwide established that the genetic information of DNA is copied into an intermediate molecule, messenger RNA (mRNA). Other adapter RNA molecules, the tRNAs, recognize a unit of three bases on mRNA called codons, and bring along the appropriate amino acids to be joined together to make a protein.
Cell biologists showed that protein synthesis in cells takes place in blobs on the surface of an organelle called the endoplasmic reticulum. When researchers isolated these blobs, now called ribosomes, the resulting particles were found to be about two-thirds RNA, with the remaining one-third comprising about 50 proteins (ribosomes from higher organisms are more complex and about 1.5–2 times larger). All ribosomes consist of two subunits. The small subunit binds mRNA, and contains the site where the tRNAs recognize the codon on mRNA. The large subunit contains the site of peptidyl transfer, where a bond is formed to attach the new amino acid to the growing protein chain.
All this was known by the 1970s, but the details remained murky. At the time, the only technique available to determine the structures of large molecules was X-ray crystallography. However, it was unclear whether an object as large as the ribosome could crystallize, and even if it could, whether its structure could be solved by crystallographic methods, given that the entire ribosome consisted of about 1 million atoms.
In 1980, Ada Yonath and Heinz Günter Wittmann made an important breakthrough when they produced the first three-dimensional crystals of the large subunit of the ribosome. A few years later, a group in Russia headed by Maria Garber produced crystals of both the small subunit and the entire ribosome. Nevertheless, 15 years after the first crystals, there was still no structure of either subunit of the ribosome. Several groups then entered the fray in the mid- to late 1990s with new ideas and approaches. These included Peter Moore and Tom Steitz working on the 50S subunit; Ada Yonath and I independently working on the 30S subunit; and Harry Noller, Marat and Gulnara Yusupov(a), and Jamie Cate, working on the entire 70S ribosome. The intense competition resulted in low-resolution structures in 1999 and atomic structures of both subunits in 2000. A low-resolution structure of the entire ribosome in 2001 was followed by high-resolution structures in 2005 and 2006. The work culminated in the 2009 Nobel Prize for Chemistry awarded to Yonath, Steitz, and me.
Solving the ribosome took many disparate technical advances. Among these were the development of intense X-ray beams from synchrotrons; cryocrystallography to minimize radiation damage; electronic detectors for X-rays; and very fast computing and computer graphics to solve and visualize structures. None of these were developed with the ribosome in mind. It shows that progress in science does not occur in a vacuum. Rather, when science and technology reach a certain stage, a few people realize that the next leap is possible.
Venki Ramakrishnan is a senior scientist at the Medical Research Council’s Laboratory of Molecular Biology in Cambridge, UK. He shared the 2009 Nobel Prize in Chemistry for his work on solving the ribosome’s structure. Read an excerpt of Gene Machine: The Race to Decipher the Secrets of the Ribosome.