Research Fellow: Martin Scheming (2006–09, Bye Fellow 2009–)
Martin Schmeing became a scientist because he was curious about the inner workings of the natural world. Over the last ten years he has been lucky to work with some exceptional researchers, two of whom won the Nobel Prize in 2009.
Protein shakes & Swedish (meat)balls
We share a drive to uncover the essence of biology and together we have been able to learn something fundamental about how nature produces one of its most important molecules: proteins.
Proteins are everywhere. They are essential to all life as we know it. Proteins are used as an energy source (as the now-ubiquitous protein shake illustrates); they define the shapes and structure of cells; they are the molecules our bodies use to digest, to synthesise chemicals, to protect us from infection, to process the air we breathe, and so on and so on.
The instructions to make these different proteins lie in the sequence of our DNA, as the order of DNA nucleotides in a gene indicates the order in which to assemble amino acids, the building blocks that make up every protein. The molecular machine that reads the gene sequence (after it has been copied from the DNA into a similar molecule called mRNA) is known as the ribosome. The ribosome is huge by molecular standards, containing around 250 000 atoms (a sugar molecule has 20 atoms). It is also extremely complicated, complete with subcomponents, moving parts and all sorts of different accessories. The ribosome lands on an mRNA and, looking at the nucleotide sequence, recruits the specified amino acids (which are linked to other RNA molecules, called tRNAs in the form of amino acyl-tRNA) to use in protein synthesis. The ribosome takes amino acids off from the tRNAs and chemically snaps them together like LEGO blocks, one at a time, to make a protein.
The basic idea behind this process has been known for decades. The ribosome was discovered in the 1950s, and by the 1960s it was known that the ribosome itself was made out of both protein and RNA components, and could be divided into a large and a small subunit. The small subunit binds the mRNA and one part of the tRNA, and the large subunit binds the other part of the tRNA and links together the amino acids. But in science, it’s all about the details. How exactly does the ribosome select the correct amino acyl-tRNA out of a cell full of incorrect ones? How does the chemical reaction that links amino acids together get enzymatically catalysed by the ribosome?
Working with Tom Steitz and his group at Yale University, I used X-ray crystallography to take three-dimensional pictures of the ribosome’s large subunit. This technique had become routine for small molecules, but it has taken researchers decades to get it to work on the ribosome. To figure out how the ribosome makes proteins, I used modified amino acyl-tRNAs, which would pause the linking reaction at different stages, and then took the pictures. This gave us a series of still frames which, when looked at quickly in order (much like a child’s flick book) provides a rough film of the ribosome building proteins from amino acids. These sequences are both a good way to share our results with other scientists and the public, and also tell us quite a lot about the process. We discovered that the chemical ‘active site’ of the ribosome responsible for adding the amino acids together was made of RNA and not protein. This had been hypothesised many years before by Francis Crick while he was thinking about protein’s version of the chicken-and-egg problem: if the ribosome, which makes proteins, is made out of protein, how was the first ribosome made? With proof that the important parts of the ribosome for making proteins were in fact RNA, this apparent paradox was resolved. We also showed that the ribosome protects the unstable linkage between amino acid and tRNA before it is time to add it to the growing protein, and figured out how the actual chemical catalysis of linking amino acids together works.
Around the same time, Venki Ramakrishnan and his group at the MRC Laboratory of Molecular Biology here in Cambridge were also using X-ray crystallography to study the ribosome, discovering how the small subunit can tell when the mRNA and tRNA are matching. I used my Research Fellowship at Emmanuel to join Venki in Cambridge and we looked at the entire ribosome with an accessory factor (called EF-Tu), which delivers the amino acyl-tRNAs to the ribosome. We discovered how monitoring of mRNA-tRNA matching by the ribosome is communicated to EF-Tu, telling it whether the proper amino acid is present and, if so, allowing the large ribosomal subunit to add it to the growing protein. This is an extremely important process, since if the wrong amino acid is linked, it causes a mutation in the protein.
One morning last October, while discussing these results with a colleague, I overheard Venki on the ’phone, saying ‘You have a lovely Swedish accent, but I don’t believe you, you must be playing a trick.’ I did believe it though, as right away I knew what was going on: the famous call from the Nobel Committee. We all realised that the ribosome work was of fundamental importance, and for years there had been whispers about recognition. I happened to have a bottle of champagne from Emmanuel’s cellars on hand, so as soon as Venki was off the ’phone I gave him a big hug and we popped the cork to celebrate with the research group. He told me he was sharing the prize with Tom and Ada Yonath, which meant I now had worked with two laureates. The call comes through 20 minutes before the prize is announced publicly, and laureates are sworn to secrecy for that time, so we shut the lab and enjoyed our morning bubbly. I sent off a congratulatory email to Tom and was thus the first to congratulate him since it was still a secret. Once the announcement was made, the lab became a madhouse. Well-wishers and reporters from around the world showed up in no time to interview Venki and us. Somewhere in Chinese TV archives there is an interview with me after my fourth glass of champagne, which I am glad never to have seen.
If the day of the announcement was a celebration, Nobel week in December was doubly so. I was invited to attend by Tom, because of my contributions to the work for which he was recognised. Indeed, the scientific explanation of the prize hailed one of my papers with Tom as the ‘jewel in the crown’ of the studies investigating the reaction linking amino acids together, something for which I’ve taken a lot of good-natured ribbing. Nobel week was a string of talks, parties and receptions, culminating in the day of the medal presentation. The festivities start at Stockholm’s opera house, where the King of Sweden bestows the laureates with their prizes. This is followed by an extravagant feast at the City Hall, televised to all of Sweden, for which formal guest nights at Emmanuel had prepared me exceedingly well. I found it amusing to watch Venki, who is most comfortable in a holey sweater and trousers still tucked into his socks from that morning’s bike ride, escorting the young Crown Princess of Sweden in the royal procession. Dancing in the Golden Hall followed, and the celebrations stretched well into the next morning as we were taken by bus to the Karolinska Institute (Stockholm’s medical university) for the after-party: a full Oxbridge white-tie May Ball style party that raged until 6 am. It was a perfect way to draw celebrations to a close.
Curiosity and drive to understand the world is what motivates scientists, and neither I nor the laureates got into science to win prizes. When our work leads to more profound understanding of important aspects of nature, that is both the goal and the reward. However, it is certainly nice to contribute both to the hard work and to the celebrations.
Tom Steitz’s Nobel Lecture (when repeated at Yale) can be seen here: http://www.youtube.com/watch?v=FgEeLRTGKwc