#1: "I'll bet you tried a lot of things that didn't work!"
That’s what Frederick Sanger, a biochemist and 2-time winner of the Nobel Prize in Chemistry, said to Harry Noller, a fellow biochemist and director of the University of California, Santa Cruz's Center for the Molecular Biology of RNA, when discussing Noller’s experiments on determining the structure of the ribosome.
Gene Machine, a memoir by Venki Ramakrishnan, physicist-turned-structural-biologist and winner of the 2009 Nobel Prize in Chemistry, illustrates that quote in vivid detail.
Ribosomes are present in all living cells - from the most primitive bacteria to humans, and were known to help make proteins, but how they did this was still not understood. Ramakrishnan’s earliest experiments aimed at determining the structure of the ribosome involved growing bacteria in heavy water to obtain deuterated proteins (deuterium instead of hydrogen in the protein), so the proteins would scatter neutrons differently from regular proteins and could be exposed to neutron beams to determine the distance between pairs of proteins. By measuring distances between pairs of proteins, you could determine how they were arranged in 3 dimensions.
The project involved making the same measurements again and again with different pairs of proteins in the ribosome.
…After about 3 years, a little over half of the proteins were placed in the small subunit, and we wrote a couple of papers on their location.
After using neutron scattering techniques for nearly half a decade, Ramakrishnan realised not much progress was being made either in determining the structure of the ribosome or in his career. In walked X-ray Crystallography and saved the day - in about 20 years.
Decoding the ribosome structure is one of the big breakthroughs in biology because knowing the structure would help understand how the ribosome worked (form determines function to a large extent in biology), which in turn would develop our understanding of how proteins were made. The experts at the time were not particularly enthusiastic - Sydney Brenner believed solving the ribosomal structure to be a ‘trivial problem’, while James Watson felt the structure was too complex and would never be known. But Ramakrishnan, Ada Yonath, Thomas A. Steitz, Harry Noller and numerous others pursued the dream with relentless tenacity.
Many attempts were made to crystallise the ribosome, harder to do than other molecules because of it’s extremely large size, which resulted in irregular crystals, easily damaged by X-rays during observation. Experiments on ribosome crystals began in the 1960s and even until 1991 no good maps of the ribosome structure existed. Numerous teams tried different crystallography methods and hopped from one particle accelerator facility to another seeking clearer pictures of the ribosomes. Gene Machine shows how many small incremental advances occur over decades, each building on previous work, some misleading researchers along dead ends, and new ideas trickling in from unrelated work suddenly make a large discovery possible. It also lets you get a glimpse inside the mind of a Nobel laureate - the doubts about pursuing research not many people think is promising, the self-belief needed to move continents with family to go after a dream, and the desire to continue doing great work even after despite winning a Nobel.
As Prof. Ramakrishnan wrote, the work never stops
When we have a clear goal in mind, we think we’re struggling to reach a summit. But there is no summit. When we get there, we realize we have just climbed a foothill and there is an endless series of mountains ahead still to be climbed.
The MRC Laboratory of Molecular Biology (LMB) at Cambridge, which features front and centre in Gene Machine, is an unusual research institution:
Many senior scientists didn’t have their own lab and often just had a shared lab or office. The lab was incredibly crowded, with equipment in the hallways and almost no free space. Crowding people together may well have been responsible for the LMB’s success because it made people talk to each other and share ideas and techniques.
…I found that unlike the vast majority of scientists, almost nobody at the LMB was working on routine problems just because they would lead to publishable results. Rather, they were trying to ask the most interesting questions in the field and then developing ways to answer them. A simple but telling question they would ask each other was ‘Why are you doing this?’. Another lesson was that even very famous scientists like Max Perutz or Aaron Klug would unabashedly ask questions at lectures that were often trivial to people in the field. It made me realise that I shouldn’t be ashamed of my ignorance and that no question is too stupid to ask if you want to know the answer.
A third lesson was that a lot of the LMB’s success had to do with limiting the size of teams to just a few people. This forced the group leaders to focus on the most interesting questions and also participate or stay in close touch with the actual work.
Lowering magnesium concentrations makes the ribosome subunits dissociate
And raising it causes them to come together again. This is because the positively charged ions mediate the connections between negatively charged phosphate groups on the RNA in the ribosomes. This is also why magnesium ions must be present for any reactions involving ATP to be carried out!
Mitochondria can multiply!
Mitochondria are the energy generators in cells - the processes that convert glucose to useful energy happen inside them.
Under the right circumstances, cells will make more mitochondria—a process called mitochondrial biogenesis. Some cells end up with a lot of mitochondria. These cells can produce more energy and function at a higher capacity. It is widely believed that the greater the number of healthy mitochondria in a cell, the healthier the cell. We know that the number of mitochondria decreases with age. We also know that the number of mitochondria decreases with many diseases. People who are considered the “fittest” among us—athletic champions—have more mitochondria than most, and their mitochondria appear to be healthier.
Chris Palmer, Brain Energy
There only 5 persons - Marie Curie, Frederick Sanger, John Bardeen, Linus Pauling, Karl Barry Sharpless - ever to have won the Nobel Prize twice.