The Nobel Prize in Chemistry in 2009 was awarded to three people including Venki Ramakrishnan. Ramakrishnan is an American-British-Indian scientist who played a key role in discovering the atomic structure of ribosomes. He wrote a book titled Gene Machine, chronicling the ribosome breakthrough, which was published in 2018.
Ribosomes are present in cells of living beings and play a vital role. They translate information (encoded in genes) to make proteins, which are the building blocks of life. Knowing the atomic structure of ribosomes is key to figuring out how they work. For example, earlier, scientists only had a limited understanding that antibiotics worked by suppressing the functioning of ribosomes. With Ramakrishnan and co.’s research findings, scientists have a much deeper understanding of ribosome function and can use that knowledge to not only create better antibiotics but unlock greater mysteries of life.
To make a scientific discovery of such significance, Ramakrishnan had to make bold moves in his career. After he got a PhD in Physics, he didn’t think physics research would be exciting. He felt the field of biology was ripe for breakthrough discoveries, so he made a fresh start by taking undergraduate classes in biology to be able to do research. Mid-career he moved his family to different cities and switched research institutions to have a real shot at the ribosome problem.
He worked in many research institutions in his career but the place where he did most of his award-winning work was the Medical Research Council Laboratory of Molecular Biology (MRC LMB) at Cambridge, UK. MRC LMB is a special place and has produced a number of Nobel laureates in chemistry and medicine, making it a kind of Silicon Valley for molecular biology.
These are some excerpts from the book.
Trillions of cells in the human body and each cell contains loads of ribosomes. Every molecule in every cell in every form of life is either made by the ribosome or made by enzymes that are themselves made by the ribosome.
To do biology you need to know a lot of facts and jargon.
Genes are units of information that allow a whole organism to develop from a single cell like a fertilized egg. Although nearly all cells contain a full set of genes, different sets of genes are turned on or off in different tissues. A gene is a stretch of dna that contains information on how and when to make a protein. Proteins carry thousands of functions in life. They let us sense light, touch, and heat and help us fight off diseases. They carry oxygen from our lungs to our muscles. Even thinking and remembering are made possible by proteins. Many proteins called enzymes catalyze the chemical reactions that make the thousands of other molecules in the cell. Proteins not only give a cell it’s structure and shape but also enable it to function.
In each dna molecule, the two strands of dna that intertwine to form a double helix run in opposite directions. Each strand has a backbone of alternating sugar and phosphate groups, and one of the four types of bases: A,T, C, G is attached to the sugar and faces the inside of the helix. While playing with cardboard cutouts, Watson realized that an A on one strand could chemically bond or pair to a T on the other but not to any of the other bases, while a G on one strand could similarly pair only with a C on the other. In doing so, the shape of each base pair, whether it was AT or CG, was about the same, which meant that regardless of the order of the bases, the overall shape and dimensions of the double helix was about the same. This formation of base pairs meant that the order of bases on one strand would precisely specify the order on the other strand. When the cell divided the two strands would separate and each would have information to serve a template to make the other strand, resulting in two copies of the dna molecule from one. In this way, genes were able to duplicate themselves.
Like many other fields, science has its fashions, and at any given time, some areas are considered more interesting than others. Often these are new areas where people are making rapid advances. Many scientists move on from a problem as soon as it gets too hard to make further progress. Those who are very creative open up entirely new areas, but others just follow one fashionable area after another. If everyone did this, our understanding of phenomena would be quite superficial, but fortunately there are other scientists who stick with a problem, no matter how old and difficult it is, to get to the bottom of things.
We say seeing is believing, and it is astonishing how often just being able to see things has changed our understanding of the world. For centuries, we had many misconceptions about the human body because our knowledge of it came from the Greek physician Galen, who based it on dissecting animals. It was only in the 1500s when Andreas Vessalius started dissecting human corpses that we started to understand our own autonomy
For most of human history we were limited by what we could see with the naked eye. The detail with which we could see dramatically expanded in the mid 1600s when a Dutch linen merchant Antonie van Leeuwonhoek wanted to examine cloth fibers more closely so went on to invent the most powerful microscope of his time. When he examined pond water or scum scraped off his own teeth he saw small creatures that he called animalcules, which we know today as microbes.
Cells are made of molecules, which are groups of atoms held together in a very specific way. The atomic theory of matter took such a long time to develop and is so important that Richard Feynman said that if all scientific knowledge were to be destroyed and only one sentence could be passed on to the next generations of humans, it should be — “All things are made of atoms — little particles that move around in perpetual motion, attracting each other when they are a little distance apart but repelling upon being squeezed into each other.”
It is astonishing that in 18th and 19th centuries, without being able to see molecules, scientists not only deduced their existence but also their structure — the arrangement of atoms that make up the molecule. They could do this for simple molecules like common salt, which only has two atoms and somewhat complicated molecules like sugar which has a dozen atoms. But with larger and more complex molecules it becomes increasingly difficuly to infer their structures without being able to visualize them directly. p28
Visible light has a wavelength of 500nm and bends around edges of objects or when it goes through tiny slits. Because of this diffraction, it’s not possible to resolve two different objects that are less than half the wavelength apart. Two objects will appear as a single fuzzy object. So, optical microscopes are not good for resolving small objects. Roentgen discovered X-rays in the late 1800s and Max Von Laue figured out X-ray wavelength to be 1000 times less than visible light and also that it creates a specific diffraction pattern when incident on a crystal lattice. He showed it was possible to infer the arrangement of atoms in a crystal lattice from the diffraction pattern.
Lawrence Bragg came up with an elegant way to infer crystal lattice from diffraction pattern. He said that any crystal can be thought of as comprising of planes. For a particular scattering angle of x-rays the x-ray has to travel a whole wavelength to cover the distance between two planes. For any set of planes, the additional path traveled by x-rays scattered off adjacent planes in a whole wavelength for a particular angle. The relationship between the angle and the distance between planes is called Bragg’s law. At any given position, there might be several planes that satisfy the Bragg condition, each giving rise to a spot at a particular angle relative to the incident X-ray beam.
(John Desmond) Bernal was a brilliant polymath, but he was something of an intellectual butterfly. He made the first pioneering forays into lots of important problems but didn’t always see them to completion. Perhaps he had too many distractions.
Advances in biology are often made by choosing the right organism to work on. For example, the study of nerve transmission was made possible by using giant axons from squid because they were large enough to see and stick electrodes into. Early geneticists used fruit flies because they breed quickly and you can follow lots of visual markers like eye color to deduce how various traits were inherited. For bacteria, the standard organism for biochemical and genetic studies of all sorts is E. Coli, because it’s easy to grow and double every twenty minutes. p48
Molecules from thermophilic bacteria are resistant to heat, they are thought to be more stable and likely to crystallize.
The ribosome is made of 2 subunits – 50s and 30s, to indicate how fast they sediment in a test tube when spun at high speeds in a centrifuge. The S stands for Svedberg units.
Venki’s 1 year at the LMB made him realize what a special place it was and changed his entire outlook on science. 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 their 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 Venki realize 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 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 at least stay in close touch with the actual work.
As is nearly always the case in science, the structures of the ribosome simply moved the questions to the next level. When we have a clear goal in mind, we think we are 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 suprise learning for me, from reading the book, was how little we know of things happening at the cellular level. We’re only now comprehending how important parts of a cell, ribosomes, function to make proteins. The field of molecular biology has numerous fundamental questions left to answer by generations of scientists to follow.