“Look, he’s on his way to the microscope!” Sjors Scheres (1975) points out a colleague striding past carrying a steaming bowl. There is liquid nitrogen at a temperature of more than 180 degrees below zero, and inside it again is a piece of gold confetti. At least that’s what it looks like, but it’s a mesh – a metal plate with a diameter of 2 mm, made of copper or gold, with a few drops of purified protein on it. Now only this protein has Flash freeze-Undergoing treatment with another cold substance, such as liquid ethane. “This ensures that the protein freezes very quickly so that no crystals form and is more clearly visible under the microscope.”
This microscope is no ordinary microscope, Sherris explains, as he quickly descends the stairs at the MRC Laboratory of Molecular Biology in Cambridge – he walks as fast as he talks. It is enthusiasm and passion for the profession. For nearly twenty years, Shires has been one of the leading scientists in the field of cryo-electron microscopy, or cryo-EM for short. A technique by which electrons are fired through an immobilized molecule (e.g. a protein) to visualize details down to the atomic level.
As a structural biologist, Shires revolutionized his field in 2012 with the Relion computer algorithm he developed. Trade magazine nature He called him one of “Ten important people this year.”“, received numerous awards and became a Fellow of the prestigious Royal Society. Because structural biologists around the world are now working with Relion: thanks to the algorithm, good 3D images of proteins can be produced for the first time, based on cryo-EM images. This is a big deal Importance for research into Alzheimer’s disease, among other things. Shires quickly passes posters containing close-ups of tau proteins, which play a crucial role in the brains of Alzheimer’s patients. “They’re made of,” he opens the door triumphantly, “this electron microscope!”
If I’m being really honest, I’m basically seeing a black and white box of blocks…
“Yes, The real magic happens on the inside…It’s running now so we can’t look at it. But imagine it this way: a robot arm holds the frozen grid in place and then shoots all kinds of electrons through it. We can then see these protein images in 3D down to the atomic scale on a computer. The microscope here is specially placed on the ground floor, on a thick concrete slab – if you’re working with atomic precision, you don’t want unwanted vibrations.
“Here, for example, you see a beautiful thread of tau protein. Elongated fibers that look innocent enough in themselves. But unwanted accumulations of these threads are occurring in the brains of Alzheimer’s patients. They appear to differ in shape from the tau proteins found in the brains of Alzheimer’s patients. In healthy people, in cross-section it has a distinctive C-shape: the “Alzheimer’s structure.”
Thanks to this microscope and your algorithm, we can study this structure in 3D?
“The first images of these accumulations were taken in the brain of an Alzheimer’s patient nearly a century ago, using polarized light. Later, these individual strands were studied in more detail using X-rays and ‘regular’ electron microscopy.” Cryo-EM was initially produced Very low accuracy.It was not without reason that it became the method blobology The name of the thing. But around 2013, a decision revolution occurred. On the one hand, electron detectors have become more precise, and on the other hand, Relion has allowed us to make good 3D images of proteins for the first time. Including tau proteins from the brains of deceased Alzheimer’s patients.
What is the function of tau proteins?
“In the brains of healthy people, they appear to ensure the stability of microtubules, which are the transport tubes in cells. In principle, our genes determine the order of amino acids, which in turn determines the three-dimensional structure and function of the final proteins. But sometimes something goes wrong. Then some proteins fold.” “Into a different form, there seems to be a snowball effect where you encourage other proteins to do the same thing. They eventually accumulate.”
So, Alzheimer’s isn’t the only disease where things go wrong?
“Strikingly, you also see C-shaped strands of tau proteins in chronic traumatic encephalopathy, a disease in which nerve cells die due to repetitive traumatic brain injury, for example in professional rugby players or boxers. But the C-shaped strands are different in shape: “They’re less closed than they are in Alzheimer’s disease. You also have neurodegenerative diseases in which another protein causes problems. Parkinson’s disease, for example. Proteins can take different shapes in different diseases.”
The MRC laboratory is built in the shape of an X – “a reference to the shape of chromosomes”. It is a world-renowned research institute in the field of molecular biology. It is no coincidence that vaccine developer AstraZeneca is moving to Cambridge. “They’re across the street now.” Sheris takes the stairs to the top floor. “From the restaurant there you can enjoy a beautiful view of Cambridge.”
Shires grew up in northern Limburg. “My father was a village vet, and I wanted to be one too. But when I was selected for veterinary medicine, I decided to study chemistry. While doing his PhD, he wanted to unravel the structure of a protein, but laboratory research – purifying proteins – did not suit him. “A lot of absurdity. Then I started developing software to help uncover those structures.
At first I worked mainly with X-rays.
“Yes, but it was already automated to the point that there was little possible in terms of software improvement. That’s when I started focusing on cryo-EM. This method was still in its infancy.”
“…The squors of twenty years ago would also find that this is not challenging enough, haha. Yes, we have come a long way with cryo-EM technology. But there are still challenges. We can already take images of solid protein molecules with an atomic resolution of 0.1 nanometers. Just: Most proteins are very mobile. That’s why we now want to use artificial intelligence to ensure that these molecules can also be imaged down to the atomic level. At the same time, we want to reveal the protein structures of neurodegenerative diseases in more detail. If we can recreate these structures, We hope this will lead to a better understanding of the molecular mechanisms behind them, and who knows, this may one day lead to better diagnosis and treatment.
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