Nobel Prize Winner 2022 in Chemistry, Physics and Medicine

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© Johan Jarnestad/Royal Swedish Academy of Sciences

Earlier today, the Royal Swedish Academy of Sciences awarded the 2022 Nobel Prize in Chemistry to Carolyn Bertozzi, Morten Meldal and K. Barry Sharpless “for the development of click chemistry and bioorthogonal chemistry”.

The announcement marked the end of science prizes awarded during Nobel Prize week, as Svante Pääbo received the 2022 Nobel Prize in Physiology on Monday and Alain Aspect, John F. Clauser and Anton Zeilinger received the 2022 Nobel Prize in Physics on Tuesday. The Nobel Prize for Literature and Peace will be awarded on Thursday and Friday.

Click Chemistry

Since the birth of modern chemistry, scientists have looked to nature for clues. Mimicking the molecular structures of plants, microorganisms, and animals has played an important role in pharmaceutical research, particularly in the development of antibiotics. However, mimicking natural molecules is time-consuming, challenging, expensive, and leads to undesirable by-products. For example, it took six years of chemical development to find a way to mass-produce the nature-inspired molecule behind the powerful antibiotic meropenem.

It was here that Sharpless entered the then-unnamed click-chemistry scene. In 2001—the same year he received his first Nobel Prize in chemistry—he wrote a journal article arguing for a new, more minimalistic approach to chemistry.

Sharpless is now only the second person to win the Nobel Prize in Chemistry twice, having previously received the award for his work on chirally catalyzed oxidation reactions. Now he’s being recognized for developing the concept of click chemistry, a form of simple and reliable chemistry that makes reactions happen quickly and avoids unwanted by-products.

Instead of trying to get reluctant carbon atoms to react with each other, Sharpless encouraged his colleagues to start with smaller molecules that already had a full carbon skeleton. These simple molecules could then be linked together by bridges made of nitrogen atoms or oxygen atoms, which are easier to control. When chemists choose simple reactions—where there is a strong intrinsic drive for binding the molecules—they avoid many of the side reactions with minimal loss of material. By combining simple chemical building blocks, an almost infinite variety of molecules can be created. Sharpless believed that click chemistry could create pharmaceuticals that were just as functional as those found in nature—and easily manufactured on an industrial scale.

In the same year, Morten Meldal presented today’s crown jewel in click chemistry: the copper-catalyzed azide-alkyne cycloaddition. While working on a routine reaction to react an alkyne with an acyl halide, Meldal noticed something that was clearly not routine—the alkyne had reacted with the wrong end of the acyl halide molecule. At the other end was a chemical group called azide. Together with the alkyne, the azide formed a ring structure, a triazole. Because triazoles are sought-after chemical building blocks, researchers had previously attempted to make them from alkynes and azides, but this resulted in undesirable by-products. Meldal realized that the copper ions had steered the reaction so that, in principle, only one substance was formed.

Curiously, Sharpless also published work on the copper-catalyzed reaction between azides and alkynes at the same time, showing that the reaction works and is reliable in water. Today, the efficient chemical reaction is widely used—particularly in the development of drugs, for the mapping of DNA, and for the manufacture of more useful materials.

The click chemistry Sharpless developed can do many things, but even he didn’t predict it could be used in living things. This incredibly difficult task was left to Bertozzi, who is only the eighth woman to receive the Nobel Prize in Chemistry since the program began in 1901.

In the early 1990s, Bertozzi began mapping a glycan that attracts immune cells to lymph nodes. However, there were no efficient tools for such a purpose. Bertozzi wanted to use a kind of chemical manipulation to get cells to produce a sialic acid. If the cells could incorporate the modified sialic acid into different glycans, it would be able to use the chemical handle to map them. For example, she could attach a fluorescent molecule to the handle. The light emitted would then show where the glycans were hidden in the cell.

In 1997, Bertozzi succeeded in proving her idea and coining the term “bioorthogonal”. Her next breakthrough came three years later when she found the optimal chemical handle: an azide. She modified a well-known reaction – the Staudinger reaction – and used it to attach a fluorescent molecule to the azide, which she introduced into the glycans of the cells. Because the azide doesn’t affect cells, it can be introduced into living things—adding a whole new dimension to click chemistry.

In addition to a pioneering copper-free click reaction published in 2004, Bertozzi has continued to refine their reactions to ensure they work even better in cellular environments. She, and now many other researchers, have used these reactions to study how biomolecules interact in cells and to study disease processes.

In Sharpless’ first Nobel Lecture in 2001, he used four keywords to describe chemical research: elegant, clever, novel, and useful.

“All four words of praise are necessary to do justice to the chemistry he, Carolyn Bertozzi and Morten Meldal laid the foundation for. Aside from being elegant, clever, novel and useful, it also brings the greatest benefit to mankind,” the Royal Swedish Academy of Sciences said in a statement.

Ancient DNA

On Monday, Svante Pääbo just finished 47thth Physics Laurat not to share the Nobel Prize award with others. Pääbo was recognized for his decades of research and discoveries related to the genomes of extinct hominins and human evolution, which led him to establish the field of paleogenomics.

Early in his career, Pääbo was fascinated by the possibility of using modern genetic methods to study Neanderthal DNA. Easier said than done, of course, thanks to the state of ancient DNA — typically massively degraded and contaminated. Still, as a postdoctoral researcher, Pääbo began developing methods to study what is now known as ancient DNA (aDNA) — an endeavor that would take several decades.

In 1990, using his sophisticated methods, Pääbo succeeded in sequencing a region of mitochondrial DNA from a 40,000-year-old piece of bone. This was the first time researchers were able to read a DNA sequence from an extinct relative – leading to the conclusion that Neanderthals were genetically distinct from modern humans and chimpanzees.

Pääbo was then offered the opportunity to establish a Max Planck Institute in Leipzig, Germany. There he and his team constantly improved the methods for isolating and analyzing DNA from archaic bone remains. They took advantage of new technological developments and engaged several critical collaborators with expertise in population genetics and advanced sequence analysis.

In 2008, Pääbo and his team extracted and analyzed well-preserved DNA from a 40,000-year-old finger bone discovered in Denisova Cave in southern Siberia. The results were as unexpected as they were extraordinary: the DNA sequence was unique compared to all known sequences from Neanderthals and modern humans. Pääbo had discovered a previously unknown hominin who was given the name Denisova. Comparisons with sequences from contemporary humans from different parts of the world showed that gene flow had also occurred between Denisova and Denisova homo sapiens. This relationship was first observed in populations in Melanesia and other parts of Southeast Asia, where individuals carry up to 6% Denisova DNA.

In 2010, Pääbo saw the realization of his great goal when he published the Neanderthal genome sequence. Comparative analyzes showed that the most recent common ancestor of Neanderthals a homo sapiens lived about 800,000 years ago.

“The Pääbo discoveries have led to a new understanding of our evolutionary history,” the Royal Swedish Academy of Sciences said in a statement.

Entangled states

On Tuesday, Alain Aspect, John F. Clauser and Anton Zeilinger received the 2022 Nobel Prize in Physics “for experiments with entangled photons, demonstrating the violation of Bell’s inequalities and pioneering quantum information science”.

In quantum mechanics, what happens to one of the particles in an entangled pair determines what happens to the other particle, even if they are far apart. For a long time the question was why? Was the correlation because the particles in an entangled pair contained hidden variables, or instructions telling them what result to give in an experiment?

In the 1960s, John Stewart Bell developed his eponymous mathematical inequality, which states that for hidden variables, the correlation between the results of a large number of measurements never exceeds a certain value. However, quantum mechanics predicts that a certain type of experiment violates Bell’s inequality, resulting in a stronger correlation than would otherwise be possible.

Clauser by JF Clauser & Assoc. was awarded 1/3 of the 2022 prize for his development of Bell’s ideas which resulted in a practical experiment. When Clauser made the measurements, they supported quantum mechanics by clearly violating a Bell inequality. This means that quantum mechanics cannot be replaced by a theory that uses hidden variables.

However, some loopholes remained after Clauser’s experiment, which Alain Aspect of the Université Paris-Saclay fixed. He could change measurement settings after an entangled pair left its source, so the setting that existed at the time of emission could not affect the result.

Finally, with refined tools and long series of experiments, Anton Zeilinger from the University of Vienna and his research group demonstrated a phenomenon called quantum teleportation, which makes it possible to shift a quantum state from one particle to a distant one.

“It is becoming increasingly clear that a new type of quantum technology is emerging. We see that the work of the laureates with entangled states is of great importance, even beyond the fundamental questions about the interpretation of quantum mechanics,” said Anders Irbäck, Chair of the Nobel Committee on Physics.

The foundations of quantum mechanics are not just theoretical or philosophical. In today’s technologically advanced world, research and development is increasing to use the special properties of individual particle systems to construct quantum computers, improve measurements, build quantum networks and establish secure quantum-encrypted communication.

Information provided by the Royal Swedish Academy of Sciences.

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