© Johan Jarnestad/The Royal Swedish Academy of Sciences
Early Wednesday morning, 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 the science awards given out during Nobel Prize week, as Svante Pääbo won the 2022 Nobel Prize in Physiology on Monday, and Alain Aspect, John F. Clauser and Anton Zeilinger were awarded the 2022 Nobel Prize in Physics on Tuesday. The Nobel Prize in Literature and Peace will be awarded on Thursday and Friday, respectively.
Click chemistry
Since the birth of modern chemistry, scientists have looked to nature for clues. Imitating molecular structures found in plants, microorganisms and animals has played a large role in pharmaceutical research, especially the development of antibiotics. But, imitating natural molecules is time-consuming, demanding, expensive and results in unwanted byproducts. For example, six years of chemical development work were necessary to find a way of producing the nature-inspired molecule behind the powerful antibiotic meropenem on a large scale.
This is where Sharpless entered the then-unnamed click chemistry scene. In 2001—the same year he won his first Nobel Prize in Chemistry—he wrote a journal article arguing for a new, more minimalistic approach to chemistry.
Sharpless is now just the second person ever to be awarded the Nobel Prize in Chemistry twice, previously being given the award for his work on chirally catalyzed oxidation reactions. Now, he is being recognized for developing the concept of click chemistry, which is a form of simple and reliable chemistry where reactions occur quickly and unwanted byproducts are avoided.
Instead of trying to wrangle reluctant carbon atoms into reacting with each other, Sharpless encouraged his colleagues to start with smaller molecules that already had a complete carbon frame. These simple molecules could then be linked together using bridges of nitrogen atoms or oxygen atoms, which are easier to control. If chemists choose simple reactions—where there is a strong intrinsic drive for the molecules to bond together—they avoid many of the side reactions, with a minimal loss of material. Combining simple chemical building blocks makes it possible to create an almost endless variety of molecules. Sharpless was convinced that click chemistry could generate pharmaceuticals that were as fit for purpose as those found in nature—and could easily be produced on an industrial scale.
That same year, Morten Meldal presented what is now the crown jewel of 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 distinctly not routine—the alkyne had reacted with the wrong end of the acyl halide molecule. At the opposite end was a chemical group called an azide. Together with the alkyne, the azide created a ring-shaped structure, a triazole. Because triazoles are desirable chemical building blocks, researchers had previously tried to create them from alkynes and azides, but this led to unwanted by-products. Meldal realized that the copper ions had controlled the reaction so that, in principle, only one substance formed.
Oddly enough, at the same time, Sharpless also published a paper about the copper catalyzed reaction between azides and alkynes, showing that the reaction works in water and is reliable. Today, the efficient chemical reaction is widely used—especially in the development of pharmaceuticals for mapping DNA and creating materials that are more fit for purpose.
The click chemistry that Sharpless pioneered can do many things, but even he didn’t predict it could be used in living things. That incredibly difficult task was left to Bertozzi, who is just the eighth woman to win the Nobel Prize in Chemistry since the program’s inception in 1901.
In the early 1990s, Bertozzi began mapping a glycan that attracts immune cells to lymph nodes. However, no efficient tools existed for such a purpose. Bertozzi wanted to get cells to produce a sialic acid with a type of chemical handle. If the cells could incorporate the modified sialic acid in different glycans, she would be able to use the chemical handle to map them. She could, for example, attach a fluorescent molecule to the handle. The emitted light would then reveal where the glycans were hidden in the cell.
In 1997, Bertozzi succeeded in proving her idea, devising the term “bioorthogonal” along the way. Her next breakthrough occurred three years later when she found the optimal chemical handle: an azide. She modified a known reaction—the Staudinger reaction—and used it to connect a fluorescent molecule to the azide she introduced to the cells’ glycans. Because the azide does not affect the cells, it can be introduced into living creatures—adding an entirely new dimension to click chemistry.
In addition to a breakthrough copper-free click reaction published in 2004, Bertozzi has continued to refine her reactions to ensure they work even better in cell environments. She and now many other researchers have used these reactions to explore how biomolecules interact in cells and to study disease processes.
In Sharpless’ first Nobel Lecture in 2001, he used four keywords to describe chemistry research: elegant, clever, novel and useful.
“All four of these words of praise are necessary to do justice to the chemistry for which he, Carolyn Bertozzi and Morten Meldal have laid the foundation. In addition to being elegant, clever, novel and useful, it also brings the greatest benefit to humankind,” The Royal Swedish Academy of Sciences said in a statement.
Ancient DNA
On Monday, Svante Pääbo became just the 47th physics laurate to not share the awarding of the Nobel Prize with others. Pääbo was recognized for his decades-long research and discoveries concerning the genomes of extinct hominins and human evolution, which led him to establish the field of paleogenomics.
Early in his career, Pääbo became fascinated by the possibility of utilizing modern genetic methods to study the DNA of Neanderthals. This, of course, was easier said than done thanks to the condition of ancient DNA—typically massively degraded and contaminated. Still, as a postdoctoral student, Pääbo began to develop methods to study what is now known as ancient DNA (aDNA)—an endeavor that would last several decades.
In 1990, with his refined methods, Pääbo managed to sequence a region of mitochondrial DNA from a 40,000-year-old piece of bone. This marked the first time researchers could read a DNA sequence from an extinct relative—which led to the conclusion that Neanderthals were genetically distinct from modern humans and chimpanzees.
Pääbo was then offered the chance to establish a Max Planck Institute in Leipzig, Germany. There, he and his team steadily improved the methods to isolate and analyze DNA from archaic bone remains. They exploited new technical developments and engaged several critical collaborators with expertise on population genetics and advanced sequence analyses.
In 2008, Pääbo and his team extracted and analyzed well-persevered DNA from a 40,000-year-old finger bone discovered in the Denisova cave in the southern part of Siberia. The results were as unexpected as extraordinary: the DNA sequence was unique compared with all known sequences from Neanderthals and present-day humans. Pääbo had discovered a previously unknown hominin, which 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 Homo sapiens. This relationship was first seen in populations in Melanesia and other parts of South East Asia, where individuals carry up to 6% Denisova DNA.
In 2010, Pääbo saw the realization of his ultimate goal when he published the Neanderthal genome sequence. Comparative analyses demonstrated that the most recent common ancestor of Neanderthals and Homo sapiens lived around 800,000 years ago.
“Pääbo’s discoveries have generated new understanding of our evolutionary history,” the The Royal Swedish Academy of Sciences said in a statement.
Entangled states
On Tuesday, Alain Aspect, John F. Clauser and Anton Zeilinger were awarded the 2022 Nobel Prize in Physics “for experiments with entangled photons, establishing the violation of Bell 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 that tell them which result they should give in an experiment?
In the 1960s, John Stewart Bell developed the mathematical inequality that bears his name, which states that if there are hidden variables, the correlation between the results of a large number of measurements will never exceed a certain value. However, quantum mechanics predicts that a certain type of experiment will violate Bell’s inequality, thus resulting in a stronger correlation than would otherwise be possible.
Clauser, of J.F. Clauser & Assoc., was recognized with 1/3 of the 2022 prize for his development of Bell’s ideas, leading to a practical experiment. When Clauser took 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 Université Paris-Saclay’s Alain Aspect fixed. He was able to switch the measurement settings after an entangled pair had left its source, so the setting that existed when they were emitted could not affect the result.
Lastly, University of Vienna’s using refined tools and long series of experiments, University of Vienna’s Anton Zeilinger and his research group demonstrated a phenomenon called quantum teleportation, which makes it possible to move a quantum state from one particle to one at a distance.
“It has become increasingly clear that a new kind of quantum technology is emerging. We can see that the laureates’ work 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 for Physics.
The fundamentals of quantum mechanics are not just theoretical or philosophical. In today’s technologically advanced world, increased research and development are underway to utilize 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.