At around 17:45 Beijing time on October 5, 2022, the 2022 Nobel Prize in Chemistry was awarded to American scholar Caroline R. Bertosi, Danish scholar Morten Medal, and American scholar K Barry Shapley, in recognition of their contributions to the development of click chemistry and bioorthogonal chemistry.
Carolyn R. Bertozzi was born in 1966 in the United States. I obtained my doctoral degree from the University of California, Berkeley in 1993. Current professors Anne T. and Robert M. Bass at Stanford University in the United States.
Morten Meldal was born in Denmark in 1954. Obtained a doctoral degree from the Technical University of Denmark in 1986. Current professor at the University of Copenhagen in Denmark.
K. K. Barry Sharpless was born in Philadelphia, Pennsylvania, USA in 1941. Obtained a doctoral degree from Stanford University in the United States in 1968. Current Professor W. M. Keck at the Scripps Research Center in the United States. He shared the 2001 Nobel Prize in Chemistry with two other scholars for his research on chiral catalytic oxidation reactions. This award makes him the second scientist, after Frederick Sanger, the pioneer of protein sequencing and DNA sequencing, to receive the Nobel Prize in Chemistry twice.
Sometimes a simple answer is the best. Barry Shapley and Morten Medal brought chemistry into the functionalist era and laid the foundation for click chemistry; They are with Caroline R Bertosi shared the 2022 Nobel Prize in Chemistry, which took click chemistry to a whole new dimension and began using this tool to draw cell maps. The bioorthogonal reaction developed by Bertosi has achieved various applications, including promoting the development of more targeted cancer therapies.
Since the birth of modern chemistry in the 18th century, many chemists have used nature as a model for their research. Life itself is the best proof of nature's supreme ability to create chemical complexity. The astonishing molecular structures discovered in plants, microorganisms, and animals have prompted researchers to attempt to construct identical molecules through artificial synthesis. In drug development, imitating natural molecules is often an important part, as many drugs are inspired by natural substances.
The chemical knowledge accumulated over centuries has proven its value. Using the complex tools developed, chemists can now create a variety of extremely amazing molecules in the laboratory. However, a challenging problem is that complex molecules must be constructed through many steps, each of which produces unwanted byproducts - sometimes more, sometimes less. In order to obtain the desired compounds, these by-products must be removed before continuing with the subsequent reaction process. For chemical structures that are difficult to synthesize, the loss of raw materials may be significant, and the products after the reaction are almost zero. Chemists often achieve challenging goals, but the routes they use can be both time-consuming and expensive. The 2022 Nobel Prize in Chemistry is about finding new and ideal chemistry, prioritizing simplicity and functionality.
Chemistry enters a new era of functionalism
Yesterday, Barry Shapley was awarded his second Nobel Prize in Chemistry. He was the first person to start rolling snowballs. Around the turn of the century, he created the concept of click chemistry for a functional chemistry. In click chemistry, molecular modules can quickly and effectively bind together. When Morten Medal and Barry Shapley independently discovered the jewel in the crown of click chemistry - copper catalyzed azide alkyne cycloaddition, the snowball turned into an avalanche.
Bertosi developed click reactions that can be applied in living organisms. Her orthogonal biological reactions can be applied in living organisms without interfering with the normal chemical processes of cells, and are currently being used globally to draw functional maps of cells. Some researchers are currently studying how to use these reactions to diagnose and treat cancer. Now let's take a look at the first of the two clues leading to the 2022 Nobel Prize in Chemistry.
Chemists need new ideals
The time to unravel this clue began in 2001, when Barry Shapley won his first Nobel Prize in Chemistry. However, when he advocated for a new minimalist approach in chemistry in a scientific journal, nothing had happened yet. He believes that it is time for chemists to stop imitating natural molecules - which often leads to difficult molecular synthesis for chemists and poses obstacles in the development of new drugs.
When a potential drug is discovered in nature, chemists can typically produce small amounts of the substance and use it for in vitro testing and clinical trials. Then, if industrial production is required in the later stage, higher production efficiency needs to be achieved. Sharpless used a powerful antibiotic called meropenem as an example - finding a way to mass produce this molecule took scientists around the world about 6 years of research and development.
The cost of arguing is high
According to Barry Shapley, one of the stumbling blocks for chemists is the chemical bonds formed between carbon atoms, which are crucial for chemical processes in life. In principle, all biomolecules have a framework for connecting carbon atoms. Life has evolved methods to create these substances, but it has proven to be notoriously difficult for chemists. The reason is that carbon atoms from different molecules usually lack the chemical driving force to form bonds, so they need to be artificially activated. This activation often leads to many unnecessary side reactions and costly loss of raw materials.
Barry Shapley did not force carbon atoms to react with each other, but encouraged his colleagues to start with smaller molecules that already have a complete carbon skeleton. These simple molecules can be connected together through more easily controllable nitrogen or oxygen bridges. If chemists choose simple reactions - where molecules bind together with strong intrinsic driving forces - they will avoid many side reactions while minimizing the loss of raw materials.
Click on Chemistry - Practical Green Chemistry with Great Potential
Barry Shapley referred to this robust method of constructing molecules as "click chemistry," believing that even if click chemistry cannot provide an exact copy of natural molecules, it is possible to find molecules with the same function. Combining simple chemical blocks can create almost endless molecules, so he believes that click chemistry can generate new drugs with similar functions to natural medicines and can be produced on an industrial scale.
In his 2001 work, Barry Shapley listed several criteria that chemical reactions belonging to click chemistry should meet. One of them is that the reaction should be able to occur in oxygen and an inexpensive and environmentally friendly solvent - water.
He also listed several existing examples of chemical reactions, which he believed realized his proposed new theory. However, at that time, no one knew about the brilliant reaction that has now become synonymous with click chemistry - copper catalyzed azide alkyne cycloaddition. This will be discovered in a laboratory in Denmark.
Change the click reaction of chemistry
When copper ions are added, the reaction between azides and alkynes becomes extremely efficient. This reaction is now widely used to connect molecules together in a simple way.
Unexpected objects in the Meldar reaction vessel
Many times, decisive scientific progress occurs at the most unexpected moment for researchers, and Morten Medal encountered this situation. At the beginning of this century, he was developing methods to search for potential drugs. He built a huge molecular library, which may contain hundreds of thousands of different substances, and then screened them to see if any of them could block the pathogenic process.
During this process, he and his colleagues had an extremely routine reaction on a certain day. You don't need to remember this, just know that their purpose is to react alkynes with acyl halides. If chemists add some copper ions and perhaps a small amount of palladium as a catalyst, the reaction usually proceeds smoothly. But when Meldar analyzed what had happened in the reaction vessel, he discovered some unexpected things. It has been proven that the alkyne reacted with the wrong end of the acyl halide molecule. On the other end is a chemical group called an azide (as shown in the figure above). Nitrides and alkynes form a cyclic structure together, known as triazoles.
This reaction is a bit unusual
People who understand some chemistry may know that the chemical structure of triazoles is very useful. Their structure is very stable and often appears in some drugs, dyes, and agricultural chemicals. Due to triazole being an ideal chemical structural unit, researchers have previously attempted to manufacture them using alkynes and azides, but this would result in unnecessary byproducts. Morten Medal discovered that copper ions could control the progress of the reaction, resulting in only one product, and the acyl halides that were supposed to bond with alkynes did not react to some extent. In Meldar's view, the reaction between azides and alkynes is clearly unusual.
In June 2001, he first presented his findings at a seminar in San Diego. The following year, in 2002, he published an article in an academic journal stating that this reaction could be used to bind many different molecules together.
Molecules make a "click" sound, quickly and effectively binding together
In the same year, Barry Shapley (independent of Morten Medal) also published a paper on the reaction of azides and alkynes catalyzed by copper, which showed that the reaction could work in water and was reliable. He described it as a "perfect" click response. Nitrides are like a compressed spring, where the force is released by copper ions. This process is very stable, so Shapley suggests that chemists use this reaction to connect different molecules. He believes that its potential is enormous. Looking back, we can see that he was right. Now, if chemists want to connect two different molecules, they can relatively simply give one molecule an azide group and introduce an alkyne group into the other molecule. Then, with the help of some copper ions, they can bind these two molecules together.
Clicking on the reaction can create new materials
The simplicity of click response has quickly become popular in laboratory research and industrial production. Moreover, clicking on the response also helps to produce new materials that meet specific needs. For example, if manufacturers add click reactive azides to plastics or textiles, material upgrades in the later stages become very simple. For example, this may enable the connection of materials that are conductive, receive sunlight, antibacterial, UV radiation resistant, or have other desirable properties. Additionally, through click reactions, softeners can be fixed in the plastic to prevent leakage. In drug research, click chemistry can also be used to produce and optimize substances that may become drugs.
There are many examples that can illustrate the power of click response. However, what Barry Shapley did not anticipate was that it would be used in the field of biology. Now, let's uncover the second clue of the 2022 Nobel Prize in Chemistry.
Bertosi began researching elusive carbohydrates
This clue began in the 1990s, when biochemistry and molecular biology were undergoing explosive development. Using new methods in molecular biology, researchers around the world are mapping genes and proteins in an attempt to understand how cells work. At that time, the academic community was full of pioneering spirit, and new knowledge in unknown fields emerged every day.
However, one group of molecules received almost no attention: polysaccharides. Polysaccharides are oligosaccharides or polysaccharides formed by the polymerization of multiple monosaccharides, typically located on the surface of proteins and cells. They play important roles in many biological processes, such as when viruses infect cells or activate the immune system. Polysaccharides are indeed an interesting class of molecules, but the problem is that new tools in molecular biology cannot study them. Therefore, anyone who wants to understand how polysaccharides work faces a huge challenge, and only a few researchers are prepared to try climbing that mountain - Bertosi is one of them.
Bertosi has a brilliant idea
In the early 1990s, Caroline Bertosi began drawing a map of polysaccharides that attract immune cells to lymph nodes. Due to the lack of effective tools, she needs several years to understand how this polysaccharide functions. This made her start thinking about whether there was a better way to make this process easier - she had an idea. At a seminar, she listened to a speech by a German scientist who explained how he successfully induced cells to produce a non natural variant of sialic acid (a type of nine carbon monosaccharide), which is one of the sugars that make up polysaccharides. Therefore, Bertosi began to consider whether she could use a similar method to make cells generate sialic acid with some kind of chemical gripper. The modified sialic acid can participate in the formation of different polysaccharides, and she can use chemical grippers to locate them. For example, she can attach fluorescent molecules to the handle. Then fluorescence can show the location of polysaccharides in the cell.
This is the beginning of a long and focused development work. Bertosi began searching for possible chemical triggers and related chemical reactions in the literature. This is not an easy task because the gripper cannot react with any other substances in the cell. Except for the molecules she will connect to the gripper, it must be insensitive to all other substances. She specifically coined a term to express this requirement: the reaction between the gripper and the fluorescent molecule must be 'bioorthogonal'.
Simply put, in 1997, Bertosi successfully proved that her idea was indeed effective. The new breakthrough occurred in 2000, when she found the best "chemical lever": azide. She cleverly modified a known chemical reaction - the Staudinger reaction - and used this method to link a fluorescent molecule to the azide compound she introduced into the polysaccharide. Due to the fact that azides do not affect cells, this compound can even be introduced into living organisms. Based on this, she has made an important discovery in the field of biochemistry. Through these chemical processes, her improved Staudinger reaction can be used to map cells in various ways, but Bertozzi is still not satisfied with this. She has realized that the "chemical gripper" she uses - azide - has more functions.
Injecting new vitality into old chemical reactions
At that time, the click chemistry reaction discovered by Morten Medal and Barry Shapley spread among chemists, and Caroline Bertosi clearly recognized that the gripper she used - azide - could quickly click onto an alkynyl group as long as copper ions were present. But the problem is that copper is toxic to organisms. Therefore, she started digging through literature again and found that as early as 1961, research had shown that if an alkynyl group was present in a cyclic chemical structure, even without the help of copper, azides and alkynyl groups could still react in an almost explosive manner. This reaction will release a lot of energy, allowing subsequent reactions to proceed smoothly as well.
When she tested it in cells, the reaction effect was very good. In 2004, she published a copper free click reaction, named strain promoted alkyne azide cycloaddition, and then demonstrated that it could be used to track polysaccharides (see figure above).
This milestone discovery is also the starting point for some greater discoveries. Caroline Bertosi has been improving her click response to make it work well in cellular environments as well. At the same time, she and many other researchers began to use these reactions to explore how biomolecules in cells interact with each other and use them to study disease processes.
One direction that Bertosi focuses on is the polysaccharides on the surface of tumor cells. Thanks to her research, people began to realize that some polysaccharides on the surface of tumors seem to protect them from damage by the human immune system, as they can prevent immune cells from functioning. To suppress this protective mechanism of tumors, Bertosi and colleagues have created a novel class of biological drugs. They added some polysaccharide specific antibodies to some enzymes, targeting the polysaccharides on the surface of tumor cells through antibodies, and these enzymes can decompose polysaccharides. This drug is currently undergoing clinical trials on advanced cancer patients. Many researchers have also begun to develop click on antibodies targeting a range of tumors. Once the antibody attaches to the tumor, a second molecule that can be attached to the antibody by clicking will be injected. For example, a radioactive isotope can be added, which can track tumors through PET scanners and also administer lethal doses of radiation to cancer cells.
Elegant, sophisticated, and innovative, but most importantly, useful
We don't yet know if these new therapies will be effective - but one thing is clear: these studies have just revealed the enormous potential of click chemistry and bioorthogonal chemistry. In 2001, when Barry Shapley gave his first Nobel Prize winning speech in Stockholm, he talked about his childhood, which was deeply influenced by the simple values of Quakers and also influenced his life ideals. He said, "When I started doing research, 'elegance' and 'refinement' were the highest honors in chemistry, and now 'novelty' is highly praised. However, as a Quaker, what I value most is' usefulness'." These four words of praise are necessary and can fairly praise the chemical reaction foundation laid by him, Caroline Bertosi, and Morten Medal. In addition to elegance, refinement, novelty, and usefulness, their discoveries have also brought the greatest benefits to humanity.
