Nobel Prize: How click chemistry and bioorthogonal chemistry are transforming the pharmaceutical and material industries

Click chemistry joins molecules together by reacting an azide with a cyclooctyne. Boris Zhitkov/Moment via Getty Images

by Heyang (Peter) Zhang, University at Buffalo

The 2022 Nobel Prize in chemistry was awarded to scientists Carolyn R. Bertozzi, Morten Meldal and K. Barry Sharpless for their development of click chemistry and bioorthogonal chemistry.

These techniques have been used in a number of sectors, including delivering treatments that can kill cancer cells without perturbing healthy cells as well as sustainably and quickly producing large amounts of polymers to build materials. One click chemistry-based drug is currently undergoing phase 2 clinical trials. Bertozzi is a scientific adviser of the company developing the drug.

We asked chemistry Ph.D. candidate Heyang (Peter) Zhang of the Lin Lab at the University at Buffalo to talk about how these techniques figure in his own research and how they have transformed his field and other industries.

1. How does click and bioorthogonal chemistry work?

Click chemistry, as the name suggests, is a way of building molecules like snapping Lego blocks together. It takes two molecules to click, so researchers refer to each one as click partners.

K. Barry Sharpless and Morten Meldal independently discovered that azide, a high-energy molecule with three nitrogens bonded together, and alkyne, a relatively inert and naturally rare molecule with two carbons triple-bonded together, are great click partners in the presence of a copper catalyst. They found that the copper catalyst can bring the two pieces together in an optimal arrangement that snaps them together. Prior to this technique, researchers did not have a way to quickly and precisely make new molecules under accessible conditions, like using water as a solvent at room temperature.

Diagram of click chemistry reaction
By combining an azide with a cyclooctyne, bioorthogonal chemistry allows researchers to join molecules quickly together without disturbing the rest of the cell. Cliu89/Wikimedia Commons

Chemical biologists quickly realized that click reactions can be a fantastic way to probe living systems like cells because they produce little to no toxic byproducts and can happen quickly. However, the copper catalyst is itself toxic to living systems.

Carolyn Bertozzi devised a workaround for this issue by removing the copper catalyst from the reaction. She did this by placing the alkyne into a ring structure, which drives the reaction forward using the ring strain produced from molecules forced into a cyclical shape. These bioorthogonal reactions, or reactions that happen “parallel” to the chemical environment of the cell, can occur in cells without perturbing their normal chemistry.

2. How do you use this chemistry in your work?

In an interview, Carolyn Bertozzi stated that the next steps for bioorthogonal chemistry are to find new reactions and applications for it. Our lab’s research focuses exactly on that.

My colleagues and I apply this technique to track molecules we are interested in as they naturally behave in a cell. In a living cell, we were able to add a probe to a receptor that plays a role in a number of cellular processes.

Carolyn Bertozzi is one of the winners of the 2022 Nobel Prize in chemistry.

To find new reactions, our lab has spent the last 15 years to push how fast bioorthogonal reactions can run. Speed is important because many molecules in living organisms are present in low concentrations, and using too much of the chemicals required for the reaction can be toxic for the cell. The faster the reaction, the fewer the unwanted side reactions.

We pioneered another way to achieve click and bioorthogonal reactions with even faster speed. Instead of using an azide and an alkyne like the Nobel Prize winners did originally, we used two other molecules that join together when a light is shined on them. With this technique, we are able to add molecules to the surface of a live cell in as little as 15 seconds. We can then observe how a particular structure on a cell functions in its natural environment, or detect how it changes when exposing it to drugs or other substances. Researchers can then more easily test how cells react to potential treatments.

Currently, we are working to develop a new method of triggering these reactions without light. We are actively working on using bioorthogonal chemistry to improve PET imaging to screen and monitor tumors.

Digram depicting
Bioorthogonal chemistry can be used for ‘click-to-release’ cancer drugs. Rossin 2018 (Nature Communications), CC BY-NC-ND

3. Why are these techniques so important to your field?

Prior to click and bioorthogonal chemistry, there was no way of visualizing molecules in living cells in their natural state.

As an analogy, imagine you needed to find a specific dollar bill with the serial number 01234567. That would be a pretty daunting task. It would require you to go through every dollar you can get your hands on and verify whether the serial number is the one you are looking for.

Tracking molecules in our body is just as hard, if not more. Because biological environments are so complex, it was previously impossible to add a probe to just the molecule of interest without accidentally tagging something else, or worse, altering the normal chemistry of the cell. With bioorthogonal reactions, however, researchers can essentially add a GPS tracker to the molecule without affecting the rest of the cell.

Heyang (Peter) Zhang, PhD Candidate in Chemistry, University at Buffalo

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Amtrak shuts down its second-busiest corridor due to coastal erosion, again

Read the full story at Motherboard.

Amtrak has once again suspended train service along the second-busiest rail corridor in the country due to the human impact on coastal erosion. Pacific Surfliner service between San Diego and Los Angeles has been severely impacted, with canceled trains and replacement bus service between Irvine and Oceanside due to coastal erosion in San Clemente where the tracks run right along the coast. The changes were announced Friday, about three weeks before a planned service expansion, and are in effect “until further notice.”

The Data Liberation Project

The Data Liberation Project is an initiative to identify, obtain, reformat, clean, document, publish, and disseminate government datasets of public interest.

It launched in September, so there isn’t a lot to explore yet, but this is worth keeping an eye on. You can view their current record requests here.

How the escalating climate crisis is impacting global livelihoods

Read the full story at GreenBiz.

The climate crisis is getting worse, impacts are intensifying and their effects are already being felt across communities, businesses and markets globally, resulting in starvation, poverty and increased financial risks.

That is the stark warning from three new reports this week that all pointed to the same stark conclusion — the climate crisis is already having a severe impact all around the world, and unless “massive and immediate” action is taken, future prospects for global businesses and communities remain bleak.  

What climate adaptation technology looks like

Read the full story at GreenBiz.

Pano AI is one example of climate tech startups emerging to tackle conditions, such as wildfires, exacerbated by climate change.

Ford breaks ground on $5.6B Tennessee EV project

Read the full story at Construction Dive.

Detroit-based general contractor Walbridge broke ground on Ford’s $5.6 billion battery and electric vehicle manufacturing campus, dubbed BlueOval City, last week near Stanton, Tennessee, according to a company announcement.

The facility, which is on track to be completed in 2025, will create approximately 6,000 jobs when it opens and is the most advanced auto production complex in Ford history, according to the announcement.

The construction of electric vehicle factories in the U.S. is expected to increase in coming years, especially due to backing from the federal government. That includes $7.5 billion in funding for battery infrastructure from the Infrastructure Investment and Jobs Act, the recently passed $52 billion CHIPS Act and the Inflation Reduction Act’s EV tax credit.

The EPA’s approach to battery recycling initiatives in tribal communities

Read the full story at Waste360.

The EPA Tribal Waste Management Program has developed a series of webinars featuring bountiful information on their goals of bringing tribal communities to circularity. In a recent webinar titled “Bipartisan Infrastructure Law: Battery Collection Best Practices and Labeling Guidelines” members of the EPA and researchers alike went live to discuss and provide context to the Bipartisan Infrastructure Law.

Termites love global warming – the pace of their wood munching gets significantly faster in hotter weather

Wood feeding termites (Microcerotermes spp) inside their nest. Johan Larson, Author provided

by Alexander Cheesman, James Cook University; Amy Zanne, University of Miami, and Lucas Cernusak, James Cook University

When we consider termites, we may think of the danger they can pose to our houses once they settle in and start eating wood. But in fact, only about 4% of termite species worldwide are considered pests that might, at some point, eat your house.

In nature, wood-eating termites play a broad and important role in warm tropical and sub-tropical ecosystems. In feeding on wood, they recycle essential nutrients to the soil and release carbon back to the atmosphere.

Our new research, published today in Science, quantified for the first time just how much termites love the warmth. The results are striking: we found termites eat deadwood much faster in warmer conditions. For example, termites in a region with temperatures of 30℃ will eat wood seven times faster than in a place with temperatures of 20℃.

Our results also point to an expanding role for termites in the coming decades, as climate change increases their potential habitat across the planet. And this, in turn, could see more carbon stored in deadwood released into the atmosphere.

Deadwood in the global carbon cycle

Trees play a pivotal role in the global carbon cycle. They absorb carbon dioxide from the atmosphere through photosynthesis, and roughly half of this carbon is incorporated into new plant mass.

While most trees grow slowly in height and diameter each year, a small proportion die. Their remains then enter the deadwood pool.

Termites and microbes release the carbon stored in deadwood into the atmosphere. Shutterstock

Here carbon accumulates, until the deadwood is either burned or decayed through consumption by microbes (fungi and bacteria), or insects such as termites.

If the deadwood pool is consumed quickly, then the carbon stored there will rapidly be released back to the atmosphere. But if decay is slow, then the size of deadwood pool can increase, slowing the accumulation of carbon dioxide and methane in the atmosphere.

For this reason, understanding the dynamics of the community of organisms that decay deadwood is vital, as it can help scientists predict the impacts of climate change on the carbon stored in land ecosystems.

This is important as releasing deadwood carbon to the atmosphere could speed up the pace of climate change. Storing it for longer could slow climate change down.

Testing how fast termites eat deadwood

Scientists generally understand the conditions that favour microbes’ consumption of deadwood. We know their activity typically doubles with each 10℃ increase in temperature. Microbial decay of deadwood is also typically faster in moist conditions.

On the other hand, scientists knew relatively little about the global distribution of deadwood-eating termites, or how this distribution would respond to different temperatures and moisture levels in different parts of the world.

To better understand this, we first developed a protocol for assessing termite consumption rates of deadwood, and tested it in a savannah and a rainforest ecosystem in northeast Queensland.

Our method involved placing a series of mesh-covered wood blocks on the soil surface in a few locations. Half the blocks had small holes in the mesh, giving termites access. The other half didn’t have such holes, so only microbes could access the blocks through the mesh.

A block of pine wood wrapped to keep out termites and left in the forest to decompose.

We collected wood blocks every six months and found the blocks covered by mesh with holes decayed faster than those without, meaning the contribution of termites to this decay was, in fact, significant.

But while the test run told us about termites in Queensland, it didn’t tell us what they might do elsewhere. Our next step was to reach out to colleagues who could deploy the wood block protocol at their study sites around the world, and they enthusiastically took up the invitation.

In the end, more than 100 collaborators joined the effort at more than 130 sites in a variety of habitats, spread across six continents. This broad coverage let us assess how wood consumption rates by termites varied with climatic factors, such as mean annual temperature and rainfall.

Amy Zanne with graduate student Mariana Nardi and postdoctoral fellow Paulo Negri from Universidade Estadual de Campinas near termite mounds in tropical cerrado savanna in Chapada dos Veadieros National Park. Photo by Rafael Oliveira.

Termites love the warmth, and not too much rain

For the wood blocks accessible to only microbes, we confirmed what scientists already knew – that decay rates approximately doubled across sites for each 10℃ increase in mean annual temperature. Decay rates further increased when sites had higher annual rainfall, such as in Queensland’s rainforests.

For the termites’ wood blocks, we observed a much steeper relationship between decay rates and temperature – deadwood generally decayed almost seven times faster at sites that were 10℃ hotter than others.

To put this in context, termite activity meant wood blocks near tropical Darwin at the northern edge of Australia decayed more than ten times faster than those in temperate Tasmania.

Our analyses also showed termite consumption of the wood blocks was highest in warm areas with low to intermediate mean annual rainfall. For example, termite decay was five times faster in a sub-tropical desert in South Africa than in a tropical rainforest in Puerto Rico.

This might be because termites safe in their mounds are able to access water deep in the soil in dry times, while waterlogging can limit their ability to forage for deadwood.

Termites thrive in hot, dry climates. Shutterstock

Termites and climate change

Our results were synthesised in a model to predict how termite consumption of deadwood might change globally in response to climate change.

Over the coming decades, we predict greater termite activity as climate change projections show suitable termite habitat will expand north and south of the equator.

This will mean carbon cycling through the deadwood pool will get faster, returning carbon dioxide fixed by trees to the atmosphere, which could limit the storage of carbon in these ecosystems. Reducing the amount of carbon stored on land could then start a feedback loop to accelerate the pace of climate change.

We have long known human-caused climate change would favour a few winners but leave many losers. It would appear the humble termite is likely to be one such winner, about to experience a significant global expansion in its prime habitat.

Alexander Cheesman, Senior Research Fellow, James Cook University; Amy Zanne, Professor in Biology and Aresty Chair in Tropical Ecology, University of Miami, and Lucas Cernusak, Associate Professor, Plant Physiology, James Cook University

This article is republished from The Conversation under a Creative Commons license. Read the original article.

How are petrochemical companies doing in shifting from virgin plastic?

Read the full story at Waste360.

The shale gas boom has made virgin plastic, a waste byproduct of oil and gas production, cheap and abundant. Global plastic production could increase by one-third in the next few years if the ongoing trend continues, threatening to undermine efforts around the world to deflate the explosive growth of this often short-lived material, says the Center for International Environmental Law (CIEL).

The State of Trust & Integrity in Research

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This report highlights the significant and critical role funding agencies and other research stakeholders have in improving the integrity of research. In the first section, experts provide context and an example from one funding agency on organisation-wide policies for improving research integrity. 

The second section of the report presents a broader landscape of data and open science policies worldwide along with an analysis of how these policies are put into practice. Finally, we present a case study and analysis of one funding agency’s practices and policies for open research as a lens for evaluating impact. 

Taken together, these articles exemplify the need for a more coordinated approach among funding agencies and other stakeholders in scientific communications and in the research workflow to comprehensively address research integrity. Central to these coordination efforts should be a focus on incentives for researchers and institutions for compliance and for training and education.