Among some of the most expensive medications are those that require a chiral center ― a property in which a molecule cannot be superimposed with its mirror image, like right and left hands. Chirality can direct a drug's biological effects including efficacy, side effects and metabolization. The price of chiral drugs is greatly contributed to the building blocks used during synthesis, which are costly to produce due to complex reaction and purification pathways.

In a new study recently published in Chem, FBRI researchers explore a new, cost-reducing pathway to produce one of these crucial building blocks, (S)-3-hydroxy-γ-butyrolactone (HBL), from glucose at high concentrations and yields.

According to researchers, HBL is a chiral species used for the synthesis of an array of crucial drugs such as statins, antibiotics and HIV inhibitors. Because glucose can be derived from any lignocellulosic feedstock ― such as wood chips, sawdust, tree branches or other woody biomass ― this process opens a new door for the sustainable production of HBL. This approach could also potentially be used to produce other types of important consumer products.

"If we use other kinds of wood sugars, like xylose that is an unneeded byproduct from making pulp and paper, we expect that we could produce new chemicals and building blocks, like green cleaning products or new renewable, recyclable plastics," said Thomas Schwartz, associate director of FBRI and associate professor in the Maine College of Engineering and Computing who was a lead author for the paper.

In addition to its use as a chiral species, HBL has been identified as a highly valuable precursor to a variety of chemicals and plastics by the U.S. Department of Energy. Previous attempts to produce HBL sustainably achieved only limited success due to safety issues, ineffectiveness or a lack of cost-efficiency.

"The competing processes either lead to low yields, use hazardous starting materials or are just generally costly because of the chosen production scheme and low output," said Schwartz. "The commercial process is expensive because you have to add the chiral center to the molecule, which doesn't occur naturally with most petrochemicals."

Not only does this new approach result in significantly reduced greenhouse gas emissions, but the production costs are also reduced by more than 60% compared to current methods that use petroleum-derived feedstocks. The process can also yield other commercially important chemicals, such as glycolic acid (GA), which presents additional economic opportunities.

The research included work from students in the UMaine Catalysis Group led by Schwartz and was conducted in collaboration with the U.S. Department of Agriculture (USDA) Forest Products Laboratory and the University of Wisconsin-Madison. Funding for the project was provided by the USDA, U.S. Forest Service and the National Science Foundation.

Published Sept. 19 in Science Advances, the research reveals that pancreatic alpha cells, once thought to only produce glucagon -- a hormone that raises blood sugar to maintain energy when fasting or exercising -- also generate GLP-1, a powerful hormone that boosts insulin and helps regulate glucose. GLP-1 is the same hormone mimicked by blockbuster drugs like Ozempic and Mounjaro.

Using mass spectrometry, Duke researchers found that human alpha cells may naturally produce far more bioactive GLP-1 than previously believed.

Led by Duke scientist Jonathan Campbell, PhD, the team of obesity and diabetes researchers analyzed pancreatic tissue from both mice and humans across a range of ages, body weights, and diabetes statuses. They found that human pancreatic tissue produces much higher levels of bioactive GLP-1 and that this production is directly linked to insulin secretion.

"This research shows that alpha cells are more flexible than we imagined," said Campbell, an associate professor in the Division of Endocrinology in the Department of Medicine and a member of the Duke Molecular Physiology Institute. "They can adjust their hormone output to support beta cells and maintain blood sugar balance."

This flexibility could change how we think about treating type 2 diabetes, where beta cells in the pancreas can't make enough insulin to keep blood sugar at a healthy level. By boosting the body's own GLP-1 production, it may offer a more natural way to support insulin and manage blood sugar.

Switching gears

In mouse studies, when scientists blocked glucagon production, they expected insulin levels to drop. Instead, alpha cells switched gears -- ramping up GLP-1 production, improving glucose control, and triggering stronger insulin release.

"We thought that removing glucagon would impair insulin secretion by disrupting alpha-to-beta cell signaling," Campbell said. "Instead, it improved it. GLP-1 took over, and it turns out, it's an even better stimulator of insulin than glucagon."

To test this further, researchers manipulated two enzymes: PC2, which drives glucagon production, and PC1, which produces GLP-1. Blocking PC2 boosted PC1 activity and improved glucose control. But when both enzymes were removed, insulin secretion dropped and blood sugar spiked -- confirming the critical role of GLP-1.

Implications for diabetes treatment

While GLP-1 is typically made in the gut, the study confirms that alpha cells in the pancreas can also release GLP-1into the bloodstream after eating, helping to lower blood sugar by increasing insulin and reducing glucagon levels.

Common metabolic stressors, like a high-fat diet, can increase GLP-1 production in alpha cells -- but only modestly. That opens the door to future research: If scientists can find ways to safely boost GLP-1 output from alpha cells they may be able to naturally enhance insulin secretion in people with diabetes.

But measuring GLP-1 accurately hasn't been easy. The team developed a high-specificity mass spectrometry assay that detects only the bioactive form of GLP-1 -- the version that actually stimulates insulin -- not the inactive fragments that often muddy results.

"This discovery shows that the body has a built-in backup plan," Campbell said. "GLP-1 is simply a much more powerful signal for beta cells than glucagon. The ability to switch from glucagon to GLP-1 in times of metabolic stress may be a critical way the body maintains blood sugar control."

Additional authors: Canqi Cui, Danielle C. Leander, Sarah M. Gray, Kimberly El, Alex Chen, Paul Grimsrud, Guo-Fang Zhang, David A. D'Alessio, all of Duke; and Jessica O. Becker, Austin Taylor, Kyle W. Sloop, C. Bruce Verchere, and Andrew N. Hoofnagle,

Funding: National Institutes of Health, Canadian Institutes of Health Research, Borden Scholars, and Helmsley Charitable Trust Foundation.

"It's called colorized hyperspectral X-ray imaging with multi-metal targets, or CHXI MMT for short," said project lead Edward Jimenez, an optical engineer. Jimenez has been working with materials scientist Noelle Collins and electronics engineer Courtney Sovinec to create X-rays of the future.

"With this new technology, we are essentially going from the old way, which is black and white, to a whole new colored world where we can better identify materials and defects of interest," Collins said.

The team found they could achieve this using tiny, patterned samples of varied metals such as tungsten, molybdenum, gold, samarium and silver.

The Basics of X-ray Creation

To understand the concept, one must understand the basics of X-ray creation. Traditional X-rays are generated by bombarding a single metal target, or anode, with high-energy electrons. Those X-rays are channeled into a beam and directed at a subject or material. Denser tissues, like bone, absorb more X-rays, while less dense tissues, like muscles and organs allow more to pass through. A detector records the pattern, creating an image.

While X-ray technology has advanced over time, the basic concept remains the same, which limits resolution and clarity.

A New Type of X-Ray Image

The Sandia team set out to solve that limitation by making the X-ray focal spot smaller. The smaller the spot, the sharper the image.

They achieved this by designing an anode with metal dots patterned to be collectively smaller than the beam, effectively reducing the focal point.

But the team decided they wanted to push the limits and took the concept a step further.

"We chose different metals for each dot," Sovinec said. "Each metal emits a particular 'color' of X-ray light. When combined with an energy discriminating detector, we can count individual photons, which provide density information, and measure the energy of each photon. This allows us to characterize the elements of the sample."

The result is colorized images with what the team calls revolutionary image clarity and a better understanding of an object's composition.

"We get a more accurate representation of the shape and definition of that object, which is going to allow us to make unprecedented measurements and unprecedented observations," Jimenez said.

Far-reaching applications

The team sees this as a major advancement for X-ray technology with a wide range of uses, from airport security and quality control to nondestructive testing and advanced manufacturing.

They also hope its impact will improve medical diagnostics.

"With this technology, you can see even slight differences between materials," Jimenez said. "We hope this will help better identify things like cancer and more effectively analyze tumor cells. In mammography you are trying to catch something before it grows. In breast tissue, it's hard to identify the different dots, but with colorization you have a sharper beam and higher resolution image that increases the system's capability to detect a microcalcification. It's really exciting to be a part of that."

"From here we will continue to innovate," Collins said. "We hope to identify threats faster, diagnose diseases quicker and hopefully create a safer, healthier world."

The team was recently awarded an R&D 100 award for their technology. They were among six winners from Sandia. Click for R&D 100 Submission video with soundbites.