Oncologists often turn to chemo​therapy, an aggressive treatment that often relies on trial and error. It can be difficult to tell how many cancer cells chemotherapy has destroyed—let alone why different tumors may respond to the same treatment in different ways. 

Hadley Sikes, the Esther and Harold E. Edgerton Associate Professor of Chemical Engineering at MIT and a principal investigator of the Antimicrobial Resistance Interdisciplinary Research Group at the Singapore-MIT Alliance for Research and Technology, has found a better way to monitor that progress. The key is something that has always fascinated her: so-called redox chemistry—reactions in which a molecule gains electrons (known as reduction) or loses them (known as oxidation). 

In the body, unchecked oxidation destroys cells’ normal function, and cancer is one of the potential consequences. The good news is that this excessive oxidation leaves a chemical signature. With the right tools, it can be detected. 

In 2014, Sikes began wondering if this chemistry could form the basis for a visual representation of chemo’s effects. What if scientists could monitor the oxidation happening in tumors—and see exactly where the treatment is and isn’t working? With the aid of fluorescent proteins gleaned from jellyfish genes, she and her team were able to apply their knowledge of the redox chemistry to create innovative biosensors that track oxidation levels to see if tumors are expanding or shrinking. 

Middle school biochemist

From a young age, Sikes looked at the world with an insatiable curiosity about how things worked. She collected and observed everything from rocks to snakes. “I drove my elementary school teachers crazy,” she says.

In middle school, she was already designing experiments to measure the chemical reactions in nature, including a toxicology study of caffeine’s effects on sea urchins. She’d hoped to persuade her father—a scientist himself—to moderate his coffee habit. While the experiment was unsuccessful in that regard, it planted a seed for something greater. Sikes was realizing how chemistry research could promote good health and benefit society.

Although her undergraduate studies at Tulane focused on physical chemistry, Sikes eventually circled back to her early biochemical research. At Stanford, where she earned her PhD, she began studying redox mechanisms, particularly how certain oxidizing agents pull electrons from other molecules. And she became interested in oxidative stress, which occurs when free radicals in the body—highly reactive molecules missing one or more electrons that readily oxidize other substances—overwhelm the antioxidants that cells normally produce to neutralize them. This can cause a variety of health problems.

In particular, cancer is characterized by higher-than-usual levels of free radicals called reactive oxygen species (ROS). In normal metabolic activity, ROS molecules promote cell regeneration and gene expression. But elevated ROS production can harm normal cells and facilitate tumor growth. 

As a biochemist, Sikes was fascinated by the prospect of sensing and manipulating these changes, which doctors have struggled to measure accurately in cancer cells. To see what was happening inside tumors, she needed to see when cells were oxidized; she turned to fluorescent proteins that emit light at different wavelengths. “To detect those redox reactions, we use chemistry that’s triggered by light,” says Sikes.

It was only a short step to translate that into therapeutic potential. If doctors can understand the actual redox activity underlying a tumor, they can better predict how chemotherapy will arrest that activity—and allow normal cells to regain control. 

Otherwise, they’ll continue shooting in the dark. Sikes had a vision of illuminating their quest—literally.

Sensors at work

Using her sensors, researchers could potentially measure when, where, and how much the tumors are experiencing oxidation—simply by lighting them up. The fluorescent sensors could also shed light on various therapeutics’ mechanism of action, thereby helping doctors select the best ones for each patient.

Since 2018, Sikes’s team has been collaborating with Tufts pathologist Arthur Tischler to use their biosensors for insight into the redox chemistry behind various cancers. In a paper published in 2020, they explored the pathology of tumors deficient in succinate dehydrogenase (SDH), a crucial metabolic enzyme and an inhibitor of ROS production. Low levels of SDH have been linked to cancers that are both rare and difficult to treat. 

By reengineering biochemical processes, she can measure the distinctive chemistry behind antibody production, tumor development, and virtually all aspects of human disease.

Using the same biosensors, Sikes and her team became the first to focus on

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By: Rachel Wayne
Title: Molecular monitor
Sourced From: www.technologyreview.com/2022/04/27/1048549/molecular-monitor/
Published Date: Wed, 27 Apr 2022 11:00:00 +0000

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