Molecular monitor | MIT Technology Review


Secondary biochemist

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

In high school, he was already designing experiments to measure chemical reactions in nature, including a toxicology study of the effects of caffeine on sea urchins. He hoped to persuade his father, a scientist himself, to moderate his coffee habit. Although the experiment was not successful in this regard, he planted a seed for something bigger. Sikes was realizing how chemical research could promote good health and benefit society.

Although his undergraduate studies at Tulane focused on physical chemistry, Sikes eventually returned to his early biochemical research. At Stanford, where he earned his doctorate, he began studying redox mechanisms, especially how certain oxidizing agents extract electrons from other molecules. And he became interested in oxidative stress, which occurs when the body’s free radicals – highly reactive molecules that lack one or more electrons that easily oxidize other substances – overflow the antioxidants that cells normally produce to neutralize them. This can lead to a variety of health problems.

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

As a biochemist, Sikes was fascinated by the prospect of detecting and manipulating these changes, which doctors have struggled to accurately measure in cancer cells. To see what was going on inside the tumors, I needed to see when the cells oxidized; resorted to fluorescent proteins that emit light at different wavelengths. “To detect these redox reactions, we use light-activated chemistry,” says Sikes.

It was just a small step in translating it into therapeutic potential. If doctors can understand the actual redox activity underlying a tumor, they can better predict how chemotherapy will stop that activity and allow normal cells to regain control.

Otherwise, they will continue to shoot in the dark. Sikes had the vision to illuminate his search, literally.

Sensors in operation

Using their sensors, researchers could measure when, where and how much oxidation tumors experience by simply illuminating them. Fluorescent sensors could also shed light on the mechanism of action of various therapists, thus helping physicians select the best ones for each patient.

Since 2018, the Sikes team has been collaborating with Tufts pathologist Arthur Tischler to use his biosensors to learn about the chemistry of redox behind various cancers. In an article published in 2020, they explored the pathology of succinate dehydrogenase (SDH) deficiency tumors, a crucial metabolic enzyme and an inhibitor of ROS production. Low levels of SDH have been linked to rare and difficult-to-treat cancers.

By reengineering biochemical processes, it can measure the distinctive chemistry behind antibody production, tumor development, and virtually every aspect of human disease.

Using the same biosensors, Sikes and his team became the first to focus on chemotherapies that induce a single oxidizing agent: hydrogen peroxide. In an article published in Cell Chemical Biology, they explain how they created a sensor specifically designed to detect rising concentrations of hydrogen peroxide, which can selectively kill cancer cells. The team examined 600 molecules as potential therapies, identifying four that increased hydrogen peroxide in tumor samples.

Achieving the equipment will facilitate the clinical trials of new pharmaceuticals. The next step, ideally, is to use these fluorescent sensors to evaluate the effects of these therapies on patient-derived tumors.

Rapid detection diagnosis

Sikes realized that his technique could also detect pathogens, including SARS-CoV-2, the new coronavirus that causes covid-19.

To make this detector, Sikes needed antibody proteins that would react with the virus’s distinctive proteins. But these reactive proteins did not exist. So he decided to create them.

In her postdoctoral research, Sikes had worked with Caltech chemical engineer and 2018 Nobel Laureate Frances Arnold, a pioneer in the creation of new proteins with desirable properties.

Sikes ’lab now designs proteins that stick to the distinctive folds of proteins characteristic of various pathogens. Designed proteins emit different wavelengths depending on how they bind to the material of the virus or bacterium.

Based on this innovative technology, Sikes has developed rapid diagnostic tests that incorporate a set of reagents that find one species and exclude the others, so that healthcare professionals can diagnose infectious diseases more quickly and accurately. His lab focuses on engineering reagents that can identify coronavirus, respiratory syncytial virus (RSV) and other causes of respiratory disease; bacteria that affect food safety (especially Listeria i E. coli); and parasitic eukaryotes such as Plasmodiumwhich causes malaria.

Fluorescence microscopy image of a tumor
Fluorescence microscopy image of a tumor sample where high levels of hydrogen peroxide have been detected.

COURTESY OF RESEARCHERS

Sikes students and postdoctoral fellows in their Singapore lab are developing tests that assess immunity against different variants of covid-19 as part of a rapid research project. As in their other studies, specially designed proteins will react uniquely to each person’s antibody repertoire, allowing the team to better understand the extent and durability of covid immunity at the individual level.

Sikes ’effort to save lives with emerging biosensor technology is only part of its mission to use chemical research for the benefit of society. He accepted his position at MIT in 2009, mainly because of his reputation for research that could be applied to solving social problems. And to further this mission, he appreciates his opportunities to advise aspiring scientists.

Every summer, MIT accepts emerging researchers from historically underrepresented areas and schools. Last summer, Sikes mentored students at Spelman College, Morehouse College, and the University of Puerto Rico – Mayagüez. The program offers practical opportunities for research and connections with the Institute’s network of scientists. As part of an MIT exchange program, Sikes also mentors college students at Imperial College London.

For Sikes, this is the epitome of what science education should be. “I probably learn as much from them as they learn from me,” he says. “I really see it as a collaboration. I’ve been doing this for 20 years … but all these students and postdocs come with their own backgrounds, experiences and ways of seeing things. They often have ideas or hypotheses that don’t “They would have gone through the head.”

Redox to the rescue

The mysteries that Sikes has been pursuing since childhood have been reduced to measure: what invisible reactions drive superficial phenomena?

Today, by reengineering biochemical processes, you can measure the distinctive chemistry behind antibody production, tumor development, and virtually every aspect of human disease. In the coming years, he hopes to finalize the biosensor proteins and bring them to market, empowering other researchers to improve patient outcomes and mitigate the impending pandemic.

That’s not to say that Sikes ’lifelong curiosity has been satiated. There are always more questions to ask. “I hope in 10 years we will do something completely different that I can’t even imagine right now,” he says.



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