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Molecular Screen | MIT . Technology Review


High School Biochemist

From an early age, Sikes viewed the world with an insatiable curiosity about how things worked. She collects and observes everything from rocks to snakes. “I drove my primary school teachers crazy,” she said.

In middle school, she designed experiments to measure chemical reactions in nature, including a toxicology study on the effects of caffeine on sea urchins. She hopes to convince her father – a scientist herself – to moderate his coffee habit. Although the experiment was unsuccessful in that respect, it planted the seeds for something greater. Sikes recognized how chemical research could promote good health and benefit society.

Although her undergraduate studies at Tulane focused on physical chemistry, Sikes eventually returned to her original biochemistry studies. At Stanford, where she earned her doctorate, she began studying redox mechanisms, specifically how some oxidants pull electrons from other molecules. And she became interested in oxidative stress, which occurs when free radicals in the body — highly reactive molecules that lack one or more electrons that easily oxidize other substances — crowd out antioxidants. that cells normally produce to neutralize them. This can cause a variety of health problems.

In particular, cancer is characterized by higher than normal 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 damage normal cells and facilitate tumor growth.

As a biochemist, Sikes was intrigued by the prospect of being able to sense and manipulate these changes, which doctors have struggled to measure accurately in cancer cells. To see what was happening inside the tumours, she needed to see when the cells were oxidizing; she switched to fluorescent proteins that emit light at different wavelengths. “To detect those redox reactions, we use chemistry that is activated by light,” says Sikes.

It’s just a short step toward translating it into therapeutic potential. If doctors can understand the actual redox activity inside tumors, they can better predict how chemotherapy will block that activity — and allow normal cells to regain control. control.

Otherwise, they will continue to shoot in the dark. Sikes has a vision of illuminating their mission – literally.

Sensors at work

Using her sensors, researchers were able to measure when, where, and how much tumors were undergoing oxidation — simply by lighting them up. Fluorescent sensors can also shed light on how different treatments work, helping doctors choose the best ones for each patient.

Since 2018, Sikes’ team has been collaborating with Tufts pathologist Arthur Tischler to use their biosensor to better understand the redox chemistry behind various cancers. In one paper published in 2020, they explored the pathology of tumors lacking succinate dehydrogenase (SDH), an important metabolic enzyme and an inhibitor of ROS production. Low levels of SDH are associated with cancers that are both rare and difficult to treat.

By reorganizing biochemical processes, she can measure the special chemistry behind antibody production, tumor growth, and virtually all aspects of human disease.

Using the same set of biosensors, Sikes and her team became the first to focus on chemical therapies that produce a single oxidant: hydrogen peroxide. In one paper Published in the journal Cell Chemical Biology, they outline how they have created a sensor specifically designed to detect increased concentrations of hydrogen peroxide, which can selectively kill cancer cells. The team examined 600 molecules as a potential treatment, identifying four that promote hydrogen peroxide in tumor samples.

The team’s achievements will facilitate clinical trials of new drugs. The next step, ideally, is to use those fluorescent sensors to assess the impact of those treatments on patient-induced tumors.

Quick detection diagnosis

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

To create such a detector, Sikes needed antibody proteins that could react with specific viral proteins. But those reactive proteins do not exist. So she decided to create them.

In her postdoc research, Sikes worked with Caltech chemical engineer and 2018 Nobel laureate Frances Arnold, a pioneer in creating new proteins with desirable properties.

The Sikes lab has now engineered proteins that lock into specific folds in proteins specific to different pathogens. Genetically manipulated proteins emit different wavelengths depending on how they bind to viral or bacterial material.

Building on this cutting-edge technology, Sikes has developed rapid diagnostic tests that combine a set of reagents that find one species and rule out others, so that medical professionals can make a quick and accurate diagnosis. than infectious diseases. Her lab focuses on technical reagents that can identify coronaviruses, respiratory syncytial virus (RSV) and other causes of respiratory illness; bacteria affecting food safety (especially Listeria and E coli); and parasitic eukaryotes like Plasmodiumthe cause of malaria.

Fluorescence microscopy of a tumor
Fluorescence microscopy of a tumor sample where elevated levels of hydrogen peroxide were detected.

COURSE OF RESEARCH

Sikes students and postdocs at her Singapore lab are currently developing tests that assess immunity against different covid-19 variants as part of a tracked research project fast. As in her other studies, specially engineered proteins respond uniquely to each person’s antibody stores — allowing the team to better understand the extent and durability of immunity. outbreak of covid on an individual level.

Sikes’ efforts to save lives with emerging biosensor technology are just part of her mission to use chemical research for the good of society. She accepted her position at MIT in 2009 largely because of its reputation for research that can be applied to solving social problems. And to push that mission further, she cherishes her opportunity to mentor aspiring scientists.

Each summer, MIT admits new researchers starting from historically underrepresented areas and schools. Last summer, Sikes mentored students from Spelman College, Morehouse College and the University of Puerto Rico – Mayagüez. The program provides hands-on opportunities for research and builds connections with the Institute’s network of scientists. As part of the MIT exchange program, Sikes also mentors undergraduate students at Imperial College London.

For Sikes, this is the epitome of science education. “I can learn as much from them as they learn from me,” she said. “I really see it as a partnership. I’ve been doing this for 20 years… but all of these students and postdocs have their own background, experience and way of seeing things. Usually, they have ideas or hypotheses that I wouldn’t have thought of.”

Deoxygenation to the rescue

The mysteries Sikes has pursued since childhood have all been measured: What invisible reactions drive surface phenomena?

Today, by reorganizing biochemical processes, she can measure the special chemistry behind antibody production, tumor growth and virtually all aspects of human disease. . Over the next few years, she hopes to perfect biosensor proteins and bring them to market, empowering other researchers to improve patient outcomes and mitigate the next pandemic.

That’s not to say that Sikes’ lifelong curiosity was heralded. There are always other questions to be asked. “I hope 10 years from now we’ll be doing something completely different that I can’t even imagine right now,” she said.



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