Molecular monitor | MIT Technology Review

Middle school biochemist

From an early age, Sykes viewed the world with an insatiable curiosity about how things work. She collected and inspected everything from rocks to snakes. “I drove my elementary school teachers crazy,” he says.

In middle school, she was already preparing experiments to measure chemical reactions in nature, including a toxicology study of the effects of caffeine on marine archeology. She hoped her father – a scientist – would persuade her to give up her coffee habit. When the experiment failed in that regard, he sowed the seeds for something more. Sykes was experiencing how chemistry research can promote good health and benefit society.

Although her undergraduate studies at Tulane focused on physical chemistry, Sykes returned to her early biochemical research. At Stanford, where she received her PhD, she began studying redox mechanisms, especially how certain oxidizing agents pull electrons from other molecules. And she became interested in oxidative stress, which occurs when the body lacks one or more electrons in free radical-highly reactive molecules that easily oxidize other substances કો cells normally stripping them of the antioxidants they produce. This can lead to 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, Sykes was fascinated by the possibility of understanding and manipulating these changes, which doctors struggled to accurately measure in cancer cells. To see what was going on inside the tumors, she needed to see when the cells oxidized; She turned to fluorescent proteins that emit light at different wavelengths. “To detect those redox reactions, we use chemistry that is triggered by light,” says Sykes.

It was just a small step towards translating it into therapeutic potential. If doctors could understand the actual redox activity under the tumor, they could better predict how chemotherapy would prevent that activity-and allow normal cells to regain control.

Otherwise, they will continue shooting in the dark. Sykes had a vision to literally publish his discovery.

Sensors at work

Using its sensors, researchers can potentially measure when, where and how much oxidation a tumor is experiencing માત્ર just by releasing them. Fluorescent sensors can also shed light on the mechanism of action of various therapeutics, helping doctors make the best choice for each patient.

Since 2018, Sykes’ team has been collaborating with Tufts pathologist Arthur Tesler to use their biosensors to understand the redox chemistry behind various cancers. In a paper published in 2020, they explored the pathology of tumors deficient in succinate dehydrogenase (SDH), a critical metabolic enzyme and inhibitor of ROS production. Low levels of SDH are associated with cancers that are rare and difficult to treat.

By reconstructing biochemical processes, it can measure the specific chemistry behind antibody production, tumor development, and virtually all aspects of human disease.

Using similar biosensors, Sykes and his team became the first to focus on chemotherapy that induces a single oxidizing agent: hydrogen peroxide. In a paper published in Cell Chemical Biology, they outlined how they developed a specially designed sensor to detect increased concentrations of hydrogen peroxide, which can selectively kill cancer cells. The team examined 600 molecules as potential therapeutics, identifying four hydrogen peroxide enhancers in tumor samples.

The team’s achievement will facilitate clinical trials of new pharmaceuticals. The next step, ideally, is to use those fluorescent sensors to evaluate the effects of that treatment on the tumors obtained by the patient.

Quick-detection diagnostics

Sykes realized that her technique could also detect pathogens – including SARS-CoV-2, the novel coronavirus that causes Covid-19.

To make such a detector, Sykes needed an antibody protein that reacts with a specific protein of the virus. But those reactive proteins did not exist. So she decided to make them.

In his postdoctoral research, Sykes worked with Celtic chemical engineer and 2018 Nobel Laureate Francis Arnold, a pioneer in creating novel proteins with desirable properties.

Sykes’ lab now engineering proteins that lock into specific folds in proteins characteristic of various pathogens. Engineered proteins emit different wavelengths depending on how they interact with the contents of the virus or the bacterium.

Based on this innovative technology, Sykes has developed rapid diagnostic tests involving a set of reagents that detect one species and exclude another, allowing health professionals to diagnose infectious diseases more quickly and accurately. Her lab focuses on engineering reagents that can identify coronavirus, respiratory syncytial virus (RSV) and other causes of respiratory disease; Bacteria that affect food safety (in particular) Listeria And E. ColiAnd parasitic eukaryotes such as PlasmodiumWhich causes malaria.

Fluorescence microscopy image of the tumor
Fluorescence microscopy image of a tumor sample where elevated levels of hydrogen peroxide are detected.

Courtesy of the researchers

Syx students and Postdox in its Singapore lab are now developing tests that assess immunity against various Covid-19 variants as part of a quick-track research project. Like her other studies, the uniquely engineered protein will react uniquely with each individual’s store of antibodies – allowing the team to better understand the limits and durability of the immune system against covid on an individual level.

Sykes’ attempt to save lives with emerging biosensor technology is part of his mission to use chemistry research for the benefit of society. She accepted her position at MIT in 2009 because of her reputation for research that could be applied to solving social problems. And to further that mission, she appreciates her opportunities to guide aspiring scientists.

Every summer, MIT embraces researchers emerging from historically under-represented areas and schools. Last summer, Sykes mentored students from Spellman College, Morehouse College, and the University of Puerto Rico-Mayaguez. The program offers opportunities to conduct research and make connections with the organization’s network of scientists. As part of the MIT Exchange Program, Sykes Imperial College also mentors undergraduates in London.

For Sykes, this is the essence of what science education should be like. “I probably learn as much from them as they do from me,” he says. “I really see it as a collaboration. I’ve been doing this for 20 years now … but all these students and postdox come with their own backgrounds and experiences and ways of looking at things. Often, they have ideas or hypotheses that I would not have considered. “

Redox for rescue

The mysteries that Sykes has been chasing since childhood have all come down to measure: what invisible reactions lead to surface events?

Today, by reconstructing biochemical processes, it can measure the specific chemistry behind almost all aspects of antibody production, tumor development, and human disease. Over the next few years, she hopes to finalize the biosensor protein and bring it to market, empowering other researchers to improve patient outcomes and mitigate the next epidemic.

This is not to say that Sykes’ lifelong curiosity has been satisfied. There are always more questions to ask. “I hope that 10 years from now we will do something completely different that I can’t even imagine right now,” she says.

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