Molecular monitor | MIT Technology Review

Secondary school biochemist

From an early age, Sykes looked at the world with unsatisfied 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 developing experimental designs for measuring chemical reactions in nature, including a toxicological study of the effects of caffeine on sea urchins. He hoped to persuade his father – a scientist himself – to moderate his coffee habits. Although the experiment failed in that regard, it planted a seed for something bigger. Sykes was realizing how chemistry research could promote good health and benefit society.

Although his undergraduate studies at Tulane focused on physical chemistry, Sykes eventually returned to his early biochemical research. At Stanford, where he earned his PhD, he began studying redox processes, specifically how certain oxidizing agents pull electrons from other molecules. And he became interested in oxidative stress, which occurs when the body lacks free radical-highly reactive molecules with one or more electrons that easily oxidize other substances – cells usually override the antioxidants created to neutralize them. 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 improved ROS production can damage normal cells and facilitate tumor growth.

As a biochemist, Sykes was fascinated by the possibility of sensing and manipulating these changes, which doctors have struggled to accurately measure in cancer cells. To see what is going on inside the tumor, he needs to see when the cells were oxidized; He goes back to the fluorescent proteins that emit light at different wavelengths. “To detect these redox reactions, we use chemistry triggered by light,” says Sykes.

It was only a small step to translate it into therapeutic potential. If physicians can understand the actual redox activity underlying a tumor, they can better predict how chemotherapy will block that activity এবং and allow normal cells to regenerate.

Otherwise, they will continue shooting in the dark. Sykes had a vision to illuminate their quest — literally.

Sensors in the workplace

Using its sensors, researchers can potentially measure when, where, and how much tumors are being oxidized – simply by lighting them. Fluorescent sensors can also shed light on a variety of therapeutic modalities, helping doctors select the best one for each patient.

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

By re-engineering biochemical processes, he can measure the unique chemistry behind antibody production, tumor development, and virtually all aspects of human disease.

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

The team’s achievement will facilitate the clinical trial of the new pharmaceutical. The next step, ideally, is to use those fluorescent sensors to evaluate the effects of those therapeutics on tumors obtained from patients.

Rapid detection diagnostics

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

To create such a detector, Sykes needed antibody proteins that would react with individual proteins of the virus. But that reactive protein did not exist. So he decided to make them.

In his postdoctoral research, Sykes has worked with Caltech chemical engineer and 2018 Nobel laureate Frances Arnold, a pioneer in creating fancy proteins with desirable properties.

Sykes’ lab now produces proteins that lock into distinct folds of proteins characterized by different pathogens. Engineered proteins emit different wavelengths depending on how they bind to the components of the virus or bacterium.

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

Courtesy of researchers

Sykes student and PostDocs in his Singapore lab are now developing tests to evaluate immunity against various Covid-19 variants as part of a fast-tracking research project. Like his other studies, engineered proteins in particular will respond uniquely to each individual’s stock of antibodies – allowing the team to better understand the amount and stability of covid resistance at an individual level.

Sykes’ efforts to save lives with the help of emerging biosensor technology are only part of his mission to use chemistry research for the benefit of society. He took up his position at MIT in 2009 mainly because of its reputation for research that could be applied to solving social problems. And to further that mission, he cherishes his opportunities to advise aspiring scientists.

Every summer, MIT receives historically emerging researchers from under-represented areas and schools. Last summer, Sykes advised students at Spellman College, Morehouse College, and the University of Puerto Rico-Mayagues. The program provides hands-on opportunities for scientists at the institute to conduct research and connect with networks. As part of the MIT Exchange Program, Sykes Imperial College also mentors graduates in London.

To Sykes, science education is a reflection of what it 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 it for 20 years now. But all these students and postdocs come up with their own backgrounds and experiences and ways of looking at things. Often, they have ideas or assumptions that I didn’t think possible.”

Rescue Redox

The mysteries that Sykes has been chasing since childhood have come down to scale: What invisible reactions drive surface phenomena?

Today, by re-engineering biochemical processes, he can measure the unique chemistry behind antibody production, tumor development, and virtually all aspects of human disease. Over the next few years, he hopes to finalize biosensor proteins and bring them to market, empowering other researchers to improve patient outcomes and mitigate subsequent epidemics.

Needless to say, Sykes’ lifelong curiosity was piqued. 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 now,” he said.