As a graduate student of organic chemistry, it became clear to Ben Gorske that the experiments he was carefully conducting in the lab were nonetheless just crude renderings of nature’s elegant chemistry.
“At that point I became interested in figuring out how nature does this so well, and how could we, at the very least, take a step forward toward the exquisite chemistry that nature displays,” he said in a recent interview. And so he has devoted his career to understanding, and replicating, natural biological processes — with the goal of benefiting humanity.
To perform this act of acceptable plagiarism, Gorske and his team of Bowdoin undergraduate lab assistants log long hours in his Druckenmiller Hall lab, figuring out how to construct new molecules. Using nature as a template, they create, tweak, and edit, inching toward Gorske’s ultimate wish: the creation of new medicines to treat diseases, from cancer to Alzheimer’s.
“The idea here is to create tools that will enable the development of new medicines. Ultimately, I want to do research that will help people.” Gorske said. He paused before adding, with a smile, “Or, I guess animals, too.”
To support his work, Gorske, an assistant professor of chemistry and biochemistry at Bowdoin, has recently been awarded a prestigious grant from the National Science Foundation — a CAREER grant, for faculty early in their careers. Gorske’s funded project is called “Fostering Innovative Scientists Through Development of Biomimetic Catalysts for Discovery of New Medicines” (NSF Award 1752912).
Gorske calls the nature-inspired work in his laboratory “biomemetic chemistry.” Specifically, he’s trying to mimic two types of molecules: enzymes and signaling proteins. While Gorske is not directly working on the development of new medicines, both of these research projects could result in new findings that lead to the discovery of breakthrough medicines in the future. (It is the enzyme-mimicking project in Gorske’s laboratory in particular that has received NSF funding.)
The biomemetic research of Ben Gorske
Signaling proteins are involved in carrying messages that are passed along, like batons in a relay race, throughout cells. Eventually these messages will instruct cellular machinery to take a certain action, such as to replicate DNA or build a new cell well.
While this signaling mechanism is critical for maintaining life, it can also turn deadly. What sets off the development of disease in some cases is when the coordinated action among signaling proteins is incorrectly triggered. “So if you can disrupt the coordination required for the disease to progress, you can stop it,” Gorske said. “For example, if cancerous cell growth occurs when a relay runner crosses the finish line, one could conceivably mitigate that growth by bringing in an impostor of one the runners that veers out of the stadium once they have the baton, rather than finishing the race. Or, I suppose one could also trip the runners.”
A mimic of an enzyme can also contribute to developing treatments for disease, but in a different way than a signaling protein mimic. Gorske is interested in developing such “biomimetic catalysts” because they are critical to the discovery and construction of many new molecules, especially medicinal molecules. If scientists can build catalysts that facilitate rapid construction of such molecules, they will have taken big steps toward the finish line: finding cures. For, before molecules can be used to treat people, they need to go through an extensive testing process to see if they are both effective and safe. So molecules that can be made quickly and relatively cheaply in a lab — both for testing and maybe one day for mass production — are very valuable to the scientists and drug companies spending many years and billions of dollars trying to develop new medicines.
Biological molecules are, however, challenging for scientists to copy because they are large and complicated, with many specialized components. Gorske compares enzymes to factories that churn out goods. Like many successful manufacturing businesses, a fair amount of the enzyme’s parts are used to supervise and manage its molecule-making activity. “Much of what is there is for taking orders and making sales, and has very little to do with the actual manufacturing. Much of it serves regulatory purposes,” Gorske said.
Scientists have realized that if they remove all the extraneous regulation pieces from an enzyme, they can distill it down to something that is simpler and more universally applicable, a tool that can build hundreds of potential medicines.
Gorske, specifically, is interested in making biomimetic catalysts that can attach the element of fluorine to a molecule, like adding a final flourish to a sculpture. Fluorine is an incredibly helpful element for drugs to have because it is provides “biostability” — it prevents our bodies from chewing up the medicine too quickly, before it can do its healing work. But fluorine is also a notoriously difficult element because it is highly toxic and corrosive, discouraging many people from working with it.
So far, Gorske’s lab has made promising progress, successfully making biomimetic catalysts that can precisely attach fluorine to molecules. “The last few decades have seen the introduction of many new methods for incorporating fluorine into molecules safely,” Gorske said. “We are working to build upon and expand these safe methodologies.” Now his team is focusing on making the process of attaching fluorine groups to molecules even easier and faster.
To do this, they’re focused on a problem that has plagued many chemists before them. They have to ensure that their enzyme mimic sticks the fluorine on the side of the molecule that will make it function in the body in the correct way. If medicinal researchers get this “handedness” wrong, a toxic molecule could be created, with disastrous effects for patients taking the medicine.
“The idea is simple but doing it is hard,” Gorske said. “Molecules are so small, and they have to bump into each other in just the right way to produce what you’re trying to make, so you need your representative on the molecular level to bring reacting molecules together very precisely.”
“Our ultimate goal is to develop a catalyst that generates the properly handed medicinal candidates from a wide range of molecules,” Gorske said. “We have a ways to go in order to make that goal a reality, but I feel that we’re off to a promising start.”