The making of a chemistry giant

The youngest of seven children, Fox grew up in a rowhouse in Northeast Philadelphia, putting his muscle to moving pianos during his summer breaks throughout high school and college.

He was in fourth grade when he first got interested in science and he was pretty good at math, too, he said. But he started his studies at Princeton University without a real plan, tilting toward engineering because some other kids in his neighborhood had done that.

Soon after his arrival at Princeton, though, a graduate student in engineering told him to go pre-med instead. Fox took that advice.

He found his match when he started taking classes in chemistry, especially organic chemistry.

Some will say organic chemistry is one of the toughest kinds of chemistry to pursue. But Fox isn’t having that.

“It’s not math-intensive,” he said. “It’s not memorization-intensive. It’s visual thinking, sort of a conceptual way of thinking about three-dimensional objects and then being able to translate that into two-dimensional drawings and being able to understand how bonds are made and formed.”

Fox discovered he had a knack for that kind of thinking.

“I was hooked and started doing research right away,” he said.

He felt like a visitor, though, in the lab of Professor Maitland Jones, Jr., his adviser at Princeton and the author of the textbook Organic Chemistry.

“I was an undergraduate, and they were the real chemists,” he said.

Jones changed that soon enough.

“I remember my adviser calling me a chemist for the first time,” Fox said. “I was an undergraduate and he talked about me as a chemist.”

Fox points to that kind of support, along with the support of his family and other mentors, as crucial to his growth.

After graduating from Princeton, he finished his doctorate at Columbia, where he was advised by Professor Thomas Katz. Fox said he was inspired by Katz’s creative approach to science and his perspective on how organic chemistry can impact interdisciplinary research. After graduate school, he did postdoctoral studies at MIT for about two years with Professor Stephen Buchwald, a leader in catalysis. 

At the time, Buchwald’s group had recently developed a group of catalysts for pharmaceutical research. But they couldn’t synthesize enough of these catalysts to meet the demand of the lab, let alone the rest of the world.

Fox proposed using strained molecules — unusual molecules with quirky, tunable properties — to synthesize these catalysts more efficiently. It worked.

He joined the UD faculty in 2001 and found a tremendous community, he said.

“The UD faculty here has always been extremely supportive,” Fox said. “It’s always been like that, even before ‘collaborative research’ was in vogue.”

His research now focuses largely on areas where organic chemistry intersects with biology and medicine, ranging from the most fundamental curiosity-driven kinds of questions to applications that now are making new clinical trials possible.

“Being able to ask interesting questions about science and make new molecules that have interesting implications for what we can do in biology or medicine is just really exciting,” he said.

Curiosity-driven, useful chemistry

Fox is fluent in chemistry, of course, and he can break it down in ways non-experts can understand — or at least relate to.

Consider his interest in strained molecules, for example. It’s not about putting molecules through a nanoscale colander. No, strained molecules are what Fox calls “oddball” molecules. They are strained because they have weaker bonds and extra energy. They are somewhat agitated by that tension — unlike stable, ordinary molecules — and they can do things ordinary molecules can’t. That makes them very interesting to chemists like Fox.

“My appreciation for strained molecules started in the same way you might appreciate artwork,” Fox said. “You see something for the first time, and you’re fascinated by it. You just want to know more.”

It’s the kind of curiosity that adds rocket fuel to research and great teachers find ways to ignite similar wonder in their students, opening new doors for them and generations of scientists to come.

Strained molecules and their quirky properties are critical to the superfast, precise reaction called tetrazine ligation, which, in turn, has been critical to the development of “click” chemistry and bioorthogonal chemistry that produced the 2022 Nobel Prizes in Chemistry for Bertozzi and two other chemists.

Click chemistry and bioorthogonal chemistry are relatively new, closely related fields of chemistry that involve making new molecules, linking them and/or introducing them into biological environments without harming the biological processes in any way.

The tetrazine ligation reaction is perfect for such work. It is harmless to living cells, enables creation of new molecules and bonds, and works extremely quickly, with great precision.

“How do you build a molecule that sort of ignores all the stuff you would find inside of a living cell?” Fox said. “That’s pretty different from traditional approaches of building molecules in a test tube and then trying to deliver them as medicine.”

The speed is mind-boggling, with these reactions completed within milliseconds.

“The speed is what makes it really special,” Fox said. “It takes place so rapidly, you can do experiments in living cells instantaneously. You can get instantaneous labeling in live cells. When we first published it, our system was roughly one million times faster than the state of the art.”

Some of the molecules can be fluorescent, which allows researchers to label precise areas for imaging or pinpointing where a drug molecule will be attached.

“We can use light as a trigger for being able to instantaneously build molecules, selectively — not only inside of a cell, but within specific compartments within cells,” Fox said.

His group is interested in finding other chemical reactions that would be useful in biology and medicine.

Impact on students

In his 22 years at UD, Fox has mentored scores of undergraduates in research and has shepherded more than two dozen students through their doctoral degrees. A long shelf on the wall of his office holds a line of champagne bottles — each bearing the name of the Ph.D. student whose successful thesis defense prompted the popping of its cork.

One of those students is Julia Rosenberger, who completed her Ph.D. this year.

“He’s an inspiring scientist,” she said, “and he lets us be independent — both as thinkers and as scientists. But he is always there for us if we need to work through a difficult problem. He’s super understanding of his students’ strengths and weaknesses and is able to either change a project to fit their strengths or — if they’re struggling with something — he’ll quickly adapt that project to fit the student’s needs.”

Fox is the kind of leader who finds ways to increase the confidence of his students — in the same way his former adviser did when he was the first to refer to the young sophomore as a “chemist.”

Christopher am Ende, a 2005 UD graduate in biochemistry who now is an associate research fellow at Pfizer, pointed to that in his letter of support.

“Joe interacts with the students like they are colleagues and any challenges they may have in their research, he provides excellent guidance and support in a manner that keeps them motivated and excited about their science,” he wrote.

Interacting with students is one of the things Fox loves most about his work.

“I love chemistry and I love working with and talking about chemistry with my students,” Fox said. “It is really exciting to me to see graduate students develop on their individual path. Everybody has their own path to their Ph.D. and they have their own story to tell at the end. And it’s a unique story.”

For some students, research can be a torturous story — especially at first. Fox has solid advice for them, having had early struggles of his own.

“You have to be prepared that there are going to be some rough spots,” Fox said. “Science can have a lot of highs and lows and maybe there will be times when it seems like there are more lows than there are highs.

“You have to look at the long game when you’re thinking about your education and trying to do something that’s never been done before. You have to remember that the reason it’s called research is that it hasn’t been done before and it might not work.”

Building UD’s chemistry ecosystem

Fox’s influence goes far beyond his students to his colleagues and collaborators at UD and beyond.

He has played a key role in the development of young faculty at UD, many of whom now are leaders in their respective fields.

“Joe has been incredibly dedicated for his entire time on our campus in terms of thinking about how we go about education in chemistry and biochemistry in a very rigorous way and an innovative way,” Rosenthal said. “How do we break the mold of the past to apply the tools of today to push education forward, to be more effective in the classroom with our chemistry students, to be more effective and modern in the teaching labs and pairing that with advocacy for the students that are enrolled in our courses and working with us to move their careers forward?”

Fox has been a pivotal influence in building UD’s research ecosystem, too, serving as the principal investigator on the National Institutes of Health (NIH) Center of Biomedical Research Excellence on Discovery of Chemical Probes and Therapeutic Leads, now in its second phase. The awards have expanded UD’s biomedical research infrastructure and drawn excellent young researchers to UD’s faculty.

“With that you’re going to build out core instrumentation and core facilities for nuclear magnetic resonance or mass spectrometry or proteomics or computational chemistry,” Rosenthal said. “These core physical resources are impacting dozens of different research groups across campus, literally impacting the education careers and scholarship of many different faculty members and  hundreds of graduate students year after year after year. So that’s the sort of impact multiplier Joe Fox has had over his career here.”

Fox is quick to point out the strength of UD’s faculty and its cohesive, collegial qualities. He appreciated the support he received from Colin Thorpe and John Koh, both professors of chemistry and biochemistry, when he first arrived at UD, and he savors the collaborative environment, including work he has done with Xinqiao Jia (materials science and engineering), Catherine Grimes (chemistry and biochemistry), the UD CHARM (Center for Hybrid, Active and Responsive Materials) team and others.

“I’m incredibly honored to receive the Francis Alison Award,” Fox said. “I’m deeply touched that so many of my colleagues would write in support of me for this award. It’s a great honor to be a faculty member at this university and to have so many wonderful colleagues at the University of Delaware. It’s obviously a very esteemed group, so I am very honored to be part of it.”

About the researcher

Joseph Fox is professor of chemistry and biochemistry at the University of Delaware. He earned his bachelor’s degree at Princeton University, his doctorate at Columbia University and did postdoctoral research at MIT before joining the UD faculty in 2001. He holds a joint appointment with the Department of Materials Science and Engineering and is the principal investigator and director of the NIH-funded Center of Biomedical Research Excellence on Discovery of Chemical Probes and Therapeutic Leads. He has won many awards, including the American Chemical Society’s prestigious Arthur C. Cope Scholar Award “for outstanding achievements in the development of organic reactions with applications in biology, synthesis and materials science” in 2022.

About the Francis Alison Award

The Francis Alison Award was established in 1978 by the Board of Trustees. It is awarded annually to the faculty member who best characterizes the “scholar-schoolmaster,” as exemplified by the Rev. Dr. Francis Alison, who founded the institution that is now the University of Delaware in 1743. His first class of students became distinguished statesmen, doctors, merchants and scholars. Three signed the Declaration of Independence, and one signed the U.S. Constitution.