Modern-day scientific research is highly specialized. In chemistry, for example, organic chemists work primarily on synthesizing carbon-containing molecules, while biochemists focus on understanding the structure and function of genes and proteins. This means that scientists tend to have niche expertise, knowledge, and perspectives as they work on compartmentalized research problems.
But in the lab of Ivan Dmochowski, researchers actively work across multiple areas to solve interdisciplinary problems. As “molecular engineers,” their goal is to create tools for biologists and medical researchers as they design and build elaborate custom molecules using molecular components that either self-assemble or are connected through chemical reactions.
Chemistry “is not so different from carpentry,” Dmochowski says. “You have a vision, you want to build something beautiful that has a particular structure and function, and you want to make it at low cost.”
Being in the Dmochowski lab means working on projects that span several fields of chemistry, be it synthetic, analytical, biological, physical, organic, inorganic, or computational. This requires group members to learn new methods, nomenclature, and experimental strategies as their work extends into areas beyond their original field of expertise.
Graduate student Josh Bulos says that the group’s identity comes not from sitting in a specific field but by the end result of their work. “We sometimes begin with the goal of developing ‘such-and-such’ chemistry, and every project eventually has a biological application,” he says.
Roughly half of the group works with xenon, a typically unreactive noble gas that can improve the resolution of magnetic resonance imaging (MRI). By delivering small molecules and proteins that interact in specific ways with xenon, researchers aim to “add color” to grayscale MRI, which could help identify cancer biomarkers in tumors.
“It’s coming along as a nice complement to traditional [MRI] techniques,” says graduate student Serge Zemerov, who works on synthesizing small molecule xenon-binding cages and characterizing these constructs using physical and analytical chemistry techniques. “We want to look at xenon hosts and ask questions like, What causes high xenon affinity for a particular molecule and how can we modulate the signals that xenon produces?”
Zhuangyu Zhao, a graduate student who is also working with xenon, is using computational and molecular biology tools to redesign natural pockets in proteins that could serve as binding sites for xenon instead. “The advantage is that proteins are biocompatible and more soluble than small molecules, and proteins can be easily delivered to specific parts of the body,” says Zhao.
Dmochowski has been working with xenon for the 16 years, having been inspired by a research seminar that he attended soon after he started at Penn.
“It allows us to get into many different areas, everything from molecular design of small molecules and proteins to magnetic resonance and fluorescence imaging experiments. There’s a lot of engineering of the host molecules and trying to understand how xenon [a prototypical gas molecule] interacts with buried sites, so we’re continuing to push those frontiers,” says Dmochowski.
The group is also working on light-activated oligonucleotides, short chains of DNA or RNA that bind to specific gene sequences after photoactivation. These approaches are used in applications such as transcriptomics, which look at RNA being expressed in a cell at a given time.
Graduate student Linlin Yang is currently developing “transcriptome in vivo analysis,” or TIVA, a tool that allows researchers to study gene expression in individual cells. TIVA has been used by James Eberwine to study specific types of RNA, known as messenger RNA, in living brain slices and even from human tissue.
“There are other ways to study single-cell transcriptomes, but usually you need to dissociate the tissue, and you lose the microenvironment and spatial context of each cell,” says Yang. She is currently working on making these light-activated oligonucleotides more stable in vivo and capable of capturing all of the RNA within the cell.
Taking inspiration from biology, Bulos studies ferritin, an iron-storage protein found in everything from humans to deep sea archaea, to see how its cagelike structure can be manipulated to put other molecules inside.
“In collaboration with Vladimir Muzykantov, we figured out we can load therapeutic proteins inside ferritin and deliver these to sites of injury in animal models. We’re investigating what other therapeutic molecules we can load inside the ferritin. We can use these protein assemblies in materials, for drug delivery, and for studying how [molecules] behave inside nanoscale, confined environments,” Bulos says.
During the summer, the lab hosts a number of visiting scholars, summer students, and undergraduate researchers. This summer is no exception, as the Dmochowski group is hosting collaborators from Puerto Rico, a Philadelphia high school teacher, and two Penn undergraduates. Each of the group’s senior students helps to mentor and guide newcomers as they share their lab’s culture of broad, chemical thinking.
“Chemistry has long been similar to trades where you have an apprenticeship: You work closely with people and learn skills, while intentionally keeping everyone safe,” says Dmochowski about his group’s “buddy system” approach to research.
Dmochowski group members work on a wide variety of projects using a diverse range of methods, and they say that being in a group with such broad expertise is incredibly useful. “It’s interesting that my colleagues are working on entirely different things. I can ask [another group member] ‘How do you approach this type of problem in proteins?’ and then I can think about how to use this,” says Yang.
Zemerov adds that, while working on a project that’s vastly different from his colleagues can be challenging at times, the experience helped him foster crucial independent research skills. “Once you put in the effort and can troubleshoot effectively, it boosts your confidence,” says Zemerov.
Dmochowski, who has been at Penn for 16 years, has worked across a wide variety of fields, including supramolecular and bioinorganic chemistry, protein chemistry, biophysics, bioengineering, and even developmental biology. Much like his group members, he knows first-hand the importance of working outside one’s comfort zone.
“One of the best parts of my job is the constant change,” he says. “I encourage students to be fearless and to not let their prior experience dictate what they do. We wouldn’t get anywhere if newcomers to the lab just came in and did exactly what they had done before.”
Ongoing research in the Dmochowski lab is supported by the University of Pennsylvania, National Institutes of Health, and National Science Foundation.