During the first decade or so of his academic career, David Smith focused his research on the fundamental chemistry of interactions between molecules. It was “the freedom to choose your own targets and to follow what’s interesting” that attracted Smith to blue-skies research. But that approach to research—and the ethos of his lab, which he set up at the University of York in the United Kingdom in 1999—began to change after he met Sam, a local government employee, in 2005.
If you carry different ideas into a new area, you might say some things that are naive or wrong, but as long as you are confident that the ideas you are carrying in are interesting, ultimately that community will come towards you.
Sam has cystic fibrosis (CF), a genetic disease caused by two inherited, faulty copies of a single gene responsible for regulating the composition of mucous fluid. During early discussions with Sam, who became his husband, Smith realized that his fundamental work could be applied to the gene therapy techniques being developed as a potential treatment for the disease. By 2009, half of Smith’s lab had moved into gene therapy. Today, Smith says, most of his lab’s other projects also have a clear application in mind. Aside from new research directions, this change in focus had other career-related benefits. “Seeing chemistry in context is always interesting, and it also helps to enrich my teaching of undergraduates,” he says.
A fundamental grounding
During his school days near Manchester, Smith’s first love was physics. He switched to chemistry due to the influence of two inspirational A-level chemistry teachers, one of whom lent him a copy of . “[M]y interest in bonding really stretches all the way back to that teacher lending me the Linus Pauling book,” he says.
Smith pursued chemistry at the University of Oxford starting in 1989. For his fourth and final year, he joined Oxford’s inorganic chemistry laboratory and used electrochemistry and spectroscopic methods to study organometallic compounds that could bind negatively charged ions. Smith liked the lab, his supervisor, and the group dynamics, so he decided to stay for a Ph.D. For his doctoral project, which he completed in 1996, he synthesized and analyzed molecules that could recognize both positively and negatively charged ions in water, and he attempted to quantify the hydrogen bonding and electrostatic interactions taking place. Down the line, these molecules could have applications as chemical sensors, but the project was “driven by understanding how those sensors worked … and how they could become more sensitive, so we were understanding the fundamentals and didn’t have someone on our shoulder saying that they really needed this to be applied in a year’s time,” Smith says.
Smith went on to do a 2-year postdoc in the chemistry department at ETH Zurich, funded by a Royal Society fellowship. “I wanted it to be in a research team with slightly different expertise so I could pick up new skills and … make more challenging, interesting molecules in the future,” he recalls.
Toward the end of his postdoc, Smith decided to apply for chemistry lectureships in the United Kingdom. He interviewed at the University of York and got the position.
A new ethos
Aiming for quick results and inspired by the “beauty and symmetry” of the dendritic organic molecules he had worked on during his postdoc, Smith and his lab members worked to create similar molecules, with a loose plan to study how they interact. A couple of years in, they discovered that two of the molecules self-assemble into new gel materials. “The first gels that we made relied on hydrogen bonding interactions between [the] dendritic branched molecules,” Smith explains. By 2005, Smith’s lab—which by then employed eight postdocs and graduate students—was building an international reputation for its work on the molecular interactions behind this self-assembling behavior. “We were making small, easily synthesized, programmable molecules”—molecules designed and synthesized with specific parts that control their behavior—“which assembled on the nanoscale into highly functional materials,” Smith says.
Smith had just begun thinking about how this work might be applied when he met Sam. When he realized that this could be a potential treatment for Sam’s CF, Smith immediately became interested in gene therapy, the goal of which is to deliver healthy genes into patients’ malfunctioning cells in order to fix them. A major challenge in gene therapy is packaging replacement genes so they can be delivered to the target cells. Smith’s reversible, noncovalent self-assembly processes could be harnessed, he realized, to produce nanoscale molecular systems able to bind and release DNA. “I didn’t know why my work was useful until I was faced with this problem,” he says, adding that their approach to gene delivery has recently “been tested in animal models, and we have demonstrated that our self-assembling nanoscale gene carriers have no adverse effects on the immune system.”
For a fundamental chemist like Smith, the project represented “a different approach to science,” he says. Not only was the work multidisciplinary—spanning chemistry, nanotechnology, biology, and medicine—it also required starting out with specific applications in mind, designing experiments accordingly, and changing how he described his work in funding applications.
Closer to the clinic
Smith realized he could—potentially—produce a safer alternative. Heparin and DNA are both long, negatively charged biomolecules. He could, he realized, create self-assembled nanoscale systems that when injected would hunt down and bind heparin in the bloodstream and then be excreted. “We had systems that bound DNA, and they can all, in principle, be used to bind heparin as well …, so we could start pretty much instantly.”
Smith is now collaborating with heparin biochemistry specialist Jerry Turnbull of the University of Liverpool in the United Kingdom and Sabrina Pricl of the University of Trieste in Italy, who uses computer simulations to help design molecules and predict how they might perform in a biological environment. Smith hopes the work will lead to clinical trials within the next few years.
Entering new fields
To move into cross-disciplinary research, Smith says, he read lots of papers and attended conference sessions in fields new to him—such as drug delivery and toxicity—not just to listen but to present his own work. “You learn far more by being prepared to stand up and present what you’re doing. If you carry different ideas into a new area, you might say some things that are naive or wrong, but as long as you are confident that the ideas you are carrying in are interesting, ultimately that community will come towards you,” he explains.
Smith encourages young researchers to move into applied research only “once you’ve found fundamental techniques that you’re good at,” he says. “Be prepared to think and hear about plenty of applications where you cannot really help, in order to find the ones you can approach in an innovative way. Treat the application a bit like an academic problem—consider which small part of it you may be able to do something about—then work from there.”
Applied work has benefits, including a wider range of potential funding sources and “highly motivated researchers” in your lab, Smith says. Introducing his partner to his lab staff inspired them to work harder to help people with CF. Knowing your research could potentially save lives, he says, “helps keep research interesting.”
Sam is unlikely to benefit from Smith’s work, because he is unlikely to need to. His donor lungs don’t have the CF gene mutation, and if things continue to go well, he won’t need another major surgery. “The inspiration came from Sam,” Smith says, “but I think the benefit is likely to be for others in the future.”