Malvern resident John C. “Chip” Tilton and his colleagues are researching ways to use the human immunodeficiency virus (HIV) for treating diseases.
By Jennifer Kuhel
In medical school, Chip Tilton knew there was a place for him in the world of medicine. That place just wouldn’t be seeing patients day-to-day.
His curiosity led him to the lab. “The way I like to think about problems is by looking at the big picture, then understanding the root causes of diseases and making little strides at the fundamental level,” explains Tilton, an associate professor and the director of Immunobiology at the Case Western Reserve University Center for Proteomics and Bioinformatics.
He joined the university six years ago following research positions at the University of Pennsylvania and the National Institutes of Health, and his family settled in a Malvern home after falling in love with Shaker’s tree-lined neighborhoods and schools.
Tilton may describe his work as baby steps, but what he’s doing in his lab is hardly insignificant: He’s searching for a way to make a friend out of a notorious foe – the human immunodeficiency virus (HIV). And what he uncovers could have huge implications on how various diseases are treated in the future.
For the past 14 years, Tilton has immersed himself in HIV research, learning which cellular proteins help or prevent the virus from replicating inside the cell. Then, he discovered some interesting things about the proteins that play a role in HIV infection. Namely, that HIV is remarkably efficient at delivering proteins into a cell, but it’s not as good at integrating its genome with the host chromosome.
A Sheep in Wolf’s Clothing
This makes HIV a poor door-to-door salesman of viruses: Its host cell customers readily open their doors to get the sales pitch, but that pitch doesn’t always convert into a sale.
In isolation, this makes HIV infection appear unlikely. But inside a human being, there’s a Roman army of these salesmen, making HIV a volume business with catastrophic results.
So Tilton began to look at HIV in a different way, wondering if he could make HIV a sheep in wolf’s clothing. He considered the possibility of modifying HIV particles enough so that they could get a diseased cell to open its doors, which by itself is enough to deliver highly specific, helpful proteins that could have positive effects on the cell – no sales pitch required. This brand of medicine, called protein therapeutics, uses naturally occurring or modified proteins that bind to a receptor on the surface of a damaged cell to initiate a reaction that’s beneficial to a patient. The difference for Tilton is that he wants to find a way to deliver a protein inside the cell.
Enter Tilton’s nanoPODs (short for nanoscale protein delivery), strategically engineered non-infectious HIV particles that sense intracellular environments and then set off a chain of events based on that environment. Tilton and his team have used nanoPODs in vitro to determine whether a cell is infected with HIV. He’s found that uninfected cells are unchanged. The story for HIV-infected cells is less rosy. The nanoPOD sets off a reaction inside the cell which results in apoptosis, or cellular suicide. “We can probe whether HIV is in a cell and then specifically kill cells that are HIV-infected and not kill healthy cells,” he says.
Down the road, Tilton is hoping to find a way to use nanoPODS loaded with therapeutic proteins to replace defective proteins, or, in the case of cancer, to eliminate pre-cancerous cells and stop the disease before it even becomes apparent. “Most small molecule drugs – the drugs we take in pill form – are well absorbed, but tend
to go all over the body, so that’s where a lot of the side effects come from,” Tilton says. “In contrast, our nanoPODs can potentially deliver protein therapeutics very selectively to target cells and have sophisticated actions that reduce side effects and add whole new classes of function.”
A Glimmer of Hope
Even more fascinating (and bordering on science fiction) is the possibility in genome editing.
Recently, Tilton and his colleagues at Case used a nanoPOD to deliver both a protein and RNA inside a cell. For those with inborn errors of metabolism (genetic errors where the body can’t convert food to energy), this discovery provides a glimmer of hope.
“Our goal would be to go in and fix their genome so that it encodes a functional gene. We would try to get the particles to deliver enough of these gene editing proteins to go in and fix the damaged cells,” he explains. Tilton emphasizes that his work is still very much exploratory. “If we can deliver proteins into cells in vivo [in a living organism], then we’ll basically have leapfrogged a majority of the protein delivery platforms out there and we’ll have been able to do something they haven’t been able to do.”
That possibility and its potential keep Tilton motivated in a field that’s plagued with one step back for every two steps forward. “I can’t even see the stuff that I work with. It’s all too small. All I can do is measure and learn whether I’ve had an effect on the cell,” he says
One day, with a little luck and lots of persistence, Tilton just may cause the effect he’s been anticipating. And if it does, his place in the world of medicine just might be one for the books.
Originally published in Shaker Life, Winter 2017.