On the verge of a medical breakthrough

Above: Some samples of the highly fluorescent dyes used by the Singaram group for glucose-sensor research. Photo: Jim MacKenzie

An innovative UC Santa Cruz
research project brings new hope
to the treatment of diabetes

—By Tim Stephens

Diabetes is a chronic disease that affects the body's ability to produce or respond to insulin, the hormone that allows glucose ("blood sugar") to enter the body's cells and be stored or used for energy. Many diabetics require insulin injections, and all must carefully monitor and manage their blood glucose levels. For millions of diabetics this means drawing blood several times a day, usually from finger pricks.

While insulin pumps offer a less painful alternative to daily insulin injections, drawing blood remains the only reliable means of monitoring glucose levels. Unfortunately, glucose levels can fluctuate dramatically throughout the day, making it difficult to know when to draw blood for testing. In addition, many diabetics don't test their blood glucose levels as often as recommended because of the pain and inconvenience of the procedure.

But research that originated in Bakthan Singaram's laboratory at UC Santa Cruz offers a promising route toward a long-sought goal—a continuous glucose monitor to replace the finger pricks that are a part of daily life for so many diabetics. In addition to helping diabetics manage their blood glucose levels, the glucose sensor could also be used to monitor glucose levels in hospitalized patients.

Dozens of other research groups, many of them large and well funded, have been working for more than a decade on various approaches to the glucose monitor challenge. In fact, Singaram, a professor of chemistry and biochemistry, says that if he had known more about the competition, he wouldn't have even tried to tackle the problem.

But progress made by these other groups has been limited, and Singaram's lab, six years into its work, now finds itself at the forefront of this exciting area of medical research.

Singaram's sensor produces an optical signal—a fluorescent green glow—that changes intensity in a chemical response to fluctuations in the concentration of glucose. The challenge now is to incorporate the sensor into a device that diabetics can have implanted under their skin. The device would include a transmitter to relay glucose readings to an external monitor.

"We have tested the sensor under conditions that are as close as possible to the physiological conditions under which a continuous glucose monitor would have to operate," Singaram says. "There may be another five or six years of development ahead before we have a viable device for continuous glucose monitoring, but we are very excited about the prospects for this technology."

Four UCSC graduate students have now earned Ph.D. degrees while working with Singaram on the glucose sensor project.

glucose-sensor research
Above: Graduate student Soya Gamsey (right) and undergraduate Nichol Baxter purify a dye using column chromatography.
Photo: Jim MacKenzie

Singaram seems amazed by the serendipitous combination of people, talents, and relationships that came together to advance his lab's sensor project. The initial impetus for the group's work came from Paul Levin, founder of Palco Labs, a Santa Cruz—based company that makes products for diabetics. Levin, a longtime supporter of the campus whose wife, Anne, is a trustee of the UCSC Foundation, mentioned his interest in developing a glucose sensor to the dean of physical and biological sciences, David Kliger. A professor of chemistry and biochemistry, Kliger knew Singaram had the expertise needed to tackle such a project.

Zach Sharrett
Watching graduate student Zach Sharrett and postdoctoral researcher Praveen Thoniyot (l-r, foreground) carry out glucose-sensing experiments on a spectrofluorimeter are (back row, l-r) Rich Wessling, Nichol Baxter, and Bakthan Singaram
Photo: Jim MacKenzie

"When Dave Kliger stopped by my office to talk about glucose sensors, I immediately thought of a paper I had just read that morning that suggested a way to approach the problem," Singaram says.

After further discussions, Palco Labs began funding Singaram's lab to work on the sensor project. "It was the easiest funding I ever got. We didn't even have to submit a written proposal," he says.

Singaram's work on the glucose sensor has benefited greatly from the contributions of visiting scientist Rich Wessling, a renowned polymer chemist who retired from Dow Chemical Company in the 1990s. After moving to Santa Cruz County, Wessling was itching to get back into the laboratory. He knew Singaram through mutual friends at Dow and has been working in his lab since 1996.

The glucose sensor project offered a perfect opportunity to combine Wessling's expertise in polymer chemistry with Singaram's knowledge of organic chemistry. While Singaram developed the combination of chemicals needed to produce an optical signal in response to glucose, Wessling figured out a way to immobilize the chemical complex in a "thin-film hydrogel," a biocompatible polymer similar to that used in soft contact lenses.

The result is the first system of its kind, providing optical sensing of glucose concentrations with durable and biocompatible materials. It works well under physiological conditions, the response time is very fast, and the compounds are stable and don't degrade over time.

"This could be the biggest thing I've ever done," Wessling says.

Palco Labs funded the first two years of research on the sensor. That initial support was crucial, says Wessling, carrying the project through the early stages when the researchers were struggling to figure out how to make the system work.

After that, the UCSC team got another lucky break. A few doors down the hallway from Singaram's office in the Thimann Laboratories building is the office of Todd Wipke, a professor of chemistry and biochemistry who has also served as the campus liaison to the UC Office of Technology Transfer. Wipke saw the potential of Singaram's research and wanted to keep the project going. He also knew about UC programs that support collaborative projects with industry, and he had firsthand experience in starting a company to develop products based on his own research.

So Wipke founded a new company, GluMetrics LLC, using his contacts to put together a group of investors and a management team. GluMetrics is now developing a line of products based on the optical glucose sensor, and Singaram's research on the sensor is being funded by UC's Discovery Grant program in collaboration with GluMetrics.

"It is a great example of successful technology transfer from the university to a company that can commercialize this," Wipke says.

The first marketable product likely to come out of this venture is a catheter device, called GluCath, for monitoring blood glucose levels in hospitalized patients.

Glucose levels must be regularly monitored in patients in intensive care units and others being fed intravenously with glucose drips. Research has shown that tight control of blood glucose levels can significantly reduce mortality of ICU patients, but the only way to do this currently is by taking frequent blood samples for analysis, which is painful for the patient and expensive for the hospital.

"The GluCath catheter is inserted into a blood vessel and gives a continuous reading, and it can sound an alarm if the glucose level goes too high or too low. GluCath should reduce pain, reduce costs, and reduce deaths," Wipke says.

"We have tested the sensor under conditions that are as close as possible to the physiological conditions under which a continuous glucose monitor would have to operate."

—Bakthan Singaram

An implantable glucose monitor for diabetics is the next product in the pipeline. While other companies have used different technologies to develop glucose monitors, there is currently nothing on the market that is effective enough to replace the standard blood tests.

Glucose Research Team
The Glucose Research Team: (l-r) Bakthan Singaram, Lacie Hirayama, Rich Wessling, Soya Gamsey, Dave Cordes, Nichol Baxter, Zach Sharrett, Luba Pasumansky, Chris Watts, Aaron Miller, and Praveen Thoniyot.
Photo: Jim MacKenzie

"That's not to say that something won't pop up tomorrow from another company," Wipke says. "Millions of dollars have been poured into this problem. A lot of people are working hard on it, and the potential benefits are enormous, so it's highly competitive. But we're definitely in the running."

One of the biggest challenges for an implantable device is the body's tendency to encapsulate any foreign substance. Encapsulation could affect the ability of glucose to reach the sensor. If this problem can be overcome, however, an implantable glucose monitor would provide the crucial "missing link" in the development of an artificial pancreas.

In concept, at least, an artificial pancreas is simply a continuous glucose monitor connected to an insulin pump that is programmed to deliver appropriate doses of insulin to maintain healthy blood glucose levels.

"That is the holy grail that many people have been pursuing," Singaram says. "It won't cure diabetes, but it would make management of the disease a lot easier."


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