Knowledge District

Five scientists whose cutting-edge research is giving the historic jewelry district a new name.

With the rerouting of I-195 in Providence and the dismantling of the decrepit old highway that cut off one corner of the city, the overlooked Jewelry District, once the city’s manufacturing engine, is now the site of high-tech economic development. Local officials are looking to rename the area the Knowledge District, and are pushing for more federal grant money to develop a job-generating cluster of medical research labs. Already there are a number of projects that score high marks on the gee-whiz scale and may someday help treat or cure some of the worst diseases.

Photography by Patrick O'Connor

Isis Biopolymer

Location: Richmond Street
Delivering drugs 
without pills or needles

The prototype “transdermal” drug delivery system being
developed by Isis Biopolymer, Inc. is an ultra-thin “Band-Aid”-like patch that contains a microprocessor and thin film polymer called the IsisIQ, 
a twenty-first-century tweak to some very old technology. The patch administers medicine through a process called iontophoresis, says Emma Durand, the company’s founder, chief executive officer and chief technology officer. The technology, first discovered by 
an Italian scholar in 1747, uses electric current to force drugs through the skin.

Her company is working on an intelligent, drug-dispensing skin patch that has the ability to modulate drug delivery to provide true personalized drug delivery remotely.

“Let’s say you’ve had a knee replacement and you’re at home,” says Durand. “It’s Saturday night and you call the doctor and say, ‘I’m in pain.’ The doctor can use his cell phone to call a Wi-Fi site, which goes to the patch and changes the programming.” That can, say, increase the dosage of a painkiller, or switch to delivery of a new drug.

The company’s new headquarters and production plant is on Richmond Street, after moving to the Jewelry District from Warwick early this year. Durand, originally from Rhode Island, has also lived in Boston and California. She has been a key player in a number of high-tech companies, and holds more than forty patents, according to Isis.

The smart patch she’s developing would have been too big and expensive to make twenty years ago, before advances in microprocessor and battery technology. “Transdermal never really came to fruition because of the inherent problems,” she says, such as skin irritation and an unpleasant tingling sensation. Durand says Isis has overcome those problems.

What’s the science behind the tech? According to scientific folklore, “in late nineteenth-century France it was demonstrated by poisoning [animals]. They’d transport arsenic, 
and it would transfer and kill a dog. It was the beginning of the industrial use of electricity. But basically the technology lay fallow for many years.”

The patch uses a weak electric current to push a drug that has been given an electric charge. “When you make an electric current you’re creating a force, and that force has to resolve itself. It resolves by pushing the drug through the skin. Then the [body’s] microcirculation sucks it up and it’s in the bloodstream.”

The Isis patch also contains an electrically charged membrane. 
By switching the polarity of the membrane — from a positive charge to a negative, for example — the microprocessor on the wafer can interrupt the electric force pushing the drug and shut off the dosage.

The device will also give doctors confidence that their patients are receiving all their medications, she says. Elderly patients are often jug-gling several prescriptions. “If they don’t like the side effects they might decide not to take it, or they forget 
to take it, and they get sicker and go back to the doctor. It’s a huge problem. If you’re not taking the medicine, you’re not going to get better.”

Durand believes a fully controllable, wireless and intelligent patch will be on the market in just a few years. In the meantime, Isis is manufacturing a patch for a cosmeceutical company to deliver anti-wrinkle agents into the skin. After more than a year of development, 
the anti-wrinkle patch launched in January, says Shawna Gvazdauskas, Isis chief commercial officer. “You may chuckle to yourself — an anti-wrinkle treatment — but it’s a brilliant way for us to generate revenue in a non-Rx way.” The patch is being manufactured in Providence over two production shifts that each employs more than sixty-five people, says Gvazdauskas. 

Gerwald JoglGerwald Jogl
Brown University Laboratory for Molecular Medicine

Location: Ship Street
Exposing the vulnerabilities of disease-causing organisms

At first glance, the computer rendering created by structural biologist Gerwald Jogl looks like a three-dimensional drip painting by Jackson Pollock, attractive in a tangled-ball-of-yarn sort of way.

The rendering is a schematic of a single component from inside a microscopic bacteria cell. The component is called the ribosome, which makes proteins necessary for the life of the cell. This is living nature as art, at the smallest level. “If you make a picture of a whole machine, then we just study a single screw,” says Jogl, a Brown University professor who performs his research at the univer-sity’s Laboratories for Molecular Medicine, on Ship Street.

Jogl creates maps to expose vulnerabilities in pathogens that human cells don’t have, so chemists can design drugs to kill the bugs without harming the patient. What makes his computer rendering special is a little spot of color inside the three-dimensional tangle, like a bracelet in a pile of fishing nets. That ring represents the antibiotic streptomycin, which just happens to fit perfectly inside a little pocket within the ribosome of bacteria cells.

“There’s a little hole in there and streptomycin goes right in and stays there,” says Jogl. “With any molecule, life is a lot of motion and jiggling, and if that thing (streptomycin) is in there, the ribosome can’t move properly. And if it can’t move properly, it starts making mistakes while it makes proteins. Those proteins don’t work any more. No living cell can tolerate that.”

It would be like disabling a battleship by jamming a screwdriver in the rudder, but that’s how drugs work, says Jogl. “They fit right in [a] little sweet spot.” His work is to define those sweet spots. “It’s like a three-dimensional puzzle,” he says. “Once you have that model, what can you find that fits into that pocket?”

Jogl creates the maps by breaking open bacteria and extracting the ribosome in the lab. He forces them to crystallize, and then exposes them to X-rays. “Sadly, you can’t see X-rays, but if you could the crystal would look like a little hedgehog, shooting X-rays in all directions.” A detector catches the X-rays and measures their intensity. “All the information for the three-dimensional structure is encoded in those intensities. You can backtrack and determine, ‘How must this structure have looked to make the X-ray sparkle in that particular pattern?’ ”

Jogl sees himself as an explorer. “In research you’re out there in the forefront of what we at this point know,” he says. “It’s similar to being out there in the jungle, where you’re at the forefront of the maps, where you didn’t know what was next. I’m at the forefront of what we know and I’m trying to chart a little further.”

Roy AAronRoy Aaron
Center for Restorative and Regenerative Medicine

Location: Point street
Decoding the development of arthritis

Medical researchers chasing cures for all sorts of diseases are often hunting for “biomarkers,” the red flags that indicate the presence or possibility of the disease, such as a certain gene that predisposes a person for a particular kind of cancer.

Orthopedist Dr. Roy Aaron, a Brown Medical School professor and director of the Center for Restorative and Regenerative Medicine, is looking for a biomarker that can help predict the development of arthritis.

In his lab at the Coro Building, Aaron listens to the subtle chemical conversations between bone, cartilage, ligaments and the membrane that lubricates the joint, called the synovium. “We want to understand arthritis, understand the biology of arthritis, what the causative features are,” he says, “and this involves cell behavior, it involves blood flow, it involves chemicals that our bodies make or don’t make.”

He studies the interplay of these tissues, particularly bone and cartilage, using MRI imaging and PET scans — a tool of nuclear medicine that uses radioactive chemicals and computers to create three-dimensional pictures. “By using these tech-niques we’re able to identify  that there are changes in blood flow in the bone that  precede a drop in the oxygen content of the bone. And in turn the bone cells are stimulated by the low oxygen level to over-secrete certain proteins, which can be damaging to the cartilage. So we think there is a loop there.”

What causes the change in blood flow? “It may be little tiny blot clots. It may be the fact that the veins that lead out from the bone are in spasm. They tighten up, close down.

“But now you have bone and cartilage and synovial membrane all talking to each other through chemical signals. And the result of that is the activation of enzymes in the cartilage, which destroys it. When the cartilage is destroyed, the bearing surface of the bone is lost. You have pain, deformity, swelling.” That’s arthritis.

“But if you could find a biomarker for early arthritis, then perhaps you could do lifestyle modifications, or design drugs to target the pathology that you have identified as important in arthritis.”

Aaron, originally from New York City, says he enjoys the analytic challenge of diagnostic medicine, but doesn’t find the work very creative. “It’s basically running through a pretty well described algorithm to work your way through a diagnosis. It’s fun to do. It’s intellectually challenging, but it’s not creative in the sense that you’re making something new that didn’t exist before.” Medical research has become his creative outlet. “Since I have no artistic talent what-soever and no musical talent whatsoever, this enables me to at least try to think originally and identify a problem, and then come up with a solution, creating information that didn’t exist before.”


Rena WingRena Wing
The Miriam Hospital Weight Control and Diabetes Research Center

Location: Richmond Street
Discovering the tricks to keep weight off

No young, healthy adult ever plans to put on unwanted weight, but statistics show that most do — about one to two pounds per year, says Rena Wing, a behaviorist who studies obesity, weight loss and weight control.

There are many reasons why young adults put on weight. They’re less active once the college sports uniform is packed away in favor of a dress shirt and a desk job. People building their careers are also short on time and quick to grab a bag, box or bucket from the nearest fast food spot.

Wing is overseeing a new study at The Miriam Hospital Weight Control and Diabetes Research Center on Richmond Street  to identify the best strategy for the eighteen to thirty-five age bracket to fend off the slow creep of bigger hips and bellies. About six Brown University faculty members and roughly forty staff people work at the center, says Wing. The center is funded mostly through National Institutes of Health grants.

“Our interest is helping people lose weight and keep it off using behavioral techniques,” she says.

Wing’s new study will compare two strategies for preventing weight creep.

The first method, called “small changes,” is a trendy concept in the pages of health magazines. A pound of fat is about 3,500 calories, which isn’t much to offset over a year with small changes, she says. Just leave the margarine off your toast, or switch from whole milk to skim.
“The idea of small changes is that they’re easy and you should be able to do them every day for the rest of your life…The concept is real popular, sounds real good, but hasn’t been tested very well.”

The second approach is to make big changes periodically. When your weight creeps up, cut your calories and exercise harder to knock off five or ten pounds “to create a buffer” against weight gain, says Wing. Repeat when necessary.

The point of this study? “What should we be telling eighteen- to thirty-five-year olds? They’re going to gain weight, unfortunately. They’re at a high risk of gaining weight and that’s not good for them. So therefore they should do…what?”

For this study, Wing will recruit 300 people of normal weight or who are slightly overweight, in addition to 300 additional people recruited in North Carolina. She’ll train them in either the “small changes” or “big changes” concept. Some will learn a more flexible combination of the two programs. Wing will monitor her test subjects for three years to see which group keeps the weight off.

Wing, originally from Long Island, has been studying obesity for thirty years, since before it was considered a serious medical problem. “It’s a fun area of research because you’re learning things but you’re also helping people.”

What’s left to learn? Behavioral science has gotten pretty good at helping people lose weight, she says. But even people who stay in treatment tend to gradually regain what they lose. Wing wants to know why. “What can I teach them? How can I organize their lives? What could I change that would stop it?”

Anne de GrootAnne de Groot

Location: Clifford Street
A breakthrough in fighting autoimmune diseases

The scientific “aha” in Dr. Anne De Groot’s research came in 2007, when her biotech company, EpiVax, Inc., turned its attention to an overlooked scrap of protein that De Groot believes will revolutionize treatment for some of the most serious chronic diseases.

“This molecule I think has the po-tential to be a complete paradigm shift for the way we’re going to think about inflammation, autoimmune diseases, transplantation, type 1 diabetes, even perhaps vaccines,” says De Groot, a researcher, professor and business owner, who founded her company in 1998.

EpiVax helps pharmaceutical companies develop vaccines. But while doing that work, says De Groot, the company stumbled upon the molecular trigger that tells the immune system to calm down. Understanding why De Groot is so excited by this discovery needs a little explanation.

Greatly simplified, the body has mechanisms to regulate the immune system. When bacteria or a virus are discovered, the immune system releases the hounds and attacks the intruder. The cells responsible for shutting down the system later — for putting the hounds back in the pen — have been known for years, but nobody knew what got them to act, says De Groot. “And we found that thing.”

Why would we want to shut down immune response?

Because sometimes the immune system gets confused and starts attack-ing things we really need. “That’s autoimmune disease,” she says. “You start attacking your nerves, that’s multiple sclerosis; you start attacking your pancreas, that’s juvenile diabetes, or you attack your thyroid, that’s thyroid disease.” The immune system also attacks transplanted organs, requiring drugs that suppress the whole system.
“We found the switch that shuts off an immune response where it’s happening,” says De Groot. “If you have inflammation in your pancreas you don’t want to be shutting down an immune response to flu in your throat. So we can target shutting off that immune response. It could replace a lot of toxic therapies. For us it’s a huge discovery and it’s exciting.”

EpiVax is collaborating with laboratories to study ways to turn the discovery into a treatment. “Ten years from now, you will see this particular molecule being a lynchpin in the first intervention for those (autoimmune) diseases. To have something that could have such a profound impact on making people feel better is what any scientist would want to achieve.”

De Groot comes from a family of artists and scientists, and she is a bit of both. “What’s so great about science is that it’s being an artist in a different medium. The kinds of connections we make between concepts are very similar to the connections an artist would make. If you question dogma, which is a great thing for an artist, then you’ll probably do really great science. That’s our motto — science without fear.”