By Karen Feldshcher - Photography by Jorg Meyer
For Northeastern’s life sciences researchers, it’s not the little things that matter. What matters is the big stuff, the life-or-death issues.
Take these five faculty members, for instance:
Penny Beuning is trying to understand how DNA damage occurs in cells.
Robert Campbell wants to improve the treatment of pancreatic cancer.
Craig Ferris seeks a technicolor lowdown on how the brain responds to environmental and genetic factors.
Alexandros Makriyannis is pursuing treatments that could control obesity, cure addiction, and relieve pain—a sweeping trifecta.
And Michail Sitkovsky is testing whether a particular molecule boosts the body’s immune response to cancer.
They’re but five examples of the many women and men doing vital work in the life sciences across the university—work that may well enhance your own health someday.
The Damage Done
DNA molecules in cells can be damaged by the body’s exposure to all sorts of things: car exhaust, cancer drugs, free radicals, ultraviolet light. These and a host of other environmental factors may destroy crucial pieces of genetic information, compromising the cells’ capacity to function.
Sometimes the cells can repair the DNA damage themselves. But sometimes the damage leads to cell death, or to mutations that cause such diseases as skin cancer or premature aging syndrome.
“DNA damage is everywhere,” says Penny Beuning, assistant professor of chemical biology and biotechnology. “You cannot escape it.”
In her lab—with the help of two postdoctoral researchers, four graduate students, and several undergraduates—Beuning is trying to pinpoint how cells respond to DNA damage.
Every time a cell divides, all its DNA must be copied. Beuning is studying families of enzymes that handle the copying.
“The enzymes that do this are efficient and accurate,” she says. “Typically, they zoom along the DNA in the cells, sort of like a thread being pulled through a needle. But if there’s damage in the DNA, it’s like a knot, and the enzyme gets stuck. Then the whole process stops and goes haywire.”
A separate family of enzymes can also copy DNA, and they don’t get stuck, even if the DNA is damaged. “There are huge questions about how they work,” says Beuning. “How can they be so similar to the regular enzymes, and yet have this specialized ability to copy damaged DNA?”
In another mystery, she says, this second group of enzymes “get used for a while, then go away.” As yet, no one knows why.
Beuning, who’s been studying the consequences of DNA damage for six years, recently won a Dreyfus Foundation New Faculty Award, which named her as one of a dozen new professors across the United States with the potential to produce outstanding contributions to chemistry. The award includes an unrestricted $50,000 research grant.
No one knows how long it will take to fully tease out the mysteries of DNA damage, Beuning says. “Science is really unpredictable. But that’s one of the things that makes it so much fun.”
Contending with Pancreatic Cancer
Pancreatic cancer is a double whammy. Because it’s so difficult to diagnose, it tends to be at an advanced stage by the time it’s discovered. And chemotherapy is often of limited use in fighting it. This one-two punch means pancreatic cancer has the worst survival rates of all cancer diagnoses.
Robert Campbell, an assistant pharmaceutical-sciences professor in Bouvé College of Health Sciences, may have found a way to make chemotherapy more powerful for those diagnosed with pancreatic cancer. Already the scientific community has begun to take notice—an article on his findings appeared in the October 2007 British Journal of Cancer.
Campbell and graduate student Ashish Kalra have discovered that substances called mucins, a family of proteins found in higher-than-usual quantities on the surface of pancreatic tumor cells, seem to act as a physical barrier to chemotherapy drugs. And reducing the mucin seems to enhance chemotherapy’s tumor-killing effect.
To find out whether mucin was inhibiting the effectiveness of 5-fluorouracil (5-FU), a popular chemotherapy drug, Campbell and Kalra used inhibitors to limit the amount of mucin on the tumor cells. They found reducing mucin on tumor cells did enhance 5-FU’s effectiveness, and healthy cells weren’t harmed by the inhibitors.
The researchers speculate that inhibiting mucin on the surface of pancreatic tumor cells could reduce the amount of drugs needed to treat the disease.
Why does the inhibition of mucin improve chemotherapy results? Campbell says he doesn’t know yet. To fight the intricate war on cancer effectively, though, it’s going to be a crucial question to answer.
In other research activities, Campbell specializes in the pharmaceutical evaluation of drug-delivery systems, tumor vascular physiology, targeted drug delivery, cellular delivery of drugs, and the biophysical analysis of drug-carrier molecules.
For instance, chemotherapy currently can’t be targeted directly at tumors. Campbell and his colleagues want to fix that, by using drug-carrier molecules that selectively deliver drugs to malignant growths and minimize the damage to healthy tissue.
Take a Mental Picture
Mental illness. Physical trauma. Drugs. All sorts of factors, environmental and genetic, can have a profound impact on brain chemistry.
The brain’s elasticity fascinates neuroscientist Craig Ferris, who is attempting to map out the dramatic changes that occur in the organ as it reacts to various stimuli.
Ferris is also looking at how the brain changes over time, from adolescence through adulthood. And he’s interested in developing drugs to combat violence and impulsivity, which are among his major areas of interest.
To see what goes on in gray matter, Ferris takes pictures of the brains of live animals using high-field magnetic resonance imaging. He developed his approach during two decades spent at the University of Massachusetts Medical School, where he earned substantial federal research support. Now he’s continuing it at Northeastern, where he began working last fall as a psychology professor and the director of the Center for Translational Imaging.
Ferris’s images highlight, in vivid color, specific areas of brain activity elicited by various situations he creates in his lab.
For example, he was interested in knowing whether lactating mothers—in this case, rats—had a stronger interest in their pups or in cocaine. A thin plastic sheet was placed between a mother and her pups. When the sheet was pulled away and the mother and pups were able to physically reconnect, Ferris took a picture of what happened in the mother’s brain.
The result was crystal clear: “The reward system lights up,” says Ferris—the same brain system that lights up in response to cocaine.
Plus, he found the mother rats, as long as they are lactating, get no kick from cocaine at all. In fact, he says, “you can see the reward system shut down.”
As soon as the pups are weaned, however, the rat moms begin to prefer cocaine over their offspring.
In a variety of other studies, Ferris examines a range of factors that could affect the brain: drugs like nicotine and MDMA (ecstasy), stress, fear, anxiety.
Most traditional brain-neurochemistry studies require brain dissection. The imaging technology Ferris has developed allows the study of animals while they are awake, and throughout their natural lifespan. In addition, his lab has created software that can analyze 1,200 distinct areas of the brain.
“Ours is one of the few labs in the world that use this technology,” Ferris says. And in comparison with the many brain-study techniques in use, he says, “I believe it is coming to the forefront.”
Remedies from Within
Imagine the benefits if someone could find a way to cure drug and tobacco addiction. Relieve pain. Control obesity.
Alexandros Makriyannis, Behrakis Trustee Chair in Pharmaceutical Biotechnology and director of the Center for Drug Discovery, is hot on the trail of doing just that. He’s spent the better part of two decades pursuing therapies to combat some of humanity’s toughest health-care problems, treatments created by harnessing substances called endocannabinoids.
Endocannabinoids are produced naturally in the human body, and interact with a biochemical network called the endocannabinoid system. This system, which responds to cannabis as well as endocannabinoids, regulates the immune and central nervous systems, including such functions as appetite, pain, and addiction.
With annual funding averaging $3 million from the National Institutes of Health, Makriyannis, who came to Northeastern in late 2004, is designing and creating new molecules that tap into the body’s endocannabinoid system. Drugs using these molecules could have myriad uses: ending food cravings; lowering cholesterol; easing nausea and stimulating appetite in chemotherapy patients; tamping down tremors caused by Parkinson’s and other motor disorders; relieving nerve-degenerative pain; and controlling addiction to substances such as tobacco, cocaine, methamphetamines, and steroids.
Although cannabis itself can be used for therapeutic treatment, the drugs Makriyannis and his team are developing will work much better, he says. He’s attempting to create compounds that will achieve targeted therapies without the psychotropic side effects.
Already, two of the drugs Makriyannis has developed—for curbing appetite and for easing chronic pain—are on the path to commercial production.
Little Molecule, Big Impact
When it comes to an injury or an infection, a little inflammation can be a good thing: It can help the body heal.
But too much can be a bad thing, especially when it’s “doctor-induced” inflammation. Here’s one example: Every year, fifty thousand people die of a lung inflammation that crops up or worsens after they’ve been given supplemental oxygen to get more oxygen to their lungs.
Michail Sitkovsky, the Eleanor W. Black Chair of Immunophysiology and Pharmaceutical Biotechnology, has spent much of his research career studying the mechanisms that promote or inhibit inflammation. Now he and assistant professor Akio Ohta have discovered how one molecule plays a key role in creating out-of-control inflammation, leading to some breakthrough ideas on how to contain it.
In a landmark 2001 study that appeared in the science journal Nature, Sitkovsky and Ohta demonstrated that the molecule adenosine is a crucial factor in inflammation. When the immune system fights an infection with inflammation, some blood cells, which carry oxygen, are destroyed, causing a localized drop in oxygen levels.
This drop, Sitkovsky found, apparently sends a signal that inflammation has moved beyond destroying pathogens and is now destroying healthy tissue. To prevent excessive collateral damage, adenosine goes to the site, and curbs the inflammation.
In 2005, Sitkovsky made a troubling related discovery: Oxygen therapy—giving supplemental oxygen to treat patients with lung inflammations or breathing problems—can actually make inflammation worse.
Why? It seems oxygen therapy prevents oxygen levels from dropping low enough to switch on the signal that normally lures inflammation-stopping adenosine to the rescue. But many patients need oxygen therapy. Sitkovsky’s solution? Administer synthetic adenosine along with the oxygen therapy.
Finding out more about adenosine could even help in the fight against cancer, Sitkovsky believes. When a tumor grows faster than its blood supply, it has a low oxygen level—which may be luring adenosine to block immune cells from killing the tumor, just as it blocks inflammation.
Before coming to Northeastern, Sitkovsky spent twenty years running a research lab at the National Institute of Allergy and Infectious Diseases, one of the National Institutes of Health. Since 2004, he has directed the New England Inflammation and Tissue Protection Institute at Northeastern.
In addition to attracting attention in top scientific publications, Sitkovsky’s work has been backed by more than $3 million in federal grants. And he says testing will soon be under way on novel therapeutic treatments based on his discoveries.
He is approaching the clinical trials on humans with a sense of humility, he says. But, he adds, “we are very hopeful that our novel approaches will save lives.”
Karen Feldscher is a senior writer.