A Tradition of Discovery

For decades, Yale University has been committed to better understanding the causes and treatment of diabetes. From the first successful studies of insulin pump technology in the 1970s, to current investigations directed at understanding the cellular mechanisms underlying type 2 diabetes and the immunologic basis of type 1 diabetes, Yale is at the forefront of diabetes research. Clinician-scientists at Yale University School of Medicine have received numerous grants from the National Institutes of Health (NIH), the American Diabetes Association, and the Juvenile Diabetes Research Foundation (JDRF) to support ongoing, innovative, and cutting- edge research in diabetes and metabolic disorders.

Like many discoveries, the development of the first insulin pump was a combination of ingenuity and teamwork. In 1979, Yale doctors were conducting studies to figure out the best way to deliver insulin to children who suffer from diabetes. They discovered that giving small amounts continuously with larger doses at meals worked better than giving one large dose because this more closely resembles the way the pancreas produces insulin. Unfortunately, there was no easy way to accomplish this. Around the same time, another Yale doctor was using a portable pump to help solve a different problem: delivering medicine to children who had a dangerous buildup of iron due to frequent blood transfusions.

The late Dr. Robert Sherwin, Dr. William Tamborlane, and their colleagues realized this pump would be ideal for applying what they had learned about insulin delivery to their patients. The insulin pump was first tested in seven children with diabetes and the results were spectacular. The doctors stayed overnight in the hospital to monitor the results. When they began to see that blood sugar levels remained stable in their young patients, they knew that they had hit upon a novel and effective treatment for diabetes.

The insulin pump, which today has evolved into a device the size of a beeper, continues to gain momentum; 350,000 diabetic patients per year using it and its popularity continues to grow. Without volunteers like the children and their families who were willing to take a chance on an exciting new treatment, this groundbreaking discovery would not have been possible.

Since 1981, more than 25 million people have died of AIDS and today, more than 33 million people around the world – including 2.5 million children - are living with HIV/AIDS. The development of one of the most important medications to treat this deadly virus involved the efforts of Yale scientists William Prusoff and the late Tai-Shun Lin. In the 1980s they were experimenting with a cancer drug known as d4T, when they discovered that it was very effective in slowing the production of HIV. It worked by incorporating itself into HIV's DNA and shutting off the reproductive mechanism, stopping it in its tracks.

In the early 1990s, while the AIDS epidemic was in full force, a clinical trial was conducted to find out how well d4T worked in patients. The results of the trial were conclusive; Dr. Prusoff recalls his delight when he realized that what he and Dr. Lin had observed in the laboratory was working in patients. In 1992, d4T became the first drug tested under the Food and Drug Administration's parallel track policy, which gave people with life-threatening illnesses access to drugs still in clinical trials. In 1994, Bristol-Myers Squibb began marketing the drug under the brand name Zerit. Today, Zerit is available to people around the world infected with HIV, thanks to a landmark decision by Yale and Bristol-Myers Squibb to distribute it at no profit to patients in Africa, a region that has been hit hard by the virus. Thanks to the volunteers who were willing to be the first to try an experimental treatment, tens of thousands of HIV/AIDS sufferers have benefited from this novel drug.

In 1982, Dr. Richard Edelson and his team were looking for a treatment for cutaneous T-cell lymphoma (CTCL), a cancer caused by the uncontrolled growth of white blood cells known as T-cells. The life expectancy of the advanced leukemic stage of CTCL was just 18 months and there was little he could do to relieve the extremely inflamed and painful skin associated with it. He knew that a powerful drug activated by light was used to stop the spread of psoriasis, so he decided to try using it to decrease the number of cancer cells in the blood, hoping to diminish the symptoms and perhaps prolong patient survival. He devised a method of bringing the blood outside the body, where it was mixed with the drug and exposed to light before being returned to the patient. He started with one patient who had not responded to high-dose chemotherapy and, in order to determine whether the procedure was safe, he initially treated the patient only two days in a row at monthly intervals for three months. It was not expected that the initial step of treating only 5 percent of the patient's malignant cells would produce any clinical results, and Dr. Edelson thought he would have to accelerate to treatments every day. But after just the third treatment, the extraordinary results surprised everyone: the patient was in complete remission! His skin was clear and there were no malignant cells detected in his blood. A larger clinical trial with 39 patients showed that one-quarter of them had a similar response, and in 1988 the Food and Drug Administration fast-track approved the treatment, known as photopheresis, for the treatment of CTCL.

Since then, photopheresis has been used around the world about 400,000 times to treat more than 20,000 patients. Today, it's used not just for CTCL, but also to treat graft-versus-host-disease (a side effect of bone marrow transplants) and to prevent rejection following heart transplants. Meanwhile, Dr. Edelson and his team have spent the last 20 years improving photopheresis and studying the mechanism by which it works. Since that first patient, they have learned that this procedure stimulates blood cells known as monocytes to transform into cells that act as an ignition to turn on the immune system. By exposing these cells to a patient's cancer cells, a kind of personalized vaccine is created in which the new cells are able to seek out and destroy cancer cells in the body. They hope to soon bring the new knowledge they acquired in the laboratory into clinical trials for other types of cancer. The support of patients willing to participate in research studies has brought an exciting new treatment to thousands of individuals and has the potential to bring it to many more.

Drugs known as nucleoside analogs that help fight HIV infection have given hope to many patients, but with long-term use they can damage certain organs. In the mid 1980's Yale pharmacologist Yung-Chi “Tommy” Cheng, PhD, was searching for the mechanism that leads to this damage, when he discovered that a mirror form of a known antiviral drug reduced harmful side effects when used in combination with AZT, which is commonly used to treat HIV. His search to find out why this was the case led to the discovery of a new class of compounds called L-configuration nucleosides that paved the way for a new direction in drug development.

One of the drugs discovered by Dr. Cheng and his colleagues in this new class is an HIV drug called Emtriva that has been approved by the FDA and is also showing promise as a treatment for hepatitis B. His continued research has led to the discovery of two additional L-configuration nucleosides: Elvucitabine is longer-acting than Emtriva and is being tested in the treatment of HIV and hepatitis B, and Clevudine, which continues to work even after patients stop taking it, is proving effective against hepatitis B. Dr. Cheng is excited that discoveries he has made in the laboratory are proving beneficial to people who need them. These new medicines would never have found their way to patients without the many volunteers who were willing to participate in clinical trials.

Developing new drugs is a lengthy process, but the discovery a new drug to treat ADHD actually began almost 80 years ago. That's when scientists at Yale began studying the prefrontal cortex, the region of the brain that is crucial to controlling our attention, actions and emotions.

More recently, Amy Arnsten, PhD, became fascinated by the prefrontal cortex when she realized that malfunctions in this brain region were the cause of many forms of mental illness, a field that had long interested her. Arnsten knew from work by other Yale researchers that the blood pressure drug clonidine helped patients with Tourette's syndrome, but it's a powerful sedative – too powerful for children. So she and her colleagues studied guanfacine, another high blood pressure medicine, to find out how it might affect the prefrontal cortex. They found that guanfacine helped neurons in the prefrontal cortex to communicate better by inhibiting certain chemical messages. Because it's more selective than clonidine – guanfacine prefers a single receptor site that's important for prefrontal cortex function – it has fewer side effects.

Doctors already knew that guanfacine was safe, but they didn't know if it would alleviate the symptoms of ADHD, one of the most common childhood disorders. To find out, Dr. Robert Hunt, then at Yale, tested it in a few adults. When it seemed safe and effective, he tried it in some of his pediatric patients with ADHD, where it also showed promise. This was good news because the few medications used to treat ADHD don't always work well and sometimes cause side effects. Because children metabolize guanfacine very quickly, an extended release version known as Intuniv was developed and tested in larger trials involving children. Today, it is helping ADHD patients to be less distracted and have better self control. Without the participation of young patients and their families, this promising new treatment would not have been possible.

When medical researchers noticed that mustard gas destroyed lymphatic tissue and bone marrow after World War I, they thought it might also be able to kill cancer cells in the lymph nodes. Experiments in mice later showed that topically applying nitrogen mustard, which was derived from mustard gas, caused tumors to shrink. No further progress was made, however, until 1942. The United States had just entered World War II and, fearing that nitrogen mustard might again be used in battle, the government's Office of Scientific Research and Development asked institutions around the country to study chemical warfare agents.

Among these was Yale, where two young assistant professors in Yale's new Department of Pharmacology, Louis S. Goodman, MD and Alfred Gilman, PhD, began to study the effects of nitrogen mustard on lymphoma. Early studies in mice showed dramatic regression of the disease, which was confirmed in further studies in rabbits. The next step was a clinical trial. The first patient in the world to be treated by chemotherapy was a 48-year-old man in the terminal stages of lymphosarcoma. Radiation no longer had any effect on his tumors and he had run out of treatment options. He was given 10 doses of nitrogen mustard at a dosage that was roughly 2.5 times what became the standard, because nobody had any idea how much to give him. Within two days, doctors noticed that his tumors were softer and by the end of treatment, they had disappeared.

Although he relapsed a short time later and subsequent courses of treatment were less effective, scientists had proof that chemicals could treat cancer. Further clinical trials followed at Yale and around the country, but the results – including the results of the first trial – remained a military secret until 1946, when they were published in The Journal of the American Medical Association.

Thanks to the patients who were willing to undergo an experimental treatment, nitrogen mustard was incorporated into multidrug chemotherapy for Hodgkin's disease and remains a potent agent against cancer today. It has also paved the way for similar chemotherapeutic agents that attack cancer cells.