From Small Molecules to Whole Organisms
The Division of Pharmacology, Physiology, and Biological Chemistry supports research that ranges from basic chemistry to how the body responds to medications or traumatic injury. The goal is to understand life processes at a molecular level and to tease out the factors that make the difference between health and disease.

This Division also supports a training program called the Pharmacology Research Associate (PRAT) Program, which sponsors postdoctoral fellows who conduct research in the pharmacological sciences at NIH or Food and Drug Administration laboratories.

Combining Chemists to Fight Lupus
Sometimes, the spark of two minds working together can reveal surprising new ideas or discoveries. Such was the case for an unusual partnership between chemists working in very different areas who designed a potential new drug to treat lupus, a chronic inflammatory disease caused when a person's immune system attacks his or her own tissues. The potentially fatal disease is incurable, and medicines used to treat its symptoms often have severe side effects.

Gary Glick of the University of Michigan, Ann Arbor, and his group were studying antibody molecules that attack DNA, causing kidney damage similar to that seen in people with lupus. The research team of Jonathan Ellman of the University of California, Berkeley, was synthesizing a vast collection of different chemicals — and designing a fast, effective way to pick out the ones with a desired activity.

By rapidly screening through their library of compounds — created through an approach called combinational chemistry — the researchers found a molecule that prevents the disease in lupus-prone mice. The chemists are especially excited about the molecule because it appears to lack the serious side effects of current drugs. If the compound works as well in people, it may be the basis for a long-sought new medicine to treat lupus.

Sugar-coated Cells and Inflammation

To study cell adhesion, Kiessling creates long, sticky carbohydrate molecules (orange and gray) that interact with receptors. Photo: Laura Kiessling

Most of our cells are studded with sticky, sugary molecules. These molecules allow cells to adhere to each other, which is key to activities that range from fertilization to infection. And they have captured the attention of chemist Laura Kiessling of the University of Wisconsin, Madison.

Kiessling focuses on sugar-coated molecules, called L-selectins, that guide immune cells to the site of an injury. The cells help fight infections, but when overzealous, they can cause inflammation.

Kiessling's group is able to control the behavior of L-selectin proteins — and entire immune cells — by baiting them with custom-made, super-sugary molecules. By acting as decoys that distract some of the immune cells, these molecules may minimize inflammation and may be the basis of new anti-inflammatory drugs.

Investigating Anesthesia — and Alcohol
From the early days of ether and strong whiskey, anesthetics have been used for more than 100 years. But until recently scientists had only a fuzzy notion of how they work.

Traditionally, scientists thought anesthetics had no particular molecular target and deadened nerves merely by seeping into cells. A team of researchers led by Neil Harrison, now at the Weill Medical College of Cornell University, dislodged this notion. The group pinpointed the part of a specific molecule on the surface of nerve cells that is responsible for the action of two common inhaled anesthetics. Interestingly, the same molecular site also governs the intoxicating effects of alcohol.

This research may help scientists develop safer and more effective anesthetics. For instance, it may allow them to reverse the effect of these medications rapidly so that doctors can awaken patients immediately after surgery. It may also shed light on the molecular site responsible for alcohol's unpleasant effects — and perhaps on a new way to help treat alcoholics.

Saved by a Skin
Beauty, as they say, is more than skin deep. But for severe burn victims, that thin layer of skin stretches precariously between recovery and disability or death.

Our skin is not merely a convenient packaging to cover up our insides. It also protects our bodies from dangerous bacteria and viruses, regulates our internal temperature, and seals in our vital fluids. Patients with severe burns face their greatest risk from infection and from rapid, life-threatening fluid loss, which jolts the body into shock and massive organ failure.

NIGMS-funded scientists developed, and continue to improve upon, a type of artificial skin called Integra® Dermal Regeneration Template™, which is now the top-selling skin substitute in the world. Integra®, which looks somewhat like clear cellophane wrap, works as a temporary, protective covering that promotes healing. After removing the damaged skin, surgeons drape Integra® or a similar material over the wound and then apply a skin graft to encourage new skin growth.

Within 2 to 4 weeks, the patient's own skin cells grow into the scaffold provided by Integra®. Because patients with serious burns covering most of their bodies may not have enough healthy skin left to use for skin grafts, researchers are developing a way to grow sheets of tissue suitable for grafts from just a few of the patient's skin cells.

Thanks in large part to Integra® and to decades of basic, NIGMS-supported research on burns and wound healing, the grim prognosis faced by burn patients has brightened significantly. Twenty years ago, patients with severe burns over half their bodies rarely survived. Today, those patients usually recover — and so, incredibly, do some patients with severe burns over 90 percent of their bodies.

Designer Mice Eat More, Weigh Less

When allowed to eat as much as they'd like, normal mice (left) tend to become overweight. Under the same conditions, mice lacking the ACC2 enzyme (right) actually eat more food but remain thinner. Photo: Salih Wakil

"Eat more, weigh less" — it sounds like the advertising slogan of a weight loss program. But it became reality recently for a certain type of genetically engineered mouse, providing tantalizing possibilities for treating obese humans. Obesity is responsible for the deaths of 280,000 adult Americans each year, making it a leading cause of preventable deaths in the United States. And it is an expensive one too — each year, the cost to treat problems caused by excess body weight reaches almost $100 billion.

Hope comes from the laboratory of Salih Wakil, a biochemist at Baylor College of Medicine. For more than 10 years, Wakil has studied an enzyme called acetyl-CoA carboxylase 2, or ACC2, that governs the body's ability to burn fat. His research group discovered that mice designed to lack this enzyme eat 20 to 30 percent more food, and yet have less body fat and weigh about 10 percent less than normal mice.

Best of all, the engineered mice are otherwise normal, living long and breeding well. According to biochemical studies, the designer mice simply burn more fat than their normal counterparts.

If these results in mice hold true for humans, then a drug that blocks the function of ACC2 might allow people to lose weight while maintaining a normal diet. That, in turn, could reduce the incidence of diseases associated with excess body weight and obesity, such as diabetes, heart disease, stroke, and various cancers.

Even if scientists are clever enough to develop and successfully deliver a drug that treats a certain disease, it just won't work for some people. For others, a normal dose could be fatal. The reason, in many cases, lies in our genes.

Genes are "recipes" for the body's workhorse molecules: proteins. When a medicine enters our body, it interacts with hundreds or thousands of proteins. Some of these proteins affect how well the medicine does its job. Tiny differences in these proteins, caused by each person's unique genetic make-up, govern how an individual will respond to a particular medicine. For instance, codeine is useless as a painkiller for a small percentage of people (the author of this booklet included) whose bodies cannot convert it into an active form.

To identify and catalog genes that affect our responses to medicines — a blossoming field called pharmacogenetics — NIGMS and other NIH components launched a coordinated, multimillion-dollar effort. Part of this initiative supports continued research, and part supports a database (http://pharmgkb.org) that catalogs the genes — and variations of these genes — involved in responses to medicines. This database will help scientists learn how common these variations are in the population and how they affect the body's response to medicines. For details, see http://www.nigms.nih.gov/Initiatives/PGRN/.

Some researchers have already transformed their pharmacogenetic studies into tests that may help physicians tailor treatments to individual patients and save lives. A team led by Richard Weinshilboum of the Mayo Clinic developed a test to predict how children will respond to a drug for leukemia. While the medicine effectively treats most with the disease, it can be fatal to children who have a tiny genetic variation in an enzyme that helps break down the medicine. In these children, the drug accumulates to toxic levels, literally poisoning them. Weinshilboum's group developed a simple blood test that they use to prescribe just the right amount of medicine to each child.

Normal Red Blood Cells

Scientists have long known that some so-called "single gene" diseases are more common among certain populations: cystic fibrosis most often strikes Caucasians, sickle cell disease most often affects African Americans, and Tay-Sachs disease is most common among certain Jewish populations. There is strong evidence that genes associated with some of these diseases arose and concentrated in specific populations because they protected individuals from certain infectious diseases. For example, one copy of the sickle cell disease gene makes people more resistant to malaria. But those with two copies of the gene have sickle cell disease.

Many of the most common diseases probably involve several genes, as well as environmental factors. In many cases, the burden is greatest on minority and less affluent citizens, who have higher rates of cancer, birth defects, asthma, diabetes, and cardiovascular disease. Resolving health and disease disparities is one of NIH's highest priorities.

Sickled Red Blood Cells

NIGMS is addressing the problem with a variety of approaches. Its pharmacogenetics initiative will likely reveal links between responses to medicines and genes that are more common in certain population groups. This knowledge could help doctors better identify and treat individuals who have these genes.

NIGMS is also investigating how various population groups respond differently to traumatic injury. An increasing number of studies hint that there are underlying biochemical variations between men and women, as well as among racial and ethnic groups, that explain some of the different responses to injury and rates of wound healing. New information about these differences could improve doctors' ability to predict how trauma patients are likely to fare, especially which patients are at higher risk of developing a potentially fatal complication called systemic inflammatory response syndrome.