Medicines By Design
Chapter 2: Body, Heal Thyself
Scientists became interested in the workings of the human body during the "scientific revolution" of the 15th and 16th centuries. These early studies led to descriptions of the circulatory, digestive, respiratory, nervous, and excretory systems. In time, scientists came to think of the body as a kind of machine that uses a series of chemical reactions to convert food into energy.
Scientists still think about the body as a well-oiled machine, or set of machines, powered by a control system called metabolism. The conversion of food into energy integrates chemical reactions taking place simultaneously throughout the body to assure that each organ has enough nutrients and is performing its job properly. An important principle central to metabolism is that the body's basic unit is the cell. Like a miniature body, each cell is surrounded by a skin, called a membrane. In turn, each cell contains tiny organs, called organelles, that perform specific metabolic tasks.
The cell is directed by a "command center," the nucleus, where the genes you inherited from your parents reside. Your genes—your body's own personalized instruction manual—are kept safe in packages called chromosomes. Each of your cells has an identical set of 46 chromosomes, 23 inherited from your mother and 23 from your father.
One important type of metabolism that occurs constantly in our bodies is the reading and interpreting of genes to make proteins. These proteins underlie the millions of chemical reactions that run our bodies. Proteins perform structural roles, keeping cells shaped properly. Proteins also work as enzymes that speed along chemical reactions—without an enzyme's assistance, many reactions would take years to happen.
Discovery By Accident
The work of a scientist is often likened to locking together the pieces of a jigsaw puzzle. Slowly and methodically, one by one, the pieces fit together to make a pretty picture. Research is a puzzle, but the jigsaw analogy is flawed. The truth is, scientists don't have a puzzle box to know what the finished picture is supposed to look like. If you know the result of an experiment ahead of time, it's not really an experiment.
Being a scientist is hard work, but most researchers love the freedom to explore their curiosities. They test ideas methodically, finding answers to new problems, and every day brings a new challenge. But researchers must keep their eyes and ears open for surprises. On occasion, luck wins out and breakthroughs happen "by accident." The discovery of vaccines, X rays, and penicillin each came about when a scientist was willing to say, "Hmmm, I wonder why..." and followed up on an unexpected finding.
Want a CYP?
Your body is a model of economy. Metabolism—your body's way of making energy and body parts from food and water—takes place in every cell in every organ. Complex, interlocking pathways of cellular signals make up metabolism, linking together all the systems that make your body run. For this reason, researchers have a tough time understanding the process, because they are often faced with studying parts one by one or a few at a time. Nevertheless, scientists have learned a lot by focusing on individual metabolic pathways, such as the one that manufactures important regulatory molecules called prostaglandins (see No Pain, Your Gain).
Important enzymes called cytochrome P450s (CYP, pronounced "sip," 450s) process essential molecules such as some hormones and vitamins. The CYP 450 enzymes are a major focus for pharmacologists because they metabolize—either break down or activate—hundreds of prescribed medicines and natural substances. Scientists who specialize in pharmacogenetics (see Medicines and Your Genes) have discovered that the human genetic code contains many different spellings for CYP 450 genes, resulting in CYP 450 proteins with widely variable levels of activity. Some CYP 450 enzymes also metabolize carcinogens, making these chemicals "active" and more prone to causing cancer.
Toxicologist Linda Quattrochi of the University of Colorado at Denver and Health Sciences Center is studying the roles played by certain CYP 450 enzymes in the metabolism of carcinogens. Her research has revealed that natural components of certain foods, including horseradish, oranges, mustard, and green tea, appear to protect the body by blocking CYP 450 enzymatic activation of carcinogens.
Since blood is the body's primary internal transportation system, most drugs travel via this route. Medicines can find their way to the bloodstream in several ways, including the rich supply of blood vessels in the skin. You may remember, as a young child, the horror of seeing blood escaping your body through a skinned knee. You now know that the simplistic notion of skin literally "holding everything inside" isn't quite right. You survived the scrape just fine because blood contains magical molecules that can make a clot form within minutes after your tumble. Blood is a rich concoction containing oxygen-carrying red blood cells and infection-fighting white blood cells. Blood cells are suspended in a watery liquid called plasma that contains clotting proteins, electrolytes, and many other important molecules. Blood also ferries proteins and hormones such as insulin and estrogen, nutrient molecules of various kinds, and carbon dioxide and other waste products destined to exit the body.
While the bloodstream would seem like a quick way to get a needed medicine to a diseased organ, one of the biggest problems is getting the medicine to the correct organ. In many cases, drugs end up where they are not needed and cause side effects, as we've already noted. What's more, drugs may encounter many different obstacles while journeying through the bloodstream. Some medicines get "lost" when they stick tightly to certain proteins in the blood, effectively putting the drugs out of business.
Scientists called physiologists originally came up with the idea that all internal processes work together to keep the body in a balanced state. The bloodstream links all our organs together, enabling them to work in a coordinated way. Two organ systems are particularly interesting to pharmacologists: the nervous system (which transmits electrical signals over wide distances) and the endocrine system (which communicates messages via traveling hormones). These two systems are key targets for medicines.
Burns: More Than Skin Deep
More than simply a protective covering, skin is a highly dynamic network of cells, nerves, and blood vessels. Skin plays an important role in preserving fluid balance and in regulating body temperature and sensation. Immune cells in skin help the body prevent and fight disease. When you get burned, all of these protections are in jeopardy. Burn-induced skin loss can give bacteria and other microorganisms easy access to the nutrient-rich fluids that course through the body, while at the same time allowing these fluids to leak out rapidly. Enough fluid loss can thrust a burn or trauma patient into shock, so doctors must replenish skin lost to severe burns as quickly as possible.
In the case of burns covering a significant portion of the body, surgeons must do two things fast: strip off the burned skin, then cover the unprotected underlying tissue. These important steps in the immediate care of a burn patient took scientists decades to figure out, as they performed carefully conducted experiments on how the body responds to burn injury. In the early 1980s, researchers doing this work developed the first version of an artificial skin covering called Integra® Dermal Regeneration Template™, which doctors use to drape over the area where the burned skin has been removed. Today, Integra Dermal Regeneration Template is used to treat burn patients throughout the world.
Like curare's effects on acetylcholine, the interactions between another drug—aspirin—and metabolism shed light on how the body works. This little white pill has been one of the most widely used drugs in history, and many say that it launched the entire pharmaceutical industry.
As a prescribed drug, aspirin is 100 years old. However, in its most primitive form, aspirin is much older. The bark of the willow tree contains a substance called salicin, a known antidote to headache and fever since the time of the Greek physician Hippocrates, around 400 B.C. The body converts salicin to an acidic substance called salicylate. Despite its usefulness dating back to ancient times, early records indicate that salicylate wreaked havoc on the stomachs of people who ingested this natural chemical. In the late 1800s, a scientific breakthrough turned willow-derived salicylate into a medicine friendlier to the body. Bayer® scientist Felix Hoffman discovered that adding a chemical tag called an acetyl group to salicylate made the molecule less acidic and a little gentler on the stomach, but the chemical change did not seem to lessen the drug's ability to relieve his father's rheumatism. This molecule, acetylsalicylate, is the aspirin of today.
Aspirin works by blocking the production of messenger molecules called prostaglandins. Because of the many important roles they play in metabolism, prostaglandins are important targets for drugs and are very interesting to pharmacologists. Prostaglandins can help muscles relax and open up blood vessels, they give you a fever when you're infected with bacteria, and they also marshal the immune system by stimulating the process called inflammation. Sunburn, bee stings, tendinitis, and arthritis are just a few examples of painful inflammation caused by the body's release of certain types of prostaglandins in response to an injury.
Aspirin belongs to a diverse group of medicines called NSAIDs, a nickname for the tongue-twisting title nonsteroidal anti-inflammatory drugs. Other drugs that belong to this large class of medicines include Advil®, Aleve®, and many other popular pain relievers available without a doctor's prescription. All these drugs share aspirin's ability to knock back the production of prostaglandins by blocking an enzyme called cyclooxygenase. Known as COX, this enzyme is a critical driver of the body's metabolism and immune function.
COX makes prostaglandins and other similar molecules collectively known as eicosanoids from a molecule called arachidonic acid. Named for the Greek word eikos, meaning "twenty," each eicosanoid contains 20 atoms of carbon.
You've also heard of the popular pain reliever acetaminophen (Tylenol®), which is famous for reducing fever and relieving headaches. However, scientists do not consider Tylenol an NSAID, because it does little to halt inflammation (remember that part of NSAID stands for "anti-inflammatory"). If your joints are aching from a long hike you weren't exactly in shape for, aspirin or Aleve may be better than Tylenol because inflammation is the thing making your joints hurt.
To understand how enzymes like COX work, some pharmacologists use special biophysical techniques and X rays to determine the three-dimensional shapes of the enzymes. These kinds of experiments teach scientists about molecular function by providing clear pictures of how all the folds and bends of an enzyme—usually a protein or group of interacting proteins—help it do its job. In drug development, one successful approach has been to use this information to design decoys to jam up the working parts of enzymes like COX. Structural studies unveiling the shapes of COX enzymes led to a new class of drugs used to treat arthritis. Researchers designed these drugs to selectively home in on one particular type of COX enzyme called COX-2.
By designing drugs that target only one form of an enzyme like COX, pharmacologists may be able to create medicines that are great at stopping inflammation but have fewer side effects. For example, stomach upset is a common side effect caused by NSAIDs that block COX enzymes. This side effect results from the fact that NSAIDs bind to different types of COX enzymes—each of which has a slightly different shape. One of these enzymes is called COX-1. While both COX-1 and COX-2 enzymes make prostaglandins, COX-2 beefs up the production of prostaglandins in sore, inflamed tissue, such as arthritic joints. In contrast, COX-1 makes prostaglandins that protect the digestive tract, and blocking the production of these protective prostaglandins can lead to stomach upset, and even bleeding and ulcers.
Very recently, scientists have added a new chapter to the COX story by identifying COX-3, which may be Tylenol's long-sought molecular target. Further research will help pharmacologists understand more precisely how Tylenol and NSAIDs act in the body.
Our Immune Army
Scientists know a lot about the body's organ systems, but much more remains to be discovered. To design "smart" drugs that will seek out diseased cells and not healthy ones, researchers need to understand the body inside and out. One system in particular still puzzles scientists: the immune system.
Even though researchers have accumulated vast amounts of knowledge about how our bodies fight disease using white blood cells and thousands of natural chemical weapons, a basic dilemma persists—how does the body know what to fight? The immune system constantly watches for foreign invaders and is exquisitely sensitive to any intrusion perceived as "non-self," like a transplanted organ from another person. This protection, however, can run afoul if the body slips up and views its own tissue as foreign. Autoimmune disease, in which the immune system mistakenly attacks and destroys body tissue that it believes to be foreign, can be the terrible consequence.
The powerful immune army presents significant roadblocks for pharmacologists trying to create new drugs. But some scientists have looked at the immune system through a different lens. Why not teach the body to launch an attack on its own diseased cells? Many researchers are pursuing immunotherapy as a way to treat a wide range of health problems, especially cancer. With advances in biotechnology, researchers are now able to tailor-produce in the lab modified forms of antibodies—our immune system's front-line agents.
Antibodies are spectacularly specific proteins that seek out and mark for destruction anything they do not recognize as belonging to the body. Scientists have learned how to join antibody-making cells with cells that grow and divide continuously. This strategy creates cellular "factories" that work around the clock to produce large quantities of specialized molecules, called monoclonal antibodies, that attach to and destroy single kinds of targets. Recently, researchers have also figured out how to produce monoclonal antibodies in the egg whites of chickens. This may reduce production costs of these increasingly important drugs.
Doctors are already using therapeutic monoclonal antibodies to attack tumors. A drug called Rituxan® was the first therapeutic antibody approved by the Food and Drug Administration to treat cancer. This monoclonal antibody targets a unique tumor "fingerprint" on the surface of immune cells, called B cells, in a blood cancer called non-Hodgkin's lymphoma. Another therapeutic antibody for cancer, Herceptin®, latches onto breast cancer cell receptors that signal growth to either mask the receptors from view or lure immune cells to kill the cancer cells. Herceptin's actions prevent breast cancer from spreading to other organs.
Researchers are also investigating a new kind of "vaccine" as therapy for diseases such as cancer. The vaccines are not designed to prevent cancer, but rather to treat the disease when it has already taken hold in the body. Unlike the targeted-attack approach of antibody therapy, vaccines aim to recruit the entire immune system to fight off a tumor. Scientists are conducting clinical trials of vaccines against cancer to evaluate the effectiveness of this treatment approach.
The body machine has a tremendously complex collection of chemical signals that are relayed back and forth through the blood and into and out of cells. While scientists are hopeful that future research will point the way toward getting a sick body to heal itself, it is likely that there will always be a need for medicines to speed recovery from the many illnesses that plague humankind.
The "Anti" Establishment
Common over-the-counter medicines used to treat pain, fever, and inflammation have many uses. Here are some of the terms used to describe the particular effects of these drugs:
ANTIPYRETIC—this term means fever-reducing; it comes from the Greek word pyresis, which means fire.
ANTI-INFLAMMATORY—this word describes a drug's ability to reduce inflammation, which can cause soreness and swelling; it comes from the Latin word flamma, which means flame.
ANALGESIC—this description refers to a medicine's ability to treat pain; it comes from the Greek word algos, which means pain.
A Shock to the System
A body-wide syndrome caused by an infection called sepsis is a leading cause of death in hospital intensive care units, striking 750,000 people every year and killing more than 215,000. Sepsis is a serious public health problem, causing more deaths annually than heart disease. The most severe form of sepsis occurs when bacteria leak into the bloodstream, spilling their poisons and leading to a dangerous condition called septic shock. Blood pressure plunges dangerously low, the heart has difficulty pumping enough blood, and body temperature climbs or falls rapidly. In many cases, multiple organs fail and the patient dies.
Despite the obvious public health importance of finding effective ways to treat sepsis, researchers have been frustratingly unsuccessful. Kevin Tracey of the North Shore-Long Island Jewish Research Institute in Manhasset, New York, has identified an unusual suspect in the deadly crime of sepsis: the nervous system. Tracey and his coworkers have discovered an unexpected link between cytokines, the chemical weapons released by the immune system during sepsis, and a major nerve that controls critical body functions such as heart rate and digestion. In animal studies, Tracey found that electrically stimulating this nerve, called the vagus nerve, significantly lowered blood levels of TNF, a cytokine that is produced when the body senses the presence of bacteria in the blood. Further research has led Tracey to conclude that production of the neurotransmitter acetylcholine underlies the inflammation-blocking response. Tracey is investigating whether stimulating the vagus nerve can be used as a component of therapy for sepsis and as a treatment for other immune disorders.
Seeing is believing. The cliché could not be more apt for biologists trying to understand how a complicated enzyme works. For decades, researchers have isolated and purified individual enzymes from cells, performing experiments with these proteins to find out how they do their job of speeding up chemical reactions. But to thoroughly understand a molecule's function, scientists have to take a very, very close look at how all the atoms fit together and enable the molecular "machine" to work properly.
Researchers called structural biologists are fanatical about such detail, because it can deliver valuable information for designing drugs—even for proteins that scientists have studied in the lab for a long time. For example, biologists have known for 40 years that an enzyme called monoamine oxidase B (MAO B) works in the brain to help recycle communication molecules called neurotransmitters. MAO B and its cousin MAO A work by removing molecular pieces from neurotransmitters, part of the process of inactivating them. Scientists have developed drugs to block the actions of MAO enzymes, and by doing so, help preserve the levels of neurotransmitters in people with such disorders as Parkinson's disease and depression.
However, MAO inhibitors have many undesirable side effects. Tremors, increased heart rate, and problems with sexual function are some of the mild side effects of MAO inhibitors, but more serious problems include seizures, large dips in blood pressure, and difficulty breathing. People taking MAO inhibitors cannot eat foods containing the substance tyramine, which is found in wine, cheese, dried fruits, and many other foods. Most of the side effects occur because drugs that attach to MAO enzymes do not have a perfect fit for either MAO A or MAO B.
Dale Edmondson of Emory University in Atlanta, Georgia, has recently uncovered new knowledge that may help researchers design better, more specific drugs to interfere with these critical brain enzymes. Edmonson and his coworkers Andrea Mattevi and Claudia Binda of the University of Pavia in Italy got a crystal-clear glimpse of MAO B by determining its three-dimensional structure. The researchers also saw how one MAO inhibitor, Eldepryl®, attaches to the MAO B enzyme, and the scientists predict that their results will help in the design of more specific drugs with fewer side effects.
How does aspirin work?
Name three functions of blood.
Give two examples of immunotherapy.
What is a technique scientists use to study a protein's three-dimensional structure?