Medicines By Design
Chapter 3: Drugs From Nature, Then and Now
Long before the first towns were built, before written language was invented, and even before plants were cultivated for food, the basic human desires to relieve pain and prolong life fueled the search for medicines. No one knows for sure what the earliest humans did to treat their ailments, but they probably sought cures in the plants, animals, and minerals around them.
Times have changed, but more than half of the world's population still relies entirely on plants for medicines, and plants supply the active ingredients of most traditional medical products. Plants have also served as the starting point for countless drugs on the market today. Researchers generally agree that natural products from plants and other organisms have been the most consistently successful source for ideas for new drugs, since nature is a master chemist. Drug discovery scientists often refer to these ideas as "leads," and chemicals that have desirable properties in lab tests are called lead compounds.
Relatively speaking, very few species of living things on Earth have actually been seen and named by scientists. Many of these unidentified organisms aren't necessarily lurking in uninhabited places. A few years ago, for instance, scientists identified a brand-new species of millipede in a rotting leaf pile in New York City's Central Park, an area visited by thousands of people every day.
Scientists estimate that Earth is home to at least 250,000 different species of plants, and that up to 30 million species of insects crawl or fly somewhere around the globe. Equal numbers of species of fungi, algae, and bacteria probably also exist. Despite these vast numbers, chemists have tested only a few of these organisms to see whether they harbor some sort of medically useful substance.
Pharmaceutical chemists seek ideas for new drugs not only in plants, but in any part of nature where they may find valuable clues. This includes searching for organisms from what has been called the last unexplored frontier: the seawater that blankets nearly three-quarters of Earth.
Having high cholesterol is a significant risk factor for heart disease, a leading cause of death in the industrialized world. Pharmacology research has made major strides in helping people deal with this problem. Scientists Michael Brown and Joseph Goldstein, both of the University of Texas Southwestern Medical Center at Dallas, won the 1985 Nobel Prize in physiology or medicine for their fundamental work determining how the body metabolizes cholesterol. This research, part of which first identified cholesterol receptors, led to the development of the popular cholesterol-lowering "statin" drugs such as Mevacor® and Lipitor®.
New research from pharmacologist David Mangelsdorf, also at the University of Texas Southwestern Medical Center at Dallas, is pointing to another potential treatment for high cholesterol. The "new" substance has the tongue-twisting name guggulsterone, and it isn't really new at all. Guggulsterone comes from the sap of the guggul tree, a species native to India, and has been used in India's Ayurvedic medicine since at least 600 B.C. to treat a wide variety of ailments, including obesity and cholesterol disorders. Mangelsdorf and his coworker David Moore of Baylor College of Medicine in Houston, Texas, found that guggulsterone blocks a protein called the FXR receptor that plays a role in cholesterol metabolism, converting cholesterol in the blood to bile acids. According to Mangelsdorf, since elevated levels of bile acids can actually boost cholesterol, blocking FXR helps to bring cholesterol counts down.
Cancer Therapy Sees the Light
A novel drug delivery system called photodynamic therapy combines an ancient plant remedy, modern blood transfusion techniques, and light. Photodynamic therapy has been approved by the Food and Drug Administration to treat several cancers and certain types of age-related macular degeneration, a devastating eye disease that is the leading cause of blindness in North America and Europe. Photodynamic therapy is also being tested as a treatment for some skin and immune disorders.
The key ingredient in this therapy is psoralen, a plant-derived chemical that has a peculiar property: It is inactive until exposed to light. Psoralen is the active ingredient in a Nile-dwelling weed called ammi. This remedy was used by ancient Egyptians, who noticed that people became prone to sunburn after eating the weed. Modern researchers explained this phenomenon by discovering that psoralen, after being digested, goes to the skin's surface, where it is activated by the sun's ultraviolet rays. Activated psoralen attaches tenaciously to the DNA of rapidly dividing cancer cells and kills them. Photopheresis, a method that exposes a psoralen-like drug to certain wavelengths of light, is approved for the treatment of some forms of lymphoma, a cancer of white blood cells.
Marine animals fight daily for both food and survival, and this underwater warfare is waged with chemicals. As with plants, researchers have recognized the potential use of this chemical weaponry to kill bacteria or raging cancer cells. Scientists isolated the first marine-derived cancer drug, now known as Cytosar-U®, decades ago. They found this chemical, a staple for treating leukemia and lymphoma, in a Caribbean sea sponge. In recent years, scientists have discovered dozens of similar ocean-derived chemicals that appear to be powerful cancer cell killers. Researchers are testing these natural products for their therapeutic properties.
For example, scientists have unearthed several promising drugs from sea creatures called tunicates. More commonly known as sea squirts, tunicates are a group of marine organisms that spend most of their lives attached to docks, rocks, or the undersides of boats. To an untrained eye they look like nothing more than small, colorful blobs, but tunicates are evolutionarily more closely related to vertebrates like ourselves than to most other invertebrate animals.
One tunicate living in the crystal waters of West Indies coral reefs and mangrove swamps turned out to be the source of an experimental cancer drug called ecteinascidin. Ken Rinehart, a chemist who was then at the University of Illinois at Urbana-Champaign discovered this natural substance. PharmaMar, a pharmaceutical company based in Spain, now holds the licenses for ecteinascidin, which it calls Yondelis™, and is conducting clinical trials on this drug. Lab tests indicate that Yondelis can kill cancer cells, and the first set of clinical studies has shown that the drug is safe for use in humans. Further phases of clinical testing—to evaluate whether Yondelis effectively treats soft-tissue sarcomas (tumors of the muscles, tendons, and supportive tissues)— and other types of cancer—are under way.
Animals that live in coral reefs almost always rely on chemistry to ward off hungry predators. Because getting away quickly isn't an option in this environment, lethal chemical brews are the weaponry of choice for these slow-moving or even sedentary animals. A powerful potion comes from one of these animals, a stunningly gorgeous species of snail found in the reefs surrounding Australia, Indonesia, and the Philippines. The animals, called cone snails, have a unique venom containing dozens of nerve toxins. Some of these venoms instantly shock prey, like the sting of an electric eel or the poisons of scorpions and sea anemones. Others cause paralysis, like the venoms of cobras and puffer fish.
Pharmacologist Baldomero Olivera of the University of Utah in Salt Lake City, a native of the Philippines whose boyhood fascination with cone snails matured into a career studying them, has discovered one cone snail poison that has become a potent new pain medicine. Olivera's experiments have shown that the snail toxin is 1,000 times more powerful than morphine in treating certain kinds of chronic pain. The snail-derived drug, named Prialt™ by the company (Elan Corporation, plc in Dublin, Ireland) that developed and markets it, jams up nerve transmission in the spinal cord and blocks certain pain signals from reaching the brain. Scientists predict that many more cone snail toxins will be drug leads, since 500 different species of this animal populate Earth.
Led by the German scientist Paul Ehrlich, a new era in pharmacology began in the late 19th century. Although Ehrlich's original idea seems perfectly obvious now, it was considered very strange at the time. He proposed that every disease should be treated with a chemical specific for that disease, and that the pharmacologist's task was to find these treatments by systematically testing potential drugs.
The approach worked: Ehrlich's greatest triumph was his discovery of salvarsan, the first effective treatment for the sexually transmitted disease syphilis. Ehrlich discovered salvarsan after screening 605 different arsenic-containing compounds. Later, researchers around the world had great success in developing new drugs by following Ehrlich's methods. For example, testing of sulfur-containing dyes led to the 20th century's first "miracle drugs"—the sulfa drugs, used to treat bacterial infections. During the 1940s, sulfa drugs were rapidly replaced by a new, more powerful, and safer antibacterial drug, penicillin—originally extracted from the soil-dwelling fungus Penicillium.
Are researchers taking advantage of nature when it comes to hunting for new medicines? Public concern has been raised about scientists scouring the world's tropical rainforests and coral reefs to look for potential natural chemicals that may end up being useful drugs. While it is true that rainforests in particular are home to an extraordinarily rich array of species of animals and plants, many life-saving medicines derived from natural products have been discovered in temperate climates not much different from our kitchens and backyards.
Many wonder drugs have arisen from non-endangered species, such as the bark of the willow tree, which was the original source of aspirin. The antibiotic penicillin, from an ordinary mold, is another example. Although scientists first found the chemical that became the widely prescribed cancer drug Taxol® in the bark of an endangered species of tree called the Pacific yew, researchers have since found a way to manufacture Taxol in the lab, starting with an extract from pine needles of the much more abundant European yew. In many cases, chemists have also figured out ways to make large quantities of rainforest- and reef-derived chemicals in the lab (see Ocean Medicines).
Searching nature's treasure trove for potential medicines is often only the first step. Having tapped natural resources to hunt for new medicines, pharmaceutical scientists then work to figure out ways to cultivate natural products or to make them from scratch in the lab. Chemists play an essential role in turning marine and other natural products, which are often found in minute quantities, into useful medicines.
In the case of Yondelis, chemist Elias J. Corey of Harvard University in Boston, Massachusetts, deciphered nature's instructions on how to make this powerful medicinal molecule. That's important, because researchers must harvest more than a ton of Caribbean sea squirts to produce just 1 gram of the drug. By synthesizing drugs in a lab, scientists can produce thousands more units of a drug, plenty to use in patients if it proves effective against disease.
Scientists are also beginning to use a relatively new procedure called combinatorial genetics to custom-make products that don't even exist in nature. Researchers have discovered ways to remove the genetic instructions for entire metabolic pathways from certain microorganisms, alter the instructions, and then put them back. This method can generate new and different "natural" products.
Toxicogenetics: Poisons and Your Genes
Just as your genes help determine how you respond to certain medicines, your genetic code can also affect your susceptibility to illness. Why is it that two people with a similar lifestyle and a nearly identical environment can have such different propensities to getting sick? Lots of factors contribute, including diet, but scientists believe that an important component of disease risk is the genetic variability of people's reactions to chemicals in the environment.
On hearing the word "chemical," many people think of smokestacks and pollution. Indeed, our world is littered with toxic chemicals, some natural and some synthetic. For example, nearly all of us would succumb quickly to the poisonous bite of a cobra, but it is harder to predict which of us will develop cancer from exposure to carcinogens like cigarette smoke.
Toxicologists are researchers who study the effects of poisonous substances on living organisms. One toxicologist, Serrine Lau of the University of Texas at Austin, is trying to unravel the genetic mystery of why people are more or less susceptible to kidney damage after coming into contact with some types of poisons. Lau and her coworkers study the effects of a substance called hydroquinone (HQ), an industrial pollutant and a contaminant in cigarette smoke and diesel engine exhaust. Lau is searching for genes that play a role in triggering cancer in response to HQ exposure. Her research and the work of other so-called toxicogeneticists should help scientists find genetic "signatures" that can predict risk of developing cancer in people exposed to harmful carcinogens.
Is It Chemistry or Genetics?
Regardless of the way researchers find new medicines, drug discovery often takes many unexpected twists and turns. Scientists must train their eyes to look for new opportunities lurking in the outcomes of their experiments. Sometimes, side trips in the lab can open up entirely new avenues of discovery.
Take the case of cyclosporine, a drug discovered three decades ago that suppresses the immune system and thereby prevents the body from rejecting transplanted organs. Still a best-selling medicine, cyclosporine was a research breakthrough. The drug made it possible for surgeons to save the lives of many critically ill patients by transplanting organs. But it's not hard to imagine that the very properties that make cyclosporine so powerful in putting a lid on the immune system can cause serious side effects, by damping immune function too much.
Years after the discovery of cyclosporine, researchers looking for less toxic versions of this drug found a natural molecule called FK506 that seemed to produce the same immune-suppressing effects at lower doses. The researchers found, to their great surprise, that cyclosporine and FK506 were chemically very different. To try to explain this puzzling result, Harvard University organic chemist Stuart Schreiber (then at Yale University in New Haven, Connecticut) decided to take on the challenge of figuring out how to make FK506 in his lab, beginning with simple chemical building blocks.
Schreiber succeeded, and he and scientists at Merck & Co., Inc. (Whitehouse Station, New Jersey) used the synthetic FK506 as a tool to unravel the molecular structure of the receptor for FK506 found on immune cells. According to Schreiber, information about the receptor's structure from these experiments opened his eyes to consider an entirely new line of research.
Schreiber reasoned that by custom-making small molecules in the lab, scientists could probe the function of the FK506 receptor to systematically study how the immune system works. Since then, he and his group have continued to use synthetic small molecules to explore biology. Although Schreiber's strategy is not truly genetics, he calls the approach chemical genetics, because the method resembles the way researchers go about their studies to understand the functions of genes.
In one traditional genetic approach, scientists alter the "spelling" (nucleotide components) of a gene and put the altered gene into a model organism—for example, a mouse, a plant, or a yeast cell—to see what effect the gene change has on the biology of that organism. Chemical genetics harnesses the power of chemistry to custom-produce any molecule and introduce it into cells, then look for biological changes that result. Starting with chemicals instead of genes gives drug development a step up. If the substance being tested produces a desired effect, such as stalling the growth of cancer cells, then the molecule can be chemically manipulated in short order since the chemist already knows how to make it.
These days, it's hard for scientists to know what to call themselves. As research worlds collide in wondrous and productive ways, the lines get blurry when it comes to describing your expertise. Craig Crews of Yale University, for example, mixes a combination of molecular pharmacology, chemistry, and genetics. In fact, because of his multiple scientific curiosities, Crews is a faculty member in three different Yale departments: molecular, cellular, and developmental biology; chemistry; and pharmacology. You might wonder how he has time to get anything done.
He's getting plenty done—Crews is among a new breed of researchers delving into a growing scientific area called chemical genetics (see main text). Taking this approach, scientists use chemistry to attack biological problems that traditionally have been solved through genetic experiments such as the genetic engineering of bacteria, yeast, and mice. Crews' goal is to explore how natural products work in living systems and to identify new targets for designing drugs. He has discovered how an inflammation-fighting ingredient in the medicinal herb feverfew may work inside cells. He found that the ingredient, called parthenolide, appears to disable a key process that gets inflammation going. In the case of feverfew, a handful of controlled scientific studies in people have hinted that the herb, also known by its plant name "bachelor's button," is effective in combating migraine headaches, but further studies are needed to confirm these preliminary findings.
To translate pharmacology research into patient care, potential drugs ultimately have to be tested in people. This multistage process is known as clinical trials, and it has led researchers to validate life-saving treatments for many diseases, such as childhood leukemia and Hodgkin's disease. Clinical trials, though costly and very time-consuming, are the only way researchers can know for sure whether experimental treatments work in humans.
Scientists conduct clinical trials in three phases (I, II, and III), each providing the answer to a different fundamental question about a potential new drug: Is it safe? Does it work? Is it better than the standard treatment? Typically, researchers do years of basic work in the lab and in animal models before they can even consider testing an experimental treatment in people. Importantly, scientists who wish to test drugs in people must follow strict rules that are designed to protect those who volunteer to participate in clinical trials. Special groups called Institutional Review Boards, or IRBs, evaluate all proposed research involving humans to determine the potential risks and anticipated benefits. The goal of an IRB is to make sure that the risks are minimized and that they are reasonable compared to the knowledge expected to be gained by performing the study. Clinical studies cannot go forward without IRB approval. In addition, people in clinical studies must agree to the terms of a trial by participating in a process called informed consent and signing a form, required by law, that says they understand the risks and benefits involved in the study.
Phase I studies test a drug's safety in a few dozen to a hundred people and are designed to figure out what happens to a drug in the body—how it is absorbed, metabolized, and excreted. Phase I studies usually take several months. Phase II trials test whether or not a drug produces a desired effect. These studies take longer—from several months to a few years—and can involve up to several hundred patients. A phase III study further examines the effectiveness of a drug as well as whether the drug is better than current treatments. Phase III studies involve hundreds to thousands of patients, and these advanced trials typically last several years.Many phase II and phase III studies are randomized, meaning that one group of patients gets the experimental drug being tested while a second, control group gets either a standard treatment or placebo (that is, no treatment, often masked as a "dummy" pill or injection). Also, usually phase II and phase III studies are "blinded"—the patients and the researchers do not know who is getting the experimental drug. Finally, once a new drug has completed phase III testing, a pharmaceutical company can request approval from the Food and Drug Administration to market the drug.
Scientists are currently testing cone snail toxins for the treatment of which health problem?
How are people protected when they volunteer to participate in a clinical trial?
Why do plants and marine organisms have chemicals that could be used as medicines?
What is a drug "lead?"
Name the first marine-derived cancer medicine.