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Chapter 5: The Healing Power of Chemistry
RUSSELL BARROW
That medicine came from where? Scientists are hunting in some very unusual—indeed, some even downright unpleasant—places for new drugs. Take chemist Jim Gloer of the University of Iowa in Iowa City who is on the prowl for new antibiotics produced by a type of fungus that thrives in animal dung. Yes, you heard it right: animal poop. These unenviable organisms, called coprophiles—literally, feces-loving—are a rarely studied microbial breed, but offer tremendous promise for finding useful drugs. Oddly enough, such fungi are fiercely territorial, spitting out chemicals that are toxic to neighboring (and thereby competing) species of fungi. That is precisely what biomedical researchers look for—chemicals that will poison bothersome types of fungi that can be dangerous to people infected with them.
That's an important goal. Due in part to the disease and part to the treatment, illnesses like AIDS and cancer often set the stage for the body to become overwhelmingly infected by microbes that otherwise would be rejected at the door. Such opportunistic infections are most often caused by just a few notorious types of fungi. Unfortunately, not many drugs are currently available to thwart these microbial menaces without causing severe side effects. A key advantage of Gloer's strategy is that his approach to finding anti-fungus compounds isn't a random one (as many antimicrobial drug screens typically are). By selecting compounds that he already knows can eradicate other fungi, Gloer is starting with a batch of molecules that all possess exactly the type of cell-killing activity he's looking for.
Looking to Sea
The vast, largely unexplored seas are another promising source for medicines. Scientists are plumbing the oceans' depths to discover novel molecules in organisms such as marine sponges, snails, and a wealth of other sea-worthy creatures. It may seem surprising that, in general, fast swimmers and successful predators are not what the researchers are after. On the contrary, scientists have come to appreciate the extraordinary chemical richness lying in wait inside the tastiest, most brightly colored "couch potatoes" of the seas—the so-called filter feeders that stick to rocks and coral. Precisely because they can't move—or because they stand out in a crowd due to their surface coloring—these animals are sophisticated chemistry labs. For protection, and to compete for food and other resources, such animals engage in chemical warfare day in and day out. Scientists have discovered that some of these potent chemicals show tremendous promise for treating cancer and other diseases. Certain compounds have passed initial muster—showing promise in test-tube and animal studies—and have now progressed to clinical trials in humans. But while there are many promising could—be medicines out yonder in the world's oceans, an imposing obstacle is getting enough of them. Researchers are finding one way around this dilemma by devising ways to make the compounds in their labs, but there are significant obstacles to efficiently synthesizing usable quantities of many of these chemicals. Aquaculture (water "farming") is an innovative strategy coming into practice, in which researchers cultivate in small, specialized ponds large amounts of the organisms that produce compounds that exist in vanishingly small quantities in nature.
It so happens that marine organisms harbor another hidden resource when it comes to finding potential drugs. Looking more closely, chemists are discovering that tiny, one-celled sea plants called microalgae that hitch a ride on larger marine organisms are also great producers of interesting chemicals. Terrestrial plants have been a source for drugs for thousands of years, so perhaps it shouldn't come as a big surprise that sea plants are turning up compounds with exciting potential uses as drugs to fight cancer, heart disease, and many types of infections. Miniature plant-like organisms called cyanobacteria that live in a variety of wet environments—fresh or salt water, or even damp soil—are also surfacing as excellent sources of powerful cancer and bacterial cell killers. Dick Moore of the University of Hawaii at Manoa successfully used a strategy to find compounds specifically effective against slow-growing and hard-to-treat solid tumors (those that accumulate as lumps of tumor cells in various organs and account for most cancer deaths in the United States). One such compound he found, called cryptophycin-8, can tear apart the cellular scaffolding in a broad spectrum of solid tumors implanted in mice, including multidrug-resistant ones that are no longer susceptible to standard cancer drugs. Moore found another cyanobacteria-derived molecule, called majusculamide C, that works in a similar fashion but hones in on fungus cells, making it potentially useful for treating fungus-provoked diseases in humans as well as in agricultural crops.
By land or by sea, tradition has it that chemists first find interesting nature-made chemicals that show promise in fighting disease, then the scientists learn how to make them synthetically. Ultimately, many of the best drugs have been born of medicinal chemists' fiddling with natural compounds in order to retain useful, therapeutic portions of the molecules, while stripping away parts that cause unwanted side effects.
A Princely Role
Everyone knows that frogs don't really turn into princes, but scientists suspect that frog skin might turn into useful medicines. In the late 1980s, while working in a lab at the National Institutes of Health in Bethesda, Maryland, biologist Michael Zasloff wondered why frogs with surgical wounds usually healed perfectly without getting infections, despite living in a relatively dirty lab aquarium. Zasloff turned his attention to this quizzical observation and went on to isolate a peptide—a string of amino acids—called magainin (coined after the Hebrew word for shield) that frogs produce in response to skin injury.
Zasloff is quick to note that nobody has a clue how a giant squid or an octopus—which have neither antibodies nor white blood cells called lymphocytes—avoids becoming consumed by microbes! Over the years, he and his colleagues have uncovered many frog—made peptides that possess potent microbe-killing properties. Such a chemical defense system operates by virtue of the peptides' ability to poke holes in the cell membranes that serve to protect bacteria from the outside world. In addition to the peptides, scientists including Zasloff have found hundreds of other types of molecules called alkaloids in amphibian skin. When inside cells, many alkaloids home in on structures called ion channels—tunnel-like assemblies through which important electrolytes pass. These are key cellular fixtures, as they police the entry and exit of charged molecules across cellular membranes. As such, they also happen to be important drug targets. Some channels, for instance, initiate a cascade of molecular events that tell the cell to "feel" pain. Researchers have discovered that one particular molecule isolated from frog skin, called epibatidine, shows powerful painkilling activity possibly due to the compound's ability to latch onto such channels. After studying it, scientists realized epibatidine was too toxic to be used as a pain-relieving drug. Researchers learned how to make the molecule in the lab and have continued to tinker with its chemical structure with the goal of making a drug that could ease pain without producing unwanted side effects.
Interestingly, scientists think that many of the alkaloid "drugs" in frog skin come from the bug meals they eat—spiders and other arthropods in particular.
Making Medicines
A key role played by chemists is learning how to mimic effectively nature's bountiful manufacturing processes. Once in a while, such a strategy—when it pans out—can tell a story of "research-to-riches." Robert Holton, an organic chemist at Florida State University in Tallahassee, discovered a way to produce commercially useful amounts of Taxol®, a top-selling cancer drug worldwide. This drug, which doctors use (often in combination with other cancer drugs) to treat ovarian and breast cancer, was first discovered in the 1960s. Scientists found Taxol in the bark of the Pacific yew tree, which grows in the northwestern United States. But there was a problem. The Pacific yew is a slow-growing, environmentally threatened species. Holton helped pave the way to Taxol's current success with a practical approach: He figured out a way to make the drug from a more readily available ingredient that is abundant in the more plentiful European yew tree. Holton licensed his semi-synthetic technology to the pharmaceutical company Bristol-Myers Squibb, and since 1992, when the FDA approved the lab-made form of Taxol, Holton has earned millions of dollars in royalties. A few years later, he went on to lead the first group of scientists to make Taxol completely from scratch. Rather than resting on his laurels, Holton poured many of his rewards straight back into research by founding the MDS Research Foundation in 1995. In turn, this nonprofit organization licensed Holton's technology from Florida State University and started a company called Taxolog to create new Taxol-like molecules (called taxanes) that are more effective at treating cancer. Through such an arrangement, profits from new anti-tumor agents are recycled back into basic research in synthetic chemistry.
Acts Like a Protein, But It's Not
Designing drugs is a tricky business. Lots of could-be medicines look good on paper, but a drug can only do its intended job of treating a symptom or fighting a disease if it gets to the right place in the body to do its job. That's tough, since many modern medicines are look-alike versions of the body's natural molecules—small pieces of proteins called peptides that are meant to nestle into other protein targets like receptors. The problem is that the body's digestive tract chews up proteins, and peptides, as a normal part of metabolism (getting energy from food). So what's a medicine designer to do? Many have opted to seek out molecules called peptidomimetics, which possess many of the useful properties of peptides (in that they mimic important biologic targets) but differ from peptides in other significant ways. Medicinal chemists in the business of designing drugs try to make mimics that are absorbed into the body, stand up to digestive enzymes, and stick around long enough in the bloodstream to get to the tissues and organs where they need to go. Drugs such as these are already used in clinical practice to treat infections, heart disease, and cancer. A key factor in making the look-alikes useful, however, is tricking the body into thinking they're natural molecules, and not drugs. That's important, because to get to their molecular job sites, peptidomimetic drugs often hitch a ride via the body's natural molecular transportation systems.
Chemical Biology in Action: Library Research Pays Off
Chemists Gary Glick and Jonathan Ellman never intended to work on the same problem, but now they do, and the collaboration is paying off impressively. Two clever minds can be better than one—out of these scientists' partnership has emerged at least one promising new drug to treat a devastating autoimmune disease called systemic lupus erythematosus, often called lupus for short. According to the Lupus Foundation of America, this disease affects 1.5 million Americans, some of whom bear a characteristic rash across the bridge of their nose dubbed the "butterfly rash," because of its shape. Lupus ravages the body's immune system by coaxing the kidneys to attack their own DNA. Current treatments are ineffective and have serious, use—limiting side effects. Glick, of the University of Michigan-Ann Arbor, and Ellman, of the University of California, Berkeley, sought to identify a drug to treat lupus by harnessing the power of combinatorial chemistry to rapidly leaf through thousands of molecules. The team started with a huge catalog of molecular structures and searched for compounds that could kill the cells responsible for causing lupus (autoimmune lymphocytes), while sparing normal immune cells. This type of drug discovery effort is only possible with the advent of combinatorial chemistry, because very large numbers of compounds (libraries) have to be tested before scientists can pluck out molecules with the desired properties. Glick and Ellman's search led them to one interesting candidate molecule that stops lupus in mice prone to developing the disease. An especially exciting feature of the newfound molecule is that after the lupus-prone mice take it, they suffer none of the serious side effects common to all current anti-lupus drugs on the market. Glick and Ellman are setting out to test the compound in humans.
Getting It Left or Getting It Right?
Making chemicals in the lab isn't quite the same thing as cooking up a pot of spaghetti, in which you simply boil the pasta, heat up the sauce, and voilà! It's not so easy to make molecules from a laboratory recipe. The thing is, many small molecules— created by scientists or by nature—come in two, mirror-image forms, a "left" and a "right." The molecules that make up sugars and DNA conform to this principle, called chirality, which is actually rooted in the laws of physics. Chemical bonds—the physical forces that attract or repel atoms in molecules—rotate in space two ways, giving rise to two complementary, mirror-image molecular forms. These are sort of like a left hand and a right hand—put them together and they match up, but they'll never align when placed atop each other. Put another way, a right hand will never fit into a left-handed glove.
Why should any of this matter when it comes to drugs? Well—take the case of a small-molecule drug that does its job in the body by nestling snugly into a particular cavity of a certain protein receptor. The left-handed version of this drug might fit perfectly into the correct space inside the receptor, whereas its right-handed counterpart couldn't squeeze in, no matter what. And in some instances, both hands of a drug (each called an enantiomer) fit into a biological spot, but one might help treat a symptom while the other causes the body harm!
A terrible tragedy occurred when this happened with a drug called thalidomide, which was used in the 1960s to treat morning sickness in pregnant women. Scientists found out too late that one of thalidomide's two hands caused horrific birth defects. What's more, researchers discovered that removing the "bad" hand from a dose of thalidomide didn't take care of the problem— the body can itself make the harmful hand from the "good" one.
Another two-faced drug in this regard was a popular allergy medicine called Seldane®, which the Food and Drug Administration removed from the market in 1997 because in combination with a certain antibiotic it caused life-threatening heart rhythm problems. Scientists determined that neither enantiomer of a breakdown product of Seldane—now marketed as a medicine called Allegra®—interacts the same way with the antibiotic, and Allegra is now used safely by millions of Americans.
To manufacture products quickly and cost effectively, traditionally pharmaceutical companies have chemically cooked up medicines that contain equal portions of the left and right hands. That is because it is usually much less efficient and more expensive to produce only one hand of a drug. Over time, however, chemists in industry and elsewhere have come to realize the importance of making single-handed compounds. There are those especially troubling cases in which one enantiomer is toxic. But in the vast majority of cases, most drugs produced as left- and right-handed mixtures are only half as strong as they could be, because one hand does nothing more than dilute the medicine produced. Chemist Eric Jacobsen of Harvard University spent years perfecting a laboratory tool—a chiral catalyst— that can purposefully produce one and only one enantiomer of a particular type of molecule. This eliminates the waste inherent in the process of making a left- and right-handed mix, or in separating the two enantiomers from each other after manufacturing. The pharmaceutical company Merck recognized the value of Jacobsen's tool and has used it successfully for the production of a widely used AIDS drug called Crixivan.® Other scientists, such as K. Barry Sharpless of the Scripps Research Institute, have tailor-made chemical reactions that produce a single enantiomer. The method is sort of like stripping the random part out of a coin toss so that the quarter always comes up heads. Sharpless' reactions, which give rise to one-handed chemical intermediates, have been important for the production of a variety of medically useful chemicals, including certain antibiotics, heart medicines, and antidepressants. Sharpless won the 2001 Nobel Prize in chemistry for his discovery of chiral catalysts.
By paying more attention to getting it right (or left, as the case may be) today's chemists have enormous opportunity for improving existing medicines—by eliminating dose-related side effects, for instance—as well as for streamlining the process of making the most effective new medicines.
In the Middle
When thinking about chemical reactions, it's tempting to focus on two things only: what goes in (the starting materials, or reactants) and what comes out (the product or products). Sometimes left out is all the exciting stuff that happens in the middle. Think of a chemical reaction as being like two valleys with a mountain in the middle. To become products (one valley), reactants (the other valley) must overcome something chemists call the energy of activation, or energy hill. In this mountain range analogy, the energy hill is the highest point of the peak between the two valleys. In molecular terms, this point in space and time is called the transition state, and it represents a freeze-frame arrangement of bonds broken or enjoined, which only lasts one thousand-billionth of a second. In a sense, the transition state is the precise point at which a seesaw tips over to the other side. Despite their fleeting existence, transition states are highly sought after by chemists who wish to purposefully alter reactions one way or another by knowing the details of this pivotal micro-moment.
A Dead-End Job
For many years, chemist JoAnne Stubbe of the Massachusetts Institute of Technology has been picking apart every step of one biochemical pathway vital to synthesizing the building blocks of DNA. In particular, she has focused her energies on an important enzyme in this pathway, called ribonucleotide reductase, or RNR. In the course of her studies, Stubbe has sleuthed the way RNR grabs its substrate—arming her with strategic knowledge she has used to design look-alike molecules that fit into the enzyme's shape, but don't make it work. Compounds such as these, called suicide substrates, completely freeze up the enzyme they're targeting. They trick the enzyme into thinking that it is doing its job, but in fact no job gets done. Cancer cells—which divide as fast as they can—are super-synthesizers of DNA, and are crippled by any drug that interferes with this process. Stubbe and her industry coworkers have shepherded one such RNR suicide substrate through test-tube and animal studies, and into testing in people. Clinical trials with this potential cancer drug are currently under way.
Losing Medicines
Finding or making effective new drugs is a challenge in and of itself. But complicating matters further, sometimes perfectly good drugs simply stop working. More often than not, these are antibiotics— drugs used to treat bacterial or fungal infections. It is true that major strides have been made in the past century in scientists' quest to treat infectious diseases caused by bacteria, viruses, and other microbes such as parasites. Humans' increased lifespan during the past hundred years is due largely to the fact that we succumb to infection far less frequently today than people did 50 or 100 years ago. But this success has come with a price—many antibiotic drugs that once stamped out bacteria effortlessly now work much less effectively, if at all. In the blip of evolutionary time in which such advances have been made and put into routine medical practice, microbes are making a comeback. They are getting "smart" and devising ways to evade poisons (our drugs). Drug-resistant organisms pose a serious health threat.
Fortunately, many chemists and biologists have risen to the occasion and are working hard to outwit microbes that develop resistance. Many new forms of antibiotic drugs are currently in the pipeline; most are being specifically tailored to minimize the chance that bacteria will become resistant to them.
Chemical Biology in Action: The Shape of Things to Come
One of the beauties of science is sharing the wealth. Sometimes a collision of discoveries in completely different areas of science brings important breakthroughs. By blending advances from the worlds of chiral (so-called handed) chemistry and structural biology (in which scientists determine the three dimensional shape of biological molecules), Arun Ghosh of the University of Illinois at Chicago has unearthed some promising potential drugs to fight AIDS. Ghosh and his colleagues pored over the results of other scientists studying the three-dimensional structure of an enzyme, called HIV protease, that is key to this deadly virus' livelihood. By using K. Barry Sharpless' method to fix the outcome of chemical reactions to produce single-handed molecules, Ghosh painstakingly designed sturdy compounds that attach themselves very tightly to an important pocket of this critical viral protein. In so doing, Ghosh landed a battery of potential drugs that in some cases are 50 times more potent than widely used protease inhibitor drugs that are a standard component of AIDS therapy in people. Ghosh has custom-designed new compounds, which are currently undergoing testing in animals, to overcome two soft spots inherent to HIV protease inhibitors currently on the market. Since the body's digestive enzymes easily chew up the chemical bonds that hold proteins together (so-called peptide bonds), Ghosh has focused on molecules that look like mini-proteins but aren't recognized as such by enzymes that break down proteins. Ghosh is attacking the resistance problem by crafting compounds that grip the HIV virus' protease enzyme in many different regions, since scientists suspect that drug resistance is often triggered by a critical lack of chemical bonds clamping the viral protease to a drug.
Making Good Medicines Better
Acetylsalicylic acid—more commonly known as aspirin—is a very old drug. It is also a very effective drug, available without a prescription for a wide variety of uses. Aspirin is an inexpensive medicine used to treat pain and swelling caused by minor skin wounds or sunburns, and as a protectant against heart disease. Yet despite its reputation as a wonder drug, scientists still don't know exactly how aspirin works so well in so many ways. Charles Serhan of Brigham and Women's Hospital in Boston is one biological chemist who is trying to figure aspirin out. Aspirin isn't a complete black box—scientists already know that the drug works to alleviate pain by blocking biochemical circuits that produce two of the body's natural compounds, called prostaglandins and thromboxanes. Based on this, many researchers have assumed that aspirin's knack for halting inflammation—the painful irritation and swelling that are born of our own immune system's chemical weaponry—is caused by the drug working through that same biochemical pathway. Serhan's work sheds new light on the issue and may even lead the way to better anti-inflammatory medicines. After he discovered that aspirin treats inflammation by prompting the body to manufacture its own anti-inflammatory compound (a molecule called 15-epi-lipoxin A4), Serhan set about to make synthetic look-alikes of this molecule. In recent animal studies, at least one of the synthetic mimics worked 100 times better than aspirin and other stronger antiinflammatory medicines available by prescription only. Serhan's research paves the way toward finding more selective treatment strategies that bring about less of the unwanted side effects produced by aspirin and many other drugs currently used to treat inflammation.
Medicines Just for You
Your diet, environment, and lifestyle can all influence how you respond to medicines. But another key factor is your genes. The study of how people respond differently to medicines due to their genetic inheritance is called pharmacogenetics. The term has been pieced together from the words pharmacology (the study of how drugs work in the body) and genetics (the study of how traits are inherited). An ultimate goal of this type of medical research is to understand how a person's unique genetic make-up determines how well a medicine works in his or her body, as well as what side effects he or she might be prone to developing. In the future, advances discovered through such research will provide information to guide doctors in getting the right amount of the right medicine to a person—the practice of "personalized medicine."
Question Box: Tools for New Medicines
Originally I wanted to be an agricultural chemist, but dealing with all the animal matter wasn't much fun. Organic chemistry was something I discovered I liked to do.
Robert Grubbs, a chemist at the California Institute of Technology in Pasadena, is changing the way people make things. All kinds of things—bike helmets, corrosion-resistant pipes...and medicines! Grubbs introduced a new twist to a brand of chemistry called "olefin metathesis" that underlies the production of a wide variety of materials. Reactions that use this chemistry hinge on one key element to pull off such a feat: an extremely versatile catalyst that uses a metal called ruthenium. As molecules that make reactions happen, catalysts are vital drivers of the chemical transformations that produce the things we use and the drugs we take. Grubbs' catalyst is currently being used to manufacture a wide assortment of things biological, and has been a huge help to pharmaceutical industry chemists, who are faced with the task of synthesizing complicated chemical structures day in and day out. The Chemistry of Health asked Grubbs, who won the 2005 Nobel Prize in Chemistry for this work, to fill in some of the details.
CH: How can the same chemical process produce bullet-proof vests, insect repellents, and medicines?
Grubbs: The ruthenium catalyst we developed opens up carbon-carbon double bonds and then attaches the pieces back together—in predictable, or even novel, ways. Essentially, the catalyst zips together chains of molecules into rings, which are a common component of all kinds of materials. But it also works to unzip the rings. It's very useful because there are double bonds everywhere.
CH: Why did the chemistry community need a new catalyst?
Grubbs: The old catalysts didn't allow you to do things very efficiently, and required chemists to use protecting groups. Metals such as ruthenium give chemists the flexibility to make things with a wide variety of starting materials, and under many different conditions. It just makes everything easier.
CH: Did you set about to find the catalyst?
Grubbs: No, although it was always a dream of mine. It's funny—20 years ago, I was asked to give a talk predicting the future in this area of chemistry. I argued—strongly at the time—that recommending support for such research shouldn't be in the report, since it would be so misleading to the community. I've been surprised that it's worked out so well.
CH: What first got you interested in science?
Grubbs: I suppose a science teacher in junior high. But things have changed somewhat. Originally I wanted to be an agricultural chemist, but dealing with all the animal matter wasn't much fun. Organic chemistry was something I discovered I liked to do.
CH: What keeps you coming back to the lab every day?
Grubbs: I keep getting surprised all the time.
Got It?
What is the function of a chiral catalyst?
How might synthetic chemistry practices help the environment?
Describe the difference between peptides and peptidomimetics.
Name one reason why filter-feeding marine organisms secrete chemicals into the water.
Discuss some of the possible advantages and disadvantages of personalized medicine.