Harriet, an 80-year-old woman in good health from Philadelphia, drove to the hospital in April 2010 for a routine procedure. She returned home from the hospital and soon began suffering spasms of pain and unpredictable bouts of diarrhea throughout the day and night. These symptoms continued — for over eight months — during which time she could not leave her apartment.
The doctors discovered that she had been infected with a bacterium called Clostridium difficile. Because this bug clings to the surfaces of many materials, defying harsh disinfectant sprays, it thrives in hospitals and nursing homes, where it can capitalize on the vulnerability of patients’ weak immune systems. It is difficult to eradicate this bacterium once it is inside the body: each time a doctor prescribed Harriet another cycle of vancomycin, the antibiotic often used to treat the bacterium, the C. diff in her gut simply hardened into tough spores, waited for the danger to pass and emerged again a week later. The doctors had no other medication to give her and nothing more to suggest. As a result of one short hospital visit for a routine procedure, Harriet almost died.
C. diff, as it is sometimes called, is a patient bacterium. It curls into tight spores inside the stomach and can lie dormant for years, unperturbed by its highly acidic surroundings. When the stomach’s natural bacteria are wiped out by a broad treatment of antibiotics for minor or routine infections, like Harriet’s were, C. diff springs alive and begins releasing toxins. It causes severe diarrhea, stomach pain and other intestinal diseases, and affects 300,000 American citizens each year. Thirty thousand of them die.
Harriet’s experience is — alarmingly — becoming increasingly common, and as a result, researchers across the globe have begun in recent years to investigate the problem. In 2005, the United Kingdom’s Sanger Institute published a full sequence of the bacterium’s genome. At least one new drug designed to treat it was developed in the last few years, but its effectiveness is not as high as it needs to be — tens of thousands of people are still dying from infection.
Ronald Breaker, a professor of molecular biology at Yale, has stumbled upon something that could radically change the landscape of C. diff research and treatment. Before coming to Yale, he received a Ph.D. in biochemistry from Purdue University and worked at the Scripps Research Institute in La Jolla, Calif., where he isolated the first catalytic DNAs. Among his more recent major discoveries is the identification of riboswitches, previously unknown small sections of RNA molecules. While this finding is important to the entire field of biology, it particularly pertains to C. diff.
Breaker’s desk on the fifth floor of the Kline Biology Tower at Yale is strewn with papers. Sitting in his office, he wears a crisp button-up shirt and wire-framed glasses, and leans back in his chair as he explains his research. He speaks softly but maintains a quiet intensity of tone. While the concepts he researches are complex, his carefully chosen words make his explanations, even to a pitifully scienceless person like me, astonishingly clear.
He describes how riboswitches are complex sequences of nucleotides built into RNA molecules. In the past, scientists labeled them as “junk,” inconsequential to the functioning of the cell. To the contrary, Breaker has found, riboswitches have real regulatory power: they control gene expression. When the right small molecule comes floating along and slots itself into a riboswitch’s structure, the mechanism changes its shape. The change determines whether the gene controlled by the switch is turned on — so that it is expressed — or off.
Breaker has identified many distinct classes of riboswitches, each with a specific small molecule that binds to it. In C. diff, riboswitches happen to regulate certain genes vital to the bacterium’s survival. Identifying and introducing a chemical to bind to the bacterium’s switches could trick the crucial genes into turning off, and putting that chemical into a capsule could cure people — or at least, that’s the theory.
Breaker has done much to test this theory himself and to push the idea towards a medicinal reality. On the fifth floor of KBT, he and his lab intently pursued the chemicals that could kill C. diff. First they established that the riboswitches were useful drug targets by creating a strain of C. diff that could survive even our most potent drugs. By analyzing the bacterium’s mutations, they showed that riboswitches were instrumental in the process of evolving resistance. With this knowledge, they began searching for the right chemical to trick the riboswitches into turning off. They ultimately created a compound that did what they wanted it to do: “We got very good at curing plastic test tubes of bacterial infections,” Breaker said with a smile.
Energized by these early successes, Breaker took his data to investors in the early 2000s. He conveyed to them the importance of his project and the very real possibility of finding an effective treatment through continued research on riboswitches, and they started a company. BioRelix, as it was called, was created to push Breaker’s findings from the realm of academic research into the arena of drug research and development, and the company initiated a vigorous research program with Breaker as its scientific adviser.
Converting an idea into a pill sold in a plastic bottle at CVS is no small task; the time, effort and money required are tremendous. Before a drug can be produced, it must progress through multiple stages of development. It starts as an idea in a lab like Breaker’s, where scientists are doing cutting-edge research. An exhaustive list of all the phases of development that follow is exhausting to read — a company like BioRelix must thoroughly research the chemical’s structure, bioavailability and toxicity; it must create a nontoxic formulation of the drug that can deliver the substance safely; and then it must complete the preclinical trials, which are monitored by certain regulatory entities. These stages together take several years, and when they are finished, it’s time to start clinical trials. Drugs in the clinical phase are striving for approval by the FDA; only those that survive the maelstrom of rigorous studies and tests on hundreds of patients have the possibility of becoming legalized for production and sale.
Apart from the huge sum of money required to drag a drug through the process from start to finish, the system of development also burdens pharmaceutical companies with a large amount of financial risk: according to the Pharmaceutical Research and Manufacturers of America, only about one in every 5,000 compounds that undergo preclinical trials is ultimately approved. Because pharmaceutical companies must devote so many resources to exploring drug ideas even though most of them will not make the final cut, they snatch up definite moneymaking drugs, and reject others based on financial constraints instead of medical need. And because companies must apply for patents during the preclinical phase of development, by the time a drug emerges from its 10-year testing ordeal and begins its time on the market, its patent life has already dwindled to 20 years or fewer.
Antibiotics in particular suffer another developmental difficulty: while good medications treating conditions such as high cholesterol generally work until humans actually mutate or evolve new cholesterol problems, antibiotics like Breaker’s drug are racing against the evolutionary time frame of bacteria. These tiny organisms multiply in minutes and whole colonies evolve in hours. An antibiotic effective today will be much less so in 20 years; this is why we have crisis of superbugs like C. diff that are resistant to our drugs in the first place.
Breaker notes that because of these compounding dilemmas, even the largest companies like Pfizer have terminated their anti-infectives divisions. The rationale is frustratingly logical, he says: “People have gotten accustomed to receiving a course of drugs over a week that will save their lives, in fact extend them for decades, for the cost of a bottle of Tylenol.” And so more expensive medications are unprofitable, and the antibiotic pipeline is clogged. “I honestly believe we’re going to die like it’s the 1930s … and then we’ll decide to do something about it.”
In its early years around 2005, BioRelix flourished. It established a strong program in antibiotic development with the help of several large investors. In April 2012, Connecticut Innovations, a group that supports high-tech growth in the state, gave the company over $250,000 as part of a plan to give $2.5 million total through its Eli Whitney Fund. In 2010, BioRelix partnered with a subsidiary of Merck, one of the largest pharmaceutical companies in the world. “In general things went very well with the partnership,” Breaker said, “but in the end the company, Merck, makes strategic decisions and decided that continued development of the technology wasn’t in their best interest.” BioRelix has since closed its entire research and development operations team, but sources are bound by confidentiality agreements about BioRelix’s business decisions and declined to elaborate further.
With BioRelix closed, riboswitch drug research and development has hit a brick wall. The technology and ideas needed to create new antibiotics exist at Yale and elsewhere; certainly there is a pressing need for new drugs to combat C. diff and the host of other increasingly lethal bacteria. But 30,000 American deaths a year is just “not a big enough market for a major pharma company to commit to developing new drugs for,” Breaker says. “That’s where the unforgiving landscape of financial realities comes into play.” What BioRelix and the antibiotic pipeline as a whole frustratingly lack are the financial incentives necessary to align drug creation with societal needs and goals.
Ultimately, Breaker thinks, it will take an “act of Congress” to unstick the antibiotic pipeline. Recent pieces of legislation, notably the Gain Act, have made strides in the fight to reform the system. While this legislation is a good start, it isn’t enough, Breaker says. He thinks a $1 or 2 billion finder’s fee for any entity, public or private, that finds cures for certain extremely resistant microbes could possibly do the trick. But Breaker doesn’t expect Congress to act anytime soon. In the meantime, he continues his research on the fundamentals of life and advocates for the repair of our broken drug development system. “We’ve again fallen into this view that for certain infections there’s just nothing we can do — all we can do is have our friends and relatives die,” Breaker says. “And we’ve got to break those trends.”