Benign by Design

The search for biodegradable drugs


By Anthony King

When Israeli scientists tested vegetables for the epilepsy drug carbamazepine, they detected it in cucumbers, carrots, lettuce, and peppers. More surprisingly, people who ate the vegetables had a surge of the epilepsy drug in their urine—albeit in the nanograms.

nbsp | AnthropocenenbspBenign by Design“So much reclaimed wastewater is being used for irrigation that we wanted to see whether some residues can pass from water to the soil to the crop to people,” explains study author Benny Chefetz of the Hebrew University of Jerusalem, Israel. The quantities were minuscule (one thousand-millionth of a gram) and there was no risk of death or instant illness from the drug residues, so the vegetables stayed on the market.

It’s an oft-told tale. Most drugs we take, we excrete. The remnants flow on to treatment plants, and some drugs flow out in treated water—more, it turns out, than we previously thought. As chemistry instruments advanced over the past decade, scientists expanded the list of leftovers detected in rivers, streams, and wildlife. The US Geological Survey reported in 2016 that it had detected at least one out of 108 pharmaceuticals it tested for in small streams in the eastern US. The average number detected was six.

When he first talked about this concept at a pharma conference, his audience sat stunned. Drug developers were horrified: it is already difficult to come up with a new drug, and now you want it to biodegrade.

Our prescription habit, it seems, has blanketed the Anthropocene with a variable drug cocktail.

One solution is to intensify the cleaning process. Switzerland has spent huge sums upgrading its treatment facilities to remove micro-pollutants. Yet many countries cannot afford this strategy. Eighty percent of active pharmaceutical ingredients are made in China and India, where water treatment standards are generally poor. What’s more, some argue, treatment is not just expensive but potentially harmful. Professor Klaus Kümmerer at Leuphana University in Lüneburg, Germany, is of this view. He says high-tech treatments can convert pharmaceuticals into biologically active molecules that we know even less about.

nbsp | AnthropocenenbspBenign by DesignKümmerer began his academic career looking at pollutants in the environment. What he saw forced him to switch his attention to the other end of the pipeline—the creation of new drugs. He advocates “benign by design,” a concept he began promoting more than ten years ago. Under this new creed, drug companies should look at biodegradability as desirable during drug development. Drugs would be designed to break down naturally.

When he first talked about this concept at a pharma conference in London in 2006, his audience sat stunned. Drug developers were horrified: it is already difficult to come up with a new drug, and now you want it to biodegrade. That’s crazy talk, they said. Drug developers and regulators seek stability, not instability. But Kümmerer persisted. Tests he carried out indicated that between 15 and 20 percent of drugs on the market were already—accidentally—biodegradable.

It is normal to have a lead drug structure and to alter parts of the molecule to improve it, to optimize its biological effect, or to reduce side effects. “Designing for biodegradable drugs would just add another criterion when selecting from promising candidates,” says Kümmerer.

There are chemistry basics that guide whether a compound will biodegrade. Many molecules in nature are linear carbon chains, made up of carbon-to-carbon bonds; natural enzymes in bacteria chew these bonds apart. However, highly branched carbon chains with three carbons stuck together resist natural enzymes and persist. Knowing and tweaking the chemistry of drug molecules could ensure they break down in the environment, not in storage.

Kümmerer hasn’t just campaigned. He’s walked the walk. As a proof of concept, Kümmerer and his colleagues modified a beta-blocker used to treat high blood pressure (propranolol). He blasted it with UV light and then picked out molecules that blocked the drug target and were biodegradable. He tested candidates for toxic effects until he selected two winners.

Societal benefits and chemical structures notwithstanding, the biggest hurdle to environmentally benign drugs may be a lack of incentives.

His lab also developed a new cipro-floxacin-class antibiotic that is biodegradable. Low-dose antibiotics in the environment encourage drug resistance. This happens when bacteria are continually pressured to defend themselves against antibiotics. Harmless bacteria in the environment can then come up with ways to evade antibiotics and transfer this ability via resistance genes to bacteria that infect patients. In fact, many of the resistance genes found in hospitals today originated in harmless bacteria. Researchers say this phenomenon threatens the usefulness of existing and future antibiotics. Yet there are few strategies to tackle this problem. One solution is for drugs to self-destruct rather than persist and encourage resistance to antibiotics.

nbsp | AnthropocenenbspBenign by DesignBut societal benefits and chemical structures notwithstanding, the biggest hurdle to environmentally benign drugs may be a lack of incentives. “We need a mix of sticks and carrots,” says Kümmerer. Incentives could include patent extension if a drug is made biodegradable, or faster authorization. The stick: to include biodegradability in the drug-approval process. The idea that drugs could be kept from market for polluting is one that the industry finds shocking. They argue that it would be unethical for regulators to stop a drug getting to patients because of pollution. Kümmerer is unrepentant.

He counters that industry will cease drug development for lethal diseases
for economic reasons. Moreover, says Kümmerer, there is a need to break the industry’s dogma that stability in a drug is desirable, instability undesirable. We tend to think of the drug industry as innovative, but they are highly conservative. They want to stick to the business strategy that has kept them profitable.

Kümmerer believes that new regulations, rather than being a burden, can spark innovation. Big drug companies will be pushed to be chemically creative or surrender market share to nimble newcomers. They could also re-examine drugs previously jettisoned for stability reasons. One market-driven solution, adopted by Sweden, is to make doctors and patients aware of the green credentials of drugs when making choices.

With water shortages a growing issue around the world, water re-use is likely to become more popular. This makes it more likely drug residues will end up in our food and drinking water.

Bryan Brooks, a biologist at Baylor University in Texas, is especially concerned about mega-cities in developing countries; most will not install sophisticated water treatment anytime soon. “There are a number of streams in semi-arid regions that would not flow at times of the year without wastewater discharge,” he says.

Brooks became intrigued by urban water cycles and subsequently made landmark discoveries of antidepressants in the brains of fish as well as subtle effects on their behavior. Like many researchers in this area, he notes the difficulty of deciphering the effects of the motley mix of drugs and other chemicals in the environment on different animals.

“Our understanding of potential consequences of pharmaceutical exposure to biodiversity is very limited,” Brooks says. The same is true for people. We do not know the damage we are doing. Moreover, the variability in what we are exposed to makes it practically impossible to set up endless experiments in a lab, so we should take a precautionary approach and minimize the risks.

Getting there will require investment, drug research, and a change in attitude. Kümmerer radiates belief that industry will eventually see the light. Attitudes in some companies are shifting. “Some people recognize that this is an opportunity for new molecules and new patents,” he says. The issue of drugs in the environment is not fading from public view, and the political pressure is heating up in Europe. “It is still in its infancy, but this can be a business opportunity,” Kümmerer concludes. “Old thinking could be dangerous to a drug company’s future.”


Anthony King is a freelance science journalist based in Dublin, Ireland.

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