The headlines were enough to give anyone a little high. “Home brewed morphine is just around the corner,” “Yeast can make morphine and ‘home-brewed’ heroin” and “Home-brewed heroin could be a thing,” to name just a few.
Underneath the hyperbolic headlines was the somewhat less-sexy scientific research that prompted them. Scientists have modified yeast to take a molecule of glucose and transform it into the chemical compound (S)-reticuline, a rest stop on the road to eventually producing the opiate morphine. Other scientists have recently tackled the other end of the pathway in different yeast strains. One step remains to bring the two ends together for a process that will eventually result in lab-produced morphine.
Headlines trumpeted what might happen. In a world where yeast can ferment glucose into morphine, what’s to stop home brewers from perfecting the process of making morphine and then cooking up bathtubs full of heroin? The worries stemmed from an important commentary published May 18 in Nature, alerting scientists to the potential for misuse of the new research, and calling for policies to regulate the future microbes.
But in all the excitement about regulating home-brewed morphine and heroin, it’s easy to forget one important fact: There isn’t any heroin. And heroin was never the goal in the first place.
Not a single yeast cell has yet taken a molecule of glucose and produced morphine in return. Instead, scientists have the components of a pathway that, when constructed, could eventually produce an opiate. But the pathway could also be used to produce many other drugs, including potential therapeutics for cancer or new antibiotics. So while it is important to plan ahead and think about regulating an organism that could easily produce large quantities of addictive drugs, it’s also good to keep in mind that any drugs produced from these yeast have far more positive potential than vats of heroin brewed in a bathtub.
The end goal is the synthesis of benzylisoquinoline alkaloids, or BIAs. This is a large class of chemicals produced in plants such as the poppy, yellowroot and Oregon grape that includes the well-known morphine, heroin — which is synthesized from morphine — and a host of other compounds. These include papaverine, which is used to treat blood vessel spasms, and berberine, which has been tested for lowering blood glucose in diabetes.
“Most of these molecules are made in vanishingly small amounts naturally,” says John Dueber, a bioengineer at the University of California, Berkeley. And the limited quantities make for limited studies of the chemicals. Getting organisms such as bacteria and yeast to make the target compounds would allow scientists to scale up the productivity of the process.
Putting the pathway for making those molecules in yeast could also result in a purer product. “The primary function of a plant is not to produce a drug,” explains Pamela Peralta-Yahya, a chemist at the Georgia Institute of Technology in Atlanta. “So purifying [to get the chemical you want] is hard.” If scientists can engineer yeast to perform the process, the organisms could produce far more end product, with far fewer complications. And with yeast, scientists could also introduce new twists in the chemical pathway to synthesize and study new drugs in this class.
The pathway is almost complete. Dueber’s collaborator Vincent Martin, of Concordia University in Montreal, successfully engineered the steps from (R)-reticuline to codeine and morphine in a study published in PLOS ONE April 23. Another group led by Christina Smolke at Stanford University also published work on the latter half of this pathway in Nature Chemical Biology in 2014. And Dueber and colleagues published the first half of the pathway May 18 in Nature Chemical Biology. Now there’s only one step left, the transformation from (S)-reticuline to (R)-reticuline.
But that step might be on the way. “It hasn’t been described yet,” Dueber says. “But we believe it’s going to be described very soon.” It will be a several-year process to combine the three pathways together in a single organism, and then make the process efficient enough to achieve measurable levels of morphine or another target compound. In the end, if all goes well, yeast will be able to take in glucose and produce morphine in useful amounts.
The most recent studies put together all the steps required for yeast to receive glucose and produce morphine. But it is still a proof-of-concept. There is a wide gulf between a series of biological and chemical reactions and a bathtub of yeast fermenting into heroin. Right now, the process is so inefficient that there wouldn’t be any morphine at all. “I should emphasize that even if you put the first part of the pathway with the middle and the end, you would almost certainly not observe any morphine,” Dueber explains. “Each of those pieces has at least one inefficient step. Many challenges need to be solved.”
But in the meantime, Dueber, Martin and other scientists working on the pathway have approached political scientists with requests to hammer out how the yeast strain might be regulated. Scientific endeavor is slow, but scientific policy is slower. In this case, the policy will have to be international, to reduce the potential for widespread narcotics made from the yeast while keeping the scientific potential intact. Kenneth Oye, a social scientist at MIT, says this means that now is the time, to make sure policies and regulations are considered “with deliberation and not in haste.”
What Oye wants to avoid is a situation similar to what happened with H5N1 flu. A group of scientists in the Netherlands successfully altered the H5N1 flu strain so that it was transmissible through the air and from mammal to mammal, an exercise carried out to show how few mutations it would take to alter the virus’s transmissibility. When the studies came out, the scientific world panicked and research on the flu strain was temporarily halted. “It went through review at all the institutions with no flags,” Oye recalls. “The issue only came to public attention when Nature and Science were presented with the manuscripts.” Presented with a fait accompli, policymakers were stuck, and “the policies were created in great haste after the fact.”
All of this is why Dueber, Oye and their colleagues want to think about regulation now. “Might the media provoke policies in haste? I worry about that all the time,” Oye says. But he thinks the possibilities of waiting until the morphine-producing yeast exists are far worse. Better to work on it now, and create careful policies, remembering that while yeast will eventually make morphine, it’s time has not yet arrived.