How to create opioids for the masses

CNN  — 

It is an aroma you would normally find wafting around a bakery, or from the cellar of a home-brew enthusiast.

At Stanford University, however, the yeast emanating this odor isn’t being used to create food or drink, but instead engineered to create powerful new medicines.

The American bioengineer pioneering this research is Christina Smolke and she’s transforming the field of drug development by creating new opioid drugs from the humble baker’s yeast.

Her research could transform the manufacture and supply of a major industry – prescription painkillers.

Opioid painkillers such as morphine, hydrocodone (the ingredient in the painkiller Vicodin) and thebaine (found in oxycodone and codeine), provide pain relief by switching off pain receptors in the brain.

The potent drugs are derived from the sap of an opium poppy, but turning them into medicines takes time – the timeframe from the farmer’s field to pharmacy typically takes a more than a year.

If made from genetically-modified yeast, however, the drugs can be created in a fraction of that time, in just three to five days.

Smolke’s complex technology involves engineering the yeast to include 23 genes taken from six organisms – three types of poppy (Californian, Iranian and opium), the goldthread herb, soil bacteria and a rat.

Once inserted, these genes bring big results.

How it works

The reprogrammed yeast are grown on sugar in the lab and their newfound genes mean they’re able to produce the right enzymes (biological catalysts) required to convert that sugar into hydrocodone and thebaine.

Engineering yeast in this way isn’t unique, but the number of genes and organisms involved is.

Genetically-engineered yeast growing in a petri dish at Smolke's laboratory at Stanford University.

“If you just think of the scale of having to put 23 new genes into yeast…and for those genes to work in this very different environment it’s a big challenge,” Smolke explains.

Her journey to transform the skills of these yeast has taken more than a decade of dedication, figuring out which genes would and would not work in the yeast environment, and which would require further engineering.

But the laborious process has paid off.

Patience and persistence, but no eureka

The results of Smolke’s work are a testament to her tenacity according to Kate Thodey, a strain engineer who has worked on the project for the past six years and watched Smolke refuse to believe it would not be possible.

“With this kind of science it’s not discovery-based, it’s engineering — so there is no ‘eureka’ moment,” says Thodey.

There were instead a collection of moments where the team would build the yeast strains, test them, repeat the test, refine the process, then start all over again to build them better.

“We’re playing the long game here and that’s not rare in academia but it is rare in Silicon Valley - people want quick turnarounds,” Thodey explains.

Home-brewed path

Smolke’s route into science, let alone bioengineering, wasn’t straightforward.

Born to an engineer father and a “homemaker” mother, Smolke had a wide range of interests growing up, including “making things.” Ultimately, she left high school unsure what to do as a career.

“For a lot of my time at school I was very into humanities – history and, actually, acting. I thought I might major in theater,” she says.

But once dreams of the stage faded and practicalities set in, Smolke settled on a more reliable career path.

“I talked to my father about a few things. The interface between biology, health and engineering seemed like a really exciting area,” she says.

Her decision proved to be timely as the field was just developing.

Smolke studied and went on to set up her own lab at Stanford almost 13 years ago.

“I was still really interested in making things with biology, but I felt like the things that were being made were fairly simple,” she remembers.

Smolke wanted a challeng and her eyes soon laid upon opioids and the millions lacking access to them worldwide.

Opioids for the masses

Opium poppies are a major crop, and source of income, for many farmers.

The target in sight involved solving some of the age-old problems of supply and demand.

“Opiates are the primary painkillers used right now,” says Smolke. “They are sourced from opium poppies – that is the only really viable way of sourcing them.”

But when relying on a single source for your product, multiple barriers can get in the way.

“There are a lot of challenges for poppy farms both from the perspective of trying to grow crops reliably each year and then the movement of narcotic materials across borders,” says Smolke.

The latter is aided by the fact the poppies are farmed in some of the most impoverished and politically charged regions of the world.

This all adds up to limit the quantity made at the end of the production line.

Beyond that, are the chasm-sized differences in opioid access between countries in the developed and developing world, leaving millions without access to even simple painkillers.

Inadequate access

The United Nations International Narcotics Control Board (INCB) estimates that more than three quarters of the world population (5.5 billion) have inadequate access to pain-relieving medicine for HIV/AIDS, cancer and even childbirth.

A 2015 INCB report cited “limited training and awareness” among key personnel – healthcare professionals, policymakers, the general public – as a major barrier to opioid access, as well as sourcing and poor infrastructure.

This unequal access to opioids is further highlighted by the fact that 92% of the world’s morphine is currently consumed by only 17% of the world’s population – primarily in the United States and Europe.

“In the United States and Europe we don’t have an access problem, we have an opposite problem of over prescription leading to addiction problems,” says Smolke.

Trouble ahead?

Fear of fuelling further addiction is one reason that Smolke’s strides forward in the field of bioengineering haven’t been met with universal approval. Some observers fear a rise in so-called “home-brew heroin.”

For now, Smolke believes this is not an immediate threat, as her yeasts are not quite ready for large-scale production and the process requires yeast by the bucketloads.

Currently, roughly 4,500 gallons of bioengineered yeast are required to produce just a single dose of pain relief, but Smolke is working to improve the efficiency and viability within a few years..

To overcome addiction, however, Smolke is changing the properties of the drugs themselves – to remove the potential for addition.

“If you can gain control over the synthesis compound…you have much more control over manipulating aspects of the molecule [and] allow for a better painkiller with less side effects [and] less addictive qualities,” she says.

Avoiding addiction

In their study published in the journal “Science” last August, Smolke and colleagues called for a discourse between developers of the new medical technologies and all parties involved in the chain, from regulators and law makers, right down to the clinicians administering them in surgeries and hospital wards.

Oxycodone pain pills

Her study led to the research becoming runner-up for the journal’s 2015 breakthrough of the year,

“I’m certainly sympathetic to concerns around the manufacturing of controlled substances [and] the abuse of controlled substances and opioid drugs in certain countries,” she says.

Smolke believes her technology is unlikely to increase addiction, and instead feels over-prescription is playing a key role in today’s rising numbers.

According to the American Society of Addiction Medicine, 259 million prescriptions were written for opioids in the United States in 2012 and of just over 47,000 lethal drug overdoses in 2014, nearly 19,000 were related to prescription painkillers.

The scale of the epidemic was underlined recently by President Obama who announced a proposed $1.1B package to address the problem in February before unveiling further initiatives to combat the scourge of prescription addiction at the end of last month.

Debates about bioengineered opioids look set to rumble as the science improves, but bringing life to her yeast products remains Smolke’s priority.

“[The strains] will be improved sufficiently and will be compelling and competitive from the commercial perspective,” she says.

Her technology is estimated to be viable within two years, with a few more years needed for it to then reach the market. To that end, Smolke and her team have founded the company Antheia to further their research and create medicines that are available to all.

Doubters and doom-mongers will likely continue to cast doubt over the efficacy of such developments, but Smolke’s believes her work could be the start of a new era in medicine.

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“Whether it’s sexual diseases, cancer, cardiovascular, neurological diseases, I think this gives us a really important tech platform to develop many new drugs beyond painkillers,” she says.