Why you should care

Because this Stanford researcher could transform drug development. 

Christina Smolke is a maker at heart. As a sunny SoCal kid, she sewed her own clothes and knitted hats, scarves and blankets. A theater nerd, she crafted characters through makeup and costume design. She loved to work with her hands.

That childlike, tactile wonder never really left — except now Smolke applies it to cutting-edge biology. In a groundbreaking move in the field, the Stanford scientist has engineered yeast to produce opioids, mainstays of medicine that relieve chronic pain and pain after surgery. Her work is some of the most complex ever performed with yeast.

Today, opium poppies — difficult, time-consuming and expensive to harvest — are the only source of medicinal opioids. The World Health Organization estimates that around 5.5 billion people have poor access to pain medications, partly because of the harvesting cost. Farming poppies also requires vast amounts of land, whose yields are susceptible to environmental factors such as climate and pests. At commercial scales, Smolke’s technology would take only a few days and could shrink production costs by at least tenfold. It would also use 500-fold less land and lower the supply risk. It might even offer a blueprint for producing other complex plant-based medicines, which comprise 40 percent of prescription drugs.

Opioid-churning yeast are among the latest advancements in the burgeoning field of synthetic biology, which treats cells like electronics, engineering them into minifactories that produce drugs, biofuels and other useful compounds through a series of chemical reactions, or pathways. Smolke is a leader in the field, pioneering the engineering of ever more complex chemical pathways. Most synthetic biologists work with fewer than 10 genes; Smolke’s managed to string together over 20 into a fully functional pathway. Working with more genes opens the door to synthesizing a wider array of products. Beyond her opioid work, Smolke also has designed several synthetic biology tools. Basically, “there isn’t anybody working in this field who wouldn’t know Christina,” says Lars Nielsen, a systems and synthetic biologist at the University of Queensland. Her work is “transforming how we can access [plant-based] compounds.”

The idea of building with biology really spoke to me.

Christina Smolke

Smolke Skypes from her brightly lit office at Antheia, the Menlo Park company she co-founded to commercialize her yeast-based technology. She wears her dark hair pulled back in a ponytail, revealing a fresh face with kind, hooded eyes. Those who know her say she can come across as shy, but “there’s an intensity about her as well,” says Kate Thodey, a postdoctoral researcher in her lab and co-founder of Antheia. Smiling every few sentences, Smolke talks about growing up in Redondo Beach, her sights at one point set on acting. Although she liked biology, she couldn’t see herself as a doctor — she preferred to build things. After seeking advice from her father, an electrical engineer, she majored in chemical engineering and minored in biology at the University of Southern California.

“The idea of building with biology really spoke to me,” she says — so much so that she went on to earn a Ph.D. in chemical engineering at the University of California, Berkeley. For her thesis research, she engineered molecules known as RNA to modify the expression of metabolic pathway proteins that lead to the production of different nutrients.

Smolke started her own lab at Caltech in 2003 at just 28 before relocating to Stanford’s bioengineering department in 2009. At first, bioengineering was “a lot of ad hoc, trial and error,” she says. “It didn’t feel like engineering.” To change that, she knew she had to build a strong toolkit. She engineered RNA devices that control the rate of production in chemical pathways and could make them more efficient.

Next, Smolke wanted to engineer a platform to produce a complex natural product. So far, her Ph.D. adviser’s lab had engineered yeast to produce artemisinin, an antimalarial extracted from sweet wormwood. But that pathway included only six genes. Smolke wanted to engineer the more daunting opioid pathway, composed of more than 20 genes. “A decade ago” — when Smolke started her project — “none of us really felt it was possible,” Nielsen says. Plant genes often don’t express in nonplant hosts. Colleagues asked Smolke why she was wasting her time.

Smolke and her team first searched for enzymes that could help convert the sugar the yeast fed on into opioid precursors. Rather than replicate the pathway found in opium poppies — which scientists still haven’t fully unraveled — they plucked enzymes from medicinal plants, yeast, bacteria and even mammals, and integrated them. In the end, they engineered yeast strains that turn glucose into hydrocodone and thebaine, the latter of which is further processed into painkillers like oxycodone.

Smolke’s technology produces opioids under controlled conditions, which makes the process hard to replicate at home for illegal use. She wants to eventually work toward a poppy-free supply chain for crucial opioid painkiller drugs. For now, though, her method yields very little opioids. Thodey, however, predicts commercialization could happen in a few years.

Some media outlets have worried that, amid the current opioid epidemic, Smolke’s product could unleash a Breaking Bad scenario, allowing everyday folks to home brew heroin. She’s not concerned, and last year published a paper showing that carrying out the procedure with beer-brewing equipment yields no opioids from the engineered yeast. The facilities that would house her technology would also need to meet statutory requirements for making controlled substances.

Smolke says she’s also working on engineering biosynthesis platforms for other opioids and medicinal compounds, including those not seen in nature — like more effective opioids that don’t cause addiction. In other words, the hat-knitting, costume-sewing teenager still exists. She doesn’t want to mimic the natural world, but rather stitch together bits and pieces of it into something better.

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