Engineers Genetically Reprogram Yeast Cells to Become Microscopic Drug Factories

By genetically reprogramming the cellular yeast machinery, they created microscopic factories that convert sugar and sugar amino acids in herbal medicines.

Since ancient times, cultures on almost every continent have discovered that certain plant leaves, when chewed, brewed, or rubbed on the body, can alleviate various illnesses, cause hallucinations, or, in higher doses, even lead to death. Today, pharmaceutical companies import these once-rare plants from specialized factories and extract their chemical agents to make drugs like scopolamine to relieve motion sickness and post-operative nausea, and atropine to curb the drooling associated with Parkinson’s disease or to keep the heart functioning properly during intubation COVID-19 Patients and place them on ventilators.

Now, Stanford engineers are recreating these ancient remedies in a thoroughly modern way by genetically reprogramming the cellular machinery of a particular strain of yeast and effectively converting them into microscopic factories that convert sugars and amino acids into these folk medicines, Similar to brewer’s yeast, sugar can naturally convert to alcohol.

“The drug shortages we are seeing in the context of the COVID-19 crisis make it clear why we need new and more reliable ways to source these herbal medicines. The growth takes months to years and comes from some countries where climate change natural disasters and geopolitical issues can disrupt supplies, ”said Christina Smolke, professor of bioengineering and senior author of a paper published September 2, 2020 in nature.

Certain plants in the nightshade and coca families produce compounds called tropane alkaloids that can interact with the human nervous system to produce medicinal effects. Stanford scientists have genetically programmed the cellular yeast machinery to create microscopic chemical factories for the production of the tropane alkaloid active ingredients hyoscyamine and scopolamine, similar to how common yeasts are used to brew beer. Photo credit: Prashanth Srinivasan and Farrin Abbott

Prashanth Srinivasan, a PhD student in Smolke’s laboratory and first author of the paper, reprogrammed the yeast in the factory. With the hiring of an engineer, he viewed each of the yeast organelles, or basic metabolic units, as workstations on the assembly line. He envisioned the core as a factory control center, regulating the step-by-step chemical process required to assemble drugs. Mitochondria, the energy-producing organelles, required special attention. Cells use electrons to hook or unhook molecules on the assembly line, and Srinivasan needed many of them to make the desired products – a family of complex chemical compounds called tropane alkaloids. Humans have been using these compounds for thousands of years for everything from relieving tooth and stomach ache to performing religious rituals and poisoning rivals.

A long history of use

The far-reaching medicinal benefits of tropane alkaloids are a co-evolutionary accident. A chemical developed by two plant families – coca, cocaine producers, and nightshade, which includes henbane and tobacco, and tomatoes and peppers – to defend themselves against insects and animals simply fits perfectly into a critical cell receptor in the mammalian nerve system. These acetylcholine or ACh receptors help convert nerve impulses into actions by muscles, glands, and other human tissues. When a tropane alkaloid enters the bloodstream, it binds to these ACh receptors and stimulates or inhibits the adjacent muscle, gland, or tissue, resulting in diverse and widespread effects.

Traditional societies did not understand the biochemistry of these compounds, but they did notice their medicinal virtues. Native Andean people chewed or brewed tea from coca leaves to suppress hunger, treat gastrointestinal complaints, and relax. From Europe to North Africa to West Asia, various peoples preferred tropane alkaloids, derived from deadly nightshade, or Atropa Belladonnaso named after its use by women as a cosmetic to dilate the pupil; Modern ophthalmologists still use it to produce the same effect in eye exams. In Southeast Asia, tropane alkaloids are made from Thorn apple Plants were taken orally for sinus infections, and Australian Aborigines based rituals on the shrub’s hallucinogenic effects Duboisiawhich is the main source of tropane alkaloids for medicinal products today.

Metabolic Engineering

Smolke and her team made a total of 34 genetic changes on the yeast over a period of three years DNA Control every step in the invisible chemical assembly process of tropane alkaloids. Their approach – called metabolic engineering – is a more precise form of biotechnology in which genetic reprogramming uses or modifies naturally occurring cellular processes to create products that meet human needs. For example, when brewer’s yeast produces alcohol, the cells naturally release the chemical so we can collect and drink it. The Stanford team carefully engineered their technical yeast’s organelles and membranes to ensure that its intricate tropane alkaloid molecules exit the chemical assembly line intact, making them useful for drugs.

Smolke, who previously bio-engineered yeast to make another family of herbal analgesics, has co-founded a biotech startup that will license the technology from Stanford to bring the experimental quantities of drugs made by these cell factories into full production, which is expected to take about two years.

“Plants are the best chemists in the world,” said Smolke. “We would like to pool their unique and useful chemical properties in domesticated microbes to build complex molecules that are inspired by nature but better tailored to human needs.”

Reference: “Biosynthesis of medicinal tropane alkaloids in yeast” by Prashanth Srinivasan and Christina D. Smolke, September 2, 2020, nature.
DOI: 10.1038 / s41586-020-2650-9

This work was supported by the National Institutes of Health and a PhD grant from the Natural Sciences and Engineering Research Council of Canada.