Medicinal Tropane Alkaloids Synthesized via Yeast Cells: Study
Wed, April 21, 2021

Medicinal Tropane Alkaloids Synthesized via Yeast Cells: Study


A group of engineers reprogrammed yeast cells to become drug factories. The goal is to repurpose an ancient technology to combat drug shortage, especially during a pandemic.

The reprogramming of yeast cells as medicine factories was led by engineers at Stanford University, a US private research university. They upgraded an ancient technique using modern technologies to reprogram yeast cells. The cellular machinery of the cells was modified to produce drug components. The modernized technique resembled the method of the brewer's yeast, which could convert sugars into alcohol. They published their research in the journal Nature.

The Shortages in the Healthcare Sector

The COVID-19 pandemic stirred panic worldwide because of the lack of specific treatment or vaccine. Public health agencies advise people to practice preventive measures to avoid contracting the disease. But the preventive measures require several items, such as face masks and hand sanitizers. In the early months of the pandemic, panic-buying of surgical masks, medicines, and hygienic products caused major shortages. While suppliers failed to meet the surge in demand due to the impaired international supply lines. The adherence to physical distancing crippled manufacturers reliant on manpower physically present in factories.

The UK has been one of many territories affected by shortages. According to Statista, as of April 30, 2020, more than 19% of hospital doctors in the UK reported personal protective equipment (PPE) shortages. About 12% reported staffing shortages, 17.4% reported personal situations, 4.7% reported medicine shortages, and 19% reported issues in COVID-19 testing. Those figures might have painted a fraction of the larger picture.

Many UK hospital doctors spoke about the problems but did not officially report them. Around 21.5% spoken about PPE shortages, 11.3% about staffing shortages, 11.9% about personal situations, 9.4% about medicine shortages, and 21.6% about COVID-19 testing issues. An estimated 61.6% of doctors had no issue to report about PPE shortages, 76.7% about staffing shortages, 70.7% about personal situations, 85.9% about medicine shortages, and 59.4% about COVID-19 testing.

As of April 30, 2020, in the UK as well, shortages were already experienced before the pandemic struck. Around 18.5 of hospital doctors experienced shortages in oxygen, while 18.2% experienced shortages in anesthetics, and 17.8% experienced shortages in antibiotics. Approximately 16.4% had shortages in sedatives, 11.8% in opioids, 8.6% in analgesics, 3.8% in hormone replacement therapy, and 3.4% in inhalers. A total of 43.9% of doctors experienced shortages in other drug classes.



Yeast Cells as Tiny Factories of Medicines

Despite the efforts in repairing the international supply lines, many countries still face shortages in medicines and medical equipment. This is because both the other industries and sectors and the public consume the same supplies. Although medical-grade face masks have been made exclusive to frontliners, supplies remain a problem due to new COVID-19 cases reported daily.

At Stanford, engineers looked back in the past and repurposed an ancient technique using modern technologies. Like the brewer's yeast, the team modified yeast cells to become tiny drug factories. Instead of producing alcohol, the yeast cells produced folkloric drugs by converting amino acids and sugars. They engineered the cellular machinery to optimize the cells' function for drug manufacturing. If upscaled and configured, it might help supply basic medicines during global medical crises or even after a pandemic. The folkloric drugs highlighted in the study were formerly unexplained by traditional societies, which could only notice the effects.

"The drug shortages we're seeing around the COVID-19 crisis drive home why we need new and more reliable ways to source these plant-based medicines, which take months to years to grow and come from a few countries, where climate change, natural disasters and geopolitical issues can disrupt supplies," said Christina Smolke, the senior author of the study and professor of bioengineering at Stanford.

Prashanth Srinivasan, the first author of the study, wanted to produce a complex family of chemical compounds called tropane alkaloids. This chemical family has been used by humans for thousands of years to relieve different types of pain. However, early humans could not really explain how the compounds worked or how they came to be. Later on, modern science managed to unravel the mystery behind it.

Tropane alkaloids are a result of a co-evolution accident between two families of plants: coca and nightshades. Coca produces cocaine while nightshades include henbane, tobacco, peppers, and tomatoes. Both plant families evolved to defend themselves against animals and insects, which featured a critical cell receptor in the mammalian nervous system. That receptor is called acetylcholine or ACh that aids in the conversion of nerve impulses into actions by certain body parts.



Once the chemicals enter the bloodstream, they bind to ACh receptors leading to either stimulation or inhibition of muscles, glands, or tissues. Early humans found ways to use these chemicals. Native Andeans either brewed or chewed teas to suppress hunger or treat stomach problems. While early civilizations in some parts of Asia and Europe add the chemicals in cosmetics to dilate pupils.

Engineers successfully made 34 genetic modifications in the DNA of yeast cells. These changes were done in three years. But the alterations control every single step in the cellular manufacturing process of tropane alkaloids. Via metabolic engineering, they were able to precisely reprogram the cellular processes through biotechnology. Several organelles were highlighted based on their new assigned task in making the chemicals.

For example, the Golgi apparatus directs new molecular machines to their final part in the assembly process. Meaning, it acts as a packaging sorting center of the cell. Another is the peroxisome that serves as a containment chamber for hazardous waste. Though, organelles like the mitochondrion and nucleus function similarly before the alterations.

Currently, the engineers are optimizing the technology for large scale production of tropane alkaloids. Smolke co-founded a biotech startup to have the technology licensed. The full-scale production of medicines using these tiny factories is expected to provide supplies in about two years. There are no specifics yet regarding other medicinal drugs they plan to produce using modified yeast cells.