Scientists Engineer Yeast to Help Make Powerful Cancer Drugs

Scientists have found a new way to make two important cancer drugs — etoposide and teniposide — using yeast, the same tiny fungus used to bake bread. Researchers published their findings in the journal Science, showing that yeast can be programmed like a small living factory. Instead of relying on rare plants, the team used a simple sugar, glucose, as the starting material. This discovery could one day help make sure patients around the world have better access to these life-saving medicines.

For hundreds of years, people have used plants to make medicines. Many of today's most powerful drugs, including cancer treatments, still come from plant chemicals. However, growing enough of the right plants is slow, expensive, and hard on the environment. Scientists have been searching for better ways to produce these medicines without depending so heavily on nature.

Etoposide and teniposide are drugs that doctors use to fight several types of cancer. They are made from a chemical found in the mayapple plant called podophyllotoxin. The problem is that the mayapple plant grows slowly and does not make very much of this chemical. Researchers wanted to find a smarter way to produce these drugs in larger amounts.

The team, led by scientist Shen and colleagues, turned to yeast to solve this problem. They added new genetic instructions to the yeast so it could follow a long series of chemical steps. These steps, called a biosynthetic pathway, turn glucose into a key ingredient needed to make both drugs. It is a bit like teaching the yeast a complicated recipe, one step at a time.

One of the first challenges was helping the yeast make a building block called coniferyl alcohol. The natural plant method did not work well inside yeast cells. So the scientists designed a brand-new, non-natural pathway using special proteins called carboxylic acid reductases. After a lot of testing and fine-tuning, they got the yeast to produce about 89 milligrams of this ingredient per liter — roughly 45 times more than their first attempt.

Next, the team needed the yeast to link two of these building blocks together in a very specific way to form a chemical called pinoresinol. Getting the shape right was critical, because even a mirror-image version of the molecule would not work for making the drug. The scientists used special plant proteins called dirigent proteins to guide the linking process. After more tweaking, they had a working starting point for the next stages of the pathway.

Building the full chemical structure required the team to screen, or test, dozens of different enzymes — proteins that speed up chemical reactions. They tested 13 versions of one enzyme and four versions of another before finding the best pair for the job. They also engineered two important enzymes called cytochrome P450s, which are known to be tricky to work with in yeast. All of these efforts pushed production of a key middle-stage chemical to measurable levels.

After that, the researchers added more enzymes in a mix-and-match system they called a 'plug-and-play' module. This clever design let them combine different enzymes to produce twelve related compounds. One specific combination led to the production of the direct chemical precursor — the last ingredient needed before the final drug can be made. They also re-engineered one of the enzymes to make it work nearly four times better.

The very last step was surprisingly simple. The team converted the yeast-made precursor into etoposide and teniposide using mild chemical reactions. Making etoposide this way worked 89% of the time, and making teniposide worked about 65% of the time. In the past, this final conversion required more than ten complicated chemical steps with a low overall success rate. The new method cuts all of that down to just one step.

Scientists are honest that the yeast factory is not yet ready to supply hospitals around the world. The amounts produced are still hundreds of times too small for large-scale manufacturing. Several bottlenecks — places where the process slows down or gets stuck — still need to be solved. Future work will likely involve finding smarter ways to organize the enzymes inside the yeast cell so they work better together.

Even so, experts say this research is a major step forward. The team identified a key enzyme, called UGT709AX1, that had been missing from scientists' understanding for ten years. This enzyme places a sugar molecule onto the precursor in exactly the right way, which is a step that used to require many difficult chemistry tricks. By moving this difficult step into the yeast itself, the scientists made the whole process much cleaner and more efficient.

The modular design of this yeast platform is also exciting for another reason. Because the system is built in interchangeable parts, scientists can swap in different enzymes to make related compounds that do not even exist in nature. This could open the door to discovering brand-new medicines. The research shows that living cell factories, carefully engineered, could one day help secure the supply of important drugs that the world depends on.