Ancient Cannabis Enzymes Revived in Lab with Medical Potential

Scientists at Wageningen University in the Netherlands have recreated enzymes from cannabis plants that lived millions of years ago. These enzymes make the key compounds THC, CBD, and CBC, which have medical uses. The work shows how cannabis chemistry changed over time and points to new ways to produce these compounds for drugs.

Background

Cannabis plants produce compounds like THC, which causes a high, CBD, used for pain and anxiety, and CBC, which fights inflammation. People have used these for medicine for years, but growing plants or making the compounds in factories has limits. Modern plants have special enzymes, one for each compound. These enzymes take a starting molecule called CBGA and turn it into THC, CBD, or CBC.

That setup did not always exist. Long ago, cannabis ancestors had different enzymes. A team led by Robin van Velzen wanted to find out how these enzymes evolved. They looked at DNA from today's plants to guess what old enzymes looked like. This method, called ancestral sequence reconstruction, lets scientists rebuild lost proteins.

The researchers picked enzymes called cannabinoid oxidocyclases. These handle the main step in making cannabinoids. By working back from modern DNA, they built three ancient versions. They made these in yeast cells to test them. The tests showed the story of how cannabis got its chemistry.

Early cannabis lived about 10 to 20 million years ago. Back then, plants made cannabinoids to protect against bugs or help growth. Over time, gene copies split, and enzymes got better at one job each. This made plants produce more of certain compounds. Humans later bred plants for high THC or CBD.

Other plants, like rhododendrons, make similar compounds, but cannabis did it on its own. The study proves cannabinoid making started in a recent cannabis family member.

Key Details

The revived enzymes surprised the team. Unlike today's ones, which stick to one compound, the ancient ones made several from the same CBGA. One old enzyme turned CBGA into precursors for THC, CBD, and CBC all at once. This shows early cannabis had flexible chemistry.

How They Tested the Enzymes

The team put the ancient enzyme genes into yeast. The yeast made the proteins and ran the reactions. They measured what came out. Modern enzymes need exact conditions and are hard to produce in large amounts. The old ones worked better. They stayed stable and made more product.

One enzyme stood out. It made mostly CBC, a cannabinoid in low amounts today. CBC helps with pain, swelling, and seizures, but studies on it lag behind THC and CBD. This ancient version acts like a middle step in evolution. It favors CBC over others.

The researchers also made hybrid enzymes. They changed single amino acids to see what shifted the output. This pinpointed mutations that made modern enzymes pick one cannabinoid. The hybrids combined old strength with new focus.

"At present, there is no cannabis plant with a naturally high CBC content," said Robin van Velzen, a biosystematics scientist at Wageningen University. "Introducing this enzyme into a cannabis plant could therefore lead to new medicinal varieties."

The work fills gaps in cannabis history. Before, scientists guessed at enzyme paths from DNA alone. Now, with lab tests, they have proof. The study came out in Plant Biotechnology Journal.

What This Means

These findings change how we make cannabis compounds. Labs now grow yeast or bacteria to produce THC and CBD for drugs. It's faster than plants and avoids farming issues like weather or rules. Ancient enzymes fit this better. They produce more and need less care.

For plant breeders, the CBC enzyme offers a tool. Add it to modern cannabis, and you get strains high in CBC. That could treat inflammation or pain without much THC. Doctors want options like that as cannabis medicine grows.

Biotech firms eye this for custom drugs. Mix enzymes to make new cannabinoid blends. Early flexible enzymes give a strong base to tweak. This could speed up tests for new treatments.

The evolution story helps plant science. It shows how gene copies and changes build complex traits. Cannabis split into drug-type and hemp-type plants millions of years ago. Retroelements, virus-like DNA bits, helped by messing up genes and pushing new paths.

Breeders might use this to make THC-free plants with high CBD or CBC. That fits places where THC stays illegal. The map of chromosome 6, where these genes sit, shows THC and CBD enzymes come from one old gene that split.

Medical use expands. THC helps nausea and appetite in cancer patients. CBD eases epilepsy seizures. CBC adds anti-bacterial and mood effects. Together, they might work better than alone, as in the entourage effect.

Companies already sell lab-made CBD. Adding ancient enzymes cuts costs. For rare compounds like CBC, it's a breakthrough. No natural plant makes much, so lab or edited plants fill the gap.

Researchers plan more. Test other ancient enzymes. Try them in real plants. Check if edited cannabis grows well. Rules on gene editing vary, but tools like CRISPR make changes easy.

This work builds on past maps of cannabis DNA. It ties genes to chemistry with hard data. As cannabis laws ease in more places, demand rises for better sources. These old enzymes meet that need.