Cancer medication by the roadside
Out of all medications, 60 per cent originates in nature or has been inspired by plant life. We depend entirely on plants and fungi for 25 to 30 per cent of it.
Wim Quax, professor of pharmaceutical biology at the RUG, is trying to manufacture cancer medication from cow parsley.
Podophyllotoxin (PPT), the raw material for an oft-used cancer medication, is currently still being extracted from the rare mayapple plant.
Cow parsley contains a substance that is very similar to PPT. It is just missing a ‘molecular hook’. Twelve years ago, Quax discovered a human liver enzyme that could attach PPT to the hook. Unfortunately, that process only works on a small scale thus far.
Als het lukt op grote schaal PPT te produceren uit fluitenkruid, staan onze bermen dus vol met kankermedicijnen.
If he succeeds in producing PPT from cow parsley on a large scale, our roadsides are brimming with cancer medication. Research in this field is going slowly, but Quax finds satisfaction in every small step he takes.
The University Museum is currently hosting the exhibition ‘Dragon’s Blood and Holy Fire’, which focuses on the use of plants as medicine.
Reading time: 7 minutes (1,300 words)
People often associate medicinal plants with alternative healing. Yet 60 per cent of our regular medicine has its origin in plant life or has been inspired by substances from nature. ‘Approximately 25 to 30 per cent of medication derives entirely from plants and fungi. That is much more than people realise’, says professor Wim Quax, who researches medicinal plants.
We are not yet remotely able to artificially produce all substances in factories. We still depend on nature for some substances. Quax: ’In Drenthe, there are greenhouses full of foxglove, which is used to extract a medicine for arrhythmia.’ Other medication can even be found on the side of the road., such as cow parsley. Quax thinks it contains cancer medication. One of his studies focuses on this plant.
Limited supply
A commonly used medication in the fight against cancer is etoposide. It is made from the substance podophyllotoxin (PPT). We are (as yet) unable to produce PPT in a test tube. Pharmacists currently extract the substance from mayapple. But there is one problem: that flower only grows in parts of Pakistan and India.
Moreover, mayapple is kind of difficult. Any attempts to grow the plant outside of the Himalayas have failed miserably. Quax: ’There are a few test fields in Western China, but the majority of the plants are still hand-picked in the wild.’ The plant is so rare that it is even on the endangered list.
Scientists have been looking for alternative ways of making PPT for years. Enter cow parsley. Wim Quax says, ‘Cow parsley contains a substance that looks a lot like PPT, namely DPT: deoxypodophyllotoxin.’ The only thing missing from DPT is a ‘molecular hook’: two atoms in one specific spot in the molecule. Without this hook, the substance does not work. If Quax succeeds in attaching this hook, that would mean our roadsides are brimming with cancer medication.
The limited supply of plants is a common restrictive factor in medication manufacturing. Chemotherapy for breast cancer often uses the substance taxol. The only source of taxol is the taxus plant, a coniferous shrub bearing bright red berries. Scientists first discovered the substance in the taxus trees’ bark.
‘After some calculations, they figured out that each cancer patient would need three trees. That was obviously not feasible’, Quax says. ‘At one point, however, several scientists discovered that the taxus needles contained a substance that looks like taxol: baccatine. We can now turn that into taxol in factories. Instead of chopping down trees, we now harvest the needles, after which the trees continue to grow.’ Private citizens can also contribute to the baccatine harvest by turning in the pruning waste from their taxus trees at garden centres.
That one hook
Quax is now trying to do the same with DPT in cow parsley. That one single hook. It sounds so easy, but appearances can be deceiving. Twelve years ago, professor Quax started his attempts to convert DPT. ‘Attaching a hook to a molecule is not that hard to do chemically. But you can’t direct it to one specific spot. You just get molecular hooks everywhere.’ In order to get the hook in one single spot, they need special molecules from nature: enzymes.
Defensive plants
There is a reason plants and fungi are such a great source of medication. The substances we use in medication are often what plants use to defend themselves. Quax: ‘Plants can’t run away. To prevent them from getting eaten, they contain all kinds of substances that affect the people and animals that ingest them.‘ After taking a bite, people become nauseated or suffer heart palpitations. So the next time they see the plant, they avoid it. Quax continues: ‘Taxol, for example, slows down cell division. This makes the taxus plant toxic, but in concentrated doses, it’s an effective medication for cancer. It allows us to use the so-called “bio-active substances”.’
Enzymes are active proteins: minuscule workers that have the ability to restructure molecules. You can find them in plants, animals, and fungi. Quax explains why they are essential to cultivating DPT: ‘An enzyme is capable of placing a hook in one precise spot on a molecule.’ When Quax started his research, he discovered a human liver enzyme that was able to attach the hook to DPT.
The first hurdle had been cleared. Together with his PhD student Christel Seegers, Quax researched the possibility of converting DPT into PPT on a larger scale. They did this by turning bacteria into tiny medication factories. They changed the DNA of the bacteria to enable them to produce the human liver enzyme. When they insert the DPT from cow parsley into the bacteria, the liver enzyme attaches the hook to the molecule.
Twelve years after taking their first steps in the research, they have come up against a new problem. The enzyme that restructures DPT needs energy to work. The energy in the bacterium runs out after a while, after which the enzyme stops moving. ‘Until we’re able to find a way to re-energise the enzyme, this method is unsuited for mass production’, says Quax.
Mouldy bread becomes drugs
Plants produce not just medication, but also drugs. In the Middle Ages, entire villages would suffer from hallucinations due to bread contaminated with ergot. This fungus contains ergotamine, which constricts the blood vessels and causes delusions.
Paintings by Hieronymus Bosch sometimes depict figures with no arms or legs. They had fallen victim to the ‘holy fire’, as the phenomenon was called at the time.
The last outbreak of holy fire took place in 1952 in the French village of Pont d’Esprit. A local baker sold contaminated bread. Dozens of people died after they jumped out of their windows thinking they could fly. In the sixties, ergotamine inspired the creation of LSD.
Patience
The development of new medication and production methods takes incredible patience, but can lead to amazing breakthroughs. In the seventies, Chinese scientists found a super efficient remedy for malaria in sweet wormwood. After this discovery, it took nearly 30 years before the remedy could be used on a large scale. Quax: ‘But thanks to this medication the number of deaths due to malaria has gone down by 50 per cent in the past decade. Plus, the female scientist Tu Youyou was the first Chinese person to receive a Nobel Prize for Medicine.’
Quax says, ‘The Chinese government under Mao was desperately searching for a new remedy for malaria. Mao had close ties to Vietnam, where there was a large malaria epidemic at the time.’ The Chinese government scientists studied thousands of traditional mixtures and plants. They discovered artemisinin in sweet wormwood, which turned out to work really well. But when they scaled up production of the medication, it frustratingly stopped working. Tu Youyou found the solution in traditional Chinese medicine. Quax: ‘She consulted a sixteenth-century recipe. It said to “steep” the wormwood “in lukewarm water”.’ But the scientists had been boiling the sweet wormwood. After following the historical advice, their problem was solved.
A success story like that is very inspiring, of course. But Quax remains humble about the impact of his own research. ‘It would be great if we could do what the Chinese Tu did for malaria’, he says with a smile. ‘If we can develop a production process that is sufficiently efficient, etoposide would become cheaper. But it’s not new medication, nothing earth-shattering. In this field, developments simply happen slowly over time. I get my satisfaction from every little step we take.’
Intrigued? Go see the exhibition ‘Dragon’s Blood and Holy Fire’ at the University Museum and walk past all the ancient herb jars that student pharmacists were taught with for years. Admission is free.
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