Sowing the seeds of hope

THE air inside the glasshouses tucked away behind the biology department at the University of York is heady: moist and humid and redolent of green, growing things.

Most of the plants growing here at the University’s Centre for Novel Agricultural Products look pretty unremarkable. There are no bursts of colour from exotic hothouse flowers; not even any trailing clusters of plump, ripening tomatoes.

Instead, there are smallish, fernlike plants known as Sweet Annie for their smell; taller plants with woody stems known as jatropha; and, in one of the greenhouses, two beds of poppies. In one bed the plants are young and green: in the other they have dried and died, the seed-bearing poppy capsules reaching toward the ceiling in mute reproach.

In their own way, however, all these plants are quite remarkable. Sweet Annie – Latin name Artemisia – produces a chemical, artemisinin, which IS one of the most effective anti-malarial drugs yet found. Jatropha could potentially offer a high-quality source of easily-harvested biodiesel fuel. And the poppies?

The ones growing here are a particular variety. You won’t get any opium out of these. But potentially they hold the clue to something much more valuable – a possible, non-addictive treatment for some forms of cancer.

Scientists at the Centre for Novel Agricultural Products (or CNAP, as it’s known for short) have been working on poppies for the last five years.

It is a plant that has become notorious because of the trade in illegal drugs: a trade indelibly associated with the poppy fields of Afghanistan.

But there is much more to poppies than opium, says CNAP’s director, Professor Ian Graham. “The poppy is quite remarkable,” he says. “It produces a class of compounds called alkaloids: and these can be used to produce different drugs. Some painkillers, such as morphine and codeine; some with anti-microbial properties; and some with anti-cancer properties.”

Many plants produce chemicals that can be turned into medicines.

There is a very good reason for that: self defence.

Plants aren’t like animals, Prof Graham says: they can’t run away from danger. If an animal is threatened, it gets out of the way. “A plant can’t do that. So what happened instead is that they use chemical warfare. They have developed a whole range of chemicals, to repel insects or other animals and stop them being eaten.”

The particular chemical that scientists at CNAP who are working on poppies are interested in is known as noscapine.

For decades, noscapine has been used as a cough medicine. But a few years ago, scientists discovered that it could also have anti-cancer properties.

The chemical works by stopping cancer cells dividing – thus halting the growth of tumours (see panel). Early studies showed it may be effective on certain types of lymphoma, as well as with some breast cancers, bladder cancer and skin cancer. Clinical trials of the drug are now taking place in the United States.

It is potentially very potent in halting tumour growth, says Prof Graham. And because it has been used as a cough suppressant for so long, we know it doesn’t have serious side effects in people.

If it does prove to be an effective anti-cancer medication, the problem will be to produce sufficient quantities of the drug.

Which is where the CNAP scientists come in. Noscapine is a hugely complex molecule to make – scientists have identified at least 11 biochemical ‘steps’ that take place in the poppy to produce it. In effect, says Prof Graham, poppy plants act like tiny chemical factories. The chemical is slowly built up as different bits are added to the molecule. “It’s a bit like the steps along the way to produce a vehicle in a car factory.”

The CNAP scientists’ aim, with the help of funding from pharmaceuticals giant Glaxo Smith Kline, is to selectively breed varieties of the poppy which reliably produce higher yields of noscapine and which are also resistant to both disease and drought. It is a process called ‘trait stacking’ – selectively breeding a variety of plant that combines all the various qualities that you want in one plant.

The difficulty is, getting all those qualities – disease and drought resistance, plus high yields of noscapine – together in the same poppy variety.

But when the CNAP scientists began the process of selectively breeding poppies to produce higher yields of the chemical, they had a huge stroke of luck.

Each of the 11 steps in the production of noscapine in the poppy is controlled by different genes. A plant like a poppy has tens of thousands of genes, clustered together in tiny ropes of genetic material known as chromosomes. The CNAP scientists expected that, because the different steps in producing noscapine are controlled by different genes, breeding new varieties of poppy that combined the ability to produce noscapine with the ability to resist drought and disease would be hugely complicated.

But it turned out to be much simpler than they expected – because they found that the genes that control ten of the 11 steps in the production of noscapine in poppies were always passed on together.

Genetic testing confirmed that this was because the genes are clustered closely together on the poppy’s chromosomes, so don’t get split up when breeding new varieties.

It was a discovery that cut years off the process of developing new, higher-yielding varieties of poppy. “With this one discovery we have been able to produce an outline of the pathway for making noscapine and define a number of the steps involved,” Prof Graham says. “That is something that normally takes years.”

The CNAP scientists’ breakthrough made headlines around the world when it was reported recently in the journal Science.

The team are now pressing ahead with developing new strains, selectively breeding the plants in their York glasshouses, then sending the seeds to Tasmania, where the poppies are grown.

If clinical trials of noscapine prove that it is successful in stopping tumour growth, they will have played a vital part in ensuring that sufficient quantities of the drug can be produced to make it an effective and viable cancer treatment.

And it is all down to those poppies growing in a greenhouse at Heslington .

It is early days, Prof Graham said: and noscapine is only one of many potential new cancer drugs under development.

“But what we’re doing here is a good demonstration of the kind of work that needs to be done to keep developing new drugs for the future.”

The science behind the discovery

All plants and animals are the way they are because of their DNA: the genetic code that decides how they develop, by controlling the biological and chemical processes that take place during growth.

DNA itself is organised into genes – tiny genetic units, found deep in the heart of every plant and animal cell, that determine in people whether our eyes are blue or brown, or what colour our hair is, or how tall we are. In a plant like a poppy, genes determine how tall the plant is, how resistant it is to disease or drought – and how good it is at making compounds such as noscapine.

A plant like a poppy has tens of thousands of genes, clustered together in tiny ropes of genetic material known as chromosomes. All poppies, even of the same variety, are slightly different, because they don’t all have exactly the same 30,000-odd genes. That difference is where the breathtaking variety of life comes from.

When a plant (or animal) reproduces, the genes of two parents are mixed together to produce the young plant or animal. It takes half its genes from one parent, and half from another.

Because noscapine is such a complex molecule, there are at least 11 steps involved in making it in a poppy plant. That means at least 11 different sets of genes, each controlling one step.

Because when you breed a new generation of plants, the genes are all mixed up – half from one parent, half from the other – scientists expected that new varieties of poppy would inherit the genes for only some of the steps for making noscapine.

But in fact, they found the genes for ten of the 11 steps were always inherited together. Genetic testing revealed that this was because the genes for those ten steps were clustered closely together, and so were always passed on together during breeding of the plant.

It made the process of producing poppies which combined the ability to make noscapine with resistance to disease and drought much easier.

If all those genes hadn’t been close together, Prof Graham said, trying to breed plants in which all the characteristics scientists wanted were combined would have been “a bit like herding cats. The genes needed for those ten steps in making noscapine would all have gone in different directions.”

How noscapine works

Noscapine works by stopping cancer cells from dividing, so that tumours cannot grow.

When a cell, such as a cancer cell, divides, what happens is that tiny little fibres within the cell called tubulin fibres pull the cells apart. Noscapine binds to these fibres, stopping them pulling cells apart and the cells can’t divide.

The drug has been used as a cough suppressant for decades, and it has not been observed to have significant side effects on patients.

The doses that would be needed if it were to be used as a cancer treatment would be much higher, however. So one of the things that will need to be tested before the drug can be developed as an effective cancer treatment is whether, at these much higher dosages, it would have harmful side effects.

• The Centre for Novel Agricultural Products is a world-leading research centre devoted to studying plants so as to discover some of the amazing chemicals they produce naturally which could be useful to us – especially medicines.

CNAP scientists are working with a whole range of different plants, with a view to producing everything from a cure for malaria to cancer drugs, and from new biofuels to plants which can ‘grow’ health-giving fish oil.

To find out more about the work of CNAP, visit york.ac.uk/org/cnap/