Tumour-loving bugs deliver killer blow

A humble and harmless soil bacterium is the latest recruit in the war on cancer. The bug is known to grow only inside tumours when it infects humans and has now been given a lethal new trick.

Researchers genetically engineered Clostridium bacteria so they were able to convert a harmless chemical into a potent toxin. Injecting the chemical into the patient's bloodstream should therefore destroy tumours from the inside, while leaving healthy tissues unharmed.

The idea of converting a harmless "prodrug" into a substance that kills cells only in a tumour is not new. "But the field has taken one step forward and one step back," says Nigel Minton at the University of Nottingham, UK.

One approach has been to attach the enzyme that converts the prodrug into the toxin to an antibody that binds only to cancer cells. But different tumour types require different antibodies, making it expensive to develop. Minton and his team hope their bacterial approach will offer a way of delivering the enzymes to any cancer cell.

Tightly packed cells

The idea that bacteria could be used as a cancer therapy originated over 100 years ago, when physician William Coley noticed some of his patients with bacterial infections were able to fight off cancer. Later work showed that Clostridium bacteria grew happily in cancerous tissue because they thrive in low oxygen conditions. The tightly packed cells and poor blood supply of a tumour make it ideal.

But attempts to use the bacteria as a treatment were disappointing. The bugs made an impressive initial onslaught on tumours in animal experiments, but a ring of cancerous tissue around the edge usually survived and went on to rejuvenate the tumour.

Now Minton is combining this technique with the prodrug method. He has engineered a harmless strain of Clostridium to carry an extra loop of DNA that contains the gene for the enzyme that converts the prodrug. Importantly, the bacteria deliver the enzyme to any tumour, he told the Society for General Microbiology's spring meeting in Edinburgh.

One initial fear was that the bacteria might find their way into other low oxygen parts of the body such as the gut. But this did not happen in tests on mice.

Another issue is whether small tumours will have too much oxygen for the bugs to survive. "It is difficult to say how large a tumour will have to be for the technique to work," says team member Philip Burke at Enact Pharma, near Salisbury. But he hopes that planned clinical trials in patients should provide an answer.

James Randerson, Edinburgh

Magnetic crystals in brain linked to Alzheimer's

Tiny magnetic iron crystals in the brain may be linked to the development of Alzheimer's disease, suggests preliminary research.

If further work confirms the hypothesis, it could be possible to diagnose patients with early Alzheimer's disease by measuring the level of iron oxide crystals, called magnetite, in their brains.

Jon Dobson at the University of Keele, UK, and his colleagues examined six brain samples and found that magnetite levels increased with Alzheimer's disease severity, the first time such a link has been shown. "If the data continues to go this way, the implications are quite profound," he told New Scientist.

Dobson says it has been known for 50 years that there is an association between excess iron and Alzheimer's disease, but that scientists had been baffled by the form in which this iron occurs.

"This is a very interesting hypothesis that definitely needs some further research," says Richard Harvey, director of research at the UK Alzheimer's Society. "But the data is from very, very limited samples so you can't draw any conclusions other than to say it's interesting and fits into some of the theories of Alzheimer's."

Dobson's group will now look at iron compounds in more brain samples. They will also examine samples from patients with other neurodegenerative diseases that are also linked to excess iron, such as Parkinson's and Huntingdon's disease. This further work will be part-funded by the UK Alzheimer's Society.

Early detection

The team measured magnetite in brain tissue taken from patients who died from Alzheimer's. They used a technique called SQUID (superconducting quantum interference device) magnetometry, which measures the samples' responses to different magnetic fields.

In the three samples from Alzheimer's patients, increasing levels of the crystal correlated with the increasing severity of the disease in that patient. Two of the three control samples showed no magnetite at all. But the third sample had low levels of magnetite despite the person having had no clinical signs of the Alzheimer's before they died.

When the team looked this person's brain in detail they found changes associated with the devastating disease, such as the formation of plaques. "The nice thing about that was that we were able to pick it up in magnetite measurements before clinical measurements," Dobson says.

Detecting early stage Alzheimer's would be "very beneficial", he says, as patients they could be treated promptly with the new therapies that are now emerging.

Magnetite could cause disease in two ways, says Dobson. It is capable of generating free radicals, which damage cells, particularly in the brain. Also, because the crystal is strongly magnetic, it may interfere with ordinary biochemical reactions within cells, which may also lead to the formation of free radicals.

Harvey says Alzheimer's disease is known to be associated with two proteins: amyloid proteins that cause plaques in the brain, and tau proteins that cause nerve cells to tangle.

"What we don't know is what triggers their production," he told New Scientist, but it is "just plausible" that magnetite will provide the answer.

Journal reference: Biology Letters (DOI: 10.1098/rsbl.2003.0012)

Shaoni Bhattacharya

uman cloning currently 'almost impossible'

A newly discovered quirk of primate cell biology suggests that monkeys - and humans - are nearly impossible to clone with current techniques.

"There's a molecular obstacle that stops the technology from working in primates," says Gerald Schatten, at the University of Pittsburgh School of Medicine in Pennsylvania. "Charlatans who claim they have cloned humans clearly don't understand the biology."

Unlike other mammal species in which adult animals have been successfully cloned, Schatten's team found that the eggs of rhesus monkeys are robbed of a key set of proteins during the cloning procedure. The same appears to be true for human cells.

That loss causes genetic chaos in cloned monkey embryos, with chromosomes distributed almost at random. As a result, the embryos look fine at an early stage, but are completely incapable of further development. The finding severely undermines claims by Clonaid, a company started by a UFO cult, to have created several cloned babies.

"It's an interesting part of the puzzle of why primates have been so difficult to clone," says Robert Lanza of Advanced Cell Technology, a Massachusetts-based biotech company that has cloned human embryos.

"Gallery of horrors"

Schatten's group want to clone monkeys to assist in the study of human diseases. The key technology is called somatic cell nuclear transfer (SCNT), where a cell from the adult animal to be cloned is fused with an egg stripped of its own nuclear DNA.

Other researchers had cloned sheep, cows, mice, goats, pigs, rabbits and a cat, so Schatten was confident monkeys could be cloned too. But despite producing perfect-looking monkey embryos using SCNT, none developed further.

New Scientist reported concerns about cloned monkey embryos in December 2001, when one of Schatten's colleagues described them as a "gallery of horrors".

The new study of 716 rhesus monkey embryos revealed the same chromosomal chaos. Some of the embryo's cells contained double the normal number of chromosomes, others had odd combinations and some had none at all. And Schatten's team have now discovered why.

Lost direction

On a hunch they examined the cells' spindles, structures that guide chromosomes into daughter cells as the embryo divides. The researchers found that SCNT primate embryos lacked at least two proteins required for proper spindle function, leaving the chromosomes to distribute randomly throughout the embryo.

These proteins turn out to be tightly linked to the chromosomes in the monkey's eggs, which are removed in one of the first steps of the nuclear transfer process. Further, unpublished work by Schatten's group and others has shown the same is true for human cells.

In contrast, mice and cows have extra copies of these proteins floating around to help out the cloned embryo. Schatten jokes: "It's almost like God in her wisdom said go ahead and clone cows and sheep, but if you clone a human I'm going to paralyse the egg."

Embryonic cells

The discovery is important, says Lanza, but there may be other important factors. Although attempts to clone a monkey by SCNT using adult cells have all failed, two animals were cloned by embryonic cell nuclear transfer, which Schatten reports also creates the damaging spindle defect.

Furthermore, even trivial differences, such as a slight changes to reagents, can turn success into failure when cloning other species, says Lanza.

Schatten intends to test his spindle idea by using a different cloning technique. He will allow the egg's chromosomes to remain in the embryo until after the donor cell has been fused, so the spindle proteins can migrate to new locations. He already has preliminary evidence that proper spindles then form, suggesting primate cloning could perhaps be feasible.

But he warns against any attempt at human cloning, given the high rate of abortions, neonatal deaths and health problems that in clones. "I hope this natural obstacle affords us time to make responsible and enforceable legislation to prevent anyone attempting human reproductive cloning," he says.

Journal reference: Science (vol 300, p 297)

Philip Cohen

'Irish coffee' injection prevents stroke damage

A caffeine and alcohol cocktail similar to an Irish coffee could prevent severe brain damage in stroke victims, new research has revealed.

The experimental drug, called caffeinol, has the potency of two cups of strong coffee and a small shot of alcohol. When injected into rats within three hours of an artificially stimulated stroke, brain damage was cut by up to 80 per cent.

Neurologist James Grotta and colleagues from the University of Texas-Houston Medical School have also now demonstrated the safety of caffeinol in a small pilot study in patients who suffered ischaemic strokes, when the artery to the brain becomes blocked and cuts off the blood supply.

"Our goal was to see if we could safely achieve the same blood levels of caffeinol that we achieved in our animal studies," Grotta said. "We discovered that we could use even lower doses than we used in the animal studies and still achieve the blood levels that were neuroprotective in animals."

Martin Brown, an expert in stroke medicine at University College London, told New Scientist: "It's a very exciting approach but we will have to wait and see how further clinical trials go. It's encouraging they've managed to produce the same levels in humans." Drugs that work in animals often fail because humans cannot tolerate the required doses.

Working together

The researchers are unclear how caffeinol protects the brain after stroke, but the rat experiments showed that neither caffeine nor alcohol offered protection alone. In fact, alcohol alone actually caused more damage.

Brown says alcohol is known to widen blood vessels, which might help. Caffeine can also act on blood vessel when treating migraines. Brown speculates that the combination might interfere with the harmful biochemical reactions triggered in cells by stroke.

The idea of mixing alcohol and caffeine was "serendipitous", Grotta told HealthScoutNews. Grotta's colleague Roger Strong was aware of the association between moderate use of alcohol and reduced stroke damage, "so we started fooling around with combinations of it with other things."

The team will now assess the effectiveness of the drug in a larger group of patients. Caffeinol will also be combined with a "thermo-cooling" method - which cools the brain of stroke patients to reduce brain damage.

Furthermore, caffeinol can be safely given to patients taking clot-busting drugs to ease the flow of blood to the brain, say the researchers. However, they ruefully note that having a cup of Irish coffee every day to prevent stroke damage will not work.

Journal reference: Stroke (DOI: 10.1161/01.STR.0000068170.80517.B3)

Shaoni Bhattacharya