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30 August 2007; | doi:10.1038/news070827-5 / http://www.nature.com/news/2007/070827/full/070827-5.html

Smoking stays in your genes after you quit

Cigarette habit may leave a molecular mark.

Heidi Ledford

Gene expression changes brought on by heavy smoking may persist long after the smoker has kicked the habit, researchers have found. The results could provide a molecular explanation for the continued increased risk of lung cancer and other pulmonary ailments among former smokers.

When smokers quit, their bodies gradually begin to undo the damage cigarettes have wrought. But contrary to popular belief, not all of the body's systems make a full recovery. Although the risk of heart disease, for example, eventually returns to that of a nonsmoker, the risk of getting lung cancer and emphysema - a progressive lung condition that leaves sufferers struggling for breath - remains elevated even if the patient hasn't smoked a cigarette in decades.

"You are reducing the risk of disease by quitting," says Raj Chari, a cancer biologist at the British Columbia Cancer Research Centre in Vancouver, Canada, "but it isn't going back to zero."

Chari and his co-workers assayed gene expression levels in tissue scraped from the airways of four nonsmokers (who had never smoked), eight current smokers, and twelve former smokers who had gone without a cigarette for at least 1 year, and up to 32 years.

They found that some genes with altered expression in smokers had returned to normal levels in former smokers. But the expression of another 124 genes had not returned to normal. The results are published today in BMC Genomics¹.

Breathe uneasy

The proteins produced by several of these genes are associated with lung diseases. For example, several genes related to the cell cycle were expressed at lower levels in both former and current smokers. This is consistent with the reduced rates of cell division in the airways of patients with chronic bronchitis or emphysema.

Similarly, several genes that encode proteins involved in DNA repair were also expressed at lower levels in former and current smokers.

Illness could be another explanation for the altered gene expression. The former smokers in the study were all heavy users who smoked at least a pack of cigarettes a day for 30 years or more, and all of them also showed signs of chronic bronchitis or emphysema. But Chari and his co-workers found that the gene expression patterns did not correlate with the severity of lung disease, which suggests that something else was to blame.


Another, as yet unpublished, study by Avrum Spira, a pulmonary specialist at Boston University, Massachusetts, supports the notion that smoking itself induces the long-lasting genetic changes. Spira says he has also found gene expression differences in a study using healthy former smokers.

"Cells in the airway appear to have changes at a molecular level that persist many years after quitting," says Spira, commenting on Chari's work. Such studies are important starting points, Spira says, but do not themselves establish a cause-and-effect relationship between altered gene expression and lung disease. To better address this question, Spira is preparing to launch a study that will track gene expression changes and disease rates in individual smokers before and after they kick the habit.

Reference : Chari , R., et al. BMC Genomics 8 , 297 (2007).

31 August 2007 | doi:10.1038/news070827-6 / http://www.nature.com/news/2007/070827/full/070827-6.html

Bacterial genome found within a fly's

DNA transfer from bacteria to animals is more common than thought.

Ewen Callaway

Wolbachia bacteria (yellow) within the developing egg of a fruit fly (red). Science

Researchers have found a surprise hidden in the DNA of a fruitfly: what seems to be the entire genome of a parasitic bacterium called Wolbachia. Smaller bits of the promiscuous parasite's genetic material turned up in worms and wasps, too.

The size of the Wolbachia insertion in the fruitfly Drosophila ananassae - more than 1 million base pairs - has caught researchers by surprise. If bacterial DNA is so common in other creatures, they caution, researchers should be careful not to mistake it for contamination and accidentally throw it away when doing genome sequencing.

It has long been known that organisms can sop up foreign genes, the most usual example being bacteria swapping DNA with each other. DNA from mitochondria and chloroplasts - cell structures thought to have evolved from specialized bacteria - have also made their way into the genomes of multicellular eukaryotes (a category including plants and animals). And a worm parasite of plants has been found to contain a gene from nitrogen-fixing soil bacteria. But transfer of bacterial genes into animals has been thought rare.

The new work, published today in Science¹, suggests that gene flow from bacteria to animal hosts happens on a larger scale and more commonly than suspected.

The discovery also hints that the bacterial genome must have provided some sort of evolutionary advantage to its host. "You're talking about a significant portion of its DNA that is now from Wolbachia," says Julie Dunning Hotopp, a geneticist at the J. Craig Venter Institute in Rockville, Maryland, who led the study. "There has to be some sort of selection to carry around that much extra DNA."

Genome within a genome

One-fifth to three-quarters of all insect species are plagued by Wolbachia, which lives inside testes and ovaries and passes from one female generation to another through infected ova. To ensure its spread, Wolbachia can skew birth ratios towards females and even prevent infected males from successfully mating with disease-free females.

The bacterium's close association with egg cells means there's ample chance for bacterial DNA to get permanently sewn into a host's nuclear genome, says Dunning Hotopp, whose team expected to find just small stretches of parasite DNA in fruitflies. A Japanese team previously found a single Wolbachia gene in the adzuki bean beetle², and Dunning Hotopp and her colleagues expected to find much the same.

Instead, they found that the tropical fruitfly has sucked up the genome practically whole. The team looked at D. ananassae free of Wolbachia infection, and checked for 45 genes selected from across the bacterial genome. They found 44 of them. Because these test genes are so widely spread throughout Wolbachia DNA, this suggests that the rest of its genome is likely in fruitflies too.

Many of the Wolbachia genes were infiltrated by strands of insect DNA that jump around the genome, and so are unlikely to be functional. But at least 28 of the bacterium's 1206 genes are active in the flies, the researchers showed. They don't yet know whether these genes are producing proteins or what effect they might have. "It could be quite profound," says John Werren, a biologist at the University of Rochester, New York, and part of the team. If the genes weren't doing anything, he says, they would have been dropped or mutated away.

There's no telling when the insertion occurred, but because the sequences are unique to D. ananassae, it probably happened after the species split from other fruitflies.

The team found much shorter stretches of the Wolbachia genome in other insects, including several species of nematode worms, wasps and a mosquito - suggesting that this kind of DNA transfer is quite common.

Not trash

The work brings a note of caution for anyone doing genome sequencing, says Ulfar Bergthorsson, a geneticist at the University of New Mexico in Albuquerque.


Traditionally, when genomes are sequenced, computer programs toss out any bacterial genes from the final code, assuming that it is simple contamination. But the existence of wide-spread gene flow from bacteria to insects suggests that sequencers should be more careful, says Bergthorsson. "It's unwarranted to exclude bacteria-like genomes from sequences."

As yet more organisms get their DNA decoded, researchers are certain to find more genes that have seeped from bacteria into animals, says Werren, particularly in reptiles and amphibians. Finding bacterial genes in mammals, however, is unlikely, because no bacteria are known to infect their sperm and egg cells.

References

1. Dunning Hotopp, J. C., et al. Science doi:10.1126/science.1142490 (2007).
2. Kondo, N., et al. Proc. Nat. Acad. Sci. 99 14280-14285 (2002).

31 August 2007; | doi:10.1038/news070827-7 / http://www.nature.com/news/2007/070827/full/070827-7.html;jsessionid=975CB0711FA6E8D7AF3128E19286E01C

HIV drug tackles cancer cells

Tumour growth blocked by anti-HIV agent.

Mary Muers

Drugs designed to attack a range of other diseases could now be trained on cancer cells. Getty

A type of drug commonly used to treat HIV can slow the growth of cancer cells, researchers have found. The discovery raises hopes that drugs developed to fight one killer disease could help tackle another.

The HIV drug nelfinavir is now going through its first trial in patients with a range of cancers, in light of the new evidence. Cancer scientists think that by 'repositioning' drugs already approved as HIV therapies, they could help to save lives by reducing the 15-year wait and estimated US$1 billion for getting a cancer drug from lab to clinic.

Phillip Dennis and his co-workers at the US National Cancer Institute in Bethesda, Maryland, began testing HIV drugs on cancer cells after noticing that the toxic effects the virus has on cells are similar to the changes seen in cancerous cells. The quest for new ways to treat cancer has previously led to painkillers and morning-sickness treatments being enlisted to fight the disease.

Double dipping

Dennis's team tried adding six approved HIV drugs to a wide variety of cancer cell types grown in the lab. Three of the drugs significantly slowed the growth of the tumour cells and increased cell death, the researchers report in the journal Clinical Cancer Research¹. The most effective of the three, nelfinavir, which impedes the activity of protein-degrading enzymes in the cell, also blocked tumour growth in mice injected with cancer cells.

The effect is not particularly surprising, says Ian Hampson from the University of Manchester, UK, who has previously found that a different HIV drug, lopinavir, has potential for stopping cervical cancer. "Cancers have many parallels to viral infection," he says.

Hampson suggests that viruses such as HIV defend themselves against the immune system by switching on the host cell's garbage disposal unit - called the proteasome - so that protective immune proteins are destroyed before they can fight the virus. Cancer-causing mutations can also activate the proteasome, so drugs that block protein breakdown, such as nelfinavir, could theoretically halt both diseases.

Nelfinavir is now in preliminary clinical trials, which should reveal the dose that can be tolerated by patients with cancer, and how it affects solid tumours in the body.

The idea of moving drugs between branches of medicine is gaining ground - HIV drugs are being tested against the SARS virus, and the anti-malarial drug chloroquine is being explored as a potential cancer therapy. Dennis says that "the concept of screening all drugs for anti-cancer properties has potential", and he hopes that a plan to test every drug approved by the US Food and Drug Administration on tumour cells will go ahead

Reference : Gills, J. et al. Clin. Cancer Res. 13, 5183-5194 (2007).