Kidney recipients freed from lifelong drugs

People who get a kidney transplant usually face a life sentence of drugs that suppress their immune systems – otherwise, their body will reject the new organ. A new cellular therapy could change that.

Immunosuppressant drugs can have severe side effects, increasing the risk of heart disease, infection, cancer and diabetes. So as well as saving money,dispensing with them would bring major health benefits.

Samuel Strober at Stanford University in California and colleagues seem to have worked out how to do it. Following transplant surgery, Strober's team first give patients ordinary immunosuppressive drugs, such as cyclosporine. They then apply mild radiation to the lymph nodes, spleen and thymus to further weaken the immune system. This kills some but not all of the patient's white blood cells.

They also inject antibodies which temporarily destroy the patient's most aggressive white blood cells. "We preferentially delete 'naive T cells', since they are the main subset of white blood cells that reject grafts," Strober says.

Your body won't like this (Image: Tino Soriano/National Geographic/Getty)

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Spit bacteria could cause of pancreatic cancer

Saliva does more than just break down your lunch. It could be key to screening for pancreatic cancer too.

The notoriously aggressive cancer has received a lot of publicity in recent years with the deaths of Patrick Swayze and Steve Jobs, both of whom suffered from the disease.

Now, researchers have found that looking for certain bacteria in the mouth could lead to earlier diagnoses and save lives.

A team led by James Farrell of the University of California, Los Angeles, compared the bacteria in the mouths of 10 healthy people with those in 10 people with pancreatic cancer. They found significant differences in the microbe populations in each group.

These changes could be used to trigger a check for pancreatic cancer. "It's the canary in the coal mine, an early-warning signal," says Bruce Paster at the Forsythe Institute in Cambridge, Massachusetts, who worked with Farrell to identify the bacteria in the samples. "If you have a disease [such as cancer], it's not usually just restricted to the pancreas or the intestine. Your whole body is affected – things change," he says.

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Sickle cell disease cured by gene knock-out

Switching off a single gene can help treat sickle cell disease by keeping the blood forever young. The illness is caused by a mutant form of adult haemoglobin, but not by fetal haemoglobin. Targeting BCL11A, the gene responsible for the body's switch-over from fetal to adult haemoglobin, effectively eliminates the condition in mice.

The mutant form of adult haemoglobin forms long sticky chains inside red blood cells. The cells containing these chains can clog small blood vessels, depriving organs of oxygen and causing pain. In severe cases, sickle cell disease can be fatal. Tricking the body into make fetal haemoglobin again can alleviate symptoms, though.

That's because fetal haemoglobin does not form sticky chains. However, it is produced in the body only during development in the womb and in the six months following birth. It has a higher affinity for oxygen than adult haemoglobin, vital in allowing the developing fetus to "steal" oxygen from its mother's blood.

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Five easy mutations to make bird flu a lethal pandemic

Editorial: "The risk of an influenza pandemic is fact, not fiction"

H5N1 bird flu can kill humans, but has not gone pandemic because it cannot spread easily among us. That might change: five mutations in just two genes have allowed the virus to spread between mammals in the lab. What's more, the virus is just as lethal despite the mutations.

"The virus is transmitted as efficiently as seasonal flu," says Ron Fouchier of the Erasmus Medical Centre in Rotterdam, the Netherlands, who reported the work at a scientific meeting on flu last week in Malta.

"This shows clearly that H5 can change in a way that allows transmission and still cause severe disease in humans. It's scary," says Peter Doherty, a 1996 Nobel prizewinner for work in viral immunology.

H5N1 evolved in poultry in east Asia and has spread across Eurasia since 2004. In that time 565 people are known to have caught it; 331 died. No strain that spreads readily among mammals has emerged in that time, despite millions of infected birds, and infections in people, cats and pigs. Efforts to create such a virus in the lab have failed, and some virologists think H5N1 simply cannot do it.

The work by Fouchier's team suggests otherwise. They first gave H5N1 three mutations known to adapt bird flu to mammals. This version of the virus killed ferrets, which react to flu viruses in a similar way to humans. The virus did not transmit between them, though.

A short journey from hens to humans (Image: Sonny Tumbelaka/AFP/Getty Images)

Then the researchers gave the virus from the sick ferrets to more ferrets - a standard technique for making pathogens adapt to an animal. They repeated this 10 times, using stringent containment. The tenth round of ferrets shed an H5N1 strain that spread to ferrets in separate cages - and killed them.

The process yielded viruses with many new mutations, but two were in all of them. Those plus the three added deliberately "suggest that as few as five are required to make the virus airborne", says Fouchier. He will now test H5N1 made with only those five.

All the mutations have been seen separately in H5N1 from birds. "If they occur separately, they can occur together," says Fouchier. Malik Peiris of the University of Hong Kong, a flu virologist, says this means H5N1 transmissible between humans can evolve in birds, where it is circulating already, without needing to spend time in mammals such as pigs.

Peter Palese, a flu specialist at Mount Sinai Medical Center in New York City who has expressed doubts that H5N1 can adapt to mammals, is not convinced.

"Ferrets are not humans," he says. "H5N1 has been around for a long time" and failed to mutate into a form that can jump between people.

"That it has not adapted doesn't mean it cannot," replies Jeffery Taubenberger of the US National Institutes of Health in Bethesda, Maryland, who studies how a bird flu became the deadly pandemic of 1918.

"It simply means that so far it has not - luckily for us."

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Resurrected ancient protein is a potent antibiotic

How clean is my pouch? (Image: Tom Brakefield/Getty)

IF MODERN medicine cannot provide an answer to multidrug-resistant microbes, perhaps ancient animals can. Biologists have resurrected a mammalian antimicrobial compound that was last seen on Earth 59 million years ago when mammals were recovering from the Cretaceous-Tertiary extinction that wiped out the dinosaurs. Even now it is potent enough to destroy some of our most troublesome pathogens.

Last year the Infectious Diseases Society of America launched an initiative with the aim of producing 10 antibiotics to tackle multidrug-resistant bugs by 2020. The lower reaches of the tree of life are being explored for those antibiotics, says Ben Cocks of La Trobe University in Bundoora, Australia.

Already, promising molecules have been found in the tissues of primitive fish called lampreys (Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.1108558108).

Such an approach is effective because these molecules are so simple, says Cocks. Conventional antibiotics target precise flaws in a pathogen's armour, such as a particular enzyme. This is similar to how the adaptive immune system found in vertebrates works: it learns how to fight a new pathogen and then remembers the lesson for future battles. The trouble is that the pathogens patch their armour, requiring the immune system - and drug companies - to identify new weaknesses.

Cocks says this evolutionary arms race can be side-stepped by falling back on the cruder innate immune system that is found in all plants and animals - and which has largely been ignored in our fight with multidrug-resistant pathogens.

The molecules of the innate immune system use simple chemistry to target the lipids in cell membranes. They can either disrupt and weaken bacterial membranes, or subtly alter the properties of the host's healthy cells so that pathogens can no longer attack them.

But there's a problem: animals with the strongest innate immune systems tend to be so distantly related to humans that molecules taken from them can have toxic effects in humans. Cocks's solution is to study the mammals with the best innate immune systems, the molecules of which are more likely to be compatible with humans. His work has taken him inside the wallaby's pouch.

As marsupials, wallabies give birth to young at a much earlier stage in their development than placental mammals. For example, the tammar wallaby,Macropus eugenii, is born after 26 days, equivalent to a 6-week-old human fetus. The tiny wallabies then crawl into their mother's pouch to grow larger.

"It's not a clean environment," says Cocks. Bacteria closely related to the superbugs affecting humans in hospitals have been found in the wallaby pouch. But the baby wallabies are so underdeveloped that they lack an adaptive immune system to fight them; their survival depends on their innate immune system.

Cocks's team scoured the wallaby genome and found genes that code for 14 cathelicidin peptides, a component of the innate immune system. Lab tests revealed that many of the peptides could kill a range of multidrug-resistant pathogens - without damaging human cells.

The team noticed that genes in five of the cathelicidins were remarkably similar and probably evolved from a single ancestor. "We thought that the ancestral form would have a special broad-range activity," says Cocks.

Using the changes within the five peptides, Cocks and his collaborators at the University of Sydney, Australia, worked backwards to predict the genetic sequence that codes for the original peptide. His team then used it to produce a synthetic version of the peptide, effectively resurrecting it.

"The amazing thing was that it worked well against a broad range of pathogens," he says. Lab tests showed it destroyed six of seven multidrug-resistant bacteria, and was 10 to 30 times more potent than modern antibiotics such as tetracycline (PLoS One, DOI: 10.1371/journal.pone.0024030).

"This is really significant," Cocks says. "Now we have access to ancient peptides for future drug development."

Damian Dowling at Monash University in Melbourne, Australia, says some ancient and extinct peptides might be more effective than those found in living creatures because bacteria haven't been exposed to them for millions of years. "Even if the bacteria once developed resistance against the peptide, it has probably lost it," he says.

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Glowing transgenic cats could boost AIDS research

Three cats genetically modified to resist feline immunodeficiency virus (FIV) have opened up new avenues for AIDS research.

Green glow the cats

The research could also help veterinarians combat the virus, which kills millions of feral cats each year and also infects big cats, including lions.

Prosaically named TgCat1, TgCat2 and TgCat3, the GM cats – now a year old – glow ghostly green under ultraviolet light because they have been given thegreen fluorescent protein (GFP) gene originating from jellyfish.

The GM cats also carry an extra monkey gene, called TRIMCyp, which protects rhesus macaques from infection by feline immunodeficiency virus or FIV – responsible for cat AIDS.

By giving the gene to the cats, the team hopes to offer the animals protection from FIV. Their study could help researchers develop and test similar approaches to protecting humans from infection with HIV.

Cat immunity

Already, the researchers have demonstrated that lab cultures of white blood cells from the cats are protected from FIV, and they hope to give the virus to the cats to check whether they are immune to it.

"The animals clearly have the protective gene expressed in all their tissues including the lymph nodes, thymus and spleen," says Eric Poeschla of the Mayo Clinic College of Medicine in Rochester, Minnesota, who led the research. "That's crucial because that's where the disease really happens, and where you see destruction of T-cells targeted by HIV in humans."

The animals are not the first GM cats, but the new method is far more efficient and versatile than previous techniques. The first cloned cat, born in 2001, was the only one to survive from 200 embryos, each created by taking an ear cell from cats, removing the nucleus and fusing it with a cat egg cell emptied of its own nucleus.

Poeschla's technique is far more direct, far more efficient and far simpler, and has already been used successfully to make GM mice, pigs, cows and monkeys. He loads genes of interest into a lentivirus, which he then introduces directly into a cat oocyte, or egg cell. The oocyte loaded with the new genes is then fertilised and placed in the womb of a foster mother.

From 22 implantations, Poeschla achieved 12 fetuses in five pregnancies, and three live births. And out of the 12 fetuses, 11 successfully incorporated the new genes, demonstrating how efficient the method is.

One surviving male kitten, TgCat1, has already mated with three normal females, siring eight healthy kittens that all carry the implanted genes as well, showing that they are inheritable.

But there are doubts about whether cats will replace monkeys as the staples of HIV research. "It's fantastic they've created GM cats," says Theodora Hatziioannou of the Aaron Diamond AIDS Research Center in New York City.

"But what makes research in monkeys so much better is that SIV in monkeys is much more closely related to HIV, so it's more straightforward to draw conclusions than it would be with FIV.

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Internet databases reveal new uses for old drugs

IT IS a disarmingly simple idea: to find out if a drug might treat a disease it wasn't intended for, check out whether it has an opposite effect on gene activity to the illness itself. How do you find such drugs? By mining large public biological datasets.

For more than a decade, so-called DNA chips have routinely measured the activity of thousands of genes at a time, and researchers have deposited the results online into the Gene Expression Omnibus (GEO), after their papers were published.

Atul Butte, a bioinformatician at Stanford University in California and colleagues reasoned that it should be possible to find new drug uses by combining data from GEO with information gleaned from another database - the Connectivity Map. In this database, biologists at the Broad Institute in Cambridge, Massachusetts, have documented how patterns of gene activity in human cells change when they are exposed to a range of drugs.

Butte's team mashed up the two datasets according to a simple hypothesis: drugs that have an opposite effect on gene activity to a particular disease could be good candidates for treating the condition. So the researchers devised algorithms to look for drugs that ramp up the activity of genes that are unusually quiet in tissues affected by a particular disease, and suppress those that are hyperactive in that disease.

Butte admits that colleagues doubted the GEO data would be good enough to provide valuable insights. "When people see something that is free and on the internet, they think it must have no value," he says.

But Butte's team proved the sceptics wrong by taking two of the strongest leads and showing in animal experiments that the drugs could treat the conditions with which they were paired. In one case, the epilepsy drugtopiramate helped rats with inflammatory bowel disease (Science Translational Medicine, DOI: 10.1126/scitranslmed.3002648); in the second,cimetidine, used to treat stomach ulcers and acid reflux, reduced tumour growth in mice implanted with human lung cancer cells(Science Translational Medicine, DOI: 10.1126/scitranslmed.3001318).

"This shows that simple, elegant ideas really can come through," saysNicholas Tatonetti, also at Stanford, who has used data mining to find combinations of drugs with dangerous side effects (New Scientist, 4 June, p 16). "Researchers will be saying to themselves, 'Why didn't I think of that?'"

One snag is that patents on the two drugs have expired, so firms won't have the financial incentive to run clinical trials to find out if the new uses are viable. But the same approach could also highlight multiple uses for drugs still in development.

"This is a technique that's very promising," says Pankaj Agarwal, director of computational biology at GlaxoSmithKline in King of Prussia, Pennsylvania.

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Introduction: HIV and AIDS

AIDS has now surpassed the Black Death on its course to become the worst pandemic in human history. At the end of 2004, 20 million people had been killed by it, and twice that number are currently infected with HIV. Barring amedical breakthrough, it could claim the lives of some 60 million people by 2015. AIDS exerts a terrible toll on societies, crippling their economies, decimating their labour forces and orphaning their children.

An AIDS patient in hospital (Image: Burger/Phanie/Rex Features

Nine out of 10 people living with HIV are in the developing world; 60 to 70% of those are in Sub-Saharan Africa. But the disease is spreading in every region, with fierce epidemics threatening to tear through countries such as India,China, Russia and the islands of the Caribbean. The statistics are sobering - in some Southern African towns 44% of pregnant women are HIV positive, in Botswana 37% of people carry the virus.

Immune assassin

The human immunodeficiency virus (HIV) is a retrovirus - a virus built of RNA instead of more typical DNA. It attacks the very cells of the immune system that should be protecting the body against it - T lymphocytes and other white blood cells with CD4 receptors on their surfaces. The virus uses the CD4 receptor to bind with and thereby enter the lymphocyte. HIV then integrates itself into the cell's own DNA, turning the cell into a virus-generating factory. The new viruses break free, destroying the cell, then move on to attack other lymphocytes.

HIV kills by slowly destroying the immune system. Several weeks after initial infection, flu-like symptoms are experienced. Then the immune system kicks-in, and the virus mostly retreats into hiding within lymph tissues. The untreated, infected individual usually remains healthy for 5 to 15, years, but the virus continues to replicate in the background, slowly obliterating the immune system.

Eventually the body is unable to defend itself and succumbs to overwhelmingopportunistic infections that rarely affect healthy people. Acquired Immune Deficiency Syndrome (AIDS) is the name given to this final stage of HIV infection, and is characterised by multiple, life-threatening illnesses such asweight loss, chronic diarrhoea, rare cancers, pneumonia, fungal conditionsand infections of the brain and eye. Tuberculosis has become especially prevalent in AIDS victims.

Natural born killer

Genetic analyses hint that ancestral primate HIV may have been born a million years ago when a chimpanzee virus hybridised with a related monkey variety. However researchers believe it was not until the 1930s that thisjumped to humans eating chimp meat in Central Africa. That variety becameHIV-1 - the most widespread type. A second type, HIV-2, restricted to West Africa, was probably contracted in the 1960s from monkey meat.

Another theory was that the AIDS pandemic was accidentally started by doctors testing a polio vaccine in the 1950s - detailed in Edward Hooper's book The River - but this has been severely criticised by other researchers.

AIDS must have been circulating in the US and Africa during the 1970s. But it was not recognised until 1981 when young gay men and injecting drug users, in New York and California, started to be diagnosed with both an unusual skin cancer called Kaposi's sarcoma, and lethal pneumonias. By the end of that year 121 people in the US had died - that number would rise to 17,000 over the next six years.

Government scientists predicted that the mysterious immune-debilitating illness was due to an infectious agent. In 1984 that agent was identified as HIV by Luc Montagnier of the Pasteur Institute in Paris, France, and Robert Gallo of the National Cancer Institute in Washington DC, US.

Soon after the appearance of AIDS in the US, the disease was detected in Europe too and epidemics affecting heterosexual men and women sprang up at an alarming rate in Sub-Saharan Africa. Today one in five people in that region are living with the virus. AIDS epidemics also threaten to devastate the world's most populous nations - India and China - and other Asian nations, if action is not taken to bring them under control.

Defensive measures

HIV is found in body fluids such as: blood, semen, vaginal fluids and breast milk. It can be passed on through penetrative sex, oral sex and sharing contaminated needles when injecting street drugs or in hospitals. It can also be transmitted from a mother to her baby during pregnancy, childbirth orbreastfeeding - though many children escape infection. HIV cannot be passed on through kissing, coughing, mosquito bites or touching.

Health authorities are focusing on prevention as a key method to limit the spread of the epidemic. Educational programs preach abstinence from sex, monogamy and safer sex using condoms, as ways to protect against infection. Many countries give away free condoms and offer needle exchange programs to try and limit transmission among injecting drug users.Microbicides in the form of creams that prevent transmission of HIV may soon offer another method of protection.

A vaccine, as an alternative method to prevent HIV infection, may still bemany years away. This is partly because the virus mutates so rapidly. A vaccine may not only have to prime antibodies to attack the virus (the way most vaccines work) but might also need to increase T-cell production. Vaccine trials have been undertaken in South Africa, Kenya, the US andThailand - though most have yet to yield promising results. Controversial vaccines made from the blood of HIV carriers, have been tested in Nigeria andThailand.

Anti-retroviral cocktails

There is no cure for AIDS, but a range of drugs - some of which haveunpleasant side-effects - are available to slow its progress. Other drugs are used to treat opportunistic infections or AIDS symptoms. Even some herbal treatments have been investigated.

Most anti-HIV drugs aim at stalling viral replication. Nucleoside analoguessuch as AZT (zidovudine) and also non-nucleoside reverse transcriptase inhibitors (NNRTIs), attack the action of the viral enzyme reverse transcriptase. This prevents it from creating functional DNA which would otherwise integrate into the DNA of infected cells.

A third class block protease, an enzyme essential for generating functional virus particles. Protease inhibitors are the most effective of the three types of drugs, and AIDS mortality fell dramatically in the US when they were first licensed during the late 1990s. Fusion inhibitors are a newer type of drug that work by stopping HIV from binding with CD4 receptors that it uses to enter cells. Drugs that block another enzyme, integrase, are also under development.

AIDS drugs are often administered in combination cocktails cocktails of three or more kinds simultaneously, as this helps slow the rate at which HIV develops resistance to drugs. But the virus is able to evolve rapidly and can eventually outpace the drugs if treatment regimens are not followed rigorously.

Though drugs are widely available in western countries, their expense means they are unavailable to the vast majority of AIDS sufferers. International bodiesare working towards widening access to treatment in the developing world. Some companies in countries such as India and Thailand are now producingcheap generic copies of drugs.

Staggering toll

The economic and social burden of AIDS exerts a great toll on developing nations in addition to that exerted by mortality itself. AIDS is hindering development and leading to negative population growth in some of the most seriously affected nations, such as Botswana.

This excessive AIDS mortality is causing a great demographic shift, wiping out young adults in the prime of their lives. This leaves children orphaned, and is destroying workforces and economies. Some predict that 50 million children in Sub-Saharan Africa will have been orphaned by 2010. The labour forces of 38 AIDS ravaged countries will be up to 35% smaller by 2020, because of AIDS.

The effect of AIDS on agricultural communities in Southern Africa is even leading to food shortages. Social stigma and discrimination is yet another problem for many AIDS sufferers, especially in Asian nations.

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