午夜福利1000集合

THIS was the coldest of cold cases. The remains of 83 people had lain under the earthen floor of a house in Dja鈥檇e el鈥橫ughara, northern Syria, for thousands of years. Who put them there was no mystery: people living in the region during the Stone Age often buried their dead beneath their homes. But the cause of death 鈥� for some at least 鈥� was totally unexpected. When archaeologists carefully examined the bones, they discovered signs that five of these individuals had tuberculosis. They are that we know of.

The discovery is significant. Finding evidence of TB in people who died some 10,000 years ago challenges a long-held idea about the origins of this, the most deadly infectious disease to afflict humanity. It is a key piece in the puzzle that researchers are trying to put together to reveal where and how TB started to sicken humans and how it spread around the world. That isn鈥檛 just academic. We need this information to find new ways to fight TB, which currently kills at least 1.7 million people every year. By looking closely at the Dja鈥檇e el鈥橫ughara remains, and other very cold cases, we might finally be able to stop this indiscriminate killer.

Tuberculosis is caused by the bacterium Mycobacterium tuberculosis, which generally infects the respiratory system and spreads from person to person via airborne droplets. From the 17th century until the 19th century, it caused 20 per cent of all deaths in the Western world. German microbiologist Robert Koch won a Nobel prize for his . A vaccine 鈥� BCG 鈥� was invented a century ago, and is widely used. The disease has been treated with antibiotics and other drugs since the second world war. But BCG is ineffective in large parts of the world and drug resistance is rife. As a result, TB currently infects around a quarter of the world鈥檚 population, especially people living in sub-Saharan Africa, South-East Asia and eastern Europe. Only around 1 in 10 infections end in disease, but given the number of people who have the bacterium, that still means a huge impact on global health.

鈥淏y looking closely at very cold cases, we might finally be able to stop this killer鈥�

鈥淚t kills more than HIV and malaria combined,鈥� says S茅bastien Gagneux at the University of Basel, Switzerland. 鈥淭he risk it poses to humanity cannot be overestimated.鈥� The World 午夜福利1000集合 Organization agrees. It declared TB a global emergency in the early 1990s, and is now committed to developing a . Scientists working to achieve this know that understanding the evolutionary origins of M. tuberculosis will be key to their success.

Biologists long thought they knew where TB came from. The human pathogen is part of a group of closely related bacteria that sicken a range of animals from badgers to seals. One of these, Mycobacterium bovis, found commonly in cattle, can also infect humans. That is why it had been assumed that TB jumped to people from cattle when our ancestors domesticated them, some time after farming took off around 10,000 years ago. Evidence from ancient human remains seemed to support this idea. The oldest known cases of TB in Europe . In ancient Egypt, they date to 6500 years ago. And in China, skeletal remains point to TB being present around 6000 years ago.

However, in 2008, research was published that totally undermined this neat story. John Kappelman at the University of Texas and his colleagues claimed to have found evidence of TB in an ancient hominin, Homo erectus. Diagnosing TB in ancient skeletons and fossils relies upon identifying physical abnormalities such as spinal deformity, rigidity of joints and pitting inside the skull. Kappelman and his team claimed to have found the last of these signs on a partial H. erectus skull unearthed at Kocaba艧 in Turkey, . Some experts . But there is much debate about the reliability of the techniques used to diagnose TB in old bones and, given the extraordinary nature of Kappelman鈥檚 findings, they were mostly met with scepticism.

However, the study of ancient diseases needn鈥檛 rely solely on this sort of evidence. In recent years, advances in genetics mean palaeopathologists can also use ancient and modern DNA to reconstruct the evolution of pathogens. And there is some genetic evidence suggesting that Kappelman may have been on to something. In 2002, a study led by Roland Brosch at the Pasteur Institute in Paris concluded that , suggesting it evolved in humans before cattle domestication. In 2005, the same team published another piece of research that concluded .

Even geneticists can鈥檛 agree, however. Almost a decade later, when Gagneux and his colleagues looked at the entire genomes of 259 strains of M. tuberculosis, this suggested that it . 鈥淒NA analysis is no silver bullet,鈥� says Charlotte Roberts at Durham University, UK, an expert on ancient disease including TB. With all the evidence pointing to the likelihood that TB emerged in humans well before we domesticated animals, researchers were spurred on to look for more evidence in fossils. That is where the Dja鈥檇e el鈥橫ughara remains come in.

鈥淩esearchers now generally agree that we didn鈥檛 originally get TB from cattle鈥�

Dja鈥檇e el鈥橫ughara, a site on the western bank of the Euphrates river, was inhabited by humans for millennia, starting around 11,300 years ago. People practised proto-agriculture there from the beginning, and the site also has the earliest known evidence of domestication of a cow-like animal, , dating from around 10,000 years ago. During three decades of excavation, archaeologists found many bodies there, the biggest haul coming from a compound they dubbed the House of the Dead, which is in fact five houses built and rebuilt over many centuries. So this seemed like the perfect place to test the idea that people were infected with TB before they farmed cattle.

With that in mind, Oussama Baker at EPHE in Paris and his colleagues carefully . They found signs of TB infection in 10, including five of the 83 discovered beneath the House of the Dead, dating to between 8000 and 10,000 years ago. Seven of these people lived during the transition to cattle domestication. However, the most ancient, which include an infant who died around the age of 1, predate domestication. Analysis of ancient DNA confirmed the diagnosis. What鈥檚 more, the team found another skeleton with evidence of TB at a Syrian site called Tell Aswad. The skeleton belonged to a young adult and dates to between 7600 and 8200 years ago, which again precedes cattle domestication there. Other researchers have found physical and genetic evidence of and her infant son who lived in what is now Israel before cattle were domesticated.

The is compelling. Despite some wrangling over the details, researchers now generally agree that we didn鈥檛 get TB from cattle and that the disease has been afflicting our ancestors for far longer than we imagined. One reason we haven鈥檛 seen this clearly in the fossil record is that human remains are scarce. Another is that, until recently, researchers massively overestimated the chances of finding signs of TB in prehistoric remains: clinical studies have shown that only 5 per cent of untreated patients with pulmonary TB develop related skeletal damage, meaning that the absence of evidence has been mistaken for the evidence of absence.

It is now thought that TB originated in early H. erectus in Africa and evolved as our species, Homo sapiens, migrated to colonise the world. Today, it takes the form of seven lineages, each prevalent in a particular geographic location. Analysis by Gagneux and his colleagues points to lineages 1, 5 and 6 being the most ancient, indicating that human TB most likely . New lineages emerged, starting about 67,000 years ago, as the pathogen co-evolved with humans, adapting to different environments around the world (see 鈥淗ow tuberculosis went global鈥�). The microbe got a boost when people started farming, not because of transmission from livestock, but as a result of growth in the size and density of human populations enabled by agriculture.

Deadly diversity

This evolutionary history is what makes TB such a deadly pathogen. We can see this clearly in Asia, where a highly transmissible form of the bacterium is still a huge killer. The combination of palaeo and genetic evidence indicates that lineage 2 appeared in Asia about 40,000 years ago, with an influx of anatomically modern humans, then increased its grip around 10,000 years ago when farming began. In China, the Beijing strain of lineage 2 is particularly problematic. Recent genetic studies show that has driven its increased virulence, and a tendency to mutate might help explain why it has become drug resistant in recent decades.

Globally, M. tuberculosis鈥榮 genetic diversity is what makes TB such a difficult disease to get to grips with. As , the in subtly different environments. That is why the BCG vaccine isn鈥檛 very effective in some places. However, genetic analysis is providing insights into how these mutations influence the transmission and infectivity of different strains 鈥� invaluable information if we are to better combat TB. 鈥淥ur understanding of the genetic evidence will play an important role in the development of a new vaccine by the WHO target of 2035,鈥� says Gagneux.

A deeper appreciation of the true origins of this ancient microbial foe is raising hopes that we can finally turn around a war that we have been losing for even longer than we thought.