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The Evolution of Tuberculosis


Sharon Levy

Genetic analysis offers new insight on the spread of an ancient disease.

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I n the 1880s, tuberculosis (TB) swept
through the Plains Indian commu-
nities of western Canada, killing two
children for every child born. The
seeds of this devastating epidemic had
been planted more than a century ear-
lier, when French-Canadian fur trad-
ers paddled through the region, living
among the native people and spread-
ing Mycobacterium tuberculosis, the
disease-causing bacterium. The infec-
tion smoldered among the indigenous
people, like an unseen fire burning
under the earth. An epidemic did not
flare up until decades later, when a new
wave of European settlers destroyed
the bison herds that had sustained the
Sioux, the Cree, and the Salteaux. The
tribes were then confined to reserves,
where they lived in windowless huts, The Inuit people of the Nunavut Territory are among those in modern Canada
slowly starving. Hunger weakens the who are threatened by the spread of tuberculosis. Photograph: Ansgar Walk
immune system, and crowded, unven-
tilated housing speeds the spread of strains of the disease are rapidly evolv- Canada by Europeans. Tribes in the
TB. Canada’s native people suffered a ing. The World Health Organization region were devastated by the disease
perfect storm of the disease. estimates that a third of the people in the late 1800s, when thousands
Caitlin Pepperell, an infectious on Earth are infected with TB. Three of white settlers were moving west,
disease specialist at the University of million people die from the disease and the government was forcing the
Wisconsin–Madison, has combined each year. tribes off their traditional lands. At
historical documents with genetic Today, the great majority of TB first glance, it seemed obvious that
studies of modern TB bacteria to open infections strike in sub-Saharan Africa, the native people caught TB from
a window into the evolution of this India, and China. The disease is rare ­members of this wave of European
ancient illness. Her study represents in  most of Canada, but it remains a migration. It took a detailed genetic
the first time scientists have been able serious problem in some indigenous analysis of the bacteria infecting widely
to track the spread of TB from one communities. For 7  years, ­Pepperell scattered groups of modern Canadians
human population to another. Under- has worked with native people in to reveal the true story.
standing the bacterium’s adaptations ­western Canada, charting the wax and Pepperell’s insight into the long,
to life in its human hosts is the key to wane of TB epidemics and seeking slow burn of TB came about by coin-
finding new ways to control its spread. the ­original source of the infection. cidence. A colleague sent her a pic-
That mission is vital: TB killed more Genetic analyses of the TB strains ture of some DNA fingerprints from
people in 2009 than in any previous afflicting the tribes showed that the M. tuberculosis that had infected native
year in history. Antibiotic-resistant bacterium was ­carried to western people in Ontario, in eastern Canada.

BioScience 62: 625–629. © 2012 Levy. ISSN 0006-3568, electronic ISSN 1525-3244. All rights reserved. doi:10.1525/bio.2012.62.7.3

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“I recognized the strain family of the people lived in small, scattered groups, Those bands that had signed treaties
bacterium, but it came from a separate so that the density of human hosts with the Dominion of Canada were
group of people, hundreds of miles was low. The germ would coexist with hard hit, because the government in
away,” Pepperell explains. “The only its host for decades, only flaring into Ottawa chose to withhold food rations
link I could think of was the fur trade.” active disease when the person was in order to force the native people onto
Luckily, her counterparts in eastern weakened by hunger or old age. People reserves and to keep them there.
Canada had also studied TB among carrying TB survived to have chil- The Standing Buffalo band of
French Canadians living in Quebec dren and to pass  the disease along to Dakota Indians had fled from perse-
and had found the defining character- them. Genetic analyses of TB bacte- cution in Minnesota and taken refuge
istics of the strain they carried. ria worldwide suggest that the disease in Manitoba. They lived near the Cree
In the early 1700s, French-Canadian evolved tens of thousands of years ago and Salteaux, who were wasted by hun-

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traders began to move west into unex- among our ancestors in Africa and ger and sickness, but because of their
plored parts of present-day Canada. spread through the world as human refugee status, they had never signed
They bought furs from native people populations expanded. When hunter– a treaty and so avoided the deadly
and lived among them. The number gatherer peoples were well fed and attentions of the government. They
of indigenous people who had close otherwise in good health, few of them grew crops of their own and worked
contact with the fur traders was rela- would have had their lives cut short for white settlers. Because they were
tively small, and few French Canadians by the M.  tuberculosis hitching a ride able to feed themselves, the Dakota
joined in the permanent settlement of inside them. remained healthy while neighboring
the west during the late 1800s. Still, the The pattern of TB outbreaks among tribes were ravaged by TB.
traders left lasting marks in the west: indigenous people in late-nineteenth-
the Métis society (people with both century Canada is revealing. By 1879, The TB bacterium is older than
indigenous and European ancestry the bison were nearly extinct, and most was once believed
and culture) and a long-lasting legacy of Saskatchewan’s tribes were starving. TB has plagued crowded human
of disease. Pepperell and her colleagues Weakened by hunger, many groups settlements for as long as they have
genotyped the M. tuberculosis bacteria suffered full-blown epidemics of TB. existed. Hippocrates described the dis-
infecting indigenous patients scattered ease among his patients in ancient
across Canada, using samples collected Greece. TB can leave lesions on
in the 1990s and 2000s. Native people bone, and archaeologists have spec-
across the continent—from Alberta, ulated that scarred skeletons found
Saskatchewan, and Ontario—all car- at sites scattered   throughout Europe
ried the same strain as French Canadi- and Asia were evidence of the bac-
ans living in Quebec, the descendants terium’s long relationship with peo-
of the long-gone fur traders. ple. Then, in the 1990s, researchers
Although one-third of the global extracted M. ­tuberculosis DNA from
human population is infected with lesions on ancient human bones—up
M. tuberculosis, 9 out of 10 people have to 1400 years old—found in Europe
a natural resistance and do not get sick. and Borneo. Soon after that, the same
Only 1 in 10 will succumb to active TB; process was used to identify TB infec-
of these, half will die without treatment. tion in the lungs and lymph nodes
This high proportion of latent infections of a 1000-year-old Peruvian mummy,
implies a long coevolution between the making it clear that the disease had
bacterium and its human hosts. So does reached the New World long before
the life history of M. tuberculosis. Many European colonists did.
other species of mycobacteria flourish Until recently, most scientists
in soils, but TB germs thrive only inside believed that TB first infected humans
human bodies. around 10,000 years ago, when people
Pepperell notes that TB can lie low began to live in permanent villages,
inside a person for decades. An 80-year- ­surrounded by the first domesti-
old man suffering from active TB may A poster from the Works Progress cated livestock. M. tuberculosis is one
have been infected as a child and may Administration (WPA) created member of a closely related group
have come down with the disease only between 1936 and 1941 urges the public of bacteria that causes disease in
as his immune system weakened with to prevent tuberculosis by having good humans and other species, known as
age. Many researchers believe that this sleeping habits, eating well, and getting the M. ­Tuberculosis complex (MTBC).
pattern demonstrates one of the ways exposure to sunlight. Photograph: WPA Mycobacterium bovis, the bacterium
M. tuberculosis survived when early Federal Art Project, District 4. that causes TB in cattle, can jump the

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species barrier and infect people— these sequences may have created The genetics of the MTBC reflects more
most often when they drink tainted strains more successful at infecting recent human migrations, too. The
milk. But an array of new research sug- people. The presence or absence of ­Beijing strain of TB, native to East Asia,
gests that TB found its niche among these sequences shows the position of is now found in South Africa, because
humans long before cattle were tamed. a bacterial strain in the line of descent Asian workers were brought there to
On the basis of genetic studies of from the earliest form of the disease. labor in South African gold mines.
TB strains infecting modern people Dramatic confirmation of the
and other animals scattered around ancient origins of TB came in 2008, TB outwits natural selection
the globe, M. bovis appears to have when Israel Hershkovitz of Tel Aviv This map of the shared history of
descended from the human-adapted University and his colleagues extracted humans and TB germs is based on
M. tuberculosis, rather than the other M. tuberculosis DNA from the bones of genetic deletions, yet the MTBC pos-

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way round. Along the way, M. bovis a mother and baby, buried 9000 years sesses little genetic diversity compared
shed some genetic sequences that ago. The skeletons were among many with many other kinds of infectious
existed in the progenitor strain that found at Atlit-Yam, a prehistoric vil- bacteria. The human immune response
gave rise to the MTBC. lage that now lies beneath the waters pushes other pathogens to shape-shift,
A molecular clock dates this ances- of the Mediterranean Sea. At least five dropping surface proteins that are
tral strain to 40,000 years ago, when of the more than 70 human skeletons ­easily recognized by macrophages and
anatomically modern humans were there had bone lesions that suggested lymphocytes, yet the TB germ has
spreading out of Africa to colonize TB infection. Atlit-Yam is among the chugged along, carried by generation
Europe and Asia. M. tuberculosis oldest settlements with clear evidence after generation of humans, with little
moved out of Africa along with its of a farming lifestyle. The site con- identifiable change.
human hosts, then split into two major tained the remains of goats, cattle, In the never-ending battle between
lineages 10,000–20,000 years later. One and pigs, along with farming tools and germ and host, natural selection usu-
line of descendants infected cattle, harvested plants. The shift from a free- ally weeds out any mutations that
pigs, llamas, and even wild carnivores, roaming hunter–gatherer existence to make bacteria less fit, but TB seems
such as foxes and weasels. Another line life in settled farming communities is oddly immune to this kind of purify-
continued to infect people through the associated with the appearance of TB, ing selection. “As few as 1–10 bacterial
ages. More-recently evolved strains of and that of other infectious diseases, cells are enough to initiate a new tuber-
TB have lost specific DNA sequences, including smallpox. Although no trace culosis infection,” explains Sebastien
including a section of coding DNA of M. bovis was found at Atlit-Yam, the Gagneux of the University of Basel,
dubbed Tbd1. The successive loss of researchers speculated that cattle may Switzerland, so each time the disease
have contributed to the spread of TB passes from one person to the next,
there by supporting a denser human the bacteria experience an extreme
population. The strain of bacteria population bottleneck. Mycobacterium
found in the bones of the mother and tuberculosis may survive by somehow
child had lost the Tbd1 DNA sequence, turning the human immune response
marking their killer as a member of the to its own advantage. Gagneux points
more modern lineage of TB. out that the most contagious form of
Ruth Hershberg, now at ­Technion the disease, cavitary TB, is driven by
University in Israel, has studied the immune responses that increase lung
genes of the MTBC infecting humans damage and make the infection more
from around the world and has found likely to spread to other people.
that people in different regions carry The bacterium’s resistance to purify-
distinct strains. The bacterium’s genetic ing selection may make it increasingly
code holds markers of human move- dangerous in the era of antibiotics.
ments over the millennia. TB arrived Drug-resistant strains appeared soon
in India and Europe with the first bio- after the introduction of ­streptomycin,
logically modern people to settle those in 1943. Standard treatments for
regions. As human numbers boomed, active TB now include long courses of
they provided an ecological niche multiple antibiotics. The regions of the
for strains of TB that live on today. world where TB is most ­widespread—
Later, in historic times, the disease sub-Saharan Africa, India, and
Some of the 9000-year-old skeletons crossed oceans with ­European colo- ­China—report rapid increases in cases
found at Atlit-Yam, beneath the nists; ­Pepperell’s finding of a distinctive of multidrug-­resistant disease. The
Mediterranean Sea, reveal bone lesions French-­Canadian strain spreading to mutations that create drug resistance
from tuberculosis. Photograph: Hanay. indigenous people is a case in point. often make bacteria less fit in some way.

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were slower to respond and produced


lower levels of cytokines.

Crowded conditions and hunger


are still catalysts for disease
A corresponding pattern has been
documented among TB patients in
Gambia. Ancient and modern strains
both spread among the human popu-
lation there, but the modern strains are
much quicker to cause active disease.

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Before people began to live packed
together in cities, the bacterium
tended to lie low, allowing the host
to live long enough to produce a new
generation of children to infect. Today,
in a world increasingly crowded with
humanity, there are plenty of hosts. It
seems the modern strains can afford
to be more virulent, because when
one host dies, there are always others
around.
The risk of infection spreading to noninfected persons from individuals with What does this complex evolution-
cavitary tuberculosis, shown here, is very high. Photograph: Yale Rosen. ary history mean for efforts to control
TB in the modern world? No effective
Strains that have evolved to resist the in settlements 10,000 years ago, and vaccine against the disease exists. New
antibiotic rifampicin, for instance, do nearly all of them carry the resistance antibiotic drugs are urgently needed
so at the cost of a mutation that impairs allele. Among the Saami of Lapland, in regions where the disease is wide-
an enzyme vital in RNA transcription. who began to live in towns only a cen- spread, yet bacteria will always be quick
Cells with this kind of mutation would tury ago, genetic resistance is rare. In to evolve resistance. The most effective
be quickly outcompeted among free- confronting TB in the modern world, weapons against TB are simple but
living bacteria, yet ­rifampicin-resistant explains Barnes, “We have to be aware elusive: good food and healthy living
members of the MTBC survive well that past selection pressures are very conditions for people everywhere. “A
even in patients who are not being important and underpin each person’s good vaccine would certainly help,”
treated with the drug. “It’s pure specu- response to the disease.” says Portevin, “but the single most
lation,” says Gagneux, “but because so More modern strains—like the important factor is a constant food
few cells are needed to initiate a new ­Beijing family of members of the supply.”
infection, the drug-resistant strains MTBC—seem to have evolved new, TB is rare in the developed world,
may be maintained in the population improved ways of subverting the but that is a result of improved stan-
by chance, and thus contribute to the human  immune response. Cytokines, dards of living, not of the power of
problem of drug resistance.” proteins released by macrophages antibiotics. In the United Kingdom,
A spate of new evidence underlines the and other immune cells, activate the number of TB cases began to drop
ancient relationship between crowded ­lymphocytes to fight infection. Patients in the mid-nineteenth century, before
living conditions and outbreaks of TB. infected with these modern strains Robert Koch identified the bacillus
A team of researchers led by geneticist produce lower levels of cytokines than and decades before the development
Ian Barnes of the University of Lon- those carrying ancient strains of the of the first antibiotics. Today’s pattern
don studied variants of a human gene, disease. In a recent study, Damien of outbreaks in industrialized coun-
SLC11A1, that codes for a protein in Portevin of the MRC National Insti- tries reflects the impact of poverty
macrophages, the sentinel cells that trig- tute for Medical Research in London and overcrowding. The worst outbreak
ger immune response against invading tested the reaction of macrophages in Europe is happening among the
bacteria. Some forms of the gene give to ancient and modern strains of TB homeless and poor on the streets of
people natural resistance to TB infec- in  vitro. Macrophages exposed to London. In the United States, the peo-
tion. The descendants of societies with a ancient forms responded by firing off ple most likely to be hit with TB are
longer history of urbanization are much an array of cytokines, signaling lym- substance abusers, including alcohol-
more likely to carry the resistance allele. phocytes to join battle with the bac- ics and people sharing close quarters
Iranians, for instance, first began to live teria. Those exposed to modern forms in drug houses.

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on commodity food shipped north by


the federal government. Noni Mac-
Donald, a pediatrician who has worked
with patients in Nunavut, explains
that conventional ways of handling
the outbreak are much more difficult
in the remote, scattered communities
of the territory. In the first half of
the twentieth century, Inuit and other
indigenous people suffering from TB
were forcibly removed to sanatoria in

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Montreal and Ottawa. Most of those
patients died alone in the alien south.
Because of that painful memory, some
residents of Nunavut are reluctant to
come forward to be treated.
“You can control the disease best
by alleviating the miserable condi-
tions people live in,” says MacDonald.
US Navy Lieutenant Lydia Battey discusses the symptoms of tuberculosis “The big push has been on using the
with local residents in Papua New Guinea as part of a medical civil-assistance anti­biotics properly, but if we don’t
program. Photograph: US Navy photo by Mass Communication Specialist address the basics of poor nutrition
2nd Class Kerryl Cacho. and overcrowding, then we are going
to keep on chasing our tails.”
Perhaps the most poignant example were documented in 2010. That is an
comes from Nunavut, in the Cana- infection rate 62 times the Canadian
dian Arctic, which is now suffering average, and most of the victims are
a serious epidemic of TB. The situa- adolescents and young adults—an age
tion echoes the story of the outbreak group that would be able to suppress Sharon Levy (levyscan@sbcglobal.net)
among the indigenous peoples in the the infection if they were healthy. But is a science writer based in Humboldt
County, California, and author of Once
late 1800s. The territory’s population most people in the territory no longer and Future Giants: What Ice Age
is small and mostly aboriginal. One live a traditional life. Instead, they ­Extinctions Tell Us about the Fate of
hundred new cases of active disease crowd into small houses and survive Earth’s Largest Animals.

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