This is not primarily a blog about evolutionary science. I am always happy to write about harms done by Islamic beliefs and the evil of the Christian Right. There are times, however, that getting down to the knots and bolts of evolutionary biology (specifically human evolution) gets quite important on a blog like this. Not because they are fascinating and (if you are like me) generate a sensation of awe and transcendentalism leading to euphoria. Because evolution is a scientific fact, and is part and parcel of biological science, of which medical science is a branch. The good Christians and Muslims, and others who deny evolution (totally or partially) for ideological reasons, including those hiding behind the “Intelligent Design” facade, are not just obscurantists trying to turn back the wheels of science. They are, quite literally, putting human beings’ life and limb in jeopardy, and they need to be called out on this. Hence, I am going to write a number of posts addressing this issue, and this is the first part of this series.
Tuberculosis is one of the oldest diseases known to man, and to this date, one of the deadliest. Most of us leaving in developed world have the good fortune of not having to think about it so often. But it doesn’t mean we should forget about it. It is a disease wreaking havoc in developing nations, and it can make a comeback in our countries as well, at any time. Let’s take a look at the some scary data.
Tuberculosis (TB) remains one of deadliest infectious diseases of humans, killing 50% of individuals when left untreated. Even today, TB causes 1-2 million deaths every year mainly in developing countries. Multidrug-resistance is a growing threat in the fight against the disease.
Resistant strains of tuberculosis are on the rise, limiting treatment options despite decades of antibiotic research. In 2010, at least 650,000 cases of the disease were resistant to the two most effective front-line antibiotics, and in 2012, totally resistant and effectively untreatable strains of Mycobacterium tuberculosis — the bacterium behind the disease — were detected in India.
Just stop to think about what this means for a moment. Totally resistant M. Tuberculosis means we have no medicine for the disease. If this strain spreads we are back in the 19th century-when all we could do was isolate sufferers in mountaintop institutions and hope they would infect fewer people before they died. Drug resistance has been a vexing and, until now, poorly understood problem for microbiologists. Now we have an idea why.
In the classical view of resistance, M. tuberculosis picks up mutations in enzymes that either activate drugs or are targeted by them. “We’ve been stuck in this mould for too long,” says Robin Warren, a TB specialist from Stellenbosch University in South Africa and a co-author on Murray’s paper. “These new studies show that there’s much greater complexity to resistance than we dreamed of.”
What studies?
Murray’s team sequenced 123 strains from a worldwide collection and mapped the sequences on to an evolutionary tree. They then searched for mutations that were independently linked to resistance across different branches. They identified every part of the M. tuberculosis genome that was already linked to resistance, along with 39 new mutations.
The second team, led by Lijun Bi from the Institute of Biophysics in Beijing, part of the Chinese Academy of Sciences, sequenced 161 samples from Chinese patients and analysed them using a similar method. They identified 84 genes and 32 other regions that were strongly associated with drug resistance.
And guess what they found (not that it was news): Darwin was right, not just about finches but about humans.
Using whole-genome sequencing of 259 Mycobacterium tuberculosis strains collected from different parts of the world, they determined the genetic pedigree of the deadly bugs. This genome comparison to be published September 1st in the journal Nature Genetics indicates that TB mycobacteria originated at least 70,000 years ago in Africa.
The researchers compared the genetic evolutionary trees of mycobacteria and humans side-by-side. And to the researcher’s surprise, the phylogenetic trees of humans and the TB bacteria showed a very close match. “The evolutionary path of humans and the TB bacteria shows striking similarities,” says Sebastien Gagneux.
This strongly points to a close relationship between the two, lasting tens of thousands of years. Humans and TB bacteria not only have emerged in the same region of the world, but have also migrated out of Africa together and expanded all over the globe.
The migratory behaviour of modern humans accompanied with changes in lifestyle has created favourable conditions for an increasingly deadly disease to evolve. “We see that the diversity of tuberculosis bacteria has increased markedly when human populations expanded,” says evolutionary biologist Sebastien Gagneux.
Human expansion in the so called Neolithic Demographic Transition (NDT) period combined with new human lifestyles living in larger groups and in village-like structures may have created conditions for the efficient human-to-human transmission of the disease, Gagneux suggests. This may also have increased the virulence of the bacteria over time.
If you ask me, I’ll say very cool, and very frightening. But what does it have to do with drug resistance?
Many of the resistance regions identified in both studies affect the waxy cell wall that surrounds M. tuberculosis cells. Some change its structure, or alter its permeability. Others influence the production of molecular pumps that evict drugs that get into the cells. And others boost the rate at which M. tuberculosis mutates, allowing it to pick up beneficial mutations more quickly.
The teams also identified mutations that are likely to influence other resistance genes, either boosting their activity or compensating for their detrimental effects, allowing the bacteria to carry them without being outcompeted by drug-sensitive strains.
Murray’s group made a start by introducing a mutation in the ponA1 gene into M. tuberculosis, and showing that the microbes could then withstand double the dose of rifampicin. “That’ll need to happen on a much larger scale for all of these genes,” she says.
These latest studies show that M. tuberculosis evolves resistance through several gradual steps with subtle effects. “It probably takes a bunch of these smaller steps to get to high-level resistance,” says Murray. David Alland of Rutgers University in Newark, New Jersey, supports this view through a third study, also published in Nature Genetics3. His team sequenced 63 clinical samples of M. tuberculosis that had been exposed to the frontline drug ethambutol. They found mutations in at least four genes that interacted to improve the bacterium’s ability to resist the drug, allowing some strains to shrug off 16-fold higher doses than others.
Understanding these step-wise pathways could help clinicians to monitor strains that are on the verge of evolving high-level resistance, or develop drugs that interfere with that evolution before it really gets going.
Next time someone tries to pull the “microevolution v macroevolution” crap, gently remind them that the above studies specifically address how the organism has evolved in tandem with humans. And that is what we need to understand if we are ever to get a handle on the crisis of multi-drug resistant TB.
Dear Ken Hams, Michael Behes, Harun Yahyas, Stephen Meyers, Bryan Fischers, and other science enemies of the world: while you are talking about human bodies “looking designed” and Jesus riding a T Rex, people are dying of TB in their millions. Your actions do nothing but undercut the scientific progress that is desperately and urgently needed.
Shame on you.
