28 | NewScientist | 21 June 2014

PHTHISIS. Consumption. King’s evil. White plague. Tuberculosis has had many names. Call it what you like, it was and still is a deadly disease, killing between 1 and 2 million people every year. But we think that humanity’s relationship with this pathogen is far more complex than it first appears. In fact, it could have played a vital role in human evolution.

This counter-intuitive idea arose from a seemingly unrelated area of study: our ancient ancestors’ meat-eating culture.

The story begins a few million years ago, when our forest-dwelling, vegetarian ancestors transformed into meat-eating hunters. A meat-based diet probably started in a modest way with the hominin species Homo ergaster, who lived in Africa from 1.8 million years ago. Later, meat became seriously important in the diet of Homo heidelbergensis, who appeared around 500,000 years ago, then more so in their descendants: the Neanderthals and modern humans.

This dietary change was accompanied by a dramatic increase in brain volume. The brain of H. ergaster was 60 per cent bigger than that of other great apes, and the brain of H. heidelbergensis was 50 per cent bigger again. This heralded a two-way relationship between brain and food. Our ancestors’ large, energy-hungry brains needed a high quality diet, and in turn, a large amount of brain power was required to forage for this food.

Many human traits are adaptations that helped our forebears become successful predators and acquire meat, despite an unpromising physique compared with competing carnivores such as sabre-toothed cats. Having an upright posture, a throwing arm and long-distance running abilities

helped them pursue prey. However, most important of all was an oversized, creative brain, capable of dreaming up ingenious ways to improve hunting efforts, from spears for killing animals to the social skills needed to hunt collectively and share the spoils.

The addition of meat to our ancestors’ diet seems to have overcome whatever had previously constrained brain size, commonly assumed to be a lack of calories or protein. However, this assumption doesn’t necessarily hold up, because there are easier ways of obtaining these – gathering foods like tubers, for instance – that involve less danger and don’t have the associated risk of a “no kill”.

We think that meat, particularly when cooked, was such a valuable food not because of its calorie or protein content, but because of specific micronutrients that it contains: namely nicotinamide (vitamin B3) and the amino-acid tryptophan, which can be converted in the body to nicotinamide. Neither is easy to obtain from plants.

Evidence for this hypothesis comes from a disease called pellagra, which occurs when economic poverty forces people into a vegetarian diet with a main staple like maize and very few animal products.

Pellagra epidemics occurred in Europe in the 18th century, where it was first described in Italian peasants by the physician Gaspar Casal. It was also seen in the US in the early 20th century during a crash in the cotton industry.

Pellagra causes people to become demented and affects their brain development, mainly by killing off brain neurons, but the condition can be readily cured with nicotinamide supplements. Nicotinamide has such potency because the body converts it to an essential fuel called reduced nicotinamide adenine dinucleotide (NADH) that is pivotal for metabolism and development, regulating everything from reproduction to DNA repair and ageing. A shortage constrains brain growth, connectivity and learning.

So where does TB fit in to all of this? We hypothesise that if nicotinamide is so essential for our species’ success and well-

A meaty puzzleThe evolution of our big brains had an unlikely helper, say Adrian Williams and Robin Dunbar

ProfileAdrian Williams is a professor of clinical neurology at the University of Birmingham, UK. He did a sabbatical MSc with Robin Dunbar, a professor of evolutionary psychology at the University of Oxford, to investigate the big brain/nicotinamide/TB hypothesis

OPINION THE BIG IDEA

Sanitorium life: TB may have had rewards, but disease was the risk R

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being, it is likely that microbial “helpers” living in the gut called symbionts would have co-evolved with humans, providing back-up supplies for periods when less meat was available (International Journal of Tryptophan Research, vol 6, p 73). This is what happens with other B vitamins. Low nicotinamide levels also make the immune system switch to welcome such symbionts.

So far, no gut organism has been identified which excretes nicotinamide. Surprisingly, however, there is a familiar microbe that does so: Mycobacterium tuberculosis – a pathogen that mainly infects the lungs and kills more than a million people each year, mostly those living in poverty. In fact, the ability of this bacterium to excrete nicotinamide was once used as a way to diagnose TB infections.

The TB bacterium co-evolved with humans at least 70,000 years ago, and possibly a great

deal earlier. Could chronic TB infections have originally been beneficial to human life? Did the pathogen act as a symbiont, supplying nicotinamide at times of meat deficiency?

The first signs of TB as a disease are found in the archaeological record between 7000 and 10,000 years ago – the time of the agricultural revolution and the rise of cereal dependence, when meat intake was declining. We think this is no coincidence. As meat consumption dwindled, TB symbionts stepped in to provide an alternative supply of nicotinamide. Only when the supply of meat deteriorated chronically did they behave as pathogens. If relied upon too heavily, the population of the “farmed” TB microbes becomes uncontrollable, and disease appears as the trade-off.

The unusual behaviour of TB infections supports our hypothesis further. The majority

of people who are infected with TB today – more than 90 per cent of them – are perfectly healthy, so catching it is not the problem. We suggest that TB, like many infections, can be tolerated so long as the host does not have an excessively poor diet. Also, the body’s immune response to TB is odd considering it is a pathogen. With many foreign bodies, white cells known as macrophages form granulomas to kill or wall off the “enemy”. However, with TB, far from killing or containing the pathogen, the granulomas can encourage its persistence, growth and spread.

Although TB produces nicotinamide, it is also sensitive to high concentrations of this substance. In fact, nicotinamide was the first

TB “antibiotic” ever described and isoniazid, a key drug used to treat the disease, is based on nicotinamide. So according to our hypothesis, we should see a fall in deaths from TB as meat consumption rises, increasing the dietary dose of nicotinamide.

To test this, we looked back at data from the pre-antibiotic era in the UK between 1850 and 1950. There is a good epidemiological record of striking declines in TB rates. This same pattern can be seen in other countries as they became richer, which has never been adequately explained despite much debate. We found that the decline in TB was strongly correlated with increased incomes and meat consumption in both sets of data, plateauing when people’s average annual meat intake rose above 60 kilograms.

Circumstantial evidence offers further support for our hypothesis. In 1925, for example, the Norwegian government built spacious new barracks in Trondheim to try to curb the spread of TB among naval recruits, but there was no improvement until their meat intake increased radically.

We believe that nicotinamide and tryptophan were so important for evolving big brains that it was originally worth taking high risks to obtain these nutrients, whether that meant going hunting, or “farming” risky symbionts such as TB. Today, reducing the huge disparities in different countries’ meat intake, ensuring poorer people have an adequate level, would go a long way towards alleviating the dangers of TB. n

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“ Did the TB pathogen provide key nutrients at times of meat deficiency?”

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