””

The upside of bad genes

Maligned variants may have value and purposes that scientists don't yet understand

There's a well-to-do couple thinking about having children. They order a battery of genetic tests to ensure that there's nothing untoward lurking in their genomes. And they discover that they each carry one copy of the sickle cell gene.

If their children inherit two copies of the gene, they could develop anaemia, which can cause joint pain, weakness and even death. So what should the couple do?

For the last two decades, they've had the option of artificially fertilising embryos and selecting only those that lack the sickle cell trait. Now a new possibility is on the horizon: They may soon be able to edit the offending gene right out of their own sperm, eggs or embryos, erasing it from their bloodline forever.

The technology that will allow this is called Crispr-Cas9. It's relatively cheap and it permits scientists to change DNA with an ease and precision that until now has been impossible. The promise is that it will transform medicine by vanquishing previously incurable diseases. The method is probably at least a few years away from being applied in clinical settings. Still, some are already worried that, when it comes to improving our own genome, we don't yet know enough about how genes work to wield this power without unintended consequences.

Get The Straits Times
newsletters in your inbox

In 2015, the journal Science declared Crispr the "breakthrough of the year", and researchers in China edited human embryos for the first time. Scientists also convened a meeting in Napa, California, to talk through the ethical implications of this new technology and to draft guidelines. A fundamental issue that came up, says Dr Jennifer Doudna, a biochemist at the University of California, Berkeley, and a pioneer in Crispr research, was that scientists really don't understand enough about the upside of genes we consider "bad" to begin editing them willy-nilly.

Sickle cell was a case in point. The gene is usually found in people who live in, or whose ancestors came from, sub-Saharan Africa, the Arab world and India; in those places, having one copy of the gene can prevent the worst symptoms of malaria. Of every four children our imaginary couple might have, one will probably have sickle cell disease, but two would most likely be protected from malarial disease.

Ditto with the gene variants that cause the lung disease cystic fibrosis. In parts of north-west Europe, about one in 25 people carries a single copy of the gene. And while two copies cause disease, it has long been hypothesised that having just one protects against tuberculosis - the White Plague that ravaged Europe for a few hundred years.


ST ILLUSTRATION: MANNY FRANCISCO

Both these genes probably helped us survive in the past, so is it wise to remove them now?

Earlier this year, the National Academy of Sciences and the National Academy of Medicine issued recommendations on editing embryos and other germ line cells, calling for a high degree of caution but not prohibition. An obvious counter-argument to the precautionary approach is that the world has changed. We in the developed world don't inhabit an environment rife with malaria and TB anymore. We have drugs to protect us when infection strikes. So doomsday preppers notwithstanding, removing injurious and outdated genes is a logical step in our (now self-directed) evolution.

The problem, Dr Doudna points out, is that new pathogens for which we don't have cures continue to emerge - like HIV and Sars and drug-resistant variants of TB. In fact, as the world has become more crowded and interconnected, the emergence of new pathogens has accelerated. Those "bad" gene variants might still come in handy, she says.

More broadly, genetically diverse populations tend to be more resilient, precisely because they have more genetic resources to draw on when unforeseen challenges arise.

To further complicate matters, some of the gene variants now linked with disease probably don't cause as many problems in other environments. Consider the border between Finland and Russia, where there's a sharp gradient in the prevalence of autoimmune disorders like celiac disease and Type 1 diabetes. These conditions have become worrisomely common in Finland in recent decades, but are between one-fifth and one-sixth as common on the Russian side, despite the fact that the Russians are just as genetically predisposed to developing them.

What protects the Russians from their own genetic inheritance? Or better phrased, what makes the Finns vulnerable?

Finnish scientists think that exposure to a particular community of microbes - one that more resembles the microbiota of our less hygienic past - prevents the diseases from emerging in Russia. That's important because at least some of the gene variants associated with autoimmune disease are probably useful; they most likely helped us battle infections in the past.

We evolved in environments that are radically different from today's, and some of our genes may work better in those environments. This complicates the idea of trying to perfect the human genome with technology. Given how much the world has changed in just the past 150 years, and how much it's likely to change again in the next 150, the question is, "What environment will we optimise our genes for?"

So instead of rewriting our genetic code, a better approach might be to change the interplay between our genes and the environment - in this case by altering the microbes we encounter.

This dynamic may also apply to a gene linked with dementia. Carriers of the ApoE4 variant have an up-to-fourfold increased risk of Alzheimer's disease. In 2010, scientists at Northwestern University found that the gene was more prevalent in tropical and polar populations than in those from mid-latitudes, presumably because it served some function in those regions. Then, strangely, the gene was linked to enhanced cognitive performance in children living in Brazilian slums. And last year, Dr Ben Trumble, an anthropologist at Arizona State University, and colleagues published an intriguing study suggesting that the gene might improve brain function in elderly people living in the Bolivian Amazon.

Members of the tribe he studied, called the Tsimane, subsist mostly on what they grow and hunt in the jungle, and about two-thirds have intestinal parasites. Dr Trumble discovered that if elderly ApoE4 carriers harboured parasites, their cognitive abilities improved relative to non-carriers with parasites. Only carriers without parasites suffered cognitively.

How this might work is unclear. The gene seems to increase the absorption of cholesterol, which is necessary for brain health. Parasites, of course, steal cholesterol and other fats, either by extracting them from your food or by drinking your blood.

Maybe people who have the gene are better at countering this thievery. Or perhaps their superior fat absorption affords them more energy to fight parasites, too many of which can also erode brain function. And maybe because the Tsimane exercise plenty and eat low-fat fare, the gene never becomes problematic for them as it does in the developed world - unless they lack parasites.

Whatever the mechanism, here's the point: A gene that we now think increases the risk of cognitive decline may actually protect against it in other environments.

Most biomedical research is done on modernised populations in industrialised cities. But if we edit out genes based on how they work in those populations exclusively, "we might disrupt processes that we didn't realise were important", Dr Trumble says.

Finally, there's diet. Back in the late 1980s, anthropologist Fatimah Jackson discovered that the prevalence of the sickle cell trait varied considerably across Liberia, a small country.

It was more common in the north-west than the south-east, even though the infection that makes the trait advantageous - malaria - was everywhere.

Scientists at Albert Einstein College of Medicine in New York City had recently discovered that ingesting cyanate salts could prevent the "sickling" of red blood cells that leads to the anaemia and pain of sickle cell disease. Dr Jackson knew that a related compound, cyanide, was common in foods across Africa, particularly in the staple crop cassava (which you may know as tapioca). She was also aware that, at the right dose, cyanide could directly protect against the malaria parasite. She realised that regular consumption of cassava - more common in the south-east than the north-west - could, by working as an anti-malarial drug, affect the prevalence of the sickle cell trait, by making it less advantageous.

Something different was happening in the north-west, though. Dr Jackson, who is now at Howard University, thinks that while cassava consumption in the region was insufficient to protect against malaria directly, people who had two copies of the sickle cell gene still ate enough to partly avoid sickling. In that population, diet may have prevented a genetic disease from fully manifesting.

Certainly, some genes will turn out to be only detrimental and provide no advantage. But there are bound to be other cases like these, in which genes deemed harmful can aid survival or at least cause less damage in other surroundings. As the epidemiologist David Barker said, "genes are not Stalinist dictators". They respond to what's going on around them - to the environment.

We evolved in environments that are radically different from today's, and some of our genes may work better in those environments. This complicates the idea of trying to perfect the human genome with technology.

Given how much the world has changed in just the past 150 years, and how much it's likely to change again in the next 150, the question is, "What environment will we optimise our genes for?"  

NYTIMES

• The writer is the author of An Epidemic Of Absence: A New Way Of Understanding Allergies And Autoimmune Disease.

A version of this article appeared in the print edition of The Sunday Times on June 25, 2017, with the headline 'The upside of bad genes'. Print Edition | Subscribe