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Genetic Linkage

The Sickle Cell/Malaria Link Revisited

Eman is a medical student in Liberia.
Today is both DNA Day and World Malaria Day. As I was pondering how to connect the topics, e-mail arrived from my “son,” a medical student in Liberia. He had malaria, again, and this time it had gone to his brain.

I “met” Emmanuel in 2007, when he e-mailed me after finding my contact info at the end of my human genetics textbook, which he was using in his senior year of high school. He is my personal link between DNA Day and World Malaria Day. But the dual commemoration also reminds me of the classic study that revealed, for the first time, how hidden genes can protect us – that carriers of sickle cell disease do not get severe malaria.

Emmanuel’s charm and intelligence came through easily in his e-mails and Facebook posts, and soon, my husband and daughters began to correspond with him too. He called us Mom and Dad, calling himself “Your Son.” This made me uneasy at first – I didn’t want to insult his mother – but Eman assured us that this is the way in Africa. When my husband had a hernia operation unnoticed by the rest of the world because Michael Jackson and Farrah Fawcett died that day, Eman somehow found a phone and called, worried.

It’s very expensive to mail anything to Liberia, and most stuff that makes it is stolen. Eman sent us traditional clothing through a friend traveling here. I sent Obama tee-shirts, which miraculously arrived, and Eman proudly gave them to his siblings. President Obama is much loved in this country founded by American slaves.

Eman wrote often that he wanted to fight the infectious diseases that plague his nation, as he did in this letter to a geneticist colleague of mine seeking sponsorship:

“I am Emmanuel, age 21. After my studies in biology, I wish to become a medical doctor. In a country of 3.5m people and a little over 200 medical doctors (mostly foreign) there remains a great distance between health workers and healthy people. Most doctors live and work in urban areas, leaving those in rural areas vulnerable to diseases and little or no health care. Every day in Liberia, people die of curable diseases and that is very devastating. I have decided to pursue studies in Medicine to help change this situation. I hope that one day I will be of help to Liberia and the world. I want to become a doctor of the people, mostly based in the rural area where people rarely get access to health care.”

We encouraged and supported Eman, and he was almost through his second year of med school in mid-March, when he sent this e-mail:

Dear Mom and Dad,
I was admitted at a local hospital yesterday after I fell off. According to the nurse, onlookers took me to the hospital. I do not know what happened. I will get to know once the Doctor gets to see me tomorrow.”

I asked what he fell off of, and this turned out to be one of several linguistic misunderstandings we’ve had. “I mean I fainted. Loss of consciousness and postural tone,” he answered, already sounding like a doctor.

Two days passed, and then we got an e-mail from Eman’s brother that he’d been readmitted, with stage 3+ malaria. I didn’t know what that meant.

“3+ means it is severe. That could even lead to madness. His blood is very low maybe due to the typhoid. We hope he gets better for school soonest,” wrote Eman’s brother. Parasite-stuffed red blood cells were obstructing small blood vessels in his brain, causing his unconsciousness. If he didn’t die, I read, he’d probably be okay. Since then, our African son has been on a roller-coaster ride of chills and fever, trying to get back to school.

I try to imagine what’s happening in his body. The life cycle for malaria is complicated. An Anopheles mosquito delivers protozoa (Plasmodium species) with its bite, and the parasites settle in the liver. Then they head to the red blood cells, where they persist in asexual forms (while fever and chills ensue). Some of them burst out, forming sex cells that are sucked up by another mosquito, which then injects the infectious cargo into another person.

Despite the decrease in annual malaria deaths by a third over the past two decades, the disease remains the #1 cause of morbidity and mortality in Liberia, where life expectancy is 59. In Africa, a child dies of malaria every 60 seconds.

Knowing the genome sequences of all the players in malaria – the vector, the parasite, and the host – is important in better understanding the disease. But when I think about malaria today, on this dual DNA/Malaria day, I cringe at some uses of DNA testing.

Here in the U.S., people are getting their exomes sequenced to know what conditions they might develop decades hence, while a world away, people still die in days from the types of infectious diseases that Eman has battled. Two years ago he had cholera, malaria, and amoebic dysentery all at once. Meanwhile, Americans send their spit to genetic testing companies that reveal such vital information as eye color, whether cilantro tastes like soap, or whether they sneeze in bright sunlight.

The worlds of DNA and malaria collided back in 1953, the year that Watson and Crick published their famous paper on DNA’s structure.

Anthony Allison, a British doctor with a degree in biochemistry and genetics from Oxford, grew up at the epicenter of human evolution, in the Great Rift Valley in Kenya. As a young man he met Louis Leakey, at the Olduvai Gorge in Tanzania. Steeped in the central idea underlying evolution — that diversity drives it — Allison set out to investigate how the one type of inherited trait that could be easily followed back then varied among tribes: blood types. In 1949, right before he left on the research trip that would lead to his string of papers in 1954, a colleague wondered aloud about the high incidence of sickle cell disease. Inherited conditions that kill early in life tend to be extremely rare — only carriers and new mutations sustain it.

Intrigued, Allison surveyed the incidence of sickle cell disease among members of 35 tribes in East Africa. And it was staggeringly high – up to 40% — but only in areas where malaria was endemic.

The mutation rate for the beta globin gene would have to be extraordinarily high to keep the disease so prevalent. Was there another explanation? Could carriers have a health advantage that enables them to survive to reproduce, passing on the mutation?

When Dr. Allison looked at maps of the distribution of both diseases, the connection jumped out at him. Where malaria was most prevalent, so too was sickle cell disease. When he counted the numbers of malaria parasites in the red blood cells of carriers versus non-carriers like Eman, the puzzle pieces assembled.

Dr. Allison concluded that “persons with the sickle-cell trait have a considerable natural resistance to infection with Plasmodium falciparum,” in Transactions of the Royal Society of Tropical Medicine and Hygiene.

A name for this dual disease phenomenon already existed, coined by Dr. Allison’s mentor at Oxford, E. B. Ford: balanced polymorphism. A heterozygote (carrier, with two different alleles of a gene) has a survival advantage over either homozygote (2 identical alleles). People with 2 copies of the mutant hemoglobin allele (hemoglobin S) die young of sickle cell disease, but those with 2 copies of the healthy allele (hemoglobin A), if bitten by a disease-carrying mosquito, contract and likely succumb to malaria.

The idea was striking, but not entirely novel. In 1948, J.B.S. Haldane had noted a relationship between another disease of beta globin, beta thalassemia, and malaria – but he didn’t connect the dots, as Dr. Allison did.

Once the malaria-sickle cell connection emerged, looking back at history explained malaria’s stronghold in Africa — and raises fears today about the effects of global warming in creating mosquito habitats.

Around 1000 B.C.E., Malayo-Polynesian sailors from southeast Asia traveled in canoes to East Africa, introducing wonderful new crops – coconuts, yams, bananas, and taros. Clearing the jungle to cultivate these newcomers provided breeding grounds for mosquitoes.

A cycle set in. Settlements with many sickle cell carriers – people who escaped both diseases – were able to clear more land to grow food. The mosquitoes, and their stowaways, flourished. This rapid changing of allele frequencies is the most profound illustration of evolution that I know.

But we still don’t know exactly how sickle cell carriers are protected against malaria. Asexual parasites soak up oxygen from the hemoglobin inside red blood cells, shriveling some of a carrier’s red blood cells into their characteristic crescent shapes. The cells are shunted to the spleen, slated for destruction along with their parasite stowaways. If carriers do get malaria, it’s mild. But other mechanisms may be at play too.

I don’t know if Dr. Allison is still around, but if he is, I hope a reader will send him this blog. He told Economist writer Laura Spinney in 2009, “Every generation likes to rediscover me.” We should celebrate his contribution today. It’s every bit as important as the DNA discovery.

Sickle cell disease and malaria remain the “textbook example” of balanced polymorphism, but others are equally intriguing:

• Cystic fibrosis protects against certain diarrheal diseases because intestinal lining cells of carriers have fewer intact chloride channels, keeping bacteria or their toxins out.

• Phenylketonuria (PKU) persists because pregnant women who are carriers don’t lose their fetuses to ochratoxin, a poison made by fungi on rotting vegetables. People ate tainted vegetables during times of famine, which is why the world’s highest prevalence of PKU is in Ireland.

• Prions are infectious proteins that lie behind mad cow disease and related conditions. People who are heterozygotes for the prion protein gene make prion protein that can’t twist into the infectious form. In the mid-1990s, the several people in the UK who developed the human form of mad cow disease were all homozygotes, with two identical copies of the gene. Again, carrier status protects.

Another example of carrier advantage is just an hypothesis, and I don’t know who originated it. Several of the dozen-and-a-half “Jewish genetic diseases” affect the brain – terrible conditions such as Tay-Sachs, Canavan, Alzheimer, Niemann-Pick, and Batten diseases. Their prevalence reflects the serial shrinking of the Jewish gene pool in the wake of purges such as pogroms and the holocaust, so that distant cousins inadvertently marry distant cousins, unknowingly joining mutant genes in small children who suffer from these brain diseases. But maybe balanced polymorphism is favoring their carrier relatives. What might be their advantage?


Might quick-witted ghetto occupants or prisoners been more likely to escape, keeping the mutations in the gene pool? If a good sense of humor is a surrogate for intelligence, then a second line of evidence might be the overrepresentation of Jewish people among comedians. Call it the Seinfeld effect.

How many other protective carrier states are hiding in our genomes? We have the computational tools to find them, but it’s difficult to detect omissions. Researchers must identify which diseases the carriers of the same single-gene conditions never get. That’s negative evidence, but it’s how we can unveil our “protectome.” We’ve been following these diseases for decades. The data await mining.

And it all started with the work of Anthony Allison, on malaria and sickle cell disease – the joining of genetic and infectious disease that we mark today.

This blog first appeared at Public Library of Science DNA Science blog.

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