Chapter 3: Finding a bean for your genes and a buffer against malaria

By Dagmar
In Interesting stuff
Dec 2nd, 2014

This is article is a summary of the third chapter of book Why Some Like It Hot: Food, Genes and Cultural Diversity, written by Gary Paul Nabhan. I have found this book fascinating and decided to introduce some of its great content to the readers of my blog. It by no means aims to substitute the original book and I have intentionally left out some interesting passages. Nonetheless, I still hope you like what you read and perhaps you will decide to explore the topic further.

Gary started this chapter by contradicting the common misconception about a rapid agriculture revolution which was believed to occur suddenly and almost simultaneously on different places of Earth at about 10 000 to 12 000 years ago. The current evidence suggests that this was rather a slow process and started long time before that and there was no clear cut between the paleolithic and neolithis eras.

“Hunter-gatherers practiced elements of plant selection, transplanting and dispersal of many thousand years before that apparent instant revolution … Farming and herding peoples like Sardinians and Cretans continued to draw upon wild herbs, legumes, snails and fish…”

The slide I have captured from one of the well delivered (in my opinion) lectures of Dr McDougall says it as well, in regards to starchy plants:

 Paleo eating starch

Broad bean disease

This chapter will be based mainly on a small piece of land called Sardinia. As you could read in the previous chapter, the genetic drift occurs more pronounced on smaller islands than on large continental land and that was exactly the case for Sardinia. Here, a specific genetic trait occurred, which shows two faces: one makes it a genetic disorder, bringing suffer to the host, but the other face makes this particular trait an evolutionary advantage in the specific environment. This genetic trait appeared as a result of gene/food interaction. The genetic trait I am talking about is favism.

Favism demonstrates on Sardinia the most during the spring when the broad beans (favas) start to bloom. Its pollen is carried by wind and fills the air. What means time of joy and enthusiasm for most of us, for affected Sardinians this is the time of hell. Even children in school are

‘drained of all their energy rather than enlived by the vernal equinox… especially the boys complain of feeling sleepy, dizzy or on the verge of vomiting.’ They often have ‘disrupted sleep and nightmares… an emergency room might admit a teenager in the middle of the night who had been frightened when he got up to relieve himself and found his urine dark and bloody.’

Then the blood transfusion is often given to the patient, until the urine clears up.

Although the description of the symptoms sound horrible, this genetic trait has provided the sufferers with a protection against malaria, which has been quite common in the Mediterranean over thousands of years. The deadly microscopic plasmodia parasites (Plasmodium falciparum), which are responsible for malaria and are spread by females of anopheles mosquito, have difficulties to breed in red blood cells of people affected with favism. The genetic mutation occurs at the section of the genome which codes for the enzyme called glucose-6-phosphate dehydrogenase (G6PD), which is needed for metabolism of glucose. Red blood cells crucially depend on the glucose metabolism and if this is disabled, they die, which puts the halt on further breeding of the plasmodia in the cell.

Sickle-cell anemia

Gary also mentioned the disease called sickle-cell anemia, which is common in African regions where malaria is also widespread. It is a disease which is different from favism, but it has similar effect on people when living in malaria infested regions. They have a faulty gene for haemoglobin and under certain conditions it makes the otherwise concave shaped red blood cells to collapse, gaining a shape of a sickle. These red blood cells become dysfunctional and plasmodia cannot breed in theme either. It also is an autosomal recessive trait, which means that both parents have to carry the gene and give both copies to the offspring for having a fully blown sickle-cell anemia, predicting a short life to the carrier. If only one affected gene is given to the child while the other, dominant, codes for the functional haemoglobin, the symptoms are less severe, but still sufficient to make the breeding of plasmodia difficult and therefore protecting the individual to some extent against malaria.

Interestingly, the favism has some other effects on the sufferers. For example they cannot ‘smell naphthalene without getting sick’ or take some medications which would send them six feet under.

Oxidative stress can kill

Similar genetic deficiency and the interaction with drugs, which was supposed to treat or prevent malaria, was responsible for unnecessary deaths of American soldiers who were sent to the Korean War in 1950s. They were given a drug called primaquine as a protection against malaria which was widespread in the wetlands of Korea. But instead of protecting some of them they died as a consequence of using the drug. Some soldiers were found to be primaquine sensitive and they were usually of the North African, Middle East of Mediterranean origin, mostly African Americans. These affected people were found to be genetically deficient in the enzyme called glutathione disulfide reductase (GSR), which is crucial in regulating the redox reactions in our cells. Without this enzyme the body is not able to continually oxidize glucose into fructose in red blood cells. Giving primaquine drug to affected people triggers a haemolytic anemia (break down of red blood cells) with often fatal consequences. In other words, what normally occurred in affected people at a slow rate and they were able to live with it, the drug made it progressing much faster and therefore produced a high death rate of the red blood cells and their owners, the patients. Interestingly, as Gary pointed out, this case was the first case documenting ‘human genetic variations in response to a drug as a result of an inherited enzyme deficiency’. Over the years, the biomedical science has progressed to the development of pharmacogenetics and nutritional eco-genetics.

The diesease in a nutshell

G6PH, similarly to GSR are crucial enzymes in reduction of oxidative stress in the red blood cells. Both, the deficiencies of these enzymes or the primaquine drug disrupt the balance of the redox reactions and the plasmodia, which require them for growth, cannot thrive. However, that also means that when either of these enzymes is lacking or dysfunctional, the lifespan of red blood cell, which is normally around 120 days will be significantly reduced, usually to several days. That is the haemolytic anemia – the person suffers from low count of functional red blood cells, which we need to transport oxygen to the tissues and removal of carbon dioxide as a waste product of metabolism. Similarly, the sickle cell anemia is characteristic with misshapen red blood cells, which become less pliable and can cause damage to the tissues, often by blocking small vesicles and disabling the exchange of gases which every living cell needs to sustain its function and life.

History of studying the genetic interactions with food and drugs

Back in 1949 there was an essay published by J.B.S. Haldane titled: Disease and Evolution. There he ‘speculated that so-called red blood cell “disorders” were somehow adaptive and had likely evolved in response to chronic exposure to malaria, affording some protection from this infectious disease’. Of course, this was not the only essay of his. However, Gary says that ‘Haldane’s iconoclastic essays were not very user-friendly for conventional practitioners of Western medicine’. Haldane was described as pioneering evolutionary biologist and agnostic and he had a narrow circle of followers among biomedical researchers ‘who shared his unswerving conviction that evolutionary insights could explain nearly any global pattern of disease, infectious or otherwise’. Indeed, the health science kept evolving. In 1974 the term nutritional eco-genetics was firstly used, studying ‘how the long-term consumption of certain sets of foods has historically shaped the distribution of human genetic variation’. Therefore, the ‘genetic polymorphisms have developed in response to deadly diseases such as malaria and to a variety of other factors, driving biological and cultural evolution.’

Since more has been learned about the favism and contraindications, children with this condition ‘wear a tag on them at all times, explaining what they must not be exposed to.’ It has also became clear that this G6PD deficiency is sex-linked condition, which affects boys the most, because they only receive one X chromosome from their mothers, whereas the Y chromosome from father does not carry the code for G6PD gene. Therefore girls have a higher chance of being affected to a lower extend than boys, because they also can receive a healthy dominant allele for the G6PD. There was found 78 variations of this gene, giving different level or protection against malaria when encountering the particular proteins found in fava beans or unsuspectingly receiving primaquine.

Furthermore, as the continuous research revealed, “the hereditary bases of these abnormal reactions were different from that of immunological responses generated by toxic allergens.” So the favism is not an allergy, to make it clear.

As Gary cited Motulsky, an enthusiastic scientist studying genetic interactions with foods and drugs:

Favism is perhaps the best example of the very concept of pharmacogenetics. If you happen to have the genetic deficiency, it is not necessarily a problem in and of itself. If you eat fava beans, but you don’t express the deficiency, as is true with many Sardinian women – again, no problem. An antimalarial drug alone – in the absence of G6PD deficiency – no problem again. But the interaction of these three factors can be deadly!

The haemolytic anemia was the reason why young boys on Sardinia were horrified with dark urine and symptoms of fever in times of being exposed to the pollen of fava beans – these were the poor folks affected badly with the G6PH enzyme deficiency. The condition not only prevented malaria to cause them damage; the condition itself was damaging the quality of their blood, resulting in various health issues, including red coloured urine.

How malaria shaped the population

Gary reports that about 7% of human population has some genetic adaptation that makes them more resistant to malaria. This is an example how people vary in their responses to various diets, drugs or contaminants due to their inherent physiological differences, providing an evidence of biochemical individuality. It took time and genuine interest to study ‘whether random mutations or natural selection had accounted for the levels of human genetic variation detectable at the time. Nonetheless, both mechanisms were often driven by human diseases, nutrition and environment. Yet, it was still difficult for some scientists in 1974 to take in that the genetic mutations were not something that happened long time ago and stayed with us until now without any change. The truth is that these mutations occur all the time. The scientists also accepted that sickle-cell anemia had an evolutionary adaptive significance in Africa and South Western parts of Asia, but it took few more decades to accept that the G6PD had the same function of natural selection in malaria beaten Sardinia.

Gary cited Peter Brown:

For two millennia, Sardinia was the most malaria-stricken region of the Mediterranean. The disease was seasonal, hyperendemic, and the greatest single cause of mortality (1986).

Moreover, the presence of malaria has been dated back to 4000 BC. Even more interesting are the figures of the change of population: at times of Christ, Sardinia had some 130 000 inhabitants. Thirteen centuries later it was only 80 000, where the most affected areas were wetlands, seeing 72% disappearance of farming villages.  After a relative recover during 19th century, the population again plummeted within as little as 6 years in 1920 when “half million Sardinians suffered from malaria”.  And then the DDT came and the mosquito control.

Paradoxically, even when there is still the G6PD quite common among Sardinians, the broad beans had been and is commonly being served at seaside restaurants as an appetizer. This is how Gary has described it: “semimashed fava beans, cooked with a half-dozen spices, cooled and dowsed with lemon and garlic, placed in a pool of deep green olive oil”. Similarly in Egypt where they call it ful mudammas, or koukia on Crete. The beans had a long history on Sardinia and in Greece, including religious, making people having a huge respect to the plant. More historical tell tales were mentioned in the chapter, some were very bizarre.

It is therefore apparent that the Sardinians traditionally consume the beans, even if they suffer from the G6PD deficiency and it is not less intriguing that the beans season starts along the season for mosquitos. However, when the people settled on Sardinia some 5 000 years ago, they firstly encountered wild fava, which they gradually domesticated. At that time the malaria was not a problem yet. It took time, settlement in the land and the growth of the population which enabled malaria to spread and the benefit of G6PD to kick off. That meant less than 250 generations. Quite impressively short period of time for the evolution, is it not? This is quite in contrast, Gary says, with the traditional theory of anthropology that “humans remained essentially the same genetically since Paleolithic times…”. As an argument in favour of a relatively fast development of favism common among Sardinans was that these had to settle down and remain all year round in the coastal regions, instead of escaping to the mountains when the mosquito season started. Having the G6PD deficiency has proven as an ecological adaptation and although often making life of the sufferers harder, it protected them from a certain death from malaria. That made them being able to forward this enzyme deficiency to the offspring and making the genetic trait common among a relatively enclosed population of Sardinia.

Mechanism of fava (broad) beans protecting effect from malaria

Finally, how the fava beans protect the inhabitants of malaria infested regions? The secret is in its powerful glycosides in green and immature beans and their seed coats. After consumption, these glycosides are broken down to pro-oxidative divicine and isouramil – increasing the oxidation stress and damaging the delicate cell structure. Because the body has its own antioxidant mechanisms, which include glutathione disulphide reductase (GSR), this enzyme is extensively used to curb down the oxidation stress. Therefore the high oxidation stress brought up by various mechanisms causes depletion of the GSR and cellular damage, responsible for early ageing, mutations or the mentioned hemolysis – deat of red blood cells.

You do not have to be sick for being resistant to malaria

Even without having such genetic condition, people can modify their body response to the parasite by consuming certain staple foods, which, like in people affected with the favism, also makes them less suitable host for the parasite and therefore being more resistant to the disease. Therefore, you do not have to be GSR or G6PD deficient or suffering sickle-cell anemia. You can simply eat too many  broad beans and you can achieve the efficacy of the proper antimalarial drugs. That is why people in malaria infested regions, when consuming fava beans, were protected against the fast and deadly spread of the parasite in their bodies. And now you know that when people lack one or both of these crucial enzymes enzymes are protected also, but suffer serious side effects or even die when consuming drug or food which further overwhelms the redox regulation inside their red blood cells. Similar effect have lima beans of New World, the glycosides of which turn to small but potent amounts of cyanide, achieving similar result as fava beans.

On the other hand, when people know how and when to handle and prepare the beans, they can significantly reduce the negative impact of their consumption, even when they are the enzyme deficient.  This includes using specific herbs during cooking that help to neutralize the potent glycosides.

The remaining portion of this chapter talks more specifically about how to reduce the negative impact of fava beans consumption, bringing more information from different parts of the world, such as Hawaii or Egypt. You will learn about other ways to fight malaria without the “physiological costs of genetic predisposition”. This included some common herbs and spices which were also pro-oxidants or, on the other hand, anti-oxidant spices to neutralize the fava glycosides, depending on the specific purpose of the meal or treatment. Here I realized how potent the plants are in influencing our health and that even many common herbs can do a great job as part of food. These plants are rich in various compounds which they use for their own protection and survival and when people learn how to use these properties correctly, it will be for their good.



Chapter 1: Discerning the histories encoded in our bodies

Chapter 2: Searching for the ancestral diet

Chapter 3: Finding a bean for your genes and a buffer against malaria

Chapter 4: The shaping and shipping away of Mediterranean cuisines

Chapter 5: Discovering why some (don’t) like it hot

Chapter 6: Should we change places, diets or genes?

Chapter 7: Rooting out the causes of disease

About "" Has 48 Posts

Graduated at London Metropolitan University: BSc (Hons) Human Nutrition in 2014. Working as a research assistant at the MRC, The University of Cambridge.

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