19 October 2021

Sickle cell anemia: How our red blood cells evolved to fight malaria

Written by Dawn Teh

Malaria is historically one of the deadliest and oldest diseases known to man. Fossil evidence indicates that the current form of malaria is at least 20 million years old. And along the way, it's estimated to have killed over half of all humans who ever lived.¹

Despite the fact that modern medicine makes it treatable, 409,000 people around the world still died from malaria in 2019 while infecting over 229 million individuals.² Furthermore, nearly half of the earth's population continues to live in areas that have malaria transmission risk.³

What causes Malaria?

The culprit of this deadly disease is the microscopic Plasmodium parasites, which are most commonly passed on from person to person through the bites of infected female Anopheles mosquitoes.

When the parasites enter the body, they first travel to the liver to mature and multiply. But the real damage is done when they get released from the liver cells and attach to red blood cells. Once there, they feed off the hemoglobin found in red cells and continue to multiply. This eventually leads to cell rupture. When the parasites are released, they continue the cycle of infecting, propagating, and damaging other cells.⁴ ⁵ ⁶

Initial symptoms of malaria include fever, headaches, and chills, but it doesn't stop there. As the parasites multiply, it can dramatically reduce the number of healthy circulating red blood cells which are responsible for transporting oxygen around the body. This can lead to much more severe health complications like severe anemia and cerebral malaria (when parasite-filled red blood cells block small veins in the brain).⁷ In the most serious cases, malaria results in death.  

What areas are most affected by malaria?

Given that the main mode of malaria transmission is through the Anopheles mosquito, tropical parts of the world tend to be most affected as the conditions are ideal for the insect's survival. This makes regions like South America, South East Asia, and Africa particularly susceptible. The African region is the most greatly impacted by the disease as 94% of cases and deaths can be found there. People with lower immunity like children or pregnant women are also most at risk.

However, malaria hasn't always been a disease that's concentrated in hot and humid regions. In fact, more than half the world in terms of the land surface (53%) used to be at risk of malaria up till the 1900s. This has reduced to 27% as of 2002.⁸

Humanity's fight against malaria

How did humanity manage this dramatic reduction in malaria risk to significant areas of the world? A large part of this is due to a combination of advancements in medical treatment, increased use of insecticides targeting the mosquito population, and improved awareness of practical steps people can take to minimize chances of getting bitten (like the use of repellents or bed nets).⁹

Interestingly, it's not only the conscious effort of human innovation and planning that is continuing the fight against malaria. Researchers have found that our bodies are naturally evolving to reduce the hospitality of our red blood cells towards the malaria-causing parasites.¹⁰ This mutation in our blood is called sickle cell disease (SCD). The issue is that this defence is a double-edged sword. To understand how this is the case, we must first clarify the mechanisms of healthy red blood cells.

Sickle cell disease: Friend or foe?

The main purpose of red blood cells is to carry oxygen around the body. To do this, they contain the hemoglobin protein for binding to oxygen molecules and maintain a flexible doughnut shape to easily pass through the smallest of blood vessels.¹¹

In SCD, the hemoglobin's structure is altered which results in red cells developing a rigid, sickle-cell form.

This greatly interferes with the red cells' oxygen-binding abilities. Also, the sickle form causes them to get stuck and blocks blood flow.

The combination of these 2 factors leads to a lack of oxygen in different areas of the body. As a result, millions of SCD sufferers experience symptoms like intense pain, fatigue, organ damage, infection susceptibility, and early death.¹² ¹³ ¹⁴

The history of how red blood cells have evolved to better combat malaria

Over 70 years ago, it was discovered that SCD was caused by a specific genetic mutation. Those that inherit the sickle gene from each parent (resulting in a pair), will experience the most severe form of SCD — commonly known as sickle cell anemia (HbSS). However, those that inherit only one sickle gene (the other inherited gene is normal), usually have no symptoms and are able to live normal lives. Such cases are termed sickle cell trait (HbAS), and they can still pass on the sickle gene to their children.¹⁵ ¹⁶

The question that had baffled researchers for years was why this genetic blood mutation continues to persist despite its serious consequences. The theory of natural selection would assume that something this harmful should have been evolutionarily eliminated to ensure survival.¹⁷

So why is it still around? It turns out that despite its life-threatening symptoms, SCD has some favourable health benefits — it protects us from malaria. The theoretical link between SCD and its malaria-protecting effects first came about after researchers started examining why SCD is so prevalent in areas where there is a high risk of malaria. For example, sub-Saharan Africa carries more than 75% of the global SCD burden, which is where malaria also remains endemic.¹⁸

Since the 1940s, researchers also found that 10-40% of their population in these areas have SCD mutation.¹⁹

Since then, other research has further confirmed the theory that SCD is an adaptation to counter malaria — especially when we look at sickle cell trait cases (those with 1 normal gene and 1 sickle gene). In such individuals, malaria risk drops by up to 30%, which is a significant level of protection.²⁰

However, questions still remain as to how exactly sickle cell trait reduces the risk of malaria. The one thing researchers agree on so far is that it's probably dependent on a mix of complicated biological processes. This includes mechanisms like:²¹ ²²

  1. Reducing parasitic growth in red cells

  2. Interfering with their pathogenic processes (for example, reducing infected cells' ability to "stick" to blood vessel walls and cause cerebral malaria) 

  3. Increasing our body's protective, anti-inflammatory response to malaria

  4. Activation of immune response to clear malaria-infected red cells from the body

Understanding how our body is naturally fighting malaria isn't just for the advancement of knowledge. It's also crucial for developing better prevention and treatment strategies for malaria. For example, some experts have suggested developing a vaccine that induces controlled sickling of red blood cells.²³

What's next in malaria treatment?

Currently, the standard treatment for malaria consists of antimalarial drugs that interfere with the lifecycle or survival of the Plasmodium parasite at different developmental stages. And the results of their effect have been positive — worldwide malaria deaths have dropped 60% between 2000 to 2015 because of antimalarials.²⁴

Unfortunately, the war with malaria is still far from over as the enemy continues to evolve as well. The Plasmodium parasite has already developed resistance to one of the earliest antimalarial drugs developed — Chloroquine. As a result, it's rarely ever prescribed anymore. Artemisinin-based drugs, which are currently the fastest-acting treatment for malaria, have also started showing reduced effectiveness in South East Asian regions over the last decade.²⁵ ²⁶

Scientists are working tirelessly to create new antimalarials, and some promising results have been shown by recombining existing drugs.²⁷ But researchers are now looking at treatment options from a different angle, and are saying gene-editing may be the solution. Interestingly, these experts from Imperial College London aren't talking about changing the DNA of humans. They're doing it to mosquitoes. Using CRISPR-Cas9 technology, scientists have been able to insert a gene that results in the expression of an anti-malarial protein in mosquitoes.²⁸

Not only that, they've managed to do this as part of a gene drive — a method of genetic engineering that dramatically increases the chances of future generations inheriting the edited gene.

When a normal mosquito breeds with another that has the gene drive package, the offspring inherits a set of normal chromosomes and another set with the drive. What happens is that the drive is able to cut and copy itself onto the normal chromosomes so that there will be 2 copies of the modification. This results in up to 100% of offspring having the edited gene, rather than 50%.²⁹

Of course, as this technology is still in its infancy, more testing to be done and ecological considerations need to be factored in when releasing genetically modified mosquitoes into the environment. However, this study has laid the foundation for how malaria might be controlled in the years to come. 

Can we conquer both malaria and sickle cell anemia?

As humanity continues to push on in the fight against malaria, we are concurrently trying to find solutions to non-adaptive forms of sickle cell diseases. And like malaria, genetic therapy is on the cards.

Current treatment options include the medication hydroxyurea (which reduces red cell sickling) and bone marrow transplants where healthy cells replace diseased cells (the bone marrow in the centre of blood cell production).³⁰ Although effective, several issues have been raised with these treatments. The long-term side effects of hydroxyurea are still unknown and bone marrow transplants are often inaccessible to many parts of the world.³¹

This is why the latest advancements in SCD are looking towards gene therapy for answers, and there are currently two ways it could work. The first option involves correcting the β-globin gene mutation that causes red cells to sickle. The other solution is to switch off the BCL11A gene which suppresses the production of a type of hemoglobin that is not susceptible to sickling — called fetal hemoglobin.

As the name suggests, fetal hemoglobin is usually produced while a baby is still in the womb. Its production gets shut down after birth by the BCL11A gene, and that's when adult hemoglobin (which is susceptible to sickling) production kicks in. Incidentally, genetic variations in those with less severe forms of SCD allow for fetal hemoglobin production into adulthood. So the strategy for this form of gene therapy is to recreate the adaptive mechanism that already exists in a percentage of those with SCD.³²

Of course, obstacles still exist even with this form of SCD treatment. The most significant of which is figuring out how to make them accessible to the areas where malaria remains endemic — which are usually poorer nations with inadequate health services. Nevertheless, lead researchers in the area are hopeful. The knowledge acquired through genetic therapy can still help in informing the creation of more accessible treatments to reach the people who need it most.³³ ³⁴

The past decade has seen great leaps in how humanity might solve both malaria and SCD issues. We may finally be able to say that we've conquered both diseases sooner than we think.

Sources:
  1. Portrait of a serial killer (2002)

  2. Malaria | World Health Organization

  3. Malaria's Impact Worldwide | CDC

  4. How Malaria Parasites Acquire Nutrients From Their Host (2021)

  5. Invasion of Red Blood Cells by Malaria Parasites (2006)

  6. Biology | CDC

  7. Malaria | Mayo Clinic

  8. Malaria was common across half the world – since then it has been eliminated in many regions | Our World in Data

  9. Malaria was common across half the world – since then it has been eliminated in many regions | Our World in Data

  10. How our red blood cells keep evolving to fight malaria | The Conversation

  11. Sickle Cell Anemia | Harvard Health Publishing

  12. Data & Statistics on Sickle Cell Disease | CDC

  13. Sickle Cell Anemia | Harvard Health Publishing

  14. How sickle cell protects against Malaria | Understanding Animal Research

  15. How sickle cell protects against Malaria | Understanding Animal Research

  16. What is Sickle Cell Disease? | CDC

  17. How sickle cell protects against Malaria | Understanding Animal Research

  18. Sickle cell anemia in sub-Saharan Africa: advancing the clinical paradigm through partnerships and research (2017)

  19. Mystery solved: How sickle hemoglobin protects against malaria (2011)

  20. Haemoglobinopathies and the clinical epidemiology of malaria: a systematic review and meta-analysis (2012)

  21. Hemoglobinopathies: Slicing the Gordian Knot of Plasmodium falciparum Malaria Pathogenesis (2013)

  22. Inherited Disorders of Hemoglobin and Plasmodium falciparum Malaria (2020)

  23. The winding road to developing a malaria vaccine. Study hypothesis. (2012)

  24. Fake drugs are one reason malaria still kills so many | The Conversation

  25. How our red blood cells keep evolving to fight malaria | The Conversation

  26. The clinical impact of artemisinin resistance in Southeast Asia and the potential for future spread (2017)

  27. The past, present, and future of anti-malarial medicines (2019)

  28. Converting endogenous genes of the malaria mosquito into simple non-autonomous gene drives for population replacement (2021)

  29. Self-destructing mosquitoes and sterilized rodents: the promise of gene drives (2019)

  30. Complications and Treatments of Sickle Cell Disease | CDC

  31. Complications and Treatments of Sickle Cell Disease | CDC

  32. Gene therapy: Erasing sickle-cell disease (2017)

  33. Gene therapy offers hope for treatment of sickle cell anaemia (2016)

  34. From Malaria To Sickle Cell Disease: How Gene Editing Technology May Change Healthcare | Forbes

The author, Dawn Teh, is a health writer and former psychologist who enjoys exploring topics about the mind, body, and what helps humans thrive.

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