Jeffrey DeLo MD - Redheads TB text

Did tuberculosis create the redheads?

Given my recurring thesis infectious disease is the major impetus behind genetic adaptation, what created redheads?

First let’s review the history of tuberculosis, the most likely culprit.

Tuberculosis is an infection caused by a bacteria called mycobacterium tuberculosis. It thrives in damp, cool environments, with people huddled in close quarters, malnourished, with poor air quality. These conditions perfectly reflect the living conditions of England and northern Europe where tuberculosis ran rampant for centuries. In the 19th century, tuberculosis killed one-quarter of the population of Europe.(1) With such a deadly pathogen, we would expect to see adaptations. Not surprisingly, redheadedness is more common in areas such as England and Scotland where tuberculosis was rampant. London was considered the tuberculosis capital of Europe.(2)

Next, let’s examine the genetic cause of redheadedness

Redheads have a mutation in a gene called MC1R. This gene codes for the receptor on the surface of pigment-producing cells called melanocytes that produce a darker form of melanin called eumelanin. Melanocyte-stimulating hormone (MSH) from the pituitary gland binds to the MC1R receptor and stimulates melanocytes to produce eumelanin. Because of the mutated receptor in redheads, melanocyte-stimulating hormone (MSH) does not result in eumelanin production. The present thinking is the mutation occurred because people with lighter skin in northern regions produce more vitamin D. However, MC1R mutations have occurred independently all over the world, including sun-drenched Africa, and are responsible for lighter skin in Asians. This seems to argue against the theory that enhanced vitamin D production is the sole driver of redheadness.

Let’s examine next where MSH is synthesized in the body. MSH occurs as a breakdown product of a larger molecule called POMC secreted by the pituitary and hypothalamus.

As you can see in the above diagram, the breakdown products of POMC are three forms of MSH called alpha, beta, and gamma MSH, as well as ACTH, gamma lipotropin, and beta-endorphin. In redheads, MSH cannot exert its effect on the MC1R receptor, therefore we would expect the body to compensate by producing higher levels of POMC, thus increasing the levels of all the aforementioned substances.

The MSH molecules are interesting because, in addition to stimulating melanocytes to produce eumelanin, they also have anti-inflammatory and anti-microbial properties. They belong to a class of immune-boosting molecules called antimicrobial peptides (AMPs). AMPs modify the immune response and have a deleterious effect on many pathogens, including tuberculosis.(3,4) Higher levels would therefore protect against tuberculosis.

ACTH is similarly interesting as it alters the immune response like MSH. When a person is exposed to tuberculosis, white blood cells called macrophages attack the infection and attempt to wall it off in scar tissue called a granuloma. Unfortunately, this immune strategy can have an adverse outcome as tuberculosis survives “protected” inside the granuloma for decades only to reactivate with lethal consequences later in life. Tuberculosis for this reason is classified as a granulomatous disease. A close cousin of tuberculosis is sarcoidosis, another granulomatous respiratory disease. Sarcoidosis can be treated with ACTH, which modulates the immune response against granuloma formation. In fact, an ACTH analog called Acthar Gel is only one of two treatments FDA-approved for the treatment of sarcoidosis.(5) ACTH also stimulates the function of the adrenal gland. Higher levels of ACTH may maintain the health of the adrenal gland, an organ tuberculosis has a predilection to infect, and offer protection against adrenal failure.

And of course, there’s the vitamin D connection. Redheads produce more vitamin D (and MSH) when exposed to sunlight than those with darker skin. Higher vitamin D levels have been shown to protect against the reactivation of latent tuberculosis.(6)

The next time you see a stunning redhead, you can thank tuberculosis… and if I’m ultimately proven right, you read it here first.

Art by gabiwnomagic@

References

“The Next Pandemic - Tuberculosis: The Oldest Disease of Mankind Rising One More Time” British Journal of Medical Practitioners. Retrieved 26 February 2021.
Wilson, Frances. “How London became the tuberculosis capital of Europe.” The Guardian. Mon 26 Nov 2018
Preethi A R, et al. Antimicrobial Peptides as Immunomodulators and Antimycobacterial Agents to Combat Mycobacterium tuberculosis: a Critical Review. Probiotics Antimicrob Proteins. . 2022 Dec 28.
Jadhav, Krishna, et al. Taming the Devil: Antimicrobial Peptides for Safer TB Therapeutics. Curr Protein Pept Sci. . 2022;23(10):643-656.
Ogugua Ndili Obi, et al. Sarcoidosis: Updates on therapeutic drug trials and novel treatment approaches. Front Med (Lausanne). 2022 Oct 12;9:991783.
Patterson, B, et al. Int J Tuberc Lung Dis. Vitamin D deficiency predicts latent TB reactivation independent of preventive therapy: a longitudinal study. . 2020 Sep 1;24(9):916-921.