The Color of Blood and “Exohematology”

David Steensma, MD
Edward P. Evans Chair in MDS Research and Institute Physician at the Dana-Farber Cancer Institute; Associate Professor of Medicine at Harvard Medical School; Editor-in-chief of ASH Clinical News

Spilled blood’s brilliant red color has a rich symbolic history. The crimson color chemistry of porphyrin-bound iron ions led our ancestors to equate red with life and vitality – and with danger and murder, too. It is no accident that the reddest planet in our solar system, Mars, is named after the Roman god of war. From the ochre rock painting of prehistoric Australia and the famed Lascaux Cave, to Lady Macbeth’s unwashable hands, Stephen King’s deeply disturbing Carrie, and (spoiler alert!) the tragic origin story of the eponymous fiddle in The Red Violin, scarlet hues have long been used by artists to signify shed blood.

But what if blood weren’t red? There is no biological reason that our blood needs to be that color, no specific physiologic problem for which evolving liquid with a ruby tint, instead of emerald or amethyst, is the best possible solution. It is merely a physicochemical accident. How might art, literature, history, and religion be different if, instead, human blood were the color of the sky, the sea, or the Sahara?

Recent advances in astronomy – especially the discovery of water on Mars, and detection of an abundance of Earth-like exoplanets – increase the likelihood that there is life elsewhere in the universe. NASA now estimates that, in our galaxy alone, there are at least a billion rocky, Earth-sized planets orbiting yellow-orange G-class stars like our Sun within a “habitable zone.” If we humans don’t annihilate ourselves through anthropogenic climate change, zombie apocalypse, or nuclear war, we may someday discover strange new organisms that circulate an entirely different liquid from what we know on Earth. If we ever do find a creature on another world with a substance resembling blood, will it, too, be red?

If we ever do find a creature on another world with a substance resembling blood, will it, too, be red?

In the meantime, as we wait patiently for extraterrestrial contact and the remarkable scientific discoveries that would result, we can learn about some of the possibilities for alien blood by observing the diversity of creatures right here on our home planet. Almost all vertebrates have hemoglobin-containing blood, yet there are plenty of terrestrial precedents for non-red circulatory fluid.

The aptly named green-blooded skink of New Guinea is one such variant: It has hemoglobin, yet its blood and muscles are lime-colored, due to enormously high concentrations of biliverdin. (The function of this high biliverdin level, lethal to non-skinks, is unknown.) Human blood also occasionally takes on shades other than red, such as the greenish tinge of sulfhemoglobin or the chocolate-brown hue of methemoglobin.

It is a common misconception, reinforced by schematic diagrams in textbooks like Frank Netter’s Atlas of Human Anatomy, that human venous blood is blue. Even in hypoxic conditions when venous blood is almost black, it still retains a mahogany tint. The more socially pernicious concept of elite “blue blood” originated with the Spanish sangre azul, a medieval term used by leading Iberian families to underscore their nobility. But this descriptor was really about melanin, not hemoglobin. Rich, pale-skinned Spaniards would point to the veins on their forearms to highlight that they were not descended from darker-skinned Moors; because they did not need to work outside, they were not tanned. In fact, human “blue blood” is a result of light scatter from the walls of deep blood vessels, not the blood within the vessels.

An octopus, in contrast, has genuinely blue blood. The octopus uses hemocyanin as a respiratory pigment. Hemocyanin is a copper-containing cell-free substance that is a brilliant sapphire when oxygenated and nearly colorless when deoxygenated. Its relative inefficiency as an oxygen transporter compared with hemoglobin has not prevented its use by other mollusks and arthropods. Insects, spiders, lobsters, and lower arthropods with an open circulatory system also have hemocyanin in their blood equivalent, hemolymph, but they don’t seem to use it for oxygen transport.

The sea squirt and a few related marine organisms have yet another kind of pigment in their “blood”: vanabin, a vanadium-binding metalloprotein that can be green, blue, or orange and circulates in a cell called a vanadocyte. Older reports suggested that this vanadium chromagen reversibly transports oxygen like hemoglobin and hemocyanin, but more recent studies have clarified that hemovanadin is not actually a respiratory pigment, and its precise function remains mysterious even to senior “squirtologists.” Curiously, the squirt’s heart flips the direction in which it squirts “blood” every few minutes – almost as often as the weather changes in New England or the Cleveland Browns sign a new quarterback.

The sea squirt also reminds us that an element need not be abundant in the environment to be used by an organism. Hematologists knew this already, given how common iron deficiency is in the population and iron’s rarity in the Earth’s crust. Vanadium ranks 31st in the abundance list of elements found in the oceans, averaging less than 1 part per billion in sea water, yet the squirt and its relatives can concentrate it more than 100-fold to make vanabin. Whatever vanadocytes do for the squirt must be important.

There is other odd blood underwater, too. Leonard Zon, MD, at Boston Children’s Hospital, bestows wine-inspired names on the pale strains of mutant zebrafish his lab uses to study hematopoiesis, including shiraz, Sauternes, Chianti, and zinfandel. The anemia of these fish make their blood hue fall short of the darker color of vintage Burgundy or of Brunello di Montalcino.

While Dr. Zon’s fish are genetically engineered artificial human creations, the ocellated Antarctic icefish, a scaleless organism that has clear-colored blood lacking both hemoglobin and hemocyanin, evolved naturally. As the icefish lives only in frigid parts of the Southern Ocean, and cold water can hold a higher dissolved concentration of oxygen than warm, icefish apparently get enough oxygen by simple diffusion – common among small insects, but incredibly rare for a vertebrate. Whether icefish blood also is “thicker than water” is something one would need to interview a variety of extended icefish families to confirm.

Transitional metals in the d-block of the periodic table have the optimal atomic properties for reversible oxygen binding, and also tend to have a particularly vibrant color palette. It is possible to imagine organisms that might use cobalt, iridium, or manganese instead of iron or copper as a reversible oxygen transporter. Chemists tell us that coboglobin would be light pink if oxygenated and amber-yellow if deoxygenated, while a manganese metalloprotein is likely to be pink, purple, or brown. There’s a precedent for a cobalt-containing porphyrin pigment: We call it vitamin B12.

Speculative fiction often explores non-human biological possibilities, including alien hematology. Star Trek’s Mr. Spock famously had green blood, allegedly because the Vulcan oxygen-containing pigment is, like that of the octopus, copper-based. Star Trek’s writers were likely more familiar with how copper roofing material oxidizes to green than they were with blue-blooded terrestrial arthropods. Since Spock was half-human, we must assume the green gene is dominant over red, unless his stem cells are chimeric and green hematopoiesis dominates. Incidentally, Vulcan “green cells” – we can’t call them erythrocytes or red cells – are lentil-shaped rather than biconcave. Ash, the nearly immortal android in 1979’s creepy Alien, “bled” a sticky white goo. Video game and anime characters often spray pixelated orange, yellow, black, or purple liquids when injured, just to emphasize how weird they are.

A few years ago, I rewatched Steven Spielberg’s E.T. the Extra-Terrestrial with my daughters. There is a bizarre moment in the resuscitation scene near the end of the movie – a scene that terrified me at age 11 and also brought tears to the eyes of my then-similarly-aged girls. Just before E.T. is given an injection of bretylium (!) and defibrillation is attempted, a scientist working on an oscilloscope-like green monochrome instrument in the background of the isolation tent announces that E.T.’s DNA has six different base pairs instead of four. How it was possible to discover this basic biology fact in the midst of a code – in 1982, no less – is left unexplained. Nor is there any discussion of why E.T.’s species would need to be able to encode at least 215 amino acids (i.e., 63 minus a stop, if his cells used three-base codons), a critical biological question perhaps edited out to make room for Reese’s Pieces product placement.

Some years ago, I attended a NASA-sponsored conference on astrobiology in Washington, DC. Astrobiology, sometimes called exobiology, is an evolving interdisciplinary field that focuses on the origin, distribution, and future of life, wherever it might be found in the universe. I had a wonderful time at the meeting, in part because it was so interesting scientifically and in part because it can be fascinating to walk into someone else’s world for a while and just listen and learn. Instead of the presentations on sickle cell disease or leukemia I was used to, the astrobiology conference’s plenary session featured talks about the design of interplanetary probes and some new discoveries in archaebacteria genomics. There was even a keynote lecture by Harrison Schmitt, the most recent human to have walked on the moon (Apollo 17, December 1972).

As always with space exploration, questions were raised at the conference about whether such costly, high-risk science and engineering is justifiable in a world with entrenched poverty and so many social ills. A reader of this essay might ask a parallel question about whether it is worth devoting space in an ASH publication to exploring the possible configurations of extraterrestrial blood. It is a fair question, but, at some level, science is its own reward. And comparison with different possibilities can make us think differently about our own blood, beginning with its color, and imagine how it might have been otherwise.