Did you know that the Antarctic icefish (comprising 16 species in the suborder Notothenioidei, family Channichthyidae) is the only vertebrate known to lack red blood cells and therefore to rely on diffusion-based transport of dissolved oxygen in the blood?
To place this remarkable finding in context, let’s start with first principles. In multicellular organisms that possess a heart, oxygen delivery is a function of cardiac output and oxygen content of the blood. Cardiac output, in turn, is positively correlated with the mean arterial pressure and negatively correlated with total peripheral resistance. According to Poiseuille equation, which describes the flow of a Newtonian fluid through a long cylindrical pipe of constant cross section, vascular resistance is determined by vessel radius (negative correlation to the power of 4) and blood viscosity (positive correlation). Oxygen content is determined by hemoglobin concentration and % oxygen saturation of hemoglobin. Since oxygen is poorly soluble in water or plasma, it normally contributes little to the oxygen carrying capacity of blood and can be ignored when considering oxygen delivery in humans. Let’s review these relationships in the form of equations:
Oxygen delivery = cardiac output x oxygen content of blood (Equation 1)
Cardiac output = Mean arterial pressure/total peripheral resistance (Equation 1)
Oxygen content of blood = [Hemoglobin concentration x oxygen saturation] + pO2 x 0.003 (Equation 2)
Hemoglobin, then evolved to optimize the oxygen carrying capacity of blood. Some invertebrates carry hemoglobin (or other respiratory pigments) in solution in their blood. Vertebrates, by contrast, package hemoglobin inside red cells, where it is protected from oxidative damage, and where oxygen binding can be finely tuned according to allosteric and cooperative interactions (giving rise to the S-shaped oxygen dissociation curve).
In addition to considering oxygen delivery to the tissues, we also need to consider oxygen consumption. That is, of the oxygen delivered, how much is actually taken up and utilized by the mitochondrial furnaces of cells. This is a function of both oxygen diffusion and mitochondrial density and function. According to Fick’s equation (Equation 3), oxygen diffusion is positively correlated with the concentration gradient and area of gas exchange surface, and negatively correlated with diffusion distance and thickness of the exchange unit.
Enter the Antarctic icefish. We are not just talking about a fish with severe anemia. No, we are referring to a creature that has complete absence of red cells and hemoglobin. First discovered by Norwegian biologist, Ditlef Rustad, in 1928, these fish have stark pale white gills and translucent milky-white blood (Figure 2). Mutations leading to the Hb-less state occurred once during the evolution of icefishes, about 8.5 million years ago following a drop in the temperature of the Southern Ocean. All 16 species within the Channichthyidae family lack hemoglobin as a consequence of a multi-step mutational process that has resulted in loss of the β-globin gene and partial deletion of the α-globin gene 1
How is this possible? How can members of a single family of fish defy an otherwise universal rule (law?) that all vertebrates possess red cells and in the process overthrow the common perception that hemoglobin (Hb) is necessary to sustain vertebrate life? And why? Is there a fitness advantage associated with loss of erythrocytes and hemoglobin? If not, how has such a trait survived the rigorous filter of natural selection? The question how requires a proximate explanation, the question why an evolutionary explanation. We will consider each explanatory framework in turn.
Because these fish do not have hemoglobin, their oxygen delivery can be simplified according to the following equation:
Oxygen delivery = cardiac output x oxygen content of blood
Cardiac output = Mean arterial pressure/total peripheral resistance
Oxygen content of blood = pO2 x 0.003
In the absence of hemoglobin, oxygen transport in blood relies on whatever gas is physically dissolved in plasma. Stated another way, oxygenation occurs purely through diffusion-based transport of dissolved oxygen in the blood. As a result, icefish blood has a 10-fold lower O2-carrying capacity compared with that of closely related red-blooded species). That’s a huge deficit! Is the fish so tiny that it can obtain all its oxygen from simple diffusion? No. The Antarctic icefish attain body lengths up to 25–50 cm. Have they managed to reduce their metabolic rate to 1/10 that of their Hb-carrying counterparts to match the reduction in oxygen content of the blood? In Antarctic fish, metabolic rates are low, but not that low. Have they benefitted from the frigid cold waters of the Southern Ocean (averaging around -2.0 degrees C year-round), which helps to optimize oxygen availability in the surrounding water (whose temperature is matches that of the environment)?[Efn_note]Oxygen solubility in seawater is inversely proportional to temperature [/efn_note] Most assuredly yes, and since fish are poikilotherms, their plasma enjoys the same cold-dependent advantage in oxygen availability.
But we are only scratching the surface with our explanation of how icefishes accomplish the seemingly impossible task of adequately delivering oxygen to tissues with a blood oxygen-carrying capacity only one-tenth of red-blooded species. The icefish exhibits an extensive suite of compensatory cardiovascular modifications that enhance oxygen delivery to tissues:
- Blood volume is 4x greater than that of red-blooded fishes, which optimizes preload and therefore cardiac output.
- Heart-to-body mass ratio of icefishes is greater than that of red-blooded fishes, resulting in a five-fold greater weight-specific cardiac output. This ensures not only increased oxygen delivery but also maintenance of a high pO2 gradient between capillaries and tissue
- Blood vessel diameter is 2-3x greater than most red-blooded fishes, reducing total peripheral resistance (see Poiseuille equation).
- Capillary density is higher in some tissues compared with red-blooded fishes. This minimizes diffusion distance in Fick’s equation.
- Increased mitochrondrial densities in oxidative muscle. This results in increased oxygen utilization and increased oxygen gradient across the cell membrane (an important determinant of diffusion in Fick’s equation).
Collectively, these adaptations, together with the low hematocrit, permit a large volume of blood to circulate throughout the bodies of icefishes at high flow rate and low peripheral resistance. Combined with the very high oxygen content of Antarctic waters and relatively low absolute metabolic rates, these unusual cardiovascular attributes ensure that adequate oxygen is delivered to tissues to support the aerobic metabolism of these animals.
Why on earth did the icefish buck the trend and lose their red cells? A central tenet in evolutionary biology is that gene mutations are selected for their fitness or reproductive advantage. One hypothesis, then, is that icefish lost their erythrocytes in order to minimize blood viscosity (hematocrit being the primary determinant of blood viscosity). However, even without doing the math, it seems unlikely that the benefit of reduced blood viscosity on cardiac output outweighs the disadvantage of a 90% reduction in oxygen carrying capacity of blood. Another possibility, unique to this particular environment, is that hemoglobin loss is a net-negative or neutral trait that evolved by chance and evaded quality control/elimination due to relaxed predator selection. Indeed, it is believed that niche competition in fish diversity dramatically crashed in the Southern ocean sometime between the mid-Tertiary and present. These extensive extinctions in the Antarctic fish fauna, together with the cooling of the Southern Ocean, likely contributed to the fortuitous survival of icefishes despite the loss of an otherwise essential trait (red blood cells and hemoglobin).
Global warming and the precarious future of the blood-less icefish
With climate change, and warming of the Southern Ocean, there is a real concern that the the Antarctic icefish will ultimately face extinction. In a wonderful piece for Scientific America, Ferris Jabr wrote:
The Southern Ocean is getting warmer and possibly more acidic and less nutritious. O’Brien [referring to a biologist with expertise in icefish] says researchers have shown that adult icefishes are more sensitive to changes in temperature than red-blooded fish—they cannot stand the heat. If Ruud [remember, he was the biologist who first identified the blood-less icefish] was right—that “only in the cold water of the polar regions could a fish survive that has lost its pigment”—then the ongoing changes to the Southern Ocean might be the icefishes’ undoing. Consider this version of their story: icefishes evolved to survive sub-freezing temperatures in one of the most extreme environments on Earth, only to lose their red blood cells to a genetic accident; despite the mishap, they kept swimming, expanding their hearts and growing more blood vessels to get enough oxygen around their bodies; now, people are turning the Southern Ocean into a habitat for which icefishes are completely unsuited, forcing them to adapt once again or perish. Personally, I’m clinging to the hope that even if icefishes do not have any hemoglobin in their blood, they have plenty of resilience coursing through their veins.
I hope you find these creatures as fascinating as I do!