Proximate and Ultimate Dichotomy

Some students have asked questions about the distinction between Proximate and Ultimate explanations for biological phenomena.

Workers have debated the utility of proximate and ultimate causation since Erst Mayr introduced the concept in 1961. See: Mayr E. 1961. Cause and Effect in Biology. Science 131: 1501–1506. It can be confusing, and I gave it a very brief overview in class.

The point I want to make is that most biomedical researchers do not think in explicitly evolutionary terms. Most explanations in medical textbooks and medical journals like the New England Journal report mechanistic explanations for the physiology and pathophysiology of disease. A pancreas cell stops making insulin, causing diabetes. Platelets clump together, blocking the flow of blood, causing a heart attack.  A trauma victim’s spleen ruptures, causing fatal hemorrhage.  Those are proximate explanations.  These proximate explanations explain disease the same way a car mechanic might diagnose your broken car: your car won’t start because the alternator is shot, or the battery is drained.

Ultimate causes are evolutionary causes. We talked about the blind spot in the retina, for example. A proximate explanation for the blind spot is this: Anatomically, the axons of retinal photoreceptors come together in one area of the retina to form the optic disc which passes through the globe to form the optic nerve. At that site there are no photoreceptors, thus the blind spot.  The Ultimate (evolutionary) explanation is different. We evolved from ancestors with a primitive retina in which the electrical conducting part of the primitive nerve lay between the light source and the light-sensitive part of the cell. During vertebrate evolution, that arrangement of proto-axon and proto-photoreceptor persisted such all modern vertebrates have apparently “backwards” retinal axons and a blind spot. We know that an alternate arrangement is evolutionarily possible, because octopus and squid have a complex eye without a blind spot. One ultimate cause has to do with the vertebrate family tree (phylogeny). Humans and all vertebrates have a family tree that includes a long series of ancestors with inverted photoreceptors. Presumably, early on and perhaps even now, there was little cost to having an inverted pattern, but once established, it became evolutionarily stable.

It is worth noting that for organisms with eyes like ours, it is likely that no series of genetic mutations could change the vertebrate eye to an eye arrangement like the octopus without imposing a large fitness cost on the early intermediates (they would likely be blind and would have a hard time reproducing). When a trait, or a disease, is explained in terms of an organism’s ability to reproduce, this is an adaptation argument. These adaptation explanations are also examples of ultimate causation.

As an example, a researcher might note that many cases of cancer of the cervix, a female reproductive cancer, are caused by a human papilloma virus. Thus a proximate cause of cancer, and an important one, is a viral infection. A student of evolutionary medicine might argue that a papilloma virus that interferes with its host cell’s ability to self destruct (apoptosis) might be more successful at establishing an infection. Further, a papilloma virus that promotes local growth of cells might make more copies of itself and be more likely to be transmitted to another susceptible human. Thus, viruses that induce those traits might have a reproductive advantage. This purported reproductive advantage for the virus is an ultimate explanation for the same trait.

The second point to be made is that both proximate and ultimate explanations can be true (or false) at the same time. I just gave two examples where both explanations might be true simultaneously. These explanations are not mutually exclusive. I will give an example. One researcher might give a presentation on “Lactose Intolerance” and explain that the deficiency of lactase is responsible for the symptoms of this syndrome. Meanwhile, an anthropologist might argue that populations with persistent lactase function can be explained by natural selection acting on human groups with a long history of cow milk consumption.  Both hypotheses might be independently true.

The key to making the distinction between proximate and ultimate causation in medicine to examine how the explanation is presented. If the explanation is descriptive, takes a reductionist approach, and seeks underlying mechanisms, it is likely a proximate explanation. If the explanation invokes evolutionary history, explains things in terms of reproductive success or changes in gene frequencies, or proposes a unappreciated benefit for genes that also cause disease, it is likely an ultimate explanation.

We will have much more to say about this topic during the course!

JA

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