The Doctor Weighs In

By Dov Michaeli MD, Ph.D

“What makes the human superior to field animals”? So mused King Solomon, the wisest man of his times (10^th century BCE), in Proverbs. Since then this question has occupied the best minds of the human race, from Plato in the 5^th century BCE to the molecular biologists, neurobiologists, neuropsychologists and philosophers of the 21^st century. For a long while we thought that intelligence set us apart. We now know better; whales, dolphins, crows, parrots, and apes, to name a few, have been shown to possess a high level of intelligence. Is it our self-awareness that makes us unique? Not quite. Apes are showing various degrees of self-awareness. Is it our communication skills? They are indeed highly developed, but they are not unique; whales and dolphins, birds and apes – all communicate via quite complex languages. It has been suggested that our capacity to feel and show empathy is uniquely human. Have you seen a mother elephant grieving over her dead infant? Have you ever seen the whole herd commiserating with her? Have you heard of the African buffaloes who form a protective shield around a female who is giving birth, to ward off predators and vultures? In short, we are becoming increasingly aware that all these “human” traits started evolving millions of years before the first human descended from the trees to take his first tentative steps in the African savannah.

Glycobiology

In an article in Nature magazine, Bruce Lieberman reviewed the fascinating work of Ajit Varki of the University of California , San Diego . Dr. Varki is trying to uncover the mystery of human uniqueness. Now, if you guessed that Dr. Varki is a trained anthropologist, or a neurobiologist, or even a philosopher – I wouldn’t blame you; these are the usual suspects in this field. But a glycobiologist? What’s that anyway?

Glycobiology is the study of sugars in biology. Until quite recently this field was the backwater of biochemical research. And why not? DNA could crow about its function in storing all our genetic information. RNA could claim to be the crucial bridge between the information stored in DNA and the formation of proteins. And proteins had bragging rights as the machinery of life, performing all the functions that are critical for any living organism. But sugars? These molecules can be solitary or monosaccharides, such as glucose or fructose, or can form chains called polysaccharides. But they are totally unglamorous; glucose provides energy to the cell. Polysaccharides mainly cover the cell surface. Basically dumb molecules; none of the sophisticated functions of information storage or enzymatic activity.

Now bear with me for a second, and don’t get intimidated by the chemical terminology; you’ll be rewarded with an amazing insight.

Vive le petit difference

What kind of polysaccharides cover the cell surface? In humans the most common is a type of sialic acid called N-acetyl neuraminic acid, or Neu5Ac. But Dr Varki discovered that we are the only animal that has this molecule exclusively. All other animals have a different sialic acid on their cell surface, called N-glycolyl neuraminic acid or Neu5Gc.

Look at the molecules. You don’t have to be a chemist to realize that the difference between us and the rest of the animal kingdom is tiny – one oxygen molecule!

In fact, Varki found that a mutation in the enzyme involved in the synthesis Neu5Gc rendered it inactive, and that’s how we humans ended up with Neu5Ac.

One small step in glycobiology – one giant step for humanity.

How so? For that we should ask a question that is basic to evolution: why did this mutation survive? What selective advantage did it confer on the newly minted humans?

The answer is not known yet, but Varki points out a tantalizing clue. Humans are not susceptible to the malaria organism that afflicts other species, Plasmodium reichenowi. This parasite attaches itself to the cell surface by binding to Neu5Gc, and we don’t have it. But on the other hand, chimpanzees are not susceptible to Plasmodium falciparum, the human malaria organism. So the overall picture is becoming clear: a single mutation allowed us to escape from at least one devastating disease, and may be more. This is an enormous selective advantage.

No free lunch

But after all we do get malaria, albeit from a different species (P. falciparum). Interestingly, genetic analysis of this species shows that the species evolved in Africa , alongside the evolving humans, and it accompanied the bands of early humans as they migrated out of Africa.

This is not the only disease we acquired by becoming human. Asthma is pretty unique to us, as is rheumatoid arthritis, and Alzheimer, and Parkinson’s, and the list goes on and on. Does the sialic acid mutation play a role in all those uniquely human diseases? We don’t know yet. But what we do know is that sialic acid, carpeting the cell surface, is critical to interactions between cells. And such interactions are critical to the immune response, to communication between neurons, to hormones binding to their target cells, etc, etc. It would not be surprising to find this molecule in the center of physiological and pathological processes that are, well, uniquely human.

So there you have it: one tiny difference in a single molecule, and what momentous consequences it has wrought.