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.

By Dov Michaeli MD, Ph.D

One of the more fascinating aspects of evolution is the continuous “battle of the species”; one species trying to fend off the attack of another, parasitic species. It is a classic warfare of measure/counter-measure, not unlike modern warfare. But unlike human warfare, a successful parasite is not the one that kills its host—that would spell  the demise of the parasite; that would be self defeating, won't it? Success is defined as the capacity to live off the host, and efficiently spread to other individuals. The host, on the other hand, is successful if it can avoid being killed by the attack and keep the attacker in check. And so we can see a battle of adaptations: a parasite honing its “skills” so as to attack, but not kill, just colonize; the host, adapting to the presence of the parasite, but keeping the damage to a minimum. You might say that both warring species arrived at an arrangement of co-habitation, or détente.

How can a species adapt?

Answer: by natural selection. Again, the example of warfare is most instructive. Imagine an enemy invading another country. As long as the invader can enjoy the abundant food and shelter the country provides—its chances of conquering this country are quite good. And if it doesn’t kill off the farmers who produce the food—it will continue to thrive in the conquered country. The British Empire is a perfect example of such “enlightened” colonization. But consider Napoleon in Russia, or Hitler in the USSR. The invaders’ brutality on the one hand, and the response of “scorched earth” strategy on the other, were ultimately responsible for the ignominious defeat of the invaders. Likewise, HIV or the Ebola virus are pretty lousy parasites: they kill their hosts. On the other hand, parasites like leeches are quite successful; nobody dies. The host may become weakened, and the leach “knows” to fall off when it is engorged with blood—but both sides survive to live another day.

Co-evolution

Now here is a truly interesting twist on the war between the species. Back to our warfare analogy. What if the conqueror conscripts all able bodied farmers to work the land to supply it with food, but spares the infirm? Wouldn’t that favor the survival of the infirm? If the conditions of labor under the conqueror are especially harsh and even deadly—then, of course, the spared sick people would constitute an increasing part of the population. So here is selection, albeit not quite natural, in action. Similarly, what would happen if a parasite infected a person with some genetic mutation that affected the parasite’s ability to survive? Obviously, the parasite would not survive, and the mutation, albeit deleterious, would confer a survival advantage on the person who carries it. And this is how a parasite that evolved to infect humans, can in turn cause a change in the human genome. If the infection is deadly enough, the individuals who possess the mutation would slowly constitute an increasing proportion of the population.

Malaria—the quintessential human parasite

Malaria, a tremendously successful pathogen that is responsible for more than 300 million cases and 1 million deaths annually, has had a large impact on the shape of the human genome. Malaria-selected mutations in human genes promote survival in areas where malaria is endemic. The parasite's substantive effect on the human genome is due to its high prevalence in areas where it is endemic and its long history of co-evolution with humans. Stop and think for a moment: we all came out of Africa at one point or another. So this lowly parasite had a hand in shaping our genome! Indeed, not only this one. We can find the fingerprints of hundreds of viruses and bacteria in our genome. What a perfect demonstration of the influence of the environment on our genes.

Several mutations that confer resistance to malaria have been identified. Interestingly, all of them interfere with the energy metabolism or with the synthesis of proteins of red blood cells. Why is this particular cell so important? Because the malaria parasite (Plasmodium falciparum) spends a phase of its life cycle in red blood cells, before moving on to the liver. Unsurprisingly, these mutations are prevalent only in areas were malaria is endemic. For instance, sickle cell anemia is prevalent in Africans and African Americans. Two other conditions, known as α and β Thalasemias are most prevalent in Africans and Mediterraneans. And yet another, known as G6PD deficiency, is prevalent among Jews and Saudis (could that form a basis for understanding between the warring neighbors?). All of these mutations inflict pain and misery on its carriers; but there is silver lining—they are all resistant to malaria.

A recent paper in the New England Journal of Medicine added another mutation to the roster: an enzyme known as PK (pyruvate kinase) which is important in, you guessed it, the energy metabolism of the red blood cell. The paper provides us with additional insight into the subtleties of “the war of the species”. We have two copies of each gene (each copy is known as an allele). If the mutation is in only one allele (the other is non-mutated, or wild type), the individual is quite healthy, and acquires moderate resistance to the parasite. But if the mutation is in both alleles, the resistance to malaria is absolute—but the person suffers from severe anemia. A medical case of “no free lunch”.

The subtleties of the struggle between invader and victim don’t end there. In addition to mutations affecting red blood cells, we have an immune response that jumps into action when confronted with the foreign invader. Furthermore, the immune response can differ between individuals in the variety of mechanisms that are employed (such as antibodies, blood cells called macrophages, other blood cells called lymphocytes). And this is just a small sampling of the variability ( called polymorphism) between individuals. But the invader doesn’t just give up and goes home. The malaria parasite evolved as a response to human polymorphism marked genetic diversity (polymorphism) of its own, which allows it to maximally adapt to the various defenses the host throws up against it, and continue transmission. As you can appreciate, co-evolution is an unending battle, where each side deploys new weapons, only to be countered but even newer weapons.

Why is it important?

Does anybody require a more compelling demonstration of evolution and natural selection in action? Or for that matter, let’s not forget the measure/counter measure war between bacteria and antibiotics. But let’s not get sidetracked by the bizarre politics of science in America. The rest of the world has accepted natural selection as a fact of life as we know it. I am sure we’ll catch up one day.

Why is the study of pathogen-selected host polymorphisms useful? Because it provides insight into naturally occurring mechanisms of host defense, which could be used to develop therapeutic agents to combat disease. The fight against malaria has been long and frustrating. Attempts to develop vaccines against the malaria organism all ended up in failure. A deeper understanding of the rules of war between us and the parasite, the measures and counter measures employed but the combatants, will give us a clue were the vulnerabilities of the enemy lie—and allow us to defeat it.