“What makes the human superior to field animals?” So mused King Solomon, the wisest man of his times (10th century BCE), in Proverbs. Since then the question of how humans are different from animals has occupied the best minds of the human race. That ranges from Plato in the 5th century BCE to the molecular biologists, neurobiologists, neuropsychologists, and philosophers of the 21st century. For a long while, we thought that it was intelligence that set us apart. But, we now know better. Whales, dolphins, crows, parrots, and apes, to name a few, have been shown to possess a high level of intelligence. Then we wondered if it was our self-awareness that makes us unique? Not quite. Apes show various degrees of self-awareness. So, is it our communication skills? They are indeed highly developed but, again, they are not unique. Whales, 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. However, have you seen a mother elephant grieving over her dead infant? Or her whole herd commiserating with her? And, what about the African buffaloes who form a protective shield around a female who is giving birth in order 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. That being said, there are some characteristics of humans that are truly unique and different from “lower animals.” Let’ explore some of them. Our exceptional neurobiology allows us to plan for the future Daniel Gilbert points out in his bestseller “Stumbling on Happiness” that “The human being is the only animal that thinks about the future.” And he adds a significant caveat, “…the long-term future.” Now, my dog does seem to plan for the near future (minutes from now). He stations himself by his food bowl about 9 AM when his breakfast time rolls around. And he starts to bark at me when it is time for his afternoon walk. But is he planning to send his offspring to dog school? Does the silverback gorilla in the impenetrable forest of Uganda worry about the potential effect of global warming on the food supply for his troupe 5 years from now? Not that we know. In fact, experimental evidence suggests that they don’t. Whatever looks like a long-term pre-planned activity in animals, like birds building a nest for the future chicks, is believed to be the result of genetically pre-determined, automatic behavior. If we accept the notion that we are only animals that plan for the future, then it begs the question: What is the underlying genetic and neuronal basis for such a breathtaking jump from an animal living in the present to one that is worried about the future and is planning for it? As an extension of that, let me add the observation that we are the only species that, as part of our awareness of the future, wonders about our role in the world, and is concerned (frightened?) about dying one day The progress of evolution Before we examine the changes in the brain that made it possible for us to plan for the future when our closest evolutionary cousins, the great apes, apparently cannot, let’s take a look at how evolution progresses. Kelley Harris, now an Assistant Professor of Genome Sciences at the University of Washington studies the evolution of mutagenesis. That is, how genomes change over time to produce variations in traits of humans and other animals, including some that allow new species to emerge. The popular “molecular clock” model of natural selection posits that mutation rates evolve very slowly over, perhaps, tens of millions of years. This is the basis of the gradual quantitative accretion of mutations during evolutionary time. For example, our biological clock and that of the lowly yeast are very similar. Yeast emerged about 1.5 billion years ago, archaic Homo evolved about 600,000 years ago. Modern H. sapiens about 300,000 years ago. Think of that, over a billion years and hardly any significant genetic change in that trait. Harris’s work, however, demonstrates that DNA replication fidelity is a lot like other biological traits, sometimes evolving at a snail’s pace and sometimes evolving by leaps and bounds for reasons that usually elude us. The evolution of our brains One could speculate, then, that if there is a qualitative difference between us and our closest relatives, the gorillas, chimps, and bonobos, it must have been one of those “leaps and bounds” that Harris’s work demonstrated. But why speculate? An international team of 38 scientists led by Nenad Sestan of Yale University published a magnificent accomplishment in the quest to understand what makes the human brain unique. The investigators focused on 16 regions of the brains of adult humans, chimpanzees (ape), and macaques (monkey) involved in higher-order cognition and behavior. They looked at the genetic information in the cells of these regions by sequencing the total mRNA of each cell. mRNA is the molecule that transcribes a gene from the DNA code into a protein. The total population of a cell’s mRNA is known as its transcriptome. Then they went further. They overlaid the data of each cell’s transcriptome on histological sections of these tissues. They did this so they could get an integrated picture of every cell in a tissue, including its genetic and protein content. Human-specific cells In addition to all kinds of variations in the molecular and cellular features between humans and chimpanzees, there was one finding that takes your breath away. They found some rare cells that are present in humans and are completely absent in chimpanzees and macaques. These human-specific cells are located in the striatum, a nucleus (an agglomeration) of neurons in the midbrain. The name, striatum, comes from its appearance as stripes of gray and white matter. Some cells in the striatum are activated by the neurotransmitter dopamine. They are known as dopamine interneurons. Functionally, the dopaminergic (dopamine-responsive) striatum cells coordinate multiple aspects of cognition, including motor- and action-planning, decision-making, motivation, reinforcement (which carried to an extreme can end up in addiction), and reward perception. The newly discovered human-specific cells (called dopamine interneurons) were found to secrete dopamine. And, these interneurons, in turn, activate the dopamine responsive neurons. Could it be that this is the location in the brain that makes us exceptionally, well…human? We simply do not know yet. Some unanswered questions There are still some important unanswered questions: Exactly which cells in the striatum do those dopamine interneurons communicate with? What functions do these cells perform? But Daniel Gilbert’s observation that humans are the only animals that think about the future may be getting a solid cellular and molecular basis. Although we don’t yet know if the anatomical finding and the psychological observation are at all related, these findings are nevertheless, quite intriguing. Anatomically, we are the only mammals that have this specific dopaminergic cell type. And we are apparently the only animal that engages in long-term planning. But that isn’t the only way in which we differ from other animals. Let’s examine another fascinating way in which we are unique. What on earth is 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 in actual fact, he is 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. They are basically dumb molecules. They have 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 la petite difference N-acetylneuraminic acid (top) and N-glycolylneuraminic acid (bottom)What kind of polysaccharides cover the cell surface? In humans, the most common is a type of sialic acid called N-acetylneuraminic acid or Neu5Ac. 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-glycolylneuraminic 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! (It’s shown in blue in the graphic.) In fact, Varki found that a mutation in the enzyme involved in the synthesis of Neu5Gc rendered it inactive. That’s how we humans ended up with Neu5Ac. In a 2019 study published in the PNAS Varki’s group showed that this human-specific genetic mutation affecting cell-surface may be one other factor. They also show that the same mutation can help explain the apparently human-specific increased risk of CVD events associated with red meat consumption. Now, here is a mutation that is not merely anthropologically intriguing, it probably of paramount importance in understanding our uniqueness in developing coronary artery disease that may be related, in part, to the consumption of red meat. 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 compared to their ancient evolutionary cousins, the chimps and bonobos? The answer is not known yet, but Varki points out a tantalizing clue. Humans are not susceptible to a type of malaria organism that afflicts our ancient ancestors the chimpanzees. That organism is Plasmodium reichenowi. This parasite attaches itself to the cell surface by binding to Neu5Gc and we don’t have it – so we don’t get it. 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 maybe 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 it evolved in Africa, alongside the evolving humans. Further, it accompanied the bands of early humans as they migrated out of Africa. This is not the only disease that we acquired by becoming human. Asthma is pretty unique to us, as is rheumatoid arthritis, and Alzheimer’s, and Parkinson’s. 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. The bottom line Humans have always thought of themselves as exceptional and unique. However, some of our early ideas about our uniqueness have been debunked. We are not the only animals that are intelligent and we are not the only animals that can communicate with each other. That being said, some amazing science has demonstrated that there are some intriguing ways in which our behavior and even our biochemistry have truly rendered us one-of-a-kind. Source
