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

I vividly remember a conversation I had with a London cab driver just before the election that unseated John Major (Conservative party) and elected Tony Blair (Labor party). I asked him who he was going to vote for, fully expecting him to make a “rational” decision and vote his economic interests. But, to my astonishment, he was going to vote for the conservatives. Why? I asked in disbelief. The answer was shocking to me. I’ll paraphrase: “because we working class blokes should know our place. The Aristocrats have been running this country forever, and they have done a bloody good job at it. And every time labor got its hands on power they made a bloody mess”.

This episode was etched in my memory, so incredible and yet so profound it was. How to explain such reverence to social hierarchy? Is it a product of generations of social brainwashing? Shakespeare, himself not an aristocrat or even a minor noble, portayed with great disdain characters of low social standing who tried to reach beyond their class. But is it really just a function of culture? Did anything change in the USSR after the revolution, when all classes were abolished with the stroke of a pen (and a bullet, for added emphasis)? Definitely not. The peasant still “knew his place”, only the superior feudal, properly addressed as “gospodin”( sir, master) was replaced by a newly minted commissar, addressed as “tovarish” (comrade).

So if it’s not purely socio-cultural, what is it?

It’s all in your head

A wonderful paper was published in the latest issue of Neuron, the neurobiology magazine. It was authored by Caroline Zink, Ph.D., Andreas Meyer-Lindenberg, M.D., Ph.D., and colleagues of the NIMH Genes Cognition and Psychosis Program.

Prior studies have shown that social status strongly predicts health. Animals chronically stressed by their hierarchical position have high rates of cardiovascular and depression/anxiety-like syndromes. A classic study of British civil servants found that the lower one ranked, the higher the odds for developing cardiovascular disease and dying early. Lower social rank likely compromises health through psychological effects, such as by limiting control over one's life and interactions with others. However, in hierarchies that allow for more upward mobility, those at the top who stand to lose their positions can have higher risk for stress-related illness. Yet little is known about how the human brain translates such factors into health risk.

To find out, the NIMH researchers created an artificial social hierarchy in which 72 participants played an interactive computer game for money. They were assigned a status that they were told was based on their playing skill. In fact, the game outcomes were predetermined and the other "players" simulated by computer. While their brain activity was monitored by fMRI, participants intermittently saw pictures and scores of an inferior and a superior "player" they thought were simultaneously playing in other rooms.

Although they knew the perceived players' scores would not affect their own outcomes or reward -- and were instructed to ignore them -- participants' brain activity and behavior were highly influenced by their position in the implied hierarchy.

What did they find?

Key study findings included:

 The area that signals an event's importance, called the ventral striatum, responded to the prospect of a rise or fall in rank as much as it did to the monetary reward, confirming the high value accorded social status.

•  Just viewing a superior human "player," as opposed to a perceived inferior one or a computer, activated an area near the front of the brain that appears to size people up -- making interpersonal judgments and assessing social status. A circuit involving the mid-front part of the brain that processes the intentions and motives of others and emotion processing areas deep in the brain activated when the hierarchy became unstable, allowing for upward and downward mobility.
•  Performing better than the superior "player" activated areas higher and toward the front of the brain controlling action planning (prefrontal cortex), while performing worse than an inferior "player" activated areas lower in the brain associated with emotional pain and frustration (amygdala).
•  The more positive the mood experienced by participants while at the top of an unstable hierarchy, the stronger was activity in this emotional pain circuitry when they viewed an outcome that threatened to move them down in status. In other words, people who felt more joy when they won also felt more pain when they lost.

Surprise?

These findings are actually not very surprising. Anybody who ever observed monkeys and apes in their natural habitat could easily pick out the alpha male and female, and the submissive behavior of the rest of rest of the clan. But a more detailed observation reveals subtle gradations in social standing among the “lower class” members. Each member of the clan ”knew his or her place”, and acted accordingly. Furthermore, violations of the boundaries of social standing were promptly punished. Is it surprising then that a specific area in the brain, called the striatum, is dedicated to assessing one’s place in a group? Furthermore, it is located right behind the prefrontal cortex, the area that is making rational decisions based on the inputs that reach it from all areas of the brain. The proximity of the striatum to the prefrontal cortex reduces the time for a message to reach the decision-making circuits--a biological testament to the importance ascribed to social animals “knowing their place” in their society.

The experiment showing that in unstable hierarchies people at the top are just as anxious and stressed as people at the bottom is truly revealing. What is the societal equivalent to “unstable hierarchies”? Democracy, of course. Today you are on top, but your position there is constantly challenged, and eventually you have to give up your exalted position. Anybody who observed our presidents at the beginning of their term, and at the end, couldn’t fail but notice how much they aged. Even a clueless president like George W has aged noticeably.

What is truly remarkable in this study is the documentation of the existence of the ‘social brain’. It has long been hypothesized that areas in the brain are specializing in directing social interactions like emulation, attunement, empathy and altruism. This study provides unequivocal neuro-anatomical proof.

Welcome to Margaret (aka Maggi) Cary, MD, our newest TDWI writer.  Maggi is a Washington DC-based physician executive and writer who will share her stories about doctors and patients.  Here is her first TDWI post - a story she previously published in The Washington Post:

Answering a Cry for Help With a Touch of Humanity

By Margaret Cary

Special to The Washington PostMonday, November 7, 2005; C10

"My papers . . . my paaaapers."

I was at a Falls Church superstore checkout counter when I heard her cry. My first reaction to nonthreatening inappropriate sounds is to ignore them and leave the area as soon as possible.

"My papers . . . my paaaapers."

I turned to look and saw three store employees around a sobbing middle-aged woman. I returned to the checkout.

"My papers . . . my paaaapers."

I was tempted to just leave the store with my purchases and go on to the next errand. I walked toward the woman instead.

By now there were four people around her, all looking uncomfortable. Store security had arrived. I said, "I'm a doctor." They looked at me with the tiniest hint of relief.

It had been so long since I was in the doctor role that I took a few minutes to think this through. I am in administrative medicine, so I do not carry malpractice coverage nor am I licensed in Virginia. Fortunately the old training seems to be hard-wired and returned immediately.

Rising above all other thoughts in my mind was that this was a person in trouble. And the folks who would like to help her were at a loss. Mental health issues are still not understood. People with them are not given the same sympathy and patience given to heart attack victims or amputees.

I took stock of her: White female, between 50 and 60 years old, she looked well kept, was wearing clean clothes, gold jewelry -- just enough, not flashy, had a nice haircut and was sitting on the bench at the store's entrance, wailing. Stroke? Maybe, but not anything that affected her physical mobility. Yes, she was using a walker, but did not seem to favor one side. Her facial muscles were intact. She was perseverating, repeating the same phrase over and over. Maybe a mental challenge? Could be. You know how you know when pets are lost and not strays? They have the look that someone cares for and about them. She had that.

I sat on the bench beside her. I looked into her eyes and said: "I'm a doctor. Can I help you?"

I wanted to touch her, to make that human connection. Touching, now there is something that has changed in the last couple of decades. The only safe place to touch someone is on the shoulder and elbow and the upper arm. I took a chance and touched her forearm, then held her hand.

"My papers . . . my paaaapers."

She started to make a call on her cell phone and then handed it to me, seeming confused. No numbers saved. When I handed it back, she called a number and howled into the telephone. She handed the telephone to me again. I introduced myself and then asked with whom I was speaking. He told me he was her husband and that she had lost her prescription, but her brother, a doctor, would call in a new one. He could not come to get her because he had bad knees.

At the end of the call, she jumped up and started across the store, tears dried, and retraced the steps several store employees had already made, looking for her lost prescription. I walked alongside and called her husband. I asked him to explain to her that she would get a new prescription, which he did and she stopped.

I retrieved my cart and started to leave. "Thank you for your help," a store employee said. "You were really good with her." I sensed that the employee wished she could have done more for the woman.

"Anyone could do it," I said. It's about talking with someone at his or her level. It's also about the physical contact. I remember a teacher once telling me to touch patients or they might believe you thought they were untouchable. Of course, you have to be careful.

I thought to myself, we lose something by being afraid of each other.

I was relieved that store personnel had not called the police, which people sometimes do when others are acting oddly, seemingly without reason and creating a scene. That is often the quickest, easiest way to eliminate someone acting out of the ordinary. We are unused to helping someone who might benefit from our taking the time to listen. We don't know what to do and so calling the police or an ambulance often seems the most expedient solution. We still have a long way to go with mental health patients.

I reflected on my initial reluctance to get involved -- too busy, I might be sued, what can I offer anyway.

Fortunately, my core, unprocessed feelings came to the surface, overriding the cool, "sane" approach. I helped someone in trouble, one of the main reasons I went into medicine. That compassion and desire to be of service were still with me.

I headed for the door.

Dr. Cary is Director of the Washington, DC office of the Institute for Medical Leadership.

A recent paper in the Journal Nature, Damage to the Prefrontal Cortex Increases Utilitarian Moral Judgments  (Nature, advance online publication 21 March 2007),  has provided strong evidence that we are indeed moral animals, and that certain aspects of our moral behavior are hardwired in our brain. The institutions involved in this research (U. Iowa Dept. of Neurology, Harvard U. Dept. of Psychology, and the Brain and Creativity Institute at the U. Southern California) reflect the multi-disciplinary approach required for such a study.

Where in the brain is Morality?

Our brain is organized in layers, somewhat like an onion. The deepest layer, like the brain stem and the structures around it, is the most ancient, or primitive, from an evolutionary point of view. These structures control vegetative functions, like heart rate, breathing, gastrointestinal motility, etc. These functions are essential for life, and are shared by organisms from the most primitive to the most complex.

Next in evolution came another layer of behavioral complexity: diverse functions such as thirst, hunger, sexual attraction, fight-or-flight responses to danger, responses to day-light cycles, short and long term memories. These functions are mediated by structures deep inside the brain called the midbrain.  The midbrain contains structures, such as the amygdala (fight of flight, rage, aggression), the hypothalamus (hunger), the nucleus accumbens (reward, pleasure) and the hippocampus (memory). These functions are not voluntary; they are found in mice and humans alike.

A more recent layer of the brain tissue, called prefrontal cortex, was added when monkeys started to evolve. In this layer resides the ability to function as a social animal, for instance traits like empathy and moral judgment. The last and outermost layer, added relatively recently, is called the frontal cortex.  It is most developed in humans. Messages from the brainstem, midbrain and prefrontal cortex feed into this area (situated right behind the eyes), where they are all integrated, weighed, judged, contemplated—and then translated into action.

What did the Nature paper find?

It has been suspected for about 10 years that an area within the prefrontal cortex, called the ventromedial prefrontal cortex or VMFC, is required for emotions and moral judgments. When subjects in a brain imaging study were presented with a scenario requiring moral judgments, the area that lit up was the VMFC. What kind of situations were they? Highly aversive ones; for instance, sacrificing one person in order to save several other. The anguish of such decisions is captured in Sophie’s Choice, or in King Solomon’s famous trial of the two women.

The vast majority of people will recoil from making a “utilitarian” calculation of killing one person so as to save others. Indeed, in this experiment over 80% refused this option. But in a group of 6 patients who had some kind of pathology in their VMFC, such as an aneurysm or a tumor, the judgment was completely utilitarian—kill the few to save the many. No hesitation, no compunction. In fact, Antonio Damasio, one of the authors of present study, published a study in 1999 of two patients who have had a defect in their VMFC since infancy ( Nature Neuroscience vol. 2, pp. 1032 - 1037 (1999). As adults, the two early-onset patients had severely impaired social behavior despite normal basic cognitive abilities.  They showed insensitivity to future consequences of decisions, defective autonomic responses to punishment contingencies and failure to respond to behavioral interventions. The authors concluded: “Thus early-onset prefrontal damage resulted in a syndrome resembling psychopathy.”

What does it all mean?

The implications of these studies are enormous. For instance:

• We may finally get a handle on extreme psychopathic behavior, such as serial killing, serial raping, extreme levels of domestic violence.
• Our legal system will have to, sooner or later, come to grips with criminal behavior engendered by structural defects in the brain. Evidence of brain imaging (fMRI), is already being introduced in court, and juries are becoming receptive to the evidence.
• On a more hopeful note, but probably less imminent, we may learn one day how to intervene and enhance individuals' moral judgments. Wouldn’t that be a welcome development of this "1984 science?"

 Moral philosophers have dismissed evolutionary biologists and neuroscientists forays into the realm of ethical and moral judgment. They are now having second thoughts, and the more intellectually open and curious among them (a more developed frontal cortex?) are listening attentively. Can the days when vexing issues such as religion and faith in a higher being find a biological explanation be far off? Is conflict resolution between individuals and nations amenable to biological treatment? Science is what we make it to be. If we put it to good use it can promise humanity.

Dov Michaeli MD, Ph.D

 I am reading Paul Cartledge’s fascinating account of the heroic Spartan resistance in 480 BC to the Persian invasion of Thermopylae (Thermopylae: the Battle that Changed the World). I came across an epigram quoting the Israeli writer, Amos Oz, who said: “I believe that imagining the other is a powerful antidote to fanaticism and hatred” This quote is from his Goethe Prize speech given on 28 August 2005. “Imagining the other” - what an insightful way to describe the essential ingredient of what we call ‘empathy’. Which begs the question, at least in my mind: why do we empathize? And how did the capacity of human beings ‘to imagine the other’ come into being? You know where I am going … right to the brain.

Mirror, mirror, in the brain

In our brain, there are specialized neurons called “mirror cells”. These neurons get input from a variety of sources, such as the visual cortex and auditory centers, whose function is to, well, mirror the outside world. For instance, if we see somebody hurting - we almost physically ‘feel her pain.’ This is the source of the well-known phenomenon of the prospective father experiencing labor pains when the mother goes into labor. When we feel sad or depressed after spending time with a depressed person, it is because of empathy. MRI studies show that the mirror cells light up (are activated) when study subjects are shown “empathy-inducing” videos (aka ‘tear-jerkers’). This is a fascinating subject that touches not only on neurobiology, but also on what makes us social beings. How does empathy benefit humans? There must be some evolutionary advantage to having empathy hard wired into our brain. It turns out, the original purpose of mirror cells probably was not to empathize, but to anticipate. Just think of it, you are negotiating with a tough and shrewd opponent—wouldn’t you have a great advantage if you could ‘get into his head’? If you see a lion walking in the distance, anticipating what the lion was up to and where it might go could, perhaps, save your life. But wait, there is more!

Babies demonstrate “mirroring” behavior too.

Babies have been known to follow and emulate the sounds and sights in their environment. Have you ever watched an infant a few weeks of age smile back at you? Indeed, one of tests of their neurological intactness is their ability to follow a moving finger. And this capacity to internalize the outside world is mediated by those wonderful ‘mirrors’ in their brains.

 Empathy: an unintended consequence or mirroring?

It is a short leap from copying and internalizing somebody’s feelings to feeling empathy. Apparently, humans are not the only living creatures to demonstrate empathy. Many animals have made the leap from mirroring to empathy. Elephant mothers gently nurse and protect their helpless newborns and they have been documented to grieve over the death of one of their tribe. Similarly lion moms join together to raises, protect, and teach life-skills to their pride’s cubs. I could go and on with examples from the animal world, but the evolutionary advantage of such ttrait of empathy is self evident –or so you might think.

But consider the alternative hypothesis: maybe animals developed the capacity to internalize the outside world to better anticipate danger. The capacity to empathize just ‘came with the territory.’ as an unintended consequence of the development of the brain. Such a debate is raging in the community of evolutionary biologists, not only with respect to the trait of empathy, but also with such baffling phenomena as religious faith and the belief in God. I promise to expand on the latter in a future posting.

 For us, laymen and mere humans, this debate may seem like an academic exercise. Who really cares? What really matters at the end of the day is that we are endowed with this wonderful capacity to empathize. Hooray for mirror cells…here’s a toast to you! If we could find a way to coax neuronal cells into developing into mirror cells, perhaps we could banish the ‘fanaticism and hatred’ that Amos Oz was talking about.

BTW, I dedicate this article toTDWI Doc, Pat Salber, whose birthday is today. Pat, my heartfelt empathy!

 Dov Michaeli