Out of Africa: The Human Saga

Anatomically modern humans (AMH)—people who looked pretty much like us—migrated out of Africa tens of thousands of years ago and settled across Asia and Europe.

Just who were these people, how long ago did they migrate, and what route did they first take? These are some of the biggest questions in archeology. Now at last researchers seem to be closing in on concrete answers.

In a report published in the November 30 issue of the open-access journal PLoS ONE, an international research team led by Jeffrey Rose presents its analysis of recent work in southern Oman, located on the southeastern corner of the Arabian peninsula.

For years, researchers have debated with each other over the earliest migration route. Was it across the Red Sea to the Arabian boot heel (sea levels being much lower then)? Or was it north from Egypt along the Mediterranean?

Rose and his team found evidence suggesting that AMH residents of the Nile valley migrated—with their distinctive tool technology—to present day Oman. Their analysis of over 100 sites in Oman led researchers to believe that the tool culture was clearly the same in both settings. In other words, one culture spans two continents, clearly supporting the idea of human migration.

Scientists have long known about the Nile valley culture, which they call “Nubian.” The breakthrough reported here is the strong evidence that Nubian toolmakers made their way out of Africa to Arabia, bringing their characteristic stonecutting techniques with them.

The date of migration, according to the report, is at least 106,000 years ago, perhaps earlier.

No human remains were found with the stone tools. This leaves open the possibility that some other humans—“archaic” and not anatomically modern—may be responsible for the stone tools. The researchers dismiss this idea on the grounds that AMH seem to be the only form of humans present in North Africa at the time of the migration.

“After a decade of searching in southern Arabia for some clue that might help us understand early human expansion, at long last we've found the smoking gun of their exit from Africa,” according to Rose, a Research Fellow at the University of Birmingham.

Another surprise contained in the report is that the stone tools were found inland rather than right along the coast. “For a while,” remarks Rose, “South Arabia became a verdant paradise rich in resources – large game, plentiful freshwater, and high-quality flint with which to make stone tools,” according to a press release issued by PLoS One. One possibility is that the “southern route” out of Africa along the southern Arabian peninsula was not so much a coastal expressway to Asia and Europe as it was a settling of the interior of Arabia.

The report, “The Nubian Complex of Dhofar, Oman: An African Middle Stone Age Industry in Southern Arabia,” appears in the November 30, 2011 issue of PLoS ONE

More on Stem Cells and Brain Regeneration

Embryonic stem cells are surprisingly capable of regenerating portions of the brains of mice according to a report published in the November 25 issue of the journal Science. What is unexpected about this report is not the extent of the repairs so much as where they occurred in the brain.

The hypothalamus, which is involved basic metabolism and complex behaviors, has usually been regarded as less open to regeneration, whether naturally or by biomedical intervention. Naturally, a limited number of neurons develop during adulthood, but these are not enough to restore this area of the brain after injury or disease. “The neurons that are added during adulthood in both regions are generally smallish and are thought to act a bit like volume controls over specific signaling,” explained Jeffrey Macklis of Harvard Medical School and one of the lead researchers in the study.

“Here we've rewired a high-level system of brain circuitry that does not naturally experience neurogenesis,” Macklis said, “and this restored substantially normal function.”

The report reached this conclusion: “these experiments demonstrate that synaptic integration… [by] donor neurons can impart an organism-level rescue of metabolic defects, thereby providing a proof of concept for cell-mediated repair of a neuronal circuit controlling a complex phenotype.”

While it is important to underscore that this work is performed on mice, the results suggest that something similar might be possible someday in human beings with brain injuries. “The finding that these embryonic cells are so efficient at integrating with the native neuronal circuitry makes us quite excited about the possibility of applying similar techniques to other neurological and psychiatric diseases of particular interest to our laboratory," according to Matthew Anderson in a press release issued by Harvard Medical School.

For now, research continues using mice as models for human disease or spinal cord injury. “The next step for us is to ask parallel questions of other parts of the brain and spinal cord, those involved in ALS and with spinal cord injuries,” according to Macklis. "In these cases, can we rebuild circuitry in the mammalian brain? I suspect that we can."

The report, entitled “Transplanted Hypothalamic Neurons Restore Leptin Signaling and Ameliorate Obesity in db/db Mice,” appears in the November 25, 2011 issue of Science.

Ancient Human Trauma

A report in the November 21 issue of PNAS opens a sobering window into the lives and deaths of Ice Age humans. The report analyses a skull found in China and dating to 126,000 years ago and showing clear evidence of blunt force trauma.

Was it aggression or an accident, deliberate violence or just an sharp but unlucky bump to the head? No one knows for sure. Based on comparison with similar findings, however, researchers suspect human-to-human violence.

One thing that makes this discovery stand out is its early date. Quite possibly, it is the earliest known evidence of human aggression against another human being.

The injury was not fatal. The trauma to the skull shows clear evidence of healing. For researchers, this healing is proof that the victim lived months and possibly years after the injury, quite possibly because of care offered by fellow Middle Pleistocene humans. If true, then the skull may be evidence of human caring as well as human violence.

According to Prof. Lynne Scheparz, one of the authors of the study, “this wound is very similar to what is observed today when someone is struck forcibly with a heavy blunt object. As such it joins a small sample of Ice Age humans with probable evidence of humanly induced trauma, and could possibly be the oldest example of interhuman aggression and human induced trauma documented.”

At the same time, the skull’s “remodelled, healed condition also indicates the survival of a serious brain injury, a circumstance that is increasingly documented for archaic and modern Homo through the Pleistocene,” according to Schepartz. In other words, this skull is not unusual in suggesting that ancient humans cared for each other after serious brain injury. As Schepartz puts it in a press release from the University of Witwatersrand, this individual “would have needed social support and help in terms of care and feeding to recover from this wound."

According to the report itself, “the lesion…appears most likely to have been the result of a localized, blunt force trauma, sufficiently strong to produce the concentric ridges, the external depression, and the internal bulge. At the same time, the bone was extensively remodeled…Such remodeling minimally takes several months to develop,” possibly longer.

According to the report, it “is probable that it [the injury] was the result of an interpersonal altercation, with blunt-force trauma, given its form, but accidental injury cannot be excluded. It may be the oldest such case known…”

The report provides a sobering picture of the past. A single skull provides what might be the oldest snapshot of human violence and human caring, a scant 14mm in length but a powerfully accurate view of the best and the worst in us.

The report, “New evidence of interhuman aggression and human induced trauma 126,000 years ago, was published in the November 21, 2011 issue of PNAS.

Stem Cells in the Working Brain

Research using human pluripotent stem cells—whether derived from an embryo or induced into a pluripotent state—holds great promise for regenerating parts of the human body by producing new cells to replace diseased or damaged cells. Nowhere is this potential more intriguing than in the human brain.

During the past decade, researchers have learned to turn human pluripotent cells into neurons. They have tested these neurons in cell cultures, where they seem to function like normal neurons. They have implanted these human neurons in mouse brains, where human cells thrive like normal cells. The big question is whether they do the work of brain cells. Long before cells are implanted in human brains, researchers want to know whether the cells will function properly in any working brain, starting with a mouse brain.

Now comes evidence that the implanted cells seem to be fully function, integrated in the basic process of the mouse brain. In the report published in the November 21 issue of PNAS, researchers at the University of Wisconsin report on their use of a new technology, optogenetics, to test the function of the implanted cells. This technology uses light rather than electricity to stimulate implanted neurons. The result, it is claimed, is the best evidence so far that implanted cells are integrated fully into the functioning brain, sending and receiving signals as part of living neural networks.

”We show for the first time that these transplanted cells can both listen and talk to surrounding neurons of the adult brain,” said lead author Jason P. Weick in a press release from the University.

By using optogenetics, this study provides evidence that implanted human neurons derived from pluripotent stem cells can become functionally integrated into systems of a living brain, sending and receiving signals from surrounding or “host” cells and interacting with brain circuitry in a way that is consistent with normal brain rhythms.

According to the paper published in PNAS, the neurons derived from pluripotent cells “can participate in and modulate neural network activity through functional synaptic integration, suggesting they are capable of contributing to neural network information processing…”

What’s more, the researchers discovered that optogenetics may someday have a clinical use far beyond its value as a research tool. The fact that implanted cells can be stimulated using a light signal may someday become part of the way stem cells are used on human patients. According to Su-Chun Zhang, also an author of the report, “You can imagine that if the transplanted cells don't behave as they should, you could use this system to modulate them using light.”

Still more challenges must be met before neurons derived from human pluripotent cells are implanted successfully in the human brain. But this study advances the field in a critically important way and provides strong evidence that implanted cells might one day take on the function of damaged cells in the living human brain.

If human brains can be regenerated even in highly limited ways, the consequences will be profound. The most obvious applications will be to treat patients who have lost some part of brain function due to stroke, brain injury, or disease.

And if that becomes possible, it is not hard to imagine that the same technology will be used to regenerate the brains of those whose only “disease” is aging. Furthermore, it is quite likely that at some point in the future, implanted neurons derived from pluripotent cells will be genetically modified first, perhaps to prevent disease but also perhaps to enhance the performance of the brain into which they become functionally integrated.

It is important to stress that treatment for complex disorders of the brain, such as Alzheimer’s Disease, are still a long way off. But this research is an important step, showing that the basic concept of stem cell treatment may provide one form of treatment. But is that becomes possible, it may also become possible to enhance the cognitive capacity of people without disease.
The report, entitled "Human embryonic stem cell-derived neurons adopt and regulate the activity of an established neural network," appeared in the Nov 21, 2011 issue of PNAS.

Resveratrol and the Ethics of Human Enhancement

Resveratrol, the natural compound found in red wine, has now been shown to improve the metabolism of human beings.

In the 2 November 2011 issue of the journal Cell Metabolism, researchers in the Netherlands and Switzerland report that a 30-day course of resveratrol brought about significant improvement in the basic metabolic functions of obese men.

Research using animals has shown that resveratrol can have a number of benefits related to how the body uses energy. In some species, resveratrol has been shown to increase average longevity. In other experiments involving lab animals, a reduction of 30-50% in calorie intake below what the animals normally eat has been shown to benefit the metabolism and extend the lifespan. Others studies show that resveratrol seems to mimic the effects of calorie restriction.

Now come hints that resveratrol may have some of these same effects on human beings. In the Cell Metabolism article, researchers report that the men who received the 150mg/day dose of resveratrol showed a number of changes that mimic what happens with calorie reduction. 150mg is about 100 times the amount of resveratrol found in an ordinary glass of red wine.

One of the researchers, Patrick Schrauwen, commented on the study in a press release issued by Maastricht University in the Netherlands: “We saw a lot of small effects, but consistently pointing in a good direction of improved metabolic health.” The study was concluded after 30 days, and so long-term benefits or side-effects are not known.

In particular, no one knows whether resveratrol has the capacity to extend the human lifespan. But the positive results published on 2 November will surely intensify the debate over the effects and the ethics of resveratrol.

In this study, resveratrol was administered to men who were obese but otherwise healthy. One way some bioethicists distinguish between morally legitimate “therapy” and morally questionable biomedical “enhancement” is by insisting that medicine must stick to treating those with disease. It is unethical, these bioethicists argue, to “enhance” people by using medicine to benefit those who are not sick. Their views are challenged by others who believe that technology should be used for human enhancement.

While this study may have observed that moral limit of treating only those with a “disease,” there is little reason to believe that the metabolic benefits of resveratrol are limited to those who are obese. On the contrary, there is every reason to think that this study will be used by advocates of human enhancement. In particular they will see this as the best evidence yet that resveratrol can be used to extend the human lifespan.

The article, “Calorie restriction-like effects of 30 days of resveratrol (resVidaTM) supplementation on energy metabolism and metabolic profile in obese humans,” appears in the 2 Nov 2011 issue of Cell Metabolism, where it is available free to the public.