Enhancement at Work: A New Report

A new report on human enhancement and its growing impact on the workplace has just been released by top-level British science and policy groups. The Royal Society, the Academy of Medical Science, the British Academy, and the Royal Academy of Engineering collaborated on a research project throughout 2012, resulting in the November 2012 report.

Image from the cover of Human Enhancement and the Future of Work.

Among the conclusions: "Advances in a range of areas in science and engineering such as neuroscience, regenerative medicine and bionics are already enhancing, or could in the next decade enhance, the physical and cognitive capacity of individuals in the workplace." The report is entitled Human Enhancement and the Future of Work.

Even the advocates of human enhancement find something uniquely troubling about the prospect of enhancement technologies in the workplace. Will employers coerce their workers? Will use of enhancement technology be a non-negotiable prerequisite for success in an increasingly competitive work environment? Will employees have full access to information about potential side-effects?

The report notes the following: "Cognitive-enhancing drugs present the greatest immediate challenge...They are already available without prescription through internet purchasing, are relatively cheap and are increasinly being used by healthy individuals."

In response to these challenges, the report does not recommend sanctions or bans, but it does press the case urgently for widening the dialogue and reforming policies and regulations.

Human Germline Modification: A Step Closer?

Human germline modification—often described as "designer babies—has come a step closer. It has been shown that in nonhuman primates, it is possible to transplant specialized cells that produce sperm. When combined with other steps, this may make germline modification feasible and safe for human use.

The new research involves nonhuman primates. Its purpose is to set the stage for clinical trials in human beings. The goal for using this technique in human beings is to overcome infertility, especially for cancer survivors who were treated with radiation or chemotherapy. In men, that treatment may destroy the ability to produce sperm. If the cancer treatment occurs after puberty, sperm can be stored in advance. But if the treatment occurs before a young boy's body produces sperm, permanent infertility may result.

"Men can bank sperm before they have cancer treatment if they hope to have biological children later in their lives," according to University of Pittsburgh researcher Kyle Orwig, lead researcher. "But that is not an option for young boys who haven't gone through puberty, can't provide a sperm sample, and are many years away from thinking about having babies," Orwig said according to a press release from the university.

Photo by Bertrand Devouard, 2006, available at Wikimedia

No medical solution is now available, but the report published today opens the possibility that in the future, young male cancer survivors will be transplanted with cells that can restore their ability to produce sperm and to become fathers. To be clear: Orwig's group did not work with human subjects. But by showing that the technique works in rhesus monkeys, they help make the case that it could work in humans and should be tried.

"This is the first study to demonstrate that transplanted spermatogonial stem cells can produce functional sperm in higher primates," Orwig said. "This is an important step toward human translation." The study is published in the November 2012 issue of the journal, Cell Stem Cell.

The cells that were transplanted into the rhesus monkeys are called "spermatogonial stem cells" or SSCs. Researchers used frozen or cryopreserved SSCs.

In the future, one possibility is that SSCs might be produced from stem cells, such as induced pluripotent stem cells. In addition, the SSCs might be genetically modified before they are transplanted. In nonhuman animals, this would provide a new way to create transgenic animals for research.

Another possibility is that this technique, if used to restore fertility to men who cannot produce sperm, might also be used for human germline modification. In a 2006 article, Hiroshi Kubota and Ralph L. Brinster (a pioneer in developing this technique) suggested that SSC transplantation may be used for precisely this purpose. "Another potential clinical application using human SSCs is GERMLINE GENE THERAPY" (Capital letters in original). They suggest that "germline gene therapy using SSCs will become a promising and feasible approach, although considerable ethical concerns exist."

What makes all this especially interesting is that by transplanting SSCs, researchers may make it possible for fertility to be restored without the use of in vitro fertilization. The Orwig paper suggests this quite clearly: SSC transplantation may be capable of "enabling the recipient male to father his own genetic children, possibly through normal coitus." If the SSCs are genetically modified first, we would have germline modification without IVF.

When human germline modification is suggested, many find the idea frightening. It is generally assumed that religious people will be universally opposed. That is not true, not even among Catholics.

What the official Catholic position opposes is the destruction of human embryos or even their creation outside the human body, which IVF requires. The Vatican is not opposed to using high tech medicine to create healthy babies.

In 2004, this is what a Vatican commission had to say: “Germ line genetic engineering with a therapeutic goal in man would in itself be acceptable were it not for the fact that is it is hard to imagine how this could be achieved without disproportionate risks especially in the first experimental stage, such as the huge loss of embryos and the incidence of mishaps, and without the use of reproductive techniques. A possible alternative would be the use of gene therapy in the stem cells that produce a man’s sperm, whereby he can beget healthy offspring with his own seed by means of the conjugal act.”

It almost sounds here like the Vatican was suggesting the technique that is being developed. It should be noted that this statement was released while John Paul II was pope. It was drafted by a commission headed by Cardinal Ratzinger, who is now Benedict XVI.

One should not expect Catholics or any other religious community to lead a chorus of praise for human germline modification. At most, one might expect guarded comments from religious leaders, coupled with the demand that this technology be limited to therapy and not used for enhancement. But the key point is this: if human germline modification technology is developed, religious leaders may actually be open to its use.

But if it is developed for therapy, who really thinks it will be limited in that way? If it works to create a healthy baby, why not use it to create a better baby?

The article, entitled "Spermatogonial stem cell transplantation into Rhesus testes regenerates spermatogenesis producing functional sperm," appears in the November 2012 issue of the journal, Cell Stem Cell.

Resveratrol and Enhancement? Not So Fast

Does resveratrol help healthy people become even healthier? Does it improve metabolic health and possibly even help us live longer?

A new study casts doubts on these hopes. In the October 25 issue of Cell Metabolism, researchers at Washington University School of Medicine publish the results of their study involving 29 healthy middle-aged women. They asked whether resveratrol boosts metabolic health. When they ran the tests and collected the evidence, the answer was simple: No.

The study divided the women into two groups. Fifteen were given 75 milligrams of resveratrol each day, the same as they would get in 8 liters (more than 10 bottles) of red wine. The other fourteen received a sugar-pill placebo.

Researchers measured the women's sensitivity to insulin and the rate of the glucose uptake. The result, according to Samuel Klein, senior investigator, is that "we were unable to detect any effect of resveratrol. In addition, we took small samples of muscle and fat tissue from these women to look for possible effects of resveratrol in the body's cells, and again, we could not find any changes in the signaling pathways involved in metabolism," Klein said in a press release issued by Washington University School of Medicine.

Photo Credit: Robert Boston. No usage restrictions.

This study is small, but what makes it interesting is that it involves healthy human beings. In nonhuman trials, resveratrol seems to enhance the health of healthy animals. And in human trials involving people with metabolic problems, resveratrol seems beneficial.

According to Klein, "Few studies have evaluated the effects of resveratrol in people," Klein explains. "Those studies were conducted in people with diabetes, older adults with impaired glucose tolerance or obese people who had more metabolic problems than the women we studied. So it is possible that resveratrol could have beneficial effects in people who are more metabolically abnormal than the subjects who participated in the study."

That point goes right to the heart of the human enhancement debate. Often, "enhancement" is distinguished from therapy. While therapy improves the health of the sick, enhancement improves the health of the healthy. This study seems to suggest that resveratrol may be therapeutic, but it is not an enhancement.

Right now, however, the picture is not completely clear. Those who drink red wine in moderation are less likely than others to develop heart disease and diabetes? Is it the resveratrol, the wine, or the interactions between them?

According to Klein, "We were unable to detect a metabolic benefit of resveratrol supplementation in our study population, but this does not preclude the possibility that resveratrol could have a synergistic effect when combined with other compounds in red wine."

The article, entitled "Resveratrol Supplementation Does Not Improve Metabolic Function in Nonobese Women with Normal Glucose Tolerance," appears in the October 25 issue of Cell Metabolism.

Human-Neandertal Interbreeding: When and Where?

Comparison between Neandertal and anatomically modern human genomes shows a history of interbreeding. Some living human beings—those with ancestry in Europe and Asia—carry the results of that interbreeding in their DNA. Those with ancestry in sub-Saharan Africa typically do not.

We also know that Neandertals lived in Eurasia from 230,000 until about 30,000 years ago. Where they came from or why they disappeared remains an open question. And we know that anatomically modern humans first appear in Africa at least 200,000 years ago. Some of them made their way to Asia and Europe sometime in the last 100,000 years.

So when did modern human/Neandertal interbreeding last occur? Did it occur deep in our past, before modern humans and Neandertal ancestors left Africa? Or did it occur after both left Africa, sometime—in other words—within the past 100,000 years?

A new study claims to find evidence that the interbreeding occurred out of Africa. Researchers argue that on the basis careful analysis of the shared DNA, the most recent interbreeding occurred sometime between 37,000 and 86,000 years ago.

Caption: Reconstruction of a Neandertal, 2006, by Stefan Scheer, from Stefanie Krull, Neanderthal Museum Picture Library, Mettmann, Germany

If so, it is pretty strong evidence that the interbreeding occurred after anatomically modern human left Africa. This may have occurred in the Middle East, researchers point out, but probably not just at the beginning of the modern human migration out of Africa. The most recent interbreeding, they conclude, occurs well after this 100,000 date, suggesting ”a more recent period, possibly when modern humans carrying Upper Paleolithic technologies expanded out of Africa.”

In that case, the conceptual challenge posed by the modern human/Neandertal interbreedng remains clearly in front of us. What is the human species? Were Neandertals human? And what are we to make of our new insight into modern human diversity. All puzzling questions, to put it mildly.

The article, "The Date of Interbreeding between Neandertals and Modern Humans," is published in the current issue of PLOS Genetics, where it is available free to the public.

Engineered Eggs

Researchers in Japan have reported success in generating mouse eggs or oocytes from pluripotent stem cells. When fertilized, these induced eggs grew into live, healthy pups capable of producing their own offspring. The work is reported in the October 5 issue of the journal Science.

The research team used two different types of pluripotent cells, embryonic and induced. In both cases, they were able to produce cells that are the precursor of the cells of the ovaries, which form eggs. Once they produced these cells and grew them in clusters, they implanted them into the bodies of female mice, where they developed into cell structures that functioned like ovaries. From these reconstituted ovaries, researchers harvested mature oocytes, much as they would for in vitro fertilization (IVF).

The next step, predictably, was to fertilize these eggs and implant them in surrogate mother mice. Once born, the pups developed and were allowed to breed, producing viable offspring.

Pups from ES-oocyte. Female offspring from primordial germ cell-like cell-derived oocytes were fully fertile. Courtesy of Katsuhiko Hayashi.

The most immediate impact of this research will be to advance our understanding of the fundamentals of reproductive biology, especially the development of egg cells. If similar strategies will work with human pluripotent stem cells—especially induced cells—this research may open new approaches for reproductive medicine in the years ahead.

What other possibilities might there be? Again, if the work can be replicated in human beings, two things might happen. Somewhat more remote is the possibility that this strategy will be used for the purposes of human germline modification or so-called “designer babies.” For example, pluripotent stem cells might be genetically modified before they are induced to become the source of oocytes. The modification could be to avoid a disease or for the purposes of enhancement.

More likely, of course, is that this strategy will be used to create human oocytes for research purposes. For example, human induced ovary-like cells could be implanted into a mouse or other nonhuman animal, grown to the right stage of development, then “harvested” in order to collect a significant number of oocytes.

Today, research in certain areas is hampered because of limited supplies of human oocytes. One area that comes to mind is nuclear transfer or cloning. While “Dolly” the sheep is now only a distant memory, this advance brings closer the possibility that with an ample supply of human oocytes for experimentation, researchers will learn how to create human clones reliably.

So the big question is whether this research can be replicated in humans. On that point, here's how the article concludes: "our system serves as a robust foundatin to investige and further reconstitution femaile germline development in vitro, not only in mice, but also in other mammals, including humans."

The article, entitled "Offspring from Oocytes Derived from in vitro Primordial Germ Cell-like Cells in Mice," appears in the 5 October 2012 issue of the journal, Science.

A New Source for New Neurons

The day when stem cell research will give us treatments for common brain disorders such as Parkinson’s or Alzheimer’s just got a little closer. So, by the way, did the day when this research will be used to enhance the capacities of the normal or healthy human brain. The latest advance comes from an international team based mostly in Germany, which has figured out a way to generate new neurons from cells that already exist in the human brain.

The human brain naturally contains specialized cells called pericytes. Usually they are located at the edge of the capillaries that carry blood to the brain. They play a vital role in maintaining the blood-brain barrier.

Neurons. Photo from National Institutes of Health.

Now, thanks to the discovery reported in the October 5 issue of Cell Stem Cell, pericytes might be about to learn a new trick: forming new neurons. Using stem cell reprogramming techniques, researchers learned that two factors—Sox2 and Mash1—would induce pericytes to change their developmental state and begin to function as newly-formed neurons.

According to the article, “these induced neuronal cells acquire the ability of repetitive action potential firing and serve as synaptic targets for other neurons, indicating their capability of integrating into neuronal networks.” In other words, they do what neurons normally do. They process signals from one end of the cell to another. They form synaptic connections with other neurons. And they integrate into larger networks.

Will this become a new strategy for treating diseases or injuries to brain cells? That is the hope, but difficult challenges remain. How can living pericytes in a functioning human brain be targeted and induced to become neurons? If they generate new neurons, will they function properly? Will they integrate themselves into a functioning brain, preferably taking up the cognitive processes that are lost because of disease or injury?

The authors conclude that “much needs to be learned” but that “our data provide strong support for the notion that neuronal reprogramming of cells of pericytic origin within the damaged brain may become a viable approach to replace degenerated neurons.”

According to Benedikt Berninger of the Johannes Gutenberg University in Mainz, a leader in the research team, “The ultimate goal we have in mind is that this may one day enable us to induce such conversion within the brain itself and thus provide a novel strategy for repairing the injured or diseased brain."

That may be the goal, but it's hard to imagine this research will be limited to therapy. In fact it may turn out to be easier to use it to enhance the cognitive capacity of normal or healthy aging brains than it is to treat disease. Anything that stimulates the growth of new neurons is likely to be very appealing to aging adults.

If human stem cell research is to reach its full promise, many more advances like this will have to occur. With each advance, however, comes growing confidence that the promise of the field may be highly challenging, but it is not hype.

The article entitled “Reprogramming of pericyte-derived cells of the adult human brain into induced neuronal cells” is published in the October 4, 2012 issue of Cell Stem Cell.

Denisovan DNA in Focus

Using new techniques to study ancient DNA, scientists have unraveled the genetic details of a young girl who lived in central Asia around 50,000 years ago. She is the only individual of her kind, a unique branch of the human family called the Denisovans, named for the cave where her remains were found in 2008.

What makes the research all the more startling is that only two teeth and one pea-size bone fragment has been found. But from those tiny fragments of humanity, the story of the Denisovans is being pieced together.

The new techniques were developed by Matthias Meyer, working at the Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology in Leipzig, a research program led by Svante Pääbo. DNA extracted from the bone fragment was separated into two strands that were amplified and analyzed separately, many times over, until a highly reliable sequence was determined.

Laboratory for the extraction of ancient DNA. [Image courtesy of Max Planck Institute for Evolutionary Anthropology].

Researchers claim that the result is as complete and accurate as the sequence of living human beings. Already, the new technique is being used to study other ancient remains, including samples of Neandertal DNA. Denisovans and Neandertals, distinct but closely related forms of humanity, overlapped with anatomically modern humans (AMH) and interbred with them.

New methods in genetics, including the technical breakthrough described in this paper, are opening new windows on the human family tree, which resembles an inter-grown vine more than a straight line of branches.

So accurate is the genetic analysis that researchers can reach some conclusions about other Denisovans, even though no samples exist for them. For one thing, despite their wide geographic spread, they apparently never reached high numbers. Their DNA lives on today in the faint echo of ancient interbreeding found in the uniquely-Denisovan sequences carried by those who live in the islands of southeast Asia.

No one knows what Denisovans looked like, but they probably resembled us in many ways. The Denisovan girl whose DNA was studied carried genes that are associated today with brown hair, brown eyes, and dark skin. Like us they had 23 pairs of chromosomes (compared to chimps with 24), making interbreeding more readily possible.

Denisova molar, distal. [Image courtesy of Max Planck Institute for Evolutionary Anthropology].

One of the more tantalizing aspects of the report is the light it sheds not on the Denisovans or the Neandertals but on us anatomically modern human beings who live today. Why did we survive and flourish culturally when they did not?

One explanation may lie in the genetic differences between us and them, which can be studied for the first time in detail. In this paper, researchers identify specific changes in genes that are associated with brain complexity, synaptic connections, and speech development. According to the paper, “it is thus tempting to speculate that crucial aspects of synaptic transmission may have changed in modern humans.” In other words, tiny differences in DNA led to still relatively small differences in brain function that led to huge differences in culture.

Future technical advances will continue to shed new light on the complex story of recent human ancestry. By gaining ever-higher clarity on the genetic differences between Neandertals, Denisovans, and modern humans, we will come to know the story of our humanity in greater detail.

The paper ends with this reflection: “This [work] should ultimately aid in determining how it was that modern humans came to expand dramatically in population size as well as culturally complexity which archaic humans eventually dwindled in numbers and became physically extinct.” The paper, “A High-Coverage Genome Sequence from an Archaic Denisovan Individual,” is published in the 30 August 2012 issue of Science, published by the American Association for the Advancement of Science.