The Surprising Story of 400,000 Year Old Human DNA

Researchers have just announced a major advance in their quest to recover DNA from ancient humans.  400,000 year old bones contain badly damaged DNA sequences, but experts in Leipzig, Germany, have developed new techniques to extract and piece together tiny fragments until they can read at least a small portion of the genes carried by ancient humans who once lived in northern Spain.

Caption: The Sima de los Huesos hominins lived approximately 400,000 years ago during the Middle Pleistocene. Credit: Javier Trueba, Madrid Scientific Films.Usage Restrictions: None

A team led by Matthias Meyer at the Max Planck Institute for Evolutionary Anthropology in Leipzig worked together with a Spanish team of paleontologists led by Juan-Luis Arsuaga to extract tiny amounts of bone from fossil remains found at Sima de los Huesos, northern Spain’s famous “bone pit.”  This site has been excavated for more than two decades.  It has yielded at least 28 skeletons, usually classified as Homo heidelbergensis, a form of humans seen as the ancestors of the Neandertals.

 

But here is where this study broke new ground.  It turns out that the Sima de los Huesos humans were more closely related to the recently discovered Denisovans than to the Neandertals.  "The fact that the mtDNA of the Sima de los Huesos hominin shares a common ancestor with Denisovan rather than Neandertal mtDNAs is unexpected since its skeletal remains carry Neandertal-derived features," Meyer said in a press release provided by the journal Nature, which carries the report in its 4 December 2013 issue. 

What makes this finding all the more intriguing is that the Denisovans were completely unknown to us until 2010, when the Leipzig team “discovered” them by reconstructing their DNA and comparing it to Neandertals and today’s humans.  Through a spectacular technological achievement, Leipzig researchers discovered that these Denisovans lived as a distinct population some tens of thousands of years ago, when they interbred with other humans. 

"This unexpected result points to a complex pattern of evolution in the origin of Neandertals and modern humans. I hope that more research will help clarify the genetic relationships of the hominins from Sima de los Huesos to Neandertals and Denisovans" says Arsuaga. 

Caption: This is a skeleton of a Homo heidelbergensis from Sima de los Huesos, a unique cave site in Northern Spain.  Credit: Javier Trueba, Madrid Scientific Films.  Usage Restrictions: None

 

According to the most recent discovery, the Sima de los Huesos hominins seem to have shared a common ancestor with the Denisovans some 700,000 years ago.  The idea that they are more closely related to Denisovans than to Neandertals suggests that these mysterious Denisovans, totally unknown just four years ago, may have played a far bigger role in the story of human origins than ever imagined. 

It is important to point out that so far, researchers have only reconstructed the DNA of the mitochondrial.  And even there, the work is not complete.  Whether they succeed in reconstructing the DNA of the far more daunting heidelbergensis genome remains to be seen.  But if past experience is any predictor, we might look for advances not just here but in other human remains from hundreds of thousands of years ago.  Each technical achievement may fill in a page in our past, maybe even re-writing whole chapters.  When it comes to human origins, we should expect more surprises. 

Putting this most recent news in a larger context, Svante Pääbo, the director of the Leipzig research, said this in the Nature press release: "Our results show that we can now study DNA from human ancestors that are hundreds of thousands of years old. This opens prospects to study the genes of the ancestors of Neandertals and Denisovans. It is tremendously exciting."

The article, “A mitochondrial genome sequence of a hominin from Sima de los Huesos,” appears in the 4 December 2013 issue of the journal Nature. 

 

 

 

Stem Cell Advance and Cloning Debates

An important breakthrough in stem cell medical research is likely to re-ignite an ethical debate about human cloning. 

Researchers at the Oregon Health & Science University reported on May 15 that they have succeeded for the first time in human “somatic cell nuclear transfer” or SCNT, a process that the public often refers to simply as cloning.  Oregon researchers were able to transfer the nucleus from one human cell into a donated human egg from which the nucleus had been removed, essentially the same process that led to the creation of Dolly the sheep more than fifteen years ago. 

Caption: The first step during SCNT is enucleation or removal of nuclear genetic material (chromosomal) from a human egg. An egg is positioned with holding pipette (on the left) and egg's chromosomes are visualized under polarized microscope. A hole is made in the egg's shell (zone pellucida) using a laser and a smaller pipette (on the right) is inserted through the opening. The chromosomes then sucked in inside the pipette and slowly removed from the egg.  Credit: Cell, Tachibana et al. Usage Restrictions: Credit Required.

 

While other teams have achieved nuclear transfer with human cells, none has been able to produce an embryo that developed long enough to yield human embryonic stem cells.  The Oregon team, led by Shoukhrat Mitalipov, achieved this long-desired goal.

 

Even more remarkably, the Oregon team achieved SCNT repeatedly and with high efficiency, in one case producing a stem cell line for every two donated eggs. Along with other researchers around the world, Mitalipov’s team has discovered many ways to fine-tune the nuclear transfer process, making it far more demanding technically than when Ian Wilmut’s team first created Dolly.

But just as we learned from Dolly, any major technical advance in somatic cell nuclear transfer is likely to trigger public controversy about cloning and about the social impact of science.  While nearly everyone applauds the goal of the Oregon research—better understanding and treatment of disease—not everyone will like the way they went about their work.

For one thing, the result of successful nuclear transfer is a kind of embryo.  Mitalipov’s paper, published in the June 6, 2013 issue of the journal Cell (online on May 15), repeatedly refers to this new entity as the “SCNT embryo.”  Is a “SCNT embryo” a “real” embryo?  If an embryo is the result of fertilization, then of course a “SCNT embryo” is not a normal or real embryo.  But if an embryo is defined by its potential to develop, then a SCNT embryo probably is very close to a normal or real embryo, biologically at least.

Suppose we accept that a SCNT embryo is real enough to warrant the same protection as embryos created by IVF.  Is it legitimate to create such an embryo for the express purpose of research that will destroy this SCNT embryo?  Many people object to this, and major religious institutions such as the Catholic Church have been unambiguous in their denunciation of this research. 

On the other hand, a few religious groups have specifically endorsed this research.  One of the clearest statements of support is entitled “Cloning Research, Jewish Tradition and Public Policy.”  The statement, published in 2002, speaks for all major groups within American Judaism: 

Moreover, our tradition states that an embryo in vitro does not enjoy the full status of human-hood and its attendant protections.  Thus, if cloning technology research advances our ability to heal humans with greater success, it ought to be pursued since it does not require or encourage the destruction of life in the process.

Another statement in support comes from a study committee in the United Church of Christ, which released this statement in 1997: 

...we on the United Church of Christ Committee on Genetics do not object categorically to human pre-embryo research, including research that produces and studies cloned human pre-embryos through the 14th day of fetal development.”

For more religious statements on embryo research, check out God and the Embryo, especially the appendics. 

I personally agree with the statements quoted above.  So I support the research performed in Oregon.  But I have to admit that among people with religious commitments, I am in a minority.  As much as I wish it were otherwise, I expect that many will object to the idea that Mitalipov’s group has created and destroyed embryos for research.

Some will argue that the technology of induced pluripotent stem cells (iPSCs) makes the use of embryos unnecessary.  While it is true that iPSC technology is a remarkable and promising advance, so far the field has run into unexpected technical complications in its quest to produce pluripotent stem cells that function like cells from embryonic sources.  A great attraction of iPSCs—beyond the fact that no embryos are involved—is that they are a genetic match to the donor.  What the Oregon breakthrough provides is the best of both: embryonic quality in donor-specific cells. 

Others will object because they don’t like human cloning—understood now as the use of SCNT to produce a child.  They will see the Oregon breakthrough as ushering in the era human reproductive cloning, and they will see this as reason enough to ban any further advances in SCNT technology.

Far more sensible, I think, would be a moratorium on human reproductive cloning.  What the Oregon group has achieved does make it more likely that someone somewhere might try to offer cloning as a reproductive technology.  The problem is that using Mitalipov’s techniques, they might succeed in creating an embryo that survives but that is beset by many unforeseeable health problems.

If we have learned anything in the past fifteen years, it is that SCNT is a tricky and complex process.  Just because Mitalipov’s team learned how to create the SCNT embryo that is healthy and viable through the blastocyst stage does not mean that anyone knows how to create an SCNT child.  Too many things could go wrong, and only now are we beginning to get some idea of how these potential problems might arise.

Someday, many decades in the future, we may understand these problems so well that we can solve them technically.  If that day ever comes, then those who come after us will have to ask: is a cloned child a good idea.  Right now we do not even have to ask that question because an SCNT is an unsafe idea. 

The press release from The Oregon Health and Science University that announces this advance makes this claim:

One important distinction is that while the method might be considered a technique for cloning stem cells, commonly called therapeutic cloning, the same method would not likely be successful in producing human clones otherwise known as reproductive cloning. Several years of monkey studies that utilize somatic cell nuclear transfer have never successfully produced monkey clones. It is expected that this is also the case with humans. Furthermore, the comparative fragility of human cells as noted during this study, is a significant factor that would likely prevent the development of clones.

The Oregon release then quotes Mitalipov:

"Our research is directed toward generating stem cells for use in future treatments to combat disease," added Dr. Mitalipov. "While nuclear transfer breakthroughs often lead to a public discussion about the ethics of human cloning, this is not our focus, nor do we believe our findings might be used by others to advance the possibility of human reproductive cloning."

The article is entitled "Human Embryonic Stem Cells Derived by Somatic Cell Nuclear Transfer" and appears in the May 15 issue of the journal Cell. 

Parthenogenesis and "Virgin Birth"? Rhetoric and Research

Despite roadblocks, the field of stem cell research remains profoundly attractive. The idea of being able to regenerate damaged or diseased cells in the human body is appealing to nearly everyone who cares about human health.

But technical problems remain. Much has been learned in the past decade, but the pathway to medical treatments still faces many challenging problems. One worry in particular is that implanted stem cells might develop into cancer. Others challenges including getting the cells to multiply, integrate with other cells, function as they should, and avoid being rejected as an infection.

A new solution may be on the horizon, one that addresses many of these problems—moral and technical—all at once. At least that’s the claim made by a team led by Wolfram Zimmerman and colleagues at Georg-August-Universität Göttingen in Germany. Working with laboratory mice, Zimmerman’s team used mouse eggs to create what are known as parthenotes. Without being fertilized, the mouse eggs were manipulated so that they began to develop as if they were fertilized, up to a point.

PHOTO: Mouse embryonic stem cells. This image is a work of a National Science Foundation employee, taken or made as part of that person's official duties. As a work of the U.S. federal government, the image is in the public domain. This image was copied from wikipedia:en.

Parthenogenesis exists in nature. It has been observed in some plants, fish, and reptiles. Over the past decade, researchers have learned how to induce parthenogenesis in mice, monkeys, and humans. In every case, however, the resulting parthenotes fail to develop normally, which means they could never be implanted to produce a child. But they do develop for a few days, long enough for the precursors of pluripotent stem cells to develop.

What is new in the research reported on February 22, 2013 is unexpected success in the use of these stem cells derived from mouse parthenotes. These cells—parthenogenetic stem cells or PSCs—were developed and eventually implanted into damaged mouse hearts. Quite simply, they worked in ways that seem to overcome most if not all of the technical hurdles.

The research appears in the Journal of Clinical Investigation, which carried a companion article claiming that the new research “may overcome all…formidable barriers” that currently stand in the way of stem cell medicine. The original article makes this claim: “One of our key observations involved the capacity of PSCs to exhibit essentially normal cardiogenesis in vitro and in vivo.” In other words, both in the dish and in the mouse, implanted cells fully integrate into the beating heart.

Both the research article and the companion piece make another claim: PSCs are ethically acceptable. That’s because parthenotes are not embryos. Taking cells from parthenotes avoids all the moral concerns that surround the use of cells derived from embryos. Here is the claim: Research using human PSCs, derived from human parthenotes, involves “no destruction of viable embryos,” according to the research article. The companion piece simply notes that compared to embryonic stem cells, PSCs “do not have the same ethical implications.”

If only it were that simple. But plain the fact is that some who object to the use of human embryos in research are already on record as objecting to the use of human parthenotes.

Their logic is fairly straightforward. If human embryos are off limits and if parthenotes cannot be clearly and definitely distinguished from embryos, then human parthenotes are equally off limits to research.
They are not claiming that parthenotes are little people, nor are they being silly or obstructionist. They are only claiming that we do not have enough scientific clarity and certitude to proceed with moral confidence in the work of creating and destroying parthenotes, regardless of the benefit.

Just to be clear, I personally disagree with this objection. But researchers and regulators should be aware that some, at least, will balk at this new line of research, technically attractive as it may be.

For example, in a statement given to the UK Parliament, the Church of Scotland made this comment:

“We reject the suggestion made by various researchers that hybrid embryos, parthenotes and embryos that have been modified to make then non-viable would be an ethical solution to deriving stem cells from embryos. Whatever the status of such creations, it is would be at least as unethical to use methods that would create an ‘embryo’ so deformed that it could not be viable and which therefore inherently denies its potential to develop.” 

Politically more important is the response that will come from Catholics. Some Catholic scholars have defended the moral legitimacy of research using human parthenotes. There is simply no way, they argue, to equate the parthenote with the embryo. The parthenote is not a product of conception. In more popular rhetoric: If “life begins at conception,” then the parthenote is not “life.” Nor can it develop normally. It meets none standard definitions of an embryo.

Others are not so certain. They translate scientific and theological uncertainty into a moral prohibition. Creating and destroying a parthenotes requires that we know for sure that they are not embryos. Such certainty is lacking, at least for now. In the face of uncertainty, they argue, we must not proceed.

On the Catholic website www.ewtn.com, E. Christian Brugger addresses the question: Is the parthenotes enough like and embryo to be considered an embryo? His answer:

“The question presently is unsettled.” He adds this: “Although the empirical question of the status of a human parthenote is unsettled, the underlying moral principle is straightforward. Unless we have moral certainty that a dividing parthenogenetically activated human oocyte is not an embryo, we have an obligation to avoid research with human parthenotes.”

And at the end he concludes:

“Having said this, the present evidence on whether parthenotes are ever embryos seems to me inconclusive. Given the evidence to date, at least with which I am familiar, I do not think it can be established with moral certitude that parthenotes are never human embryos.”

Personally, I want to see this research go forward, and so I have some suggestions for researchers and reporterss in this field.

First, help religious scholars build the case scientifically, showing in clear terms to the wider public why parthenotes are not functionally like embryos and why a morally robust boundary separates the two. Science itself cannot create that boundary, but it can provide evidence supporting moral and philosophical arguments in favour of such a boundary.

Second, stop using provocative phrases like “virgin birth.” Regrettably, the companion piece in the Journal of Clinical Investigation is published with this title: “Virgin birth: engineered heart muscles from parthenogenetic stem cells.”

Sure, “parthenos” is Greek for virgin, so the etymology supports the use of the term “virgin birth.” But for billions of Christians around this world, this term has a very special religious meaning, one that many associate with the most tender core of their faith.

For scientists to claim they are simulating the “virgin birth” is offensive to anyone who takes the religious meaning of the phrase seriously. It is needlessly provocative, almost the worst thing that could be said if religious support for research is desired.

What’s more, associating parthenogenesis with the “virgin birth” has the bizarre effect of equating the parthenote with the embryo. Christians who hold to the “virgin birth” will claim that in one profoundly non-trivial example (Jesus), what scientists now claim they are creating turned out to be a fully viable embryo. And then they say, “But don’t worry; it’s not a human being”?

The original article, entitled "Parthenogenetic stem cells for tissue engineered heart repair," is published in the February 22, 2013 issue of the Journal of Clinical Investigation, together with the companion piece.

Brain Renewal? Enhancing Aging Brains

An aging mind may be a fountain of wisdom, but an aging brain is not very good as a source of new neurons. As we age, quite apart from diseases like Alzheimer’s, we lose our ability to remember and to concentrate. It seems that in order to remain sharp, the brain has to regenerate itself by forming new neurons. While neurogenesis continues throughout life, it declines markedly in old age.

Photo credit: published under GNU Free Documentation License, uploaded 23 Sept 2007 by Ccrai008.

Research published today may suggest a way to change that. Scientists at the German Cancer Center in Heidelberg report on their work with mice. They identified a molecule called Dickkopf-1 or Dkk1 in the brains of old mice. When they blocked the production of Dkk1, old mouse brains began to create new brain cells.

“We released a brake on neuronal birth, thereby resetting performance in spatial memory tasks back to levels observed in younger animals,” said Ana Martin-Villalba in a press release from Cell Press, which published the results.

It turns out that clinical trials are already underway involving antibodies for Dkk1. These trials are not related to neurogenesis but to prevention of osteoporosis. What is learned there, however, may be directly helpful to the possibility that blocking Dkk1 is feasible, safe, and effective in countering the effects of declining neurogenesis, which includes both memory loss and depression.

The report concludes with these comments: “Our study raises the possibility that neutralization of Dkk1 might be beneficial in counteracting depression-like behavior and improving cognitive decline in the aging population….The contribution of newly generated young neurons to memory and affective behavior opens tantalizing opportunities for the prevention of affective impairments and age-related cognitive decline.”

These words are carefully chosen, first to caution against undue optimism but also to steer away from the idea of “human enhancement.” But unless we think of aging as a disease, what is envisioned here is clearly a form of enhancement. Normally aging human beings may, someday in the future, be treated not because they have a disease such as Alzheimer’s but because their memory is not as sharp as it once was or as retentive as they would like.

But labeling this an “enhancement” is not likely to dampen public interest. On the contrary, the enhancment potential of blocking Dkk1 is the very thing that is most likely to drive public support.

And that suggests we need to consider once again just what it is we say we do not like about enhancement.

The article is entitled "Loss of Dickkopf-1 restores neurogenesis in old age and counteracts cognitive decline" and appears in the February 7, 2013 issue of Cell Stem Cell.

Asians, Europeans, and Neandertals

New research suggests that Europeans and Asians diverged at least 40,000 years ago, starting a process leading to the subtle differences that distinguish people to this day.

Working with bones discovered in 2003, researchers at the Max Planck Institute for Evolutionary Anthropology in Leipzig were able to reconstruct portions of DNA from an individual who lived in China about 40,000 years ago. Earlier analysis of the bones suggested that this individual showed “archaic” features, somewhat like Neandertal bones.

Credit: A Photograph of China's Empress Dowager, taken in the 1890s by Xunling, the Imperial Court Photographer. In the public domain.

The Max Planck team, led by Svante Pääbo, is well-known for work in producing the virtually complete Neandertal genome. In addition, using just a tiny fragment of a finger bone, this team produced the genome of a previously unknown form of humanity, called the Denisovans.

In their earlier work, they discovered that Europeans and Asians are descended in part from Neandertals, who disappeared about 30,000 years ago. In addition, some Asians, especially those living on the islands south of Asia, are partly descended from the Denisovans.

One of the reasons why the team was interested in this new sample was to look more deeply into the relationship between Europeans and Asians and to ask what role Neandertal and Denisovan interbreeding might have played.

Comparing the newly-reconstructed DNA sequence from the 40,000 year old bones, they found they were looking at an individual who also was descended from Neandertals, pretty much the way Europeans and Asians are today. And they also learned that this individual showed no evidence of Denisovan interbreeding.

What this means, they suggest, is that 40,000 years ago, an early version of anatomically modern Eurasians lived in China, near Beijing. While this human community was very much like the humans moving into Europe at about the same time, these two lineages were beginning a process of divergence.

On the basis of additional comparisons, the team concluded that the early-modern human community in China 40,000 about years ago was closely related to today’s Native Americans.

The report is also significant because it shows the power of new approaches to DNA extraction and sequencing. In their raw form, the samples extracted from the bones contained mostly DNA from microorganisms. In fact the human DNA was less than one-tenth of one percent of the total DNA. Even so, researchers were able to establish reliable human sequences, suitable for comparison with other human genomes.

What does that mean? At the very least, it means that many more discoveries like this lie ahead. The new technology means that old findings take on new significance.

The research appears online January 22, 2013, in the Proceedings of National Academy of Sciences, as "DNA analysis of an early modern human from Tianyuan Cave, China."

Past and Future Selves

Are you done changing? Are your values and personality pretty much set for life? Regardless of our age, most of us seem to think so.

According to new research, people generally recognize that they have changed over the past decade. But in the decade ahead? Overwhelmingly, people think their biggest changes are behind them. It’s as if their present state is the defining moment, when values and personality traits are fully realized and fix forever. The research team, led by Jordi Quoidbach, called this the “End of History Illusion.”

In six studies involving more than 19,000 participants, researchers “found consistent evidence to indicate that people underestimate how much they will change in the future,” according to the study appearing in the 5 January 2013 issue of the journal Science.

Like most illusions, this one comes with a big cost. Thinking they won’t change makes it more likely they will “make decisions that their future selves regret.”

What’s most amazing about this illusion is that it seems to hold true at all ages. In fact, some of the results suggested that more than their grandparents, young people think they are done changing.

Caption: Painting, Girl in a Mirror (1632) by Paulus Moreelse, purchased by the Rijksmuseum Amsterdam with support of the Vereniging Rembrandt. In the public domain.

This much, at least, was clear to the researchers: “At every stage of adult life that we could analyze. Both teenagers and grandparents seem to believe that the pace of personal change has slowed to a crawl and that they have recently become the people they will remain. History, it seems, is always ending today.”

While the researchers are clearly speaking of the history of the individual, their research raises the question of whether there’s a similar illusion when it comes to human history. For example, do we routinely underestimate the amount of technological change that lies ahead or its cultural and social impact? We acknowledge the profound cultural changes in past decades, but do we underestimate what is coming?

We marvel at the transformations of human evolution, but do we fail to imagine the changes that lie ahead? According to the researchers, "people may confuse the difficulty of imagining personal change with the unlikelihood of change itself." If that is true of the human individual, might it also be true of the human species?

The research appears as “The End of History Illusion” in the 4 January 2013 issue of the journal Science, a publication of the American Association for the Advancement of Science.

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.

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.

Art in an Age of Neandertals

The oldest confirmed date for cave art has just been pushed back again. New research re-dates paintings in caves in northern Spain to a staggering 40,800 years ago, right at the time when anatomical modern humans (AMHs) like us were just arriving in the region and encountering Neandertals.

In fact, this art is so ancient that it raises the haunting possibility that Neandertals were the painters. If so, then modern humans are not the only form of humanity to create cave art. For now, however, the question of who painted this art is a matter of speculation, something that might be settled by further research.

In work published in the June 15, 2012 issue of Science, researchers studied 50 paintings in eleven caves in the northernmost part of Spain, including the UNESCO World Heritage sites of Altamira, El Castillo and Tito Bustillo. The work was conducted by an international team led by Alistair Pike of the University of Bristol.

The Corredor de los Puntos, El Castillo Cave, Spain. Red disks here have been dated to 34,000-36,000 years ago, and elsewhere in the cave to 40,600 years, making them examples of Europe's earliest cave art. Image courtesy of Pedro Saura.

This research comes on the heels of a re-dating of cave painting in France, recently pushed back to 37,000 years. The latest study adds almost another 4,000 years to the confirmed date of the oldest art. What’s the combined effect of the two studies? In just the past month, our view of the antiquity of art has jumped by nearly 10,000 years, prompting us to wonder how much further back it might go. After all, it is known that AMHs mixed pigments as far back as 100,000 years ago.

Using a new method called uranium-thorium dating, Pike’s research team took a closer look at an old find. They extracted tiny samples of naturally forming deposits that covered the paintings. By dating the deposits, scientists are able to discover the date before which the paint was applied. The date of more than forty thousand years ago, therefore, is a minimum date, suggesting that some of the paintings—here or elsewhere—may be even older.

The specific painting that exceeds 40,800 years is a simple red disk, seemingly primitive when compared to paintings made later in the same caves. More striking are the handprint paintings on the wall of El Castillo cave, made by blowing paint and common in early cave art but now dated to 37,300 years ago.

Commenting on the age of the oldest painting, Pike pointed out the tight fit between the painting and the arrival of AMHs in northern Spain: “Evidence for modern humans in Northern Spain dates back to 41,500 years ago, and before them were Neanderthals. Our results show that either modern humans arrived with painting already part of their cultural activity or it developed very shortly after, perhaps in response to competition with Neanderthals – or perhaps the art is Neanderthal art,” Pike said in a press release issued by the University of Bristol.

The Panel of Hands, El Castillo Cave, Spain. A hand stencil has been dated to earlier than 37,300 years ago and a red disk to earlier than 40,600 years ago, making them the oldest cave paintings in Europe. Image courtesy of Pedro Saura.

Pike also speculated further on the possibility that researchers may someday identify some European cave art as Neandertal. He suggested that perhaps, “cave painting started before the arrival of modern humans, and was done by Neanderthals. That would be a fantastic find as it would mean the hand stencils on the walls of the caves are outlines of Neanderthals' hands, but we will need to date more examples to see if this is the case."

The article in entitled “U-series dating of Palaeolithic Art in 11 Caves in Spain” and appears in the June 15, 2012 issue of the journal Science.

Merging Humans and Robots--More Coffee, Please

With the help of a tiny chip implanted in the brain, human beings who cannot move their own limbs are able to move a robotic arm, in one case taking a drink of coffee on one’s own for the first time in fifteen years.

"The smile on her face was a remarkable thing to see. For all of us involved, we were encouraged that the research is making the kind of progress that we had all hoped," said the trial's lead investigator, Leigh Hochberg, M.D., Ph.D., in a press release issued by the National Institutes of Health, which provided some of the funding. Hochberg is an associate professor of engineering at Brown University and a critical care neurologist at Massachusetts General Hospital (MGH)/Harvard Medical School.

The field of brain-computer interface research is not new, but this is the first peer-reviewed report of people using brain signals to control a robotic arm, making it perform in three-dimensional space much as their natural arms once did. By imagining they were controlling their paralyzed limb, they were able to move the robotic arm. Brain activity is detected as electrical activity by the BrainGate chip, processed by an external computer, and fed into a robot that translates the signals into movement.

More research is underway, and in fact this clinical trial is recruiting more volunteers.

Caption: The BrainGate array, which is implanted on the motor cortex, comprises nearly 100 electrodes on a chip the size of a baby aspirin. Credit: www.braingate2.org Usage Restrictions: With Credit.

With future advances, researchers hope to be able to improve the quality of movement in prosthetic limbs or to restore in part the function of paralyzed limbs, perhaps by creating an electronic by-pass to normal nerves.

"This is another big jump forward to control the movements of a robotic arm in three-dimensional space. We're getting closer to restoring some level of everyday function to people with limb paralysis," said John Donoghue, Ph.D., who leads the development of BrainGate technology and is the director of the Institute for Brain Science at Brown University.

Beyond therapy, it is possible to imagine other uses as we humans and our machines co-evolve and increasingly converge, probably to do more than drink coffee.

This report is published in the May 17, 2012 issue of Nature.

Human Intelligence: Does It Depend on a Genetic Error?

What makes humans different from the great apes? What makes our brains larger and more complex? We know that our DNA is remarkable similar to other mammals. What subtle genetic changes can explain such huge behavioral differences? One surprising possibility is that our brains are bigger and more complex not so much because of new genes but because of gene duplication.

One gene in particular—SRGAP2—plays a role in how brain cells migrate. It is found widely in mammals of all sorts, from mice to humans. In the great apes, the more archaic form of SRGAP2 results in a relatively slow spread of neurons throughout the brain. Twice in the ancient past, however, SRGAP2 was duplicated, first about 3.4 million years ago and then again around 2.4 million years ago. The second duplication occurred right around the time when the genus Homo separated from Australopithecus. It appears that as a result of these duplications, brains in the Homo lineage—including our own as Homo sapiens—are both large and complex in their number of neuronal connections and in their ability to process information.

A key piece of supporting evidence comes from recent discoveries of the role of SRGAP2 in the development of the human neocortex. When the distinctly human SRGAP2 variants are missing, normal human brain development is impaired. This research appears in two papers appearing May 3, 2012 in the journal Cell. According to one of the papers, “It is intriguing that the general timing of the potentially functional copies…corresponds to the emergence of the genus Homo from Australopithecus (2-3 mya). This period of human evolution has been associated with the expansion of the neocortex and the use of stone tools, as well as dramatic changes in behavior and culture.”

Caption: A team led by Scripps Research Institute scientists has found evidence that, as humans evolved, an extra copy of a brain-development gene allowed neurons to migrate farther and develop more connections. Credit: Photo courtesy of The Scripps Research Institute Usage Restrictions: None

The uniquely human duplications work in a surprising ways, especially the second duplication. The original SRGAP2 remains present in humans today, along with the duplicated versions. The second duplication—SRGAP2C—has the effect of interfering with the original SRGAP2. The reason why SRGAP2C interferes with SRGAP2 rather than boosts it is because the duplicated version is incomplete—in other words, an advantageous copying error.

According to one of the studies, once SRGAP2C appeared about 2.4 million years ago, it created a “dominant negative interaction equivalent to a knockdown of the ancestral copy…The incomplete nature of the segmental duplication was, therefore, ideal to establish the new function by virtue of its structure,” acting in a way that was “instantaneous” in terms of evolution.

"This innovation couldn't have happened without that incomplete duplication," according to Evan Eichler, another leader in the research team. "Our data suggest a mechanism where incomplete duplication of this gene created a novel function 'at birth'."

Even though SRGAP2 duplications seem to play a significant role in distinguishing human beings from the apes, other duplications and mutations are very likely to be involved in the story of human evolution. "There are approximately 30 genes that were selectively duplicated in humans," said Franck Polleux, one of the lead researchers involved in the study, in a press release from the journal. "These are some of our most recent genomic innovations."

Rather than standard mutations, "episodic and large duplication events could have allowed for radical – potentially earth-shattering – changes in brain development and brain function," according to Eichler. For these reasons, this is one of the most intriguing areas for research into the origins of human intelligence.

Whether other duplications—including “incomplete duplications or erroneous copies—also explain our complex brains is something that will be discovered in the next few years.

But what is surprising and somewhat sobering, just based on this SRGAP2 discovery, is how our much-vaunted human uniqueness seems to hang on such a fine thread. If the SGGAP2 duplication is even partly responsible for our complex brains, should we think that our intelligence arose because of a copying error or an incomplete duplication? Is the rise of intelligence and consciousness—truly one of the great events in the story of cosmic evolution—really just based in part on a fluke of nature? Religious or not, hardly anyone is likely to think that thinking is sheer accident.

The papers, Charrier et al.: "Inhibition of SRGAP2 function by its human-specific paralogs induces neoteny during spine maturation" and Dennis et al.: "Human-specific evolution of novel SRGAP2 genes by incomplete segmental duplication," appear in the journal Cell.

Extending Healthy Lifespans? A Pill on the Horizon?

Resveratrol, the much-hyped ingredient found in red wine and sold widely as a nutritional supplement, is known to improve the health and extend the lifespan of mice. Can it do the same for humans? Without nasty side effects? And at what dose?

A study published today in Cell Metabolism helps unravel a few more of resveratrol’s mysteries. In particular, researchers have shed new light on how resveratrol works. Key to its effectiveness is a gene known as SIRT1, found in slightly different forms in species as different as yeast and humans. SIRT1 plays many roles, some tied to core metabolic processes. The new study shows that in mice, even a low dose of resveratrol interacts with SIRT1 to improve metabolism.

What makes this study especially interesting is that researchers had to create a special strain of mice in order to test whether SIRT1 is necessary for resveratrol to work. If mice have no SIRT1, they do not develop properly. So two graduate students, Nathan Price and Ana Gomes, developed a novel strain of mice with an unusual copy of the SIRT1 gene, one that could be switched off at adulthood.

By administering a drug (tamoxifen), researchers can “induce” or switch the SIRT1 gene on and off, a strategy that will likely be used in other studies. "This is a drug inducible, whole body deletion of a gene," David Sinclair, the study's senior author, said in a press release from Harvard Medical School. "This is something that's rarely been done so efficiently. Moving forward, this mouse model will be valuable to many different labs for other areas of research."

Photo by R. Cole-Turner

In this case, the switchable SIRT1 mouse provided proof that SIRT1 is key to resveratrol’s effectiveness. Why is that important? Because resveratrol is a complex molecule that interacts with the body in many unknown ways. While it may be beneficial, it may have unwanted side effects. So researchers are trying to design a more simple molecule that provides the benefits of resveratrol without all the risks. One strategy is to boost SIRT1 activity. By proving that SIRT1 is involved, this study provides support for that strategy, which is already being pursued by pharmaceutical firms.

"The results were surprisingly clear," said. "Without the mitochondria-boosting gene SIRT1, resveratrol does not work."

Are we any nearer a magic pill that slows aging or promotes longevity? Perhaps. The headline of the press release from the publisher, Cell Press, claims that this work “restores hope for anti-aging pill.” Remember, of course, that the work reported here is entirely with mice.

Even so, the paper itself concludes with this statement: “This model supports the enticing possibility of designing and developing potent small molecules that provide the health benefits of resveratrol by activating SIRT1 and downstream pathways to treat metabolic and other age-related diseases.”

The treatment of age-related diseases, including diabetes, is a huge target for pharmaceutical firms. But beyond that lies that even bigger market for human enhancement, specifically for enhancing the span of healthy decades.

The study, "SIRT1 Is Required for AMPK Activation and the Beneficial Effects of Resveratrol on Mitochondrial Function," appears in the May 1, 2012 issue of Cell Metabolism.

Synthetic Biology: Is There Life beyond DNA?

Life as we know it is based on DNA and RNA. Could it have been otherwise? Might other worlds have life based on a different “genetic” system? We may never know for sure.

But we do know that synthetic biology is moving briskly toward the goal of engineered life beyond DNA and RNA.

Recall that in “DNA” and “RNA,” the “NA” part stands for “nucleic acids.” It’s the four nucleic acids that carry the genetic information in a chemical code. The “D” and the “R,” however, stand for sugars that hold the nucleic acids in place, allowing them to form pairs and to copy themselves. Can other sugars work as well?

Recent work in synthetic biology has led beyond DNA and RNA to xeno-nucleic acids or “XNAs.” Now, using six different forms of XNAs, an international team of researchers led by Vitor Pinheiro reports success in getting XNAs to store and propagate information. One of their XNAs actually “evolved” by responding to imposed selective constraints. Their work is published in the April 20, 2012 issue of the journal Science.

Caption: Courtesy--National Human Genome Research Institute

In a commentary on the research, Gerald F. Joyce writes in Science that this work has implications for the “understanding of life itself.” In addition, it opens new insight into the possible origins of life on our planet or else where in the cosmos.

At the same time, far more work lies ahead before synthetic biologists create XNA-based life. Pinheiro’s team was able to get their synthetic XNA “genes” to interact with DNA, but “they have not yet realized a synthetic genetic system.” One big challenge is in getting XNA sequences to copy themselves the way DNA does. Some XNAs can copy themselves to DNA and back again to XNA, but XNA-to-XNA copying is not reliable.

According to Joyce, however, “future studies are likely to yield improvements of the the various XNA-to-XNA copying reaction.” If that happens, synthetic biology will take yet another step toward “synthetic genetics.”

All this prompts a warning from Joyce: “Synthetic biologists are beginning to frolic on the worlds of alternative genetics but must not tread into areas that have the potential to harm our biology.” As ever, greater knowledge brings greater risks. More than ever, public awareness and careful thought are needed.

The research article, "Synthetic Genetic Polymers Capable of Heredity and Evolution" and the commentary, "Toward an Alternative Biology," are both published in the April 20, 2012 issue of Science, the journal of the American Association for the Advancement of Science.

Oldest Art from the New World?

In a cave in Brazil, researchers have found what they claim may be the oldest known art from the western hemisphere. Dating from between 9,000 and 12,000 years ago, the simple petroglyph pictures a human-like figure that is roughly 30cm tall.

The report of the discovery is published in the February 22, 2012 issue of PLoS ONE, an open access journal. The team was led by Walter Neves of the University of Sao Paulo.

Caption: This is the oldest reliably dated petroglyph ever found in the New World.

Credit: Citation: Neves WA, Araujo AGM, Bernardo DV, Kipnis R, Feathers JK (2012) Rock Art at the Pleistocene/Holocene Boundary in Eastern South America. PLoS ONE 7(2): e32228. doi:10.1371/journal.pone.0032228

Early New World art is rare, and the oldest examples are not nearly as old as art discovered in Europe and Africa, which ranges back 30,000 years or more. But this finding is interesting nonetheless. Odd features of the drawing--is it human or a bird or reptile, and does it include an oversize phallus--are sure to fuel speculations about the religious or shamanistic origins of ancient art. The earliest expressions of symbolic culture in any setting or context provide additional insight into the cultural origins of modern humanity.

"Rock Art at the Pleistocene/Holocene Boundary in Eastern South America" is published in the February 22 issue of PLoS ONE and is available free to the public.

Single-Atom Transistor: Why Small Is a Big Deal

A tiny achievement with huge significance was reported today by physicists at the University of New South Wales (UNSW). They have created a transistor that uses a single atom. Their work is described in a paper and an editorial published in the February 19 issue of Nature Nanotechnology.

Using a scanning tunneling microscope—the essential tool in nanotechnology that allows researchers to visualize and manipulate single atoms—the UNSW group positioned a phosphorous atom between nano-scale electrodes. A video explaining the feat is available.

CAPTION:This is a single-atom transistor: 3D perspective scanning tunnelling microscope image of a hydrogenated silicon surface. Phosphorus will incorporate in the red shaded regions selectively desorbed with a STM tip to form electrical leads for a single phosphorus atom patterned precisely in the center. Credit: ARC Centre for Quantum Computation and Communication, at UNSW.

What seems to be most important about this achievement is the accuracy of the placement of the phosphorous atom. This opens the possibility that precisely placed atoms may be used to create a whole new generation of computer chips that are both reliable and smaller than anything used today.

"Our group has proved that it is really possible to position one phosphorus atom in a silicon environment—exactly as we need it –with near-atomic precision, and at the same time register gates," said lead author Dr Martin Fuechsle in a press release from UNSW.

The leader of the research group, Professor Michelle Simmons, claims that "This is the first time anyone has shown control of a single atom in a substrate with this level of precise accuracy." Simmons is director of the ARC Centre for Quantum Computation and Communication at UNSW.

According to the famous “Moore’s Law,” which argues from past achievement in chip design and predicts future a doubling in chip power ever 18 months, single atom or quantum computing should be achieved by the year 2020. Fuechsle and Simmons are speculating that because of this breakthrough, technology is ahead of schedule.

If so, then arguments advanced by futurists such as Ray Kurzweil take on added significance. As chips grow in power and shrink is size, more and more powerful computing becomes possible. Smaller chips are more implantable, bringing us closer to they day when they are implanted not just for medical but for other purposes (see previous post).

Even more significant is that smaller and more powerful processing paves the way for more highly intelligent machines. Kurzweil predicts that within a few decades, machines with greater than human intelligence will be produced. What then? Will our inventions become the inventors of the future, and will they still need us? The report, "A Single-Atom Transistor," is published in the February 19 is of Nature Nanotechnology.

Humans Beings, DNA Nano-Robots, and Implantable Chips

Technological devices inside the human body are fast becoming more fact than fiction, and two reports released on February 16 are significant milestones along that path.

In one study, appearing in Science Translational Medicine, microchips were implanted in women suffering from osteoporosis. Researchers at Harvard Medical and Case Western worked with MicroCHIPS, the manufacturer of the device.

Patients with advanced osteoporosis, whose bones have weakened and lost density, are currently able to give themselves with a daily injection of a drug that requires refrigeration. By implanting a device, researchers want to make the process easier compliance more consistent.

The microchips implanted in the study contain tiny reservoirs of the drug. The device releases a daily dose when it receives a wireless signal. It also monitors the release of the drug and reports back to the physician, who is able to modify the prescription by sending new instructions to the device from another wireless device, such as a smart phone. This is believed to be the first wirelessly controlled implanted drug-delivery device.

"This trial demonstrates how drug can be delivered through an implantable device that can be monitored and controlled remotely, providing new opportunities to improve treatment for patients and to realize the potential of telemedicine," according to Robert Langer of MIT and the cofounder of MicroCHIPS, Inc. "The convergence of drug delivery and electronic technologies gives physicians a real-time connection to their patient's health, and patients are freed from the daily reminder, or burden, of disease by eliminating the need for regular injections," Langer said in a release issued by the MicroCHIPS.

The drug delivery device (on right) next to an everyday computer memory stick. Courtesy of MicroCHIPS, Inc., Massachusetts.

The company also reported that it is currently developing new designs of its microchip-based implant to include as many as 400 doses per device providing daily dosing for one year or multi-year therapy for less frequent dosing regimens.

In another study reported today, a team of researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University report on their work in assembling tiny robots out of DNA.

Building on previous advances in what is popularly known as “DNA origami,” the Wyss team used a computer to fabricate a barrel-like structure capable of containing specific molecules for delivery to targeted cells in the body. For example, cancer cells could be targeted with molecules that cause them to self-destruct, much the way the body’s own immune system carries out its functions.

“DNA origami” allows researchers to use DNA as a construction material. They are able to fold it and weave its strands together. What’s more, since DNA is a chemical code, specific patterns or sequences in the DNA can be used to “read” a signal and “act” accordingly. In this study, researchers built a DNA “latch” or locking mechanism. Their DNA barrel kept its molecular payload safely under wraps until it arrived on the surface of the target cell. On the surface of the target cell is a protein that unlocks the DNA latch, releasing the molecule at just the right location.

Cell-targeting DNA nano-robots bearing antibody-fragment payloads. [Image created by Campbell Strong, Shawn Douglas, & Gaël McGill using Molecular Maya & cadnano]

"We can finally integrate sensing and logical computing functions via complex, yet predictable, nanostructures—some of the first hybrids of structural DNA, antibodies, aptamers and metal atomic clusters—aimed at useful, very specific targeting of human cancers and T-cells," said George Church, Ph.D., a Wyss core faculty member and Professor of Genetics at Harvard Medical School, who is Principal Investigator on the project.

One way in which the researchers tested their DNA nano-robots was by programming them to target and destroy cancer cells growing in culture, including leukemia and lymphoma cells. The results were promising. According to the study, ” These findings demonstrate that the robots can induce a variety of tunable changes in cell behavior. Furthermore, biologically active payloads may be bound indirectly via interactions with antibody fragments, enabling applications in which the robot carries out a scavenging task before targeted payload delivery.”

The work reported here is built on advances around the world in nanotechnology and synthetic biology. What is new is the way the Wyss team combined several of these advances for the first time. For example, the release mechanism used here responds to the presence of a protein, not just to the presence of DNA or RNA. That feature alone makes this work more immediately applicable for medical purposes.

Put together, these two reports are part of a far wider panorama of basic advances in biomedical research. They stand out in part because of what they promise in terms of future treatment strategies. But more than that, they catch our attention because advances like these continue to blur the lines between ourselves and our technology.

In the first case—a wireless implanted drug-delivering chip—we are not simply injecting a medication or implanting a device. The patients in this study are hosts to a high-tech subsystem implanted within them that interacts in sophisticated ways with another human being (their physician). What’s more, that other human being—even if half a world a way attending a medical conference—can send instructions that immediately cause an effect within the body (but perhaps without the knowledge) of the patient. Surely there’s a spy story here just waiting to be written. More than that, this seems to be another significant milestone on the way to the (post?-) human future.

In the second case (the DNA nanoscale robot), nothing is yet implanted, but that’s clearly a next step. What are we to make of this elegant piece of tiny engineering? It is so small that it can only be made using computers. It is built from the same sort of DNA that we have in every cell, but it's engineered to hold a desired shape and to respond to a specific signal. Then, if inserted in great numbers into the human body, it can emulate the human immune system but take it in directions far beyond evolution.

The report on the implantable chip is entitled "First-in-Human Testing of a Wirelessly Controlled Drug Delivery Microchip" and appears in the February 16 issue of Science Translational Medicine. The report on DNA robots, "A Logic-Gated Nanorobot for Targeted Transport of Molecular Payloads," appears in the February 17 issue of the journal Science. Both journals are publications of the American Association for the Advancement of Science.

Regenerative Medicine: Repairing the Heart

A breakthrough in the use of stem cells for regenerative medicine has just been reported by researchers at Cedars-Sinai Heart Institute. Patients who suffered heart attacks were implanted with cells derived from their own hearts. Some of the scars left by the heart attacks dissolved and new heart muscle cells re-grew, according to a report in the February 14 issue of The Lancet.

Patients involved in the study had all experienced recent heart attacks that damage heart muscle. The first step in the procedure involved inserting a catheter through a vein in the neck under local anesthesia. Using the catheter, researchers withdrew a small sample of healthy heart tissue. The tissue contains some stem cells, but the key step in the procedure is to multiply and purify the small number of stem cells so that they number in the tens of millions.

These cardiac stem cells, multiplied but originally from the patient’s own heart, were then infused back into the site of the heart attack. The result seems to be a nearly 50% drop in the size of the scar and a re-growing of healthy heart muscle, at least as far as could be determined using imaging technology.

It is important to note that this study is a Phase I clinical trial. Its main purpose is to show that there is no unwarranted risk in the procedure. The outcome of this trial, however, shows a real likelihood of benefit. The evidence is strong that scaring is reduced and heart muscle regenerated. It is too soon, of course, to know the long-term benefits.

What is new in this study is the strong likelihood of actual regeneration of heart cells. Whether the implanted cells produced the new muscles or whether they acted indirectly, triggering neighboring cells to divide and regenerate tissues, is still not clear.

The lead researcher in the study, Eduardo Marbán, made this claim about the finding: "This has never been accomplished before, despite a decade of cell therapy trials for patients with heart attacks. Now we have done it. The effects are substantial, and surprisingly larger in humans than they were in animal tests." Marbán is the director of the Cedars-Sinai Heart Institute who invented the procedures and technology involved in the study, including the procedures for multiplying the stem cells.

"These results signal an approaching paradigm shift in the care of heart attack patients," said Shlomo Melmed, MD, dean of the Cedars-Sinai medical faculty and the Helene A. and Philip E. Hixon Chair in Investigative Medicine. "In the past, all we could do was to try to minimize heart damage by promptly opening up an occluded artery. Now, this study shows there is a regenerative therapy that may actually reverse the damage caused by a heart attack."

The study itself concludes with this claim: “Our study provides an initial indication that therapeutic regeneration might indeed be possible in cardiac tissue.”

The goal of regenerative medicine—the use of stem cells to help patients regrow cells and regenerate tissues or organs—has long been central to the dreams that surround stem cell research. Even though this in only a Phase I study and still must be replicated, it seems to be an important step in the development of regenerative medicine.

Many of course will be especially delighted that no embryonic stem cells were directly involved in this procedure. Those who object to the use of human embryos in research will regard these cells as “morally unproblematic.” It is also very significant to point out that because the cells come from the patients, there should be no issue of tissue rejection.

At the same time, it should be noted that the field of stem cell research advances as a whole field. Knowledge gained from one area (for example, using embryonic stem cells) opens the door for advances across the whole field.

The article, “Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial,” appears appropriately in the Valentine’s Day issue of the medical journal, The Lancet.

Designer Babies Revisited

“Designer Babies” are back in the news. Scientists and medical experts in Australia have asked the government to allow the use of a controversial technique to allow couples to conceive without passing on a genetic disease.

The technique is controversial, at least in the media accounts, because the child that is conceived would have three parents.

The truth is a little more complicated but a lot less dramatic. Most of the genes in our cells are located in chromosomes, which we get from both our parents. A very few genes are located outside the chromosomes in small structures called mitochondria. These genes—our “mitochondrial DNA”—are necessary for energy production in the cell. If they are defective, the result can be a number of diseases.

We get our mitochondria only from our mothers. That means that if a woman has a defect in her mitochondrial DNA, she will inevitably pass it on to all her children, who may be more or less ill than she has been during her lifetime.

But what if a couple could conceive a child using their own chromosomal DNA while using a donor’s mitochondria? That would give the couple the best opportunity to have a child that is almost entirely “their own” genetically while avoiding diseases associated with mitochondrial irregularities. That’s the hope that doctors in Australia are holding out.

In 2001, word leaked out that a fertility clinic in New Jersey was quietly offering this technique. The report triggered a bit of a flap, mostly over issues of safety and the utter lack of government oversight or public moral reflection. The best account of that episode is found in an essay by Erik Parens and Eric Juengst, “Inadvertently Crossing the Germ Line,” appearing in the journal Science in April of 2001.

Is the strategy safe? Should it be permitted? Is it moral? Is “germline” modification in general ethically defensible? Is it religiously objectionable?

I try to address some of these questions in my 2008 collection of essays, Design and Destiny: Jewish and Christian Perspectives on Human Germline Modification. Among other findings: Catholic teachings may object to specific techniques but not so much to the core idea. As long is “in vitro” techniques are not used, what could be wrong with helping a couple conceive a healthy child? (See my earlier post.) But for all religious people, is there a line to be drawn between germline modification aimed at avoiding disease and the very same technique that might be used to produce a “better” child—one that is smarter or healthier than normal?

To be clear, the Australian scientists are proposing no such thing. But as they know, these techniques will likely advance along a common front. The minimal modification to avoid mitochondrial disorders will help pave the way to germline modification to avoid other diseases. And those techniques will almost certainly lead in time to the possibility of enhancing our offspring.