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.

Hope for Aging Brains

When electrical wires lose their insulation, they have to be replaced. When the nerves and brain cells in our bodies lose theirs, they regenerate it naturally.

Up to a point, that is. As the decades pass, our bodies lose the ability to regenerate themselves. The results are obvious: wrinkled skin, weak muscles, and forgetful brains.

All the more tragic for those among us with diseases that attack the very processes of regeneration. Multiple sclerosis (MS), for example, keeps the body from restoring the insulating layers that protect nerve fibers. The insulation—“myelin”—breaks down naturally. In most human brains, “remyelination” is a constant process, rebuilding the myelin that protects the brain cells and allows them to do their work. For people with MS, remyelination is under attack.

Working with mice, researchers seem to have found a way to reinstate the remyelination process. In a report in the January 6 issue of Cell Stem Cell, researchers at Harvard and Cambridge Universities show that the capacity for remyelination can be restored in aging mice.

The cells that are responsible for remyelination are still present in the aging mouse. It’s just that they have been switched off. By exposing these cells to switching signals present in a much younger mouse, researchers were able to reverse the effects of aging on the cells that do the work of remyelination.

How did they do this? They literally joined the old and the young mouse together surgically. This allows their blood to circulate together. In the young blood, apparently, were various chemical signals that reset the switches in the cells of the brains of the aging mice. The result: spontaneous remyelination.

According to Robin Franklin, one of the researchers, the study shows that “age-associated decline in remyelination is reversible. We found that remyelination in old adult mice can be made to work as efficiently as it does in young adult mice.” Franklin, who is Director of the MS Society's Cambridge Centre for Myelin Repair at the University of Cambridge, made her comments in a press release issued by her university.

What’s perhaps most interesting about this report is that it is a kind of stem cell research that doesn’t implant stem cells. It works on the principle that stem cells already exist in the patient’s body but that they’ve been silenced by age or disease. They need to be switched back on or rejuvenated. According to Franklin, “remyelination therapies do not need to be based on stem cell transplantation since the stem cells already present in the brain and spinal cord can be made to regenerate myelin - regardless of the patient's age."

As interesting as this is, it is important to stress that this is a “proof of concept” study. The techniques here are simply not applicable to human beings. They are encouraging because they suggest that perhaps some day, researchers will discover just what it is in the young body that keeps it young. What are the specific factors that keep the body’s own stem cells switched on? And if it circulates in the blood as this study shows, perhaps these factors could simply be injected.

Of course, if researchers discover how to do this, it’s not just people with diseases like MS who will be interested. One of the interesting social features about this work is that it is funded in part by the UK MS Society and the American MS Society. In other words, the funding is motivated by the search for a cure for a very specific disease. But the mice is the study were aging, not ill. That suggests to me, at least, that the larger portion of the “beneficiaries” of this work will be aging humans, not those with MS. If so, then this study is one more step in the quest of human enhancement, suggesting that it may be possible to reverse aging in the one part of the body where it is most feared—the human brain.

The journal report ends with this comment: “Moreover, this work demonstrates that the CNS maintains its responsiveness to age-regulated circulatory factors, such that age-dependent deficiencies in repair of these tissues can, in part, be reversed by circulating factors.”

The paper, “Rejuvenation of regeneration in the aging central nervous system,”' is published in the January 6 issue of Cell Stem Cell.

Is Aging a Disease of Stem Cells?

Is aging a disease? And if it is a disease, what “causes” it? Is it simply natural for bodies to age over time, or is something wrong with them, something that could be “fixed”?

In a report in the January 3 issue of Nature Communications, researchers at the University of Pittsburgh School of Medicine report on work with mice that are bred especially to age quickly. The mice have a version of progeria, a disease in humans that causes children to age well before their time.

The research team looked at differences in stem cells or progenitor cells, which healthy bodies naturally keep in reserve as a source for new cells to replace worn-out cells. Not surprisingly, they found that the progeria mice had fewer progenitor cells than their healthy counterparts. What’s more, the few progenitor cells in the progeria mice failed to function normally. For example, they didn’t produce replacement cells as needed.

If that’s the problem, can it be “fixed”? The researchers, led by senior investigators Johnny Huard and Laura Niedernhofer, injected the rapidly-aging progeria mice with progenitor cells from the muscles of healthy mice. The result was pretty amazing.

"We wanted to see if we could rescue these rapidly aging animals, so we injected stem/progenitor cells from young, healthy mice into the abdomens of 17-day-old progeria mice," Dr. Huard said in a press release issued by the University of Pittsburgh. "Typically the progeria mice die at around 21 to 28 days of age, but the treated animals lived far longer—some even lived beyond 66 days. They also were in better general health."

How did this work? Did the injected cells start producing replacement cells? Possibly, but the main effect of the injected cells seems to have been to change the host cells in the body of the progeria mice. In other words, the injected healthy progenitor cells changed the progeria mouse’s own cells into more healthy, more normal cells.

"This leads us to think that healthy cells secrete factors to create an environment that help correct the dysfunction present in the native stem cell population and aged tissue," Dr. Niedernhofer said. "In a culture dish experiment, we put young stem cells close to, but not touching, progeria stem cells, and the unhealthy cells functionally improved." Fascinating!

What about mice that are aging normally? Would the injection of progenitor cells from younger mice, for example, also “rescue” non-progeria but aging mice?

Whether anything like this could be done safely in human beings is a big question that will require a lot more research. It may turn out that injecting progenitor cells into a human patient with premature aging might help stall the aging but might also create other problems, such as cancer. In time, it may be possible to get the benefits while managing the risks.

The Pitt research, although dealing with mice with progeria, opens profound questions about humanity, aging, enhancement, and the possibility of extending the human lifespan.

The biggest question of all is whether something like this would slow the aging process in normal or healthy human beings. In other words, is this yet another possible pathway to human enhancement? Could this be used to “treat aging as a disease”?

Is aging a disease? Dr. Niedernhofer’s comment is revealing: "Our experiments showed that mice that have progeria, a disorder of premature aging, were healthier and lived longer after an injection of stem cells from young, healthy animals," Dr. Niedernhofer said. "That tells us that stem cell dysfunction is a cause of the changes we see with aging." A dysfunction? A disease? A difference?

On the question of religion and the morality of extending the human lifespan, probably the best book on the market is Religion and the Implications of Radical Life Extension, edited by Calvin Mercer and Derek Maher. I have an essay in the book reflecting on the question from the standpoint of Christianity.

My take? Extending the human lifespan is not immoral or obviously wrong, but Christians hope for a transformation, not an extension. More of the same is too little.

The report appeared in the January 3 issue of Nature Communications. It is entitled Muscle-derived stem/progenitor cell dysfunction limits healthspan and lifespan in a murine progeria model and is available free to the public.

Eating, Aging, and the Brain

Two recent studies shed new light on the relationship between food and the brain.

The first study involves mice on a calorie-restricted diet. Restricting calories to about 70% of normal intake kept the mice—and their rodent brains—young when compared to control mice who could eat whenever they wanted. And while there’s no proof yet that this works with human beings, there is a lot of interest by researchers in finding out what is going on in the relationship between aging and eating.

The latest research is reported in the December 19 of PNAS. Researchers at the Catholic University of Sacred Heart in Rome report their finding that a naturally-occurring protein, CREB1, plays a key role in mediating between caloric restriction and the delay of aging. Caloric restriction seems to trigger CREB1, which in turn activates many other genes involved in longevity and brain function.

What is new in this research is the relationship between caloric restriction and CREB1 activity. Discovering how these molecules interact opens the possibility that the activity of CREB1 can be increased without having to keep to a fairly austere diet.

According to Giovambattista Pani, one of the lead researchers, “Our hope is to find a way to activate CREB1, for example through new drugs, so to keep the brain young without the need of a strict diet.”

“This discovery has important implications to develop future therapies to keep our brain young and prevent brain degeneration and the aging process. In addition, our study shed light on the correlation among metabolic diseases as diabetes and obesity and the decline in cognitive activities,” according to Dr. Pani.

The second study is published in the December 28 issue of Neurology and does involve human beings. Just in time for New Year’s resolutions, researchers at Oregon State University report on the brains and the diets of 104 seniors with an average age of 87. The result is pretty sobering. Those who ate fast foods and snack loaded with trans-fats scored much worse on cognitive tests than those who ate diets rich in the healthy oils commonly found in fish or consumed high levels of vitamins B, C, D, and E.

How much worse? The fast-food seniors scored 17% lower on thinking and memory tests and had a shocking 37% lower active brain size based on an MRI. And that’s after other factors such as age or education level are removed. Diet alone, it appears, makes a significant difference. Eating the right food seems to help slow down the age-related shrinkage of the brain.

Someday there might be a pill that makes us and our brains resist aging. For now, it’s what we eat that counts. These results need to be confirmed, but obviously it is very exciting to think that people could potentially stop their brains from shrinking and keep them sharp by adjusting their diet," according to Gene Bowman of the Oregon Health & Science University in Portland and author of the study.

This would not have surprised Saint Athanasius, bishop of Alexandria in the mid-4th century. Like many of his age, Athanasius was fascinated by the story of Saint Anthony of Egypt, one of the earliest Christian ascetics. Athanasius wrote a spiritual biography of Anthony, interpreting his life and turning him into the prototype of Christian monks.

Anthony gave away the family fortune and lived in isolation in the Egyptian desert, eating almost nothing. The result? He lived to 105 and was known for his wisdom to the very end.

Todd Daly has written about Athanasius and Anthony, including an essay in my recent book, Transhumanism and Transcendence. Daly makes it clear that Anthony’s purpose was not longevity or a youthful brain. This is no science experiment, and if Anthony is the first monk, he’s not the first transhumanist. But according to Athanasius (and to Daly), Anthony is conducting a spiritual experiment. His question is whether it is possible to regain some small portion of the original human condition…humanity as God intended, in other words, rather than the fallen humanity we experience. By denying his body, he sought to expand his soul. Without realizing it, he kept his brain from shrinking.

The amazing thing is that by asking a seemingly arcane theological question—and by sticking with it for decades—Anthony anticipates today’s research.

The PNAS article was published on December 19. The Oregon study was published online on December 28 by the journal Neurology.

New Book on “Transhumanism and Transcendence”

My latest book is Transhumanism and Transcendence: Christian Hope in an Age of Technological Enhancement. It is a collection of essays from leading Christian theologians responding to various aspects of transhumanism and of the growing potential for technology to “enhance” human beings. The book is on display for the first time at the book exhibits at the American Academy of Religion, 19-22 November 2011 in San Francisco. The publisher is Georgetown University Press.

On the back cover of the book, Philip Clayton comments:

This is the most important Christian debate on transhumanism that I have ever read. Those who prefer fawning acceptance or frightened rejection of human enhancement can find simplistic monographs aplenty. But if you want to think theologically about the transformation of humanity through technology—what's already here, and what lies ahead of us—this collection is mandatory reading.

I wrote the first and the last chapters of the book, framing the argument and summarizing the findings.
The eleven chapters in between are written by established scholars and younger thinkers, some of whom were finishing doctoral studies on transhumanism just as the book was being written.

Michael Burdett, for example, drew upon his studies at Oxford in writing about Francis Bacon, N. F. Fedorov, and Teilhard as early examples of transhumanist thinking. David Grumett, an emerging expert on Teilhard, follows Burdett with a deeper look at this pioneering theologian and scientist.

J. Jeanine Thweatt-Bates drew upon her doctoral work to criticize transhumanist thinking on gender, while Stephen Garner and Todd Daly provided fresh thinking about themes of cyborgs and extended lifespans in traditional Christian theology. Michael Spezio, a theologian who does advanced research in neuroscience, engages some of the projects of the Defense Advanced (DARPA).

Established scholars such as Ted Peters, Karen Lebacqz, Gerald McKenny, Brent Waters, and Celia Deane-Drummond also contribute chapters to this book. While all of them raise criticisms of transhumanism and of the growing use of technology for human enhancement, all recognize that transhuman poses a challenge for Christian theology.

Here’s one way to think about the challenge. Religion promises but technology delivers, so who needs religion anymore? For example, Christian theology holds up a promise of some form of life beyond the present. Technology, on the other hand, sees aging as a problem to be overcome, and it sets out to slow or even reverse it.

Whether it will truly succeed is, of course, debatable. But that’s not that point. The key question is where we place our hopes and what form of life do we hope for.

Through technology, transhumanists hope to transcend the limits of our biology. But is this the truest and highest form of human transcendence? It is not that technology is rejected or feared. But does teach us to settle for too little?

A New Approach to Enhancement?

Some people object to human germline modification because they do not like the idea of one generation messing with the DNA of future generations. Even worse, they say, is modifying the genes for the sake of…gasp!...enhancement!

But now comes a tantalizing study in tomorrow’s issue of Nature hinting at the possibility that what we do to live longer may change the lifespan of our grandchildren. It’s only a hint—the research reported here involves the faithful nematode, Caenorhabditis elegans. By exposing one generation of these tiny worms to just three proteins, researchers in Anne Brunet’s lab at Stanford produced worms that live up to 30% longer. The surprising thing is that the enhanced lifespan was passed to the next 2-3 generations. The really surprising thing is that the lifespan of the C. elegans great-grandchildren was enhanced even though no DNA sequences were modified. In other words: germline enhancement without genetic modification.

How is that possible? Epigenetics. The three proteins changed the way the DNA is structured or packed without changing the DNA code itself. Such epigenetic changes can change the way genes are expressed. The effect can be dramatic—in this case, a 30% longer lifespan. What’s more, the epigenetic change can be passed to future generations. Most often, epigenetic changes are reset during reproduction. But in some cases, epigenetic modifications are passed to the next 2-3 generations. When that happens, the structure and the expression of DNA are changed even though the DNA sequence remains unchanged. Over time, however, the effect washes out so that the great-great-grandchildren are back to the starting point.

Will this epigenetics-to-lifespan relationship be found in human beings? Who knows. Again, it must be repeated: this research involves flatworms. Humans are just a bit more complicated. Already, however, Brunet’s lab is looking for something similar in mice and in African killfish.

Whether anything similar will be found in human beings, this research already suggests a truly interesting thought experiment. Suppose this leads someday to a human-application technology. Would it be opposed by those who object to human germline modification? Sure, future human beings would be changed without their consent. But no genes are changed, and the changes are not permanent.

Perhaps the more sobering thought is this. Maybe this research will lead to a startling discovery. Never mind some new technology. Might it turn out that what health-minded human beings normally do—eat their green vegetables, get their exercise—has the effect of enhancing their offspring by modifying the expression of their genes by means of generating inheritable epigenetic changes? Could be. If just three proteins make C. elegans progeny live 30% longer, just imagine how your dinner might change your grandchildren (assuming, of course, that you’re in your reproductive years or younger).

The article, “Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans,” appears in the October 20 issue of Nature.