"Three-parent babies" and the Human Germline Modification Debate

Human germline modification is back in the news. The current round of public conversation was launched in the UK by the Human Fertilisation and Embryology Authority (HFEA). In the past few days, the media and the blogosphere have lit up with an intensifying debate. 

What HFEA wants people to consider is whether it is acceptable to use in vitro fertilization to try to avoid a specific category of genetic disease. Is it OK to help couples at risk for mitochondrial disorders by supplying donor mitochondria to the new embryo? If mom’s own mitochondrial DNA will lead to a disease, is it OK to add mitochondria from an outside donor?

PHOTO Transmission electron microscope image of a thin section cut through an area of mammalian lung tissue. The high magnification image shows a mitochondria. Source: Wikimedia. Credit: Louisa Howard, PhD. This work has been released into the public domain by its author.

Many refer to this as the “three-parent baby.” And for that reason alone, they object.

Others raise the stakes in the argument. They insist that the “three-parent baby” is just the tip of the looming germline modification iceberg. What’s really coming, they claim, is the era of “designer babies,” enhanced or improved versions of ourselves, a new form of high-tech eugenics.  And with that comes more mischief.

Consider what Stuart Newman (New York Medical College) had to say in his comment in The Huffington Post. Newman starts by asking whether the procedure is really as safe as it seems. Fair question. But then Newman writes that what is really going on here is “a new form of eugenics, the improvement of humans by deliberately choosing their inherited traits.” And then, a few short paragraphs later, he’s off to the Nazis, forced sterilization, and the Nurenberg Code.

Now it may be true that the “three-parent baby” is a pretty bad idea medically. But morally, is it really the fast-track to Nazi medicine?

Or consider Marcy Darnovsky’s comments in a press release from the Center for Genetics and Society:

“Changing the genes we pass on to our children is a bright ethical line that should not be crossed,” said Marcy Darnovsky, PhD, the Center's executive director. “It has been observed by scientists around the world, adopted as law by more than 40 countries, and incorporated in several international treaties. It would be wrong for the UK to disregard this global bioethical consensus, especially when there are safe alternatives available for the very few people who would be candidates for the procedures.”

The release concludes: “The Center for Genetics and Society calls for a domestic and international moratorium on approval of any procedures involving inheritable human genetic modification…”
Or consider the comment of David King of Human Genetics Alert as quoted by the BBC: 

Dr David King, the director of Human Genetics Alert, said: "Historians of the future will point to this as the moment when technocrats crossed the crucial line, the decision that led inexorably to the disaster of genetically engineered babies and consumer eugenics.

Is the “three-parent baby” really “crossing the germline barrier”? Back in 2001 when the first “three-parent babies” being created here in the US, Erik Parens and Eric Juengst wrote a response in the journal Science. They called it “Inadvertently Crossing the Germline.” Ever since then, many have agreed. Despite some really important distinctions, mitochondrial replacement is a kind of human germline modification.

A bit of a stretch, but OK, let’s call it that. But is that reason enough to condemn it? Is human germline modification itself morally wrong? It may be biomedically impossible. It may be excessively expensive considering all the other needs facing the world’s children. But is it intrinsically wrong? 

 

In 2008, I published an edited book that tried to take the temperature of religious opinions on the morality of germline modification. What I discovered surprised even me. Most religious scholars in my collection were not particularly troubled by the prospect of germline modification. Sure, they had their concerns—safety, social justice, over-controlling parents, an attitude of commodification. But in the end, almost without exception, they agreed: what can be religiously or morally wrong with wanting to use the latest technology to help parents have healthy children? For more on this, see Design and Destiny from MIT Press.

 

For many people, it comes as a total shock to hear that even some Vatican statements support the notion that germline modification is not inherently immoral—that, in fact, it could be “desirable.” The Vatican has specific constraints that must be met. No IVF, for one, so the “three-parent baby” strategy fails on that score. But if the means are acceptable, then the goal is laudable, at least according to this statement made by Pope John Paul II:

A strictly therapeutic intervention whose explicit objective is the healing of various maladies such as those stemming from chromosomal defects will, in principle, be considered desirable, provided it is directed to the true promotion of the personal well-being of the individual without doing harm to his integrity or worsening his conditions of life. Such an intervention would indeed fall within the logic of the Christian moral tradition.

I agree with the “three-parent” critics about the importance of the debate over human germline modification. For that very reason, I hope they tone down the rhetoric. This is not Nazi medicine.

 

There are sound moral reasons for wanting to move forward on human germline modification. Of course, there are incredibly important technical hurdles that must be overcome. Some of them, in fact, may prove impossible. If so, then of course human germline modification would be a bad idea because of the risks.

 

But if biomedical research can find its way through these technical barriers, what then? Yes, there are other objections, more religious or moral in nature, but there are also strong reasons for going forward. That, I suggest, is where the real discussion should focus.  

Stem Cell Advance: Brain Cells Inserted in Monkey Brains

Researchers at the University of Wisconsin-Madison are reporting a significant step forward toward the day when stem cells may be used to treat brain diseases such as Parkinson’s.

Working with three rhesus monkeys, the research team created a personalized stem cell culture for each monkey.  Cells taken from the skin of the monkey were induced to a state of pluripotency by means of a process called “induced pluripotency.”  Once in a state of pluripotency, the cells were guided forward in the process of differentiation until they became neurons and glial cells.  Along the way, the cells in the culture were given a genetic tag so the cells would glow under a florescent light. 

Then the cells were implanted in the brains of the rhesus monkeys.  Because the source of the cells was the monkeys themselves, the DNA matched and there was no immune reaction.  After six months, researchers discovered that the cells were so fully integrated into the monkey brains that in many cases, they could only be recognized by their green florescent glow.

"When you look at the brain, you cannot tell that it is a graft," says senior author Su-Chun Zhang, according to a press release from the University of Wisconsin. "Structurally the host brain looks like a normal brain; the graft can only be seen under the fluorescent microscope." 

Caption: This neuron, created in the Su-Chun Zhang lab at the University of Wisconsin–Madison, makes dopamine, a neurotransmitter involved in normal movement. The cell originated in an induced pluripotent stem cell, which derive from adult tissues. Similar neurons survived and integrated normally after transplant into monkey brains—as a proof of principle that personalized medicine may one day treat Parkinson's disease. Date: 2010.  Image: courtesy Yan Liu and Su-Chun Zhang, Waisman Center, University of Wisconsin–Madison.

The three monkeys involved in the experiment were given tiny lesions or scars in their brain to mimic Parkinson’s disease.  Another lead researcher, Marina Emborg, commented on how the inserted cells integrated themselves into the brain.  “After six months, to see no scar, that was the best part."

What makes this work significant is that it is the first use of induced pluripotent stem cells (iPS) involving a primate, setting the stage for further work someday involving human beings.  According to Zhang, "It's really the first-ever transplant of iPS cells from a non-human primate back into the same animal, not just in the brain," says Zhang. "I have not seen anybody transplanting reprogrammed iPS cells into the blood, the pancreas or anywhere else, into the same primate. This proof-of-principle study in primates presents hopes for personalized regenerative medicine."

One of the keys to their success is that the iPS cells themselves were not transplanted into the monkeys.  Because iPS cells are pluripotent, they can give rise to cancer or other problems.  In this work, the researchers carefully guided the iPS cells so that they were almost at the final stage of differentiation, and then made sure that their cell culture was completely purified so that no potentially cancer-causing cells would slip through.  Quoting Zhang once again: "We differentiate the stem cells only into neural cells. It would not work to transplant a cell population contaminated by non-neural cells."

Because of these precautions, the experiment succeeded in introducing new cells into the monkey’s brains without any obvious problems.  But in this experiment, too few cells were introduced to help the monkeys overcome the symptoms of Parkinson’s.  Solving that problem is the obvious next step.

According to the paper, “this finding represents a significant step toward personalized medicine,” which may someday be used to treat a wide range of diseases in humans.  Because the original source of the cells was from the individual monkeys themselves, there was no immune rejection.  If the same technique can be applied to human beings, it may mean that an individualized culture of iPS cells could be created for each patient, then carefully guided forward in the process of differentiation, and then implanted to regenerate organs or tissues damaged by injury or disease.

What makes iPS cells especially attractive is that no embryos are used in their creation, and so almost no one objects to this line of medical research.  But if regenerative medicine is successful, someday it will be used not just to treat disease but to off-set the effects of aging or to enhance those who are well.  Then, we can be sure, many will object to this technology, but even more will use it.

The article, entitled “Induced Pluripotent Stem Cell-DerivedNeural Cells Survive and Mature in the Nonhuman Primate Brain,” is freely available at the open access journal, Cell Reports in its March 28, 2013 issue. 

 

Enhancing Healthy Kids: A Warning, But Who's Listening?

The American Academy of Neurology (AAN) has just issued new guidelines calling on doctors to stop prescribing cognitive-enhancing drugs to healthy kids.

Drugs like Ritalin and Adderal are widely used, not just by adults and university students, but increasingly by children, and not just those who are appropriately diagnosed as experience difficulites with attention or focus, such as Attention Deficit Disorder. 

PHOTO: Ritalin SR (a brand-name sustained-release formulation of methylphenidate, from Wikimedia, 16 June 2006, created by Sponge. 

Perviously, the AAN raised concerns drug enhancement by adults.  It concluded that there is no moral basis for objecting, provided that the patient is acting autonomously in requesting the prescription.  But when it comes to prescribing for healthy children, the AAN report makes this claim:  "Pediatric neuroenhancement remains a particularly unsettled and value-laden practice, often without appropriate goals or justification."  

The Report notes that enhancing children is fundamentally different from enhancing adults.  For doctors, it raises concerns for "the fiduciary responsibility of physicians caring for children, the special integrity of the doctor–child–parent relationship, the vulnerability of children to various forms of coercion, distributive justice in school settings, and the moral obligation of physicians to prevent misuse of medication."

Based on these concerns, the AAN Report advises that "the prescription of neuroenhancements is inadvisable because of numerous social, developmental, and professional integrity issues."

The primary objection raised by the AAN is that children lack the competency to act as autonomous moral agents.  If they were competent, then their request for enhancement would be honored.  Sure, children can be coerced, manipulated, confused, and ambivalent about their needs.  Kind of like the rest of us. 

Whether age brings moral competence is a good question.  But perhaps what this report shows us once again is that when secular bioethics meets enhancement technology, about all it can say is this: If you want it and if you can prove your competence, you can have it. 

The AAN report, “Pediatric neuroenhancement: Ethical, legal,social, andneurodevelopmental implications,” is published in the March 13, 2013 issue of Neurology.

What a Smart Mouse Can Tell Us about Evolution

Just a few years ago, we thought that brains were all about neurons.  Sure, we also have glial cells, but the job of the lowly glia is to take care of the neurons, which do all the serious cognitive work. 

But why are the glia of humans and other primates so large and varied in their shape and structure?  Why are they so different from the simpler, smaller glia found in mice and other rodents?  Could the difference play a role in the evolution of human intelligence?

One way to compare a mouse and a human is to create a mouse that is part human.  That’s exactly what researchers at the University of Rochester did.  They implanted human cells into mouse brains.  More precisely, they implanted human glial progenitor cells into newborn mouse pups. 

What they got were chimeras, mice with human cells integrated into their brains.  When the researchers examined the brains of these chimeric mice, they found that the human cells proliferated and were widely present throughout the brain. Although interacting with mouse brain cells, the human cells remained distinctly human in their unusually large size and varied structures.

Photo credit:  A 23 week human culture astrocyte stained for GFAP.   From Wikimedia Commons.  Date: 24 February 2012.  Author: Bruno Pascal. 

Most surprising is that the chimeric mice were  smarter than unaltered mice born in the same litters.  Human glia in a mouse brain seems to make a smarter mouse.  

Why?  The answer probably involves one type of glial cell called astrocytes. Compared to other species, human brains have many more astrocytes.  Ours are larger and more varied in their structure, capable of connecting many neurons and coordinating the activity that occurs at many synapses. 

Based on this study, published in the March 7, 2013 issue of Cell Stem Cell, we now know that human astrocytes boost intelligence in chimeric mice as measured by standard testing procedures.  

This is pretty good evidence to suggest that the evolution of the larger, more complex glial cells was a critical aspect of the evolution of higher intelligence.  At least that is the conclusion drawn by one of the senior authors of the paper, Steven Goldman. “In a fundamental sense are we different from lower species,” he said, according to a press release from the University of Rochester. “Our advanced cognitive processing capabilities exist not only because of the size and complexity of our neural networks, but also because of the increase in functional capabilities and coordination afforded by human glia.”

What makes this study intriguing is that it uses stem cell technology to study brain function and to learn something important about evolution.  By implanting stem cells in create chimeric mice, researchers learn that glia play a critically important role in intelligence and that evolved changes in glial cells are a key part of the story of the rise of intelligence. 

Concerning the role of glial cells in the complex brain, Maiken Nedergaard, another senior author, had this to say:  “I have always found the concept that the human brain is more capable because we have more complex neural networks to be a little too simple, because if you put the entire neural network and all of its activity together all you just end up with a super computer.”

“But human cognition is far more than just processing data, it is also comprised of the coordination of emotion with memory that informs our higher abilities to abstract and learn,” Nedergaard added.

And concerning what chimeric mice have to teach us about evolution, Steven Goldman made this comment: “This study indicates that glia are not only essential to neural transmission, but also suggest that the development of human cognition may reflect the evolution of human-specific glial form and function.”

Or to quote the original paper: “These observations strongly support the notion that the evolution of human neural processing, and hence the species-specific aspects of human cognition, in part may reflect the course of astrocytic evolution.”

The paper does not address the interesting ethical questions raised by making smarter mice.  Over the past decade, ethicists have debated the moral legitimacy of chimeric animals.  One point of concern has been the creation of nonhuman animals with human brain cells.  To defend this practice, it is often said that a mouse brain with human cells is still a mouse brain.  It still has the structure or architecture of a mouse brain.  It may have human cells, but in no way is it a human brain or even a half mouse/half human brain.

This study suggests we should take a closer look at that line of thinking.  Maybe it is true that adding human neurons to a mouse brain does not change the mouse brain structure.  But this study implies that adding human astrocytes to a mouse brain may begin some small but significant change in structure and function. 

The study is clear about the fact these chimeric mice are more intelligent than the unmodified mice.  Their brains are quite literally faster. 

Once again, Goldman: “The bottom line is that these mice demonstrated an increase in plasticity and learning within their existing neural networks, essentially changing their functional capabilities.”

These animals have been cognitively “elevated,” to use a word sometimes found in the debate.  Probably no one will object to the idea of a slightly smarter mouse.  Researchers take special care to make sure these mice do not breed and produce pups of their own.  But even if they did, the added intelligence would not pass to future generations.  They would produce normal lab mice. 

Even so, this study—combining stem cells technology, neuroscience, and evolution in one elegant package—raises intriguing moral questions.  Are we smart enough to know how far we should go in creating smarter mice?  

The study, entitled “Forebrain engraftment by human glialprogenitor cells enhances synaptic plasticity and learning in adult mice,” appears in the March 7, 2013 issue of Cell Stem Cell.