Genetically Modified Monkeys: What's Next?

Researchers in China have used a new method to produce genetically modified monkeys.  Their purpose is to advance medical research by creating monkeys genetically predisposed to develop human diseases.  But the new method is so precise and so successful that one might imagine it leading to genetically modified humans.   

Caption: Researchers achieved precise gene modification in monkeys.  Credit: Cell, Niu et al.

According to a report published in the January 30 issue of the journal Cell, scientists used a new gene editing technique known as the CRISPR/Cas9 system.  The technique allows for very precisely targeted modification of DNA sequences. 

It also allows researchers to trigger more than one modification at a time. And it seems to avoid causing extraneous mutations where they are not wanted.  

With the CRISPR/Cas9 technique, researchers edited the DNA in monkey embryos at the one-cell stage.  As that cell multiplied, all the cells of the body contained the gene edits, probably including the cells the newborn monkeys might someday pass to their descendants. In other words, this is precise germline genetic engineering in primates.  

"Our study shows that the CRISPR/Cas9 system enables simultaneous disruption of two target genes in one step without producing off-target mutations," claimed Jiahao Sha, one of the lead authors at Nanjing Medical University.

The goal for now, Sha said, is to refine the technique and to be able to create "many disease models...in monkeys," according to the press release issued by the journal Cell.  

Just how refined will the technique become?  Consider that the first successful germline modified monkey was only reported in 2001. The current advance offers far more precision.  With enough precision, it might become possible to apply this technique to a single-cell human egg.  

The modification could be verified before the embryo is implanted, using the well-established technique of pre-implantation genetic diagnosis or PGD.  If implanted and brought to term, the human life created this way would have its germline DNA modified, meaning that the modification would pass to future generations.  

No one knows now whether this technique will offer the kind of precision that would be required to move from monkeys to humans.  But just how much precision is, in fact, required?  With PGD as a way to catch any "mistakes," might ethics committees, in a few decades or even sooner, permit couples and researchers to use this technique in order to avoid transmitting genetic problems to future generations?  Will it then be used to add something new or desirable to the genetic inheritance of our offspring?

The article, Niu et al., "Generation of gene-modified cynomolgus monkey via Cas9/RNA-mediated gene targeting in one-cell embryos," is published in the January 30, 2014 issue of Cell.  

"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.  

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.