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Chinese researchers alter embryo DNA: Do results cross ethical tripwires?

The study has added urgency to recent calls from scientists, ethicists, and leaders in the biotech industry to take immediate, serious steps globally to weigh the legal, ethical, and social implications of manipulating DNA within heritable cells.

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    A recently developed tool for editing an organism's genetic make-up has led scientists in China to cross a boundary that researchers have avoided since the dawn of genetic engineering 42 years ago – altering genes in fertilized human embryos.
    Jonathan Bailey/National Human Genome Research Center
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For the first time, scientists have altered genes in human embryos and allowed them to briefly develop.

The research crosses a boundary that scientists have avoided since the dawn of genetic engineering 42 years ago. It marks the first time researchers have attempted to modify the genetic makeup of a human embryo in ways that would allow the genetic change to be passed to succeeding generations.

For some researchers working to develop gene therapies, in principle such genome editing could be used to combat inherited diseases. But to others, it also could lead to attempts to genetically enhance humans in ways that could last for generations with unpredictable results.

Once again, humanity is faced with the fundamental question of  “whether humans should have this degree of control over their own physical futures,” says Alta Charo, a professor of law and bioethics at the University of Wisconsin at Madison. “We’re hitting the point where people are asking: Do we really want to have the power not just to select among the choices given to use by nature, but to create entirely new choices of our own specification?”

The ethical concerns surrounding genetic manipulation of reproductive cells are so weighty that many scientists and bioethicists are urging colleagues to begin substantive conversations with colleagues, biotech-industry leaders, regulators, interest groups, and the public to figure out what clinical uses, if any, would be acceptable. Others, including some in the biotech industry, argue for a moratorium on any germ-line research involving human reproductive cells.

One measure of the ethical minefield into which the Chinese team marched: Two of the most high-visibility science journals, Science and Nature, refused to publish the results on ethical grounds, the project’s lead scientist, Junjiu Huang, explained to reporters from Nature's news division.

Many of the initial concerns in the scientific community involve safety and efficacy for a tool they see as having potentially powerful therapeutic applications. The Chinese team shares this concern and cites its own results as evidence that CRISPR-Cas9 is nowhere near ready for the clinic.

"That type of use of the technology needs to be on hold pending a broader societal discussion of the scientific and ethical issues surrounding such use," writes Jennifer Doudna, a molecular biologist at the University of California at Berkeley and a member of the team that developed the tool, in an e-mail.

The tool is designed to cleave DNA, the molecule that carries the basic instructions covering the formation and functions of most organisms. The ability to intentionally snip a segment of DNA and replace it has been around for four decades, but in more cumbersome forms. 

The new tool, first described in the journal Science in 2012, combines small strands of RNA, molecular middlemen influential in a range of genetic processes, with an enzyme effective at snipping DNA. 

This new system is unique because the enzyme, Cas9, is delivered to a specific sequence of DNA "with something really easy to generate – this guide RNA," which researchers can program to hunt for the DNA segments they are interested in cleaving, explains Kate O'Connor-Giles, a molecular biologist a the University of Wisconsin at Madison.

This relative ease of production and use has led labs around the world to quickly adopt the tool for genetic research, particularly related to disease. But it also has brought the potential for conducting experiments in so-called germ-line engineering within the range of even modest laboratories that at least in some countries can fly under the regulatory radar.

“The technology is getting ahead of the ethical and regulatory discussions,” Dr. O’Connor-Giles says. “This is evolving rapidly because it's so easy to use. But it's easy to use in the sense of making something happen. It's not easy to use necessarily in the sense of making what you want to have happen.”

The new study helps make that point. Dr. Huang’s team at Sun Yat-sen University started with 86 fertilized but defective eggs from a fertility clinic. They used defective eggs that couldn’t have resulted in live births because of ethical concerns surrounding the use of normal embryos, the researchers explained.

Seventy-one of the resulting embryos survived the introduction of the CRISPR-Cas9 package which was aimed at a gene researchers have associated with a serious blood condition that can be fatal. They also introduced a molecular template for repairing sequence they aimed to snip.    

Of the 71, the team analyzed 54 embryos the team analyzed, 28 showed evidence that the CRISPR-Cas9 package has snipped the DNA. Seven of the 28 showed evidence that they had undergone some form of repair, but only four used the template the team introduced. But the researchers also detected what they interpret as so-called off-target activities – genetic mutations that the CRISPR-Cas9 package had triggered elsewhere along the genome and whose numbers could well be underestimated.

Those inadvertent mutations underscore concerns that even a single edit could set into motion an unpredictable series of events that could, in theory, be worse than the problem being targeted.

In 1975, when scientists and ethicists gathered in Asilomar, Calif., to recommend boundaries to recombinant DNA research, most of the concerns centered on the risk of altered organisms escaping into the environment. Even then, however, some were envisioning the possibility of treating disease by repairing genetic defects associated with a disease.

In one sense, CRISPR-Cas9 and the Chinese experiment "is an attempt to do what gene-transfer folks have been trying to do all along, but to do it better," says Erik Parens, a senior scholar at The Hastings Center, a bioethics-research institution in Garrison, N.Y.

The new tool for editing genomes is valuable for basic research with model organisms, such as fruit flies, to understand how genes, individually and in groups, function and the interplay between various components of a genome, notes the University of Wisconsin's O'Connor-Giles. That work lays a foundation for understanding genetic mechanisms in more complex organisms, including humans.  

Beyond basic research, scientists also see the new tool as useful for genetic therapies whose repairs cannot be passed from one generation to the next. 

But when it comes to germ-line editing, in the eyes of many, what didn't seem possible until now “all of a sudden is possible,” Dr. Parens says.

In addition to the issue of introducing unintended mutations, stability remains a question: If a new gene is introduced, how likely is it to mutate at a pace faster than the one it replaced? 

The sheer complexity of the human genome and factors outside of the presence of a particular segment of DNA that influence its expression remains presents its own challenge.

Yet for many people, safety is important but misses what they see as a bigger picture. An increasing control could lead to hubris that could led to applications of gene-editing that either are inadvertently harmful or harmful by design, ethicists say. 

For others, the unease is likely to be deeply rooted in religious convictions or in a reverence for natural order that deems human intervention as contamination.

Whatever the mix, even those in the scientific community are raising the caution flag. In March, two groups published calls to begin a serious general conversation on germ-line editing now.

Writing in the journal Science, a group of scientists and bioethicists, including Charo, that includes Nobel Prizewinners David Baltimore and Paul Berg – who also played key roles in the 1975 Asilomar meeting – offered several recommendations that range from strongly discouraging work on clinical applications for germ-line editing, particularly in countries with lax regulations, to conducting the needed studies with high degrees of transparency, using "human and non-human model systems" to resolve questions about what, if any, clinical applications might be acceptable.

A second group, writing in the same week's issue of Nature, called for a halt to research on editing genes in reproductive cells. 

"What we've called for is a moratorium on research in fertilized human embryos such that we don't perfect and publish on the Internet these techniques before there's an opportunity to have a robust discussion about whether there is any circumstance where we as a human species would think this makes sense," says Edward Lanphier, president and CEO of Sangamo Bioscience in Richmond, Calif., and chairman of the Alliance for Regenerative Medicine in Washington.

Once the germ-line Rubicon is crossed, the group noted, even clearly identified therapeutic uses could eventually lead to the use of germ-line editing to enhance humans, rather than treat them for a disease.

Outside of the science community and the biotech industry, CRISPR-Cas9's potential impact has been flying under the radar, says George Annas, who heads the department of health law, bioethics, and human rights at Boston University.

But now that it’s appearing on the radar screen, researchers, ethicists, and the public are going to have to confront the issues it raises sooner rather than later, he suggests.

“If we keep waiting until it can be done, is that too late?” Dr. Annas says. “It would be nice if we could all agree on a line we don't want to cross, knowing that when we get to that line, we’ll revisit it again.”

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