Over the past few days, my twitter account has been filled with calls for a moratorium on the genetic editing of the human germ line, that is, any cell that will eventually give rise to either a sperm or egg.
Two and a half years ago, the breakthrough development of a new technology termed CRISPR/Cas9 genomic editing was reported in the high profile journal Science; it is widely assumed that development of this technology will be awarded a Nobel prize. It appears that in the two and a half intervening years, work on human embryos has already been undertaken.
From an aritcle published March 5th, italics mine
Several people interviewed by MIT Technology Review said that such experiments [human germ line editing] had already been carried out in China and that results describing edited embryos were pending publication.
Engineering the Perfect Baby, MIT Technology Review
If true, it means we have very quietly entered a new, ethically uncertain, era of human genetics. If you want to learn about the biotechnology, or discuss the ethics, read on.
First, some very basic biology. A human body is made up of trillions of cells, each of which contains a nucleus, and each nucleus contains a pair of each of 23 different chromosomes. Each chromosome is composed of millions of DNA nucleotides, the ATGCs that make up the genetic code. Clusters of hundreds to hundreds of thousands of these nucleotides make up protein coding genes, of which there are an estimated 20-25 thousand in humans. Along with all the non-protein coding DNA (sometimes called junk DNA), these genes make up the human genome. Our genome, in extremely complex interactions with our environment, gives rise to us as individuals.
Geneticists have been modifying genomes from species ranging from bacteria to yeast to plants to human cells to humans themselves for decades now. In addition to doing this for basic research, there have also been commercial and medical applications. Perhaps the most well known example are GMO crops (Wiki - genetically modified crops)- corn, soybean, cotton, and a few other crops that have had a gene inserted that provide resistance to a herbicide, or that produces an insecticidal bacterial-toxin. The most recent example are arctic apples which fail to turn brown after being cut. This is a particularly interesting GMO case as the company put portions of genes already present in apple back into the apple. These extra portions of the genes actually lead to lower levels of the proteins they code for through a process termed RNA interference (wiki).
In addition to plants, genetic modification has also been used extensively in human cell cultures for research purposes, but also in people for medical purposes. Termed gene therapy (wiki) the goal is to replace a defective gene with a functional copy. The first gene therapy was as far back as 1990, and most of the early trials were designed to treat SCID - severe combined immunodeficiency disorder. Since then, several small trials have seemingly successfully treated diseases from cancer to blindness to HIV.
The major issue with current genetic modification technologies is that they are relatively crude. Doctors or researchers introduce DNA into the cell, and hope that it inserts into the chromosome. The DNA floating around in the cell is recognized by the cell's DNA repair machinery and repaired by inserting it somewhere in the genome. In research situations, the DNA is usually accompanied by a gene that allows for selection of cells that have incorporated the foreign DNA (at which point they are called transformed). But, and this is the big but, the DNA inserts randomly into the genome. There is essentially no ability for researchers or doctors to control where the inserted gene lands. In the case of the first large gene therapy trial for SCID, two of the ten patients treated with gene therapy developed leukemia after the genes were inserted next to, and subsequently activated, a gene known to induce cancer.
This is the problem that CRISPR/Cas9 technology solves. It is based on an anti-viral system recently worked out in bacteria. Bacteria were collecing short snips of viral genomic DNA and inserting it into a cluster in their own genome. They were identified due to specific structural properties and named CRISPR. The bacteria express these short snips of DNA as RNA. This RNA, which is specific for attacking viruses, interacts with the protein Cas9. Cas9 uses the RNA as a guide, enabling it to specifically recognize the genome of an invading virus. It then cuts the viral genome at the region matching the RNA, effectively killing the virus.
What the researchers who developed this technology realized is, they could modify the system to give it any 20 nucleotide sequence they wanted, and Cas9 would cut any DNA containing that specified sequence. There has been roughly a decade of work on similar technologies called zinc-finger nucleases and TALENS, but the CRISPR/Cas9 system offered an enormous increase in specificity and ease of use. And the use of this technology has exploded in the subsequent two and a half years.
The big advantage gained by cutting a genome at a specific location is that now, the cell's DNA repair machinery has a defined position of where to put the DNA that researchers are trying to insert, enormously increasing the efficiency of transformation itself and also defining exactly where the DNA is going to go. Beyond that, it has provided a tool for not simply blinding modifying the genome, but modifying it in very specific ways. This greater degree of specificity has been termed genome editing to differentiate it from older, cruder genetic modification. As an example, perhaps a researcher wants to change just one of AGCT nucleotides in the genome. If they cut the genomic DNA with Cas9 at that site, and provide the cell with a piece of DNA containing the exact change they want, the frequency with which that exact change happens increases from a frequency of perhaps 1 in 100,000 to as high as 1 in 2. This increase in frequency has moved genome editing from dream to reality.
With this breakthrough in technology also comes the question of how it should most ethically be used. Gene therapy has so far only been used to modify somatic cells, those cells not involved in reproduction. However, as the article from MIT Technology Review indicates, researchers may have already used this technology to edit the genomes of human embryos. It has certainly been used to edit the genomes of monkeys, which will prove to be a huge boon for medical research. But many researchers argue that there is no reason for genetic modification of human embryos, as parents at risk for having children with a genetic disease already have options available through IVF. Two paragraphs from the MIT tech review article:
Others believe the idea’s downfall is that medical reasons to follow through on it are lacking. Hank Greely, a law professor and ethicist at Stanford University, says proponents “can’t really say what it is good for.” The problem, says Greely, is that it’s already possible to test the DNA of IVF embryos and pick healthy ones, a process that adds about $4,000 to the cost of a fertility procedure. A man with Huntington’s, for instance, could have his sperm used to fertilize a dozen of his partner’s eggs. Half those embryos would not have the Huntington’s gene, and those could be used to begin a pregnancy.
Indeed, some people are adamant that germ-line engineering is being pushed ahead with “false arguments.” That is the view of Edward Lanphier, CEO of Sangamo Biosciences, a California biotechnology company that is using another gene editing technique, called zinc finger nucleases, to try to treat HIV in adults by altering their blood cells. “We’ve looked at [germ-line engineering] for a disease rationale, and there is none,” he says. “You can do it. But there really isn’t a medical reason. People say, well, we don’t want children born with this, or born with that—but it’s a completely false argument and a slippery slope toward much more unacceptable uses.”
Others, disagree
italics mine
What is Church’s [George Church researcher at Harvard]style is human enhancement. And he’s been making a broad case that CRISPR can do more than eliminate disease genes. It can lead to augmentation. At meetings of groups of people known as “transhumanists,” who are interested in next steps for human evolution, Church likes to show a slide on which he lists naturally occurring variants of around 10 genes that, when people are born with them, confer extraordinary qualities or resistance to disease. One makes your bones so hard they’ll break a surgical drill. Another drastically cuts the risk of heart attacks. And a variant of the gene for the amyloid precursor protein, or APP, was found by Icelandic researchers to protect against Alzheimer’s. People with it never get dementia and remain sharp into old age
While I certainly don't have an answer to the ethical questions, I can answer a lot of questions of the biotechnology. What is also clear is that, as with all groundbreaking technology, we are entering a new era that is going to bring with it lots of new questions.