02/29/2016 06:11 pm ET Updated Mar 01, 2017

Human Babies from CRISPR Pigs

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New genetic technologies like CRISPR/Cas9 gene editing and synthetic biology are leading us to entirely new definitions of disease. Now "patients" include people who want children who lack some of their own genes, or have additional ones that they themselves lack. Also among the new patients are people who in the past were too old to have children as well some women who get sick from pregnancy and childbirth, or even the idea of them. Technological advances on the horizon may eventually offer treatment for such conditions.

In February 2015 the British Parliament approved production of "three-parent" children by transferring the nucleus of one woman's egg into the nucleus-less ("enucleated") egg of a second woman to avoid the propagation of certain rare "mitochondrial" diseases. Though there were acknowledged risks of the unprecedented procedure (including the possibility of producing novel birth defects), the argument that prevailed was that some mitochondrial diseases are so devastating that it should be tried in the narrowly defined group of prospective mothers carrying defective mitochondria.

Not long afterward, news articles began to appear discussing use of the technique for an entirely different purpose. The procedure's inventor, the Oregon Health & Science University biologist Dr. Shoukhrat Mitalipov, was now proposing to treat infertility in older women by transferring their egg nuclei into the enucleated eggs of younger women.

With its presumptive safety certified by Parliament, Dr. Mitalipov was eager to move forward with his new plans for the technique. "Compared to a rare condition like mitochondrial disease, infertility is a big, big problem for modern society because of women delaying their first baby. When they finally decide, the delay has already affected their egg quality," he told a reporter from The Independent. "We consider infertility a disease, and you treat the patients as you do for mitochondrial disease. I wouldn't say one disease is more severe than another. Infertility is a very serious problem and these women deserve treatment as for any other disease. If the procedure is effective and safe, why would you hold it for one group of patients, but not for another?" John Harris, a professor of bioethics at Manchester University stated, "If the technique is safe enough for it to be used for the one purpose, I don't see why it wouldn't be safe enough to use for the other."

Infertility has many causes apart from presumed age-dependent impairment of mitochondria, and affects a much wider group of prospective patients. For women, the most common and uncontroversial cause is the failure of embryos to implant in the uterus, or to be retained once implanted. Such problems have increasingly been addressed by use of gestational surrogates. While a satisfactory solution for some, surrogacy incurs its own difficulties. Although women of similar socioeconomic status to those undertaking the procedure have sometimes been willing, for altruistic reasons, to serve in this capacity, most often the surrogates are drawn from poorer sectors, including those of the developing world. This had led to the possibility, and sometimes the reality, of economic exploitation of women who enter into such contracts out of need. This, along with the sense in some cultures that subcontracting these aspects of motherhood violates human dignity has led to gestational surrogacy being banned in some countries and jurisdictions.

But with the growing use of CRISPR/Cas9 gene editing methods it should eventually become possible to produce farm animals for use as gestational surrogates. George Church and his colleagues at Harvard University have used CRISPR/Cas9 to remove the DNA sequences of endogenous retroviruses from the genomes of pigs so as to make their tissues and organs suitable for transplantation into humans. To fully implement this plan it will be necessary to further genetically modify the pigs so that their cells are not recognized as foreign by human graft recipients. Given these efforts, we can anticipate that analogous manipulations can be done to ensure that the uteruses of female pigs (or sheep, or other large domesticated animals) provide receptive environments for the growth of human embryos. But this will not be an easy task. The biological properties of endometria (uterine linings) of different mammals are highly varied. The CRISPR/Cas9 methodology, however, has the capacity to modify many genes simultaneously. Church's retrovirus-free pigs, for example, had 62 of their genes removed, and adding new genes is similarly straightforward.

Another obstacle stems from the fact that the human placenta has unique characteristics. To make human embryos and fetuses compatible with a sow's uterus (however well-prepared genetically it may be), would likely require genetic modification of the embryos themselves prior to implantation. Because the fetal contribution to the placenta comes from a population of embryonic cells separate from those that form the prospective body, this kind of genetic engineering should not interfere (or at least not too much) with features of the eventual person - height, musical ability, personality. (The desirability of deliberately making such modifications is a separate issue.)

Once these coordinated sets of modifications in the human embryo and the porcine surrogates have been accomplished, a large step will have been taken toward curing the disease of infertility. But success along these lines would open the possibility of treating the many millions of prospective sufferers from a still different set of adverse conditions. It is well recognized that pregnancy and childbirth are health hazards, and in the current social environment they can often be professional liabilities. Applying Professor Harris's precept, quoted above, that "[i]f the technique is safe enough for it to be used for the one purpose, I don't see why it wouldn't be safe enough to use for the other," it would only be natural to alleviate the condition of pregnancy, insofar as it comes to be understood to be an illness, by employing farm animal gestation.

It might seem that there will social resistance to such redefinitions and technological fixes. But this would be to underestimate the popular appeal of life-transforming technologies, particularly in a market society. Less than 20 years ago, a U.S. patent application was filed for "chimeric" embryos and animals that were part-human and part-nonhuman. The intention was to shock the public into recognition of the power of the period's emerging biotechnologies, and how their implementation for useful purposes could violate deeply held social values. In response to the filing, the chair of Harvard Medical School's Department of Genetics stated, "[t]he creation of chimeras is an outlandish undertaking. No one is trying to do it at present, certainly not involving human beings."

Times change, however. Although the U.S. government still declines to fund such work, it is now being performed openly and enthusiastically with private financing and state funds from the California Institute for Regenerative Medicine. Outlandish no more, one of the California researchers told a Science magazine reporter, "I am very excited about this project." "We need to do the experiments and see."
It has been nearly 300 years since the Irish pamphleteer Jonathan Swift urged his countrymen to look past their prejudices in addressing social problems. Since that time, the success of technology in meeting consumer needs has increasingly lowered the barriers to doing so. Can anyone doubt that the grandchildren of some people born this year will be delivered fresh off the farm?