(H I-SIS was first! We circulated this report May 2, 2001. It was picked up by BBC and then by all the major newspapers of the world.)
While debate on germline gene therapy is still going on worldwide, geneticists have gone ahead. Prof. Joe Cummins and Dr. Mae-Wan Ho report on how scientists have side-stepped regulators and created the first GM human beings, in the face of fierce public opposition.
"Researchers have announced "the first case of human germline genetic modification resulting in normal healthy children." Specifically, the researchers transplanted ooplasm [contents other than the nucleus] from donor eggs into the eggs of women whose infertility was due to ooplasmic defects. One side effect of those transplants was the transfer of mitochondria, introducing new mitochondrial DNA (mtDNA) into the eggs. This news should gladden all who welcome new children into the world. And it should trouble those committed to transparent public conversation about the prospect of using "reprogenetic" technologies to shape future children." So began an editorial in the April 20 issue of Science magazine [1].
Germline gene therapy amounts to changing the gene pool of the human species by genetic modification of the gametes produced by individuals. While the pros and cons of GM crops and GM animals are still being debated, genetic modification of human beings has met with almost universal condemnation. The prospect of maniacal dictators trying to produce super races is none too theoretical for those who have lived under the Nazi regime. And all the more abhorrent that academic science should be perverted to such ends. Human germline therapy has been shelved, if not rejected, by most advanced countries, and copious volumes have been generated by ethicists, philosophers and geneticists from ivy league universities, telling us why rushing into human germline therapy is not prudent.
In spite of those academic reservations and widespread public concern, a form of germline therapy has already been performed in New Jersey, with little fanfare and no opportunity for public input. A university laboratory completed an experiment that led to the birth of fifteen apparently healthy babies as the result of germline gene therapy [2]. But they intimated that worldwide, there have already been 30 babies born that have been created in this way.
In the US, the Recombinant DNA Advisory Committee (RAC) was created to oversee and publicly discuss federally funded gene transfer research. RAC's guidelines say that it "will not at present entertain proposals" for germline interventions. "Given RAC's de facto ban on germline intervention, what reasons might have moved highly respected researchers to announce that they had achieved just that?" Science magazine asks [1].
The experiment was justified on the specious claim that egg cytoplasm (ooplasm) alone was transferred to the defective eggs of infertile women which would not allow normal development. In fact the researchers had assumed mitochondrial defects in the eggs and corrected them by injecting egg cytoplasm containing presumed normal mitochondria.
The RAC dicta were side-stepped on the basis that the research intervention did not use recombinant DNA (rDNA) technology. . However, a recent American Association for the Advancement of Science (AAAS) report [3] already pointed out that RAC's purview is unduly restricted to techniques (rDNA) that now are more than two decades old. The AAAS working group argued that if new techniques raise the same ethical concerns as those raised by "traditional" germline gene therapy, then either RAC's purview should be expanded to encompass them, or a new, RAC-like body should be created to oversee them. More importantly, they should be subject to the same public scrutiny if they raise the same ethical questions as the traditional germline interventions. Examples of new techniques considered in the report include the introduction of artificial chrom-osomes, the use of oligo-nucleotides to repair genes in situ and the transfer of mtDNA.
Another caveat is that federal funds were not used, and RAC guidelines are binding only on those who receive federal funding. However, other privately funded researchers whose work raises novel issues have consulted with RAC. Given that the researchers recognised they were engaged in "germline modification", Science magazine considers it "unfortunate - though perfectly legitimate - that they did not bring their protocol before RAC" [1].
Frankly, that narrow view reeks of academic sleaze. Genetic recom-bination involves both gene exchange on a chromosome and re-assortment of chromosomes. When new mitochondrial DNA was introduced in ooplasm, the eggs produced were, strictly speaking, made recombinant as the result of an artificial recombinant DNA technology. The claim that the experiment falls outside RAC purview is therefore spurious.
The apparent cure of infertility by creating heteroplasmic individuals (those with a mixture of cytoplasm and hence mtDNA) may also give rise inadvertently to individuals who have the extreme diseases associated with mitochondrial heteroplasmy, most frequently expressed beyond puberty, or much later in life (see Box).
So, what exactly was the genetic defect corrected in the GM babies produced [2]? It turns out to be highly ambiguous. The researchers state, "The basis for this work is the supposition that embryonic failure may be related to hitherto unknown cytoplasmic pathology." In other words, the experiments were not based on any scientific finding. The inheritance of mitochondria was studied after the ooplasmic transplant. The report focuses on two one-year old children.
Significant differences were found in the hypervariable (D loop) region of the mitochondrial chromosomes between donor and recipient in both children using DNA fingerprinting technique to identify single base changes. No other mtDNA region was investigated. It was assumed that the D-loop mutations were useful as markers, but did not relate to the dysfunctional ooplasm. In other words, those mutations are assumed to have no relevance for mitochondrial disease. However, the D-loop mutations observed in the human recipient eggs were never given a clean bill of health for the fetus resulting from the eggs. It is clear that the D loop region regulates replication, transcription and translation. Moreover, those D-loop mutations in the recipient eggs are flanked by genes, mutations in which are known to be associated with mitochondrial diseases involving severe neuro-degeneration that appear after the onset of puberty. Barritt and coworkers [2] hypothesize that the defective eggs may be deficient in ATP content, but assumed that the D loop mutations were unrelated to the presumed ATP deficiency.
The researchers appear to have been prepared to risk the health and long term prospects of infants created in their experiments even though the oocyte defect was undefined. Were the parents informed of the lack of fundamental knowledge when they gave their consent?
Finally, it seems bizarre that RAC should allow 'recombinant' to be redefined to exclude the traditionally accepted definition. Certainly, ooplasm grafting is a rDNA technology; it produces a recombinant mtDNA genotype differing from either parent. In normal reproduction, mtDNA inheritance is exclusively maternal from a single woman, and not two as in the GM babies created.
Now is not the time to bring human germline therapy in through the back door and to promote it through claims of "success" which may be premature and announced after the experiments. Genetic engineering may be proceeding along the lines taken in the development of nuclear weapons. The scientific "elite" may have convinced the political "elite" that the masses need to be led like cattle to the brave new world.
Sure enough, several weeks after we broke the story, it transpired that along with the 15 so far apparently healthy babies, two other babies had been born with rare genetic disorders [6].