Recent advances in IVF embryos make scientists stand at crossroads of crossing limits or not
Two studies published last month show that it is possible to keep human IVF embryos alive and developing for up to 13 days after fertilization. The scientists involved believe that they could have gone further because of the 14-day rule adopted around the world that states that no human IVF embryo should be allowed to live beyond this point outside a human’s body.
A criminal offence in Britain, many scientists are questioning this 14-day law. Gastrulation is just too important, they say, to be left unobserved, unstudied and, ultimately, unknown.
Allowing IVF embryos to develop through this critical stage of development could shed light on a spectrum of medical problems, from infertility and recurrent miscarriages to congenital conditions such as spina bifida, cancer and even age-related diseases, they say.
“We could be missing out on discovering some very key aspects of human development because we have this rule,” says Azim Surani, a cell biologist at Cambridge University’s Gurdon Institute. “It results in a waste of material because we have lot of embryos left over from IVF treatment, so by extending the time limit we can
use them in research to obtain first-hand information about early human development that has an impact much later on in life. Why not make optimum use of this precious material, extend the time limit and use it for something that could benefit advances in medicine?”By allowing some of these spare IVF embryos to reach gastrulation, scientists would be able to understand some of the most important events in early human development. It could, for instance, transform our understanding of how to use stem cells in regenerative medicine or inform us about key stages in the development of the “primordial germ cells”, which go on to produce sperm and eggs. These germ cells are effectively immortal because they are continually passed on through the generations and knowing how they form during gastrulation could help to make sperm and eggs in the lab from skin cells, already achieved in the mouse.
Many scientists see the 14-day rule as an anachronism. It can be traced to 1979, when it was proposed as a limit by the ethics advisory board of the US Department of Health, Education and Welfare, just a year after the birth of Louise Brown, the world’s first IVF baby. In 1984, it was endorsed in Britain by the Warnock committee, whose seminal report became the basis of the 1990 Human Fertilisation and Embryology Act.
The logic behind a 14-day limit was a peculiar combination of religious and scientific thought. It was the point when twinning – the natural splitting of an embryo into two further embryos – became impossible, so some theologians were happy with it on the grounds that prior to this the “soul” had not entered the embryo, otherwise twins would have to share the same soul, a theological conundrum too far.
A more scientific reason for 14 days was that it was before the appearance of the “primitive streak”, a set of tissues that unambiguously become the foetus and baby, rather than the extra-embryonic tissues of the placenta.
“It’s before the formation of the primitive streak, and the first signs of the nervous system development, so the argument was it was well before embryos could possibly feel anything. Of course, they are not in fact going to feel anything until months later because that’s when you have differentiated nerves,” explains Robin Lovell-Badge, a mammalian geneticist at the Francis Crick Institute in London.
“The 14-day rule was a compromise between the scientific and the non-scientific arguments. But certainly at that time it was a philosophical rather than a practical limit, given that it is only now that it has been possible to maintain approximately normal development beyond seven days,” he says.
This changed dramatically last month with the publication of two studies showing that it was possible to culture human embryos in vitro right up to the legal limit. One was led by Magdalena Zernicka-Goetz at Cambridge, who built on her work of two years ago showing how mouse embryos can be made to live long outside the body with a little help from 3D scaffolding material and some additional growth factors and hormones added to the IVF culture medium.
What was surprising, according to her paper in Nature Cell Biology, was the innate ability of the human embryo to “self-organise” itself in the absence of a womb into the distinctive, disc-shaped layers of tissues that appear several days after implantation has taken place.
A rush of excitement followed the publication of the two studies, the second (in Nature) being from the lab of Ali Brivanlou at the Rockefeller University in New York. For the first time, scientists seemed to have acquired the technical ability to breach the legal limit, a bit like suddenly having cars that could go faster than 70mph on a motorway. So the obvious question was, why shouldn’t they?
In the US, where the anti-abortion movement has had more influence historically on this kind of scientific research than in the UK, there are siren voices urging caution. Henry Greely, director of the Center for Law and the Biosciences at Stanford School of Medicine, says the 14-day limit shouldn’t be breached just because it is now possible.
“Frankly, I am not convinced… Given the questionable scientific value of the research, no case has been made for even revisiting the line, let alone changing it,” he says.
Lovell-Badge and Surani are more concerned with the medical benefits that might come out of research on older IVF embryos. They believe these benefits are most likely to be felt first in improvements in fertility treatment, with better IVF pregnancy rates, fewer miscarriages and instances of eclampsia.
They also feel there will be much to learn about how genetic disorders are triggered in early embryonic development.
Like so many scientists around the world, they have been astounded by the power and yet simplicity of a new gene-editing technique called Crispr-Cas9, which has been likened to the “find and replace” command of word-processing software – only working on the DNA of the genome. The Crick Institute has the first licence to use Crispr-Cas9 on day-old embryos, donated for research purposes, specifically to understand the causes of recurrent miscarriages.
As for the possibility of completing a full-term pregnancy completely outside the womb, Lovell-Badge simply says it won’t happen, at least not in his lifetime. The spectre of a brave new world of full-term, test-tube babies will remain fiction. “No one is close to doing it in any mammal species,” Lovell-Badge says.
In reality, the pressing need is to see and understand gastrulation, which can only be done by extending the 14-day limit by a week or two, he says. “I think it ought to be looked at again. I’m in favour of that, but as a scientist I also think we’ve got to take people along with you. The arguments for extending the limit are pretty strong.”
And on the 14th day, some light could finally be shed on the “black box” of human existence.
