Editing Embryos – Six Steps to an Informed Opinion

For the first time, a government has approved research involving modification of human embryos, but there’s a heavy context underlying this decision that needs to be considered before forming any kind of opinion.

Step 1: Understand why a scientist studies embryos

Hundreds of little physical, biological and chemical events have to take place before every human being is born. A sperm cell in the female reproductive tract has to overcome fatally acidic atmospheres, attacks from immune cells and multiple physical traps to finally reach the egg, then the nuclei of the egg and sperm must fuse correctly, and finally the resultant zygote cell must develop into a multicellular embryo and follow a fixed blueprint to successfully develop into a complete healthy human being.

Tiny mistakes in this chain of events suffice to give rise to problems like infertility, miscarriages or developmental disorders. One job of developmental biologists is to fully understand the genes without whose functioning healthy embryonic development would not take place.

Step 2: Understand why scientists modify genes

One of the most popular strategies to investigate the role of a gene in an organism is to create a “knock-out” version where that gene is inactivated and see what happens. Any deviation from normal behaviour indicates to the researcher what the function of the knocked-out gene could be.

The challenge with most traditional gene knock-out techniques is their efficacy. “While they work relatively well for simple organisms like bacteria and yeast, editing mammalian genes requires much more precision and control,” said Sunil Laxman, who uses gene modification techniques to study cell fate at the Institute for Stem Cell Biology and Regenerative Medicine (inStem) in Bengaluru. The number of cells that end up successfully incorporated with the desired alteration are far too few, and there is a very real risk of creating unintended mutations.

However, in 2012, a new technology called the CRISPR-Cas9 system burst into the scene and made gene editing easier, more efficient and quicker than ever before. “With CRISPR, the efficiency and performance of gene editing experiments, especially involving single point changes, becomes orders of magnitude better,” said Laxman.

Step 3: Understand the limitations of animal models

Since human embryos aren’t easy to get access to, owing to the ethical and safety implications of mutant humans, most developmental biologists have to make do with experimenting on model organisms like mice. “Mouse embryos are sufficient to answer some of our questions, but they’re not ideal for many others,” said Ramkumar Sambasivan, a developmental biologist at inStem.

For example, a 2015 paper titled ‘Only humans have human placenta’ concluded that the mouse’s is an inadequate representation of human placental development. “Many aspects of human placentation can only be understood on the basis of experiments on human cells and tissues in combination with data collections from human subject studies,” the authors of the paper wrote. In such scenarios, it becomes important for developmental biologists to seek human embryos to conduct research with.

Step 4: Understand why are wary of using human embryos

Studies involving genetic modification have so far mostly been limited to animal cells or non-reproductive human cells that pose no risk of passing on the mutation to future generations. This application is quite common and relatively non-risky, especially now with the advent of CRISPR-Cas9.

Experimentation on human embryos, on the other hand, is highly controversial. The fear is that embryonic research, owing to their heritability, is a slippery slope into the era of designer babies and unsafe and unapproved gene therapy rackets. But Sambasivan reminds us that this fear existed as long as gene modification existed. “Of course, CRISPR may have made this eventuality more imminent,” he acknowledges.

The specific regulations as well as the broader legal system around human embryonic research and gene modification are stringent yet blurry in most countries – since the nature, the technologies and implications of the research are so rapidly evolving. The US government, for example, will not fund research involving modified embryos.

The UK is a bit more relaxed. While it bans modifying embryos for clinical or therapeutic purposes, it leaves it up to its Human Fertilisation and Embryology Authority (HFEA) to approve modification of embryos for research. This is what allowed Kathy Niakan from the Francis Crick Institute to file her application to HFEA last October. And HFEA’s thumbs up earlier this month made this the first ever such governmental approval in the world.

In countries like Japan and India, the practice in restricted, but only by guidelines and not by law – and that’s neither here nor there. This blurriness, coupled with the large number of fertility clinics that exist in these two countries, prompted Nature to predict that India or Japan will be the first to produce live babies with edited genomes.

In fact, there is a dialogue that seems to be happening in India. At an international meet in December 2015, K. VijayRaghavan, the secretary of the Department of Biotechnology, said that a committee meeting discussing gene modification had taken place around the time and that the decision to organise public discourses had been taken. However, no more details were shared.

Step 5: Understand the motive of Kathy Niakan’s research

Once Niakan gets a final approval from one more ethics committee, she will gain access to spare embryos from in vitro fertilisation clinics with the consent of donors. Niakan’s team will then begin to examine the role of a set of genes suspected to be in charge of determining the fate of early embryonic cells.

“When the embryo is only about 16 to 32 cells big, each of these cells faces a fork in the road. They can either develop into the foetus or into the protective placenta and egg sac,” explained Sambasivan, who is not involved in Niakan’s research.

This choice is not random but is dependent on whether certain genes are switched on or off in those cells. One gene for example, OCT4, has been shown to be switched on in cells that become foetal cells but switched off in cells that develop into the placenta.

Niakan’s lab will be studying OCT4 and other genes. This could be fundamental to understanding issues like infertility and miscarriages. ““An imbalance created at this point could be the factor that triggers problems like defective placental development resulting in limited success of assisted reproduction techniques,” according to Sambasivan.

Step 6: Understand the difference between editing for research and editing for clinical purposes

Comprehending this difference is the debate’s keystone. It is the latter case that presents the risk because, here, the changes are introduced in an embryo with the intention of letting it continue to develop into a human baby. The changes probably involve correcting a disease-causing gene, but our level of knowledge is still not advanced enough for us to be fully confident that no unintended mutations will take place.

Creating unintended mutant humans may be inevitable if “clinics” claiming to provide gene therapy sprout up without any regulation. Then, of course, there’d be no reason to keep us from skipping over to the realm of the ‘designer baby’, whose genes have been modified to bestow traits that are considered desirable.

In April 2015, a team of Chinese scientists attempted to correct a gene causing beta thalassaemia in human embryos (without governmental approval). They achieved very limited success and concluded that gene editing as we know it isn’t yet ready for the leap into clinical applications. Though the team used only non-viable embryos, which wouldn’t have resulted in a live birth anyway, this episode sent shockwaves across the community and even prompted an international summit to discuss the implications of the CRISPR ‘revolution’.

On the other hand, editing human embryos for research purposes alone, like Kathy Niaken at the Crick Institute wants to, is generally considered okay. Moreover, it can prove crucial to understanding human development better.

The statement that emerged from December’s International Summit on Human Gene Editing had this to say: “If, in the process of research, early human embryos or germline cells undergo gene editing, the modified cells should not be used to establish a pregnancy.” (Emphasis added.)

In their application, Niaken & co. have guaranteed that the embryos will be destroyed in a week and that they won’t be implanting any of the embryos to establish pregnancies. “I’m quite sure that if the project is fully monitored like it will be at the Crick Institute or at other places, where there is a strong ethics committee, it’s possible to avoid misuse,” concluded Sambasivan.