New genetic technology raises ethical questions

Which genetic changes should be permitted? This question is being brought to the fore by the rapid development of genetic technology in recent years. The new genetic tool CRISPR may lead to improved treatments for severe diseases in the future – but is also a topic of debate.

Text: Anders Nilsson, first published in Swedish in the magazine Medicinsk Vetenskap no 1, 2016.

It has been possible to change the genetic code since the 1970s. Researchers have learned to cut and paste DNA into bacteria, plants, animals and even human cells.

But a revolution is now taking place in this field. A new powerful genetic tool, CRISPR-Cas9, often shortened to just CRISPR, has become one of the hottest areas of life sciences in the past three years. Researchers all over the world are competing with each other to become the first to use this new tool for various applications within medicine, as well as other applications such as the development of new crops.

Compared to earlier gene-modification techniques, CRISPR is cheaper, faster, more easily available and simpler to use. The discovery that kick-started this was published in 2012 and as early as the following year, the journal Science declared there was a CRISPR craze sweeping the world of science.

The fervour has not been doused since then. In December 2015, this technology was named as the breakthrough of the year in the scientific journal Science. But the rapid development is also causing worries: What boundaries should there be for genetic technology and is there a risk of them being set to one side in the hurry.

Giulia Gaudenzi
Giulia Gaudenzi, credit: Ulf Sirborn.

Giulia Gaudenzi** is a PhD student in the Department of Neuroscience at Karolinska Institutet and is researching brain development – primarily the cerebral cortex. She is attempting to understand fundamental mechanisms of brain development from a few stem cells to a structure with millions of cells of a thousand different types.

“One common way of researching questions like this is to block the effect of a gene in cells and see what the difference is. This has been possible for a long time, but with CRISPR, I can do it better. It means that I can study a purer system,” says Giulia Gaudenzi.

IT WILL SOON BE THREE years since she began her preparations for using CRISPR and two years since her experiments began.

“It didn't start well. The type of cells I would prefer to use do not do well as single cells, which is required here. Now I've introduced CRISPR in other cell lines that are easier to deal with, at the same time as I'm continuing to try to get the first experiment to work”.

While she has been working with CRISPR, she has seen how quickly the interest in the technology has increased – first within the research community, then outside of this as well.

“Three years ago, a search for the term largely only returned academic articles. Now you get a huge number of hits. A lot is being written, even in the normal media.

The benefits of CRISPR are that it is easy for anyone with biochemistry or molecular biology training to use and that it does not require any special equipment either,” she says.

“You buy the preparation online for thirty dollars. The only difficult aspect I am struggling with is to get it to work in the special cells we have chosen”.

What does she think the long-term benefit of CRISPR will be?

“Alongside research, I am involved in an organisation that works with public health in East Africa and I think about what this technology can mean for low-income countries. A cheap and easily available tool such as CRISPR provides more opportunities for these countries' researchers to conduct good research. And in discussions about CRISPR, both improved crops and the opportunity to fight malaria have been mentioned. It would be fantastic if CRISPR is able to save people from dying of hunger and tropical diseases”.

Iluustration CRISPR-Cas9
In August 2012, the researchers Emmanuelle Charpentier, Umeå University, and Jennifer Doudna, University of California, published the idea that the CRISPR-Cas9 complex could be used as a genetic technology. There has been rapid development since then. Charpentier and Doudna's idea proved to be possible, CRISPR-Cas9 has been adapted to work in ever more organisms – eventually even people. Image: NIH.

IN ANOTHER PART OF Karolinska Institutet, the Department of Clinical Sciences, Intervention and Technology, Division of Obstetrics and Gynaecology, Fredrik Lanner and his research group have just begun to use CRISPR. Their research involves the first few days of human embryo development. At this stage the embryo is called a blastocyst and is a microscopic clump of cells. The aim of the research is basic science: understanding more about what regulates the embryo's development. Fredrik Lanner hopes that this knowledge will contribute to improved infertility treatment in future.

“Fifteen per cent of all couples who want to have children have some form of fertility problem. So the more we know about normal embryonic development, the better we will be able to understand the causes of various fertility problems,” he says.

Fredrik Lanner is planning to use CRISPR in the same way as Giulia Gaudenzi and many other researchers; in order to disable the function of a gene and see what difference this makes. But the fact that his research involves human embryos makes this a special case.

“Embryonic stem cells and altering the genome are each individually research areas that are subject to ethical discussion – and we combine them. Of course we are aware that this is a charged issue. But we also feel that we have a great deal of support from the patients who donate to us.

Close to 80 percent of patients who have undergone IVF treatment that we ask choose to donate their left over embryos to this research, embryos that would otherwise be destroyed.

One benefit of conducting embryo-related research in Sweden is that the legislation is straightforward and clear,” says Fredrik Lanner.

“In Sweden, following strict ethical scrutiny, it is possible to conduct research on human embryos up until the fourteenth day. They must then be destroyed.

We conduct research up to day seven, before the embryo would normally have attached to the wall of the uterus. At this stage it is no larger than a grain of sand and consists of about 200 cells.

In April 2015, a Chinese research group became the first in the world to report CRISPR-modified human embryos. This experiment was performed on defective IVF embryos that would not otherwise have developed into children, but it was still much discussed.

“Their study led to much debate, and to people pushing for a general ban on all CRISPR research on human embryos. It is good that this is being discussed, but a ban would be very unfortunate.

The argument in favour of a general ban is to prevent genetic changes being made that would be inherited by future generations. Such interventions are already banned in Sweden and many other countries, but not all”.

Fredrik Lanner, credit: Ulf Sirborn.

Fredrik Lanner himself thinks that development of CRISPR will not go venture that way in any case. The most likely reason for daring to make genetic changes to your child would be to prevent the child from developing a genetic disease that you yourself have”. There is already a much simpler and safer method that is used for this purpose: PGD, preimplantation genetic diagnosis. PGD involves the testing of IVF embryos prior to implantation so as to avoid implanting embryos that are predisposed to a disease.

“It is thus currently technically possible to choose embryos on the basis of any characteristic we known the genetics of,” Fredrik Lanner points out. “Nevertheless, PGD is only used for avoiding serious diseases, not to choose gender or eye colour or anything else. Society has put in place rules for this activity and they work. I think that society will be able to deal with the issue of how CRISPR should be used just as well”.

CRISPR IS PREDICTED TO BECOME significant within a range of areas: Regenerative medicine and for the development of gene therapies for genetic diseases, as well as for medical treatments within other areas such as infectious diseases and cancer. On top of this there are applications outside of biomedicine: The production of crops that provide greater harvests and are more resistant to drought and pests, modified microorganisms for everything from bioenergy to the purification of emissions, genetically modified mosquitoes that stop spreading diseases. The expectations linked to this new genetic tool are quite simply enormous. “The only limit is your imagination”, as one researcher put it when interviewed by Radio Sweden.

However, it is not uncommon for new scientific innovations to attract exaggerated expectations that gradually come to nothing. That CRISPR should be counted as one of the most important events in the history of genetics is already clear, but it is not yet possible to say exactly how revolutionary it will become.

“It is difficult to predict what problems may arise when a new promising technology appears,” says Fredrik Lanner. Minor details that complicate matters. We have already seen that making new mouse models using CRISPR is not actually as simple as it first appeared.

The problem with CRISPR that has gained the most attention is the risk of what are known as “off-target effects”, i.e. that the small genetic scissors mix up two similar places on the DNA so that the genetic change ends up in the wrong place. Consequently, it is probably that treatments using CRISPR will, to the greatest possible extent, take place in cell cultures in which the result can be checked before the cells are returned to the patient.

BUT IF CRISPR can still live up to the extremely high expectations – how can humanity deal with such a powerful genetic tool? There are differing opinions. At one end of the scale: those who argue that CRISPR is so dangerous that it should not be permitted at all. At the other end: the transhumanist philosophy, which sees scientific advances as suitable tools for remoulding Homo sapiens into something better and more noble – from humans to posthumans. This movement even has a term for its opponents: biofundamentalists.

Niklas Juth, credit: Stefan Zimmerman.

Niklas Juth, who researches medical ethics at the Centre for Healthcare Ethics, Karolinska Institutet, thinks that there are grounds to criticise the arguments of both these groups.

“Some arguments return again and again when talking about new medical technologies. One such is the argument that it is unnatural or that we are playing God – that people would be crossing the boundaries that nature or God have given us. Another is the slippery slope argument: that if we take this step now, we are going down a path that inexorably leads to dystopia.

In the past, both artificial insemination and antibiotics have been criticised using the argument that they are unnatural,” observes Juth. And active euthanasia was perceived as a slippery slope to a murder state 30 years ago.

“I don't set much store by this type of argument. If you scratch the surface of the argument that it is unnatural, you find that is mostly because of personal antipathy”.

But giving people full freedom to use CRISPR to edit their genes and become posthumans – it is at this point that Niklas Juth has objections.

“If it were to be possible to improve the entire human race, for example increase our sense of justice, I have difficulty seeing what would be bad about that. That's as far as I'm prepared to agree with the transhumanists. But should a powerful genetic tool be released freely into the marketplace, there is a risk that the economic upper class would in the long term become a genetic upper class. Maybe cognitively superior to the rest of us. They could turn us into slaves!”

Niklas places himself somewhere in the less spectacular middle ground in terms of his opinion, where the use of CRISPR is permitted but carefully regulated.

“Against the risk of using CRISPR, you have to balance the consequences of not using this method: That we refrain from eliminating disease and suffering,” he concludes.

Text: Anders Nilsson, first published in Swedish in the magazine Medicinsk Vetenskap no 1, 2016.

** Update October 2020: Please note that Giulia Gaudenzi, since this article was published, has presented her doctoral thesis. She is now affiliated to KTH and KI as a post-doctoral researcher. 

The genetic scissors in short

CRISPR, which stands for clustered regularly-interspaced short palindromic repeats, is a type of DNA sequencer that is naturally present in the immune defence of bacteria.

Together with small pieces of RNA and the protein Cas9, CRISPR forms a complex that searches for and neutralises viral DNA in the bacterium. Cas9 cuts up the harmful DNA.

Researchers have modified CRISPR-Cas9 so that it is now able not only to cut up, but also to act as a search-and-replace function, which can both remove and add DNA.

It is the piece of RNA that determines where in the DNA the complex will cut. By producing and introducing different RNA, CRISPR-Cas9 can be controlled to edit anywhere at all in the genome.

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