roger_highfield's picture
Director, External Affairs, Science Museum Group; Co-author (with Martin Nowak), SuperCooperators
Cellular Alchemy

A remarkable convergence of technologies is sending shockwaves through genetics and medicine: the widespread adoption of easy-to-use, inexpensive, and effective genome-editing techniques has made recent headlines. But it's just as significant that their power has been hugely amplified because we live in the era of cheap genome sequencing. There are ways to regulate how genes are used without making permanent changes to DNA, and we now have the ability to reprogram adult cells to return them to an embryonic state and then convert them into any desired cell type.

This is the era of cellular alchemy.

To underline why today's gene editing methods are so important, look back to 1990, when John Clark's team in the Roslin Institute near Edinburgh unveiled Tracy the sheep. Tracy, the first transgenic farm mammal, was a pharming pioneer that made 30 grams of a human protein in every liter of her milk (Tracy was considered so significant that, after her death in 1997, she was stuffed and placed in the Science Museum's collections).

She had been genetically altered to make alpha 1-antitrypsin, AAT, a substance regarded back then as a potential drug for the treatments of cystic fibrosis and emphysema. But the Roslin team could only use crude methods that offered no control over where DNA would end up. They could add calcium salts to make DNA precipitate out of a solution onto the embryo and hope that some would migrate inside; use electrical pulses to punch holes in the membranes of embryos to drive DNA inside; package DNA in fat particles (liposomes), which dissolve in cell membranes; or, best of all, inject a few hundred copies of the DNA directly into the nucleus of a zygote, a one- celled embryo. The Roslin team attached the AAT gene to the promoter region of a gene responsible for a sheep's milk protein and injected a thousand embryos with this "construct" to end up with one sheep—Tracy—that could make alpha-1-antitrypsin in her mammary gland, and thus her milk.

The use of such crude genetic engineering methods on people is inconceivable. But today we have a way to change DNA at a precise spot. Gene editing permits specific stretches of DNA to be deleted from genomes, and also allows new stretches to be inserted into the gap in a much more precise, reliable way. Gene editing methods can also insert or remove a number of genes at a time, offering huge opportunities when it comes to altering crops, animals, and even people.

The reason that this subtle knife is so powerful is that we wield it at a time when we can cheaply and easily sequence DNA to check edits. We know how to manipulate genes without altering them by inducing epigenetic changes that regulate how they are used, and we know how to manipulate cells too, notably by the use of "Yamanaka factors" to turn adult cells into embryonic cells.

When it comes to people, this will pave the way for model systems to test drugs, the creation of T cells designed to fight cancer, a way to create a patient's own disease-free cells for therapies, humanized pig organs, and so on. Work by Mitinori Saitou of Kyoto University in Japan and Azim Surani in the Gurdon Institute in Cambridge has even shown that these reprogrammed embryonic cells can even be turned into "immortal" germline cells.

By combining these technologies, one can envisage taking a skin biopsy from a person with a serious disease, correcting the underlying genetic defect in these cells, converting them to primordial germ cells and then into healthy, corrected sperm or eggs. Given the limitations of embryo screening, and assuming that the wider ethical concerns will be tempered by reasonable pragmatism, it is inevitable that one day children will be born with a skin cell as a parent. When that day dawns, the convergence of gene editing, sequencing, and reprogramming into cellular alchemy will have led to the permanent alteration of the human genome. With significant numbers of people born this way, human evolution will be heading on a new course.