For many people, the word “transgenic” conjures up the idea of genetically modified crops. For scientists, however, to speak of transgenic or genetically modified organisms is something infinitely broader and more transcendent; it is to speak of one of the pillars of science today, a field of infinite applications without which a large part of the biomedical and biotechnological advances of the last half century would not have been possible. This includes, of course, the fight against COVID-19.
In 1981, researchers Jon W. Gordon and Frank H. Ruddle published a study in Science describing the breeding of the first genetically modified mice, “which we call transgenic mice,” they wrote. It was then that the term was first used. But while the associated technology was then only a decade old, knowledge of its foundations dated back half a century earlier. Yet, for nature, the foundations are as old as life itself.
In the first half of the 20th century, there was talk of a “transforming principle” that some bacteria were able to transfer to others in order to modify their virulence. This discovery paved the way for the identification of the molecule of heredity, DNA, which in the 1960s and 1970s would give birth to a new science and a new technology: molecular biology and DNA recombination, respectively.
From the origins of agriculture to Dolly the sheep
Changing, cutting and pasting DNA is something nature has been doing for millions of years; those bacteria were transgenic. And although there is in principle a species boundary in complex organisms, it has only recently begun to be discovered that nature sometimes breaks through this barrier as well. For thousands of years, since the invention of agriculture and animal husbandry, humans have been indirectly modifying the DNA of species to obtain varieties to their liking.
Recombinant DNA technology was presented as a shortcut that allowed this to be done directly and without species barriers. The historical account of the first genetically modified organism varies according to the criteria used, but it was Rudolf Jaenisch and Beatrice Mintz who in 1974 succeeded in introducing foreign DNA into mouse embryos, and Gordon and Ruddle who did it in a single cell embryo by microinjection.
Another type of microinjection was the technique that in 1996 produced the first mammal cloned from an adult cell, Dolly the sheep. Although transgenesis (the process of introducing foreign DNA from one organism to another) and cloning are often confused, they are in fact very different, although they often go hand in hand, the latter allowing genetically identical copies of transgenic animals to be obtained. From cancer to neurodegenerative disorders, from obesity to infectious diseases, genetically modified or defective animals—known as knock-outs because one of their genes has been made inoperative or “knocked out”—have been crucial to progress in all branches of biomedicine. Mice with human transgenes have also been indispensable for studying the SARS-CoV-2 coronavirus and COVID-19.
Beyond research, transgenesis has made it possible to produce valuable therapeutic compounds. Today, transgenic animals and cell cultures coexist in this field, but a future in transplantation is also emerging for the former: in 2021, a pig kidney that had been genetically modified to avoid rejection was transplanted into a human being for the first time. However, this path is facing a growing sensitivity about the use of animals for research and therapy; while this debate is undoubtedly necessary, it must not be forgotten that transgenic animals continue to be an essential tool for modern science.
Interview with Angelika Schnieke
“We must generate disease resistant transgenic animals”
Molecular biologist Angelika Schnieke is an expert in genetically modified animals, mainly pigs, for biomedical research. In the past, she worked on the manufacture of pharmaceutical products in livestock milk, but she is known for one extraordinary scientific achievement: she is the mother of Dolly the sheep, the world’s first animal to be cloned from an adult cell.
German biologist Angelika Schnieke was part of the team responsible for cloning Dolly the Sheep. Image: University of Edinburgh
Why to produce transgenic pigs for biomedical research?
The pig is an easy animal in between humans and mice. You can do a lot more in a single pig, because the mouse is so small that you need a lot of animals. With pigs, you can follow one animal from very early stages, get blood samples, test if you already have a biomarker for diagnosis and then go to the next stage and just follow it through.
In the past you also produced drugs in large transgenic animals. Are you no longer interested in this line of research?
No, because the market has changed and most of the products are now done in cell cultures. At the time when we worked on it, it was not clear if cell cultures could ever produce enough of recombinant proteins, so you can treat all the patients. And now the cell cultures have increased, have become more efficient. So it is not clear if the animal is really a good choice anymore.
Why does society need xenotransplantation (the transplantation of living cells, tissues or organs from one species to another)?
We have a large shortage of organs. We have people on waiting lists for heart transplants, particularly for kidney transplants and also islets of pancreas. Both islets and kidneys have to do with the epidemic in diabetes and that is why the number of kidney transplants is going up. In Germany very few people will give her organs away. There is even a discussion to change the law so you don’t have to opt in to become a donor. So everybody principally is a donor unless you specifically say you don’t want to be a donor. As long as we don’t have enough organs, people will always die.
As a result of the debate on transgenic crops, do you think that we must also generate disease resistant GM animals?
Yes. Something that is beneficial for the animal that would be a great thing to do. And with global warming, the threats of particular diseases which right now are only in Africa, they will soon become a problem for us. African swine fever is now moving all the way through Russia and Poland. And Poland is not very far away from the rest of Europe. So if we could make animals which are resistant to African swine fever that would be a fantastic idea. And people are working on making chickens resistant to bird flu. You will save the animals and you will save also a very important food source.
Do you understand concerns about transgenic products in society?
Yes, you can understand. From the outside it is very difficult to understand the way we do genetic manipulation. People don’t understand that system very well.
This interview was published in May 2014 on the occasion of the publication of the article the article ‘Cloning animals: more than just another sheep’