How is cloning possible?

Bioethics

Prof. Dr. rer. nat. Jens Clausen

Prof. Dr. rer. nat. Jens Clausen

is head of the department "Ethics and Life Sciences and their Didactics" at the University of Education in Freiburg.

Cloning is the artificial production of genetically identical organisms. How exactly does it work and which ethical aspects play a role in the cloning debate?

January 22, 2018: The cloned monkeys Hua Hua and Zhong Zhong in a laboratory of the Chinese Academy of Sciences in Beijing. The two monkeys were created using the same method as the clone sheep Dolly in 1996. (& copy picture-alliance / AP)

Probably the most famous sheep in the history of science was born on July 5th, 1996. The sheer existence of the cloned sheep "Dolly" has sparked an intense controversy around the world about the limits of what is ethically justifiable, because it was the first cloned mammal. A limit previously considered insurmountable in the scientific sense had been crossed. The possibility of cloning humans seemed at hand. Therefore, the ethical responses were mostly not about the cloning of sheep or other animals, but an application of the cloning technique in humans was discussed. Since there is currently only very sporadic data on cloning experiments with human cells, the ethical assessment of human cloning must, however, be based on the extrapolation of the results from animal experiments.

Scientific basics

What is cloning
Cloning is the artificial production of genetically identical organisms. Each and every one of these organisms is called a clone. In plant breeding and horticulture, the partially natural ability of asexual reproduction is used. It is widespread to reproduce plants with defined characteristics in an asexual way in order to retain these characteristics in the next generation (e.g. potatoes or strawberries). In mammals, however, asexual reproduction is not possible naturally. In order to produce a mammal that is genetically identical to another already born individual, a complex biotechnological process is required.

method
The method used to clone mammals that have already been born is called "nuclear transfer". The nucleus of a single body cell of the organism to be cloned is transferred to an "enucleated" egg cell. Almost the entire genome of the cell is located in the cell nucleus (exception: a few genes in the mitochondria, these are cell organelles for energy metabolism -> "power plants of the cell"). Since with few exceptions every cell contains a complete (diploid: every chromosome is present twice) chromosome set and thus the complete genome of an organism, it is at all possible to create a new organism from a single body cell. The new, cloned organism again needs a diploid set of chromosomes. Therefore, before the cell nucleus can be transferred to the egg cell, the egg cell's chromosomes must be removed; they are simply sucked off. The nucleus of the original body cell is then transferred to the egg cell that has been enucleated in this way. After the transfer, the process that is decisive for the development of the cloned organism follows: the transferred genome, which was specialized in the function of the original body cell, must be returned to the embryonic state. This deprogramming is a highly complex biochemical process that is controlled by protein molecules in the cell sap of the enucleated egg cell. After completing these extensive changes in the programming of the transferred chromosome set, the embryonic development of a new, cloned organism can begin.

Results
Clone sheep Dolly, born on July 5th, 1996. In February 2003, Dolly had to be put to sleep. (& copy AP)
The birth of Dolly was a sensation because it proved that the nuclear transfer method could actually produce viable mammalian clones. However, the efficiency of this experiment was very low: out of 277 attempts, only one succeeded. Many other experiments with different animal species have not fundamentally changed this low efficiency. Only about one percent of nuclear transfers result in the birth of a viable mammal. About 70% of nuclear transfer embryos do not even develop to the point where they could be transferred to the uterus of another animal to be carried to term. About 3% of the clone embryos transferred into a uterus then develop by the time they are born. Often, however, these cloned animals have a shorter life expectancy than naturally occurring ones. In addition to the high number of sometimes very late miscarriages, an important result of the animal experiments on cloning by nuclear transfer is that many of the animals have severe organic malformations.

Objectives
In principle, two different goals are specified for the use of cloning technology:
  1. Regenerative / therapeutic cloning is primarily aimed at establishing embryonic stem cell lines that are genetically identical to the original organism. The aim is to use these cells in regenerative medicine to generate transplantable cells that do not induce immune defenses (for an ethical assessment, see stem cell research).
  2. Cloning for reproductive purposes with the aim of giving birth to a viable cloned organism. There is no need for totalitarian omnipotence fantasies to be in the background, which could then lead to entire armies of cloned soldiers, dictators or supermodels. At first glance, a much more harmless and perhaps also more realistic objective would be the use of cloning as an additional option in reproductive medicine if the previously established methods do not promise success. But ethical questions must also be asked in this context.

Ethical reasoning

The arguments on the ethical aspects of reproductive cloning usually relate to one of two different scenarios. The first scenario is the current reality. The general ethical question is then: Is cloning of humans ethically justifiable on the basis of the knowledge about the process and the results available so far? This question is almost unanimously answered in the negative - regardless of political convictions, philosophical tradition, religious affiliation or nationality. Against the background of the expected malformations, the cloning of humans by means of nuclear transfer is classified as ethically unacceptable because it would expose the clones to unreasonable health risks. The second scenario is based on the premise that the method of nuclear transfer would be just as safe as established forms of human reproduction. Then the question is: beyond security considerations, are there fundamental ethical arguments against cloning? The arguments put forward in this context are very controversial in the ethical discussion. There are the arguments that cloning would a) violate human dignity, b) endanger the identity and individuality of the clone and c) have unreasonable psychosocial consequences for the clone.

a) human dignity
One of the most common arguments against cloning is that cloning people is against human dignity. Usually a horror scenario is then designed in which cloned people are kept under unworthy conditions like animals, the sole purpose of which is to serve as genetically identical organ donors for the original original if necessary. Such an approach would undoubtedly be a blatant violation of human dignity. Critics of this argument point out, however, that the violation of dignity consists in the imprisonment and the instrumentalization as organ replacement parts store, regardless of the way it was created - cloned or naturally conceived.

b) identity
When cloning, clone critics see the individual uniqueness of the cloned person as endangered, because they are genetically identical to the person from whom the transferred cell originated. The objection is that genetic makeup is an essential biological basis for humans. Although this is the case, people who are genetically identical are, however, each separate person. With identical twins, each twin has its own personality. Therefore, it cannot be assumed that this would be any different for cloned people.

c) Psychosocial effects
A somewhat more cautious counter-argument also admits that a clone is unique, but sees the ethical problem in the fact that the clone would have to lead its life in the shadow of the original and / or would be exposed to particularly high expectations and pressure on the part of the parents to perform. This would unreasonably restrict the clone's right to lead his own life. However, this argument is countered by the fact that the right to lead one's own life cannot be restricted by the fact that someone has already lived with the same genetic makeup. The right to make your own decisions exists regardless of genetic makeup and would of course also apply to clones.

d) Research ethics on reproductive cloning
From the philosophical criticism of the above-mentioned fundamental arguments against cloning, however, it cannot be concluded that cloning actually does not pose an ethical problem at all. Because in order to be able to make cloning a method that is safe for humans, experiments with human cells would have to be carried out before it is clear how great the health risks for humans would actually be. The latest results (June 2013) confirm the establishment of the first cell line of human embryonic stem cells after nuclear transfer. Since the method for producing cloned stem cells is basically the same as for cloning for reproductive purposes, the new results for the first time raise not only hypothetical, but also real, research-ethical questions about reproductive cloning of humans. In principle, the freedom of research enshrined in the Basic Law also applies here, which is expressly not subject to legal reservation and can therefore only be restricted by referring to other fundamental rights or to human dignity. At the same time, a wide range of regulations have been established that specify the framework conditions for the admissibility of clinical trials on humans. The informed consent of the clone parents and an acceptable risk-benefit ratio are particularly relevant in this context.

There is a special situation with cloning in that the clone parents include the egg donor and the somatic cell donor as well as the woman carrying the cloned embryo and the social parents with whom the clone then grows up. All of these people must have consented to the experiment before beginning. In a special constellation, only a single consent is required here, namely if the woman from whom the egg cell originates also donates the somatic cell and carries and raises the clone. In principle, however, there are no other requirements than the usual requirements for informed consent. Of course, while the clone itself cannot consent, it bears the majority of the risks.

At present, the anticipated health risks for a potential human clone are estimated to be too high to begin research into cloning for reproductive purposes in humans. However, it is quite conceivable that the further development and refinement of the nuclear transfer processes in animal experiments and stem cell research will reduce the high error rates. It should therefore be asked when an acceptable risk-benefit ratio would exist that would be compatible with research into cloning in humans. For example, one could orientate oneself on the results of the common reproductive medicine procedures such as in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI).

Application for organ cultivation?

As a way out of the organ shortage that limits transplant medicine, it is suggested, among other things, to resort to cloning technology and to allow human organs to grow in genetically modified animals in order to then use them for transplantation.

In order to be able to transplant a kidney with this procedure, a pig embryo is first genetically modified so that it cannot form a kidney. From the embryos that do not actually form a kidney, cells are removed from around the 80th day of their development, from which embryos are in turn cloned. Human induced pluripotent stem cells from the patient are implanted into these cloned pig embryos, which are incapable of kidney formation. Since these human cells can make kidneys, the kidneys in the growing pigs are made from human cells. These organs would then be available for organ transplantation after birth. This has already been achieved in animal experiments.

The high expectations of this research direction, in particular a possible transplant success, need to be weighed against other ethical questions. In addition to questions of animal ethics about the admissibility of such experiments, specific questions of patient safety arise, in particular with regard to the risk of infection and rejection, as well as ethical questions in the context of the production of human-animal hybrids.

In this process, the organs to be transplanted consist of human cells, but these have grown in an animal. In contact with the pig tissues, the organs could be infected with animal pathogens, which only develop their pathogenic potential when transmitted to humans and trigger diseases there that may have been completely unknown before. These so-called xenozoonoses stir up serious concerns, particularly due to the limited experience, which suggests a cautious approach. One should therefore start with a few, strictly controlled individual studies, which can be expanded further if the results are appropriate.

The genetic modification in the organ farming process is intended to ensure that the organ to be transplanted consists of human cells that are immunologically similar to the patient. Since the specific cells of the organ cannot be produced by pigs, they are replaced by human cells, as described above. Whether this also applies to the supplying blood vessels and nerve cells is currently still questionable. This could cause devastating rejection reactions that would jeopardize a successful transplant. Before the first experiments with human patients, it is therefore important to ensure that all cells of the organ to be transplanted actually come from the patient's stem cells.

Organ farming creates hybrid creatures: a human organ grows in a genetically modified pig. Such organisms, which consist of tissues and organs from different animal species, are called chimeras. This can lead to confusion in normative terms if it is no longer clear how the hybrid beings that have arisen should be treated. Do we have to treat every organism that contains human cells like a human, or in organ farming does the pig simply remain a pig that only has an organ made up of human cells? When human cells grow and develop in an animal, it is particularly problematic if the human cells are involved in brain development or colonize the germ line. While the germline should be excluded from chimerism in order to rule out the inheritance of the mixed status into the next generation, the brain affects the moral self-image and it should be prevented that a pig with cognitive properties of a human is created.