Chimera on a red-figure Apulian plate, ca 350-340 BCE (Musée du Louvre) Credit: Marie-Lan Nguyen/Wikimedia Commons

Man and beast mingle in the mythical creatures of classical literature. The centaur combines man and horse; the mermaid joins girl with fish. Now several research groups in the UK are seeking permission to mix humans and animals in a different way. Rather than creating fantastical beasts, scientists hope to make lenses to peer into real human diseases. By combining human nuclei with unfertilized animal eggs, they are seeking better understanding of and treatments for inherited diseases.

These proposals have sparked serious debate and some ludicrous headlines, but there is already a distinguished record of research that mixes human nuclei with eggs of another animal. Then, as now, researchers sought and followed ethical guidelines to answer scientific questions. In fertility clinics human sperm have been allowed to fertilise hamster eggs to assess their fertilising ability1. This was strictly on condition that no development was permitted beyond the two-cell stage. In addition, human nuclei have been introduced into amphibian oocytes to study the mechanisms that bring about successful cloning2.

The most recent proposal is to swap the nucleus of an unfertilized animal egg with one from a patient carrying a genetic disease, with the hope of deriving embryonic (ES) stem cell lines. These cells would carry the genetic susceptibilities of the disease and could be used in drug screening to find compounds that prevent changes characteristic of the disease.

The controversy of creating these animal-human combinations is both scientific and ethical. Can it be done? Should it be done?

The questions extend to the very name for the procedure. Candidates include “chimera” or “hybrid”, but in fact the proposed technique would produce neither. A chimera is an entity produced by the mixing of cells from two different embryos, typically from two species. A hybrid, such as a mule, is produced by mating of animals from two different species.

The proposed procedure is nameless because it is so new. The technology to transfer a nucleus from one cell to an oocyte brought the birth of the first cloned mammal. That technology came along much more recently than the ability to persuade a donkey to mate with a horse, which dates to the Middle Ages. In lieu of creating new organisms by combining gametes from different species, the term cytoplasmic hybrid has been coined to describe creating new cells by combining cells from different species.

More information with less effort

Cells derived from cytoplasmic hybrids would be among the most powerful tools available for identifying potential treatments for inherited diseases, particularly when the genetic cause has not been identified. Within the family of diseases that are variously known as motor neuron diseases, amyotropic lateral sclerosis (ALS), or Lou Gehrig's disease, represents just one case where cytoplasmic hybrids could provide opportunities that would otherwise not be available.

ALS is a relentlessly progressive muscle wasting disease that kills 130,000 people worldwide each year. No treatment significantly improves survival3. Degeneration of motor neurons is the common cause of this fatal condition, but the cause of the degeneration is poorly understood.

Experiments using ES mouse cells point to toxic effects from an abnormal protein4, but no one really knows how similar the actual human disease is to the condition studied in genetically engineered mice. A recent study with cells derived from mouse ES cells showed that glial cells carrying the known causative human mutation SOD1 caused degeneration of motor neurons that did not have the mutations5; This is a clear effect that is not cell autonomous. Whereas this study in the mouse demonstrated the potential value of research with stem cells for drug discovery, studying nerve cells from patients with ALS from unknown genetic causes can uncover secrets that the mouse model cannot.

In particular, these hybrid cells could be used to develop rapid assays for screening potential drugs. This would identify compounds that might stabilise the condition of the patient and prevent progression of disease. In a single year, cellular assays could screen thousands of compounds in high-throughput screens. Over the same time period at the same cost, only a handful of compounds could be tested in mouse models.

If cytoplasmic hybrids can't make screens, they could help perfect SCNT

Even when methods are established to create ES cells by placing human nuclei into human eggs, there will always be a limit to the number of diseases that can be studied so long as donated human oocytes are the only ones available.

Somatic cell nuclear transfer (SCNT, or swapping out an oocyte's nucleus with one from another cell) has been used for the production of mouse ES cell lines in several different laboratories. The proportion of embryos from which stem cell lines can be obtained is much greater than the proportion that would have developed to become offspring had they been transferred into surrogate mothers (2% vs. 16%)6. Furthermore, the small number of mouse cell lines that were tested had an apparently normal ability to form all of the different tissues of an adult7.

Typically in SCNT the egg and donor cell come from the same species, but recent work indicates that this is not a requirement. Cells with many of the characteristics of ES cells have been derived from embryos in which human nuclei were transferred into rabbit oocytes8. Thus, ES cells might well come from cytoplasmic hybrids before efforts with their human-human counterparts succeed.

Whereas stem cell lines have been obtained from human embryos produced by in vitro fertilisation, there is at present no unequivocal report of the derivation of stem cells from a human embryo produced by SCNT. Only two laboratories have described using SCNT to produce human blastocysts9,10, the necessary first step for deriving ES cell lines.

The inability to produce cell lines through SCNT may reflect general limitations of the technique; alternately, primate-specific modifications to the technique might be necessary. There are no reports of cloned nonhuman primates, and experience shows that protocols for SCNT have to be optimised individually for different species.

Ideally, research with nonhuman animal oocytes would yield ES cell lines suitable for research. Concerns remain about the possible effect of a mixture of mitochondria in the developing embryo11,12 and about the potential impact of species differences in proteins on epigenetic mechanisms in reprogramming and early development13. Even if the quest for new ES lines failed, scientists could compare early development after transfer of nuclei into human oocytes and into oocytes from a species in which SCNT is successful. At the least, this should help researchers demarcate difficulties of human-human SCNT.

Whether the objective is new ES lines or new SCNT techniques, a great deal remains to be learned about the most effective combination of species, the optimal procedures for these unusual circumstances and the potential for development of embryos produced in this way. Although barriers to producing embryos and ES cells from cytoplasmic hybrids could be large, so too are the lessons that could be learned from them.