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Lab-Grown Humans

A brief excursion into the weird and wonderful world of archaeogenetics: in order to better understand our own brain, we are reconstructing a Neandertal's.a And, while we're at it, why not a whole Neandertal, or a Homo erectus?

Bring out the Neandertal

One of the places where we are gaining a closer understanding of the extinct Neandertal by bringing parts of him/her back to life is the Max Plank Institute for Evolutionary Anthropology (MPI EVA). This institute is a world leader in genetic research into Neandertals, our closest extinct relatives. In 2010, after years of DNA sequencing and research work, a team led by one of the institute's directors, Svante Pääbo, published the genome of female Neandertals who last walked the earth around 40,000 years ago (all genomes decoded to date are from female specimens). This work won Pääbo the Nobel Prize in Physiology or Medicine in 2022. One of the most important discoveries made at the time was that Neandertals had not really died out, in fact all modern humans outside sub-Saharan Africa still carry genes of these early hominins. Hence early modern humans must have interbred with them when they emerged from Africa to colonize the entire world.

Figure 1 The human family tree.

Since then, the MPI EVA has consolidated its lead in early human research by proceeding not just to sequence other whole Neandertal genomes, but also to analyse the DNA of Denisovans. This archaic human species split off from the Neandertal lineage at a very early stage and lived in Asia, in some cases alongside Neandertals and modern humans, up until around 50,000 years ago. It, too, left genetic traces in some modern human groups, namely the Indigenous populations of the Philippines, Papua New Guinea, and Australia, which carry an average of 5 per cent Denisovan DNA in their genomes. Crucial to the discovery of this hitherto unknown hominin was an approximately 70,000-year-old finger bone found at the Denisova Cave in the Russian Altai Mountains in southern Siberia whose DNA was decoded at the MPI EVA in 2010. No Denisovan skulls, let alone skeletons, have been identified to date: all we have is DNA from tiny new bone fragments that are periodically unearthed in the same cave in Siberia.

Far more bones - a large number of well-preserved skulls and, occasionally, whole sections of skeletons - have been found in the case of Neandertals: their genome is, next to ours, the best researched of all prehistoric human forms. The fact that the Leipzig team has been able to grow archaic human brain cells - and even miniature organs, 'organoids' - is the result of this comprehensive sequencing work and of a strong similarity to the blueprint of a modern human: the differences amount to a tiny fraction of a thousandth in an otherwise identical genome. Even our nearest non-human relatives, the chimpanzee and the bonobo, differ from us in genome by little more than 1 per cent, although the last common ancestor of these three great apes lived some 7 million years ago.

It wasn't until around 600,000 years ago that modern humans parted company with the Neandertal and Denisovan lineages. Although the genetic differences are marginal, they produce very clear contrasts between Neandertals and modern humans in physiognomy and physique. There are about 30,000 fixed differences - positions where the DNA of all modern humans differs from that of the Neandertal women analysed at the MPI EVA, who resemble chimpanzees at these points in their genome. But most of these differences do not lie in the genes, as these make up only about 2 per cent of our genome. Indeed, there are only ninety genetic differences that actually encode different proteins in the genomes of Neandertals and modern humans and hence are responsible for potentially divergent physical features.

In the past few years, genetic engineering has made it possible to reset a human cell, at certain locations in its genome, to its 'original state' from before the split between modern humans and Neandertals. In other words, it has made it possible to take the genome of a modern human and reverse the evolutionary steps it followed after branching off the line that led to the Neandertals. This is, if you like, a 'neandertalization' of those genomic locations. The process is extremely fiddly and involves introducing into the genetic information of a human cell some of the genetic differences vis-à-vis the Neandertal women. Once this task is completed, the modified cell can grow in a culture into a small clump of brain cells, for example. Such hybrid cells and cell clumps can already be seen in the Leipzig laboratory. The hope is that this would be the next step in the science of evolutionary genetics: we would no longer read DNA differences between archaic and modern humans only from fossilized bones but would observe them directly, in living human cells. This way we would be able to identify the genetic variants that define us as modern humans and are missing from Neandertals. Not all body cells are suitable as a base for neandertalizing human cells.1 For this operation we need stem cells, which can now be easily produced in the laboratory. At the MPI EVA, this is currently being done using human blood cells, which are then genetically modified with CRISPR/Cas9 'genetic scissors'.2

The feasible and the impossible

When it comes to the manipulation of human DNA and the production of hybrid cell structures, the moral implications, though obvious, are by no means entirely predictable, not even for scientists. In 2018, as if to prove that there is also a dark side to our power over our genes, the Chinese researcher He Jiankui, who has since vanished from the academic radar, claimed to have used genetic scissors on human embryos. He justified this molecular biological intervention as an attempt to protect the resulting babies against HIV by modifying one of their genes. He Jiankui never published a paper on his intervention, however. All that the (largely horrified) scientific community got to see was a publicity stunt at an international congress. A year later, the Russian biologist Denis Rebrivok wrote in the journal Nature of a plan to edit the genes of human embryos in order to prevent congenital deafness in newborns, albeit with the assurance that he would only do so subject to approval by the relevant authorities. Nothing has been heard of the experiment since.

Cases like these illustrate what a fine line genetic research is currently treading: it is of course easy to conceive of genetic scissors being used to 'neandertalize' a human embryo. In ten years' time at the latest, scientists will have reached the point where they are able to modify numerous genomic locations at once, even without a high-tech laboratory. Unscrupulous researchers wouldn't even need much imagination to achieve a scientific breakthrough of an extremely dubious kind.

At the MPI EVA, the genetic scissors are used to neandertalize human cells, but emphatically not embryos. The aim is not to breed Neandertals or archaic humans - or even whole organs - but merely cell clusters (see Figure 2). For these, too, can be used to observe biological processes such as the contractions of a heart muscle or the growth and interactions of brain cells.

Figure 2 A cell culture 'bred' from brain cells © Daniel Wolny

This already produces biochemical processes that can be observed in the laboratory, although such cell clusters are still a far cry from real organs.

So far, eight genetic differences between humans and Neandertals have been introduced into the cell cultures grown at the MPI EVA. But it will be a few more years before a cell culture can be grown with all ninety genetic variants. That said, the exponential acceleration we have seen since the turn of the millennium in the field of genetics and, by extension, archaeogenetics is likely to continue. By the end of the twenties it should thus be perfectly possible to incorporate into a human cell not just the ninety genetic differences that separate us from the Neandertals but all 30,000 genetic locations where all humans differ from the Neandertal genome. That would include those bases in the genome that don't encode any proteins but may still fulfil a function.3

The Frankenstein genome

For the record, the ninety genetic differences are not the only differences between humans and Neandertals, but they are the only ones between all humans and all Neandertals. In other words, none of the million decoded genomes of modern-day humans looks like that of a Neandertal in any of those ninety locations. This means that they cannot have developed anywhere but in modern humans, and must have asserted themselves when our ancestors interbred a second time with the Neandertals. So clearly these variants, or at least some of them, must be integral to being human. Nevertheless, there are other segments of the female Neandertal genome that we still carry to this day: all humans outside Africa have an average of 2 per cent Neandertal DNA.4 In some people, the Neandertal genes are responsible for a particular skin texture, in others for an immune response, and in others for nothing at all - or at least nothing that we can identify.

When the successful decoding of the Neandertal genome was announced in...