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Globe 1Is it possible to clone a Neanderthal? In theory, maybe.

Last year the scientific community was outraged when the Daily Mail published an article claiming that George Church, from Harvard, was trying to clone a Neanderthal. What a nonsense! I wrote a blog post concerning the scientific illiteracy of the Daily Mail editors and wondering what to do about the problem. Don’t take it personally Mr Dacre; your paper is still worth a guilt-ridden roaming, especially on Sundays.

The Daily Mail claim was -of course- false; professor Church was not trying to clone Neanderthals. But could it be possible to clone one? Back then, I said no. Now however, it may be time to give it a second thought.

Recently, Svante Paabo and colleagues have sequenced the entire genome of one of our late relatives, a big achievement. They found that Neanderthals differed from us in only 87 genes and the differences between those genes were indeed small, just one or two substitutions. Differences in what used to be called “junk” DNA were bigger: around 31000 (but that represents just a 0.001% of our entire genome, still pretty close).

Homo Frankenthalensis ready to take revenge on the world (Modified fron Neandethal museum)

Homo Frankenthalensis ready to take revenge on the world (Modified fron Neandethal museum)

True, a present-day Neanderthal will never be generated like Dolly the sheep was; that would require a Neanderthal’s healthy cell. However, now it could be possible to use a “Jurassic Park” approach: The small number of genes that separate us from them may allow the use of gene editing techniques -such as CRISPR/cas9- to transform human embryonic stem cells into Neanderthal-like embryonic stem cells.

From embryonic stem cells an embryo can be generated, and from embryos grown up individuals can be produced.

Globe 2Generating adult mice from mouse embryonic stem cells is more or less a routine procedure. Nobody has yet succeeded in producing a higher primate from embryonic stem cells. Creating embryos that are viable and able to implant is clearly more difficult with primates. To the best of my knowledge nobody serious has ever tried with humans nor have I any reason to believe that anybody will want to clone a human or a Neanderthal any time soon. Even if nutty professor –just a caricature from popular culture- were willing to do it, this kind of research is extremely expensive. With no governmental agency ever going to finance it that leaves only the three richest Saudi princes in a position to try cloning a hominid, and they are not scientists.

It is an interesting proposition nonetheless that Neanderthal-like stem cells can be generated. These cells could be used to study basic mechanisms such as metabolic pathways and neurogenesis. These studies could in turn shed light into what really separated our ancestors from our primitive cousins.

 

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  • Gold Lions 07/04/2014 at 2:21 am

    Time to clone one already. Only then will our questions concerning these long gone ancients be finally answered.

  • Mosheh 27/01/2014 at 7:46 pm

    The problem with the concept of “species” is that many people are trying to look at the concept through its pre-Darwin meaning. Modern evolutionary thought has shown us that “species” is not a platonic concept, the way Linnaeus thought of a species. defining species as discrete sets of individuals, separated from each other by clear physical traits, has the implicit assumption that evolution has stopped, and that phylogeny is frozen in time. It is partly the legacy of pre-Darwinian biology, and partly the result of our using phylogentic trees with modern species at the terminal points. We simply have difficulty in envisioning a phylogenetic tree as something that is actually growing, and that our set of species is just as transitional as the set of species in a Cretaceous fossil bed.

    Speciation is a dynamic process, and we have populations in many stages of this process. because the process has a strong component of punctuated equilibrium, we are much more likely, at any moment in time, to find populations in the “equilibrium” stage. This means that most organisms belong to fairly discrete morphological and genetic groups that we can define as “species”. However, there will be many organisms and populations that are in groups that are not as discrete, and cannot be differentiated as cleanly.

    What this means, ultimately, is that, any absolute standards for species definition will not be adequate to categorize all organisms in the world. You will have “ring species”, clearly defined species which will successfully interbreed, etc. Thus, a species is not the discrete set, as was defined in “individuals that can potentially interbreed”, but a more fuzzy concept. Perhaps we can call species:
    “A set of individuals that are more similar to each other, genetically and morphologically, than to all other organisms on earth. If these individuals reproduce sexually, they prefer to breed with other individual of this group a lot more than with other organisms, and the progeny of this breeding survive and have better breeding success themselves than the progeny of breeding with any other organism.” It is a definition using relative measures, rather than absolute measures.

  • Mosheh 26/01/2014 at 8:57 am

    Paul,
    I also hate when people use terms like “they became extinct for a reason”, as though there were a higher power sitting in judgement on each species and determining whether that species was “worthy” of continuing.

    In any case, I think that Balaganesh got it right. An individual is A, the result of genes within cells. A set of genes requires a specific cell environment to function. To produce this cellular environment, somewhat paradoxically, would require at least an almost identical set of genes, within the same environment. Basically, to produce a neanderthal, you need not only a neanderthal genome, but a neanderthal cell. Of course, you could start with a Homo sapiens cell with the DNA removed, and hope for the best. There is, of course, as others have pointed out, the ethics of this, since you would not only need a H sapiens embryonic cell, but a H. sapiens womb for it to develop. However, as Balaganesh pointed out, even if we ignored the ethics, the developing embryo has to interact with the mother’s body, and there is already a fairly delicate balance between the mother and a human embryo which is half foreign genes. Surrogate pregnancies of other humans are difficult enough to pull off, I can’t imagine how one would successfully pull off a surrogate pregnancy for a non-human baby.

    Perhaps, one day, when people have successfully A, translated the genome in way that would allow us to figure out how a genome relates to its cellular surroundings, B, are able to successfully create cell organelles artificially, using DNA templates, and C, are able to create functioning artificial wombs. All of these are, indeed, technical, not conceptual, however, they are beyond the technology we have today, and what we’ll have in the foreseeable future. So talking about “cloning a neanderthal” is way premature at the best.

    PS. Ariel – there is good evidence that neanderthal and sapiens interbred, and there is decent evidence supporting neanderthal as a separate species from sapiens. These are not contradictory – the “red wolf” is an entire population of wolf-coyote hybrids, and I do not think that anybody would claim that wolves and coyotes are the same species.

    • Paul 26/01/2014 at 9:21 am

      Ariel, the data indicates that, somewhere in the past, there was gene flow from neandertals to H. sapiens. As I recall, the data does not indicate gene flow from H. sapiens to neandertals. In fact, I wonder if the sequences found are not simply from the common ancestor to both sapiens and neandertal. Anyway, speciation is not an all or nothing process, but a stepwise one. The idea is that the offspring is not totally fertile with either of species. Sapiens has had 70,000 additional years since the last neandertal to continue to diverge, so it is very unlikely that, today, neandertals and sapiens are interfertile.

      That does raise some issues about cloning that Mosheh and Balaganesh brought up. During development, there have to be signals from the membrane receptors to the cytoplasm to the regulatory region of transcription factors to turn on developmental pathways. Also, the DNA has to have these pathways available to be turned on. This is a matter of chromatin, not the DNA itself. It is this latter concept that seems to stop cloning in humans: the adult DNA can’t make the transcription factors to start the genes necessary for early development. So it is very possible that the human ovum will not contain the correct chromatin or cytoplasmic signals that would allow neandertal DNA to have a correct developmental cascade. Surrogate pregnancies have the problem of immunorejection. Will neandertal cells process proteins similarly enough to sapiens that the sapiens female will be able to tolerate the blastocyst and not reject it or the later fetus?

      • Ariel Poliandri 26/01/2014 at 9:23 am

        Allow me to move from the cloning Neandethals issue because it is too far fletched. I’d like to go back to the species issue.
        Is species a physical or a semantic concept? If two different species are unable to interbreed or to produce fertile descendants, it is the former; a natural barrier that does not depend on our intellect or existence. If it is just individuals that look different, it is the later and it is irrelevant in nature.
        Many taxonomists prefer the later because this allows them to name things without having to do any experiments. I can see why this is the prevalent view but unfortunately sometimes it leads to the type of philosophical discussions we are having.
        So, humans had 70000 years to diverge from Neandethals? They had probably more than 50000 to diverge from Australian aborigines; Europeans and Australian aborigines still interbreed, as far as I know, so maybe a modern human could interbreed with a present day Neanderthat if there were one.

  • Paul 25/01/2014 at 9:33 am

    Derek, in this case “clone” only refers to getting a neandertal other than by sexual reproduction of 2 existing neandertals. This isn’t the same as cloning you, and then claiming the clone is not identical to you. We don’t really care if the “clone” is identical to some long-dead neandertal, only that it would be a member of that species. IF Paabo actually had a complete genome, then yes, the process envisions getting a genuine neandertal. It’s not as simple as the 87 genes, since there are over 31,000 changes in the non-protein regions, and we now know that the regulatory regions and microRNAs from these regions play a huge role in control of development and cellular processes. You’d have to get those changes, too.

    Making a male and female (even if that were done) so that there is a potential sexual mate doesn’t solve the problem of being isolated as a species. For instance, we know Neandertals did not have our allele of the FOXP2 gene, so the individuals would never be able to speak like H. sapiens. That isolates whatever number of them you make from our society. Also, they are genus Homo, which anthropologists refer to as “human”. A question would arise: what is their legal status. Are they classed as legally human as H. sapiens and given protection of the law, or are they experimental animals?

    Sometimes the reason species become extinct is that they simply become too specialized for an environment and the environment disappears. Neandertals were adapted to living near the glaciers in an Ice Age, so when the Ice Age ended, their range decreased. And then again, neandertals also appear to have been outcompeted for resources by H. sapiens. But the argument “they became extinct for a reason” is not a valid one.

    All of this, of course, ignores that there are special problems associated with nuclear cell transfer in H. sapiens, problems so severe that no one has gotten the resulting blastocyst beyond the 16 cell stage. Very likely, the same problems would apply to our evolutionary siblings, so right now the whole point is moot: neandertals cannot be generated by nuclear cell transfer (cloning).

    • Ariel Poliandri 25/01/2014 at 9:35 am

      Hey chaps,
      It is always good to have enlightened debates about research ethics. It’s also fun to speculate about what it could come out of something (such as a different FoxP2 variant). I’d just like to point out that in essence what I suggested was that “edited” ESCs or iPSCs could be used to study basic differences between the two “species”. At no point I stated that actually cloning a full blown individual would be right or even possible, on the contrary.
      Now for the sake of arguing: it’s been suggested that neanderthalensis and sapiens interbreed, hence I am not so sure about them being two different species… It is my view that palaeontologists and taxonomists name different species very lightly based -some times- in irrelevant differences.

  • Balaganesh Kuruba 25/01/2014 at 9:08 am

    In agreement Paul’s statement and Derek’s too., The point on “Emotional Suffering” got my attention ., Point worth considering that knowledge and science has to be put to good use ., but I would also encourage to consider the emotional sufferings of other beings into account (exploitation of animals to be specific.,) on the same lines .,, but on the whole – “Neanderthal ain’t happenin” ..

  • Derek 25/01/2014 at 8:48 am

    I agree, no matter what type of sample of DNA you “make”, it’s still not a true Neandertal sample. Everyone also has to remember that a clone is only the physical replica of it’s original form. There’s still always going to be outside factors that will not make it the same.

    IF it could be done, I’m sure you could make both sexes Paul. The main question as you stated, is WHY should it be done? IMO they became extinct for a reason and we shouldn’t mess around with that type of stuff.

    Although a VERY poor example, just watch Jurassic Park. It’s more of an ethical quesion than feasibility.

  • Paul 25/01/2014 at 8:46 am

    As I understand it, Paabo has very good reads on Neandertal DNA. That, however, is not the same as having the DNA strands to do cloning. Paabo got those reads by interpolating a lot; he does not have intact Neandertal DNA. Nor does he have the rest of the nucleus to do nuclear transfer. And editing a few dozen genes from H. sapiens (which we might be able to do with CRISPR) is still not the same as having a Neandertal genome. Instead, we would have an altered H. sapiens genome. No one has been able to clone an H. sapiens, so why would anyone think that H. neandertals would be easier?

    And, of course, there is the whole question about SHOULD we do it? Just because we can does not mean we should. The result would be an single individual not only isolated in culture, but isolated as a species, with no other member of his species around. Is a scientist’s ego worth the emotional suffering of the clone?

  • Balaganesh 23/01/2014 at 9:31 am

    In my opinion , even if cloning a neanderthal would be a feasibility, it would be next to impossible to implicate the epigenetic influence of mother nature on the pre-existed neanderthals, hence the correlations we try to draw wouldn’t be precise or accurate enough to generalize with the current generations. Yet, as previously mentioned unavailability of uterus undertaking the mortal risk shall be the primary concern here followed by ethical and governing boards. Good thought, :)

  • Sohan Modak 21/01/2014 at 9:50 am

    Why do you want to do it? There are enough Neanderthals among dictators, druglords and poilitians.

    • Ariel Poliandri 21/01/2014 at 9:51 am

      Hi Sohan,
      I see what you mean. Anyway, I don’t want to do it; I work on a different field. But reasons for generating Neanderthal-like cells are mentioned in the last paragraph: They could point at ways in which our ancestors were able to out compete Neanderthals.

      • Sohan Modak 22/01/2014 at 11:01 am

        Well, Ariel, what i mean is that we don’t even have human genome fuylly annotated and only a few genes that have been compared for their broad based phenotypic effects with the corresponding ones in monkeys )chimp, bgorilla…). so what are we talking about? This is just a hype to sell Illumina or other NGS systems that are flodding the market without knowing what to do except for producing a ball/roll of dreams, oops..lies…

      • Ariel Poliandri 22/01/2014 at 11:02 am

        What is your counterproposal then?

      • Sohan Modak 22/01/2014 at 2:28 pm

        First annotate properly from the Transcriptional Unit to polypeptide and not the other way around. Find them all those we know of, propose that look bonafide but not known so far and engineer them and querry whether these really exist and so on…

      • Ariel Poliandri 22/01/2014 at 2:29 pm

        There are tens of thousands of genes and maybe hundreds of thousands of peptides. You cannot annotate them -even less check them- one by one only by hand. More problems:
        Annotations are made by hundreds of scientists who work independently on their own projects not by a centrally coordinated group. Add to this that there is not ONE genome; everybody in the planet has their own (except identical twins of course). There will always be discrepancies.
        You cannot start from each individual mRNA of each human in the planet, clone it into an expression vector and see what it does. At some point you have to trust bioinformatics and move on.

  • Derek 21/01/2014 at 6:23 am

    It’s probably a lot easier than people think. The two draw backs are a sample from a Neanderthal and finding surrogates willing to participate. ;)

    • Ariel Poliandri 21/01/2014 at 6:55 am

      Hi Derek,
      I am afraid you might be right, especially if you have many technicians, unlimited eggs, unlimited surrogates and a lot of time and money. Anyway, here we are just talking about editing a few dozen genes in a human cell not nuclear transfer from a Neanderthal cell.
      Mitalipov, as far a I know the only scientist that has succeeded producing hESCs by nuclear transfer, was unable to clone monkeys from monkey stem cells in 2013.

  • Eugenije 20/01/2014 at 7:58 pm

    What would be the purpose of doing it?

    • Ariel Poliandri 20/01/2014 at 7:59 pm

      The possible uses of Neanderthal-like cells are mentioned in the last paragraph, after discussing that nobody is planning (or can) grow up a full blown individual.
      Cells could be used to investigate how modern humans out competed Neanderthals. Neanderthal cells could be transformed into neurons to investigate in what ways their neurons differed from ours. For example, neurons derived from patients with Dawn Syndrome tend to connect less with each other and die early. Other cells could be used to study how their metabolism differed from ours and so on.

  • Kerry Jonas 20/01/2014 at 7:53 pm

    I don’t think they need to. During my long and varied life, I’m sure I’ve met a few socially.

  • Alain Anselmet 20/01/2014 at 7:52 pm

    Your article reminded me of an article written some years ago by Oliver Morton in the New York Times, which also quoted Dr. Church: “Biology’s New Forbidden Fruit”.
    http://www.nytimes.com/2005/02/11/opinion/11morton.html?pagewanted=print

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