Back in the late 90s, I remember hearing that scientists “cloned a sheep”. What actually happened with the cloning, and what advancements have been made as a result of that?

Submitted by foxmag86 t3_10s85uu in askscience

I was in 5th or 6th grade when I remember hearing this and never really read to much into it. I remember seeing a cover on some magazine with a picture of two sheep side by side and a big headline about them being cloned.

What exactly was cloned and how did that help with future scientific research/discoveries?

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happyhourscience t1_j707yiq wrote

The process that resulted in Dolly was somatic cell nuclear transfer (SCNT). The process was a big deal because it demonstrated that there was a way to reprogram a cell from a "somatic" state to an earlier developmental state.

This method was developed roughly at the same time that scientists first isolated and grew human embyonic stem cells, which were isolated from pre-implantation embryos. (as an aside, mouse ES cells have been around for much longer, but hESCs proved tougher to keep going in culture).

Human ES cells are super useful in research because they can be used to generate many different cell types, which we can use to model disease and generally understand tissues that might be otherwise hard to get from humans (think neurons or heart cells).

The limitation of human ES cells is that they're hard to make with the exact genetic makeup that you might want to study. For example, let's pretend that I care about a genetic disease like Huntington's disease, which affects specific regions of the brain. If I want to study human cells in a dish, my options are limited, since getting a biopsy of the brain and growing neurons isn't going to be easy.

If you could make ES cells with a Huntington mutation, you would have a basically endless supply of human neurons, but to do that you'd need an embryo with the Huntington disease genotype.

This is where the insight from Dolly comes in: because of Dolly, scientists knew that reprogramming was possible, and a few labs set out to figure out how to do it without physically transplanting a nucleus into an egg cell. The result was the induced pluripotent stem cell (iPSC), which was a big deal and won a nobel prize. Basically, the recipe to reprogram cells using just 4 proteins was identified, and has led to a tool that is widely used around the world. Any patient's somatic cells can now be reprogrammed into iPSCs, which can in turn be used to generate all sorts of cell types to help explain the underlying biology associated with many conditions.

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Zondartul t1_j718iil wrote

So iPSCs are sort of like off-brand stem cells that can be produced without messing with embryos?

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FirstSynapse t1_j71ttjq wrote

Yes, pretty much. You can produce them from many different tissues, but most scientists (myself included) use iPSCs derived from fibroblasts (connective tissue), which can be easily obtained from a biopsy and cultured. Another main advantage of iPSCs over ESCs is that you can obtain iPSCs from patients of any genetic disease and produce any kind of cell you want to study, which will express the dysfunctions associated with that disease.

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ElxirBreauer t1_j724ftc wrote

That is a HUGE boost to research for both treatments and potential cures, I'd imagine.

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FirstSynapse t1_j727ikl wrote

It is pretty nice, and the models get better every day. As a caveat, I must say that there are LOTS of things to consider when doing research with iPSCs, mainly related to how accurately your cells represent actual human cells. For example, I work with iPSC-derived neurons and any change in the process of maturation of iPSCs into neurons vastly changes the properties of the final cells. Also, neurons and other cell types take long to mature from iPSCs. In the case of my cells, it takes around two months until they are at a stage I can use for my experiments, and they have to be maintained for that long and lots of things can go wrong.

All of this is, of course, also a problem with ESCs, but not with animal models. If human genetics are important for your experiments, iPSC models are almost the only choice you have. If there is a good animal model for the disease you're studying and organism physiology is more important, then animal models are better.

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Foreign_Implement897 t1_j724gzo wrote

So do you actually need stem cells for anything after this? Is it a complete substitute?

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FirstSynapse t1_j72b0mn wrote

If you mean embryonic stem cells, their main advantage over iPSCs is that ESCs have been around for longer and can be considered somewhat more reliable. iPSCs need to be generated in the first place from mature cells, and although this process is relatively simple (only four factors in the case of Yamanaka's Nobel prize-winning research), there is still a lot of debate over how it should be done and how it can affect the resulting phenotypes.

ESCs, on the other hand, are already naturally capable of generating tissues, so there is a larger likelihood that the resulting mature cells will resemble more the actual human ones. In studies in which the mutations of the diseases that are being studied are generated by genetic manipulation, ESCs are still preferred by many labs because of this reason.

But this is an issue for iPSCs just because it is still a very young technology, and huge advances are being made constantly that make ESCs less relevant. Being able to obtain cells directly from patients is a huge advantage as it allows to study diseases that have an important but not entirely known genetic component, like most neurological disorders.

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baumpop t1_j74uyv9 wrote

What about regrowing tissue? And does this tangentially related to the new knowledge that cells are sending information and can be "reprogrammed" (like in the anti aging studies on mice).

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aotus_trivirgatus t1_j75ysk0 wrote

When iPSCs first appeared, many people doubted that they would truly be functionally identical to ESCs. After a few years, I stopped following the field. Is the verdict in?

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Dmains t1_j70o40w wrote

Great explanation. Thank you

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zxyzyxz t1_j70z5u2 wrote

Thanks for the answer. What advancements have been made since Dolly in these fields?

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MrPsAndQs t1_j71tj9a wrote

Well, Dolly was the first mammal that was cloned, but already in the late 1950s John Gurdon used the same procedure to clone frogs.

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thismightbsatire t1_j73npxe wrote

How does the completion of the human genome project affect our ability to clone DNA?

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daaabss t1_j76cew7 wrote

Okay. Is that the simpliest explanation? Still have no clue

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EducationalCan3358 t1_j722ei3 wrote

Is this how CAR-T cancer treatment came about?

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CrateDane t1_j7297wt wrote

No, CAR-T simply uses T cells extracted from an adult. Either the patient themselves or a donor. The cells are then gene edited to express the chimeric antigen receptor, and the successfully edited cells are put back in the patient.

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saturns_children t1_j74pue2 wrote

Can this be used to create stem cells for different tissue types. For example, teeth stem cells, I know there are multiple types of teeth stem cells? And grow new teeth for example?

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Equoniz t1_j7221z8 wrote

I like how you introduce an acronym you never use, then never introduce the acronyms you do use throughout.

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ilikemycoffeealatte t1_j703n91 wrote

Her name was Dolly. She was euthanized after about 6 years due to a handful of genetic issues.

Other animals have been cloned since then, and it's been very advantageous in stem cell research.

The Wikipedia article about Dolly is well put together and very informative!

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Mp32pingi25 t1_j7045go wrote

She had lung issues and No cause which linked the disease to her cloning was found

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CappinPeanut t1_j71kfcr wrote

Did the original Dolly have a lung issue or just the clone?

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wglmb t1_j71lv1v wrote

From the Wikipedia article linked above:

>she had a form of lung cancer called ovine pulmonary adenocarcinoma, also known as Jaagsiekte, which is a fairly common disease of sheep and is caused by the retrovirus JSRV.

So it was a viral infection, not a genetic issue.

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atomfullerene t1_j70wkid wrote

Aside from the other answers, cloning has gone on to see commercial use and use in conservation (although that's just starting). There are a handful of companies (like ViaGen in the USA) who clone pets and livestock (useful for animal breeders). Cloning has also been done on a few endangered animals, for example a few years back a black footed ferret was cloned.

So the technology has moved out of the lab and into some practical applications.

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efh1 t1_j73bv0e wrote

The next question is addressing the fact that we could do this to humans if we wanted and whether or not that could be happening. There have been claims by groups with clear intentions to clone humans despite the obvious legal and ethical issues. Is it absurd that such interested parties would proceed covertly?

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Corrupted_G_nome t1_j73ivzg wrote

There was a case of human cloning in China and the government jailed that doctor and their staff. It was illegal and lacked permits officially and the results came out after the child was born via surrogate. I never did hear much follow up so I don't know if that was a hoax or fake news story.

I heard another of a family cloning a young child who was hit by a car and died. Again I did not confirm that story. It does bring up some weird ethical questions tho about potential uses of this technology.

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efh1 t1_j73jxr5 wrote

I know this is going to sound crazy and people get weird about ufo stuff and cults but there is literally a ufo cult that claimed they cloned a human awhile ago and they still offer cloning services on their website. I wish I was making this up and at the time it was regarded as a hoax and it may have been but if you research the cult they have a PHD in charge and are pretty serious about wanting to clone people. I cover it all in the article below.

https://medium.com/predict/a-ufo-cult-that-offers-alleged-human-cloning-services-b1a95874f83b

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Corrupted_G_nome t1_j73kbme wrote

Now that you mention it I linda remember the headline on this case. Super weird imo but the tech is very existing and very possible. Morally and ethically its super questionable tho.

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efh1 t1_j73kh7l wrote

That’s the thing about cults. They have different moral and ethic codes.

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Corrupted_G_nome t1_j73kv3w wrote

To be fair the article shared also included embryonic stem cell research which is banned in some US states but was a critical point of research of all kinds for some time (maybe still is) so I can see how that would go underground.

Designer babies should be a forbidden technology. Cure illnesses ore birth and remove genetic defects, fine. Choosing phenotype traits is creepy af imom

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atomfullerene t1_j73rqap wrote

It's not entirely clear to me what benefit there would be to a research team in covertly cloning a human. You obviously can't publish on it, which is the lifeblood of academic researchers. There's no obvious practical benefit to a for profit corporation, unless you want to, like, sell cloning services to rich people...in which case you have to advertise that you can do it. And it's not super clear why most governments would be interested in it.

It's certainly not impossible (especially for groups in the early stages who want to stay quiet until they have success), and after all it's a big world full of all sorts of people who try all sorts of things. I wouldn't be shocked. But I don't in general see a big motivation for people trying to covertly clone people. And generally speaking, people need motivation to spend a lot of money.

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bonkly68 t1_j79scmq wrote

Human development is so complex, with so many influences, it's quite likely that a cloned "Einstein" would not be the same person, may not necessarily be drawn to the fields or acquire the abilities that distinguish the original. But someone will have to try before we know.

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efh1 t1_j740o5u wrote

One scary answer you are not thinking of that is documented to exist is religious belief.

https://medium.com/predict/a-ufo-cult-that-offers-alleged-human-cloning-services-b1a95874f83b

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atomfullerene t1_j742yyz wrote

eh, I mean...random tiny cults aren't really a big source of funding for research teams. They do often pull scams though.

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Atypical_Mammal t1_j7a8q8a wrote

I don't think human cloning is going to take off because there's kind of no point. You are not going to get anywhere near the same person as the original.

Yeah, sure, DNA might be the same - but there are so many variables from embryonic stage all the way to adulthood that might make the end result completely different. Nature versus nurture blah blah blah

The only way it might work is Maybe lonely narcissistic people raising clone babies of themselves

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common_sensei t1_j71ja1p wrote

A human version of sort of the same technique is used to make three-parent babies: https://www.nature.com/articles/nature.2017.21761

This avoids mitochondrial diseases by transferring a nucleus from a fertilized egg to a donor fertilized egg that had the nucleus removed. The baby ends up with the nuclear DNA of its biological parents but the mitochondrial DNA from the donor, hence three parents.

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Pigs_in_the_Porridge t1_j706dnj wrote

Turns out a bunch of research groups tried to clone monkeys and couldn't make it work. I know one scientist at Wake Forest who spent close to a decade on it. There's something about primates that make the cloning technique used for Dolly untenable. I think that Oregon Health Sciences University also tried for years.

Interesting thing...this scientist primarily studied alcohol addiction and wanted cloned monkeys to eliminate a bunch of variables. The idea was that a whole bunch of life sciences would like to use cloned monkeys for more control in their experiments.

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bt-venger21 t1_j70pf3q wrote

It's been done tho, the failure of SCNT in primates and other mammalian models was found to be due to inappropriate reprogramming of the somatic cell nucleus, which then couldn't support the embryo development. Zhong Zhong and Hua Hua are a couple of Macaca Fascicularis monkeys that were born via SCNT, and the use of new strategies for the epigenetic reprogramming of RRRs that yielded two healthy baby monkeys from enucleated fetal fibroblasts.

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Isotope_Soap t1_j70lf25 wrote

Interesting. There was a BBC documentary about drinking habits of monkeys (short excerpt) that stated their alcohol consumption habits mimicked humans. Some would get drunk once and avoid alcohol, some would drink casually, while others would be considered alcoholic.

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NohPhD t1_j75fb48 wrote

I would hazard a guess and say any normally physically active group of one species, kept in a small cage, fed chow and never seeing natural light, should choose to consume alcohol this way.

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Goodgoditsgrowing t1_j70t7yb wrote

More control in the experiment that results in a lack of natural variation, which is vital for understanding how it would impact a population rather than a single individual? I can understand certain aspects it might help, but that seems awfully foolhardy to think it wouldn’t result in such a lack of diversity among study subjects that it’s as if you only had a sample size of one.

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Pigs_in_the_Porridge t1_j70xwgr wrote

Well we already have that.

I wasn't privy to their specific research plans but I imagine they had plenty of reasons to try this route. Didn't work anyway.

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SGTWhiteKY t1_j730yqm wrote

You got it backwards. They want to eliminate the natural variation to test many different formulas for their treatment. Without clones, it is impossibly to be completely sure if the effects of different formulas are caused by them being different formulas, or the each person’s body just reacted differently.

It would be incredible because you could choose a group of monkeys that have genetic traits you want to test, then clone all of them so that you have multiple of the exact same test environment to test different treatments. It would push medicine rapidly.

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HaggisPope t1_j712qfo wrote

Dolly the Sheep can now be found in the National Museum of Scotland where the experiments took place. She's taxidermied and slowly rotating on a platform.

I've heard there's some kid sheep related to her still going because they're examining if cloned animals develop in the same way and they're going for several generations to check.

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NockerJoe t1_j72rb6c wrote

Cloned animals are now commercially available. I remembera news story several years ago about a polo player who liked a specific horse so much that he had it cloned five times so that he could run a team with only that horse.

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Smedleycoyote t1_j73s3zu wrote

Olympic horse show jumper Gem Twist was cloned after he retired from competition. Since he was gelded, he was not able to be bred, so he was cloned after his retirement. The clone, Gemini Twist, has never competed, but has been a part of a breeding program for years.

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WWMRD2016 t1_j71rs3h wrote

I know that they are now used to provide consistency in scientific experiments.

There's one farm/lab? nearby me that clones sheep for science and then the researchers use them for whatever experiments they're doing. It limits the variable of different sheep impacting the results which helps when interpreting data. The university near me that had a contract to get these sheep were using about four a week.

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thismightbsatire t1_j73nchp wrote

On March 31, 2022, the Telomere-to-Telomere (T2T) consortium announced that they it had filled in the remaining gaps and produced the first truly complete human genome sequence.

I also recommend looking up epigenetic research and the studies on gene expression. It's extremely interesting.

https://www.genome.gov/about-genomics/educational-resources/fact-sheets/human-genome-project#:~:text=On%20March%2031%2C%202022%2C%20the,truly%20complete%20human%20genome%20sequence.

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gilgwath t1_j760ttt wrote

TL;DR: I think cloning will never be a really viable technology for industrial use. At least not on its own. Not because it's hard problem to solve, but it doesn't scale well. That's why there is little investment and slow development.

Let's assume you cloned a sheep. Congratulations, you now get to care for a baby sheep. You need sheep milk to feed it, you need to provide it with shelter, warmth etc.

That's cool if you cloned one sheep for the lulz. But we want to make some money here. So we clone 1000 sheep. Now where do you get the milk from? From a 1000 other mother sheep who also had at least 1000 baby sheep. You also need a massive lab AND a massive pen to keep your sheep. Workers to do the cloning AND workers to take care of the baby sheep.

If you just want to double your sheep output, it's much easier to just have double the amount of sheep and have them reproduce naturally. No lab required, the herd mostly takes care of their needs.

You've also sloved none of the other problems big scale animal farms come with: methan emissions, land and water usage, animal cruelty etc. You also opend the pandoras box of ethical questions around cloning.

Next question is, will you be able to sell you produce at a competive price ahd enough customers?

Assuming you somehow manage to make it profitable, all of this only works until someone really figures out how to grow meat in a lab at a large scale.

There's no really goo business case for it, so there's no one who's really keen on spending millions to perfect the technology, industrialise it and then build a business on it.

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Zeraphym47 t1_j72p92g wrote

You can legally clone your pet in many Asian countries like South Korea for example....you don't even wanna know what the usa and China are doing on black budget programs....the cloned animals have a very high rate if defect and their souls or personality whatever u wanna call it are never the same when cloned into inferior copied bodies.

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