Why Cloning Is Not Cause for Optimism, and Why We Should Stay Wary: 7 Questions

It touches on kinship, morality and technical barriers

This Wednesday the Chinese Academy of Sciences announced that it had cloned monkeys: on November 27, 2017, a cloned monkey named "Zhong Zhong" was born at the CAS Institute of Neuroscience; on December 5, a second one, "Hua Hua," arrived. It is the first time a primate has been cloned from a somatic cell. The paper appeared this week in the biology journal Cell.

That is more than 21 years after Dolly the sheep, the first mammal ever cloned successfully, was born.

In those 21 years, scientists used the same technique to clone 23 species of mammal, including mice, cattle, pigs, cats and dogs.

But with primates — monkeys — many teams tried similar methods for years and never produced live offspring.

Cloning a primate is plainly an important breakthrough. Beyond what the researchers themselves say, that it is better suited to medical research on human disease, it matters more as a necessary step on the road to cloning humans.

Over the past 21 years, the animal experiments have been accompanied by commercial ones, with real applications in medicine, pets, racehorses and livestock farming. Those commercial prospects have in turn pushed the technology forward.

The argument over what cloning might do wrong has never ended. In 2015 the European Parliament banned the use of cloned animals in livestock farming. Several countries, and bodies such as the United Nations, explicitly forbid research into cloning humans, and the researchers behind this experiment have flatly denied that they have the technology to do it. But with a primate cloned, new territory is opening up. And history suggests that no technology with a use for it stops evolving because of an administrative order or a moral objection.

The potential problems with cloning are the same ones that existed 21 years ago when Dolly was born. The technology may advance slowly, but over the long run it is still something to watch warily.

Cloning a monkey is essentially no different from cloning a sheep, but it is still nothing like a reliable assembly line

"Ninety-six identical twins working ninety-six identical machines!"

In the novel Brave New World, Aldous Huxley described a future in which a single fertilized egg is used to mass-produce 96 people. That was 1932, when science still knew very little about DNA. The "Bokanovsky's Process" Huxley imagined out of what he knew about animal breeding is widely regarded as an early sketch of cloning.

Animals are cloned today mainly by transplanting a cell nucleus, which carries nearly all of an organism's genetic information. In somatic cell nuclear transfer, the nucleus of an egg cell is removed and replaced with a nucleus taken from a somatic cell of the animal being copied. An embryo forms and is implanted in a mother's body to develop.

The process sounds simple and fails almost every time. Dolly was the single success in more than two hundred attempts, and when the research was published there was no second cloned sheep. The Nobel laureate Philip Sharp questioned it at the time: "If I tried 215 times and only succeeded once, and didn't try to repeat it, I would doubt whether this is science."

Dolly's team did clone more sheep a few years later, and the same method went on to guide the cloning of horses, cattle, sheep, rabbits and other mammals.

The technique for cloning a monkey is, in essence, the same one.

Macaques had already been copied in 1997 and 2000, by blastomere nuclear transfer and by embryo cloning. But cells divide very fast at those two stages, so identical genes cannot be guaranteed. Somatic cells, by contrast, can be replicated without limit. Cloning from them would shorten the breeding cycle and speed up research, and it would also keep the offspring genetically consistent and reduce the variation between individual animals in an experiment.

For 20 years, though, one leading team after another was beaten by low reprogramming rates: the transplanted nucleus struggles to adapt to its new surroundings and then struggles to develop into an embryo, and even the embryos that do form tend to have defects. The best previous result was a pregnancy that miscarried at 81 days.

In 2012, somatic cell reprogramming won the Nobel Prize in Physiology or Medicine, and Mu-ming Poo, a CAS academician and director of the Institute of Neuroscience, decided to take on the problem of cloning a monkey from a somatic cell. Under him, the institute's Sun Qiang led a team built around the postdoctoral researcher Liu Zhen, and the work ran for five years.

Reading through the accounts of earlier failures, Sun Qiang's team pinned down what makes primate somatic cell cloning so hard: macaque egg cells activate prematurely, which makes it difficult to start the cloning process properly; cloned embryos develop inefficiently; and the somatic cell nucleus has trouble adjusting to its new identity as a fertilized egg.

To get past the barrier to embryonic development, the team tried adding an injection of a demethylating enzyme during the process, refining the method.

Otherwise the method was the same one used on Dolly twenty years earlier: the researchers took somatic cells from a macaque fetus and put a nucleus into an egg cell whose own nucleus had been removed. The two fused into an embryo, which was activated and then went through development, cleavage and implantation before an animal was finally born.

Genetic testing showed that the nuclear genomes of "Zhong Zhong" and "Hua Hua" matched the donor somatic cells exactly, confirming the clones. A third cloned monkey, "Meng Meng," is expected before long.

But this is still nothing like an assembly line. The two living monkeys are the only two individuals the team got after five years, 79 embryos made from 127 eggs, and 22 successful pregnancies out of 42 surrogate implantations.

For more than a decade cloning has been put to commercial use, from medicine to agriculture — and that is where the problems begin

Dolly's creator, Ian Wilmut, was funded by a biotechnology company that had already shown that genetically engineered sheep could produce certain drugs in their milk — drugs for hemophilia, cystic fibrosis and other human diseases.

The original plan was that if such sheep could be cloned, the company could simply extract the drug compounds from the milk and sell them. If it could clone both rams and ewes carrying the extra gene, it could breed them and own a self-sustaining "living drug factory."

"Zhong Zhong" and "Hua Hua" were cloned for medical purposes too. Bai Chunli, president of the Chinese Academy of Sciences, said the birth of somatic cell cloned monkeys had cracked a key technology badly needed for building non-human primate models for life science and human disease research, and would greatly advance basic life science research and translational medicine.

Beyond medicine, some people will spend a fortune to bring a pet back.

In 2015 a British couple, Laura Jacques and Richard Remde, paid £67,000 to a South Korean cloning company for a puppy with exactly the same genetic information as Dylan, their dog, who had died earlier that year.

They had frozen Dylan's body and taken tissue samples from it twice. The first sample was unusable and would not grow in the lab, so a week later they took a second one, then flew from Britain to South Korea twice to hand the samples over in person.

"After they brought him out, I still couldn't believe this was happening. But the moment he started whimpering, I knew it was real. Even though he was only minutes old, I couldn't believe how much he looked like Dylan. All the colors and markings on him were exactly the same as Dylan's," Laura Jacques said. The Twitter account she opened for Dylan is still active.

Apart from breeding animals for their direct commercial value, some people clone racehorses or breeding bulls.

A good polo pony can be "worth" more than $200,000. But many owners of thoroughbreds have their horses gelded, because a gelded horse is calmer and more likely to perform well in competition. It also means the horse's genes cannot be passed on.

Adolfo Cambiaso, a five-time winner of top-tier polo tournaments, worked with the American company Crestview Genetics to clone eight horses, all copies of his beloved Aiken Cura. In December 2016 he rode six of them to victory in a polo match in Argentina.

Cattle came earlier still; farms in many parts of the world have been raising cloned cattle for a decade. But the animals are not there to be eaten — they are far too expensive for that. They are mainly breeding stock.

In 2016 a black Angus bull sold for a record $350,000. In its first year it put on 730 kilograms, an average of 1.92 kilograms a day, 20% more than an ordinary premium bull. Over the bull's life its semen was collected again and again to sire offspring, making it worth more than $1 million in total.

The advantage of cloning a bull like that is obvious. And the commercial prospects are what send large sums of money into cloning research.

Handled badly, a clone's lifespan does not start at zero

Dolly was born to worldwide attention and died to regret: on Valentine's Day of her sixth year, a lung infection led to her being put down.

Scientists disagree about her death.

Some believe Dolly was already 6 years old at birth — the age of her mother when the cloning was done. The guess rests on research showing that Dolly's mitochondrial telomeres were relatively short, which is usually a sign of aging.

But the Roslin Institute, which cloned her, said thorough health checks found no abnormal signs of aging.

With that question in hand, scientists began studying the relationship between cloning and premature aging. They ran experiments on cattle and mice, and even cloned a fresh batch of "new Dollys", showing that cloning need not affect a cell's life cycle — at least as measured by mitochondrial telomeres, a lifespan can start at zero.

But other research on cloned cattle has shown that if the biological clock is not fully reset, a clone's lifespan is still affected.

For cloned pigs, dogs and other animals, not enough time has passed to know whether such a difference exists.

For now, at least, Dolly's death remains a mystery.

The FDA cleared meat and milk from cloned animals, but the ethics of the process are unresolved

In 2008 the US Food and Drug Administration cleared meat from cloned animals for the food market, on the grounds that it had found no sign of anything wrong with the food.

The decision took the agency a long time. As early as 2003 it had hinted that it would approve the sale of meat and dairy from cloned animals. At the end of 2006 it publicly declared such meat and milk safe, but not until early 2008 did it formally approve meat and dairy from the offspring of cloned animals for sale.

Carol Tucker Foreman, food policy director at the Consumer Federation of America, said that even with FDA approval, consumer groups would still ask food companies, retailers and restaurant chains not to use products from cloned livestock.

A poll taken earlier that month by the Pew Initiative on Food and Biotechnology found that while most consumers knew little about animal cloning, 64% said they were not very willing to accept it and 46% said they were "very uncomfortable" with it.

Europe went the other way. In 2015 the European Parliament banned cloning animals for livestock farming outright, and extended the ban to all livestock, their offspring and products derived from them, including imports.

The sponsor of the proposal, the German member of the European Parliament Renate Sommer, said cloning is not only cruel to animals but dangerous to people, because some will try it on humans. She also said the technology had made no major progress and had little to show for itself, and that most of the few cloned animals that survive have congenital defects and immune problems.

The Parliament did not reach that conclusion overnight. Europe's inquiry had started a decade earlier: in 2008 the European Group on Ethics accused agricultural cloning of cruel breeding methods and excessive death rates. One test then showed that in cattle cloning experiments about 20% of cloned calves died within 24 hours of birth, and another 15% died before weaning.

The cell donors themselves are also dogged by illness and other health problems — weight gain, breathing trouble, enlarged livers, internal bleeding and kidney abnormalities.

By 2015 the low success rate had not improved: survival for cloned cattle was still only 15%, and newly begun pig cloning experiments succeeded as rarely as 6% of the time. That is why the Parliament shut them down.

Cloning animals could also make species more uniform, and so more fragile

After the FDA said cloned food was safe to eat, a New York Times editorial argued that cloning could have worse consequences, because this form of asexual reproduction moves the propagation of a species from the relative randomness of sex to the marked sameness of copying.

Because cloning makes genetically identical animals, it shrinks the broad gene pool that agricultural abundance depends on, and any serious narrowing of genetic diversity carries enormous health risks for a species.

The problem is not obvious yet, because so far only farm animals are being cloned, not whole species. But if particular breeds of cat and dog, or racehorses and breeding bulls, are cloned in future — once it can be done at scale with a high success rate, prices will drop and the uses will spread — the diversity of species will very likely be threatened.

And even if cloned animals gain the advantage of numbers, that does not cancel out the disadvantage the species faces under natural selection. Their genomes are uniform, so when they meet the very conditions that are driving them toward extinction, they cannot show any trait better than the ones the existing animals have — that is, than their own donors.

For animals already made fragile by modern farming, what human cloning technology can do is probably only to increase the number of individuals that suffer.

Bringing extinct species back through cloning looks promising, but it creates new problems

As early as 1990 the science fiction writer Michael Crichton — also the author of Westworld and a graduate of Harvard Medical School — wrote about reviving dinosaurs in Jurassic Park.

In the story, scientists take dinosaur DNA from the blood of an ancient mosquito trapped in amber, then patch the incomplete stretches with fragments of modern frog DNA.

Dinosaurs have been dead for 65 million years and DNA cannot last that long. In theory, though, the trick could work — provided humans had saved the DNA of some extinct species in advance.

The Pyrenees, straddling France and Spain, were once home to the bucardo, or Pyrenean ibex.

Hunted too heavily by people, this stocky goat, whose males carry a pair of large curving horns, dwindled fast. When a female nicknamed "Celia" was confirmed dead in 1999, the bucardo was declared extinct.

But before Celia died, researchers had taken skin cells from her ear and frozen them in laboratories in Madrid and Zaragoza.

A team led by the physiologist José Folch has since tried to use those surviving cells to bring the bucardo back. They took the nucleus from Celia's cells and put it into a domestic goat's egg whose own nucleus had been removed, then used an electric shock to start the egg developing into a reconstructed embryo.

After 57 attempts, only 7 goats became pregnant, and 6 of those miscarried. Folch and his colleagues performed a cesarean on the last and delivered a 2-kilogram kid.

The kid died seven minutes after birth, struggling to breathe because of a congenital lung defect. Tests showed its genes matched the wild bucardo's, so it counted as a brief but successful clone.

It sounds like a remarkable achievement. National Geographic wrote that "a team of Spanish and French scientists had turned back time."

Then came the doubts. For a species that has already gone extinct, the ecosystem it was adapted to has changed. To keep it alive, people might also have to alter the existing environment, or build one for it, at great effort and cost.

Suppose a revived species breeds prolifically, or has no natural predators left where it once lived. For the ecosystem that exists now, that is a catastrophic invasion.

Australia brought in the cane toad in the 1930s to deal with pests, but the toad secretes a highly toxic mucus, and the native lizards, snakes, wild dogs and even crocodiles that prey on it die.

As the toads take over Australian territory at 30 kilometers a year, the government spends 300 million Australian dollars a year on ways to stop them, so far with nothing to show for it.

"Biotechnology should be used to protect biodiversity, not fixated on reviving extinct species," said Deng Tao, deputy director of the CAS Institute of Vertebrate Paleontology and Paleoanthropology.

Besides the risk of ecological disaster, there is the worry that reviving animals will leave the public with the false impression that extinction no longer matters.

"People might think deforestation is no big deal, we can restore the forest. If we drive a species extinct, that's no big deal either, we can bring them back," said Professor Douglas McCauley of UC Santa Barbara.

So how far are we from cloning humans?

Judging by the technology as it stands, we are not about to face the world of The Island or Never Let Me Go.

In this study the donor cells for the surviving cloned monkeys came from the fibroblasts of a monkey fetus. The researchers implanted 79 cloned embryos in 21 surrogate mothers; 6 became pregnant, 4 produced fetuses, and only "Zhong Zhong" and "Hua Hua" came from normal pregnancies and cesarean deliveries.

In the group that used cumulus cells from adult monkeys as donors, of the 181 embryos implanted only two fetuses developed past 130 days, and after cesarean delivery they lived just 3 hours and 30 hours.

In other words, in this experiment the attempts to clone from adult monkey somatic cells failed. Only two clones made from fetal cells survived, and the overall success rate was low.

The team also said that in theory the obstacles and bottlenecks to cloning a human have essentially been broken and it could in principle be done — but that the point of developing the technique was not to clone humans, and there are no plans to do so.

Human cloning is strictly banned as things stand. Applying an embryo death rate like this one to people raises not only policy questions but obvious legal and ethical ones.

If human cloning became real, the ethical problems would be too many to count

In bioethics, the ethics of cloning covers the range of positions on the practice and the possibility of cloning, human cloning above all. Many of those positions come out of religious belief, but some of the questions cloning raises come from secular thinking too.

Opponents worry that the technology is not yet safe enough, that it could easily be abused — producing humans whose organs and tissue are harvested — and that cloned individuals may have trouble fitting into a family and into society.

George Q. Daley, a stem cell expert at Boston Children's Hospital, believes that human cell cloning and gene editing throw bioethics "the most fundamental question": how humanity will regard its own future, and whether we will take the dramatic step of modifying our own reproductive cells, even to the point of controlling our genetic destiny.

"This puts humanity at enormous risk," Daley said.

Dr. Calum MacKellar of the Scottish Council on Human Bioethics said plainly that copying and destroying human embryos "is deeply offensive to millions of people in the UK."

In 2015 a paper in Nature made a similar argument. Edward Lanphier of Sangamo Biosciences in Richmond, California, and his colleagues wrote: "In our view, editing the human embryo genome with current technology could have unpredictable effects on future generations. This is dangerous and ethically unacceptable."

In an interview Lanphier added: "The question, at its core, is how you view the human race and the human species."

Glenn McGee, a professor of health policy at the University of New Haven, has argued that human cloning could change the shape of the family, tangling relationships inside it.

What role, for instance, would a woman cloned from her mother's DNA play for the rest of the family? Mother? Wife? Daughter? Older sister? Younger sister?

Scientists on the US President's Council on Bioethics put a series of questions to human cloning: what harm might a cloned child suffer? Does a cloned child have any choice in the matter? Would that choice conflict with the donor's right to decide for herself?

Animal data also show that cloned fetuses miscarry more often than naturally conceived ones. That clearly raises further questions about kinship and ethics. In humans, miscarriage can also sharply raise maternal illness and death.

The rights of cloned humans are still unclear, but discrimination against them looks certain

Because the prospect is so distant, there is no settled view anywhere in the world — not even among different bodies inside the United Nations — on whether a cloned human would have human rights.

In a 2007 report, UNESCO said cloned humans should have the same rights as anyone else, but UN bodies have not agreed on this, and neither has UNESCO entirely agreed with itself.

Article 11 of its Universal Declaration on the Human Genome and Human Rights states that the reproductive cloning of human beings is contrary to human dignity, and that using embryonic cells destroys the potential life the embryo represents. It adds that cloning is inherently unreliable, so a cloned individual is likely to suffer biological harm.

Or, to put it more precisely, most institutions have not examined the question seriously, and few countries have either. That is understandable: the prospect is so far off that debating it is barely more practical than debating whether aliens have human rights.

On the rights and dignity of clones, Erik Möller, vice president of the Wikimedia Foundation, asked whether a child brought into the world by an infertile or same-sex couple through "asexual reproduction" — cloning — would be born carrying the label "clone," and so be more exposed than a "normal" child to social distance and psychological harm.

If the child's personality and physique turned out very different from the donor's, might the parents be disappointed? And if so, what right would the cloned person have to say no to being brought into the world at all?

Who is a cloned person, really? Where does he come from? Why is he here? These are questions a clone may have to answer.

The Guardian once reported the story of a deaf couple. Their child was deaf too, which at first they had not wanted. Over time the three of them came to like the life and adapt to it, and the couple even wanted a second deaf daughter, using genetic technology to get one. Suppose cloning matures and this couple uses it to make another deaf daughter: for those later daughters, it amounts to taking away the ability to speak and to hear.

The couple's own view is that if some people want to remove the gene that causes deafness from an embryo, deaf people should equally have the right to discard the gene for hearing — once cloning and gene editing are mature.

Cloning and gene editing replacing sexual reproduction could shrink genetic diversity

According to World Health Organization figures for 2005, 536,000 pregnant women worldwide died from various causes. Even now, difficult childbirth is among the leading causes of death for young women around the world.

Set feeling aside and consider only the production of a next generation: after several hundred thousand years of mammalian evolution, mating is not an efficient method. It is not just the difficult births; the road from finding a suitable partner to conceiving to giving birth is a long one.

Research at the University of New South Wales in Australia found that, all else being equal, asexually reproducing populations grow twice as fast as sexual ones.

Cloning looks like a fairly efficient form of asexual reproduction. Imagine using it to obtain large numbers of embryonic copies of yourself, then using CRISPR and similar tools to adjust them and cut out the bad genes. That sounds far more efficient than sex, with all its chances of failure.

Lutz Becks, an evolutionary biologist at the University of Toronto, once sketched that future: "Cloning yourself would be easy — you wouldn't have to look for a partner, or spend time dating to get the chance to have sex."

But sexual reproduction exists for practical reasons, even judged purely as a way of propagating a species.

The idea of biodiversity was put forward in 1986. Biodiversity explains the greatest advantage of sex: at the level of the species, it gives humans more ways to survive a changing environment.

Asexual reproduction produces a population whose genes are highly uniform, while sex produces more mutated genes. That is also why humanity is so varied, despite the racial, religious, sexual, ethnic and regional prejudices that have been with human civilization since it began.

David Buss, a professor at the University of Texas, explains in the second edition of Evolutionary Psychology what the genetic diversity from sex is worth in a changing environment.

The Earth's whole ecology is made of plants, animals, fungi and microorganisms, and it is always changing.

Suppose the change gets sharper, so that every individual that cannot adapt dies — as in the ice ages. An asexual population, its genes highly uniform, lacks the constitution to stand the cold and goes extinct. A sexual population, thanks to its genetic variety, is bound to contain some individuals who can live under the new conditions.

"Don't put all your eggs in one basket" describes the benefit of sex well. Another benefit of variety is that individuals with different genes need different things to survive, and so need a wider range of habitats. It also means that genetically varied members of the same species rarely have to compete head-on for survival.

So the biggest problem with letting cloning replace sex is that it could reduce a species' genetic diversity. Even with gene editing, the genes a clone passes on are still highly uniform. To support cloning as a way of propagating humans is to weaken human biodiversity.

The gene editing that arrives alongside cloning carries the same risk.

Whether human cloning is illegal is still very much disputed from place to place

In early 1997 Ian Wilmut, who bred Dolly, said in an interview: "Many things in life have two sides. I have no doubt that the potential benefits of this cloning technology far outweigh the harms."

The day before he said it, President Bill Clinton had signed an order barring federal money from human cloning experiments, and called on every American scientific and medical body, foundation, university and other private institution to refuse such research. But research is not funded by government alone.

Dolly's birth threw the whole world into a religious, moral and ethical argument about cloning humans.

Scientists had in fact been arguing about the ethics of cloning since the 1960s. In 1967 the bioethicist Leon Kass said that "reproduction designed by human will strips cloned humans of their humanity."

Humanity is the most-discussed ethical question behind cloning. Opponents ask: if "humans" can be mass-produced, what happens to the value of the "human rights" that come attached to being human? And how should illegally cloned "humans," or cloned "humans" born deformed because of the technology, be dealt with — burned like counterfeit bills?

Religion has objected strongly. The world's main faiths, from the three great Christian traditions to Islam, have all insisted that "the soul is sacred" and credited the making of humans to God. Any cloning is seen as an intrusion on divine authority. Some religious figures also hold that a human embryo only days old already has life, and that destroying it casually is immoral.

Cloning research currently falls into two categories: reproductive cloning, which aims to produce a whole human being, and therapeutic cloning, which mainly uses the technique to obtain organs or to conduct research on treatments.

By one count, reproductive cloning is banned in nearly every country, with 70 countries having issued explicit rules. Therapeutic cloning, though, has cautious support in some.

A year after Dolly, in January 1998, 19 European countries including France and Italy signed the European Convention Against Cloning, the world's first legal document collectively banning the cloning of human individuals.

Germany had already banned human cloning research in its 1990 Genetic Engineering Act. France, Italy, Canada, Japan, Denmark, Spain, Portugal, Brazil, Argentina and other countries have all said they prohibit cloning humans.

On November 11, 1997, UNESCO adopted the Universal Declaration on the Human Genome and Human Rights, which states plainly that the reproductive cloning of human beings violates human dignity and should be banned.

The US government under Clinton ordered that federal funds not support human cloning research. But the United States still has no federal law against human reproductive cloning; Clinton's successor, President Bush, publicly opposed cloning more than once and called for legislation, but no bill ever passed.

Fifteen US states now have laws banning human cloning, and three prohibit the use of public money for it. The Food and Drug Administration has said that every human cloning experiment inside the United States needs its consent to be legal.

Britain, the first to clone a sheep, banned human cloning in 2001 but allowed cloning research aimed at medical problems. The law has been taken to court repeatedly by anti-abortion groups and religious organizations, and amended many times.

In August 2004 researchers at Newcastle University in Britain obtained the first license for cloning research, applying the technique to treatments for diabetes, Parkinson's disease and Alzheimer's disease.

Reproductive cloning is banned, but because of the enormous possibilities behind the technology some countries have not opposed research into therapeutic cloning — China among them. The Chinese government's stated position is that it does "not endorse, not permit, not support and not accept" any reproductive human cloning experiment, but it does not oppose using cloning to treat disease.

In March 2005 the United Nations adopted the United Nations Declaration on Human Cloning. Because the phrase "prohibit all forms of human cloning" in it was ambiguous — readable as banning reproductive cloning or as banning therapeutic cloning — 34 countries including Belgium, China, Britain and Singapore voted against it. All of them support medical research using the technology.

Cover image: The Island