Twenty Tiny Fingers

“Twenty tiny fingers, Twenty tiny toes
Two angel faces, Each with a turned up nose
One looks like Mommy, With a cute little curl on top
And the other one’s got, A big bald spot
Exactly like his Pop…”

Alma Cogan

Like many people, I have pet cats. My two cats are called Marvel and Oba. I look after them and they look after me. I am devoted to my cats and, as far as I can tell, my feelings are reciprocated. Even the idea that they wouldn’t be around one day fills me with grief. I am quite certain that millions of people throughout the world feel exactly the same way about their cats, dogs, bunnies, hamsters and the numerous other types of animals that share their lives. But obviously there is nothing one can do to prevent the death of a beloved companion—or is there?

A recent news story described events in China concerning a man named Huang Yu and his cat, a British shorthair named Garlic. Huang and Garlic were deeply attached to one another. But then Garlic developed a urinary tract infection and died. To begin with, Mr. Yu buried Garlic in a park near his home, but then he had another idea. He had read an article about the possibility of cloning pets and, as he was a well-off business man, he decided to give it a shot. So, he contacted a cloning company named the Sinogene Biotechnology Company. Following Sinogene’s instructions, Huang exhumed Garlic’s corpse, wrapped it carefully in a towel and placed it in his refrigerator. He then waited for a Sinogene employee to arrive from Beijing to extract skin cells from Garlic and deep freeze them while Huang decided what to do. About a month after Garlic’s death, Huang decided to take the plunge and to go through with the procedure for cloning Garlic for a fee of around $40,000. Sixty six days later, Garlic junior was successfully born to a surrogate mother—he was the first cat to have been cloned in China. Stringent biochemical tests confirmed that Garlic Jr. was in fact genetically identical to Garlic Sr. However, as things turned out, baby Garlic didn’t really look all that much like his “parent.” For example, Garlic Sr. had a very marked black spot in the middle of his face and baby Garlic didn’t. Nevertheless, Garlic junior is a really adorable kitten, and perhaps he may one day develop behaviors that will remind Mr. Yu of his beloved forebear.

Garlic Sr.
Garlic Jr.

The fact that Garlic junior didn’t actually look much like his clone parent isn’t all that surprising given previous experience with cat clones. The first cloned cat was produced on December 22, 2001, when scientists at Texas A&M University, in collaboration with the pioneering pet cloning company Genetic Savings and Clone, announced the birth of the world’s first cloned cat which they named “Copy Cat” or “CC.” CC’s clone mother was a calico cat named Rainbow. Rainbow’s coat was made up of a mixture of orange, black and white patches, whereas CC was a tiger tabby—a completely different coat pattern. Again, biochemical tests confirmed that Rainbow and CC had exactly the same genes. But if all their genes are identical, why don’t cloned cats like CC or Garlic Jr. resemble their clone parents? Let’s consider how the cloning procedure actually works.

Rainbow, left, nuzzles the ear of her clone, named “CC,” on a table at Texas A&M University a little more than a year after CC’s birth. Even though the cats share the same DNA, each uses it differently, leaving them with different markings and personalities.

Now remember Dolly the sheep? Dolly was an example of a cloned animal and, as she was cloned from an adult mammalian cell, she was the first of her kind. How exactly does this work? Consider that all animals arise from a single fertilized egg through a developmental program which is directed by their genes. The first few cells in a dividing embryo are pretty much the same. However, they gradually become more “restricted” in their properties as different tissues develop. Genes are made of large strings of the biochemical polymer, DNA. With a few exceptions (known as mitochondrial genes), the DNA that directs the development of an animal is localized in the nucleus of each cell. During development, certain genes get turned on or off resulting in the development of different tissues. However, the nucleus of virtually every cell in the body still contains the full complement of an animal’s DNA, although in each tissue only certain genes that are specific for that tissue are activated. The idea of cloning, then, is to take an animal’s cell, remove the nucleus (which contains all of its genes), and coax it to develop into a new animal—a “clone” of the original animal. The cell could be taken from the skin of the animal or some other convenient source. How exactly can this be done, considering that—although this nucleus has all of the required genes—many of them have been turned off? To obtain a cloned animal, these genes need to be turned on again. This is achieved by taking an egg cell from the same species. The nucleus of that egg cell is then removed and the nucleus derived from the clone parent’s cell is inserted in its place. Under the right circumstances, the nucleus becomes “reprogrammed” to return to its original embryonic state. Now, the newly reconstituted egg cell is electrically zapped and begins to divide just like a zygote—an egg cell that has been fertilized by a sperm. The developing embryo is now implanted into a surrogate mother who will carry it to term if all goes well. As the DNA of the original animal and the clone are identical, the two should resemble each other exactly. Or at least, that’s the theory. The entire procedure is known as Somatic Cell Nuclear Transfer (SCNT). Development of this process by the scientist John Gurdon won him the Nobel Prize.

SCNT was the method used to clone Dolly. The original cloning of Dolly was a tour de force and represented a positive result obtained in the midst of innumerable failures. Since the cloning of Dolly, animal cloning has become much more efficient and reproducible and is now considered to be a part of agricultural science where it is applied to the production of livestock. In addition, a vast array of other animals including deer, horses, rabbits, cats, rats, mice, dogs and monkeys have also been successfully cloned. Yes, monkeys—indicating that cloning humans isn’t going to be far behind if somebody actually wants to go down that path. Indeed, human embryos have been cloned, but just never implanted into surrogate mothers and brought to term. Cloning people’s pets is an interesting offshoot of animal cloning science, and companies that perform these procedures are hoping to find a niche in the pet market. At the moment, cloning pets is very expensive—maybe somewhere in the region of $20,000–$50,000—so the number of people who are in a position to do it is relatively small and restricted to wealthy businessmen like Mr. Yu, or superstars. Indeed, another recent example that was widely discussed in the media concerned the famous singer Barbra Streisand. For many years, Ms. Streisand had a dear pet dog—a Coton de Tulear called Samantha or “Sammie.” Eventually, Sammie passed away, leaving Ms. Streisand distraught with grief. She had a friend who had cloned her pet and who was very satisfied with the results, and so Ms. Streisand decided to do the same thing. In an interview, Ms. Streisand said that when she saw her beloved pet dying she realized she “couldn’t bear to lose her” and so decided to attempt cloning. “I think any pet lover will really understand this,” added Ms. Streisand. One cannot help but agree with her. Among the offspring were two beautiful dogs that looked exactly like Sammie, their clone parent. Ms. Streisand named these dogs Miss Violet and Miss Scarlett. However, in spite of the fact that they certainly resemble their forebear, Ms. Streisand reported that their personalities were quite different and that they did not display the degree of “wisdom” associated with their clone parent. Nevertheless, she said she was hopeful that this trait might emerge with age.

Miss Violet and Miss Scarlett (left and right ) with their cousin Fanny in the center, visiting Samantha’s grave.

Why is it, then, that in the case of the cats we have discussed, the cloned progeny look so different from their clone parents? And furthermore, why is it that even in the case of Ms. Streisand’s two cloned dogs, their personalities are different from that of their clone parent, even though they closely resemble her? If their genes are the same, which they certainly are, how can they be different? The fact is that our genes are rather like a recipe. They give you the basic instructions and ingredients for baking a cake but, as we know, things will turn out differently depending on who is doing the baking. There are actually a whole host of mechanisms which are known as “epigenetic” effects which may result in a clone being different from its parent. Epigenetic effects operate by altering the way gene products are expressed. They are mechanisms that can affect how an animal develops (its phenotype) that are not due to changes in the DNA sequences of genes per se. Among other things, such mechanisms can allow a developing animal to respond to changes in its environment, either in utero or once it is born. How does this happen? There are enzymes that can chemically modify DNA, for example by adding methyl groups to cytosine bases resulting in changes in gene transcription. Moreover, the histone proteins that wrap themselves around DNA and control the way genes are turned on and off can also be modified by methylation or acetylation, and this can also alter their activity. The activity of genes is also controlled by proteins called transcription factors which can respond to environmental influences. Overall, therefore, there are numerous ways that the expression of genes in two identical organisms (clones or identical twins) can be modified by environmental influences and lead to identical twins or cloned progeny who begin to differ from each other or their clone parent as they develop.

As we have seen, neither Garlic Jr. nor CC looked like their clone parent. In fact, the coat color of a cat is also an interesting example of epigenetic influence. There are several different genes that determine the coat pattern of a cat. One gene, named O/o, is found on the X chromosome. “O” determines whether there will be any orange tones in the fur color due to the synthesis of the pigment phaeomelanin. Its variant—or “allele,” to use genetic terminology—“o” produces the non-orange pigmentation eumelanin (black or brown). Because males have just one copy of the X chromosome, they can carry only one of the alleles of this gene—either O or o. If they carry the allele O, they will be red, orange or creamy (depending on the variation), otherwise, they won’t have any orange tones to their fur. Females have two X chromosomes which means they will carry two alleles of the gene. However, in cells from a female, one X chromosome is always inactivated and this is a random process. Hence, in a cat who is O/o, the O- or o-containing chromosome is randomly inactivated in some clusters of skin cells and activated in others. When O is activated, the skin cells produce orange fur and when inactivated they produce black fur. This process usually results in a mosaic of orange and black or what is known as a tortoiseshell pattern. Another gene called “white spotting” can also play a role in determining coat pattern. During fetal development, melanocytes, the pigment-producing cells in the skin, migrate across the skin starting from the back and moving towards the belly. If the melanocytes get a late start on their migration, which is what happens when white spotting is active, they pull up short, leaving the cat with a white non-colored pattern primarily on their underside and legs. When this gene comes into play, the female cat can be tricolor or calico rather than just tortoiseshell. The mechanism for expression of the white spotting gene is also random, meaning that even clones of say a simple black and white tuxedo cat could exhibit patterns with noticeable variations. Of course, it is not only coat color that can result from processes such as this. Interactions with the environment in utero can have a pronounced effect on epigenetic processes. Consider that the womb of a surrogate mother is not the same as the womb where the clone parent developed. Following birth, many factors including nutrition, nursing and stress may affect the activity of enzymes that place epigenetic tags on histones and regulate development in different ways. Hence, there are numerous reasons why a cloned pet may vary from its parent. Indeed, it is difficult to see how a cloned pet could ever be exactly like its clone parent.

Although the idea of people cloning pets has its charms and the idea of cloning cattle might be important for agricultural reasons, the entire idea of cloning animals has a dark side, even if we dismiss the idea of cloned humans. We need to give the entire subject some careful consideration as to what things should or should not be done. Where do we draw a line in the sand, why or when would we cross some ethical Rubicon? Consider an important story earlier this year resulting from work going on in China. The report described the cloning of a group of genetically modified monkeys. These weren’t the first monkeys to be cloned using the SCNT method. This event took place in 2018 when a paper in the journal Cell described the cloning, also in China, of two long-tailed macaques named Zhong Zhong and Hua Hua. One American scientist commented, “Working with cloned animals greatly reduces the variability of the genetic background, so fewer animals are needed,” something that could be true if the entire procedure is considered purely from a practical point of view. The story that broke earlier this year was an extension of these events. In this case, scientists at the Institute of Neuroscience in Shanghai reported that they had used gene editing to disable the gene BMAL-1, which is involved in regulation of the sleep/wake cycle in macaque monkeys, humans and other animals. The scientists then produced 5 clones of this monkey. This is the first time that scientists have cloned gene-edited monkeys which, in this case, have severely disrupted sleep patterns. This is what the scientists responsible call a “proof of principle” experiment, indicating what can potentially be achieved. As far as the future is concerned, the leader of the group has stated that as monkeys are much closer to humans than any other animal, in the future they will “revolutionize research” by being able to make monkeys with genes that give rise to complicated human diseases like schizophrenia and other disorders which involve higher cognitive functions. Dr. Poo, who leads the group, opined that this is much better than trying to study these diseases in mice which don’t resemble humans in most respects. Dr. Poo thinks that schizophrenic mice simply don’t do the job.

How should we feel about the work of the Chinese scientists? It is certainly quite true that genetically modified cloned monkeys may help people investigate scientific questions. But hold on a minute. The cloned monkeys, and those that are in the planning stages, are being created to have terrible diseases. Monkeys are very sophisticated animals and can certainly experience emotions of many types. They can certainly suffer, as can any sophisticated animal with a terrible disease. It is interesting to note that the creators of these monkeys spend a lot of time explaining how accurately the cloned monkeys will model the diseases that they carry. Conveniently, there is no discussion of the emotional toll of these diseases, which are certainly major components of each syndrome. In other words, apart from anything else, what the scientists are creating are a group of animals that are designed to suffer throughout their lives. Of course, science makes use of animal models very extensively, especially mice. There has been considerable discussion about the ethical appropriateness of doing such experiments and it might be argued that such considerations are particularly relevant in the case of monkeys. When one thinks about the complete spectrum of biological consequences of making genetically modified cloned monkeys that are destined to carry horrible diseases, I think that the appropriate reaction is one of revulsion and horror. It really isn’t a question of whether we can potentially obtain useful scientific information from these creatures. This fact is trumped by the sheer inhumanity of the entire enterprise. We shouldn’t do such things, and that is that.

Whatever we think about the cloning and modifying of animals to be used in scientific research, it will be clear that pet cloning has arrived to stay. At this particular time, it is very expensive and so access to these procedures is restricted. However, like all techniques in the burgeoning field of molecular genetics and cell biology, the prices will fall rapidly in coming years. Even in such situations, should one do it? People who criticize the technique, I think, fail to understand its appeal. Even if your cloned cat doesn’t look or behave exactly like its parent, one imagines that it will be imbued with aspects of the “spirit” of the dearly departed and that is something that people recognize and want to hang on to. Nevertheless, there are probably better alternatives. While researching this article, I found several companies online that will synthesize an artificial cloned pet for you. This is prepared from photographs of your pet taken from different angles which are then analyzed to provide a design that is then used as a basis for making an artificial animal. The results can certainly be very striking.

Which is which? Pet cat and its “cuddle clone”
https://cuddleclones.com/

Moreover, these artificial animals really do look like your original pet. Of course, given the fact that they aren’t actually alive, some aspects of your pet will clearly be missing. I should also point out that there are millions of beautiful stray cats and dogs living in animal shelters all over the world who need a good home with loving owners. So, perhaps even if you are tempted to clone Fluffy or Rover, adoption of a stray and generally participating in animal welfare is the way to go.

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