Two macaque monkey clones, named Zhong Zhong (ZZ) and Hua Hua (HH). Image from original publication. Liu et al., Cell, 2018.
In the days where science fiction stories seem to keep becoming reality, Mary Shelley’s Frankenstein turns 200 years old and scientists in China have cloned a pair of macaque monkeys.
It’s a big year for science so far and it’s only February.
Since Dolly the sheep in 1996, multiple species have been successfully cloned, including mice, cattle, cats, rats, and dogs. While the advancement in monkeys is an incredible scientific advance, what kind of ethical questions does it raise? And are we ready to answer them?
The use of animals in scientific research is highly controversial. However, there is a scientific argument for animal research for the advancement of medical science. The use of human cells on a plastic dish can answer many questions, but will never approach the human relevance of an animal model with functioning organs and an immune system. Although non-animal models are being developed and evaluated, animals are currently the most relevant system we have to understand more about human disease and develop new therapies.
If we accept that animal research is a necessary evil, we then must ask ourselves about scientific responsibility and when animal research is appropriate.
Here, the cloning of monkeys for use in biomedical research is rationalized by the authors of this study as follows:
"As species closer to humans, non-human primates are ideal animal models for studying physiological functions unique to primates and for developing therapeutic treatments of human diseases (Izpisua Belmonte et al., 2015; Jennings et al., 2016). Animal models with genetic uniformity are often desirable (Schramm and Paprocki, 2004), but an inbreeding approach as used in generating rodent models is not practical for non-human primates because of their long generation time."
Essentially, the authors are arguing that primate research is necessary to perform the most relevant research about human disease and development of potential therapies. To allow this research to progress effectively, they state that first, cloning will speed the generation of monkeys for research, and second, will provide the desired genetically matched subjects.
For example, should the researchers want to test a certain anti-cancer drug, the ideal system would be identical subjects, one that receives the drug and one that receives the placebo. Ideally, these two subjects would be treated at the same time, but with a long gestation time, this is not always possible.
With cloning, these challenges can be overcome.
With the ethical questions in the back of our minds, we can't ignore that this is a great scientific advance. So how are monkeys cloned?
These scientists actually used the same technique to clone two macaque monkeys that was used to clone Dolly in 1996, called somatic cell nuclear transfer, or SCNT. A somatic cell refers to any cell of the body that is not a sperm or egg (these are called germ cells or gametes). Here, the researchers used cells isolated from a macaque monkey fetus, a type of cell called a fetal fibroblast.
The nucleus of a cell contains the entirety of that cell’s DNA (see this previous post for a review of how DNA is organized). The second half of SCNT is the nuclear transfer, which is exactly what it sounds like: the transfer of the nucleus of one cell (the fetal fibroblast) into another cell (egg cells, called oocytes) whose nucleus has been removed.
Imagine that the nucleus-less oocyte is a mystery book whose pages have been ripped out. Then, a coverless romance novel’s pages are bound in the mystery book’s cover. Now the mystery book’s nucleus has DNA, but it’s the wrong kind.
To get the romance novel to turn into a mystery and to get the somatic cell DNA to act like that of a fertilized embryo, they both have to be reprogrammed.
One of the major roadblocks to successful cloning of monkeys has until now been a reprogramming challenge. As you might imagine, once a cell decides to be one type of cell, it is difficult to make it decide to be a very different type of cell.
In a previous post on gene therapy, we learned about genes and how they can be turned on and off in different cell types, which explains how cells with the exact same genetic code can build the complexity that is the human body. For example, different combinations of genes are turned on in our skin cells than in our brain cells. These unique combinations of gene activity and inactivity make each cell type of our body unique.
Whether a gene is turned on or off is regulated by molecular flags, molecules that are added to or removed from DNA that physically mark whether a gene should be on or off.
So if the nucleus is the book cover, the words on the pages are the DNA code, and the sentences are the genes, these molecular flags are impermanent highlighted and redacted sentences, whereby a highlighted gene sentence is on and a redacted gene sentence is off. Remember that although a gene might be redacted, it is still physically there, just not read.
Therefore, each cell type is unique because is has a unique combination of highlighted and redacted genes.
So to reprogram our mystery/romance SCNT experiment, we have to erase all highlights and redactions that made the romance and make new highlights and redactions that are more suited to a mystery.
These researchers did just that. To improve the efficiency of oocyte reprogramming, they added two factors that act like the highlighter and redactor to modify the DNA flags. This changed how the DNA was marked and made it look more like a fertilized embryo. Finally, once embryos were successfully reprogrammed, they were injected into surrogate mothers who brought them to term.
Now let’s talk numbers.
The researchers began with 109 embryos generated by SCNT using fetal fibroblasts. Therefore, the monkeys that were born are clones of the original fetus from which the fibroblasts were isolated. The group transferred 79 of these embryos to the oviducts of 21 female surrogate monkeys. Of these 21, four became pregnant, and two fetuses were brought to term after 155 and 141 days. The two baby macaque monkeys, named Zhong Zhong and Hua Hua were confirmed to be clones using genetic analysis, and at the time of publication, they had lived 50 and 40 days.
There is no doubt these scientists made an incredible scientific step forward. But with all the scientific discoveries of this magnitude, it is critical to examine the implications.
Which brings me to Mary Shelley’s Frankenstein. You might have heard a lot about Frankenstein lately and that’s because it is celebrating its 200th anniversary.
Frankenstein is about a lone scientist, Victor Frankenstein, who harvests body parts from corpses, puts them together, and creates life. He is horrified by the appearance of the creature he has made and abandons it. The creature is an intelligent being and learns language and begins to understand humankind. However, when he appears to humans, they continually flee in fear. Given this treatment, he becomes vengeful and goes on to kill all whom Victor loves.
One of the questions Frankenstein asks is what is the responsibility of scientists for their discoveries and creations? This is (unsurprisingly) still a question we must grapple with today.
Now, as a scientist myself, I am all about scientific exploration as a means to discover how life works. However, we must remember that the relationship between science and the public depends on scientists taking responsibility for their creations, ensuring the public does not run in horror as they did from Frankenstein's creature. To do this, we must remain open with the public and retain their trust.
One of the questions you may be thinking is will we be able to clone humans? If we can, does that mean we should?
In a world that is quickly advancing artificial intelligence and self-driving cars, technology and science are progressing at breakneck speed. The Chinese have also genetically modified a human embryo, bringing us one step closer to curing certain genetic diseases. But this also raises the question of whether designer babies will be possible.
What used to be hypothetical questions are now facing us as real-life scenarios and we have to be ready to face them.
At what cost do we extend the boundaries of medicine? Are we ready to take responsibility for our discoveries?
What do you think about the cloning of monkeys? Share your thoughts in the comments!
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Original Study: Liu et al., Cell, 2018.