OMNIA Q&A: China, Cloning, and Gene Editing

In 1996, Dolly became the most famous sheep in the world, the first mammal to be cloned from an adult cell. Her arrival sparked heated debate about the ethics of cloning and that controversy has intensified with the further maturation of biotechnology. Fast forward to today. China revealed in January 2018 that it successfully cloned the first primates, two identical macaque monkeys, while The Wall Street Journal broke the story that Chinese researchers became the first to use CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) gene editing on live human subjects.

We spoke with Jonathan D. Moreno, a Penn Integrates Knowledge professor, about the promise and perils of these biotechnology advances.  Moreno is also Professor of Medical Ethics and Health Policy, of History and Sociology of Science, and of Philosophy, as well as the organizer of the Penn Bioethics Film Festival taking place March 20-22, 2018.

China has now cloned macaque monkeys, becoming the first to clone a primate. What was the process they used to accomplish that?

Chinese researchers made these monkeys in a similar same way to how Dolly the sheep was produced, but with an important difference. Dolly was produced from an adult cell without the nucleus that was plopped into an egg cell that had its nucleus removed. These monkeys were made from the embryos of fetal tissue cells because the researchers couldn’t manage it using the DNA from the adult cells of the adult macaques. It’s more complicated when you get into primates. But, this group in China figured it out, according to their report.

Why is cloning often considered so controversial?

Cloning for reproduction is dangerous. In the case of Dolly, it took hundreds of tries and dozens of sheep, embryos, and fetuses before she was created. In China, they lost a lot of monkeys in the process. There is no question that they will refine this and make it more efficient. That’s already been done in the case of farm animals. So, it will, unfortunately, give us more understanding of how we might be able to do it with higher primates. However, you would still, in that process, surely have dozens of anomalous human fetuses and dozens of dead women. That is why many people have continued to say you will never see a cloned human being. However, the fact that they’ve got these genetically mostly identical macaques doesn't mean they can’t do all kinds of interesting experiments and compare their reactions—from neurological to behavioral. That could, without a doubt, have scientific value.

What are some of the potential medical research applications of cloning primates?

Everyone is trying to figure out how to get back on course with Alzheimer’s because, at this point, people are sort of throwing their arms up. People don’t understand the mechanisms with Alzheimer’s. Researchers got preoccupied with plaques and tangles for years: are they the cause or an effect? Unfortunately, knowledge has not led to any kind of drug discovery.  So, now, they’ve got these cloned animals to research. However, let’s remember that cloned animals are less identical than human identical twins. This is because human identical twins share the mitochondrial DNA. These clones do not.

If the mitochondrial DNA is not the same, does that have implications for the research?

People don’t know. Back in high school, I was taught that the mitochondria is the battery pack of the cell and that’s pretty much all it does. Turns out there’s more to it than that. Now, we know there are mitochondrial disorders. One thing about cloning is you can’t clearly avoid transmitting mitochondrial disorders, which are really bad because of neurological disorders.

China also became the first to use CRISPR gene editing on live human subjects. What is CRISPR gene editing?

There have been ways to “recombine” genes since the mid-70s. However, about 10 years ago, researchers discovered that there is an ancient system that bacteria have used to protect themselves from viruses. That system can be used in laboratories to insert, move, and delete DNA. This is commonly called CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) gene editing and it’s the most efficient way found to move and remove DNA in genes and chromosomes. It’s also relatively inexpensive and easy for teams of researchers to learn how to do.

How is CRISPR being used?

There are two general areas of this work: “gene editing,” which applies to medical purposes and research, and “gene drive,” which actually might be more important and high impact in the short run. Gene drive has to do with the modification of genes to eliminate the spread of unwanted genes in insects, agricultural pests, or potentially, anything that reproduces sexually in the wild. For example, in theory, the genes of the mosquito population could be modified in such a way as to ameliorate the spread of diseases like malaria, the Zika virus, and yellow fever.

What could be the impact if labs widely adopting the CRISPR technology?

When people realized the power of this new gene editing technology and saw how rapidly it was being picked up by laboratories, the scientific community decided it needed to have a large meeting to talk about the implications. That meeting took place in December of 2016--a summit with the U.S. National Academy of Sciences, the Chinese Academy of Sciences, and the U.K. Royal Society. As a result of that meeting, the U.S. National Academy of Sciences appointed a committee to write a report on the implications of CRISPR. That report took about a year to produce and made the important distinction between using CRISP technology to edit genes for somatic cells, or the cells of an individual, versus editing germline cells that affect the DNA of all of a couple’s descendents, which is far more controversial.

What did the report findings say?

Basically, it was decided that somatic cell gene editing is a gene therapy that doesn’t raise any new regulatory issues. So, even though CRISPR is a new technology, for purposes of somatic cell gene editing, the regulation, ethics, and governance remain the same. More controversial is modifying human germ cells. For example, let’s say you had BRCA 1 or 2 in your DNA. You’ve had close female relatives with breast cancer or male relatives with prostate cancer. You really want your future children not to have that problem. So, you and your partner decide to make embryos in a laboratory dish and have BRCA 1 and 2 edited out. Then, you put the edited embryos back in the uterus and have normal gestation and delivery.

This may sound like a great idea, but technically, it's easier to talk about than do. There could be lots of errors. Even if you could successfully do it, what else could happen to the genome of your descendants? Maybe there is something about the genome or organism that, when taken out, changes something else. Not to mention, of course, the more symbolic philosophical issue about whether it's appropriate to modify our descendants.

Germ line editing is the over-the-horizon stuff that gets us into eugenics, which makes people incredibly nervous. What if this technology is used to not only end disease but make “improvements” to an embryo by making a future child smarter or taller? The report concluded that there’s just no good justification for using resources to do germ line editing in human embryos in pursuit of “enhancements,” although they didn’t rule out the possibility of editing for heritable diseases in the future.

What did China recently do with CRISPR gene-editing and why has it created a stir?

The Chinese jumped over the somatic cell standards and tried to edit the body cells of cancer patients and put them back in. It’s not necessarily a surprise that China would leapfrog over the international standards. We’ve known from the stem cell era a dozen years ago, that this kind of biotechnology is poorly regulated in China. What China did with gene editing would not be acceptable in the United States.

What have the results been thus far?

Of the 86 patients they did this with, it’s been reported that at least 15 have already died. The director of the clinic says the deaths have nothing to do with the gene editing, rather, any problems were because of the patients’ disease. In my opinion, the big problem is that these patients could have gotten some other intervention to relieve their suffering. This is probably a distraction from what could have kept them more comfortable. 

What do you think is the biggest news in the gene editing space right now?

The big news in gene editing is that the NIH has committed $190 million dollars to improving the tools for gene editing, while people are continuing to figure out how to make sure that people are playing by the rules. The larger picture is that China is on the hunt. Their GDP is going to surpass ours, probably by 2030, and they recognize that science and biotechnology are part of their future. They have an advantage. Their system of state- sponsored companies that are quasi-private and quasi-public are proving to be far more agile than the old Soviet communist system that had so much trouble innovating. They can make a lot of things happen and are very ambitious. They continue to send some of their best and brightest to places like Penn but now they have the resources to bring those students back to China.  Our challenge will be to work with them so that it’s not a zero-sum game. It’s going to be interesting to watch.

What do you see happening with this technology 25, 50, 75 years down the road?

A lot is going to end up in targeted therapies or personalized medicine. If we don’t run up against big biological obstacles, in the next 20-30 years, there will be various approaches to figure out not only your own genetics, but the genetics of your children, and how DNA can be exploited for new therapies to help you.  But then we will have to have an insurance system so that benefits are fairly distrbuted to those who need them.  Politics often turns out to be harder than science.