Monkey A6 is not having a good time of it. The male macaque is being videoed by researchers and has retreated to the corner of his steel cage, burying his head in his hands.
The unfortunate primate is the subject of an experiment that has removed a gene called BMAL1, which makes him prone to the monkey version of human psychiatric disorders, including depression and anxiety.
Is China breaking ethical rules to become a science superpower? And might the West need to relax its own rules to keep up?
“Monkey A6 exhibited particularly strong fear and anxiety, showing clear avoidance of the care personnel,” reports an article detailing the experiment.
The study, published by Chinese researchers in January, has two features that are putting Chinese science in the spotlight like never before.
First, it is right at the cutting edge of biomedicine.
The macaque was one of five cloned from a single monkey, gene-edited to lack BMAL1, the first time this has been done. In fact, China is the only country to have cloned primates at all, announcing the birth of identical long-tailed macaques Zhong Zhong and Hua Hua in January 2018.
Second, the experiment hovers near a precarious ethical line that many think shouldn’t be crossed. British professor of Animal Welfare and Ethics Andrew Knight called it “disturbing news”.
But it also comes hot on the heels of November’s “CRISPR baby scandal”, in which Chinese scientist He Jiankui used the gene-splicing technology to create the world’s first genetically modified humans, twins Lulu and Nana. His actions sparked a global outcry and were labelled by the World Health Organisation as “irresponsible”.
An analysis in the journal Nature in June found the gene tweak, aimed at making the twins resistant to HIV, may have shortened their life expectancy.
Such advances are raising troubling questions. Is China breaking ethical rules to become a science superpower and, in the process, turning into what some have dubbed the biomedical “Wild East”? More worrying still, might the West need to relax its own rules to keep up?
Jing-Bao Nie is a professor of Bioethics at the University of Otago in New Zealand, and was co-signatory to a March article in Nature that called for a global moratorium on the making of babies from gene-edited embryos in the wake of the He scandal.
Nie has been a vocal critic of He in US ethics journal The Hastings Center Report. But in a Skype interview, he is quick to point out that more than 100 Chinese researchers joined the world in condemning He’s actions.
Nie also says the three main Chinese philosophical traditions – Buddhism, Confucianism and Daoism – place ethical limits, to varying degrees, on the kind of research that can be done with animals.
“There is a kind of assumption that Chinese culture somehow gives a green light to those kinds of activities,” Nie says. “Those are really often misconceptions.”
But Nie confirms there are factors that might pull research ethics down a few rungs in China.
“There is a nationwide push for China to become a superpower in science and technology. The government’s efforts could benefit Chinese people and humankind greatly, but in time ethics and moral considerations may become secondary,” he says.
That push to science superstardom is yielding dividends. Last year China overtook the US as the world’s largest producer of scientific papers. And it is propelled, says Nie, by a number of key traits in Chinese culture.
Scientism, a veneration of science as key to social progress, is widespread. Anti-traditionalism, celebrated annually in the May 4 movement, elevates science and even democracy over traditional Confucian values such as “filial piety” – respect for parents and ancestors. And there is another popular attitude in China which has a disturbing resonance in the West.
“He Jiankui’s experiment is part of the eugenics discourse,” says Nie.
“Even though He called his experiment a therapy, it was a eugenic effort. To cause Lulu and Nana to have genetic resistance [to HIV] is to enhance their genetic makeup rather than treating any existing genetic disease,” he says.
The Chinese phrase for eugenics is you sheng xue (literally “the science of superior birth”) which is, says Nie, a much more positive concept in China. Could you sheng xue make Chinese people more receptive to monkey harms that benefited humans? Nie gives an emphatic “yes”.
Those potential harms hit the headlines again in April when a team, led by Bing Su at the University of Chinese Academy of Sciences in Beijing, bred monkeys with the human gene MCPH1. The change slowed their brain maturation, mimicking what happens in humans, and led to better memory and faster reaction times.
I asked David Hunter, associate professor of Medical Ethics at Flinders University in Adelaide, whether these monkey experiments are ethical.
“In my view, and it’s my personal view, it probably is unethical”, says Hunter. “It is certainly very, very close to the line of stuff that we ought to be quite troubled about.”
Hunter spells out something of a grim paradox in non-human primate research. You want a model of disease that is close enough to humans to make finding the cause or a cure a real possibility; monkeys are clearly better than mice. But the closer something gets to a human, the closer it gets to having a human’s moral status.
“A large part of the reason we think humans have moral status or moral standing has to do with them being thinking, rational, feeling beings,” says Hunter.
To the extent that non-human primates can think and feel, explains Hunter, experimenters are left with an unpleasant question. “Are you basically testing this on humans by proxy?” he says.
Bing Su defends the human gene experiments in his article, writing that the rhesus monkeys used are distinct from humans by a “relatively large phylogenetic distance (about 25 million years of divergence from humans)”. This, he says, “alleviates ethical concerns”.
Hunter is not so sure. He calls it a “category error”.
“The category error is thinking that it is genetic closeness to humans that is what gives something moral status,” he says. Rather, says Hunter, it is that creature’s capacity to think and feel that really matters.
“Once you start commodifying things that are close to people, it’s really easy to move from that to commodifying people,” says Hunter.
It is an observation with relevance to other fears about Chinese science.
In 2015 Chinese scientists created beagles Hercules and Tiangou, the world’s first gene-edited dogs, using CRISPR to alter a gene that made them ultra-muscly. One group in particular is very keen to know if that could ever work in humans.
A 2017 article, published by US think tank the Atlantic Council, quoted Pierre Noel, now medical director of the Mayo Clinic Center for Military Medicine, who said gene editing could in future be used to “to design … super soldiers … with great muscle force and strength”.
The author of that article was Brent Eastwood, a professorial lecturer at George Washington University’s Elliott School of International Affairs. Eastwood is hawkish on science as a tool of Chinese military ambition.
“Pure research for the sake of knowledge-building has changed in China to developing technology for aspirations such as soldier survivability. They want research to be adapted into military doctrine, hit the battlefield, and get down to the individual soldier,” Eastwood said in an email.
I asked Eastwood if Chinese science advances should be viewed by other countries as a military threat. He answered: “Yes. They have the ambitious biomedical strategy, the leadership, the military objectives, the means … that’s a recipe for dominance in synthetic biology that can lead to … a huge advantage on the battlefield.”
Indeed US international affairs academic Caroline Wagner, writing recently in The Conversation, has said that “military advancement and science and technology discovery are symbiotically linked”. In China’s case, she writes, that centres on AI and supercomputing.
Hard evidence of any such program in Chinese military medicine is, however, hard to come by.
Associate Professor Hallam Stevens, a historian of science and technology at Nanyang Technological University in Singapore, sees evidence for two goals in Chinese bioscience, neither of which is military.
“They want a healthy population and they want to try to ensure that health remains as strong as possible,” says Stevens.
“The other thing is really food. They have a very large population to feed … when people don’t have enough to eat, governments fail … so this is genetically modified foods that will continue to feed the Chinese population through the 21st century,” he says.
Since 2014 Stevens has been visiting genomics company BGI, located in Shenzhen, as research for a forthcoming book. From its inception in 1999 to 2001 BGI helped in the momentous mapping of the human genome and is now the world’s biggest genome sequencing facility, with offshoots in 66 countries including Australia.
But the organisation has also pushed its own ethical lines.
In 2012 it began a program to sequence the genomes of more than a thousand US maths whizzes, looking for the genetics of genius. The study was hit by allegations it was engineering “genius babies” and oversimplifying the origins of intelligence. Amid unwelcome press attention, including Dutch documentary DNA Dreams, which painted BGI as something of a dystopian eugenics nightmare, the research stalled.
Stevens says BGI has generally dragged its heels bringing ethics oversight up to scratch. It was only in 2011 that it convened an institutional review board to oversee the ethics of experiments, something that is standard in Western research facilities. Stevens also says their approach to informed consent has been sub par.
“I think, especially in the early days, that probably some of their work did not conform to the kind of structures that exist in the West,” he says.
It’s a difference of approach that may reflect a broader Chinese disconnect with Western medical ethics, something Stevens has experienced firsthand.
“I’ve been to the doctor in China and it’s a pretty amazing experience. The door is never closed,” says Stevens, of his visit to a clinic on a university campus. “You stand in line. The doctor is there and the door is a couple of feet away and the door is open. And there is a whole line of people waiting for their turn. There is a different sense of privacy.”
If Chinese science is advancing on the back of more permissive ethics, there are also voices suggesting excessive regulation in the West may leave it a bioscience laggard.
In early June the US reaffirmed its ban on creating heritable “germline” changes in embryos, the kind engineered into Lulu and Nana. It is a ban that prompted two US scholars, writing in the journal Science in 2016, to say that without a course correction, “the United States is ceding its leadership in this arena to other nations”.
But in a possible sign of East-West convergence on the issue, ethics oversight in China has tightened since the He incident. In February China’s National Health Commission issued draft regulations that require gene editing of embryos to get its approval. And in May four Chinese bioethicists called for a “reboot” of biomedicine regulation to protect people from “the potential effects of reckless human experimentation”.
Amid all this, what is the view from the laboratory floor in China?
Erwan Bezard is Director of Research at the Institute of Neurodegenerative Diseases at the University of Bordeaux in France. Bezard has been visiting China, where he has his own lab at the Chinese Academy of Medical Sciences in Beijing, for 20 years.
“I needed to work on a large number of monkeys,” says Bezard. “You need to be sure that the answer that you are going to provide is sound, and for the answer to be sound you need to involve a number of individuals that is statistically relevant.”
In fact, says Bezard, experiments on just one or two animals are more likely to be unethical because, without generating results that are statistically significant, the animals have been used in vain.
Apart from Mauritius, China is the only country with sufficient animals to make the research possible. Bezard said Mauritius, where around half the population are Hindu, wouldn’t permit monkey research for religious reasons.
His own lab in Beijing follows European Union regulations and he says many other labs in China follow US animal welfare guidelines. Many too, says Bezard, have a ritual that is quite separate from any formal regulation.
“I was puzzled, around 2005, when I noticed that in several research institutions there was always a small yard … with a few trees and one carved stone. And the stone features three or four Chinese characters painted in red. One day I asked ‘what is it?’,” says Bezard.
The stone, he was told, was a memorial to the animals used in research.
Bezard’s ethical concern focuses away from the animals. If China is now the world’s science paper supremo, fakery is also rife; in 2017 the journal Tumor Biology retracted 107 articles, all from Chinese researchers, setting an ignominious world record.
“One way of enforcing the Western view of ethics for the Chinese will be really to change the way they promote the researchers,” says Bezard. “In China … your income is directly linked to the number of papers you publish and to the impact factor of papers.
“If they don’t deal with that they will have huge ethical issues in animal research and science ethics in general. It is a clear open door for manipulating and forging results,” he adds.
China put in place a raft of reforms last year aimed at stamping out scientific misconduct, including a blacklist that would preclude dodgy researchers from future funding or research positions.
In the meantime Chinese research keeps heading into places we’ve never been. In that Dutch documentary, BGI chairman Yang Huanming gives a speech while, behind him, a slide bears a quote from the company’s president Jian Wang. “There is another sky above the sky,” it reads.
As things stand, Chinese researchers may well be first to break through the firmament.
Credit to: Paul Biegler
Sources: the Sydney Morning Herald