Is China Winning the Innovation Race?
Over the past two millennia, Chinese ingenuity has spawned some of humanity's most consequential inventions. Without gunpowder, guns, bombs, and rockets; without paper, printing, and money printed on paper; and without the compass, which enabled ships to navigate the open ocean, modern civilization might never have been born.
Today, a specter is haunting the developed world: Chinese innovation dominance. And the results have been so spectacular that the United States feels its preeminence threatened.
Yet China lapsed into cultural and technological stagnation during the Qing dynasty, just as the Scientific Revolution was transforming Europe. Western colonial incursions and a series of failed rebellions further sapped the Celestial Empire's capacity for innovation. By the mid-20th century, when the Communist triumph led to a devastating famine and years of bloody political turmoil, practically the only intellectual property China could offer for export was Mao's Little Red Book.
After Deng Xiaoping took power in 1978, launching a transition from a rigidly planned economy to a semi-capitalist one, China's factories began pumping out goods for foreign consumption. Still, originality remained a low priority. The phrase "Made in China" came to be synonymous with "cheap knockoff."
Today, however, a specter is haunting the developed world: Chinese innovation dominance. It first wafted into view in 2006, when the government announced an "indigenous innovation" campaign, dedicated to establishing China as a technology powerhouse by 2020—and a global leader by 2050—as part of its Medium- and Long-Term National Plan for Science and Technology Development. Since then, an array of initiatives have sought to unleash what pundits often call the Chinese "tech dragon," whether in individual industries, such as semiconductors or artificial intelligence, or across the board (as with the Made in China 2025 project, inaugurated in 2015). These efforts draw on a well-stocked bureaucratic arsenal: state-directed financing; strategic mergers and acquisitions; competition policies designed to boost domestic companies and hobble foreign rivals; buy-Chinese procurement policies; cash incentives for companies to file patents; subsidies for academic researchers in favored fields.
The results have been spectacular—so much so that the United States feels its preeminence threatened. Voices across the political spectrum are calling for emergency measures, including a clampdown on technology transfers, capital investment, and Chinese students' ability to study abroad. But are the fears driving such proposals justified?
"We've flipped from thinking China is incapable of anything but imitation to thinking China is about to eat our lunch," says Kaiser Kuo, host of the Sinica podcast at supchina.com, who recently returned to the U.S after 20 years in Beijing—the last six as director of international communications for the tech giant Baidu. Like some other veteran China-watchers, Kuo believes neither extreme reflects reality. "We're in as much danger now of overestimating China's innovative capacity," he warns, "as we were a few years ago of underestimating it."
A Lab and Tech-Business Bonanza
By many measures, China's innovation renaissance is mind-boggling. Spending on research and development as a percentage of gross domestic product nearly quadrupled between 1996 and 2016, from .56 percent to 2.1 percent; during the same period, spending in the United States rose by just .3 percentage points, from 2.44 to 2.79 percent of GDP. China is now second only to the U.S. in total R&D spending, accounting for 21 percent of the global total of $2 trillion, according to a report released in January by the National Science Foundation. In 2016, the number of scientific publications from China exceeded those from the U.S. for the first time, by 426,000 to 409,000. Chinese researchers are blazing new trails on the frontiers of cloning, stem cell medicine, gene editing, and quantum computing. Chinese patent applications have soared from 170,000 to nearly 3 million since 2000; the country now files almost as many international patents as the U.S. and Japan, and more than Germany and South Korea. Between 2008 and 2017, two Chinese tech firms—Huawei and ZTE—traded places as the world's top patent filer in six out of nine years.
"China is still in its Star Trek phase, while we're in our Black Mirror phase." Yet there are formidable barriers to China beating America in the innovation race—or even catching up anytime soon.
Accompanying this lab-based ferment is a tech-business bonanza. China's three biggest internet companies, Baidu, Alibaba Group and Tencent Holdings (known collectively as BAT), have become global titans of search, e-commerce, mobile payments, gaming, and social media. Da-Jiang Innovations in Science and Technology (DJI) controls more than 70 percent of the world's commercial drone market. Of the planet's 262 "unicorns" (startups worth more than a billion dollars), about one-third are Chinese. The country attracted $77 billion in venture capital investment between 2014 and 2016, according to Fortune, and is now among the top three markets for VC in emerging technologies including AI, virtual reality, autonomous vehicles, and 3D printing.
These developments have fueled a buoyant techno-optimism in China that contrasts sharply with the darker view increasingly prevalent in the West—in part, perhaps, because China's historic limits on civil liberties have inured the populace to the intrusive implications of, say, facial recognition technology or social-credit software, which are already being used to tighten government control. "China is still in its Star Trek phase, while we're in our Black Mirror phase," Kuo observes. By contrast with Americans' ambivalent attitudes toward Facebook founder Mark Zuckerberg or Amazon's Jeff Bezos, he adds, most Chinese regard tech entrepreneurs like Baidu's Robin Li and Alibaba's Jack Ma as "flat-out heroes."
Yet there are formidable barriers to China beating America in the innovation race—or even catching up anytime soon. Many are catalogued in The Fat Tech Dragon, a 2017 monograph by Scott Kennedy, deputy director of the Freeman Chair in China Studies and director of the Project on Chinese Business and Political Economy at the Center for Strategic and International Studies. Among the obstacles, Kennedy writes, are "an education system that encourages deference to authority and does not prepare students to be creative and take risks, a financial system that disproportionately funnels funds to undeserving state-owned enterprises… and a market structure where profits can be made through a low-margin, high-volume strategy or through political connections."
China's R&D money, Kennedy points out, is mostly showered on the "D": of the $209 billion spent in 2015, only 5 percent went toward basic research, 10.8 percent toward applied research, and a massive 84.2 percent toward development. While fully half of venture capital in the States goes to early-stage startups, the figure for China is under 20 percent; true "angel" investors are scarce. Likewise, only 21 percent of Chinese patents are for original inventions, as opposed to tweaks of existing technologies. Most problematic, the domestic value of patents in China is strikingly low. In 2015, the country's patent licensing generated revenues of just $1.75 billion, compared to $115 billion for IP licensing in the U.S. in 2012 (the most recent year for which data is available). In short, Kennedy concludes, "China may now be a 'large' IP country, but it is still a 'weak' one."
"[The Chinese] are trying very hard to keep the economy from crashing, but it'll happen eventually. Then there will be a major, major contraction."
Anne Stevenson-Yang, co-founder and research director of J Capital Research, and a leading China analyst, sees another potential stumbling block: the government's obsession with neck-snapping GDP growth. "What China does is to determine, 'Our GDP growth will be X,' and then it generates enough investment to create X," Stevenson-Yang explains. To meet those quotas, officials pour money into gigantic construction projects, creating the empty "ghost cities" that litter the countryside, or subsidize industrial production far beyond realistic demand. "It's the ultimate Ponzi-scheme economy," she says, citing as examples the Chinese cellphone and solar industries, which ballooned on state funding, flooded global markets with dirt-cheap products, thrived just long enough to kill off most of their overseas competitors, and then largely collapsed. Such ventures, Stevenson-Yang notes, have driven China's debt load perilously high. "They're trying very hard to keep the economy from crashing, but it'll happen eventually," she predicts. "Then there will be a major, major contraction."
"An Intensifying Race Toward Techno-Nationalism"
The greatest vulnerability of the Chinese innovation boom may be that it still depends heavily on imported IP. "Over the last few years, China has placed its bets on a combination of global knowledge sourcing and indigenous technology development," says Dieter Ernst, a senior fellow at the Centre for International Governance Innovation in Waterloo, Canada, and the East-West Center in Honolulu, who has served as an Asia advisor for the U.N. and the World Bank. Aside from international journals (and, occasionally, industrial espionage), Chinese labs and corporations obtain non-indigenous knowledge in a number of ways: by paying licensing fees; recruiting Chinese scientists and engineers who've studied or worked abroad; hiring professionals from other countries; or acquiring foreign companies. And though enforcement of IP laws has improved markedly in recent years, foreign businesses are often pressured to provide technology transfers in exchange for access to markets.
Many of China's top tech entrepreneurs—including Ma, Li, and Alibaba's Joseph Tsai—are alumni of U.S. universities, and, as Kuo puts it, "big fans of all things American." Unfortunately, however, Americans are ever less likely to be fans of China, thanks largely to that country's sometimes predatory trade practices—and also to what Ernst calls "an intensifying race toward techno-nationalism." With varying degrees of bellicosity and consistency, leaders of both U.S. parties embrace elements of the trend, as do politicians (and voters) across much of Europe. "There's a growing consensus that China is poised to overtake us," says Ernst, "and that we need to design policies to obstruct its rise."
One of the foremost liberal analysts supporting this view is Lee Branstetter, a professor of economics and public policy at Carnegie Mellon University and former senior economist on President Barack Obama's Council of Economic Advisors. "Over the decades, in a systematic and premeditated fashion, the Chinese government and its state-owned enterprises have worked to extract valuable technology from foreign multinationals, with an explicit goal of eventually displacing those leading multinationals with successful Chinese firms in global markets," Branstetter wrote in a 2017 report to the United States Trade Representative. To combat such "forced transfers," he suggested, laws could be passed empowering foreign governments to investigate coercive requests and block any deemed inappropriate—not just those involving military-related or crucial infrastructure technology, which current statutes cover. Branstetter also called for "sharply" curtailing Chinese students' access to Western graduate programs, as a way to "get policymakers' attention in Beijing" and induce them to play fair.
Similar sentiments are taking hold in Congress, where the Foreign Investment Risk Review Modernization Act—aimed at strengthening the process by which the Committee on Foreign Investment in the United States reviews Chinese acquisition of American technologies—is expected to pass with bipartisan support, though its harsher provisions were softened due to objections from Silicon Valley. The Trump Administration announced in May that it would soon take executive action to curb Chinese investments in U.S. tech firms and otherwise limit access to intellectual property. The State Department, meanwhile, imposed a one-year limit on visas for Chinese grad students in high-tech fields.
Ernst argues that such measures are motivated largely by exaggerated notions of China's ability to reach its ambitious goals, and by the political advantages that fearmongering confers. "If you look at AI, chip design and fabrication, robotics, pharmaceuticals, the gap with the U.S. is huge," he says. "Reducing it will take at least 10 or 15 years."
Cracking down on U.S. tech transfers to Chinese companies, Ernst cautions, will deprive U.S. firms of vital investment capital and spur China to retaliate, cutting off access to the nation's gargantuan markets; it will also push China to forge IP deals with more compliant nations, or revert to outright piracy. And restricting student visas, besides harming U.S. universities that depend on Chinese scholars' billions in tuition, will have a "chilling effect on America's ability to attract to researchers and engineers from all countries."
"It's not a zero-sum game. I don't think China is going to eat our lunch. We can sit down and enjoy lunch together."
America's own science and technology community, Ernst adds, considers it crucial to swap ideas with China's fast-growing pool of talent. The 2017 annual meeting of the Palo Alto-based Association for Advancement of Artificial Intelligence, he notes, featured a nearly equal number of papers by researchers in China and the U.S. Organizers postponed the meeting after discovering that the original date coincided with the Chinese New Year.
China's rising influence on the tech world carries upsides as well as downsides, Scott Kennedy observes. The country's successes in e-commerce, he says, "haven't damaged the global internet sector, but have actually been a spur to additional innovation and progress. By contrast, China's success in solar and wind has decimated the global sectors," due to state-mandated overcapacity. "When Chinese firms win through open competition, the outcome is constructive; when they win through industrial policy and protectionism, the outcome is destructive."
The solution, Kennedy and like-minded experts argue, is to discourage protectionism rather than engage in it, adjusting tech-transfer policy just enough to cope with evolving national-security concerns. Instead of trying to squelch China's innovation explosion, they say, the U.S. should seek ways to spread its potential benefits (as happened in previous eras with Japan and South Korea), and increase America's indigenous investments in tech-related research, education, and job training.
"It's not a zero-sum game," says Kaiser Kuo. "I don't think China is going to eat our lunch. We can sit down and enjoy lunch together."
Scientists Are Working to Decipher the Puzzle of ‘Broken Heart Syndrome’
Elaine Kamil had just returned home after a few days of business meetings in 2013 when she started having chest pains. At first Kamil, then 66, wasn't worried—she had had some chest pain before and recently went to a cardiologist to do a stress test, which was normal.
"I can't be having a heart attack because I just got checked," she thought, attributing the discomfort to stress and high demands of her job. A pediatric nephrologist at Cedars-Sinai Hospital in Los Angeles, she takes care of critically ill children who are on dialysis or are kidney transplant patients. Supporting families through difficult times and answering calls at odd hours is part of her daily routine, and often leaves her exhausted.
She figured the pain would go away. But instead, it intensified that night. Kamil's husband drove her to the Cedars-Sinai hospital, where she was admitted to the coronary care unit. It turned out she wasn't having a heart attack after all. Instead, she was diagnosed with a much less common but nonetheless dangerous heart condition called takotsubo syndrome, or broken heart syndrome.
A heart attack happens when blood flow to the heart is obstructed—such as when an artery is blocked—causing heart muscle tissue to die. In takotsubo syndrome, the blood flow isn't blocked, but the heart doesn't pump it properly. The heart changes its shape and starts to resemble a Japanese fishing device called tako-tsubo, a clay pot with a wider body and narrower mouth, used to catch octopus.
"The heart muscle is stunned and doesn't function properly anywhere from three days to three weeks," explains Noel Bairey Merz, the cardiologist at Cedar Sinai who Kamil went to see after she was discharged.
"The heart muscle is stunned and doesn't function properly anywhere from three days to three weeks."
But even though the heart isn't permanently damaged, mortality rates due to takotsubo syndrome are comparable to those of a heart attack, Merz notes—about 4-5 percent of patients die from the attack, and 20 percent within the next five years. "It's as bad as a heart attack," Merz says—only it's much less known, even to doctors. The condition affects only about 1 percent of people, and there are around 15,000 new cases annually. It's diagnosed using a cardiac ventriculogram, an imaging test that allows doctors to see how the heart pumps blood.
Scientists don't fully understand what causes Takotsubo syndrome, but it usually occurs after extreme emotional or physical stress. Doctors think it's triggered by a so-called catecholamine storm, a phenomenon in which the body releases too much catecholamines—hormones involved in the fight-or-flight response. Evolutionarily, when early humans lived in savannas or forests and had to either fight off predators or flee from them, these hormones gave our ancestors the needed strength and stamina to take either action. Released by nerve endings and by the adrenal glands that sit on top of the kidneys, these hormones still flood our bodies in moments of stress, but an overabundance of them could sometimes be damaging.
Elaine Kamil
A study by scientists at Harvard Medical School linked increased risk of takotsubo to higher activity in the amygdala, a brain region responsible for emotions that's involved in responses to stress. The scientists believe that chronic stress makes people more susceptible to the syndrome. Notably, one small study suggested that the number of Takotsubo cases increased during the COVID-19 pandemic.
There are no specific drugs to treat takotsubo, so doctors rely on supportive therapies, which include medications typically used for high blood pressure and heart failure. In most cases, the heart returns to its normal shape within a few weeks. "It's a spontaneous recovery—the catecholamine storm is resolved, the injury trigger is removed and the heart heals itself because our bodies have an amazing healing capacity," Merz says. It also helps that tissues remain intact. 'The heart cells don't die, they just aren't functioning properly for some time."
That's the good news. The bad news is that takotsubo is likely to strike again—in 5-20 percent of patients the condition comes back, sometimes more severe than before.
That's exactly what happened to Kamil. After getting her diagnosis in 2013, she realized that she actually had a previous takotsubo episode. In 2010, she experienced similar symptoms after her son died. "The night after he died, I was having severe chest pain at night, but I was too overwhelmed with grief to do anything about it," she recalls. After a while, the pain subsided and didn't return until three years later.
For weeks after her second attack, she felt exhausted, listless and anxious. "You lose confidence in your body," she says. "You have these little twinges on your chest, or if you start having arrhythmia, and you wonder if this is another episode coming up. It's really unnerving because you don't know how to read these cues." And that's very typical, Merz says. Even when the heart muscle appears to recover, patients don't return to normal right away. They have shortens of breath, they can't exercise, and they stay anxious and worried for a while.
Women over the age of 50 are diagnosed with takotsubo more often than other demographics. However, it happens in men too, although it typically strikes after physical stress, such as a triathlon or an exhausting day of cycling. Young people can also get takotsubo. Older patients are hospitalized more often, but younger people tend to have more severe complications. It could be because an older person may go for a jog while younger one may run a marathon, which would take a stronger toll on the body of a person who's predisposed to the condition.
Notably, the emotional stressors don't always have to be negative—the heart muscle can get out of shape from good emotions, too. "There have been case reports of takotsubo at weddings," Merz says. Moreover, one out of three or four takotsubo patients experience no apparent stress, she adds. "So it could be that it's not so much the catecholamine storm itself, but the body's reaction to it—the physiological reaction deeply embedded into out physiology," she explains.
Merz and her team are working to understand what makes people predisposed to takotsubo. They think a person's genetics play a role, but they haven't yet pinpointed genes that seem to be responsible. Genes code for proteins, which affect how the body metabolizes various compounds, which, in turn, affect the body's response to stress. Pinning down the protein involved in takotsubo susceptibility would allow doctors to develop screening tests and identify those prone to severe repeating attacks. It will also help develop medications that can either prevent it or treat it better than just waiting for the body to heal itself.
Researchers at the Imperial College London found that elevated levels of certain types of microRNAs—molecules involved in protein production—increase the chances of developing takotsubo.
In one study, researchers tried treating takotsubo in mice with a drug called suberanilohydroxamic acid, or SAHA, typically used for cancer treatment. The drug improved cardiac health and reversed the broken heart in rodents. It remains to be seen if the drug would have a similar effect on humans. But identifying a drug that shows promise is progress, Merz says. "I'm glad that there's research in this area."
This article was originally published by Leaps.org on July 28, 2021.
Lina Zeldovich has written about science, medicine and technology for Popular Science, Smithsonian, National Geographic, Scientific American, Reader’s Digest, the New York Times and other major national and international publications. A Columbia J-School alumna, she has won several awards for her stories, including the ASJA Crisis Coverage Award for Covid reporting, and has been a contributing editor at Nautilus Magazine. In 2021, Zeldovich released her first book, The Other Dark Matter, published by the University of Chicago Press, about the science and business of turning waste into wealth and health. You can find her on http://linazeldovich.com/ and @linazeldovich.
Did Anton the AI find a new treatment for a deadly cancer?
Bile duct cancer is a rare and aggressive form of cancer that is often difficult to diagnose. Patients with advanced forms of the disease have an average life expectancy of less than two years.
Many patients who get cancer in their bile ducts – the tubes that carry digestive fluid from the liver to the small intestine – have mutations in the protein FGFR2, which leads cells to grow uncontrollably. One treatment option is chemotherapy, but it’s toxic to both cancer cells and healthy cells, failing to distinguish between the two. Increasingly, cancer researchers are focusing on biomarker directed therapy, or making drugs that target a particular molecule that causes the disease – FGFR2, in the case of bile duct cancer.
A problem is that in targeting FGFR2, these drugs inadvertently inhibit the FGFR1 protein, which looks almost identical. This causes elevated phosphate levels, which is a sign of kidney damage, so doses are often limited to prevent complications.
In recent years, though, a company called Relay has taken a unique approach to picking out FGFR2, using a powerful supercomputer to simulate how proteins move and change shape. The team, leveraging this AI capability, discovered that FGFR2 and FGFR1 move differently, which enabled them to create a more precise drug.
Preliminary studies have shown robust activity of this drug, called RLY-4008, in FGFR2 altered tumors, especially in bile duct cancer. The drug did not inhibit FGFR1 or cause significant side effects. “RLY-4008 is a prime example of a precision oncology therapeutic with its highly selective and potent targeting of FGFR2 genetic alterations and resistance mutations,” says Lipika Goyal, assistant professor of medicine at Harvard Medical School. She is a principal investigator of Relay’s phase 1-2 clinical trial.
Boosts from AI and a billionaire
Traditional drug design has been very much a case of trial and error, as scientists investigate many molecules to see which ones bind to the intended target and bind less to other targets.
“It’s being done almost blindly, without really being guided by structure, so it fails very often,” says Olivier Elemento, associate director of the Institute for Computational Biomedicine at Cornell. “The issue is that they are not sampling enough molecules to cover some of the chemical space that would be specific to the target of interest and not specific to others.”
Relay’s unique hardware and software allow simulations that could never be achieved through traditional experiments, Elemento says.
Some scientists have tried to use X-rays of crystallized proteins to look at the structure of proteins and design better drugs. But they have failed to account for an important factor: proteins are moving and constantly folding into different shapes.
David Shaw, a hedge fund billionaire, wanted to help improve drug discovery and understood that a key obstacle was that computer models of molecular dynamics were limited; they simulated motion for less than 10 millionths of a second.
In 2001, Shaw set up his own research facility, D.E. Shaw Research, to create a supercomputer that would be specifically designed to simulate protein motion. Seven years later, he succeeded in firing up a supercomputer that can now conduct high speed simulations roughly 100 times faster than others. Called Anton, it has special computer chips to enable this speed, and its software is powered by AI to conduct many simulations.
After creating the supercomputer, Shaw teamed up with leading scientists who were interested in molecular motion, and they founded Relay Therapeutics.
Elemento believes that Relay’s approach is highly beneficial in designing a better drug for bile duct cancer. “Relay Therapeutics has a cutting-edge approach for molecular dynamics that I don’t believe any other companies have, at least not as advanced.” Relay’s unique hardware and software allow simulations that could never be achieved through traditional experiments, Elemento says.
How it works
Relay used both experimental and computational approaches to design RLY-4008. The team started out by taking X-rays of crystallized versions of both their intended target, FGFR2, and the almost identical FGFR1. This enabled them to get a 3D snapshot of each of their structures. They then fed the X-rays into the Anton supercomputer to simulate how the proteins were likely to move.
Anton’s simulations showed that the FGFR1 protein had a flap that moved more frequently than FGFR2. Based on this distinct motion, the team tried to design a compound that would recognize this flap shifting around and bind to FGFR2 while steering away from its more active lookalike.
For that, they went back Anton, using the supercomputer to simulate the behavior of thousands of potential molecules for over a year, looking at what made a particular molecule selective to the target versus another molecule that wasn’t. These insights led them to determine the best compounds to make and test in the lab and, ultimately, they found that RLY-4008 was the most effective.
Promising results so far
Relay began phase 1-2 trials in 2020 and will continue until 2024. Preliminary results showed that, in the 17 patients taking a 70 mg dose of RLY-4008, the drug worked to shrink tumors in 88 percent of patients. This was a significant increase compared to other FGFR inhibitors. For instance, Futibatinib, which recently got FDA approval, had a response rate of only 42 percent.
Across all dose levels, RLY-4008 shrank tumors by 63 percent in 38 patients. In more good news, the drug didn’t elevate their phosphate levels, which suggests that it could be taken without increasing patients’ risk for kidney disease.
“Objectively, this is pretty remarkable,” says Elemento. “In a small patient study, you have a molecule that is able to shrink tumors in such a high fraction of patients. It is unusual to see such good results in a phase 1-2 trial.”
A simulated future
The research team is continuing to use molecular dynamic simulations to develop other new drug, such as one that is being studied in patients with solid tumors and breast cancer.
As for their bile duct cancer drug, RLY-4008, Relay plans by 2024 to have tested it in around 440 patients. “The mature results of the phase 1-2 trial are highly anticipated,” says Goyal, the principal investigator of the trial.
Sameek Roychowdhury, an oncologist and associate professor of internal medicine at Ohio State University, highlights the need for caution. “This has early signs of benefit, but we will look forward to seeing longer term results for benefit and side effect profiles. We need to think a few more steps ahead - these treatments are like the ’Whack-a-Mole game’ where cancer finds a way to become resistant to each subsequent drug.”
“I think the issue is going to be how durable are the responses to the drug and what are the mechanisms of resistance,” says Raymond Wadlow, an oncologist at the Inova Medical Group who specializes in gastrointestinal and haematological cancer. “But the results look promising. It is a much more selective inhibitor of the FGFR protein and less toxic. It’s been an exciting development.”