Editing Humanity: The CRISPR Revolution and the New Era of Genome Editing

CHAPTER 15 THE BOY FROM XINHUA

The most common picture conveyed by the media of the unheralded scientist at the center of the #CRISPRbabies firestorm was that of a modern-day Victor Frankenstein, an unscrupulous rogue operator secretly experimenting on human embryos in his underground lair surrounded by flasks of colorful bubbling liquids and galvanic sparks of electricity. In other narratives, He Jiankui was a 21st century Sorcerer’s Apprentice, naïve, ambitious, reckless, and hopelessly out of his depth. But as more details emerged about JK’s confidants and movements leading up to 2018, we glimpsed a more complex, nuanced narrative. As one Chinese commentator suggested, “the story that emerges is more Elizabeth Holmes”—the disgraced founder of Theranos—“than Dr. Frankenstein.”¹

So who is He Jiankui and where did he come from?

He Jiankui was born in 1984, of all years, in Xinhua, a small village in central Hunan province in southern China where the average income was just $2 a week. His parents were both farmers, working in the fields bordering the Yangtze river. In the summers, JK would have to pick leeches off his legs while helping his parents. He shone academically and attended the best high school in the region.² Poor and with no political connections, his only way out was to excel in the gaokao, China’s punishing college entrance exam held over two consecutive days each June. He earned a coveted spot at the University of Science and Technology of China (USTC) in Hefei, the “Caltech of China.” With some 30 percent of graduates continuing their education abroad, USTC earned another nickname: “United States Training Center.”

JK enrolled at USTC in the summer of 2002, one year after the publication of the first draft of the human genome sequence. He wasn’t able to enroll in his first-choice program, but after a freshman year in the Department of Precision Machinery and Precision Instrumentation, he transfered to modern physics. His father bragged to the Chinese media that his son always came top of his class (although this may not be entirely true). Whenever JK came home, “everyone wanted to meet him and hear his tips for good grades.”³

In 2006, scholarship in hand, JK joined the flock of migrating USTC graduates heading to America, winning a PhD slot in the bioengineering program at Rice University in Houston. JK’s interests were shifting to the life sciences, believing that the golden age of physics had passed. He joined the lab of Michael Deem, who had studied at the real Caltech. Deem’s ambition was to define an example of Newton’s famous F=ma equation for biology. His diverse research interests—genetic engineering, mathematics, physics, and astronomy—suited JK. Together they coauthored five papers published in various physics and biology journals on an eclectic range of subjects, including the hierarchical evolution of animal body plans; the impact of globalization and recessions on the world trade network; and a computational analysis of emerging flu strains to guide vaccine development, another of Deem’s principal interests.

It was during his PhD that JK got his first taste of CRISPR—Deem and JK published a mathematical model of CRISPR arrays in 2010 in a respected physics journal. The paper, which had nothing to do with gene editing, featured lots of advanced mathematics that went over my head, including the Lebowitz-Gillespie algorithm, Latin hypercube sampling, and the Shannon entropy.⁴ Three months later, there was a double celebration. JK was awarded his PhD for his thesis, “Spontaneous Emergence of Hierarchy in Biological Systems,” completed in very quick time. And he got married to Yan Zeng in the Rice University Chapel. A local Chinese-language newspaper, the Southern Chinese Daily News, covered the nuptials under this headline: “With outstanding morals, excellent academics, and infinite potential, a union for life complete with both good looks and scholarly talent.”

Soon thereafter, JK and his new bride moved to the Bay Area, where JK took up a postdoctoral position at Stanford University with leading biophysicist Stephen Quake, the entrepreneurial cofounder of a string of biotech companies including publicly traded Fluidigm, Verinata Health, a non-invasive prenatal testing (NIPT) platform, and a next-generation sequencing (NGS) company called Helicos.⁵ One colleague said Quake was “out to hunt death down and punch him in the face.”⁶ After developing the technology for a new NGS instrument, the Heliscope, Quake volunteered to be one of the first people to have his genome fully sequenced for an estimated $50,000.⁷ He posed for the cover of a biotech magazine in front of the state-of-the-art instrument,⁸ while a paper on the Quake genome, aka “Patient Zero,” appeared in the Lancet.⁹ His colleague Euan Ashley told Quake that he carried a gene that predisposed him to cardiomyopathy, but Quake wasn’t comfortable following all the well-intentioned medical advice. “We still haven’t found the compliance gene,” joked another colleague, Atul Butte.¹⁰

NGS, Quake said, was a cross between a microscope and a washing machine. Helicos was based on a proof-of-principle report that Quake published in 2003, describing the sequencing of “a ridiculously small” string of bases—four to be exact—along a single molecule of DNA. The article was spotted by a biotech entrepreneur named Stanley Lapidus, who flew out to San Francisco to persuade Quake to build a company around this embryonic single-molecule sequencing technology.

Five years later, Lapidus’ company had built a prototype “DNA microscope” and set course to take on the market leader, Illumina. But the Heliscope was a monstrous slab of hardware—some customers had to reinforce their lab floors to accommodate the instrument—with an equally hefty $1 million price tag to match. Worse, there were chemistry glitches that compromised accuracy. Helicos went public in 2007 but that too was a miscalculation. “We were trying to IPO with no revenue. We got killed!” recalls Steve Lombardi, who succeeded Lapidus as CEO.¹¹ By the time JK arrived at Stanford, Helicos was delisted from Nasdaq and shedding staff—a rare defeat for Quake.

Another Quake innovation would have a direct bearing on JK’s future path. In 2008, graduate student Christina Fan led an NGS study to survey the cell-free (cf) DNA in maternal blood to measure the relative contribution of each chromosome. By literally sampling millions of free-floating DNA fragments, she could diagnose cases of trisomy 21 (Down syndrome) and other chromosomal disorders or aneuploidies.¹² This breakthrough—similar results were reported by Dennis Lo and colleagues in Hong Kong—gave birth to the technology of NIPT. Quake’s spin-out, Verinata Health, was later acquired by Illumina.

JK spent twelve months in the Quake lab, working mostly as a computational biologist, publishing a paper on the sequence analysis of genes in the immune system.¹³ But he didn’t have to wait long before he landed a golden opportunity to return to his homeland. In late 2011, JK met Zhu Qingshi, the former president of USTC, during a recruiting trip. Zhu had been named founding president of an ambitious new private university in Shenzhen modeled on Stanford—the Southern University of Science and Technology, or SUSTech.

JK returned home on the wings of the Peacock Plan, a multimillion-dollar program to attract outstanding talent to Shenzhen. (The name comes from an old Chinese proverb, “The peacocks fly to the southeast.”) JK announced the “He Jiankui and Michael Deem Joint Laboratory” on his blog before he’d even left Stanford, along with the SUSTech Gene Sequencing Center, which would feature “a world-class next-generation DNA sequencing platform.”

The location of SUSTech in Shenzhen, neighboring Hong Kong, was significant. Just twenty-five years earlier, Shenzhen had been little more than a fishing village. In 1980, the Chinese government declared Shenzhen an economic prosperity zone. The subsequent expansion has been astonishing: today, Shenzhen is a sprawling city of 20 million people, dominated by high-tech, manufacturing, and China’s largest genomics company, BGI (formerly the Beijing Genomics Institute).

BGI was officially born in September 1999—or more precisely, at “9 seconds past 9 minutes past the 9th hour of the 9th day of the 9th month of the 99th year of that century,” as the founding chairman Yang Huanming told me several years ago.¹⁴ We met following a party at Boston’s famous tourist spot—the Cheers pub—to mark the opening of BGI’s operations in the United States. The cultural entertainment included a sand painter, artfully sculpting pictures in sand on an overhead projector, charting the course of history from the big bang to the birth of BGI. The institute had grown from a bit player in the international Human Genome Project supplying about 1 percent of the total genome sequence, to one of the world’s genomics powerhouses. BGI deciphered the rice genome in 2002 and six years later published the genome sequence of the first Asian person, an anonymous individual named “Y.H.” (“If someone says it’s me, it’s a rumor,” Yang smiled.)

Under the leadership of Yang, president and cofounder Wang Jian, and a talented young bioinformatician, Wang Jun, in 2011 BGI bought a fleet of 130 Illumina NGS instruments to establish the world’s largest genome sequencing center in Hong Kong.¹⁵ BGI compiled a “genomic zoo” of plant genomes, including rice, cucumber and soybean, and animals, including the honey bee, silkworm, and of course, China’s beloved giant panda.¹⁶ The secret to BGI’s success—apart from quality, speed, and price—was scale. “We must be the biggest,” Yang said.

In 2013, BGI became the first Chinese organization to buy an American public company when it acquired Complete Genomics, a San Francisco–based company with its own NGS technology, which now features in a new spin-off. This company, MGI, has released its own benchtop sequencer that has quickly attained a domestic market share approaching 50 percent, and in 2020 announced it had reached the “$100 genome.”¹⁷

In addition to pushing into the clinical market, BGI embarked on a Cognitive Genomics project, in collaboration with Michigan State physicist Stephen Hsu, to investigate the genetics of cognition and intelligence. The controversial project has since been shelved, but it epitomizes Wang Jian’s attitude to the genetics market. In the West, “you have a certain way,” Wang said. “You feel you are advanced and you are the best. Blah, blah, blah.” Wang has no interest in following the fussy rules and regulations decreed by American institutes and think tanks. “You need somebody to change it, to blow it up,” Wang said. “For the last five hundred years, you’ve been leading the way with innovation. We are no longer interested in following.”¹⁸

That spirit and resolve was infectious. Whether studying the genetic basis of intelligence or running experimental clinical trials or editing human embryos, Chinese scientists were determined to push the envelope, with little concern for the cultural, ethical, or regulatory strictures that might govern such endeavors in the West.

With BGI dominating the genomics landscape in China, Shenzhen was a dynamic location for an ambitious young researcher looking to make his mark both in academia and business. JK was lavished with millions of dollars’ worth of government funding—$5 million in 2016 alone.¹⁹ “Shenzhen has transformed itself from labor-intensive industry to high tech,” JK told my former colleagues at Bio-IT World in 2015. “The government has ambitions. They’re trying to switch from ‘Made in China’ to ‘Invented in China.’ ”²⁰

Part of that reinvention was to retool the dormant Helicos sequencing technology following the company’s demise in 2012. While a Boston company called SeqLL bought up Helicos’s hardware in a fire sale, JK licensed Quake’s intellectual property to build a new company. Following in BGI’s footsteps, he aimed to release a domestic DNA sequencer deployed in Chinese hospitals addressing domestic health problems, servicing the largest population in the world.

To assist with the company’s launch, JK contacted HDMZ, an American PR company that had produced a magazine article on sequencing technology for Nature. The company’s director of science communications, Ryan Ferrell, flew to Shenzhen in 2015. JK’s preferred name for the company was Public Genomics, which signaled its aim to serve the Chinese people. But the leadership team voted for Direct Genomics, or Hanhai in Chinese. “We’re a new generation of entrepreneurs,” JK said. “We’ve had great discussions with the Chinese FDA… They really hope our Chinese brand could be used in hospitals.”²¹

JK invited Deem, his PhD mentor, to become a scientific advisor. He redesigned the Helicos platform so that the target enrichment for a simple diagnostic test could occur on the same flow cell that performed the DNA sequencing. With improved optics, lenses, and cameras, his company shrank the sequencer from the size of an industrial fridge to a portable dehumidifier, and named it the GenoCare analyzer.

In December 2015, JK posted a photo on WeChat, the ubiquitous Chinese social media platform, taken next to prototype instruments alongside Deem and Quake, everyone wearing lab coats and disposable booties. He also persuaded Helicos’s former chief science officer, Bill Efcavitch, to join the advisory board. JK and Deem traveled across China surveying the exploding clinical market. The GenoCare still suffered some limitations, but in specific applications such as searching for cancer gene mutations or hepatitis, JK was confident the technology would suffice. Others were skeptical: “The company is just dodging GenoCare’s faults as a sequencer by picking clinical targets where its flaws are irrelevant,” Bio-IT World concluded.²²

Later that year Quake called Lombardi, who had moved to Connecticut and launched a consulting business after Helicos folded, to see if the former CEO would like to serve as JK’s business mentor. For the next two years, Lombardi helped JK manage the financial and strategic aspects of growing his company. He introduced him to some leading Wall Street analysts covering genomics. “He bought my rolodex,” Lombardi told me.²³ In July 2017, JK proudly posed for photographers next to the prototype GenoCare at the instrument’s official debut in Shenzhen. The launch of the world’s first “third-generation sequencer” featured congratulatory speeches by various government dignitaries and senior Chinese scientists. By 2018, the company had raised nearly $35 million and claimed to be manufacturing 1,000 instruments a year to meet burgeoning demand.

All very impressive, as was JK’s involvement in several other business ventures, including a liquid biopsy company called Vienomics. But apparently it was not enough. Like Icarus, the son of a master craftsman, the boy from Xinhua was setting a course perilously close to the sun.

A few months after the furor surrounding the first Chinese embryo editing study in 2015, the British government granted its official seal of approval to a very specific form of germline editing called mitochondrial replacement therapy (MRT). Sometimes called “three-parent IVF,” MRT was pioneered by Douglas Turnbull at the University of Newcastle. His inspiration was meeting Sharon Bernardi, a mother from nearby Sunderland, who had buried seven children in three different cemeteries because of a mitochondrial disease called Leigh syndrome. Her fourth son Edward lived until twenty-one, but was often writhing in pain. “I don’t want my son to have just died for nothing,” Bernardi said. “We’re trying not to pass it on to children and make it better for future families.”

Mitochondria are the capsule-like power-stations inside our cells that create adenosine triphosphate, ATP, the molecule that provides energy for myriad cellular processes. Mitochondria contain a tiny circular piece of DNA, almost insignificant compared to the size of the nuclear genome, encoding just a few dozen genes—less than 0.2 percent of the human genome. But just like the 20,000 or more genes on our twenty-three pairs of nuclear chromosomes, these mitochondrial genes can suffer damaging mutations. These mutations result in a range of debilitating, sometimes hard-to-diagnose genetic diseases, including Leigh’s disease, that affect 1 in 5,000 births. Importantly, mitochondria are only inherited through the maternal line. That means if the mother has a mitochondrial disorder, she will inevitably pass it onto her children, boy or girl.

Designed to help at-risk pregnancies, MRT is a modified version of IVF. Before fertilization, the nucleus of an egg from the affected mother is swapped into an enucleated egg from a donor that has healthy mitochondria. Following IVF, the resulting embryo can claim three parents—the complete set of twenty-three chromosomes provided by both father and mother plus the smidgeon of mitochondrial DNA from the woman who donated the hollowed oocyte. (If you want to get mathematical about it, it’s not so much “three-parent” as “2.001 parent.”)

In October 2015, the British parliament became the first country to legalize MRT with the passage of the Human Fertilization and Embryology Act. With almost fifteen years of research and preparation in the balance, Turnbull was understandably stressing out in the public gallery when the House of Commons voted on the bill. As the vote totals were announced showing comfortable passage, cheers of delight burst out from Turnbull’s guests, patients, and family members, followed by tears of relief. The bill was ratified in the House of Lords, where Viscount Matt Ridley voiced his support. “Britain has been the first with most biological breakthroughs. In every case we look back and see we did more good than bad as a result,” he said. Failure to act to prevent suffering would be on their consciences, adding: “There is nothing slippery about this slope.”²⁴

But there were still regulatory hurdles to overcome before the first clinical experiments could take place. In April 2016, the world’s first “three-parent” baby boy was born to Jordanian parents in Mexico City. The mother had lost two children and suffered four miscarriages because of Leigh’s disease. John Zhang, a Chinese-born, British-educated fertility expert based in New York, performed the spindle nuclear transfer procedure that produced five embryos. Only one developed normally, which Zhang implanted. He defended his decision to do the procedure in Mexico, saying “to save lives is the ethical thing to do.”²⁵

Through his spin-off company, Darwin Life, Zhang attempted to offer a similar service for older women to transfer the nucleus into the egg cells of a younger woman. The FDA quickly stepped in, citing a 2015 Congressional amendment that forbids the agency from considering applications in which a human embryo is deliberately created or modified to include a heritable genetic modification. Zhang’s company complied but he still believes that germline editing will be useful in the future. Any technology that will eventually benefit humankind should be allowed, he told the Washington Post. “Look at history: People were against antibiotics, general anesthesia, vaccines.”²⁶ Zhang has partnered with a Ukrainian physician, Valery Zukin, as reports of MRT babies in countries like Ukraine and Greece continue.^{27 28}

Turnbull and his colleagues weren’t overly upset by Zhang’s scoop. “The translation of mitochondrial donation to a clinical procedure is not a race but a goal to be achieved with caution to ensure both safety and reproducibility,” said Alison Murdoch.²⁹ In 2018, the British Government’s Human Fertilization & Embryology Authority (HFEA) granted permission for the first MRT procedures to take place for two women. Within twelve months, a dozen more applications were approved. We await news of the first pregnancy.

Meanwhile, using philanthropic funds, Dieter Egli at Columbia University has used MRT to create “three-parent” embryos for several women with mitochondrial disorders. Those embryos remain frozen in legal limbo until US regulations change,³⁰ either through legislation or possibly litigation. Whether MRT is a natural extension of IVF or a crossing of the Rubicon is open to debate. But the families affected insist they’re not trying to fashion designer babies or playing God. They just want a healthy, biologically related child.

“Extend your arm. Expose a vein. Make a fist. And it’s 50 yuan.”

In the early 1990s, China’s rural Henan province was the epicenter of a devastating black-market blood drive. “Blood heads” set up stations across the province to buy blood from hapless peasants, from which plasma could be separated and sold abroad. For the farmers, the “plasma economy” was a godsend worth the princely sum of fifty to seventy yuan, enough to buy kilos of rice, save for a portable television, pay school bills, or even build a small house. Tragically and predictably, the use of unsterilized needles and the mixing of blood samples before reinfusing to volunteers led to an HIV epidemic, a “nameless fever,” to which the local authorities turned a blind eye. It took a local doctor, Shuping Wang,^I to finally get the attention of authorities in Beijing, which has provided free HIV drugs since 2003.

In 2016, JK visited Wenlou—the “AIDS village” four hundred miles south of Beijing.³¹ Hundreds of villagers—almost one in two blood donors—contracted the disease. By the end of 2015, more than two hundred residents had died. Similar tragedies played out in dozens of villages across the province. Aside from the gravestones, JK saw few signs of a national scandal. There are no longer emaciated patients walking in the streets. Many of the orphaned children have left or been sent far away to start a new life, sometimes under a false identity to escape discrimination. In the elderly villagers’ faces, he might have seen flashbacks to his own family and childhood.

Much like China’s initial response to the coronavirus outbreak twenty-five years later, the government’s response to the AIDS crisis was denial or inept. But more recently, the cause of HIV awareness received a high-profile champion—China’s First Lady, Peng Liyuan. In 2017, she received the UNAIDS award for her work fighting HIV discrimination. Surely success in developing a bold new strategy to combat HIV would have support in the highest echelon of the Chinese government.

With Chinese scientists launching the first gene-editing experiments on human embryos, JK saw an opportunity to make an even bigger name for himself. His biggest inspiration was an Englishman almost sixty years his senior—Nobel laureate Robert “Bob” Edwards, the father of IVF. After Edwards died in 2013 at eighty-eight, Nature wrote: “Several scientists have made discoveries that have saved millions of lives. Robert Edwards helped to create them.”³²

Edwards met Patrick Steptoe, an obstetrician who worked at Oldham General Hospital, near Manchester, at a conference in 1968 in London. The same year, using oocytes recovered from a woman at Edgware General Hospital^II in north London, Edwards performed IVF for the first time. Edwards and Steptoe published their initial results in Nature in 1969, prefaced by one of those classic understatements for which Brits (and Nature) are famous:

Human oocytes have been matured and fertilized by spermatozoa in vitro. There may be certain clinical and scientific uses for human eggs fertilized by this procedure.³³

The study didn’t mention “test tube babies.” But Nature’s savvy editor, John Maddox, played up the study in a piece for the Times that appeared on Valentine’s Day. Subsequent newspaper headlines fretted about a “human time bomb,” a “test tube baby factory,” and “the end of human beings as a wild breeding race.” Third World nations could improve their influence and wealth by breeding “a race of intellectual giants.” All this was, I suspect, much to Maddox’s journalistic amusement. It ensured that Edwards and Steptoe’s future work was carried out under the intense glare of the media, not to mention the church and the government.

In 1971, Edwards reported his first success in culturing human blastocysts. “There should be no criticism in giving these [infertile] couples their own children: comments about overpopulation seem to be highly unjust to such an underprivileged minority,” he wrote.³⁴ Despite having their funding proposal rejected, Edwards and Steptoe persevered. Their first attempt at re-implanting an IVF embryo in 1976 resulted in an ectopic pregnancy. But on July 25, 1978, Steptoe delivered Louise Brown, weighing in at 5 pounds, 12 ounces, by cesarean section. Edwards and Steptoe suggested Louise’s middle name be “Joy,” for what she would bring to so many couples. Among the worldwide well-wishers was the Queen’s gynecologist.³⁵ Only two more IVF babies were born in the first couple of years after Brown’s birth, the first in the United States not until 1983. IVF wasn’t legalized in the UK until 1990. But from such small beginnings, the technology blossomed. In the first forty years since Louise Brown’s birth, an estimated eight million IVF babies were born.³⁶

Edwards was finally awarded the Nobel Prize in physiology or medicine in 2010. The honor came too late for Steptoe, who was deceased, and almost too late for Edwards who, suffering from dementia, was unable to travel to Stockholm. His Nobel Prize was roundly criticized by the Vatican but his friends said the honor delighted Edwards—and many grateful fans. One comment left on the Nobel website said: “Dr. Edwards, thank you for my life.”³⁷

JK listed Edwards among his medical role models, along with the time it had taken for them to be duly recognized, in a PowerPoint presentation that he showed to his lab:³⁸

Christiaan Barnard: Domestic, 3 weeks, International, 1 Year

Robert Edwards: 7 years

Edward Jenner: 1 year.

Drawing encouragement from these examples of scientific trailblazers, JK imagined his own future reflected in their image: initially controversial perhaps, but ultimately celebrated as having been in the vanguard. It was all about having the courage to take a controversial first step—breaking the glass—and thereby pushing science and humanity forward.

I. Shuping Wang, a naturalized American citizen, died in 2019 after suffering a heart attack while hiking outside Salt Lake City. Her whistleblower experience inspired a play, The King of Hell’s Palace, which premiered in London. Wang publicly called out the pressure placed on her family in China from authorities to call off the production. Twenty-five years later, China again showed its disdain to the medical whistleblowers of the coronavirus pandemic.

II. Also my birthplace, it should be noted.