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Cambridge company is making designer pigs with transplantable (to people) organs.





CAMBRIDGE — Where other people see bacon, biologist Luhan Yang sees lifesaving organs — hundreds and thousands of them, pig livers and pig kidneys and diabetes-curing pancreases, and possibly hearts and lungs, all growing inside droves of pampered swine.

More established scientists than Yang have dreamed of creating animal organs that are suitable for transplantation into people waiting for a human donor. But until recently, experts said it would take decades to genetically alter pig organs to make them work safely in people. Most dreamers gave up.

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Giving up is not in Yang’s lexicon. Urgency is. In her native China, she told STAT, 2 million people need organ transplants, “and people are dying before they get one.”

The intensely driven 31-year-old has a few things going for her that other would-be pioneers did not. As a Harvard graduate student, Yang was a lead author of a breakthrough 2013 study on the genome-editing technology CRISPR-Cas9. And in 2015, she cofounded the biotech company eGenesis with her mentor, legendary Harvard bioengineer George Church, with whom she’s also worked on trying to resurrect the Ice Age wooly mammoth through genetic legerdemain. From eGenesis’s tiny headquarters in Kendall Square, she intends to use CRISPR to accomplish what the world’s largest drug companies failed to do despite investing billions of dollars: create “designer pigs” whose organs can be transplanted into people.

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“Luhan is a remarkable person,” Church said, “and a force of nature.”

She better be. Daunting hurdles stand between where biology is now and where it needs to be to make transplantable pig organs. The old problems of infection and rejection of another species’ organs seem almost quaint compared to those facing eGenesis.

There’s the challenge of CRISPR’ing an unprecedented number of genes without compromising the viability of the designer pigs and without introducing aberrant edits. And of optimizing mammalian cloning, which is how the company creates the pigs. And of persuading investors and doctors that xenotransplantation, as the process is called, is safe, effective, ethical — and lucrative.

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Yang, eGenesis’s chief scientific officer, has already made enormous strides, both scientific and financial. In 2015, she and colleagues in Church’s lab used CRISPR to eliminate from pig cells 62 genes so potentially dangerous their very existence nixed previous efforts to turn pigs into organ donors. Last month, eGenesis announced that it had raised $38 million from investors. The next hurdle: get the surrogate-mother sows that are pregnant with genetically altered embryos to give birth to healthy piglets.

“Her work has the potential to change the face of transplantation and to save countless lives,” said Dr. James Markmann, chief of transplant surgery at Massachusetts General Hospital.

Yang is not only confident of success, she also sees eGenesis’s xeno work as a sort of trial run for even bolder goals. In 2016, she helped conceive Genome Project-write, whose aims include assembling a synthetic human genome from off-the-shelf parts and — because, really, as long as you’re making a human genome, why not? — doing it better than nature.

By starting from scratch, she wonders, “could we make the human genome cancer-resistant? . . . Or make it virus-resistant? . . . There is a great opportunity that xeno can tell us what would happen in humans after dramatic genome engineering.”

But if eGenesis is to succeed in making designer pigs, let alone paving the way for new and improved humans, Yang will need to fix the miscarriage problem.

A ton of genetic handiwork

On a frigid March morning, Yang is holding her monthly meeting with Church and the company’s half-dozen employees, getting updates on the designer-pig pipeline and lighting a fire under her team. The big conference table in the windowless basement room is strewn with 8.5-ounce cans of “Wild Jujube Drink” and snacks that Yang brought back from her Lunar New Year visit to China, where she spent five days with her parents and visited eGenesis’s pig colony.

The “highlight of the month,” biologist Marc Guell tells Yang, is that surrogate mother pigs didn’t reinfect fetuses with “PERVs.” That’s crucial, because the memorably named infectious agents, short for porcine endogenous retroviruses, could cause tumors, leukemia, and neuronal degeneration if transplanted into patients. To make xenotransplantation succeed, PERVs have to go.

PERV genes are interwoven into the genome of pig cells, so eGenesis scientists start their work with CRISPR-Cas9, which has made editing organisms’ genomes so simple high-schoolers can do it. It takes far more expertise, however, to remove dozens of PERV genes at once, as eGenesis does in pig fibroblasts, which are connective-tissue cells.

EGenesis ships batches of these cells to China, where each de-PERV’ed pig cell is fused with a pig ovum whose own DNA has been removed. The ova, which now contain only the PERV-free genome, start dividing and multiplying, beginning the journey to becoming pig fetuses. The embryos are implanted into surrogate mothers and, if all goes well, born 114 days later. (Yang won’t say how many sows are or have been pregnant.) Unfortunately, all has not gone well.

The anti-PERV work is only the start of the changes eGenesis is making to pig genomes. Its scientists are also slipping into the pig ova up to 12 human genes “to make the pig organs more human-like,” Yang said in an interview. One gene, she said, would shield its organs from attack by the human immune system; another would revamp its coagulation system to reduce the risk of clots.

That’s a ton of genetic handiwork for one little pig to handle, and early signs are it might be too much.

One batch of embryos all died, Yang said, possibly because their chromosomes had gotten scrambled by either the genetic changes or the lab manipulations. Another batch had “a lot of miscarriage,” she said.

There are other concerns, scientists noted at the March meeting. Sometimes PERVs are found in the embryos before they’re implanted into surrogate mothers. The problem, Yang says as she leaps to the front of the conference room, is that removing the DNA-containing nuclei from pig ova isn’t always complete; occasionally some of an ovum’s own PERV-infested genes remain behind, so the embryo created from it also has PERVs, genetic analyses showed.

Yang grills her team. How prevalent is this? May I see the genetic profile again? What can we do quickly to correct the protocol? A gene that was inserted to protect other genes “is the problem,” she says with finality. “Maybe we should pause this one and look for other solutions. It’s better to figure out where the problem comes from, then we don’t have the problem anymore.”

‘We’re short of time’

A clue to how Yang’s mind works is that she counts. Ask her about the ethical issues around xenotransplantation and she will immediately tell you there are three, then elaborate on them. Ask her what characteristics make up the “entrepreneurial spirit” and she will say there are four, then reel them off. Colleagues say she has an uncanny knack for working backward from an ultimate goal and breaking it into a manageable sequence of steps.

She darts down corridors, speaks quickly, hates waiting, and expects others to move at her speed. Some colleagues call her impatient. Biologist Dong Niu, who worked in the Church lab and is now at eGenesis, joined Yang on a recent blitz of apartment hunting. Yang set such a breakneck pace, Niu said, “I couldn’t even watch.”

She pushes colleagues to accomplish tasks now, if not sooner, and when she asks a coworker to explain a scientific detail, she says, “We’re short of time; just get to the point.”

Yet colleagues sing her praises, saying she motivates them and brings “extraordinary passion” and a “laser focus” to her work. “Whenever you have a question, she has an answer, almost before you get it out,” said Niu.

Yang was born and grew up in a small town in a mountainous region of southwest China. Her parents were “ordinary working-class people,” she said, her father a government employee and her mother an accountant.

In 2004, as a high school senior, she was chosen for China’s four-person team in the 15th International Biology Olympiad, held in Australia. Yang was one of 16 contestants to win a gold medal, coming in 13th.

After majoring in psychology at Peking University, Yang entered graduate school at Harvard, where she rotated through three labs before joining Church’s. It was a crash course not only in biological engineering but also in what success means.

“I think my generation of Chinese, we are very aggressive and very optimistic,” Yang said. “Sometimes I think we all want to be successful and to find a shortcut to be successful, because the competition [for academic success in China] is so fierce.”

The different “worldviews and value systems” she saw at Harvard, she said, “made me open my eyes and reassess what kind of person I want to be. I want to pay back to society.”

Encouraged to think big

Yang stumbled out of the gate in Church’s lab, nearly failing her PhD qualifying exams because her English was so poor. It was her first academic setback, but in relating the story, Yang betrayed no more emotion over the experience than if it had been another gene she had to CRISPR. “George asked the committee to let me pass with the condition that he would spend more time with me for English training,” Yang said.

She played point on some of the lab’s most important experiments. In 2012, she and postdoctoral fellow Prashant Mali teamed up on CRISPR-Cas9, a molecular complex that bacteria use as a primitive immune system; other scientists had recently gotten it to cut specific locations on DNA floating in test tubes. Mali and Yang got a single cluster of CRISPR molecules to edit multiple genes in human and mouse cells in one fell swoop, a breakthrough published in early 2013. Although Mali and Yang had equal billing as first authors, the paper is always referred to as “Mali et al.” Yang said that doesn’t bother her.

Soon after, physicians approached Church about using CRISPR to alter the genomes of pigs so their organs would not be rejected by the human immune system. The very question was a triumph of hope over experience. In the 1990s, a handful of drug companies, including Novartis, had collectively spent north of $2 billion to use genetic manipulation to make human-friendly pig organs.

She said she feels “a strong sense of responsibility” to help the millions waiting for organs in her homeland: “I regard myself as a Chinese scientist. Something that can potentially solve a huge health care and social problem for China and for the world? I feel it is a privilege to work on that.”

With hundreds of labs catching CRISPR fever since 2013, most experiments have altered one or two genes at a time, maxing out at five. Yang’s challenge was audacious: To knock out all the PERVs would require a tenfold improvement.

“But if we could make it work,” she said, “the impact would be huge.”

They did, and it has been. In 2015 the Church lab announced it had CRISPR’d out 62 PERV genes in pig kidney cells growing in lab dishes. It was a record, and it still stands.

“George always encouraged me to think bigger,” Yang said.

Pushing the limits of technology

Determined as she is to make xenotransplantation succeed, Yang also sees it as “opening a back door for me to push the limit of [genomic] technology.” For one thing, “xenotransplantation requires large-scale genome engineering,” she said. In addition to knocking out PERVs, which is relatively easy, making organ-donor pigs requires inserting large chunks of human DNA into the pig genome.

“Our ability to knock in a large fragment of DNA is still limited,” Yang said.

Working out how to do it in the pigs would point the way toward, say, adding copies of the cancer-fighting gene p53 into a person’s genome.

“That’s why I love xeno,” she said. “It’s a platform to help us assess technology.”

Yang has immersed herself in the ethical issues around xenotransplantation, but they haven’t slowed her pursuit of transplantable pig organs.

Some scholars argue that it is morally wrong to value human life more than animals’, but “so many people are eating pork every day,” Yang said. As for “playing God” — the argument that it is unethical to change a pig in the way that genome-editing does — she retorts that “the highest moral standard is human life. I think it’s a personal choice whether you use a pig organ or die. But you shouldn’t prevent other people from using it.”

As of early March, two of eGenesis’s cloned and CRISPR’d pig fetuses were just “a few weeks from delivery,” Yang said. “We checked the genotype and were surprised but also delighted to see that the fetuses [in one surrogate mother] are 100 percent PERV-free.”

Yang is more than ready to be a proud mother: “I feel it’s our time.”

Sharon Begley can be reached at sharon.begley@statnews.com. Follow her on Twitter @sxbegle.


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