by Robin Cook
“It’s amazing you could do it so quickly,” Jack said. “A virologist at the Public Health Laboratory as well as one at the CDC whose specialty is unknown viruses haven’t succeeded as of yet, as far as I know.”
“I’m not surprised,” Wei said. “This virus has never been seen as a human pathogen. We were able to identify it because we had an idea of what it was. And we have the best and latest equipment.”
“What kind of virus is it?” Jack asked.
“It is a gammaretrovirus,” Wei said.
“Interesting.” Jack wondered how many more times he’d parrot the word before this case was over. In reality, he had no idea what a gammaretrovirus was. He didn’t even think he had ever heard the term, which wasn’t surprising. Like insects, new viruses were being discovered all the time. And the cynic in him made him question whether Wei was toying with him for sport. If Dover Valley Hospital and GeneRx were doing something shady as Jack suspected, there was no way Wei would be telling him truthful secrets.
“I’m sensing skepticism,” Wei said, again surprising Jack with his apparent clairvoyance. “I think I should give you the big picture,” he continued. “It might be the only way to sway you. Are you game?”
Unable to control himself, Jack raised his eyebrows and cracked a disbelieving, crooked half-smile. “I’m game. Why not? Fire away!” He had absolutely no idea what Wei Zhao had in mind.
39
THURSDAY, 1:42 P.M.
“Before I begin,” Wei said. “Are you comfortable here?”
Jack glanced around at the lounge’s decor, appreciating its sublimity and wondering how anyone could be more comfortable. They were in the most luxurious private home Jack had ever visited, sitting in canvas director’s chairs at the small round dining table with views into a huge indoor pool on one side and an enormous private gym on the other. Jack had a half-full bottle of pomegranate juice in front of him and had just inhaled a freshly made, healthy vegetarian sandwich.
“We could go over to the great room, if you would prefer,” Wei suggested.
“I’m fine right here,” Jack said. “Let’s hear the big picture.”
“I’m assuming you remember what I told you yesterday about the Chinese government, particularly under Xi Jinping, and how it is restricting capital outflow from the People’s Republic.”
“I remember,” Jack said. He fidgeted. He sensed this was going to be a long explanation, and business details weren’t of much interest to him.
“Currently GeneRx and the Dover Valley Hospital are running slightly in the red, which I have been covering by drawing capital out of China. With Xi Jinping in power, which looks like a long-term situation after he managed to have the Chinese Constitution amended, I need to find alternate capital sources. GeneRx has thirteen very promising drugs in phase three clinic trails. Any one of those could solve our near-term capital needs, but whether that happens or not depends on FDA approval, which can be frustratingly slow.”
“I hate to interrupt,” Jack said. “But could you speed this up? How about giving me the condensed version of the big picture?”
Wei paused and glared at Jack for a beat. “The dossier also said you could be tactless as well as vocal,” he snapped, showing irritation for the first time. “I’m finding it unpleasantly accurate.”
“I can be impatient,” Jack admitted. “But remember that I am not here totally on my own volition.”
“Do you feel you are not being treated with appropriate hospitality?” Wei challenged.
“Here, yes,” Jack said. “But the ride to get here left something to be desired, as did my treatment at your hospital after I finished the autopsy.”
For a moment Wei stared off into his gym, as if to get himself under control. He then got up and went to the refrigerator to get himself a pomegranate juice. After taking a healthy swig, he came back to the table and sat down. He cleared his throat and continued. “Dr. Markham informed me yesterday that he had told you about how the unique relationship between GeneRx and the Dover Valley Hospital was going to make it possible to bring the benefits of CRISPR/CAS9 to clinical medicine before anyplace else in the world. From a humanitarian and business perspective, it is a huge opportunity. It’s going to change cancer therapy, gene therapy, organ transplantation, and what IVF can offer its clients like nothing else in the history of medicine. I am absolutely convinced, and so are a lot of other people.”
“I’m happy for you,” Jack said. “Sounds like a business bonanza. But how does all this relate to the deaths of Carol Stewart and Margaret Sorenson?”
Again, Wei stared off, this time into the pool area. As a billionaire businessman and active philanthropist, he was accustomed to fawning attention from his subordinates and just about everyone else. He was clearly finding Jack progressively more vexing, but after a second pause and a deep breath, he was able to continue. “Of all of the fabulous advances in clinical medicine that are coming thanks to CRISPR/CAS9, the first one to pay off right out of the gate is going to be organ transplantation. Do you know how many people die every day in America waiting for a transplant organ?”
“Not offhand,” Jack said, rolling his eyes. “But I have the feeling you are about to treat me to the answer whether I care about it at this moment or not.”
“You are a trying man,” Wei said evenly, again taking offense at Jack’s acerbic flippancy.
“I also find your sense of entitlement trying,” Jack said. “I suppose you think it’s entirely appropriate to have me shanghaied out of your hospital and brought here whether I wanted to come or not and then forced to listen to a lecture about your business problems. The irony is that I did want to come, but not under these circumstances. I’m interested in the deaths of two young women and the possibility of a new pandemic with a heretofore unknown virus.”
“I’m getting to that,” Wei retorted.
“You could have fooled me,” Jack snapped back.
For a few beats the two men looked daggers at each other across the small table. The tension in the air was as palpable as static electricity. Jack in particular was struggling to rein in the churning emotions that had been honed to the breaking point. The helplessness he felt in the face of Emma’s plight combined with the events of the past week—being forced out on leave, having to deal with his in-laws, being manhandled out of a community hospital, and possibly being shot at—had him on the edge of the precipice. Getting harangued by someone he was beginning to believe was probably a narcissistic megalomaniac was almost too much to bear.
“Maybe we should have beers instead of pomegranate juice,” Wei said, breaking the tense silence. He got up, went to the refrigerator, and retrieved two bottles of Tsingtao. Returning to the table, he pushed one in front of Jack, then popped the top on his. Although Jack questioned the advisability of alcohol in his state, he went along. They both took long pulls.
“Okay,” Wei said. “Back to how many people die every day in this country waiting for an organ. The answer is about twenty to twenty-two people. There are over a hundred thousand people on the UNOS waiting list, and almost one hundred fifty are added to the list every day. All of them are suffering. Why this is such a tragedy is that there is a solution to this problem. It is pig organs.”
“Xenotransplantation?” Jack said. “It’s been tried. The rejection phenomena make it prohibitive.”
“That was before CRISPR/CAS9 was available,” Wei told him. “This new gene tool is a game-changer.”
Jack suddenly put his beer down on the table and eyed Wei. His jaw slowly dropped open. He was stunned. “Are you trying to tell me that Carol Stewart and Margaret Sorenson were transplanted with pig hearts?”
“No,” Wei said. “They were transplanted with human hearts grown in pigs.”
“Good God!” Jack exclaimed. He was aghast. “Did these women have any idea of what was happening to them? Did they know they
were getting pig hearts?”
“Correction,” Wei said. “As I already said, they were getting human hearts grown in pigs. There is a huge difference, and it is all thanks to CRISPR/CAS9. Essentially these were not only human hearts, but they were customized human hearts immunologically matched to the recipients.”
“But did Carol and Margaret know where the hearts were grown?” Jack asked.
“Absolutely,” Wei said. “We were totally up front with the women. They were both very smart and understood everything. They were scrupulously apprised of the work we have been doing for the last three to four years, including our extensive baboon experiments that started with appropriate-size pig hearts being transplanted into the baboons’ abdomens as assist devices and then later into the chests as full cardiac transplants. We also were able to do some chimpanzee work in my Chinese institute, where we could still get away with it. As astounding as it may sound, we had no fatalities with either species over the entire period.”
“I’m having trouble believing all this,” Jack mumbled.
“Using pig organs for human transplantation is not some way-out idea,” Wei said. “It’s been touted in the scientific journals, and there are a number of companies here in the USA working on this technology at this very moment. Everyone knows it is going to happen. It’s a horse race, and the spoils are going to go to the first company out of the gate. Knowing this, I committed our company to being the winner.”
“So that I completely understand, both Carol Stewart and Margaret Sorenson agreed to be guinea pigs unbeknownst to anyone other than you and your people.”
“That’s correct,” Wei said.
“This is insane,” Jack said. “Why would they be willing to do this?”
“They believed in the evidence we were able to show them,” Wei said. “They also knew that the chances of their getting a donor heart were small to none. Both had been on the UNOS waiting lists for over a year. With the rare blood types of AB-negative and A-negative, they knew their chances were nil, while we could engineer a perfect match.”
“Why was Carol Stewart’s transplant done under somewhat strange circumstances at Manhattan General Hospital?” Jack asked.
“That was an unfortunate timing issue. The reason was that her clinical condition deteriorated rapidly and necessitated she get her transplant prior to Dover Valley Hospital receiving its certification. We didn’t have any choice if she was going to live.”
“So the donor heart she got didn’t come from James Bannon,” Jack said.
“You are correct,” Wei said. “Her new heart came from a cloned pig. We were forced to come up with an alternate story because the procedure was done at MGH, even though it was performed by our Dr. Stephen Friedlander. We were not prepared to announce our breakthrough until we could present both cases five or six months post-operatively.”
“So the Bannon story was all an elaborate ruse to avoid a potential violation investigation by United Network for Organ Sharing,” Jack said disdainfully.
“I suppose you could say that.”
“Good grief!” Jack exclaimed. He ran a nervous hand through his hair. He was dumbfounded about what he was learning. His mind was struggling to comprehend it all while his emotions were like an overstretched, taut piano wire. After a short pause he said, “I was brought out here today purportedly to make a comparison between Carol’s and Margaret’s donor hearts,” he continued. “Dr. Friedlander said that there were technical differences between the two cases but didn’t explain. Was that true, or was that another ruse merely to get me back here?”
“It was true,” Wei said. “With the help of CRISPR/CAS9 we have developed two fundamentally different ways to produce human transplant organs in pigs. Our research has not proved one better than the other. Are you interested in the details? It requires a bit of technical genetic understanding. Would you like to hear? A few minutes ago, you were complaining your patience was waning.”
“Let’s give it a try,” Jack said. He was interested and listening, but he was also getting concerned about being caught in the web of Wei’s world.
“I’ll try to make it brief,” Wei began. “The basic idea in both approaches is to use CRISPR/CAS9 to alter the genetic makeup of pigs to create a customized organ. We started by using the same cloning techniques as were used with Dolly, the first cloned sheep. Once we had created an embryo, we used CRISPR/CAS9 to knock out all sixty-two known porcine retroviruses, called, appropriately enough, PERVs. From this embryo we created a line of pigs with no retroviruses, which we raised in a pathogen-free environment. Are you with me so far?”
“Keep going,” Jack said.
“Now, the goal was to make a PERV-free pig that would produce a customized heart for a specific individual,” Wei continued. “This required knocking out the pig genes responsible for creating the major histocompatibility complex, or MHC, along with the genes responsible for blood groups and then replacing them with the comparable genes from the patient who needs the heart. Again, this was accomplished with CRISPR/CAS9. So far so good?”
“So far,” Jack said.
“Now, here’s where the two approaches differ,” Wei said. “One involved creating only a transgenic pig, meaning a pig containing human genes. This included the genes I just mentioned, as well as the genes responsible for the creation of the heart itself. As it turned out, that was how Carol’s donor heart was created. The decision was made by a coin toss, in which the women participated. Questions?”
“I’m okay,” Jack said.
“Margaret’s heart was created slightly differently,” Wei said. “In her case it was the creation of a transgenic/chimeric pig. What we did was to make a pluripotent stem cell from one of her skin fibroblasts and add that to the developing PERV-free pig embryo containing her MHC and blood groups but without the genes required to make the heart. This information for forming the heart had to come from Margaret’s stem cells, so once again it was a human heart but grown in a pig that was composed of both porcine and human cells, which is what is called a chimera. Are you clear on these two approaches? Obviously, they both worked, but the pure transgenic is easier and results in a higher percentage of piglets.”
“What I’m clear about is your brazen presumption,” Jack said. “I’m appalled that you were willing to do all this with no sanction from any regulatory organization like the FDA or even a legitimate Institutional Review Board.”
“Knowing your reputation as someone who chooses not to suffer fools gladly, I’m surprised to hear you say that,” Wei said with equal disdain. “I for one have little respect for such regulatory bodies. Biological science is moving much too quickly for bureaucrats to comprehend, much less regulate.”
“The goal is patient safety and autonomy,” Jack reminded him. “It’s to prevent desperate people from being taken advantage of.”
“We were absolutely convinced of the safety and the efficacy of what we were doing. We were not taking advantage of anyone.”
“Oh, sure,” Jack sneered. “I’m blown away to hear you say that after both patients died. This was a freakin’ megalomaniacal experiment gone bad.”
“Let’s not be too quickly and falsely condemning.” Wei bristled, clearly taking offense.
“How can it be falsely condemning when the patients died?” Jack demanded. “And not only did they die, they might have started a goddamn pandemic in the process.”
“You are an opinionated, uninformed, self-righteous Western hypocrite,” Wei snapped. “Instead of actually doing something, you’re one of those people who just throw up their hands in the face of twenty-some people dying every day from the lack of transplant organs here in the USA alone and up to five hundred worldwide. And you do this with the solution right there, staring you in the face.”
“But the two patients died!” Jack yelled. “How can you overlook this immutable fact?”
�
��They died, but their hearts were functioning superbly,” Wei stated. “And both would have died months ago without the organs they received. You saw both hearts. They were perfectly accepted and functioning beautifully. Can’t we have a civilized discussion here?”
“You are too much,” Jack scoffed. “You want to have a civilized discussion over an uncivilized, unauthorized, unethical experiment that took advantage of two desperate young women. Even you said they died of a retrovirus, which they must have contracted from their pig hearts. That’s the reality.”
“The reality is that they were human hearts,” Wei corrected. “And yes, they died apparently of porcine retrovirus, but not because of our protocol. What we didn’t expect was sabotage.”
Jack was about to shout back at Wei to give further vent to his self-righteous indignation when the meaning of the word sabotage penetrated his consciousness. It took some of the edge off his emotions. He stared at the billionaire, wondering if he had heard correctly.
“Just last night, or actually early this morning, we found something that we certainly didn’t expect,” Wei continued. “Both donor hearts contained a PERV, gammaretrovirus B, in very low titers that had been eliminated in our cloned line of pathogen-free pigs. After sequencing it and comparing it to the usual PERV, we found differences, meaning it had been artificially introduced. There is only one way such a situation could have happened. Someone planted the PERV deliberately to sabotage our experiment. And it wasn’t a random choice. It happened to be one of the PERVs known to infect human cells.”
“Why would someone sabotage your work?” Jack asked. He couldn’t help but be skeptical. Was this some other strange ruse from this devious man?
“Obviously we do not know for sure,” Wei said. “But we have suspicions. The Chinese government, which has an oversized presence in Chinese universities, as we all know, requires us to accept a large number of Chinese biotech graduate students as part of their training. Over the last number of years these millennials have been progressively imbued with a new Chinese nationalism that you have probably seen in the newspapers in relation to Chinese students at Western universities. Among this group, there is a growing intolerance to anything construed as negative propaganda directed at the new China. The Chinese government is behind it. I have been aware that some of these students who learned of my interest in getting my assets and myself out of China want me to fail. I have no proof they were behind this sabotage event, but I believe so nonetheless.”
