by Sarah Gray
Whatever the truth of the complicated nature of the relationship between research participants and scientists, something more important was true: there it was, proof of Thomas’s contribution to science. Now I could finally celebrate the work I had done to provide decent blood samples. Just as the folks at the study were grateful for our donation, so I was grateful to Deidre and the team for taking the time to explain this important study to us.
This was part of Thomas’s legacy, more work to which he had contributed. Maybe, thanks at least in part to him, babies of the future wouldn’t suffer from the awful affliction that took his life. I was so proud of my son.
After we met the researchers, Karen Soldano, a lab research analyst, gave us a tour of the facility and showed us where the FedEx package of test tubes would have arrived, and where the blood was currently being stored (along with thousands of other samples). We saw rows of microscopes and equipment I had seen only on forensic science shows.
We were asked not to lean on the $150,000 DNA coding machine.
At the conclusion of the tour, we said our good-byes and hugged the researchers. Dr. Gregory thanked us for visiting, and told us that meeting us had reminded him of the personal investment in every blood sample they get.
We left with a new perspective on the complicated biological processes that result in human beings being born healthy—or not. Dr. Gregory had explained that they still couldn’t tell us exactly what caused a defect or how to cure or prevent it—but it gave me great hope to know that the work they were doing could lead to clinically actionable information down the road. Maybe not for me, but for other people in the world who might one day be in my shoes.
This visit gave me a better appreciation for what researchers do, too. They face years of trial and error before they can ever point to a success. Dr. Gregory put it like this: “You have to be something of a masochist to be a scientist, because not every experiment works. It’s 95 percent disappointment. We live for the 5 percent, when we are able to identify something no one has ever seen before.” It occurred to me that scientists have something in common with organ, eye, and tissue donor families: we all do something to help people we may never meet.
We stopped off at the Duke University gift shop and got Callum another T-shirt.
CHAPTER NINE
The Quest Continues—Cytonet
A Tour of Cytonet, LLC
Later the Same Day
Our next stop was Cytonet, the international biotech company that received Thomas’s liver.
Cytonet is a for-profit, privately funded company. I imagined that Cytonet would have been founded or funded by someone with a personal connection to liver disease, but that was not the case. The Cytonet Group was founded at the turn of the new millennium as a small spinoff from the cell-therapy division of the German biotech giant Roche Diagnostic GmbH, which itself was started in 1896 by Fritz Hoffmann-La Roche, an entrepreneur who believed that the mass production of medicine would be a major advance in treating disease.
Dr. Wolfgang Rüdinger, the physician who founded Cytonet, had been managing various programs within Roche, including a cell-therapy program. He realized he had a soft spot in his heart for treating patients with the lowest chance of survival and the fewest options, and had been working on developing a liver-cell therapy. When Roche decided to divest itself of its noncore assets, he left and took the technology with him to launch the new firm. Rüdinger joined forces with the investor Dietmar Hopp, a billionaire software expert who had recently resigned his position as co-CEO of the software behemoth SAP. Once an avid investor in such diverse holdings as breweries and sports teams, Hopp had since become an avid investor in biotech companies in Germany, in the hope of making his country a leader in the field. (Hopp’s initial and continuing investment in Cytonet makes him its largest shareholder.)
In 2006, Cytonet partnered with, and ultimately took over various assets of, an American company called Vesta Therapeutics, Inc., based in Durham, North Carolina, giving them a toehold in the United States. Mark Johnston, a London Business School–trained entrepreneur who had been president of Vesta Therapeutics, became president and COO of Cytonet in 2009. Today Cytonet’s staff of fifty is evenly divided between its Durham headquarters and its German location. Its focus is in the field of regenerative medicine, and its self-proclaimed mission is to “provide alternatives to existing therapies for many diseases with a particular emphasis on liver diseases.”
When I first emailed Mark Johnston to follow up on the appointment that Maureen Balderston at WRTC had arranged, he graciously invited us to join him and his staff for lunch, in addition to the tour and presentation he was planning for us. And like others before him, he wanted to know what we wanted to know.
There was so much. I told him that in my fantasy world I’d love to see Thomas’s liver cells under a microscope, but I knew that his cells were probably confidential, unidentifiable, and might not even still be there, so I’d be grateful to see any liver cells. Then I fired off a list of other things on my mind:
Who orders the liver samples, and when?
How do they decide when it’s time to order a new one?
Where do the samples come from? The United States only, or all over the world?
What information is provided about the donor? Age, cause of death . . . ?
What happens after a sample arrives?
Who receives it, and where does it go next?
How many scientists use one sample?
How long is one sample typically used until it’s used up? How long does one sample last?
How many samples are ordered in a normal year?
Has there ever been a sample shortage (a backorder situation)?
When we arrived at Cytonet’s headquarters, located in an unassuming office park, Mark Johnston was there to greet us. Mark looked to be in his forties, had a close-cropped beard and hair, and was wearing a sharp blue suit. “We are really glad you came,” he said. And like others before him elsewhere, he commented that this was the first-ever donor visit.
Mark introduced us to several members of the Cytonet staff—Sonya Meheux, manager of the manufacturing process; Jennifer Michaux, senior development scientist; and Janera Harris, quality assurance manager—and he led us to the conference room for lunch. Ross and I handed out some pictures of Thomas and told the story of his short, precious life, and then Mark gave us a full presentation, complete with slides and photographs, on Cytonet’s groundbreaking work.
Many biotech firms like to focus on treatments for common ailments, thereby maximizing their potential for profit. But Cytonet’s work began with a much smaller focus—children under the age of five with a liver disease called a urea cycle disorder. Just one hundred children are born in the United States each year with this rare genetic disorder. The mutation causes a deficiency in one of the six liver enzymes whose job it is to remove nitrogen from the bloodstream and convert it to urea, which is transferred to the urine and safely exits the body. In urea cycle disorders, the nitrogen builds up as highly toxic ammonia, a life-threatening condition. If the ammonia in the blood reaches the brain, it can result in brain damage, coma, or even death. Most babies who receive this diagnosis die within a few weeks of birth.
There is no cure for this condition; a liver transplant is the only option. The catch is that newborns are too small to receive a transplant safely.
Therefore, instead of transplanting entire organs, the company has developed a method for isolating healthy liver cells and transplanting those into diseased organs; the transplanted cells will engraft into the recipient’s liver and take up the work that the diseased liver cannot do.
Cytonet receives donated healthy livers that are unsuitable for transplantation—they may have been damaged in surgery or not completely flushed of blood, which causes bruising. The researchers have developed, and are constantly refining, a process by which they can extract cells from these healthy but nontransplantable organs. The first stage of the process
introduces an enzyme called collagenase, which cleaves the collagen that holds the liver cells. What’s left is a liquid form of the liver, which is then put into sterile bags.
There are a number of different cell types in the liver, and the ones they want to isolate for transplant are called hepatocytes. To get the hepatocytes, the bags are put into a simple centrifuge, which causes the heavier hepatocytes to fall to the bottom; the other cells float to the top and are then aspirated off.
The remaining hepatocytes are cryopreserved—a.k.a. frozen—until they can be injected into a recipient.
Cytonet is offered hundreds of livers every month from the fifty-eight OPOs across the country, but after weeding out organs that are very fatty or cirrhotic (the enzyme can’t penetrate that kind of tissue), they are able to accept and use on average around just eight each month. Of those, approximately half go to what is called the manufacturing lab—where the livers are processed into sterile bags of hepatocytes ready for cell transplantation—and the other half go to the R & D lab, where they help refine and improve their processes. I didn’t know which lab Thomas’s liver went to, but I was grateful that it had made it through the Cytonet gauntlet of criteria. Being a Cytonet donor struck me as an elite status that many of us, probably me included, might never attain.
Cytonet’s first milestone was the successful implementation of its liver-cell therapy in 2004. The recipient was a sixty-four-year-old woman who had eaten poisonous death cap mushrooms, the culprit in most human deaths by mushroom. The deadly fungus causes organ failure within days, but two weeks after she received liver-cell therapy the lucky woman went home.
The first four children with urea cycle disorders were treated in what are called therapeutic attempts, before the company had approval to begin a clinical trial. The patients—one in Italy and three in Germany—had no alternative treatment, so their physicians contacted Cytonet and asked the company to provide the liver cells; after receiving the cells, the physicians injected them into their patients. The company was able to use the anecdotal data from those four patients in their application to conduct a clinical study in Europe, the United States, and Canada. Another sixteen patients were successfully treated in that study. The youngest patient treated with this therapy was just six hours old.
Cytonet has since treated two patients with different kinds of rare liver metabolic disorder: One kind is Crigler-Najjar syndrome, an inherited condition caused by a malfunctioning enzyme that can lead to jaundice as well as muscle, nerve, and brain damage. The other is hyperoxaluria, which can result in lethal damage to the kidneys.
Starting in 2016, Cytonet plans to begin a new study for treating acute liver failure resulting from an external toxicity, such as might result from alcohol poisoning or an acetaminophen overdose. Mark Johnston told us that the therapy is not suitable for patients with viruses such as hepatitis or cancer, since those diseases will also infect the transplanted donor cells. But in an otherwise healthy liver that has been damaged by some external toxicity—as was the case with the woman who ate the wrong mushrooms—the liver cell treatment gives the liver time to heal itself.
When I asked Mark why the company was so enthusiastically focused on treating a disease with so few patients—he considers it lucky if Cytonet can treat fifteen to twenty patients a year—he said, “Our strategy was to go after this particular condition to prove the concept would work and was safe. Then we’ll broaden it to other liver diseases.” In the long run, the company hopes to not only take people off the organ-transplant waiting list, but perhaps eliminate the need for liver transplants altogether.
While we were eating lunch, the “liver phone” rang. The entire Cytonet team was on alert, because they were expecting an organ that was traveling from California. It was on the way.
I was impressed by all the systems that were in place to monitor everything. There was an extraordinary amount of thought going into every detail. Janera Harris explained that she was responsible for making sure that even the vendors of the medical supplies that the scientists at Cytonet used, like gloves and tubes, had the right quality-control measures in place.
After lunch, we took a tour through the facility and saw where Thomas’s liver would have been prepared for the cell isolation procedure. We were shown a laminar airflow hood, which prevents contaminants in the air from touching the liver, and which I thought looked like the sneeze guard over a salad bar.
Mark had promised that I would be able to see liver cells under a microscope, but they would not be Thomas’s. Before we arrived, Jennifer Michaux had taken some liver cells out of cryopreservation and magnified them for us to see on a computer monitor. For the Cytonet staff, looking at liver cells seemed like no big deal. But I had never seen real liver cells in my life, and I probably never would again. For me, this was a really special occasion.
As we walked through the staff break room to another part of the building, I was delighted to see that our visit had already had an impact on these busy people’s lives: One of the pictures we had just distributed had been hastily taped to a whiteboard, with an arrow pointing to Thomas and these words handwritten in dry-erase marker:
Thomas Gray was a Cytonet donor. Died 3/29/10.
It had been so difficult for me to give away Thomas’s organs and not know what happened to them. I imagined that it must be hard for researchers to receive an organ from a fellow human being and not feel some kind of curiosity, or sympathy, or connection. I took that message on the break room wall as a sign: they have been wondering about us, too.
During our lunch, we had learned that it was Sonya who received the package with Thomas’s liver and, in fact, held my son’s liver in her hands. Part of Sonya’s job was validation, which means coming up with new ways to clean and freeze the liver cells, then testing these methods over and over and over to make sure they are really working.
Before we left, Mark looked up the liver-processing records from the week Thomas died. Though the name was not revealed, Mark found the records of a baby boy who had died on March 29, 2010, and whose liver was recovered and donated through WRTC. Since this was the only neonatal liver to arrive at Cytonet around that time, it was clear to me that the liver in this record was Thomas’s.
When Thomas’s liver arrived at Cytonet, it showed some signs of bruising, which was a result of pooled blood that could not be flushed out after surgery. Sometimes this is the result of an abnormality in the anatomy of the liver. As a result, his liver was not in the best condition for the cell isolation procedure for patient treatment purposes, so the cells were not injected into a baby with a urea cycle disorder. Instead, Thomas’s liver was used in a study that Cytonet was performing on the ideal temperature for freezing neonatal liver cells. This study required the donation of six neonatal livers; that might not sound like much, but it took approximately five months for Cytonet to get all six. The child who had died on March 29, 2010, had donated liver number three.
I pictured Thomas as a member of a six-baby NBA dream team.
When the study was complete, it showed that neonatal liver cells can be frozen at the same temperature as adult and pediatric liver cells, which is minus 150 degrees Celsius. For the scientists, this information was vital for the work they were doing. From then on, minus 150 degrees Celsius would be a secretly special number to me.
“You remember that there are names, there are sisters and mothers and fathers of these donors,” Sonya said that day. “It’s not just a liver. Without the family making that sacrifice even though they know it’s not going to another person directly—we have to remember that their sacrifice is helping someone else.”
Though it was clear that the liver that arrived that day was Thomas’s, we could never be 100 percent sure because of the agreement of confidentiality. We heard another story that brought home the challenges the staff faced in working with anonymous, or “de-identified,” samples. One day, an employee was leafing through a copy of the Southwest Airlines in-flight magazine during a
trip and stumbled across an ad for the Yale Medical School, touting its successful treatment of a baby with a new liver-cell therapy. Was this the Cytonet therapy? Though the scientists at Cytonet developed the process, they didn’t interact directly with patients. The Cytonet staff could finally see the face of someone who just might be a patient.
Subsequently the Yale Pediatric Update published a story about the “first pediatric liver-cell transplantation in the Northeast.” Dr. Sukru Emre, M.D., director of the Yale–New Haven Transplantation Center, performed the procedure on three-week-old Abbas Syed in 2010. Accompanying the article was a picture of Veena Chowdhan holding her laughing toddler.
Later, I would ask Dr. Emre about Abbas, and he would confirm that Abbas had been treated with donated hepatocytes from Cytonet. Abbas received hepatic cell infusions every day for six days. All the cells he received came from the liver of one unidentified deceased donor. This donation played a vital role in saving Abbas’s life. This was especially poignant given that Veena and her husband had previously lost a baby girl to the same condition. When she learned that there was a new treatment that had worked for at least one patient in Germany, she jumped at the chance. Nine months after Abbas received the liver-cell therapy, he received, in an eleven-hour operation, his full liver transplant. As of early 2016, Abbas was a thriving and healthy kindergartener.
Although Thomas would not have been directly involved in this treatment, I couldn’t help but feel a connection to Abbas and his family from that moment on.
At the end of our afternoon at Cytonet, we reluctantly removed our visitor badges and got back in the car to begin the long drive home. I felt physically exhausted, but emotionally buoyed by the new answers, new friends, and further evidence of human compassion. In school, science had been one of my worst subjects. I thought it was too difficult to understand and boring, but I was starting to see things differently. No, science was definitely not boring. To paraphrase Neil deGrasse Tyson, I started appreciating science as being something close to magic, except it’s better: it’s real.