Ethical worries have slowed medical research into applications for stem cells. But scientists like Robert Lanza have developed less controversial ways to derive stem cells from normal body cells rather than embryos and are already launching the first clinical trials.
By Philip Bethge
Stem cell researcher Robert Lanza hopes to save thousands of lives — and for a long time this caused him to fear for his own.
“They bused these crazy people up from Kansas, and then they picnicked right outside our front door,” he says as he gazes out of his window at the gray winter landscape of Marlborough, Massachusetts. “The public thought we had these little buggy-eyed embryos here and were ripping apart their limbs to get these cells.”
The physician always feared “somebody hiding in the bushes,” waiting to attack him. At the time, a doctor was threatened at a nearby fertility clinic, and a pipe bomb exploded at a bio lab in Boston.
“Back then I thought that there was probably a 50-50 chance that I was going to get knocked off because I was so visible,” says the doctor. Then he leans back in his chair and laughs. Lanza likes to flirt with danger: “I said, okay, try to kill me — I’m still going to do what I think is right.”
In Lanza’s case, doing what is “right” involves working with therapies based on human stem cells. The blind shall see again; the paralyzed shall walk again; the hemophiliac shall not bleed anymore. That may sound like something out of the Bible, but Lanza is no faith healer. In fact, the US business magazine Fortune called him “the standard-bearer for stem cell research.” The 57-year-old is the chief scientific officer at the US company Advanced Cell Technology (ACT) and one of the most flamboyant and controversial figures in this field of research.
Militant anti-abortionists tried to hunt Lanza down because embryos had to die for his research. Just last year, the scientific journal Nature wrote that ACT has “a history of public blunders” and a reputation for “overhyping results.”
At the same time, however, Lanza is writing medical history. For over one year now, eye patients in the US and the UK have been treated with cells from ACT laboratories — the first clinical stem cell trial worldwide.
And there is a world premiere in the making: Lanza’s team has cultivated blood platelets that could be tested in hospitals as early as this year. The researcher and his team didn’t harvest the cells from embryonic stem cells, but rather from induced pluripotent stem (iPS) cells derived from normal body cells.
“It took a decade,” says Lanza, “but now we are finally ready to move into the clinic with our stem cell therapies.”
The Making of a Rebel Scientist
Lanza is a slender man with short hair that stands on end, and he speaks so quickly that his sentences tend to be cut off. His laboratory is located in an ugly commercial building on the outskirts of Marlborough. It’s hard to imagine that a medical revolution is brewing in this dreary setting. The petri dishes, test tubes and steel containers filled with liquid nitrogen are teeming with human cells. The ACT “Master Cell Bank” cost $1 million (€770,000), says Lanza, “but these things grow like weeds once a stem cell line has been established.”
The cell factory is currently producing batches of iPS blood platelets. Emergency wards have a huge demand for these helpers in the body’s natural clotting mechanism. Lanza explains that a lack of these elements can have dramatic consequences: His sister was seriously injured during an accident. The hospital didn’t have enough blood platelet concentrate. “She bled to death,” he says.
Lanza wants to prevent something like that from ever happening again. His team has found ways to cultivate an “unlimited supply” of the cells. When frozen, he says, they can be kept for months. He is currently negotiating the final details of the planned study with the Food and Drug Administration (FDA). “We don’t need any embryos to make iPS,” Lanza says with pride. “If this type of stem cell works,” he adds, “the whole ethical controversy will be eliminated.”
Venturing to start clinical trials now is seen as a bold step. But Lanza is used to falling out of line. Even back when he was a schoolboy — just after the genetic code had been deciphered — he decided to alter the genetic makeup of a white chicken to make it black. “So I went to my teacher and told him that I was going to change the genetic makeup of the birds,” Lanza recounts. “He said: ‘Lanza, you’re going to go to hell.’”
This merely encouraged the 13-year-old. He cobbled together some laboratory equipment. To gain support for his experiment, the youngster boarded a bus in his hometown of Stoughton, close to Boston, and went “looking for a Harvard professor,” as he explains with a grin. At first, his journey appeared to end at the closed gates of Harvard Medical School. But Lanza soon saw “a short, balding guy” coming across the parking lot. “He was wearing khaki pants and had a bunch of keys,” he says. “I thought he was the janitor.” The boy had no idea that this was Stephen Kuffler, one of the most famous neurophysiologists of his time.
Kuffler played along: He opened the door for Lanza, allowed the boy to explain to him how genetics worked, and pushed him up the stairs. This opened up a new universe for the up-and-coming scientist. He repeated his chicken experiment and landed his first publication in Nature.
The Dawning of a New Medical Era
Lanza likes to tell this story to visitors. It shows how zeal can overcome all obstacles. He is often compared to the main character played by Matt Damon in the film “Good Will Hunting,” a highly talented outsider who, like Lanza, comes from a humble background.
“Right from the beginning, I probably didn’t follow the rules,” says Lanza with a certain amount of pride. He studied medicine at Harvard. In South Africa, he worked with Christiaan Barnard, the surgeon who performed the world’s first human heart transplant in 1967, and with Jonas Salk, who developed the polio vaccine in the 1950s. Then, in 1996, the world’s first cloned sheep, Dolly, was born in Britain — and Lanza sensed that his hour had arrived.
“I knew right away that cloning could revolutionize medicine,” he says. With the help of cloned stem cells, the young researcher was convinced that a wide range of top-notch replacement parts could be created for the human body.
The physician signed up with the biotech startup ACT. Working for the company in 2000, he cloned a gaur, an endangered wild bovine native to Southeast Asia. Later, his team managed to transform the frozen skin cells of a banteng into a living sample of this Asian wild cattle. The skin cells came from an animal that had died a quarter of a century earlier in the San Diego Zoo.
For Lanza, these were just practice exercises. The ultimate goal for him was always people — and he was at just the right place for that: In 2001, then-ACT CEO Michael West went before the press and announced that his company had cloned a human embryo for the first time. West spoke of the beginning of “a new era of medicine.” Then all hell broke loose.
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Obstacles Along the Way
When Lanza harkens back to those days, he becomes more serious. Although the ACT embryos had only grown to tiny balls consisting of six cells, for anti-abortion activists and pro-lifers the researcher was now the Antichrist incarnate.
“I remember that I went down to Tennessee, to the Bible country, and I went to one of those churches to explain what we were really doing. As I went through the door with the minister, a guy got up and shouted “Murderer! Murderer!” Lanza hired a bodyguard.
In the wake of the media coup, ACT started to founder. Investors withdrew from the company, and with George W. Bush in the White House, public funding for stem cell research dried up. “We went through multiple times where we lost the whole team,” says Lanza, who notes that they even had their phone disconnected for a while. “Rather than curing diseases, we were trying to resolve theological problems,” Lanza says bitterly. “And that’s not what I studied medicine for.”
Talking about the issue has slowly made the doctor furious and, almost imperceptibly, his tone of voice is becoming shriller. Another story has to be told, that of a policeman standing in front of the door one day. Lanza was afraid that he would be arrested. But no: “He came into my office and said that he had a child who was slowly going blind,” the physician recalls. “He said that he had heard of these cells that could supposedly help, and I said: ‘Yes, I have these cells in a freezer, but I don’t have the $20,000 to test them on mice.’”
Lanza had to turn the man away. It pains him to this day. “I don’t want to know how many people went blind because we lost our public funding,” he says angrily. “Nobody gets it; they say everything is fine; no, it’s not fine!”
Changes in the Political Environment and Scientific Advances
Attention shifted away from ACT. Instead, everyone started talking about Geron, another biotech company on the West Coast. Researchers there had succeeded in cultivating nerve cells from embryonic stem cells. With support from Christopher Reeve, the paralyzed “Superman,” there was renewed hope that spinal cord injuries could be healed. Three patients were treated using the therapy developed by Geron. But in November 2011, the company put the brakes on the research due to a lack of funds.
That was the moment when Lanza realized that he once again had to play the role of stem-cell-research poster boy. But this time he had something to show for his efforts. Benefiting from progress that Geron had made, ACT had also managed to gain FDA approval for a clinical trial.
Researchers had cultivated so-called retinal pigment epithelium (RPE) cells, which form a thin layer over the retina and keep the photoreceptor cells nourished and healthy.
In July 2011, doctors at the University of California in Los Angeles (UCLA) injected the first two patients directly behind the retina, each with some 50,000 RPE cells from Lanza’s cell factory. There are now 36 patients in the US and the UK taking part in the trials. They either suffer from the hereditary Stargardt disease or age-related macular degeneration (AMD), both of which are conditions in which RPE cells slowly die, resulting in a loss of vision.
Initial Success and Tempered Optimism
One of the Stargardt patients is David Lee, from the northern English town of Leigh, just outside of Manchester. Following a routine eye checkup 25 years ago, Lee was told that he suffers from the disease. Over the ensuing years, he has had to idly stand by while he progressively loses his eyesight. “Watching television has become very hard, and reading is impossible without magnification,” the 47-year-old says.
Then Lee heard about the stem cell trials and submitted an application to become a subject in the study. In late July 2012, he was operated on by a team working under surgeon James Bainbridge at Moorfields Eye Hospital in London. The doctors injected RPE cells in Lee’s left eye. “I was exceptionally happy about it,” he says.
Lee regularly travels to London to have his eyes examined. His physicians are satisfied. The RPE cells from the bio lab are thriving in Lee’s retina. “I see definitely brighter on the eye that was operated on,” he says.
He runs a bakery out of a small brick house in the center of Leigh, and he can still see just well enough to be able to sell cakes, pastries and bread. “I know that I won’t get my sight back”, Lee says. “But, for me, it would already be a big success not to lose any more of my sight.”
Many of the patients report that the therapy is effective. “We have some surprisingly good visual outcome,” says Steven Schwartz, an eye surgeon at UCLA. He says that one of his patients can read a clock again and go shopping, while another can recognize colors again. In addition to AMD and Stargardt patients, Schwartz plans to integrate extremely nearsighted individuals into the test program soon. The FDA has already approved the clinical trials.
Lanza is a “genius” and his work is “stellar,” Schwartz says. “The patients seem to tolerate the cells well,” he says. But the researcher warns against overly optimistic expectations, adding that it remains completely uncertain whether the innovative eye therapy will actually heal these ailments. He notes that the trials are mainly meant to test the safety of the procedure.
Stem cells can transform into virtually any type of body cell. Once they have become differentiated, they tend not to cause any problems. But what happens if they continue to develop, and one of the RPE cells from the lab mutates in the eye and becomes malignant?
“I worry that a single case of cancer in a stem cell model like this could set the field back enormously,” says Arthur Caplan, a bioethicist at the University of Pennsylvania. He is concerned that ACT may be pursuing its clinical trials far too aggressively. After all, the company has to placate its investors and outdo the competition.
Competitors and Risks
Indeed, Lanza will have to hurry up if he wants to be the first to come up with a clinically tested application for iPS cells. His greatest rival is located in Kobe, Japan, at the RIKEN Center for Developmental Biology. There, Dr. Shinya Yamanaka is working on groundbreaking stem cell therapies.
And the Japanese researcher is a very capable contender. After all, he received the Nobel Prize in physiology or medicine last October for his method of producing iPS cells. Like Lanza, Yamanaka is striving to use stem cells to cure blindness from macular degeneration (AMD). But, unlike Lanza, he plans to use iPS cells.
“Lanza is under tremendous pressure to show some positive results,” Caplan warns, adding that he is without a doubt a serious researcher. “But ACT has a history of overselling. They made a lot of promises in the past that just haven’t delivered.”
Lanza is aware of the bad press. “Mistakes have been made,” he admits. But he remains feisty. For instance, he accuses Yamanaka, his Japanese counterpart, of venturing an experiment that is particularly risky. “We still don’t entirely understand how safe iPS cells are and how they work,” says Lanza. Using them to cultivate RPE cells to treat eye diseases is dangerous, he adds, because the cells could possibly become cancerous in patients’ eyes.
“By contrast, we picked platelets for our first clinical trial with iPS because they have no nuclei,” he says. There is no chance of them growing out of control.
Enthusiastic about the Future
“Come have a look, I’m going to show you something else,” Lanza says at the end of the interview, as he opens a binder and pulls out a diagram that charts age relative to degree of paralysis. It has to do with multiple sclerosis. Lanza has studied mice that suffer from this crippling neurological disorder. The curve documents the sad fate of untreated animals: At the age of two, they drag their hind legs behind them. At the age of three, they are completely paralyzed.
But it’s a completely different story among the mice that were treated with stem cells: The curve of this group can hardly be differentiated from that of healthy animals. “One shot of these cells and they are jumping around completely normal,” Lanza says with enthusiasm. The researcher treats the animals with so-called mesenchymal stem cells (MSCs), which are cultivated from embryonic stem cells or iPS cells. They resemble bone marrow cells and secrete substances in the body that work like a fountain of youth.
“That’s the future,” Lanza says. He points to an entire list of diseases that could potentially be treated with MSC cells, including chronic pain, arthritis and Parkinson’s. “The biological potency of these cells is just incredible! And we can make them by the millions,” he exclaims.
This is what Lanza is like when he’s in the grips of enthusiasm. His eyes sparkle and his gestures underscore each word. At moments like these, one senses how far his enthusiasm can take him.
“Before ACT hired me, they gave me a task,” he explains. “I was asked to get all the Nobel laureates in the country to sign a letter to support embryonic stem cell research.”
Lanza put his fax machine to work. Ever since then, he has had a stack of letters in his desk drawer — with the signatures of 70 Nobel Prize laureates.
Translated from the German by Paul Cohen
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