Dear SZ-Magazin reader,
Over the years, Dr. Klein received many accolades for his work. In 2010, he was honored with the Gottfried Wilhelm Leibniz Prize, the most prestigious research award in Germany. The following year, he was named director of the “Dr. von Haunerschen Kinderspital”, a children's hospital in Munich.
However, the outcome of his study was devastating. Dr. Klein treated ten children who suffered from the life-threatening Wiskott-Aldrich syndrome with a course of gene therapy. Eight of the 10 children subsequently developed leukemia, and three of them have since died.
Dr. Klein took legal action after our story was published, challenging seven text passages in the eleven-page story. Through a preliminary ruling by the Hamburg District Court, he was successful in having five of these passages removed. However, SZ-Magazin appealed the decision on May 24, 2016. On July 19, the Hamburg District Court upheld its decision that the five text passages in question may no longer be published.
After that, Prof. Klein legally demanded an addendum of almost half a page. On the last day in court (Oberlandesgericht Hamburg, June 18, 2019) SZ-Magazin and Dr. Klein came to a mutual agreement. SZ-Magazin agreed to publish a »Nachtrag« (SZ-Magazin, July 19, 2019). Additional claims for compensation were dropped by Prof. Klein.
The core of the story, which the author and editorial team spent more than two years researching in-depth, remains unchanged. We still believe that publishing the story was in the public interest. For this reason, we have decided to make the text available online immediately, free of charge. For the sake of transparency, we have marked the text passages that had to be changed because of the court ruling.
Since the devastating aftermath of the study and our story attracted a great deal of international attention, we have now also translated the text into English.
At the end of the text, we have provided several links to the articles of other media outlets, including Die ZEIT, Spiegel Online and the Hannoversche Allgemeine Zeitung, where further articles concerning our research and its aftereffects have been published.
After the story broke, Ludwigs-Maximilian University of Munich (LMU) and the Hannover Medical School, where Dr. Klein initiated the study, established an examination board to investigate the issue. The commission presented its findings on July 17, 2017, and concluded that there was »no indication that Professor Christoph Klein breached any scientific, medical, or ethical standards.«
The Süddeutsche Zeitung and Die Zeit have commented on the final report.
In response to an SZ-Magazin request for comment on July 17, 2017, the head of public relations at Hannover Medical School stated that the commission’s investigation had not yet been completed. He was neither able to say when this would occur, nor who sat on the commission.
Michael Ebert
Editor-in-chief SZ-Magazin
When Mahmoud* was born in September 2004, he was seriously ill. His parents are Syrian, but the family lived in Kuwait as guest workers. It took a long time for Kuwaiti doctors to understand what Mahmoud was suffering from, because his condition was extremely rare. Only boys suffer from his disease, which afflicts one in 250,000. In Germany, about only three dozen boys have it.
Nine years later, Mahmoud died, but not directly because of his illness. Before you can understand Mahmoud's story, the story of his ambitious young doctor, and the story of the other dead children, you must know their common enemy: Wiskott-Aldrich syndrome, or WAS for short. The disease is caused by mutations in a particular gene now known as the Wiskott-Aldrich syndrome gene. The German physician Alfred Wiskott discovered it in 1937. Children with WAS suffer, depending on the severity of their disease, from bleeding and infections, eczema and vasculitis. Some get lymphoma or leukemia. If a child is not treated, he or she can die as a baby. Some patients reach their teens, and few grow up.
When Mahmoud was born in 2004, WAS was treated in most industrialized nations with a stem cell transplant, which involves injecting a patient with the stem cells of another human being. The same method is also used to treat blood cancer. It is a grueling, brutal treatment. First, doctors kill off the patient's own stem cells with chemotherapy, then they transplant the donor cells. This is only possible when the donor stem cells match those of the patient. Doctors can check this by comparing ten different characteristics of the donor and recipient stem cells. The search is often lengthy. In the best case scenario, all ten characteristics match up. If the donor is related to the recipient, there is a 90% chance the transplant will go well and the recipient can recover to long-term health. Non-family donors who have a ten-characteristic match are often referred to as »genetic twins.« If doctors find a »genetic twin« for a boy suffering from WAS, there is about an 80% chance that the transplant will be successful.
For many WAS patients, life is much better after the stem cell transplant. Their life expectancy increases by decades, and some are considered completely healthy. However, there are still patients - though they are very rare - who die after the stem cell transplant, especially if the donor and recipient do not match up well.
After he was diagnosed with WAS, Mahmoud's life took a different turn. His doctor heard that physicians in Hannover were developing a new treatment for boys with the disease, treating it at the point where it originated: in the genes. Patients wouldn't receive someone else's stem cells. Rather, the doctors would use native stem cells from the patient's own genes. At the time, this new therapy had not yet been tested with WAS patients, so the treatment was carried out in the form of a study.
To participate in the study, a patient needed to meet several criteria. He needed to be at least one year old, and the expression of his disease needed to be a "classic case of Wiskott-Aldrich syndrome." That's all according to the protocol, the document that defines what exactly happens during a study. A study protocol also includes ethical discussions and defines the purpose of the study.
Mahmoud met all the criteria. His parents signed a consent form: eight pages of text covering the disease, the threats and opportunities of gene therapy, even insurance. It explained the alternative to a foreign cell transplant, but only in a few lines. The doctor, Christoph Klein, emphasizes that he himself had explained the alternative treatment presented in the written consent form - the transplantation of donor stem cells - to the parents of his patients before they agreed to gene therapy. Mahmoud's parents opted for the new gene therapy. In November 2009, the study began. Mahmoud was five years old. (1)
Other parents were also convinced by the prospect of the new gene therapy. In Bünde, North Rhine-Westphalia, Svenja Höke awoke in November 2008 to find her son Tom crying tears of blood, just a week after his second birthday. At the hospital in Minden, a doctor gave her the good and bad news. The good: Tom's bone marrow was okay. The bad: The doctor did not know exactly what was causing the illness. The Hökes ended up with a professor in Bremen who told them: "Your son has Wiskott-Aldrich syndrome. But we're still investigating. Don't Google it just yet..."
The Hökes went home and Googled anyway. Svenja read that her boy had perhaps just a few more years to live. But the professor from Bremen told them about the study in Hannover. And a few days later, Svenja Höke went with Tom to Hannover to visit the children's hospital at the medical school.
Gene therapy is perhaps the greatest medical promise in history: Diseases can be remedied right where they began, in the genes of patients. Past the symptoms, directly to the root causes. Gene therapy is a promise of salvation. For patients like Mahmoud, whose diseases are extremely rare, this is particularly true. Rare diseases are poorly understood - for about 7,000 of them, there are only 120 drugs. In Germany alone, 3,000 children die every year from rare diseases. Doctors are often unable to help because there are so few patients to learn from. And research is expensive, especially for those few people.
But the history of gene therapy is also a history of risk. It's impossible to remove its association with the name of Jesse Gelsinger, an American who died in 1999 just four days after undergoing gene therapy. The University of Pennsylvania had broken clinical research rules in treating the 18-year-old, who was not particularly sick compared with other patients suffering from the same illness as he. Gelsinger likely could have lived using a strict diet and good medicine. As it turned out, he wasn't just killed by his illness, but by the gene therapy treatment itself. Since that first death it's been clear: Gene therapy doesn't just offer hope.
On November 10, 2009, Mahmoud was treated in Hannover, in this foreign country where late autumn is already frigid. But the doctors were friendly, and they were the world's best. The files from the study call Mahmoud »WAS8«: He was the eighth Wiskott-Aldrich patient worldwide to receive this gene therapy. The doctors in Hannover planned to treat a total of 15 children.
The therapy was developed by Christoph Klein. At turn of the millennium, Klein was in his thirties and in the midst of an exceptionally brilliant career. In high school, his classmates in Oberschwaben in Ulm looked up to Michael Jackson, but Klein looked up to Albert Schweitzer. He wondered whether he should become a musician or physician. Today he is a doctor, but he likes to emphasize that he's also an organist. Professionally qualified to play church music, Klein works as an organist and choirmaster part-time. As a youth he was an altar boy. He studied medicine in Ulm alongside psychology and philosophy, and also studied at Harvard Medical School, home to some of the best physicians in the world.
Klein specialized in pediatric oncology, the treatment of children with cancer. His colleague in a neighboring laboratory worked with mice. If he switched a gene off, the mice would become sick. Klein wondered: Could that work the other way around? If you could change a mutated gene, could you make a patient healthy?
In the nineties, Klein spent three years in Paris with Alain Fischer at the Necker-Enfants Malades hospital for children. Fischer became one of the most famous pediatricians in France when in 1999 he treated a sensational case of the disease SCID, which is not unlike WAS. The rare congenital immunodeficiency usually leads to death in childhood within months or a few years. Fischer fought SCID successfully with gene therapy. It was a medical breakthrough that Klein, who was studying under Fischer and teaching at Harvard, was able to witness firsthand.
After moving to Lower Saxony, Klein became a senior physician at Hannover Medical School (MHH). Colleagues from that era remember him as an excellent scientist who was quickly able to assemble a team. Doctors who worked at that time or later also describe a man whose identities as physician and scientist were not quite balanced: He was an ambitious researcher, but not always a doctor committed to his patients.
In 2008, Klein was promoted to director of the children's hospital in Hannover. It had only taken him about eight years. In the meantime, he had won five major awards for physicians. Already in 2001, he was head of a research group: »Stem cell transplantation and immunomodulation - development of new cellular and molecular therapies in pediatrics«. Klein was intensely concerned with gene therapy, that idea with the mice and the idea that brought his old supervisor so much attention. Instead of transplanting stem cells from other human patients, he believed patients could be re-injected with their own stem cells after those had been removed and stripped of their altered genes.
The group was funded by the Deutsche Forschungsgemeinschaft, one of the largest independent research funding organizations in Germany. It was an exciting time for scientists who dealt with genetic engineering. In the nineties, researchers around the world began to develop gene therapies for children suffering from immunodeficiency disorders. Apart from Alain Fischer's work in Paris, there was, for example, a study in London, another in Milan, and that of Klein's team in Hannover. Given that gene therapy was still pioneering work, each step was difficult and results were uncertain. And as Klein was drawing up the plans for his study, researchers knew significantly less about gene therapy than they do today. In retrospect, Klein said: «On the basis of pre-clinical trials, we moved step by step toward the clinic.» Klein also said he had always considered the ethical issues involved.
In gene therapy, individual genes are not easily moved back and forth. In order to move the improved Wiskott-Aldrich gene back into the genome of a patient, it must first be packed up, like a passenger put back into a taxi. Gene scientists call the taxis of the genome »vectors«. Vectors must penetrate into the genome and then insert new genetic information that won't cause disease. These vectors are a complex invention, and they have improved over time, as new generations of vectors replace the old ones. When he began his study, Klein was working with a very early generation.
Gene therapy can be a long and trying process for the doctors who perform it. But there are also few types of medical work that can lead to so much glory if successful. Klein knew that well. He said he was guided by his youthful dreams of Albert Schweitzer, noting that: »My path leads me not so much to Africa, but to the frontier of knowledge in pediatric medicine.«
Klein found several children who met the criteria of his study, and for him, this was a chance to cure a previously incurable disease. But for the kids, what was it?
Klein remembers the time just before the study began. »We didn't just say, let's do this. There were many long nights spent discussing it«, he recalls. On July 29, 2004, he submitted his study proposal to the ethics commission in Hannover. Klein only needed to cross the hospital grounds to turn it in.
The ethics committee met under the chairmanship of Professor Hans-Dieter Tröger in the basement of a large high school building. Tröger himself, an excellent doctor, was an institution not only at the clinic, but throughout the city, where he was well-known by patients, doctors and citizens because over several decades he had provided expert testimony in numerous high-profile court cases.
The ethics committee's ultimate task is to protect patients. The protocol, trial plan and patient information all must be scientifically accurate, and only then should the committee approve a study. However, the committee still only examines a proposed study on paper.
When the committee received Klein's proposal, it had additional questions, so it wasn't until February 15, 2005, that all of the study documents were finally ready to be examined.
Klein was lucky to have turned his documents in when he did in 2004, even though they were incomplete. Four days later, a change to German medical law went into effect. The new law was more stringent, but since Klein had already begun the approval process, his study could be grandfathered. Nevertheless, Klein said he voluntarily imposed the stricter rules on himself for the study, calling the Hannover Clinical Trial Center (HCTC) in as another auditor. The Institute was headed by Heiko von der Leyen, then husband of current German Defense Minister Ursula von der Leyen.
That Klein's planned study came with risks was already evident at the time the ethics committee was deliberating - Fischer was encountering problems with his own trials in Paris. At the end of 2002, two of the French physician's ten patients became ill with leukemia. When a third patient became sick, Fischer cancelled a planned study. In London, scientists were trying to heal ten children with a similar therapy, and there, too, a child fell ill with cancer.
All told, one child in London and four in Paris contracted leukemia. One of the children from the French study died. The British ended their study. At that time, evidence already indicated that the vectors caused the cancer, although other studies had used similar vectors without children falling ill.
A researcher from London who was involved in the British study said the team decided at that time to wait for a new generation of vectors, noting: »The technology was already in the making then, and is much safer now.«
If Klein had decided to wait for new vectors, he would have had to start from scratch. New technology also means new research, a new study, new methods. Years would have passed and he would have returned to the field that scientists call preclinical research. So instead, and despite the risks, Klein opted to use the already available vectors. He told SZ-Magazin: »The risk of developing leukemia in the WAS gene therapy could not be ruled out prior to the study.«
The ethics committee in Hannover had no objection. The German Medical Association (GMA) was also interested in Klein's study; at that time, there was a special commission for gene therapies, headed by the biochemist Klaus Cichutek, who recommended the study in a letter. Cichutek was already working for the Paul Ehrlich Institute (PEI), the German federal agency responsible for vaccines and biomedicines. After the GMA's approval of Klein's study, the University of Hannover's ethics committee also came back with a unanimous »yes« vote, backed by ethics chair Tröger.
The first patient was a four-year-old boy from Russia. He came with his mother to Germany. She was a seamstress, money was tight, and the boy was already seriously ill. He was treated on October 28, 2006.
The second boy was from Hungary, the third from Lebanon, and the fourth from Germany, as was the sixth: Tom Höke, who traveled to the clinic with his mother and sometimes his grandfather from a farm in North Rhine-Westphalia. The fifth patient - like Mahmoud, patient number eight - was a Syrian who was flown in from Kuwait. He was twelve years old when he was treated in Hannover. The seventh patient was Russian. Boys nine and ten were from the U.S. and Australia.
The young Australian, number ten, lived in Queensland. The course of his life was typical for a child with WAS: His parents found out that he was sick just three months after his birth, but it wasn't until he was 13 that the real diagnosis came. For years, physicians who did not know any better had given him the wrong treatments, until an American doctor his parents visited in desperation finally called their attention to the German study. In December 2009, three years after WAS1 from Russia, the Australian boy was treated in Hannover. At the time, no one thought he would be the last patient to join the study, which was originally to include 15 patients, not ten.
In the hospital room where the children were treated, there was constant pressure to clear out all bacteria and viruses, as even the smallest bug can be dangerous to a child with a weakened immune system. There, the boys received only chemotherapy drugs. Because they were to receive their own modified stem cells, and not those of a donor, the chemotherapy dose was relatively low.
Before the second step, the stem cell extraction, a doctor would inject each boy with a special medicine to ensure that the stem cells from the bone marrow would migrate into the blood. This made the process easier for the children, because doctors were then able to filter their patients' blood to access the stem cells, instead of operating directly on their bone marrow, where stem cells are normally found. A machine would then take each child's blood, filter it, and pass it back into the body. A white, cloudy substance would remain in a container nearby: white blood cells. Within these, recognizable to the naked eye, were stem cells. The entire process took four to five hours.
A study employee would then take the stem cells to Idar-Oberstein in Rhineland-Palatinate. There, specialists would spend four days editing each patient's cells in a high-tech laboratory. Vectors with the corrected Wiskott-Aldrich gene in the stem cells were then sent back to the hospital and injected back into the children.
The therapy did not take for the Lebanese boy, WAS3. Doctors noted a »clinical deterioration« in the study files. The child began bleeding again and suffered from life-threatening infections. Even with a second attempt, doctors failed to extract sufficient stem cells from his blood. So although the files show ten children taking part in the study, it was finally a matter of only nine children. (2)
And Klein succeeded in doing what no one before him had done. In October 2008, the German Medical Journal reported: »At Hannover Medical School, pediatric hematologists have conducted the world's first gene therapy for children with Wiskott-Aldrich syndrome - so far it's successful.«
Klein wrote to the ethics committee in Hannover: »I am pleased to inform you that our clinical gene therapy trial to treat patients with Wiskott-Aldrich syndrome continues to show very positive results and that we have seen no undesirable side effects.« He published his study in the most prestigious medical journal in the world, the New England Journal of Medicine.
In the following years, Klein was showered with recognition and prizes, including the Deutsche Forschungsgemeinschaft's Leibniz Prize, worth 2.5 million euros, and the Eva-Luise Köhler Prize for the study of rare diseases, worth 50,000 euros, which Klein received alongside Christopher Baum, a researcher from the same group who also worked with vectors. Like Klein, Baum was on the path to a brilliant career. Today, he is the president of the MHH.
Then Klein received the Paul Martini Prize, worth 25,000 euros, »for outstanding clinical and therapeutic drug research«; the William Dameshek Prize of the Association of American Hematologists; and additional research funding from the European Union. The Frankfurter Allgemeine Sonntagszeitung wrote a lengthy piece about patient number four, a boy from Germany, and his successful doctor. In the article, Klein spoke about the history of gene therapy, and about Jesse Gelsinger. That tragic case showed how doctors had acted imprudently in the early years of gene therapy, he told the newspaper.
Klein's story continued to get media attention, from the television station 3sat and from other newspapers. Pictures showed Klein holding his small patients' hands at their bedside. In September 2010, a northern German broadcast group ran a television series in which the Hökes spoke, through tears, of their son Tom's gene therapy, and in which Klein explained the medical basis of the procedure. Off camera, a narrator says the therapy has worked well, »and so the Hökes have finally made it.«
At the end of October 2010, just three days after he reported his success to the ethics committee, Klein wrote a letter to the PEI, which since December 2009 was headed by Cichutek, the man who had supported Klein's study on behalf of the GMA.
The world of top researchers who are familiar with genetic engineering is small. Whereas previously the PEI only conducted research on medicines, today, it also approves clinical trials. Klein didn't go through the institute to approve his study because he filed his request before changes to the German Medicinal Products Act went into effect. Therefore, while the institute did not have to approve his study, it asked to be informed of its progress, as did Heiko von der Leyen's HCTC.
As the head of the trial, Klein was obliged to report any unusual incidents. That is why he wrote a letter to the PEI in 2010. It was a so-called SUSAR message, which stands for Suspected Unexpected Serious Adverse Reaction. Less scientifically, it means: Something went horribly wrong.
Svenja Höke says that in her family, Tom's twin brother Luka was always the first to get sick. So when Tom began to cough a week after Luka in the autumn of 2010, he took the same antibiotics as his brother. But what worked for Luka did not help Tom.
At a hospital in Minden, the doctor who first examined Tom's bone marrow diagnosed the now almost four-year-old with leukemia. Höke grabbed the phone and began making calls to Hannover until Klein was finally summoned from a meeting. On the same day, she and Tom traveled to Hannover, where they were told they could not go home. Tom was classified as a high-risk patient and his chemotherapy began six days later. A few weeks later, the Hökes saw a rerun of the television broadcast celebrating Tom's recovery. They called the station to have the program removed. In the following months and years, one study participant after another became ill. For several of the boys, their illness began with a viral infection. Then came the cancer: Tom, the two Russians, the American, the Australian and the two Syrians from Kuwait, including Mahmoud. Emergency messages piled up in Klein's records.
Some experts observing the clinical trial became restless. When Klein reported the fourth case of blood cancer in March 2012, the deputy head of the PEI suggested that all the study's children be treated as if they had leukemia. Specifically, she asked whether all patients should be given a standard therapy against blood cancer as a precautionary measure: massive chemotherapy and stem cells from a foreign donor. Her proposal shows how dire the conditions of the patients had become and how much confidence in the study had plummeted. In the end, the parents decided against that treatment, according to Klein. But he decided to cut the study short, with ten, rather than 15, total participants.
While Klein and a team of cancer specialists fought to save the children's lives in the fall and winter of 2010, Klein also pursued another idea. He wanted to expand his study: After all, why, if you have started a major study, would you give up the opportunity to answer more scientific questions? Klein wanted his patients to take another drug that would analyze the function of certain cells. Until that point, the drug had not been allowed in the trial.
The ethics committee in Hannover agreed with Klein's suggestion within two days. The committee members had no qualms, and a re-consultation was not necessary, wrote Tröger, chairman of the commission, to Klein.
But the PEI rejected Klein's plan. International experts were horrified.
»Not one benefit of administering the drug to each of the children has been established«, reads an internal email from the Institute, which also states that the method of administering the drug did not comply with »generally accepted scientific knowledge«. The institute reminded the award-winning doctor of basic clinical rules: A new substance cannot be tested as an add-on in an existing study: It requires its own, separate study.
In January 2011, Cichutek, by then the president of the PEI, picked up the phone and explained to Klein that he needed to give up the test. Klein eventually relented.
In the summer 2011, Klein moved to Munich. It was perhaps the most important step in his career: He became the clinic director at the Dr. von Hauner Children's Hospital. On the way to his new office, Klein passed photographs of an older, friendly-looking man, one of his early predecessors. It was Alfred Wiskott. Klein now held the same position as the man who had discovered the illness he was hoping to cure. Wiskott was known as a great doctor, but his image was tarnished when it emerged that he knew one of his interns helped transport children to the Nazi hospital in Eglfing-Haar, where at least two dozen were murdered.
When Klein moved to Munich, he took his study with him. That meant responsibility for the trial was transferred to the children's hospital of Ludwig Maximilian University.
Baum, Klein's former colleague and the current president of the MHH, said he thought it was very responsible of Klein to take the study with him, »even though it was already known that the study had these complications.«
In Hannover, Klein had worked under the professor and pediatrician Dirk Reinhardt, a specialist in pediatric cancer. Reinhardt is now director of the children's hospital in Essen. He was in Hannover when the children who later contracted leukemia were treated as a part of Klein's study, and said he was glad the study moved as he »wanted to have nothing to do with it.«
In November 2011, Mahmoud was at home in Kuwait when he suddenly experienced cold-like symptoms. For three days, his fever rose, reaching 39 degrees Celsius (102.2 Fahrenheit). Kuwaiti doctors diagnosed him with a respiratory disease. From December 12 to 19, Mahmoud traveled to Munich for a routine check up. He spent a week under examination before the German doctors sent him home.
But only days later, his doctor in Kuwait sent a note to Munich: Mahmoud's blood values were off. Now the investigators were alarmed. Mahmoud flew to Germany again. An exam on January 11, 2012, confirmed the worst: Mahmoud, too, had blood cancer.
He was treated with chemotherapy. He fought for his life. The Munich doctors also struggled. By this point, cancer specialists in the Munich children's ward had become extremely critical of the study their new boss had brought them from Hannover. They began to talk. Some began reading about what had happened years before, in Paris and London.
Klein invited all of the children from the study to come to Munich for cancer treatment. Not all of the parents chose to bring them there, but most saw no alternative.
The Dr. von Hauner Children's Hospital has one of Europe's best pediatric cancer wards. In Russia or in Kuwait, doctors are often not as well-trained, and medical techniques are less developed. Mahmoud continued to fly back to Munich for treatment, but they only ever brought temporary relief. In May 2013, during one of his visits, doctors confirmed that his cancer was back. They suggested a bone marrow transplant from a donor.
The Hökes only brought Tom to Munich once. They arrived on a Thursday, and his check-up was on Friday. Tom, it seemed, was much doing much better. On Saturday, the family went to Legoland before the trip home. A week later, Klein called the parents at their farm. The data showed Tom's leukemia was back.
By the time Mahmoud went back to Munich, another child from the study, the other Syrian from Kuwait, had already died. After being treated by Klein, he lived for three and a half years, dying at the age of 15. Two years later, on October 4, 2013, Mahmoud died at the age of nine. One of Klein's assistant physicians noted in the study files: »Study: Wiskott-Aldrich syndrome gene therapy Memo: Patient died.« Mahmoud was buried in his homeland.
Two years later, in December of 2015, the Australian died aged 21. He was the tenth and last patient treated under Klein's gene therapy study. His parents had decided to have his cancer treated in Brisbane, and then in the U.S.
Of the nine children who completed Klein's gene therapy, seven have suffered from cancer, some more than once. Three have died.
When the first children began to be diagnosed with leukemia, Reinhardt, who would later become Klein's interim successor, was among the doctors at MHH who treated them. Reinhardt said he first searched for stem cell donors, because a stem cell transplant from a foreign donor is the most classic way to treat blood cancer. That was and is the standard therapy for young boys who suffer from WAS. When Reinhardt began his treatment, he was, like many of his colleagues, operating under the assumption that Klein had looked for donors for the children and had found none, because if you can treat a child's WAS with a known, relatively safe and relatively promising therapy, there's no reason to subject him to experimental gene therapy - especially when such therapy is known to have caused cancer in other studies.
Even Klein's former colleague Baum, who worked with him and has defended him, believes to this day that Klein might at least have avoided picking children who had good matching stem cell donors. Baum says that is a »standard« of science, and so it must have been in the study protocol.
But when Reinhardt began looking on behalf of one of his patients, he found a match almost immediately. It was a moment of great happiness for the boy. But his oncologists wondered: Why is it that these children, who would have been cured of WAS had they had matching donors in the first place, suddenly have donors only once they have blood cancer?
As it turns out, Klein's former colleague Baum was mistaken: Klein's study protocol made no mention of whether a child might have a suitable donor or not.
To date, nine of the study's ten children have received a stem cell transplant from a foreign donor. These are the seven who suffered from cancer after the gene therapy, another boy who was diagnosed with a precursor to leukemia, and patient number three from Lebanon, for whom the gene therapy never worked in the first place. He received a mixture of stem cells from his father and from an umbilical cord to treat his WAS. In retrospect it was a windfall for the boy, but there is evidence that some of the other children could have been treated using a donor from the outset, without ever needing the experimental gene therapy.
The cancers of the seven boys and the precursor to cancer of the eighth boy would probably never have developed without the gene therapy. For four of the patients, the cancer doctors found donors who matched all ten characteristics. The now deceased Australian received stem cells from a relative who was not eligible to donate before the gene therapy because he was mentally ill and still underage. However, there may have been an unrelated matched donor for the Australian. So three, maybe four, of the study's children could have been cured of WAS with a high probability of success and without the risk of leukemia.
Among them was Tom Höke, who twice received stem cells from a foreign donor after his leukemia diagnosis. His mother said Klein did inform her before the gene therapy about the possibility of finding donors for Tom. His twin brother had been examined, and was not a match. But traditional therapy, including the search for unrelated donors, never came up after her first conversation with Klein. At that time, she was told that chemotherapy and cells from with a foreign donor would be a more serious undertaking; that treatment time would be longer; and that life for Tom on the farm, with its many germs, would be tricky. She didn't want to put her son, or her family, through that trouble. »That was entirely our decision«, Svenja Höke said, and she reached it after the first visit to Hannover.
Doctors found donors with a nine-out-of-ten-characteristic-match for three children in Klein's study during their cancer treatments. Two boys were treated with stem cells from a significantly poorer match of a donor, with only five matching characteristics out of ten.
Once it became clear in Hannover and Munich that Klein's team didn't conduct a complete search for unrelated donors before starting the children's gene therapy, some doctors became upset. That they were able to find donors quickly after the children were diagnosed with cancer did not surprise them: These days, 80 to 90% of all children in Europe or North America are able to find matching donors for leukemia.
It is unclear whether Klein told all of the other parents, as he did the Hökes, that there was a donor alternative to gene therapy, or whether this option only came up later. About patient number three, for whom the gene therapy did not work, he wrote in a letter to the HCTC: »After a new gene therapy proved to be unsuccessful, an alternative stem cell transplant option was presented to the parents.«
Today there are some professionals who believe Klein's study was a disaster and that the death of these children could have been prevented.
Klein himself recalls the long nights he spent discussing the project before it began. He says he believed it was equally justifiable for the study to include children without donors as it was to include children with donors, perhaps more so for the latter because if »the experimental gene therapy were not successful« or had »early side effects«, then those patients could resort to using treatment from foreign donors.
Other experts say that's nonsense: Experimental therapy is used only if no other means are available.
»Patients for whom there is a suitable donor may in no case be included in a study. Such a donor must be found«, said Christian Pestalozza, emeritus professor of public law at the Free University of Berlin and a member of another ethics committee. He argues that even if you can't find a donor initially, you should keep looking after you begin the study.
But Klein said that after considering many ethical arguments, at the time he began his study he had decided »not to include the question of the availability of an allogeneic stem cell donor in the inclusion criteria«, in any sense. His team only checked whether the children had suitable family member donors available. None of them did, except for the Australian, whose sibling was still a minor and thus forbidden from donating under the country's law.
Klein's explanations are detailed. Are they enough to justify his actions? Even Klein's doctoral supervisor Alain Fischer does not think so: »If we had done a WAS-study at that time, we would not have included WAS patientes with a matched related or a matched unrelated donor.« Fischer also says: »I am also surprised that the German authorities approved the study.« (3)
In a letter to Tröger written two days before Mahmoud's death, Klein gave an overview of the children's illnesses and said that his publications on the study had been »hampered in the past two years by very critical reviewers.« This was a restrained way of putting it. In professional circles, Klein has been confronted many times with the question of whether he should have foreseen the risk of cancer for the children in his study, especially after seeing the results of similar studies in Paris and London. Should he at least have waited for new vectors to become available?
Fischer said the situation was not as clear-cut at the beginning of Klein's study as it is today. But he also said: »I think the anticipated risk level was incorrect. The decision was made at a time when everything was still a gray area.«
But isn't that exactly what Klein wanted to do - to push the boundaries of pediatric medicine?
In any event, he had been exploring the idea for years. As children began to fall ill in Paris, the situation came to a head in his study. In January 2008, an employee of the PEI issued a written warning: In light of cases of »children treated with gene therapy in France and the recent onset of leukemia cases in England, a new risk-benefit assessment is deemed necessary.« Klein responded that he saw »in principle, no new considerations with regard to the risk-benefit profile of our study«.
At this time, only two children had been treated in Klein's study. Of the eight who subsequently began treatment, three died. It wasn't as if Klein hadn't responded to the reports of diseases in London and Paris. In December 2008, in a letter to the ethics committee, he wrote: »As you know, unwanted side effects have occurred in the context of two other gene therapy studies.« He specifically mentioned the cases of cancer in the Paris and London studies. He changed the treatment protocol, another official document within the study. In the new protocol, he outlined how patients should be monitored: Their bone marrow should be checked every six months instead of every twelve. Besides, he wants to update information for the patients and to store the children's stem cells in order to be able to treat them with gene therapy again, for example in the case of leukemia. (4)
»Research at the expense of life is never acceptable«, however, according to emeritus law professor Pestalozza. »For a researcher who wants to promote research today, this might mean forgoing a trial. Everything else is unethical.«
A researcher who »knowingly, despite existing standard therapies, puts the life or health of a patient at risk« is acting contrary the Hippocratic oath, Pestalozza insists, and against the Declaration of Helsinki, which lays out ethical principles for medical research involving human subjects. This code is binding for physicians. A trial that violates its guidelines can become »criminal«, namely when »the risk materializes« – that is, when participants get cancer or die.
When SZ-Magazin first approached the MHH for this piece, the school stonewalled us. Only after lawyers for the Süddeutsche newspaper asked a local court to hand over medical records were our reporters able to get a meeting.
On a tour of the hospital grounds, the press secretary for the medical school said that during his tenure, Klein did not like his offices in Hannover, saying that the best in medicine needs to look the part. The concrete building that houses the rooms where the children were treated with stem cell transplants didn't meet his criteria.
In Munich, Klein planned an entirely new building for the children's hospital. In a pamphlet advertising the plans, he wrote that a modern clinic for children must »have state-of-the-art research facilities.« In November 2014, Sultan Qaboos bin Said al-Said of Oman said he would donate 17 million euros to build a new clinic.
In Hannover, Tröger still rolls his r's like a Bavarian, despite having lived most of his life in the north of Germany. An elderly man with horn-rimmed glasses, dressed in a jacket and corduroys, he thinks fast and is quick to judge. He himself suffers from a serious illness.
For this interview, he sat alongside the president of the MHH, Baum, who wore a burgundy shirt and bespoke suit. During our conversation, Tröger spoke respectfully of Klein, and expressed frustration that his complex work had been questioned the way it had.
All three of them - Baum, Tröger and Klein - possess the same toughness. All three men have learned over the course of their careers to adhere to protocols and probabilities. They are the people who drive research, and the ones who must live with the consequences if their files fill up with SUSAR alerts. Of the early days of Klein's study, Baum said: »That was the pioneering era of gene therapy, there weren't many data. There was a risk you had to weigh and consider.«
How exactly the study got the approval of the Hannover ethics committee is unclear. Over the course of our research, we came across multiple versions of the story. In the end, it is probably an insignificant detail. The committee members all knew and understood each other. The panel's decision was unanimous. (5)
In an interview at Dr. von Hauner Children's Hospital in Munich, Klein weighed his words carefully. Sitting in his office, he repeatedly hesitated, corrected himself, and hesitated again. He cares deeply about how the public perceives him and his work, especially in critical situations. In the letter in which he first reported to the PEI that Tom Höke had cancer, he first mentioned the cancer and then press coverage of the study, writing: »In light of media attention, I encourage close consultation.» And: »There will be questions. We should broach the problem proactively.«
Again and again, Klein used the official letters about his patients' cancer to make proposals for dealing with the press. After the nine-year-old Russian boy was diagnosed with cancer, Klein wrote to Cichutek, who had just become president of the PEI, saying: »Personally, I see no need for a press release, since we published the first case last year.«
But a year later, in January 2012, the Münchner Merkur newspaper wrote a detailed report on the boy from Moscow and raised money for the child's treatment. The journalist mentioned the gene therapy in her article. She wrote: »Whether the once life-saving therapy has led to Sergey's cancer is not yet known. For clinical manager Klein, only one thing matters: saving Sergey's life again.«
In truth, it was already known that the gene therapy had caused the cancer. Two years prior, Klein himself had written as much in a letter to the PEI: »We have to assume that the leukemia has developed on the basis of the hematopoietic stem cell gene therapy.« It was already clear that what happened in Hannover and Munich was what had happened in London and Paris.
But with Klein, bad news always travels more slowly than good, even to the authorities who expect to be informed as soon as something happens. On April 9, 2014, the PEI complained in writing to a medical practitioner from Klein's team after learning of Mahmoud's death from an article in a medical journal - Klein's team had never reported what happened. Similarly, the institute found out about the young Australian's death in December 2015 through reporting by SZ-Magazin. The ethics committee wasn't informed until March 2016.
At the Dr. von Hauner Children's Hospital, employees recalled that once, when Klein was unhappy about an article in the local press - about something unrelated to gene therapy - he looked for the culprits and threatened staff members, who were relieved when it turned out that the father of a patient had been the one to speak to the press.
Several oncologists and primary care physicians also refused to speak with SZ-Magazin. When reached by phone, a senior physician at a German hospital said only: »Please discuss that with Mr. Klein.«
Many others were already expecting a call from journalists when their phones rang. Over the phone, a German cancer expert and supervisor of thirty doctors at a prestigious German institute that has worked on Klein's study spontaneously said the study was »devastating in its outcome.« Then he said he didn't want to say anything further.
According to this doctor, Klein liked to be in control. Parents whose children are still being treated by Klein broke off contact with this paper apparently after consulting with him. One mother said on the phone: »Mr. Klein wants to keep control over bad stories.« She didn't even have a bad story to tell, but still didn't dare speak. Tom Höke's parents were willing to be interviewed, but they are no longer in contact with Klein.
Klein connected the magazine with the family of a child from the study only after repeated pleas. A December 2014 email exchange with the mother of the Australian boy was open; her son was doing well at the time, and she wrote that the young man hoped to become a nurse. He died a year later.
Klein did not want to facilitate contact with families who might not be satisfied with his treatment, and certainly not with those whose children had died. He seemed certain that they would not want to tell their stories, saying: »We ask for your understanding in respecting the suffering of those parents who have lost children.«
Although Klein has been criticized in the small world of genetic medicine, his image still shines brightly. In 2014 he received the Hector Science Award, a prestigious prize endowed with 150,000 euros. He donated the prize money to his foundation Care-for-Rare, which advocates for children with rare diseases.
Tom Höke received full-body radiation treatment six times. It's impossible to predict what the long-term damage might be. On the farm in Bünde, his family has a blue file folder for WAS and a green folder for leukemia. Tom is a few centimeters shorter than his twin brother Luka. There was a time where he had stopped growing altogether.
During a recent visit, the brothers learned their multiplication tables together before playing with their tablet computers. When a question came up about his disease, Tom poked his head out from behind his screen with a half-bored »What?«
Svenja Höke said: »For me, the study has failed, completely.«
She looked for a moment at the table, the two thick folders in her hands. »But if it had worked, it would have been the best thing ever.«
*not his real name
Due to an appeal Dr. Klein has lodged following the publication of our story, five text passages out of the 11-page story are edited to this passage.
In this paragraph:
(1) one sentence is added
(2) a clause is slightly edited
(3) one sentence is deleted and Prof. Alain Fischer's quote is changed after consultation with Prof. Alain Fischer
(4) one sentence is added
(5) several words are added and deleted, among them a quotation sent by Prof. H.-D. Tröger via e-mail.
Links:
Die ZEIT
Spiegel Online
Hannoversche Allgemeine Zeitung
Illustration: Grace Helmer