Cancer. Timothy sat in a lonely, crumbling room at Charité hospital in 2006, trying to decide what to do. He had just learned that his cancer had come back. The hospital felt so old that it was hard to believe anything innovative could be happening within its walls. To enter a hospital and not know when you will leave, or if you will ever leave, is a horrible, hopeless feeling. Timothy, who had undergone three rounds of chemotherapy, hourly imagined the worst. Chemo made Timothy so ill that, each time, he didn’t want to go through another round. The alternative, however, was worse.
He dreamed of Italy, where he had just taken what might be his last vacation. He had wandered Italy alone, traveling to Genoa and then along the coast for a few weeks. It was not an easy trip. After learning that his cancer had relapsed, his oncologist, Gero Hütter, had encouraged him to take a vacation. He had told him to get away and relax. The scenery was nice, but mortal feelings loomed. The time had come to decide whether to get a procedure that would be incredibly painful and life-threatening: a bone marrow transplant.
He knew how risky the procedure was. The doctor giving him a second opinion at a different hospital advised him against it, warning him of the risk. He had hoped the chemotherapy would work and he could return to a normal happy life. He had already endured so much. Why did he have to have cancer, too?
When he arrived in Milan, the rain was coming down softly on the cobblestone streets. He felt so alone. His boyfriend, Lucas, had stayed behind. Now that he was in the hospital again, the beauty of Italy came back to him. If he closed his eyes, he could still feel the warm welcome from his friends in Genoa, the taste of fresh seafood prepared just so. When he opened his eyes, the hospital glared at him. Cancer, not AIDS.
It started with the cold he couldn’t shake. It felt as if he’d been sick for months, weariness, congestion, and pain flashing in and out of his life. HIV had become a minor concern. By 2006, HIV had become a manageable condition. The infection was no longer regarded as the death sentence it had been when Timothy was first diagnosed in the 1990s. He couldn’t say the same about leukemia.
Just as when he was diagnosed with HIV, he heard the doctor speak to him slowly and softly in German. “Gibt es keine heilung.” There is no cure. Timothy had been diagnosed with acute myeloid leukemia, or AML, a deadly cancer, with only about 25 percent of adults surviving five years after diagnosis.
As cancers go, AML is a particularly sneaky one. The cancer begins growing in the bone marrow. Hidden in the core of our bones lies a powerful soft, flexible tissue. The bone marrow is a font of the precious stem cells that grow to become all the mature cells we need in our blood. Every day, our bone marrow produces billions of blood cells. In addition to red cells, bone marrow also produces our white blood cells, or lymphocytes, which comprise our immune system. AML starts in the bone marrow, where the cancer spurs normal lymphocytes to grow wildly and replace the healthy blood cells. The cancer eats away at our immune system until we have nothing left; we can no longer protect ourselves. Or, from all appearances, you could say Timothy got a cold that he couldn’t seem to shake.
Doctors don’t know what causes AML. It might be exposure to certain chemicals, a blood disorder, or even having a weakened immune system. An HIV infection, which weakens the immune system, might be a factor. Being diagnosed with leukemia is a terrible blow for anyone. But for Timothy, the unknown effects of putting leukemia and HIV in the same body germinated a new kind of fear. He worried about the side effects of the cancer therapy as anyone would, but he also worried about having to stop his HIV therapy in order to be treated for his leukemia.
After his HIV diagnosis, he had told as many people as possible, to fight the isolation. Now he remained quiet. His many friends and the charismatic man he had once been, all faded into the distance that seemed a lifetime ago. All he had was the tiny dank hospital room, a boyfriend he loved to pieces, and Gero Hütter.
Following the very first meeting with Dr. Gero Hütter, in November 2006, he knew he could trust him. Hütter was a sharp contrast to Heiko Jessen. Sitting in Jessen’s modern, white waiting room was loathsome to Timothy. Back in the mid-1990s, Timothy would enter that patient room timidly. Jessen’s patients loved him like a father and he loved them right back, hugging his way into their hearts. But for Timothy, who had never experienced warm, fatherly concern, this level of intimacy was unwelcome. He didn’t want to be touched; he didn’t want to feel Jessen’s penetrating gaze, his soft concern, and his open heart. He wanted a physician, not a friend or a father.
Unlike Jessen, Hütter was focused solely on the clinical outcome. As a young oncologist, he had little experience in dealing with the emotional side of medicine. When Hütter met Timothy, he found him open, friendly, and very quick. He was tall and thin and looked nothing like a cancer patient. But this was clinically expected. Hütter had seen this phenomenon in many leukemia patients. They all looked healthy—until they started chemotherapy.
Their relationship unfolded with businesslike distance. Hütter explained very little of the science to Timothy at their appointments. He spoke instead of options, alternatives, and survival rates. Timothy responded well to Hütter’s brisk nature, finding comfort in the impersonal yet scientific personality of the young oncologist.
Chemotherapy began. At Charité hospital, where Hütter saw Timothy, all leukemia patients under sixty years old are offered a stem cell transplant. Cancer patients often benefit from the transplant because the chemotherapy they take, while able to kill off cancerous cells, also kills off healthy cells. By transplanting new stem cells, the blood gets refreshed with a new supply of immune cells. The transplanted cells are not the embryonic stem cells that have been at the center of so much controversy. Instead, hematopoietic stem cells are transplanted. These cells, although they can’t form any cell of the body like their controversial counterparts, can develop into any cell of the immune system. The cells are found concentrated in the bone marrow or diluted in the bloodstream.
Cells can be donated from someone else, often a stranger the patient has never met, or concentrated and expanded from the patient’s own body. For an allogeneic transplant, one in which the cells come from someone else, it takes time to match up the genetics from the person who needs the transplant to the person who’s willing to have stem cells harvested from their bone marrow. The genetics that must be matched up are the HLA, the same set of genes that Bruce Walker was examining in his HIV research. Because we’re matching up stem cells that form the immune system, the HLA, which are the genes that govern that immune system, have to be carefully checked to make sure there is a perfect match between donor and recipient. The search to find the right match for Timothy began, but of course he hoped he’d never have to have a stem cell transplant. He hoped the chemotherapy would work and he’d be back to his old self.
No one wants to get a bone marrow transplant. The procedure is dangerous. Before the transplant takes place, ablative treatment is given to prepare the patient’s body. These drugs, like chemotherapy and radiation, make space in the bone marrow for the new transplant. Stem cells are then taken from the donor, either from their hip bones or concentrated from their blood. Cells can also be taken from umbilical cord blood after a baby is born, a rich source of hematopoietic stem cells. Wherever and whomever they come from, the cells are delivered through a tube into the blood of the patient, and they make their way to the core of the bone, where they build a brand-new immune system. How well the transplant goes depends on how closely the donor and recipient are genetically matched. If the match isn’t good, the cells from the donor will attack their new body and the result can be severe, even fatal.
Despite Hütter’s conservative manner, he was a man not afraid to take considerable risk in his research. Hütter was planning a bone marrow transplant like none performed before. He had an idea, born from that paper he’d read a decade earlier. That paper, published in 1996, described the Δ32 mutation and its protection from HIV infection. It was the catalyst for Hütter’s experimental therapy but it was by no means a sure thing. Many a physician would not have wanted to take such a gamble. When an experienced virologist tried to explain to Hütter why it wouldn’t work, he would only nod and acknowledge the risk; he still believed in the approach. Now he had to convince the hospital.
No HIV patient had ever received a bone marrow transplant in Charité hospital before. The hospital administrators said no, clinging to protocols from the 1980s, when AIDS was considered a death sentence. By this outdated logic, they reasoned that any patient with this deadly disease should be denied a costly bone marrow transplant, which would prolong life only for a limited time. Hütter, pressing his case, presented studies showing that HIV patients were now routinely given bone marrow transplants. He argued that HIV was no longer a valid reason to deny lifesaving treatment for cancer.
It was the first of many fights Hütter faced as Timothy’s doctor at Charité hospital. Hütter was, after all, proposing a radical new method of treating HIV infection. Despite the fact that Timothy was Hütter’s first HIV patient, the moment he met him, he had begun formulating a plan that encompassed not only treating his cancer but ultimately curing his HIV infection.
Like Jerome Horwitz before him, who envisioned a new way to cut off cancer from the cell, Hütter clearly recalled his first insight into the problem—that cold winter afternoon in his medical school library. HIV uses the cell in many ways, but when it comes to entering a human cell, HIV needs only two things: CD4 and CCR5. The target was therefore obvious.
CCR5, a gene that humans don’t seem to need, is something that HIV absolutely needs. The plan was simple: Take out CCR5. The mechanism just as simple: a stem cell transplant. Timothy would receive chemotherapy and a stem cell transplant to fight his cancer. The opportunity was right in front of them. Instead of transplanting cells from any donor, they could find a donor with the Δ32 mutation. That way, when the stem cells formed a brand-new immune system, they would also form one that did not express CCR5 on the surface of T cells. These T cells, then, would be resistant to the virus. Even better, the virus would kill off the cells they could enter, selecting for a strong immune system capable of beating both cancer and HIV. It was a bold, elegant plan. Hütter fervently believed that it could work.
Charité hospital was, like many hospitals all over the world, a cutthroat, competitive environment for young doctors. They knew that permanent faculty positions were limited and only those who practiced both exceptional medicine and research would be promoted to one of the coveted posts.
Hütter felt the effects of this oppressive environment. As long as he possibly could, he withheld the details of his plan and of the presence of Timothy himself, for he knew that his competition would quickly try to squash such audacious plans from a junior doctor. Worse, for a long time, he hid Timothy’s case from his own chief.
So it was no surprise to Hütter when infectious disease doctors at Charité hospital took up strong opposition. They argued that HIV can use receptors other than CCR5 to enter T cells. Consequently, transplanting Timothy with cells lacking the CCR5 receptor could not possibly keep HIV strains that use these other receptors from infecting Timothy. In fact, since Timothy had been HIV-positive for decades, it was more likely he harbored the CCR5-independent strains that become, for unknown reasons, more common later in infection.
The vast majority of HIV strains use the CCR5 receptor on the surface of immune cells to infect humans, but it is true that a small percentage of viruses use a different receptor: CXCR4. Viruses that use CXCR4 tend to be more pathogenic; they accelerate the virus’s disease course in patients, causing rapid T cell death and general immune system destruction. Like the CCR5 receptor, the CXCR4 receptor influences how cells move around the body, but unlike CCR5, CXCR4 is an important receptor biologically. It is critical to how immune cells develop from the bone marrow and move into the peripheral blood. Humans who are born without the CCR5 receptor live normal, healthy lives. However, we have no examples of a human able to live without CXCR4.
This is why infectious disease doctors were challenging Hütter’s proposed therapy for Timothy. While eliminating CCR5 could undoubtedly contain some of the virus, the CXCR4 virus that Timothy likely harbored would still be able to grow. In fact, the approach could potentially result in a more dangerous HIV infection than Timothy had before receiving the transplant. And this was all supposing that it was even possible to get rid of CCR5 in patient cells, something that had never been done before.
Hütter, for his part, had far fewer studies to support his theory. There were no animal models he could point to where loss of CCR5 was linked to HIV protection. He worried that the reason no animal model had been published was because the experiments had failed.
His main argument rested on papers that had been published fifteen years previously. But the heart of his argument was not based on a model or theory; it was based on people, thousands of people who naturally lacked the CCR5 gene and yet lived healthy lives. It was based on the hundreds of people who, without the CCR5 gene, were resistant to HIV. Hütter’s research did not address those people who, despite their lack of the CCR5 gene, still became infected with a CXCR4-using virus.
A stem cell transplant was different, he reasoned; they had the opportunity to reset the immune system, to turn back the viral evolutionary clock. He reasoned this because Timothy would be receiving not only a stem cell transplant but also a conditioning, or ablative, regimen to ensure that he didn’t develop graft-versus-host disease. To avoid the disease, drugs are given to the patient before the transplant that dampen the immune system. In addition to suppressing the immune system, the conditioning therapy “makes room” in the bone marrow, by killing cells, for the new stem cells to expand. Between the chemotherapy and the conditioning regimen, Hütter believed it was likely that they were “resetting the immune system clock” by replacing so many cells, presenting a new opportunity to fight the virus.
He argued the case to Eckhard Thiel, the chief of transplantation medicine at the hospital. After months of hiding Timothy’s case from his chief, afraid that both his idea and his patient would be stolen from him, he knew it was time to unveil his plan. As he sat in Thiel’s first-floor office, he was nervous. He looked out the windows at the park just a few feet away. The paths were crowded with patients and their families outside on the mild day. As a junior faculty member, he had little sway, but what he lacked in seniority, he made up in passion. Although it would be expensive and have little chance of success, Thiel finally agreed. He was not sure Hütter’s plan was reasonable, and certainly didn’t believe that it could ever result in eradicating HIV, but he wanted to give it a chance.
Finding a transplantation donor would be a challenge. All potential donors for Timothy had to undergo additional screening to sequence their CCR5 gene. Only those with the mutant CCR5 gene, the Δ32 mutation, would be considered eligible. This severely whittled down the number of potential donors. This is the kind of experiment that would be difficult to do anywhere other than Germany. Unlike the United States, Germany maintains a large database of bone marrow donors. In 1991, German donor registries received funding to build an extensive database of donors. In that single year, the number of donors went from around 2,000 to more than 50,000. Today the German registry, ZKRD, is the largest in the world and has access to more than 19.5 million patients worldwide. Through the registry, 75 percent of all patients receive a matched donor within three months; overall, 90 percent of patients are matched to a donor. Compare this to the United States, where only 65 percent of patients will ever find a donor through our national bone marrow registry.
Another advantage Germany has in the hunt for the mutant gene in the haystack is the high rate of this particular mutant gene in Europe. Fourteen percent of Europeans carry one copy of this mutation in their genes, a freakishly high number when compared to the rest of the world. In about 1 percent of all Europeans, both copies of the CCR5 gene are mutant. When both copies are mutated, the body can’t make the CCR5 protein, and HIV is left standing at the door, unable to turn the key.
Timothy was born with only one functional copy of the gene. That one copy was producing all the CCR5 that HIV needed to enter. If Hütter wanted to shut HIV out, he had to stop Timothy’s intact CCR5 gene. To do that, he had to find a donor who had no functional copies of the gene. That meant only 1 percent of the population was eligible.
No one knows why Europeans have such a high propensity for mutant CCR5. The mangling of CCR5 arose as a single mutating event about 700 years ago. This is considered a young mutation. Compare it to one of humanity’s eldest mutations that allowed us to properly convert plant fatty acids some 85,000 years ago. Some believe bubonic plague was the original instigator for the mutant CCR5. Plague, the “Black Death,” the pandemic that killed an estimated 100 million people in the Middle Ages, is caused by a bacterium, Yersinia pestis. These bacteria hijack macrophages, an immune cell that expresses CCR5. Some researchers think the bacteria enter our cells by a means similar to HIV, through our CCR5 receptor. However, studies on mouse susceptibility to the bacteria, in animals both with and without the CCR5 receptor, disagree on this point. The bubonic plague wiped out one-third of the European population. Given this widespread death, it makes sense that if a tiny mutation is able to keep the bacteria at bay, the mutation could become influential. Other theories have focused on smallpox, a virus whose entry into our cells remains mysterious. Some evidence exists that the poxvirus uses CCR5 to enter human cells. Whether powered by the bubonic plague, smallpox, or some driving force not yet identified, those with the Δ32 mutation had a survival advantage so powerful that their children carried that mutant in their genomes, to be passed down the generations. That survival advantage would lie dormant for centuries until the AIDS epidemic woke it from its slumber, extending its ancestral protection across time.
As the Charité team scoured Western Europe in search of Timothy’s perfect HIV-resistant match, Timothy felt lucky to have Lucas in his life. He didn’t want to have the frightening stem cell transplant at all and especially didn’t want to go through it alone.