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Human Stem Cells at Johns Hopkins: A Forty Year History

Using Bone Marrow Transplants to Cure Patients
Johns Hopkins Researcher Lays the Groundwork for Bone Marrow Transplants
Making the Bone Marrow Transplant Accessible
Hopkins Continues the Legacy of Bone Marrow Transplantation Research
Moving Beyond Blood


While many people have heard of bone marrow transplants, few realize that this procedure is a stem cell therapy—in fact, the only stem cell therapy commonly in use today. And, thanks in large part to Johns Hopkins researcher George Santos (1909-2001), the procedure has been around for more than 40 years.

Bone marrow houses stem cells. These stem cells, in turn, make the specialized blood cells we need to survive, namely red cells, white cells and platelets. We need red cells to deliver oxygen to our bodies, white cells to fight off infection, and platelets to form clots when we are cut or bruised. 

People experiencing bone marrow failure disorders typically have a problem with their blood cells. Genetic blood disorders such as sickle cell anemia—a condition where red blood cells grow sickle-shaped instead of round—are inherited from our parents.  Other conditions such as aplastic anemia and leukemia can develop as we age. Aplastic anemia, an autoimmune disease, causes white blood cells to attack blood stem cells, resulting in low red cell, white cell and platelet counts. Leukemia, a cancer, causes blood stem cells to go awry and start creating more of themselves instead of specialized cells.

Using Bone Marrow Transplants to Cure Patients

Doctors realized decades ago that patients with bone marrow failure disorders could benefit from a bone marrow transplant, in which marrow is taken from a healthy donor and injected into a patient.

Ironically, says Rick Jones, M.D., professor of oncology, the history of the bone marrow transplant—a procedure that has today saved countless lives—has its roots in one of humanity’s darkest creations: the nuclear bomb.

Some 60 years ago, worried about the threat of a nuclear reaction, either accidental or hostile, scientists began studying ways to save patients exposed to radiation. At high enough levels, radiation destroys a person’s bone marrow, so scientists hoped to transplant those exposed to radiation with marrows from healthy donors.

But the procedure didn’t work as planned because radiation exposure destroys not only the bone marrow but also other organs of the body. Thus, those who receive too much radiation will lose not only bone marrow but also other vital organs, while those who receive little radiation exposure likely will recover without a bone marrow transplant, Jones says.

But the idea of using radiation to kill off the bone marrow caught the attention of doctors specializing in the treatment of bone marrow failure disorders. They reasoned that if they could kill off a patient’s diseased bone marrow using controlled levels of radiation, they could then transplant the patient with new, healthy donor marrow. By the 1960s, E. Donnall Thomas of Cooperstown, N.Y., began experimenting with total body radiation therapy prior to bone marrow transplant. But even in a controlled setting, he found that total body exposure to radiation led to lung problems in patients.  

At Johns Hopkins, meanwhile, George Santos began studying another way to kill off diseased bone marrow: administration of a chemotherapeutic drug cocktail that included busulfan and cyclophosphamide. Santos soon found that cyclophosphamide not only killed off bone marrow without the toxic effects observed in total body radiation but also had strong anti-cancer properties. His research into this drug, in particular, paved the way for modern-day bone marrow transplant efforts.

In 1972, Thomas performed the first successful bone marrow transplant on a patient with aplastic anemia using Santos' chemotherapy approach. Since that first successful surgery more than 30 years ago, bone marrow transplants using Santos’ preparatory regimen have become the treatment of choice for everything from cancers to genetic diseases of the blood. 

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Johns Hopkins Researcher Lays the Groundwork for Bone Marrow Transplants

Santos was a man well ahead of his time, says Jones, director of the Johns Hopkins Bone Marrow Transplantation Program—a program that Santos himself founded in 1968 and headed until his retirement in 1994.

Santos was among the first to recognize and study the positive effects of a postoperative condition known as graft-versus-host disease, or GVHD. In this condition, the transplanted, new immune system fails to recognize the transplant recipient’s body and attacks it. While GVHD can be deadly, it is a classic double-edged sword, says Robert Brodsky, chair of hematology at Hopkins. That’s because GVHD also has a strong anticancer effect. Thus, mild GVHD works in tandem with chemotherapy by killing cancerous cells the chemotherapy may have missed.

In addition to discovering of the benefits of the drug cyclophosphamide, Santos also found benefits to another chemotherapeutic drug,  4-CH. When Thomas conducted the first successful bone marrow transplant in the early 1970s, doctors only knew how to conduct allogeneic transplants—those requiring two individuals, a donor and patient. But Santos soon realized that 4-CH helped purge cancerous cells in a damaged marrow, thus paving the way for self, or autologous, transplants. In this type of transplant, blood stem cells are collected from a patient, frozen while the patient undergoes chemotherapy, and then re-injected several months later. The 4-CH drug, says Jones, is very good at attacking cancerous cells in lymphomas.

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Making the Bone Marrow Transplant Accessible

Santos’ early research into GVHD, says Brodsky, looms very large today. Until recently, he explains, allogeneic bone marrow transplants were limited to patients who could find a donor with matched tissue types since transplants between totally unmatched individuals cause lethal GVHD. 

Because these tissue types are determined by one’s genetic makeup, the best donor typically is a sibling. But, exact matches between siblings occur only 25 percent of the time. Only in the late 1980s did volunteers create the National Marrow Donor Program (NMDP), a database to help patients connect with potential donors.

“It turns out that about one in every 50,000 people just by chance will have the same constellation of tissue typing and be a match,” Jones says, adding that matches typically occur between people of the same ethnic background. But because the majority of NMDP participants are Caucasian, ethnic minorities still have a very difficult time finding an exact match on the registry, Jones says.

But Santos began studying ways to address this shortage in the 1970s as the result of a curious observation of some bone marrow recipients. About 20 percent of bone marrow transplant patients ended up recovering their own marrow instead of the donor marrow. He eventually discovered that unlike total body radiation, which wipes out a patient’s entire immune system, cyclophosphamide only kills blood cells and leaves the blood stem cells intact.

Santos wondered if cyclophosphamide, administered both before and after a bone marrow transplant could help fight GVHD. The drug would kill the cells causing GVHD, but not the stem cells needed to grow new cells. Santos suspected that if his theory was correct, doctors might someday be able to conduct transplants between nonmatching donors.

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Hopkins Continues the Legacy of Bone Marrow Transplantation Research

And, indeed, that is the case today. During the last 10 years, Hopkins researchers, including Jones and Brodsky, have followed up on Santos’ early efforts to create a new procedure known as the half-matched bone marrow transplant. Because half matches occur between all siblings, parents and one's own children, virtually everybody requiring a bone marrow transplant now has a suitable donor, says Brodsky.

The results have been astounding. “Ten years ago if you had a half-matched transplant, the chance of getting serious graft-versus-host disease was about 100 percent,” Jones says. “More than half of all patients would die from it. Now the chance of getting serious graft-versus-host disease is about 30 percent, and only one-third of patients will die from it." 

Half-matched bone marrow transplants now enable doctors to treat more and more patients who used to be ineligible for the procedure, says Brodsky. This breakthrough has shown particular promise in treating patients with sickle cell anemia. Finding an exact match for these patients has been almost impossible, he says, as most eligible donors are siblings who also carry the disease trait. But in March 2009, Brodsky, Jones and the Johns Hopkins bone marrow transplantation team successfully cured a 31-year-old woman (watch the video below) of the disease using bone marrow donated by her mother.

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Moving Beyond Blood

The hope, says Brodsky, is to someday use bone marrow transplants to cure nonblood-related diseases originating in the bone marrow. For instance, Brodsky draws a parallel between aplastic anemia (where white blood cells attack the blood stem cells) and other diseases, such as type 1 diabetes and multiple sclerosis, where white blood cells attack insulin-making cells of the pancreas and the myelin sheath covering nerve cells of the central nervous system, respectively. 

Using bone marrow transplants to treat nonblood-related diseases is already in its clinical phase, Brodsky adds. In a preliminary trial at Hopkins, 40 patients suffering from multiple sclerosis experienced either remission or a complete reversal of the disease following a bone marrow transplant. “Patients who could hardly walk or needed to walk with a cane are running two to three miles a day,” he says. “This is really exciting and it's happening right now.”

--by Sujata Gupta

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