Only Dr. Samuel Charache knows precisely where to place the needle. He can't put it in the arms of his sickle cell patients. Long ago, their veins collapsed, punctured too many times.
To draw blood from John Paul, Dr. Charache deftly locates the place on the man's right index finger -- on the knuckle. To draw blood from William Thorn Jr., the doctor pierces the outside of his thumb.
Dr. Charache, 65, knows these two patients almost as well as family. Out of this close relationship -- 28 years in Mr. Paul's case -- has grown a research effort that culminated last week in the announcement of an effective treatment for severe sickle cell anemia.
Appearing with Dr. George Dover, his collaborator, Dr. Charache said the drug hydroxyurea cuts in half the painful attacks, hospitalizations and transfusions endured by victims such as Mr. Paul and Mr. Thorn.
Dr. Charache has treated the men in the middle of the night and diligently answered their phone calls. In turn, they have given their blood and cooperated with drug research. Each considers Dr. Charache a close friend.
"They were sick. They were hoping something would work. But all they had really was the trust between them and Sam," said Dr. Dover, 48, a pediatrician. Through his research with Dr. Charache at the Johns Hopkins University School of Medicine, he, too, has grown close to Mr. Paul and Mr. Thorn.
For the four men, the breakthrough in treating the genetic disease is almost too good to be true. At a news conference, they smiled at one another but seemed reluctant to celebrate.
The doctors cautioned that hydroxyurea is not a cure, and that it is unclear if the drug will give patients -- who usually die in their 40s -- longer lives.
Mr. Thorn, 57, and Mr. Paul, 42, were among the first in the world to begin taking hydroxyurea 12 years ago.
"You just don't want to jinx it," Mr. Paul said. "Maybe if you start talking about it, you'll start getting sick again."
Sickle cell anemia is a blood disease that cripples and shortens the lives of about 150 of every 100,000 African-Americans. In Africa, the toll is much greater.
Inside a victim's red blood cells, molecules knock together and eventually bond. That makes the cells rigid, so they can't squeeze through tiny blood vessels and deliver oxygen. Deprived of oxygen, tissues die and organs are damaged.
Because hydroxyurea appears to hamper this process, a U.S. clinical trial has been stopped four months early so the drug can be made widely available.
The trial's early end has left Dr. Charache and Dr. Dover, the lead investigators, uncomfortable.
"Suppose we did make some . . . fool mistake, then it's our fault," said Dr. Charache, a hematologist whose work in the disease at Hopkins has earned him the nickname "Sickle Sam."
The doctors agonize that despite the statisticians, investigators and oversight panels, they might have been off in the calculations. Maybe their enthusiasm hurt their objectivity, Dr. Dover said. Both work more than 12 hours a day, six days a week.
"We have a credibility that we cherish. We have a name -- 'D Hopkins -- that has not been questioned," said Dr. Dover. "But we have to balance that against our responsibility to patients."
Despite the discovery of the gene that causes sickle cell anemia in 1950, medical science has made scant progress in stopping the suffering. With no effective treatment, all victims could do when the disease flared up was go to emergency departments. There, skeptical physicians were often reluctant to give pain medicine because the damage felt by the patients couldn't be seen.
"The doctor thought I was being phony," said Mr. Paul, recalling the night he was sent home three times from an emergency room. He was 14, and in so much pain that he was ready to jump off the Lafayette Street bridge. Panicked, his mother made several phone calls that led her to Dr. Charache.
"He believed what I was telling him," Mr. Paul said.
Mr. Thorn also had been ravaged by the disease when he found his way to Hopkins in 1983. He had suffered strokes, a hip and knee were being destroyed and pain medication disoriented him.
L "I was at my wit's end and almost suicidal," Mr. Thorn said.
Both men had come to the right place.
As far back as 1922, when a resident physician named the disease "sickle cell anemia," Hopkins has been at the forefront of sickle cell research. Some of the original genetic studies were done there.
In the early 1960s, Hopkins physicians found a woman who provided a major clue in stopping the cells from becoming rigid, which causes the damage from the disease. She had tested positive for sickle cell anemia but had none of its effects. Researchers around the country were studying similar cases and came to realize these people had fetal hemoglobin -- a part of the blood usually present only in infants -- and that it was somehow preventing the cells from becoming rigid.
Dr. Charache, who had worked at the National Cancer Institute and the Hospital of the University of Pennsylvania, arrived at Hopkins around this time. He and others tested several drugs in futile efforts to trigger production of fetal hemoglobin. Some caused side effects such as seizures.
Dr. Dover came to Hopkins in the early 1970s to train as a pediatrician. But frequently, he found himself telling parents of children with sickle cell that the children would suffer sudden painful attacks, like someone was repeatedly striking them with a hammer. Even worse, there was nothing anyone could do.
By the early 1980s, Drs. Charache and Dover were collaborating and had hopes for a drug that suppresses cell growth, speculating that it might hinder the "sickling" process. Mr. Paul and Mr. Thorn volunteered to try the drug, 5-Azacytidine. But there was little change in their conditions -- and an outcry from scientists who thought it was unsafe.
Then Dr. Dover's former mentor at Harvard University School of Medicine suggested a similar drug that had a safer record. The drug, which had been used in the treatment of cancer and a rare blood disease, was hydroxyurea. The two tested it on a patient in Massachusetts. The results surfaced on a Friday afternoon on a Labor Day weekend.
"I broke the code, and I knew it worked. But I couldn't reach anybody, because they were all at Cape Cod," Dr. Dover said. "For three days, I was the only one in the world who knew it worked."
Through precise testing methods Dr. Dover had developed, he could measure if fetal hemoglobin was being produced and how much. But it wasn't clear if the changes would translate into fewer attacks in people like Mr. Paul and Mr. Thorn.
The men agreed to try hydroxyurea. Over a few years, the drug began to help them. Attacks were further apart and were less excruciating. They began to gain control over their lives.
To scientifically prove what the two men were experiencing, Drs. Charache and Dover wanted a large, controlled study with one group taking the drug and another taking a placebo. But the National Institutes of Health turned down their grant proposal in 1989. Among other points, reviewers said the drug couldn't induce enough fetal hemoglobin production to matter.
"We both pretty much threw our hands up," Dr. Dover said. But they didn't give up. Being physicians as well as researchers, they saw too many patients suffering.
"I've been in pain so bad where I could actually see tears in this man's eyes because he understood the pain I was going through," said Mr. Paul, whose brother died of the disease and whose cousin is on his fifth hip replacement because of it. "I could see Dr. Charache getting exasperated because nothing was helping."
Finally, a national study of sickle cell patients indicated that even a small percentage increase in fetal hemoglobin could help. Drs. Charache and Dover reapplied, got the grant and started their national study in 1991. And in December, the weight of evidence was clear.
Adults with severe sickle cell disease will now begin taking daily doses of hydroxyurea pills. Still unknown are long-term side effects. Also, studies have begun to determine if the drug will be safe for children.
All the while, the physicians didn't say much about their struggle in the lab to Mr. Thorn and Mr. Paul.
"I always got a sense that eventually, we were going to find it, that eventually, it would be all right," Mr. Thorn said.
Mr. Paul has had the same feeling. At 19, he woke up after surgeons removed his spleen, appendix and gall bladder, all damaged by sickle cell. Things were hazy.
"I opened my eyes, and Dr. Charache was smiling down at me. He said, 'You're going to be all right, kid.' I just faded on back to sleep."