Search for Breakthrough a Long, Arduous Journey : Science: A possible cure for a specific type of leukemia is causing great excitement. It did not happen overnight. It was the result of 25 years of tedious work.

In 1964, Utah researcher Roland K. Robins added yogurt-like bacteria to two chemicals to synthesize a new compound, one of several first-ever extracts that Robins speculated might attack cancer cells. The compound was known as 2-CdA.

Twenty-five years later, the drug was administered to 62-year-old Anne McKinley, and she became living testimony that the fruits of biotechnology have arrived.

During that 25-year journey, from Robins’ lab in Provo, Utah, to McKinley’s cure, 2-CdA was studied, rejected and resurrected. Later this year, the Scripps Clinic and Research Foundation, one of the pillars of San Diego’s thriving biotech community, will ask that 2-CdA be approved as a new drug with virtually miraculous results against a specific form of leukemia.

This is the story of 2-CdA, told through the people who identified it, concocted it, developed it, tested it, administered it and whose lives were saved by it.

It is, by extension, also the story of biotechnology--its serendipity, its challenges, its tediousness, its gaffes, its calculation and, in the end, its payoffs.

The payoff for McKinley came none too soon. In early 1989--just after putting her fashionable Hancock Park home in Los Angeles back to rights after the holidays--she had her annual physical and was stunned by her doctor’s findings, that her healthy white blood cell count was dangerously low.

She was told she had a rare form of leukemia, a cancer characterized by the unfettered proliferation of abnormal white blood cells, a kind of biological treason by cells that are supposed to be fighting disease. McKinley’s cancer is known as hairy-cell leukemia, for the physical appearance of the errant cells.

About 6,000 people in the United States have hairy-cell leukemia, and 600 new cases are reported every year. It can kill within months, or gnaw at the body for years, damning its victim with constant fatigue as it consumes oxygen-carrying red blood cells, and exposing him to illness as it destroys infection-fighting white cells.

“I was numb. I didn’t believe it,” McKinley said. “I felt just fine. My energy level hadn’t dropped, I hadn’t been getting any colds or any of that.”

She was referred to an oncologist, who--despite the disease’s relative rarity, especially among women--determined that McKinley had hairy-cell leukemia. He recommended that she get a second, and third, opinion.

Oncologists at both UCLA and USC confirmed the diagnosis, and each recommended that she be treated at his own university hospital with interferon, a relatively new chemical therapy for leukemia that has had mixed results.

But McKinley’s personal oncologist--the man who first diagnosed the leukemia--recommended that she go to the Scripps Clinic and Research Foundation in San Diego, where doctors were testing a new anti-cancer drug.

The doctor told McKinley what he knew of this apparently remarkable medicine. There are no side effects, except maybe a fever. The drug is administered just once--dripped into the arm over a week through a tube connected to a small, portable pump that can attach to a belt like some high-tech fanny pack. No further injections are needed.

Then blotto--the drug is supposed to outright kill the leukemia cells. Not just corner them in remission, but eliminate them altogether.

Scripps was contacted, and it accepted McKinley as another volunteer to test 2-CdA during its clinical trials, a precursor to approval by the U.S. Food and Drug Administration.

McKinley was hairy-cell leukemia patient No. 13 when she arrived in August, 1989. Her healthy white cell count was plummeting. She was admitted and confined to the clinic, hooked up to the IV for seven days.

“I had no sense of being a guinea pig,” she said. “I had complete confidence in everyone at Scripps. They all had such a very positive attitude.”

At one point during the week, she was gripped by fever. Because she was allergic to two common antibiotics, McKinley was treated for the fever with two blood transfusions, and her body stabilized.

“Nobody panicked,” she said.

After a week, most of her body’s white cells had been destroyed, according to plan. But there were none of the debilitating side effects that typically accompany chemotherapy. The 2-CdA, it seemed, was targeting just what it needed to eliminate the leukemia, exactly as doctors thought it would.

McKinley stayed at the hospital another week while her bone marrow replenished her white cells with healthy ones. Then she went home to finish recuperating. Today, she said, there’s not a trace of hairy-cell leukemia in her body.

“I’ve been cured,” she proclaims. “They say it’s a miracle drug.”

McKinley has yet to meet the man who helped deliver the miracle to her bedside. He is 44-year-old Dr. Dennis Carson, who grew up in Queens, N.Y., and lives in Del Mar with his wife, Sandy, and their four children, ages 6 to 18.

Identifying 2-CdA as an apparent cure for hairy-cell leukemia was Carson’s first “hit,” his first success in matching a novel medicine to a disease.

He had spent years at the federally funded National Institutes of Health in Bethesda, Md., studying the chemical aspects of immunology and searching for certain molecules that could interfere with the body’s immune system.

At about the same time--in the mid-1970s--researchers around the country were studying severe combined immuno deficiency disease, which was popularized in a television movie starring John Travolta as the so-called Bubble Boy. The real-life Texas youngster had no immunological defense system and had to live in a “spacesuit” constructed by NASA and, later, in a sterile “bubble” environment, because any infection he developed would be fatal.

By 1977, Carson had joined the Scripps staff of scientists and was studying the specifics of the rare immune deficiency. He discovered that the body needs a particular enzyme to balance the production of deoxyadenosine, which is created by each cell’s own metabolism. If the body lacks the enzyme, there’s an excess--and toxic--amount of deoxyadenosine, which then destroys white blood cells, the backbone of the immune system.

Looking at that scenario from the opposite direction, Carson reasoned that, if he could prompt the body to create an excess of deoxyadenosine--or if he could synthesize the analog, or molecular equivalent, of the toxin and inject it in the body--it would destroy white blood cells. In the case of leukemia, which is characterized by too many white blood cells, the result could be beneficial.

In effect, Carson would try to create a Bubble Boy syndrome in a leukemia patient, by purposely killing off the leukemia-stricken white blood cells. Then the body could begin its production of healthy white cells and be back in business.

By July, 1979, Carson was studying the literature to find the molecule with the properties he wanted.

“Millions of molecules have been made just for the fun of it,” he said. It was now a matter of going shopping for the general type, testing them and determining which came closest to his ideal.

“I had already dealt with the bigger challenge, of identifying the target. Now it was just a matter of identifying which molecule would meet my needs,” he said.

Among the analogs Carson believed might hit the target was 2-Chlorodeoxyadenosine, or 2-CdA, because it had chemical properties closely aligned with the body’s natural deoxyadenosine.

Carson was already somewhat familiar with 2-CdA because a UC San Diego professor of medicine and friend of his was studying the effect 2-CdA would have on gout.

The chemical had been synthesized in 1964 in a lab run by Roland K. Robins, a chemist at the University of Utah. Researchers there were studying possible anti-cancer agents based on the chemical adenosine because of success it had shown in inhibiting cancer cells.

Like a chef trying to improve on a recipe, Robins set off to synthesize as many analogs--or look-alikes--of adenosine as he could imagine, to see if any might come closer to hitting the mark. Among them was 2-CdA, which was synthesized by Robins’ second cousin, Morris J. Robins, who was pursuing his own doctorate in chemistry under Roland Robins’ direction.

In 1966, Roland Robins submitted 2-CdA to the National Cancer Institute, where researchers injected it in lab animals once a day. They eventually rejected it as ineffective against cancer.

Carson examined the paperwork from the cancer institute research and concluded that the 2-CdA testing was procedurally flawed.

He decided to pursue the compound on his own, and asked a friend of his, John Montgomery, a synthetic organic chemist at the renowned Southern Research Institute in Birmingham, Ala., to examine 2-CdA further.

“The National Cancer Institute had only injected 2-CdA once a day (in the animals), and I didn’t think that would be enough. John agreed with me,” Carson said.

Carson asked Robins to send him a sample of 2-CdA so he could synthesize his own and compare the two. Satisfied that he was able to make the real thing, he sent some to Montgomery’s lab--where tests showed that half the animals injected with it showed positive results against cancer.

“The Southern Research Institute is the most famous place in the world for testing anti-cancer drugs on animals,” Carson said. “When they tested it, and we got very fine results, we knew we were on the right track.”

The news pleased Robins. “I think it’s just tremendous that Dennis decided the compound was worthy of further study,” he said. “It takes someone like Dennis to pick up on a possible compound that had been rejected by others. He continued to work on it, and to believe in it.”

Carson and Montgomery wrote a paper on their findings--but Carson wasn’t about to put all his eggs in one basket. He and his lab technician, Bruce Wasson, created several other candidate drugs in their lab, and sent away for several others, testing them all. Then they broadened the field with another 15 compounds that, on paper, looked hopeful.

Throughout, 2-CdA performed best.

“In a sense, I thought this was just another esoteric study--that maybe it would eventually be useful, but that it wouldn’t lead directly to a drug,” said the 39-year-old Wasson.

He and his wife of 13 years, Sandy, had been living in Pittsburgh, where he was a lab technician at the local university and she had a computer software job. She was offered a good job in San Diego, and he figured he could find a similar lab job in San Diego. He saw a listing at Scripps for a technician with “knowledge of biochemistry and cell biology.” He was to report to Carson, just as the doctor was beginning his research on 2-CdA.

Wasson became the day-in, day-out nursemaid of the drug-in-the-making, collecting the samples, testing them in cell cultures, applying various white blood cells and watching what happened.

“I was the pessimist, and he was the optimist,” Wasson said of his relationship with Carson. “Early on, he saw this leading to the development of a new drug.”

Wasson acknowledges being bored by some of the early work.

“If I was doing the experiments without understanding what I was doing, I would have been incredibly bored,” he said. “We were dropping the compound onto cell plates to check on toxicity. We’d check them three days later, to see how many of the cells had been killed.”

The cells were taken from the tumors of cancer patients, and killing them wasn’t a problem. Cancer cells are relatively easy to kill. The trick was to find a molecular compound that would not kill other, non-cancerous cells. So, for each compound, the survival rate of normal cells was tested with even greater interest.

In time, Wasson began anticipating the results.

“You’d say to yourself, I think this compound will kill these certain cells, but not these other ones. You’d try it and check a few days later, and you’d go, ‘Ooops.’ ”

Wasson and Carson soon realized how potent 2-CdA was: Very little of it was needed to kill the cancerous cells, and just a little too much would destroy the good ones. Some cancers were more sensitive to 2-CdA than others.

“We had a cure in search of a disease,” Wasson said.

Although Carson had identified the basic disease to be studied, he now had on his hands a specific drug that, he figured, would work better on one form of cancer than another. “There was no one experiment that said, ‘This is it!’ You just became more and more certain about what was happening,” Wasson said.

By August, 1980, Wasson was making his own 2-CdA in the lab. All they had been sent by Robins was 5 milligrams--about five-thousandths of what the contents of a packet of artificial sweetener weighs. Home-grown 2-CdA was needed to continue the testing.

Making the stuff was somewhat tedious.

It involved buying 500 liters of yogurt-type bacteria, liquefying it in a large vat and, essentially by adding salt, separating the chemical contents so the sought-after enzymes would settle to the bottom. The 500 liters would yield a quart of the brownish-gray enzyme material.

Next, Wasson drained the enzyme into separate, 5-gallon vats and added precursor chemicals necessary to turn the enzyme into 2-CdA. The liquid was maintained at 98.6 degrees and stirred for about two days, then poured through a resin ion exchanger. The coveted 2-CdA adhered to the resin as the other liquids were drained off. The resin column was washed with other chemicals to release the 2-CdA. The end result--seven to 10 days later--was 5 grams of crystallized 2-CdA--about the amount necessary to fill a small salt shaker or a shot glass.

By the end of the first year, Wasson had made 20 grams of the stuff, at a cost in raw materials of about $10,000.

He and Carson tested the toxicity of 2-CdA on mice, but the results were inconclusive, and in February, 1981, they began human clinical trials. They gave the compound to terminally ill leukemia patients at Scripps to determine whether it would kill their cancerous cells without destroying their good ones.

At this point, Dr. Ernest Beutler, then Carson’s boss and the chairman of the department of molecular and experimental medicine at Scripps, joined directly in the work.

“We didn’t know very much about how to use this drug,” Beutler said. “We were trying to learn how best to administer it, to learn how toxic it was.”

He remembered giving the drug to the first human. “We decided to use one one-hundredth of the dose that would kill 50% of the mice. That’s 1 milligram per kilogram of body weight. We wanted to be very conservative. It became apparent, though, that even this small dose had a very marked effect on the patient’s leukemia cells. They all but disappeared in three or four days. We were using too high a dose.

“I began to see how potent this drug was,” Beutler said.

This phase of the studies, to determine what dosages of 2-CdA were beneficial without being toxic, lasted more than two years as recipients were monitored for short- and long-term effects. For the most part, the scientists continued to scale down the dosage.

By late 1984, Beutler, Carson, Wasson and other doctors who had joined the project began testing patients specifically to determine which leukemias were being most effectively killed by 2-CdA.

Beutler was joined by Dr. Lawrence Piro, who heads Scripps’ Green Cancer Center, in focusing on those patients getting 2-CdA who had B-cell leukemia--a family of diseases that includes hairy-cell leukemia. It wasn’t until 1986 that the first hairy-cell patient received the drug--and a year later before the next one did. Anne McKinley, in August, 1989, was the 13th.

“The results of 2-CdA on hairy-cell were without any doubt the most spectacular,” Beutler said.

Piro found personal satisfaction in the fact that a cure for cancer was being developed at Scripps. Even in grade school, he was pulled toward medicine, wanting to emulate his own personal physician, whom he described as a “kind and caring man.”

His interest grew more serious when his grandmother contracted breast cancer.

“My experience of taking care of her was very difficult,” Piro said. “We wanted to care for her at home, with pain injections, but her oncologist flatly refused. I was in college, and that experience made me decide oncology was the place for me.”

Piro was on the staff at Washington University in St. Louis before moving to Scripps as a fellow eight years ago. Today, Piro--who gives his age only as “late 30s”--his wife of 10 years and their 7-year-old daughter live in La Jolla.

Working with 2-CdA, he said, has been fascinating. “It’s been very, very successful--especially considering the minimal side effects and the fact that you just use a single injection. It’s astounding--and hard to understand.”

By now, several hundred cancer patients were volunteering to receive 2-CdA. And Patty Morin was beginning to know most of them.

Morin, 33, is a registered nurse who came to San Diego in 1987 after growing bored with Kansas City. She had worked eight years in a suburban hospital, two of them with cancer patients.

Working with those patients, she said, was professionally exciting.

“They’re acute. They’re really sick. There’s a breakdown of the entire body, so you’re providing total support--emotional support, too--for them and their families,” she said.

“You can really help them, and be there for them. But still, you’d watch them die.”

In San Diego, she took a variety of nursing jobs, including home care and working with AIDS patients. Later, in 1987, she took a nursing job at Scripps Clinic, floating from one assignment to another and eventually settling in the oncology unit. Six months later, Piro asked her to work with him.

“He said he had a new drug,” Morin said. That was welcome news to someone who remembered well the downside of working with cancer patients being treated with more traditional therapy.

“I had been pushing chemotherapies, which was depressing because it can be so toxic. People get nauseous. They lose their hair. They have more infections, mouth sores. I remember going after work to the gym to work out my stress.

“From my standpoint, it was great to get into a new drug with no bad side effects,” she said.

One of Morin’s first jobs was to screen, over the telephone, volunteers who had heard of the experimental testing and wanted to be included. In time, she had signed up more than 300 patients, was setting up their records, arranging for their visits, and instructing them on how to use the portable IV pump.

Increasingly, patients were allowed to take the pumps home for the weeklong administration of the drug. In subsequent weeks, they were told to lay low so their bodies could regenerate healthy, antibody-producing white cells.

Over time, Morin acknowledged, some of the excitement and romance of providing patients with a new wonder drug has worn thin as routine set in. Still, every once in a while, something happens that grabs her heart.

“I had a man come in today for me to check out. He had a great response (to the drug), and I wanted to tell him so, but I knew it was the doctor’s job. He came back later, though, to tell me. He was so happy, he was crying.”

Morin’s office is on the third floor of Scripps Clinic, behind a door bearing the simple sign, “Experimental Clinical Oncology.” Inside are three barber-style chairs--tan, brown and orange--where patients sit to be fitted with their IVs, or to be checked after receiving the treatment.

Inside one of the cabinets is a handful of portable IV pumps. In a small refrigerator are pre-measured doses of 2-CdA, awaiting new patients. So far about 400 people have received the drug, with varying degrees of success and remission--including about 175 patients who had hairy-cell leukemia and have been in total remission. If the leukemia remains shut down for five years, they’re told, they can be considered cured.

Scripps officials expect to ask the FDA before the end of the year to approve 2-CdA for public marketing. Scripps has a pre-existing agreement with Johnson & Johnson for the manufacturing, marketing and distribution of Scripps-created drugs, and officials hope that a J & J subsidiary, Ortho Biotech, will take on 2-CdA as a commercial drug.

Company spokeswoman Sarah Colamarino said the company will manufacture, market and distribute the drug as soon as it’s approved. Because of Johnson & Johnson’s existing 10-year agreement with Scripps to support research there in exchange for commercial rights, there will be no additional exchange of money.

“I’m really proud of what we’ve done,” said Morin. “I just wish it was already approved, so people wouldn’t have to come all the way out here from other parts of the country to receive it. It would save them some money.”

Piro said he’s anxious to investigate what effects derivatives of 2-CdA will have on other cancers.

Beutler calls the application of 2-CdA to hairy-cell leukemia one of the highlight successes of Scripps Clinic, because it was resurrected, tested and developed within the walls of the institution.

“We have created something here that is now an important new treatment at bedside. We have other irons in the fire, but it’s conservative for me to say I’ve been very gratified with what we’ve accomplished with 2-CdA,” he said.

Wasson, the lab technician, is looking ahead to other projects. “I did my part with CdA. Now it’s other people’s turn to work with it.

“Research is incredibly boring, but punctuated by rushes of exhilaration, knowing you’ve done something that no one has ever done before,” he said.

Robins, in whose lab 2-CdA was first synthesized, is today on the staff of the department of pharmacology at UCSD’s School of Medicine, where he is studying still new compounds to stop cancer and where he has become a close friend of Carson.

The 64-year-old chemist figures he has synthesized literally thousands of chemical compounds.

“That’s what I do, all day, every day. I think about compounds, and I expect to develop still more over then next 10 years,” he said matter-of-factly. One of his analogs, known as tiazofurin, is being studied at the University of Indiana’s School of Medicine as a possible anti-cancer drug.

Carson has also joined the staff of UCSD, where he has received funding to try to find a cure for another manifestation of the immune system gone bad: arthritis.

Above his desk is a crayon drawing of Don Quixote, titled “Charge!”

WEDNESDAY: The future of biotechnology in San Diego, and the hopes and fears of one scientist as he embarks on his own dream.