It takes little imagination to understand why insulin-dependent diabetics hate their illness. Every day, often several times a day, they load a syringe with the hormone that tells their body's cells to pull sugar out of the blood, and then they stab the syringe into their skin. Without the shots, the diabetic would starve no matter how much he or she ate.
For some diabetics, the daily treatment also has a psychological downside. "I have a morbid fear of needles," said Robert Tripp, 60, of Washington. Although Tripp has required extra insulin twice a day for the last three years, he has not been able to bring himself to pinch his skin, jab in the needle and inject the life-sustaining hormone. Instead, he loads the syringe into a pistol-like automatic injector, closes his eyes and shoots himself in the buttocks.
"I have never seen myself get a shot," Tripp said with a small, embarrassed laugh. "I don't look. I dread the shots, and I dread needles. I'd rather you kick me in the shin."
Tripp is not alone in this fear. Millions of others hate the thought of a shot. Although many drugs can be given in pill form, medicines made from proteins, such as insulin, cannot. They must be delivered directly into the bloodstream because they cannot survive the passage through the stomach or intestines.
The problem is the proteins themselves. They are as different from other chemicals as an auto is from a bicycle. Both the auto and the bike can be used for transportation, but the car is bigger, more expensive, more complex, and, most important, more likely to break down.
Physically, proteins -- the more complex "autos" -- are about 10 times bigger than traditional drugs. That makes them more easily deactivated by changes in their shape. The body has also evolved a number of systems designed to prevent active, intact proteins from entering it, or to quickly destroy them if they do get in. When either food or a protein pill is swallowed, for example, powerful acids in the stomach and enzymes in the intestines break down the protein into amino acids. The amino acids can be absorbed into the blood and used by the cells to make new proteins, but they no longer have the original protein's biological activity.
Scientists have been searching for years to find ways to overcome these problems, to get insulin or similar protein-based drugs into the body. So far, they have been unsuccessful, and their failure raises serious questions about how easy it will be to use many of the new genetically engineered drugs -- all of them proteins -- now pouring out of the nation's biotechnology labs.
"For the current generation of drugs, this does not limit us a whole lot," said Rodney Pearlman, director of pharmaceutical research and development at Genentech Inc. of South San Francisco, one of the oldest biotechnology companies. "But it will limit us to the therapeutics that we can come up with."
The solution is not close at hand. "It is a very tough problem," Pearlman said. "We have looked long and hard at what companies are developing, but we think we will be using the injection for a long time to come as the primary delivery route."
One English company claimed to deliver insulin, growth hormones and a hormone that stimulates red blood cell production through the intestine, said William Lee, head of the drug delivery department at California Biotechnology of Mountain View, Calif. The English company never published its results in scientific journals, and now some scientists suspect that it didn't work.
Even so, a number of pharmaceutical companies have reported some progress, primarily with insulin preparations that can be sprayed into the nose.
Novo Nordisk, a drug company in Bagsvaerd, Denmark, has developed a new nasal method that did get insulin into the blood of 11 healthy volunteers without the nasal irritation associated with other preparations, according to Kirsten Drejer, a research chemist who reported the results this month to the European Association for the Study of Diabetes.
"It gives a very rapid absorption into the blood, and that is what we are after," Drejer said. Normally, the body produces a surge of insulin in response to a meal; the nasal spray can produce a similar surge.
The nasal preparation won't be on the market until the mid-1990s, Drejer said, because Novo Nordisk has a long way to go in proving that enough drug gets into the body to actually control the disease. Only about 8 percent of the insulin sprayed into the nose gets into the bloodstream.
CalBio has developed its own nasal insulin system, which relies on a modified version of bile to carry insulin into the bloodstream. "We can get 10 to 20 percent of the drug across," Lee said. But there have been problems with nasal irritation. "We had some successes and some failures in the clinic."
After six studies over three years, including tests of the drug's effectiveness in diabetics, Eli Lilly Inc., CalBio's partner in developing the treatment,, dropped out of the study.
"We still feel it may work," Lee said of the nasal approach. According to a CalBio spokeswoman, the company is currently looking for another partner to help fund additional human studies.
"A lot of people have been working on the nose, but it is difficult," said Robert Langer, a chemical engineer at the Massachusetts Institute of Technology and author of a review paper on drug delivery systems in last week's issue of Science. "The problem is that the things that disrupt that barrier may cause irritation. This is a problem if you are giving something twice a day, every day. The advantage of the nasal approach, however, is that if it worked, it would be easy."
Even if the nasal preparations work, said Denmark's Drejer, the spray will not eliminate the need for daily injections. Diabetics will require daily injections of slow-acting insulin to maintain a basic level in the body. The nasal spray will just be used to get fast-acting insulin into the body during meals.
Langer, however, described a number of approaches now being explored in which drug-containing reservoirs are surgically implanted in the body to release drugs slowly over long periods of time. A number of these approachs already are being studied in people.
If they work, Drejer said, long-lasting reservoirs of insulin could be used in conjunction with nasal insulin to virtually eliminate the need for insulin injections.
Drug companies have looked at a number of other ways to get protein-based drugs into the body, including through the skin, the stomach and intestines, the colon and the lungs.
And, while all the biotech companies would like to crack the problem, "we can't compromise the safety or the efficacy of the drug for patient convenience," Pearlman said.
Still, the patients are hopeful and waiting.
"I get a lot of calls from people asking if there is some way besides the needle," said Tripp, a volunteer at American Diabetes Association headquarters in Alexandria.. "I'm just waiting for the day that they can surgically implant something that can be used to test the blood and give the insulin. I really look forward to getting rid of those needles."
Most people would rather swallow a pill than receive an injection. But some drugs made from proteins -- such as insulin -- can't be swallowed because the proteins are destroyed by stomach acids or enzymes in the intestines. Scientists are developing other ways to get these into the body:
Blood vessels in the nose rapidly absorb chemicals sprayed into the nostril.
Some drugs can be turned into a mist that is sprayed into the lungs and absorbed by its blood vessels.
Drugs such as aspirin or antibiotics can be packed into pills that survive harsh stomach acids and are absorbed into the intestines.
Some drugs, including nitroglycerin for heart disease and anti-nausea drugs, can be soaked into a patch that is placed on the skin. The drug is absorbed through the skin.
Drugs like insulin work better when given at a low, continuous dose. Special pumps - some implantable - infuse a drug gradually.
Small implantable containers made from synthetic chemicals that slowly dissolve inside the body can release the drug into the body.