July 5, 1996
Page 3 of 3
In 1970, I left the NIH to obtain more training and also because of the National Institute of Arthritis and Metabolic Diseases (NIAMD) chose not to continue supporting its intramural research program on cystinosis. In retrospect, this may have been an early sign that some parts of the NIH were already beginning to feel pressure for cost containment. The good news, however, was that I was able to presuade Charles Lowe, then scientific director of the National Institute of Child Health and Human Development (NICHD), to let me return after training to create a new unit for research on cystinosis and other genetic disorders. Charlie saw research on genetics as a coming thing of the future importance and wanted it in NICHD. He liked me personally and his name was attached to the disorder called "Lowe's syndrome" which, like cystinosis, is a cause of the Fanconi sydrome. Charlie understood hereditary renal diseases.The next decade (1970s and early 1980s) saw substantial advances in cystinosis research on several fronts, mostly emanating from Dr. Schneider's laboratory in San Diego and our own in NICHD. Dr. Schneider was joined in these efforts by other scientists including Dr. Thoene, and I was joined by Dr. Gahl, Dr. Steinherz and others.
Prenatal diagnosis of cystinosis became possible in this decade. This was most important, but was a relatively simple thing to achieve scientifically.
Much harder was to understand what was the cause of cystinosis -- why the cystine accumulated in lysosomes. Many, many experiments were done, and false leads followed. These could be the subject of a very long research seminar. They taught us the value of tenacity in research. They also taught us how often biological reality fails to confirm elegant -- even brilliant -- hypotheses. Science is not just creativity; it also involves harsh confrontation with the unpleasant truth, of being wrong over and over again.
In one of Arthur Conan Doyle's novels, the detective Sherlock Holmes says to his compainion, Watson, that he had solved a crime by using the following method: "If every other hypothesis has been excluded, the remaining explanation, however unlikely, must be the correct one."
Enzymatic and other studies over many years had failed to explain cystinosis. No one had found any lysosomal enzymes that normally metabolized cystine, or converted it to cysteine. The only explanation left, we believed, was that the vision of the lysosome held by science at that time was not correct -- it did not just break down proteins into smaller units like cystine; it also had to have a special transport system to let the cystine get out! We believed this transporter was deficient in cystinotic lysosomes. But how could you prove this?
It proved devilishly difficult until Frank Tietze discovered a published investigation unrelated to cystinosis showing that cells and lysosomes were permeable to the methyl esters -- a chemical derivative -- of amino acids, and that the lysosomes would then convert the esters back to the original amino acids.
Here at least was an idea that might enable us to load up normal lysosomes with cystine and then compare cystine egress from loaded normal and cystinotic lysosomes containing comparable amounts of cystine.
Frank succeeded in synthesizing a new chemical compound, cystine dimethyl ester. Reuven Steinherz and Nava Bashon, both from Israel, undertook the biological and transport experiments. Bill Gahl joined our team when this work was well underway and added powerful new insight and experiments. And at last it was possible to show that cysitnosis was due to a defective transoport system for lysosomal egress of cystine. Jerry Schneider and his team, using another experimental system, came to a similar conclusion.
This work was subsequently confirmed and extended and led to the recognition of a whole new class of lysosomal storage diseases, such as sialic acid storage and B12 transporter deficiency.
The other major breakthrough -- and clearly the one with the greatest value to patients -- was the discovery by Schneider, Thoene, and coworkers of the cystine-depleting power of cysteamine. It worked better than any other compound tested. It could enter the cystinotic lysosomes of intact cells and convert the cystine to cysteine and the hybrid molecule cysteine-cysteamine mixed disulfide, these could then escape even from cystinotic lysosomes.
As many of you know, this has been followed by extensive research, continuing to the present, on cysteamine and its variations such a phosphocysteamine and Cystagon. Cysteamine has transformed the treatment of cystinosis and it would not be available today but for the tenacity and dedication of Drs. Schneider, Thoene, and Gahl and their many collaborators in overcoming numerous research, financial, and administrative barriers.
Cysteamine has also been valuable in eye drops for relieving some of the ocular symptoms of cystinosis. Bill has talked about problems, FDA approval, etc. with this form of the drug. These eyedrops are generally considered to be a recent development, but the history is actually a bit different.
About 1980 or so, there was a famous ophthalmologist at NIH named David Cogan. He was the former head of the eye department at Harvard Medical School, and a renowned physician and scientist who had described "benign cystinosis." Cogan and I conceived the idea of using a concentrated cysteamine solution and applying it repeatedly to the cornea to relieve photophobia by dissolving the cystine crystals. Cogan himself prepared the concentrated cysteamine solution and tested it for safety in rabbit eyes. One of my patients, then bothered by bad photophobia, began to receive the cysteamine drops in one eye several times a day and began to undergo periodic slit-lamp examinations to see what would happen.
Before the study was long underway, an anonymous tipster reported Cogan and me to NIH authorities for perfoming "unapproved" clinical research. I was severly reprimanded and threatened with dismissal from NIH. In those days, Cogan was a very influential and powerful man; he threatened to resign and publicly expose what was going on if I was fired. The outcome, tragically, was that Cogan and I were forced to promise that we would discontinue this line of research, and the "charges" would be dropped! Some years later after Cogan and I had left NIH, work on cysteamine eye drops was resumed with the great benefits of which you are all aware.
It is time to stop my story. Cystinosis research continues, and it will continue to lead to new advances in diagnosis, prevention and treatment. New techniques of DNA analysis and cloning will eventually lead to identifying and sequencing the cystinosis gene and understanding more about the gene product and its biological role as a cystine transporter. Cystinosis research may also have implications in the future, as in the past, for knowledge about other inherited or metabolic diseases. But this will be a tale for others to tell. My hopes and prayers are with all of you in the battle to conquer cystinosis. Thank you.