The development of many innovations in ophthalmology did not happen in a straightforward manner as shown in these case examples.
By Lynda Charters; Reviewed by Herbert E. Kaufman, MD
Many technologies that clinicians take for granted had extremely humble, unnoticed, and in some instances, underhanded beginnings. The development of a range of products for a number of ophthalmic subspecialties has involved a deal of looking outside the box to take existing primal technologies to their next level.
In his first foray into what now he described as a possible crime, Herbert E. Kaufman, MD, began his career as an upstart first-year resident at Massachusetts Eye and Ear, Boston, by presenting his superiors with an unnecessary truckload of toxoplasmosis-infected animals that ultimately served to guarantee him laboratory space.
Dr. Kaufman explained how he addressed the concept of viral chemotherapy; that is, by doing the opposite of every other viral investigator in the country.
“Most tried to interfere with the synthesis of nucleotide-building blocks of viral DNA by reducing the viral load in culture,” said Dr. Kaufman, who is the Boyd Professor of Ophthalmology, Pharmacology, and Microbiology, Louisiana State University Medical School, New Orleans. “However, that starves both the cell and the virus.
“I thought that the virus coded its own special assembly enzyme, which would be the opportune place to work,” he explained, regarding his unsupported hypothesis and found a drug (IDU) that would meet this end. This proved to be a Herculean feat that required sleeping in an animal room and treating rabbits every 2 hours around the clock.
Dr. Kaufman was correct in his hypothesis. This discovery reactivated an antiviral program run by GlaxoSmithKline that had been closed because of the considered impossibility of treating viral infections without killing the cells.
His discovery was met with great fanfare, but not in the ophthalmic community, because the drug was not treating keratitis or iritis. This lead to the recognition by Dr. Kaufman that he could treat keratitis and iritis with a combination of a topical steroid and the antiviral drug (Viroptic/IDU). The reluctance on the part of clinicians to treat herpes with a steroid was overcome by his guess that the steroid overcame the hypersensitivity to viral antigen and antiviral prevented making infection worse.
“To my astonishment, this turned out to be correct,” he said.
Addressing fungal infections
In the 1960s, there was no cure for corneal fungal infections arising from accidents with vegetation that occurred among itinerant workers in Florida, but Dr. Kaufman knew about a substance, Pimaracin (natamycin), in use in Holland that kept cheese from getting moldy.
He designed an animal model of a fungal infection with which he and his colleague, Emanuel Newman, proved that the substance was efficacious for treating human infection. They then provided it to clinicians for free for 2 years. This application ultimately achieved FDA approval without a clinical trial or a manufacturer. Alcon Laboratories later entered the picture and manufactured the drug.
“Pimaracin remains the most effective drug for treating especially commonly fungus keratitis,” Dr. Kaufman said.
A consultancy for Merck resulted in the birth of what would become a mainstay treatment for glaucoma. Up to that point, only pilocarpine and oral Diamox with their severe side effects had been available.
Yale researcher Marvin Sears, MD, observed that timolol had an IOP-lowering effect in rabbit eyes when used to dissolve zonules. There was reluctance among industry to investigate this drug further in trials because of the absence of a large market. Dr. Kaufman persuaded a former assistant resident and then head of Merck to conduct an investigation.
“This turned out to be the first good drug to treat glaucoma and a blockbuster product for Merck,” he said.
While Dr. Kaufman’s interest was in treating corneal diseases, he saw the potential to use this product in another capacity other than refraction. At the time, Bausch + Lomb was making low-power soft contact lenses. When the company refused Dr. Kaufman’s appeal to use the bandages to treat diseases, he and two colleagues started a competitive lens company to study the effect of the use of the bandage lenses on corneal diseases.
Again, the contact lenses initially were met with skepticism by the ophthalmic community, as so many other innovations had been, but they are now a staple in clinical practice.
This innovation was born out of need because of the dearth of usable tissue. The removed tissue at that time was inexpertly preserved and the enucleated eyes were stored intact. Because of the absence of glucose to nourish the corneas, the enucleated tissues died rapidly.
Dr. Kaufman proposed removing the corneas from the enucleated eyes and immersing the corneas in a nourishing solution. “That was the breakthrough. The solution was easy,” he said.
Dr. Kaufman immersed the corneal tissue in a tissue culture solution and later Dextran to dehydrate the tissue at the suggestion of colleague, Bernie McCarey, PhD, who validated the idea. But the eye banks refused to follow this protocol because of the extra costs of technicians who were trained in sterile technique and removing the corneal tissue and the charges necessary for tissue preparation.
Finally, support from Ed Maumenee, MD, head of ophthalmology, Johns Hopkins University, Baltimore, was key to acceptance of the new protocol by Eye Banks International.
But the story wasn’t over. The eye banks needed more time, and Dr. Kaufman and Richard Lindstrom, MD, improved the medium storage time for HIV and other tests. Optisol remains the most commonly used eye bank preserving medium, according to Dr. Kaufman.
With all the previous successes, failures were inevitable. William Bourne, MD, and Dr. Kaufman developed the clinical specular microscope and observed endothelial damage resulting from contact between IOLs and the endothelial tissue.
To counteract this, viscous methylcellulose was used with the hope that it would provide protection for the endothelium. He evaluated and published a series of randomized cataract surgeries with and without the viscous methylcellulose and showed the degree of protection provided by the product.
“But I failed, because I did not patent it or push it sufficiently hard and no company manufactured it,” Dr. Kaufman recounted.
Healon was patented later as a viscoelastic.
A number of surgeons had the idea that the excimer laser could be used to reshape the cornea, but no one was using it for that purpose. Lasers contained argon and fluorine gases and the instruments were not readily available in practice.
“It was a good idea that was useless,” he said.
Dr. Kaufman and fellow faculty member Marguerite McDonald, MD, had another idea. They convinced VISX to make a laser for use on animals. However, because the laser contained deadly fluorine gas, they had to segregate themselves in a double-wide trailer away from the eye center, so if the deadly fluorine gas leaked, only they would die, he recounted.
This endeavor to develop the early excimer laser involved the most basic of modifications, such as adding rotating prisms to the laser to avoid creating divots in the corneas from the laser’s hot points of light as well as use of steroids and special solutions. Once the laser worked in animals, only the FDA stood in their way. Vaporizing the corneas of normal eyes was not permitted.
Ultimately, the first human to undergo treatment was a patient with a choroidal melanoma in an eye slated for enucleation who allowed Dr. McDonald to perform PRK. Following enucleation, they performed histologic studies. This was followed by the same work in a series of blind patients who allowed PRK to be performed despite the absence of a benefit to them to forward this technology.
“This is the story of the birth of the excimer laser,” Dr. Kaufman said.
“None of these innovations were straightforward,” he said. “None would be available without these strange machinations, but this is what happened.”
Herbert E. Kaufman, MD
This article was adapted from Dr. Kaufman’s presentation as the Jones/Smolin Lecturer at the 2017 meeting of the American Academy of Ophthalmology. Dr. Kaufman has no financial interests to disclose in relation to the subject matter.