Forty Years Young

By Eric Sauter and Mika Ono

Richard Lerner's landmark study, The Role of Anti-Glomerular Basement Membrane Antibody in the Pathogenesis of Human Glomerulonephritis, is 40 years old this year but hardly shows its age. First published in December 1967 in the Journal of Experimental Medicine, the study identifies a particular antibody—the anti-glomerular basement membrane (GBM) antibody—and shows it causing a type of inflammatory kidney disease in humans.

"I am gratified that our paper has stood the test of time," says Lerner, who is now president of The Scripps Research Institute. "Its main lesson was that antibody alone was responsible for the pathogenesis of Goodpasture's glomerulonephritis. The study also represents the first and, as far as I know, the only transfer of an autoimmune disease from human to animal."

The study was co-authored by Lerner and Richard Glassok, then fellows in the Department of Experimental Pathology at the Scripps Clinic and Research Foundation (a forerunner of The Scripps Research Institute), and Frank J. Dixon, the pioneering immunologist who established the scientific group in La Jolla in 1961.

Goodpasture's disease, as now defined, is based on the presence of the anti-GBM antibody, an autoantibody that attacks the body's own tissue, in this case, the glomerular (pronounced glo-MER-yu-ler) basement membrane of the kidney. This attack interferes with the kidney's work of removing waste and excess fluids from the system, and the damage can quickly lead to kidney failure if not treated. The relatively rare condition may be temporary or it may grow progressively worse, eventually resulting in end-stage renal failure. 

The paper was, and remains, a landmark—helping to open the door to a new understanding of the immune system's role in renal disease as well as shaping the nascent discipline of immunopathology. 

As Andrew Rees of the University of Aberdeen notes in a commentary that accompanied a 1999 "Milestones in Nephrology" reprint of the study by the Journal of the American Society of Nephrology (JASN), "[The paper] was a revelation… Even today, I cite it in most of my grant applications because it established anti-GBM antibodies as one of the few autoantibodies of proven pathogenicity… The measure of a 'classic paper' is the degree to which it diverted the course of the subject it addresses. Certainly this paper changed the study of glomerular disease, and advanced it by many years."

Elegant Answers

The idea that anti-glomerular antibodies might cause glomerulonephritis dated back to the turn of the century, but no one had proven this in humans until the landmark 1967 paper.

"Even though one had a model of renal disease, there remained the question of whether the models had anything to do with human disease," says Lerner in his JASN "Milestones in Nephrology" commentary on the paper. "In fact, there was a prominent school of thought centered on the East Coast that believed (and told anyone who would listen) that these models had nothing to do with human disease. We were certain they did…"

To prove this contention, the Scripps team used several experimental approaches. In research supported by grants from the John Hartford Foundation and the U.S. Public Health Service, the researchers first obtained human kidney samples, finding and characterizing tissue-bound antibody. Next, they examined sera from human subjects with glomerulonephritis, identifying anti-basement membrane antibody in the sera of two anephric patients (those without kidneys) and of six patients with kidney disease.

Once the researchers had established the presence of anti-GBM antibodies in people, they still faced the problem of proving that these autoantibodies could cause disease. The researchers surmounted the challenge by injecting circulating autoantibodies from a glomerulonephritis patient into lab animals. The animals immediately contracted the disease, offering proof that anti-GBM antibodies were a contributing factor, if not the contributing factor, at the root of the disease. The conclusion was inescapable.

Interestingly, the study also raised the possibility that patients who had anti-GBM antibodies in their system might not be the best candidates for a kidney transplant since those antibodies were likely to produce the same disastrous changes in the newly transplanted kidney that were already destroying their own. 

And, in fact, the paper's warning about anti-GBM glomerulonephritis in kidney transplants was prescient—later reports estimated the recurrence of the disease as high as 50 percent in transplant patients with circulating antibodies. That problem was solved quite simply, however, by holding off transplantation until the patient was antibody-free for at least 12 months. As a result, recurrence has become extremely rare. 

A Sign of Things to Come

In addition to its contributions to public health and the emerging field of immunopathology, the paper was important in another respect—as a sign of things to come for The Scripps Research Institute. The handful of researchers in the Department of Experimental Pathology in the 1960s were laying the foundation for today's incarnation of the institute as a scientific powerhouse spanning two coasts.

Glassock describes the "dynamic and rich intellectual milieu" of these early years in his "Milestones in Nephrology" commentary: "The laboratories of Frank Dixon and his colleagues (Drs. Feldman, Vasquez, Muller-Eberhard, Cochrane, and Weigle) at the Scripps Clinic and Research Foundation (now the Scripps Research Institute) in La Jolla, CA, were at the vanguard of the brisk pace of discovery," he writes. "There were no regular hours. The laboratories were 'open' 24 hours a day, seven days a week, and often work was under way well into the early morning hours and on weekend afternoons and evenings."

The openness, innovation, and rigor of the scientists in these initial years set standards that remain central to the institute. And, of course, there was Richard Lerner, who was to become a key figure in shaping the institute's future.

Arriving at Scripps in 1965 fresh out of Stanford Medical School, Lerner had been attracted to Dixon's group by the stellar science. "The Dixon laboratory was arguably, at that time, the most important laboratory in the world engaged in the study of the immunopathogenesis of renal disease," Lerner recalls. "Dr. Dixon already had a worldwide reputation for his work in immune complex disease."

The 1967 paper, The Role of Anti-Glomerular Basement Membrane Antibody Pathogenesis of Human Glomerulonephritis, was the fifth to be added to Lerner's c.v. (the first four co-authored with Dixon, laying groundwork for the 1967 breakthrough). Today, his c.v. has expanded greatly. Lerner, now Lita Annenberg Hazen Professor of Immunochemistry, Cecil H. and Ida M. Green Chair in Chemistry, and member of the Skaggs Institute for Chemical Biology at Scripps Research, has received more than two dozen awards and honors, including the prestigious Wolf Prize, University of California's President's Medal, and the Paul Ehrlich and Ludwig Darmstaedter Prize. He will receive an honorary degree from Oxford University this summer. And, of course, there are now many, many more publications—at last check, more than 400 of them.

Of special note among these are Lerner's advances in the field of catalytic antibodies, showing that antibodies can be employed as enzymes (work conducted simultaneously with Scripps Research Professor Peter Schultz, then at the University of California, Berkeley), and pioneering advances in combinatorial antibody libraries. Today, about 55 percent of all new drug applications are antibodies.

In fact, Lerner's c.v. serves to reminds us of another historical milestone. Not only is 2007 the 40th anniversary of the Lerner, Glassock, and Dixon paper on glomerulonephritis, it is also the 20th anniversary of another seminal event—Richard Lerner's appointment as head of Scripps Research.

But perhaps that is a topic for another day.

Send comments to: mikaono[at]scripps.edu

"I am gratified that our paper has stood the test of time."

—Richard Lerner

"The measure of a 'classic paper' is the degree to which it diverted the course of the subject it addresses. Certainly this paper changed the study of glomerular disease, and advanced it by many years."

—Andrew Rees