Professor Robert Stern MD- a long life of inspiring scientists to sift through the goo for what was clinically relevant.

Many will mourn the loss of Robert Stern, but with the number of scientists and medical students he inspired over the years I am confident his memory still has quite a long healthy life ahead of it.

Robert Stern

While Robert was a board-certified pathologist by trade and taught pathology to the medical students, many clinician scientists and doctoral candidates found their way to glycosaminoglycan biology through his laboratory in Health Sciences West at UC San Francisco over the years. In the early 1990’s, Robert’s laboratory in the Department of Pathology had assembled a mosaic of small grants along with some RO1s. The lab was well seasoned with chromatography columns of all shapes and sizes, buffer carboys, cold rooms and other basic biochemistry equipment from decades of experimentation, along with a tissue culture room that housed a museum quality coulter counter from the 1960’s. While perhaps not as modern as the neighboring cell, molecular and immunology labs in the department it was a remarkable scientific sandbox that Robert created for scientists setting out on their journey to solve medical challenges that might have a relationship to glycosaminoglycan biology.

Roberts lab meetings, (called ‘therapy sessions’ as I recall) were held in a small adjacent office that housed all the scientists together and was decorated with pathology artifacts, microscopes, countless racks of slides and parrafin blocks of rare pathologies. The -80C freezers were always overflowing with serum samples collected from fascinating diseases, many waiting for just the right hypothesis and analytical test to be thawed and tested.

Nearly every lab meeting was preceded with a lecture about a particular clinical observation on the hospital wards over the years. And every disease in Robert’s lab was observed through the eyes of the extracellular matrix. Some were anecdotal observations from publications back in the 1950’s and 1960’s, or the ‘golden age of carbohydrate chemistry’ as Robert defined it. But these clinical challenges and observations from the wards and old papers were rapidly devoured by eager young students that he inspired to start building hypotheses towards what might be a worthy experimental investigation.

Analytical tools were all applied in a similar way. First the clinical problem, then the blood or tissue samples arrived, then testing, followed by analysis of whether any association existed. With the analytical data in hand, new hypothesis developed. Was the abnormal laboratory value in a patient population a result of a stimulatory protein, an enzyme or an inhibitor? From there the long journeys often began.

Robert Stern ISHASRobert Stern at an ISHAS reception party

A biochemical observation such as elevated tissue levels of hyaluronan during fetal development that might relate to scar-free wound healing, or how HA accumulation during ductal branching morphogenesis might link to cancer invasion were common early themes. Every clinical problem was viewed through the gooey lens of how the extracellular matrix or hyaluronan might be a culprit. In some cases, hypotheses evolved after retrospective analysis of clinical outcomes in malignancies to HA, hyaluronidase or CD44 splice variants. Some had diagnostic implications to treating patients more accurately. And others called for someone to go isolate the factor responsible.

There was a constant mantra from Robert when it came to solving biochemical problems. “Without a good assay there is nothing you can do, but with a great assay there is nothing you cannot do!”

Some of these assays had unique reagents that required everyone to participate in annual rituals, such as regenerating the annual supply of biotinylated hyaluronan binding protein or bHABP as it was known at the time. Bovine nasal cartilage would arrive, scalpels and dishes would be distributed, and all would join in to trim kilograms of nasal cartilage of contaminating tissue and prepare it for dissolution into potent chaotropic salts and trypsin with affinity isolation on HA resins. One wrong step and everything would have to start over. Worse yet, a subpotent batch might be generated that would be unsuitable for all of its great uses after calibration with the prior standard.

This biotinylated tryptic fragment of aggrecan in Robert’s lab was an analytical workhorse in the early days for every assay it seemed: histochemistry, measuring HA in samples and measuring hyaluronidase activity. In short, all the precious assays relied upon this fickle little reagent from a cows nose.

And in the ‘grind and find’ world of pathology, Robert’s lab required that all factors be isolated to homogeneity and characterized fully with careful accounting for loss or gains (removal of inhibitors) at each step along the way. Whether fractionating liters of conditioned cell media, extracting kilograms of porcine livers, spleens or lymph nodes, or even tens of liters of human plasma or hundreds of liters or urine in the cold room, the biochemical journey to purify the factor responsible was often a multi-year journey.

And when something came out that looked really pure and antibodies made then the gene had to be cloned the old fashioned way from peptide fragments and degenerate PCR. There were many projects that purified things some of the way but fell short of completion. The HA stimulating activity or HASA, which seemed to fall apart on columns faster than the bioassay could measure its potency in column fractions. Or the porcine liver enzyme that looked like it was a hyaluronidase but also looked remarkably very close to the hemopexin it really was. Nevertheless, the small laboratory was able to tease out entire hyaluronidase gene families after many years of grinding up tissues and made a number of remarkable contributions to the HA community. Roberts laboratory also made some truly remarkable findings surrounding HA associations in wound healing, cancer and fetal development that continue to fuel hypotheses to this today. Several medicines that are approved around the world can trace their roots back to Robert’s laboratory and many good scientists and clinicians emerged from his laboratory with so much enthusiasm about applying science to understand those clinical observations.

On the lighter side, it is also quite worth noting that Robert Stern was a truly exceptional writer. And he demonstrated exceptional pleasure when applying his red pen to any first draft a student hoped would be their finest work. I am confident this tribute will break nearly every rule he tried to instill into our scientific writing. But at a certain point, we must accept our limitations with the time we have available to correct or improve them. So the materials and methods are not perfectly organized, the conclusion loquacious, and the title quite boring indeed. But I think the content is still worthy of peer review.

Robert Stern provided guidance to many many people in the hyaluronan community. And he will be remembered by more than just his publications in the field.

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