John A. Glomset (1928—2015)

“Nature is trying to tell us something. In fact, she’s screaming in our ears. If we would only listen”

I’ve long forgotten the topic of the seminar in which John Glomset offered these remarkable words. But I jotted them down and am sharing them here because they so succinctly describe his approach to science. John’s career was large in scope: from the biophysics of lipid–lipid interactions to medical aspects of cholesterol transport. All along, his consideration of natural processes was at the fore of his work. I keep this in mind as I attempt to summarize his long and eventful life in the sciences.

John was born in Des Moines, Iowa, on Nov. 2, 1928. Following something of a family tradition, he attended the University of Chicago as an undergraduate. He went on to medical school at the University of Uppsala in Uppsala, Sweden, where he met his future wife, Britt. They were together happily for the rest of his life.

Having completed both a medical degree and a Ph.D. in medical chemistry at Uppsala, John obtained a faculty position at the University of Washington in 1960 and would stay there for the rest of his career. His early work focused on cholesterol metabolism and transport, with his major contribution being the discovery of lecithin-cholesterol acyl transferase, or LCAT, a central enzyme in the packaging of cholesterol into lipoproteins. This was a heady time in cholesterol research, and John’s work contributed significantly to the field.

While following this research path, John always was listening to nature. That’s how he did science. Instead of forcing information out of natural processes, he designed scenarios in which nature could provide information in its own time. This approach paid off at least twice for him. The first time was his discovery of platelet-derived growth factor with Russell Ross in the 1970s. The finding came out of their serum preparations for cell-culture experiments. Changing the centrifuge used in the preparation significantly altered the cell growth activity of the resulting serum. Many might have discounted this as an irritation. But John felt that nature was screaming in his ear. He and Ross determined that the difference was in the degree of platelet contamination, which led them to purify this important growth factor.

The second discovery was protein prenylation. At the time, John was tracking cholesterol metabolism by treating cells with a radioactive synthetic intermediate. While isolating cholesterol fractions from the cells, he continually found that a portion of the radioactivity ended up in a nonlipid fraction. He could have ignored this fraction, but again he listened to nature. He teamed up with Mike Gelb in a very fruitful collaboration, and together they identified a protein (lamin B) that was covalently modified by a farnesyl moiety.

In 1991, I joined John’s lab as a graduate student and was captivated by his research passion at the time — phospholipid heterogeneity in mammalian cells. Why do cells have hundreds of different phospholipids, varying in headgroup and fatty acyl chains in a dizzying array of combinations? John’s idea was that their specific chemical properties would cause subtly different packing properties, resulting in membrane domains. These domains would be small and highly transient entities that could reorganize dramatically at the slightest change (e.g., phospholipase activity). In this way, membrane signaling could induce much more than the simple modification of an individual lipid or protein, instead creating larger-scale changes in membrane organization.

The idea of lipid domains now is generally accepted, thanks to the work of many labs. As was typical with John, most of his work remained unpublished and would have been difficult to interpret as work on lipid domains even if published. John took two approaches: the examination of biosynthetic pathways and molecular modeling. In the first approach, John would force cells to synthesize certain phospholipid species that they did not ordinarily possess. The cells would rapidly remodel these lipids to very specific combinations of fatty acyl chains through transacylation and acyltransferase reactions, with distinct fingerprints of fatty acyl combinations for each headgroup. John was fascinated by both the intricacy and the robustness of these responses. Nature was most definitely trying to tell us something. John’s hypothesis was that these precise combinations of lipids were essential for appropriate membrane domains.

John’s molecular modeling approach was a collaboration with Howard Brockman. The two found that phospholipids containing one saturated and one polyunsaturated chain could pack more tightly than lipids containing one saturated and one monounsaturated chain. These findings ran counter to the prevailing simplistic idea that more unsaturation causes looser bilayer packing. The key here, again, was John listening to nature by modeling phospholipids that actually exist in mammalian membranes. These late works rarely got published, which is a shame, because the findings were profound and somewhat ahead of their time.

John referred to his life as charmed. He knew how lucky he was to be able to follow his scientific passions. While not universally known, he was a Howard Hughes Medical Institute investigator for many years, was elected to the National Academy of Sciences in 1990 and was well regarded by those who did know him. Nobelists Michael Brown and Joe Goldstein would say, “Read Glomset’s papers. They will seem odd now, but they will be crucial in 10 years.”

Outside of science, John and Britt raised two sons, Peter and Nils, who have successfully pursued their own paths. Carpentry was John’s passion, and he built much of the family home near Seattle as well as their vacation home on the Olympic Peninsula.

One final word on John’s somewhat unusual scientific philosophy. I have been told many times, “Do not fall in love with your models; they compromise objectivity.” John’s philosophy was almost diametrically opposed: Fall in love with your models, nurture them, and turn them over lovingly in your hands. All the while, however, test them critically. The instant you get clear evidence that your model is wrong, change it. You must have the sense to balance the love of your model with what the data tell you. The benefit of this love affair is that even if it is ill-fated, it will take you on a wonderful journey, and you will learn something. John would engage others in these love affairs through long conversations. Unbeknownst to him, the lab defined the John Unit, or JU, as one hour spent “discussing” science, which took the form of listening to John. I logged many JUs in all sorts of places.

Through these conversations, one could understand John’s ideas, which were deep if not always testable. They painted a picture, a beautiful one. I think John would allow me to modify his original lines: Nature is painting a picture for us. It is right before our eyes. If we would only open them and see it.

Henry N. Higgs is a professor of biochemistry at the Geisel School of Medicine at Dartmouth College.