Alfred Goldberg: Pioneer in the life and death of proteins

On April 18th, 2023, we lost one of our scientific giants. Alfred (Fred) Lewis Goldberg passed away at the age of 80 after a long bout with cancer. All those who knew Fred were struck by his warmth, humor, and drive to pursue knowledge. One of the things that always stood out was Fred’s insatiable curiosity. This extended to all subjects, but especially science. His curiosity led him to studies that have had a profound impact on many aspects of biology and medicine.

Fred grew up in Rhode Island in a family that valued education. Curious from the start, he was drawn to science at an early age, entering science fairs and generally winning first prize. He matriculated as an undergraduate at Harvard University, where among other accomplishments, he founded the Gargoyle Undergraduate Tiddlywinks Society (whose acronym, not accidentally, was GUTS). Despite its short duration, GUTS was memorialized in the premier magazine of the day, Life—perhaps this set the standard for Fred’s many later accomplishments being published in elite journals. At Harvard, he performed undergraduate thesis work in the laboratory of the Nobel Laureate, James Watson, and graduated with honors.

After graduating, Fred spent one year as a Churchill Fellow at Cambridge University in England. He then came back across the “pond” to enter Harvard Medical School, much to the delight and pride of his family. But “my son the doctor” was not to be. After two years in medical school, Fred’s path took a detour. Seduced by the mysteries of science, he left the MD track to pursue a PhD in Maurice Goodman’s lab. After graduating, he joined the faculty at Harvard Medical School to pursue a career in research, which for the betterment of science and us all, we can thank the gods that he did. It was kismet for another reason as well: as a starting faculty member, Fred met his wife Joan Goldberg, née Helpern, who became his lifelong muse and the love of his life.

Early on, Fred began to investigate why muscles atrophy after events like disuse or denervation. Surprisingly, he found that in this state muscle cells still synthesized their proteins at normal rates, but lost them more quickly, leading to a net loss of mass. Curious, he wanted to understand this increased catabolism. At the time, protein catabolism was far from the mainstream of scientific inquiry, and generally considered uninteresting. However, to paraphrase Pasteur, chance favored the curious mind (Fig. 1).

Fig. 1.

Fred Goldberg wearing a t-shirt emblazoned with proteasomes. Image credit: Bruce Furie.

When Fred began his research, it was known that cells contained proteases in their lysosomes that could hydrolyze proteins. What he discovered was that there was a totally different pathway that degraded a majority of intracellular proteins. Moreover, this process required energy in the form of ATP. This was surprising because, according to thermodynamics, energy should not be needed to break peptide bonds, and all known proteases at that time were ATP-independent. These observations led Fred to discover ATP-dependent proteases in both bacteria and mammals (the latter also independently found by Martin Rechsteiner). Fred named his mammalian “child,” the proteasome. It turned out that the proteasome has ATPase subunits that are needed to unfold and feed protein substrates into its catalytic chamber (Fig. 2). The other half of the puzzle was contributed by Hersko, Ciechanover, and Rose, who discovered ATP-dependent ubiquitinylation of proteins, for which they were awarded a Nobel prize. The covalently attached polyubiquitin chains target proteins for degradation by the proteasome.

Fig. 2.

Fred Goldberg using a banana to illustrate how the proteasome cleaves a substrate. Image credit: Keiji Tanaka.

A Backwater No More: A literature search on “proteasomes” reveals that there are now over 45,000 papers published on Fred’s protease. This is because the ubiquitin-proteasome pathway has turned out to be fundamental to many biological processes. It provides a mechanism by which cells can selectively eliminate a particular protein, and thereby very rapidly terminate or activate a pathway and/or cellular function. Fred and many others have shown that this is fundamental to controlling diverse processes, ranging from cell division (cyclin degradation) to gene expression (e.g., NFkB-IkB hydrolysis), to cell survival (apoptosis), and many others. It also is the major mechanism for eliminating abnormal or damaged proteins, whose accumulation would otherwise damage cells. As Fred and others have shown, certain neurodegenerative diseases occur when proteins mutate in ways that prevent proteasomal degradation and thereby accumulate. The proteasome also regulates the steady-state levels of most cell proteins. When it is out of balance, it can lead to cachexia, the morbid condition of body wasting that is seen e.g., in many cancer patients. On the flip side of destruction, the proteasome’s hydrolysis of proteins creates a library of oligopeptides from all expressed genes, from which peptide-binding receptors (MHC class I molecules) capture a fraction of these protein fragments and display them on the cell surface. This allows killer (CD8+) T cells to detect and eliminate cells that synthesize abnormal proteins, such as viral proteins in infected cells or mutant proteins in cancers.

Fred had the imagination and vision to see that inhibitors of the ubiquitin-proteasome pathway could be useful to treat diseases and founded a company to develop such agents. This effort gave birth to the first small-molecule proteasome inhibitors. To help develop such drugs, small biotech companies often try to partner with established pharmaceutical companies. But Fred’s and his company’s pitch for this novel therapeutic target and its inhibitors received a frosty reception from several major drug companies, with one pharma company executive declaring that “this stuff is rat poison.” As it turned out, Fred and his collaborators had a much clearer vision than the executives. Proteasome inhibitors are now effective drugs in the treatment of mantle cell lymphoma and multiple myeloma, which hitherto had few good treatment options. Moreover, ongoing preclinical studies point to possible uses of this class of drugs to treat inflammatory and autoimmune diseases.

In starting the quest for proteasome inhibitors, Fred always said, even if we are unable to develop these as drugs, they will be very useful as reagents in the laboratory. Boy was he ever clairvoyant, as proteasome inhibitors have proved extraordinarily useful in the biomedical sciences.

Fred also continued to pursue his early interests in muscle wasting and cachexia. He made important further contributions in this area beyond the proteasome. These included the identification the transcription factor FoxO3 and its downstream gene targets, called atrogenes, which control atrophy.

As befitting his numerous accomplishments, Fred received many awards. To name a few, he was elected to the National Academy of Science, American Academy of Arts and Sciences, and National Academy of Medicine. He received a number of Doctor of Science (DSc) degrees from other institutions and was awarded many prizes. In the opinion of many, one award that he did not get, but was deserving of, was a Nobel Prize.

Fred’s love and enthusiasm for science made him a natural teacher. In his laboratory, he mentored a large cadre of students and fellows that are now highly successful scientists. I have met many of these individuals, and they all speak about Fred with affection. Fred was very proud of his trainees and saw this as one of his important legacies. We can look forward to his “progeny” continuing to move the field forward. Fred also taught generations of medical students about the wonders of physiology. Whether they were as appreciative of this, I don’t know, but they did make him a star in some of their class plays.

Those of us who had the privilege of working alongside and collaborating with Fred count ourselves lucky. He was a warm individual who would be interested and engaged with you. He had a sense of humor and a hearty laugh. His breadth of knowledge was encyclopedic. It was always fun to talk science with him and enjoy the lively repartee and mental jousting. On the other hand, in writing a paper together, Fred insisted on chasing the asymptote of perfection. Deadlines imposed by the editors of elite journals would be ignored, as would the time on the clock during drafting (and most other) meetings. In the end, it was always worth it, for if you read his papers, you will appreciate their artistry.

When Fred developed his lymphoma, he was subjected to many conventional and experimental treatments, which initially worked, but then eventually failed. He took this as an opportunity to learn about his pathophysiology and treatments and felt like he had returned to medical school. He even tried to teach his doctors some physiology. Up until his final days, he was actively engaged in experiments and writing papers, and this sustained him through difficult times. At the end, when talking to him about his mortality, he said he had lived a good life and was at peace with what was coming. As is often the case, his death was harder for the living. We weren’t ready to say goodbye and now sorely miss him. Luckily for us, he left behind a legacy both personal and scientific that will last for many lifetimes.