Raymond L. Erikson was born on a Wisconsin dairy farm in 1936 and grew up near the village of Eagle that had been settled by his father and grandfather in the early 1900’s. “I did not have what today might be regarded as a propitious early education,” said Erikson,
American Cancer Society Professor of Cellular and Developmental Biology, Emeritus. “I attended a one room rural school initially with one first grade classmate, Jim Carpenter, from a neighboring farm. Jim and I remained classmates through the eighth grade offered in that school and in a larger consolidated high school, and eventually became roommates at the University of Wisconsin-Madison.”
Erikson began studies at Madison with the intention of eventually teaching agriculture sciences at a high school. In his junior year, he enrolled in a course taught by prominent population geneticist which inspired Erikson to become excited about the science of biology. Erikson recalled, “I soon realized I had insufficient enthusiasm for agricultural science experiments on butterfat.”
He found himself spending as much time reading original research literature as the material covered in Professor Crow’s lucid lectures. Then he read an intriguing article on viruses, and that led him towards a field that has evolved from microbiology to molecular biology, thanks to progress in biochemistry – a field to which Erikson contributed significantly.
Transition from RNA Bacteriophage to RNA Tumor Viruses
In 1963, after earning a bachelor’s, master’s and doctorate from UW-Madison, Erikson began postdoctoral research with Richard M. Franklin at University of Colorado School of Medicine, where he studied the replication of RNA bacteriophages (viruses that infect bacteria). He then transitioned to investigations of tumorigenic animal RNA viruses and started his independent lab in the pathology department at Colorado, focusing on the RNA genomes of oncogenic retroviruses.
In 1976, the Bishop-Varmus lab at University of California at San Francisco reported that normal chicken cell DNA contained genetic information related to the region of the Rous Sarcoma virus genome (termed v-src) that was known to be required for tumor formation. This finding, which was ultimately recognized by a Nobel Prize, indicated that normal cells contain genetic information that could cause tumor formation.
Studies of mutant variants of Rous Sarcoma virus that caused reversible, temperature-sensitive transformation, by Steve Martin at U.C. Berkeley and later, Hidesaburo Hanafusa at the Rockefeller University, strongly supported the existence of a protein product of the ‘src’ region of the genome. Together, these findings led to an all-out search for the ‘v-Src’ protein.
“Everyone talked about oncogenes, but no one had described one,” recalled Marc S. Collett, a postdoctoral researcher in Erikson’s lab in the late 1970s. Identification of the v-Src protein was critical to understanding how alterations in a normal cellular gene could lead to cancer. Erikson’s group addressed that critical conundrum and in 1977, after 5 years of hitting dead ends, finally identified the protein. In doing so they not only explained how Src actually causes cancer but also discovered a pathway now considered among the most important cancer-promoting signaling cascades.
Finding Src, the First Onco-Protein
One of the approaches that led to finding the first oncoprotein involved attempts to develop antibodies to the v-Src protein by generating tumors in a variety of animals. Another approach was based on a new technology that used antibodies and an immunoabsorbent molecule that could bind to a protein and separate it from thousands of other proteins. Erikson was an early adoptor of this ‘immunoprecipitation’ technology, according to Joan Brugge, one of his postdoctoral mentees at the time, who went on to chair Harvard Medical School’s Department of Cell Biology and then become Co-Director of the Ludwig Center at Harvard. They used this technique with the serum of animals that had developed tumors after injection with Rous Sarcoma virus. Running a gel to separate proteins from the precipitates would hopefully reveal a band indicating the protein that had attached to the antibody.
One day, Brugge developed her film and saw a band that suggested it was the src gene product. “I was very excited because after so many years there was a faint glimmer of hope that we had found the protein product of src,” Brugge recalled. “I wanted to get a bottle of champagne to celebrate, but Ray, keenly aware of the human mind’s confirmation bias said, ‘It’s not time for champagne yet, Joan.’ Erikson was unusually cautious about supposing the existence of more order in the world than was actually there.
Using peptide mapping, Tony Purchio, a student in the lab, provided the analysis that confirmed the identity of the immunoprecipitated protein as the Src protein. These experiments, conducted by Erikson and his group are counted as some of the most important insights that have led to our current understanding of cancer genesis.
Tracing Tyrosine Kinases to Cancer
The understanding of how Src causes cancer began unfolding on Thanksgiving Day in 1977, when Erikson and Collett found that Src is a kinase, an enzyme that adds phosphate groups to other proteins (and, in this case, also to itself). Such phosphorylation dramatically changes the function of that other protein, often activating an entire pathway.
“This explained the reversible effect observed in src,” Erikson explained. “If you take the phosphate away, the protein returns to its quiescent state.” They showed that the mutated Src kinase over-activates the downstream proteins, driving massive cell proliferation.
Moreover, Tony Hunter’s laboratory at the Salk Institute found that it attaches the phosphate group to an amino acid not previously known to be a target of a kinase – tyrosine. That Src was a kinase, and a new brand of kinase at that, was “another eureka moment for the field,” Brugge said.
“This discovery supported the new concept that our own cells contain proto-oncogenes that have a benign function until some mutation transforms them,” Erikson reflected. “It showed how understanding a pathological situation in a tumor could tell us something about normal cell proliferation.”
Mapping Signaling Pathways
Unbeknownst to them at the time, this research would open up the field of signal transduction as researchers know it today. “The foundation for the study of tyrosine kinases came from those years,” Collett said. Tyrosine kinases are now known to be essential in normal cell biology and to be deregulated in many cancers. They are also the targets of anti-cancer drugs that inhibit aberrant kinase activity.
These contributions earned Erikson–“a pioneer among pioneers”–the Lasker Award in 1982, and an invitation to join Cellular and Developmental Biology, . There, he continued investigating how Src transmits information downstream to other kinases. Thus began the next phase of the Erikson legacy of defining cancer cell signaling.
“Those were very exciting days both due to the science and the amazing group of junior scientists Ray had recruited,” explained John Blenis, one of Erikson’s first postdocs at Harvard, who is now at Weill Cornell Medicine. “We talked a lot about Erikson’s philosophy of science, and the importance of being careful and thorough. With his biochemical background, Ray wanted to understand at the molecular level how things work.”
“For me, it began when I discussed wanting to work on src tyrosine kinase targets. He challenged me to think deeply, citing the fact that most of the downstream changes were in serine/threonine phosphorylation,” recalled Blenis. “Our early studies showed that v-Src, growth factors, and tumor promoters promoted the ser-phosphorylation of 40S ribosomal protein S6. Erikson was happy with this finding but not truly impressed, he wanted to know ‘HOW?’. He was true to his convictions, he didn’t want correlations, he wanted molecular mechanisms. To do this required biochemistry, Erikson’s love.”
Calvin Kuo, an outstanding Harvard undergraduate at the time, and Blenis went on to purify and characterize the 40S ribosomal S6 kinase (S6K). “To purify and characterize S6K required that we make our own [g-32P]ATP; 25 mCi every other week. For my first ATP prep Erikson always pushed for careful experimental science, from the ground up.”
S6 kinase was purified in 1997, Steve Jones and Jo Erikson purified and cloned another Src-regulated ser/thr kinase, RSK, and in the process discovered the first two-headed serine kinase, likely the result of an ancient fusion between two different kinases. Laurel Sweet and Blenis went on to characterize RSK, demonstrating a unique mechanism of regulation.
The biochemical approach was also central to the work of Craig Crews and Alessandro Alessandrini, which led to the discovery of MEK. Crews then demonstrated that MEK was the first dual-specificity protein kinase capable of phosphorylating ERK on the tyrosine and threonine sites required for ERK activation. MEK inhibitors are now important FDA-approved drugs being utilized for cancer therapy. As an aside, and consistent with Erikson’s philosophy of fairly recognizing previous work, the name MEK was in acknowledgment of prior work on its target by the Tom Sturgill and Melanie Cobb labs, MAP kinase – ERK activating Kinase.
Taking lessons from Marc Collett and Tony Purchio, who developed the first Src immune-complex kinase assay, antibodies to ERK, RSK, and S6K were used to perform immune kinase assays. Using this technique, the Brugge and Blenis labs then demonstrated that the oncogene RAS was mediating the transmission of tyrosine kinase signaling to the ERK-MAP kinase cascade. The Blenis lab also demonstrated that PI3K and a rapamycin-sensitive kinase (mTORC1) were upstream regulators of S6K providing another mechanism for signaling downstream of tyrosine kinases. These accomplishments again reflect the impact of Ray Erikson and his influence on his mentees and on our current understanding of growth factor and oncogenic signaling.
However, what made the lab at that time truly exciting was its comradery and the diversity of ground-breaking work. Erikson lab members in the late 1980s, postdoctoral fellows were characterizing gene expression regulated downstream of Src. This eventually led Simmons, in his own lab, to identify COX2, resulting in the development of the medically important COX2 inhibitors. Andre Bedard identified quiescence-associated gene expression, now a huge field on its own. Marilyn Resh, a graduate student in Erikson’s lab who went on to run her own lab at Sloan Kettering, was completing very thorough structure/function analysis of the Src protein.
Ben Neel, already well known for his work on the promoter insertion model for oncogenesis, began his search for tumor suppressors, including work with Jonathan Chernoff on tyrosine phosphatases. Eventually, Neel, in his own lab and collaborating with Erikson and the Chernoff lab, cloned the tyrosine phosphatase, PTP1B, providing a mechanism for reversibly regulating Src-like tyrosine kinases. Simmons and Neel also collaborated to identify polo-like kinases as Src-regulated genes leading to the next phase of Erikson lab scientific endeavors.
Looking at Cell Division
These biochemistry studies were elucidating what drives cell proliferation early in the cell cycle – during both cancer and normal cell growth. By the early 1990s, a member of another class of enzymes, polo-like kinase 2 (Plk2), was also implicated in the early growth response that signals a cell to divide.
Erikson suspected that different polo-like kinases might come into play at different stages of the cell cycle. The lab began studying Plk1 and discovered that it was involved later in the cell cycle, regulating proper mitotic progression and completion of cell division. During mitosis, chromosomes are duplicated and the sister chromatids must align along a plane, where spindles pull them towards opposite poles. Erikson showed that Plk1 helps spindles form and attach to the proper location on the chromatids. One domain of the protein acted as a catalyst for this attachment, and another domain – the polo box – sent it to the precise “zip code” on the chromatid.
Without Plk1, cells cannot divide. Because cancer cells divide so frequently, they require more Plk1 than normal cells, so this protein made an appealing target for anti-cancer drugs. In fact, it provides a dual target. Inhibiting the catalytic domain makes it inactive, whereas inhibiting the polobox domain makes it “blind” to the zip codes and dysfunctional. Several companies are developing these inhibitors.
But since Plk1 is necessary for normal cell growth, would an inhibitor have unacceptable side effects? Perhaps not, according to Erikson’s later experiments using RNA interference (RNAi) to decrease the synthesis of Plk1. A decrease of 80% stopped cell division in cancer cells, but not in slower-growing normal cells. Still, normal cells needed some Plk1. Erikson then began investigating what biochemical events lead to cell death in Plk1-deficient cells.
Dedicated Scientist and Beloved Colleague
To his lab members, Erikson was more than a great scientist. “Ray is a concept pioneer who identified protein kinases and phosphorylation events as significant in tumorigenesis, and he will forever be one of our nation’s best biochemists,” said Xiaoqi Liu, a former postdoctoral researcher, who is now at Purdue University.
“He was 63 when I joined the lab in 1999 to work on polo-like kinases, so I didn’t expect him to talk to me very often,” Liu added. “But surprisingly, he was always there with guidance, mentoring and encouragement, which I especially appreciated during the periods when my experiments did not out work as well as I’d hoped. The seven years I spent in his lab were the happiest of my entire life so far. I really miss it!”
Erikson also stayed close to his roots, in both his personal and research lives, something that amazed Kyung Lee, who did the early work on Plk1 and is now at the National Institutes of Health. Lee would find Erikson in the lab on a Saturday morning, making his own gel preparations – except during two weeks each summer, when he returned to the family farm so that his brother, who still runs the farm, could take a vacation. “If you called Ray after he’d been working in the field all day,” Lee says, “he would be too tired to even talk.” Later, the farm became less active, providing Erikson a somewhat more relaxing sojourn from his lab at MCB.
As so nicely stated by Departmental colleague John Dowling, “Ray was a perfect gentleman as well as a wonderful scientist. Whenever we saw each other, which was often since our labs were on the same floor, we always stopped to chat about whatever – science, departmental affairs, mutual friends and so forth. I very much miss those chats and Ray!”
And as movingly recalled by former postdoctoral fellow John Blenis, “I had lunch with Ray once a month or so before leaving Boston and a few times after, including recently meeting with him while he was in the hospital. His eyes would alway brighten and his energy would rise when we began discussing our research efforts. He was an amazing scientist, loved good experimental design and always challenged us to think deeply. I miss him.”
NOTABLE CONTRIBUTIONS in the Erikson Laboratory
Joan S. Brugge, “Generation of antibody for identification of a transformation-specific protein: The putative avian sarcoma virus(ASV) src gene product,” Nature 1977 269 346-8.Tony Purchio, Eleanor Erikson, “Identification of the ASV src gene product by in vitro translation of the viral src gene,” PNAS 1978 75 1567-71.Marc S. Collett, “Demonstration of src gene product protein kinase activity” PNAS 1978 75 2021-4.
Eleanor Erikson, “Synthesis of protein kinase activity by in vitro translation of viral src gene RNA,” Nature 1978 274 919-21
Collett, Brugge, Erikson E., “A normal cell protein structurally and functionally related to the ASV src gene product,” Cell 1978 15 1363-9.
Blenis J and Erikson RL. “Stimulation of ribosomal protein S6 kinase activity by pp60v-src or serum: Dissociation from phorbol ester-stimulated activity.” Proc. Natl. Acad. Sci. USA 1986; 83: 1733-1737.
Blenis J, Kuo CJ and Erikson RL. “Identification of a ribosomal protein S6 kinase regulated by transformation and growth-promoting stimuli.” J. Biol. Chem. 1987; 262: 14373-14376.
Steve W. Jones, Erikson E., “Molecular cloning of a ribosomal S6 protein kinase,” PNAS 1988 85 3377-81
Craig Crews, “Purification, characterization and cloning of MEK, a protein kinase that phosphorylates and activates MAP kinase,” Science 1992 258 498-80
Daniel L. Simmons, “Gene expression in ASV-transformed cells: Molecular cloning of Cox2 and polo-like kinase,” PNAS 1991 88 2692-6
Chernoff J, …, Erikson RL, Neel BG. “Cloning of a cDNA for a major human protein-tyrosine-phosphatase” PNAS 1990 87 2735-9
Simmons D., Neel B.G., “Molecular cloning and gene expression of polo- like kinases,”. Mol Cell Biol 1992 12 4164-9.
Kyung S. Lee, “Pioneering studies on the structure and function of polo-like kinase1,” PNAS 1998 95 9301-6
Xiaoqi Liu, Hyungshin Yim, “Demonstration that cancer cells are addicted to high levels of Plk1 expression,” PNAS 100 5789-94, Mol Cell Biol 2006 26 2093-108.
Ray leaves behind his wife of nearly 32 years Donna and daughter Amanda.
In memory of Erikson, Donna and Amanda have established an endowment fund at University of Wisconsin-Madison. “The Raymond L. Erikson Exceptional Thesis Award will benefit graduate students in the University’s Cellular and Molecular Biology Program,” they wrote in request for donations. “Raymond was the second person to receive his PhD from this program. The program helped launch his career, and your gift will help launch the careers of other students in this program.”
Checks for the endowment fund should be made out to the UWF/ Raymond L. Erikson Exceptional Thesis Award with a memo saying “in memory of Raymond Erikson” and mailed to: UW Foundation, U.S. Bank Lockbox 78807, Milwaukee, WI 53278-0807
The UW Foundation, UWF, will send tax receipts. Anyone who wishes to make their gift in another way should contact Maureen Dembski at 608-206-6073. Amanda and Donna say that they are deeply thankful to everyone honoring Raymond’s memory with a gift.