When Alfred H. Merrill launched his career as an assistant professor at Emory University in 1981, he wanted to carve out his own unique niche, to do something that would distinguish himself while contributing to the growing body of research in biochemistry and molecular biology. So, he jumped into an enigma.
Merrill, a professor in the School of Biology in the College of Sciences and Smithgall Institute Chair of Molecular Cell Biology at the Georgia Institute of Technology, became a pioneering researcher in the field of sphingolipids (named “sphingo,” for “sphinx,” because sphingolipids are considered as enigmatic as the Great Sphinx).
Now, 30 years later, his early work is being recognized as some of the most influential research of its kind – classic stuff, literally.
“Right off the bat, my lab had the good luck to find that the textbook pathway for biosynthesis of sphingolipids was wrong,” says Merrill.
Niche carved, first contribution made.
Then came the bigger surprise: that sphingolipids are involved in cell signaling. This came through an exciting collaboration that resulted in publication of three back-to-back papers in 1986 that have just been designated as “Classics” by The Journal of Biological Chemistry (JBC). The Classics are selected from articles that have previously appeared in the JBC (since its founding in 1905), and considered particularly impactful. They’re reprinted in their original form, along with an explanation of the research’s groundbreaking contribution to science.
“The JBC is considered one of the most prestigious journals in basic biochemistry, so for one’s work to be selected as a ‘Classic’ is a real honor,” says Merrill, a researcher in the Petit Institute for Bioengineering and Bioscience, who finds himself in some elite company, as the Classics series includes papers by many of the all-time legends in biological chemistry.
“In some cases, such as ours,” he adds, “the specifics of the papers are probably not as important as that they turned people’s minds around and got them to look at a field from a different angle.” The JBC Classics entry calls out the research’s impact right there in the headline: “Solving the Riddle of the Role of Sphingolipids in Cell Signaling.”
Merrill likes to emphasize that these findings were the synthesis of ideas and expertise from many scientists, not just one investigator. It started with his former post-doctoral mentor, Robert M. Bell at Duke University.
“In Dr. Bell’s lab, the major focus was glycerolipid metabolism, but he had become intrigued that diacylglycerols were being claimed to be signaling molecules that activate protein kinase C (PKC),” Merrill says. “Skeptical of the idea at first, Yusuf Hannun and others in his lab developed sophisticated ways to study PKC and they not only became leading experts in how lipids activate this kinase but also happened to notice that a sphingolipid, sphingosine, could inhibit it.”
This was the underpinning of the first of the three papers, entitled, “Sphingosine inhibition of protein kinase C activity and of phorbol dibutyrate binding in vitro and in human platelets.”
“Since these were compounds that my lab had been studying, we became heavily involved,” says Merrill, whose only other co-author for all three papers was Bell. Hannun co-authored two of the papers.
“But as the project became even more sophisticated, additional collaborators were needed,” Merrill adds.
Two were other faculty at Emory, Dr. Jack Kinkade for the paper entitled, “Inhibition of phorbol ester-dependent differentiation of human promyelocytic leukemic (HL-60) cells by sphinganine and other long-chain bases,” and Dr. J. David Lambeth for the third paper, “Inhibition of the oxidative burst in human neutrophils by sphingoid long-chain bases. Role of protein kinase C in activation of the burst.”
According to George Carman, director of Rutgers University’s Center for Lipid Research (and the JBC associate editor who nominated the trilogy for Classic status), the papers “showed that a lipid backbone of sphingolipids could affect a cell signaling pathway (Protein Kinase C) at not only by inhibiting the in vitro activity but also by affecting diverse cell functions dependent on protein kinase C (platelet activation, the neutrophil respiratory burst and cell differentiation). This work started a whole sub discipline of lipid signaling that affects cell physiology.”
Before these papers, according to Merrill, there was no clear understanding of why sphingolipids were built upon the sphingosine backbone, which differs from all other lipid categories. The research demonstrated that sphingosine is a highly bioactive molecule capable of altering cell signaling and a wide spectrum of cell functions.
"Once the papers stimulated scientists to think about sphingolipids from that perspective, additional bioactive metabolites were discovered and characterized, resulting in a now very large field of cellular regulation by sphingolipid mediators,” Merrill says. “This, in turn, led to discoveries about how defects in these pathways result in disease and new strategies to prevent and treat disease.”
Almost everything that Merrill’s lab has subsequently discovered has been built on this new perspective on sphingolipids, and involved some sort of collaboration: The connection of sphingolipids with diseases caused by the fumonisin mycotoxins, in collaboration with Ron Riley at the USDA; that dietary sphingolipids suppress colon cancer with Dirck Dillehay, and development of drug leads based on sphingolipids with Dennis Liotta (both at Emory); development of mass spectrometric methods to quantify all of the known bioactive sphingolipids and discover new ones, with Cameron Sullards, director of the Georgia Tech Department of Chemistry and Biochemistry Mass Spectrometry Center; characterization of the mammalian genes and enzymes that make ceramides, with Tony Futerman at the Weizmann Institute; changes in sphingolipid metabolism in ovarian cancer, with John McDonald (Petit Institute); and so on.
With the assistance of research technician Samuel Kelly, Merrill has returned to working fulltime in the lab, to develop new ways to study sphingolipid structure and function. Thinking back over his career, Merrill is proudest of the approach his lab and collaborators have taken in their research, rather than any one specific finding.
“We have expended a lot of effort to develop better methods to analyze sphingolipids and model systems to study them more definitively,” he says. “This has often been slow and sometimes tedious, but it has resulted in solid data that have stood the test of time, and in many unexpected discoveries.”
LINKS:
The Journal of Biological Chemistry "Classics"
CONTACT:
Jerry Grillo
Communications Officer II
Parker H. Petit Institute for
Bioengineering and Bioscience
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Jerry Grillo
Communications Officer II
Parker H. Petit Institute for
Bioengineering and Bioscience
