PROFILE

Profile of David J. Mangelsdorf

wo decades ago, David Man- Earth,” he recalls. “Nevertheless, I got to gelsdorf did not expect his basic watch the space flight, send the rats up, research findings to help launch and keep the NASA mission patch,” T fi an entire eld of biology with far- he chuckles. reaching implications for a raft of human The NASA experiment may have led diseases, including cancer, metabolic dis- nowhere, but Mangelsdorf’s work bore orders, and parasitic infections. Man- fruit in bigger ways. Because the vitamin D gelsdorf, a Howard Hughes Medical receptor controls the excretion of calcium Institute investigator and a professor of by the kidneys, Mangelsdorf’s graduate pharmacology at the University of Texas work held medical promise (5). “Until Southwestern Medical Center at Dallas, you had the sequence for the receptor’s began his career by cloning the cellular gene, it was impossible to understand the receptor for vitamin D, which later helped genetic basis of diseases like vitamin D- other researchers uncover the genetic resistant rickets, which is caused by mu- basis of osteoporosis and rickets (1, 2). tations in the receptor’s ligand-binding, Insights from that initial work veered DNA-binding, and dimerization domains,” Mangelsdorf in a direction that spawned Mangelsdorf explains. “The cloning of the field of orphan nuclear hormone the receptor was the biggest thing in the receptors. field since the discovery of the hormonal Raised in Kingman, a sunswept town in form of vitamin D,” he adds, proudly. the Mojave Desert of northwestern Ari- zona, Mangelsdorf says his love of nature Testing Uncharted Waters preceded his love of science. Although Around the time Mangelsdorf announced much of his work has focused on molecules the cloning of the vitamin D receptor, Salk hidden in cells, his interest in biology began David J. Mangelsdorf. Institute molecular biologist Ronald as a passion for marine life in open oceans. Evans cloned the glucocorticoid receptor, Impelled by the breathtaking imagery of When Mangelsdorf was casting about for an important drug target in asthma and French naval explorer Jacques Cousteau’s a doctoral project upon his arrival at arthritis that is ancestrally related to the films of marine life, Mangelsdorf decided Haussler’s laboratory, Haussler offered vitamin D receptor. “Ron Evans pub- to become a marine biologist. “During my him a choice: biochemically identify the lished the idea of a family of proteins of sophomore year in high school, I wrote hypothetical vitamin A receptor or clone which the receptors for vitamin D, to The Scripps Institution of the gene for the biochemically identified vitamin A, glucocorticoids, and miner- [in San Diego] to explore the option of vitamin D receptor. Despite the allure of alocorticoids were members,” Man- as a career. I naively thought the unknown in the former, Mangelsdorf gelsdorf says. Like a returning ghost, the I could go there straight from high school, picked the latter. Armed with antibodies vitamin A receptor, whose biochemical but Scripps did not take undergraduate to the vitamin D receptor, Mangelsdorf set characterization he had passed up in students,” he says. However, Mangelsdorf out to clone the gene for the receptor by Haussler’s laboratory at the start of his learned that one of the best schools in the using a then-novel, bacteriophage-based doctoral project, came hauntingly back. United States for undergraduate aquatic cloning technique described in a now “This time, I wanted to identify the vita- biology, Northern Arizona University at highly cited PNAS paper (3). A fruitful min A receptor, and I thought his lab was Flagstaff, was a mere 150 miles from his collaboration with a graduate student in the best place to work on it,” he adds. In hometown. In the fall of 1977, he enrolled in the group of Baylor College of Medicine 1987, Mangelsdorf joined Evans’s labo- the school’s aquatic biology program. endocrinologist Bert O’Malley culminated ratory as a postdoc. While taking a beginner’s course in in a 1987 paper in Science describing the Members of Evans’s laboratory had chemistry to fulfill the program’srequire- drawn-out cloning of the chicken gene for been frantically cloning receptors of this ments, Mangelsdorf met one of his early the vitamin D receptor (4). Mangelsdorf’s family when Mangelsdorf decided to work mentors, John Wettaw, a chemistry pro- PhD thesis won the biochemistry depart- with Evans. Progress came so swiftly that fessor who introduced him to biochemistry. ment’s dissertation of the year award. another of Evans’s postdocs had identi- During the early 1980s, researchers were The award was not the only recognition fied the vitamin A receptor by the time making strides in the march against cancer. that Mangelsdorf’s graduate work gar- Mangelsdorf joined the laboratory in the Smitten with a 1980 Time magazine cover nered. In 1985, NASA accepted Man- fall. What could have been an un- story on the promise of interferon treat- gelsdorf’s proposal to conduct experi- fortunate development for Mangelsdorf ment for cancer, Mangelsdorf soon found ments with rodents aboard the Challenger proved to be a propitious turn of fate; his that his fascination with biochemistry sup- spacecraft to study the receptor’s role in gift for self-invention helped him forge planted his passion for marine biology. the alarming loss of bone density suffered a new field of research. After graduating with a bachelor’sdegree by some astronauts returning from space. Mangelsdorf embarked on a quest to in aquatic biology in 1981, he decided to Mangelsdorf’s idea was to compare the discover unknown receptors in the slowly spend the next 6 years in graduate school expression of the receptor’s gene in the growing superfamily. To find new recep- at the University of Arizona in Tucson, kidneys of rats sent into orbit with that of tors involved in hepatic function, Man- studying biochemistry in the laboratory of rats kept on Earth. “Unfortunately, it gelsdorf sifted through a genetic library of Mark Haussler, who discovered the hor- turned out that the space shuttle had to monal form of vitamin D called calcitriol. sit on the ground for almost 12 hours be- “It was Mark Haussler who really changed fore we could harvest the rats’ kidneys. By This is a Profile of a recently elected member of the Na- my mind about marine biology. I fell in love that time, whatever happened in space tional Academy of Sciences to accompany the member’s with his work,” Mangelsdorf says. might have been reversed by being back on Inaugural Article on page 9138 in issue 23 of volume 106.

www.pnas.org/cgi/doi/10.1073/pnas.1012718107 PNAS Early Edition | 1of3 Downloaded by guest on September 29, 2021 DNA sequences expressed in liver cells by Mangelsdorf says. Although he had ap- helped lure from GlaxoSmithKline to UT using as a probe the DNA-binding domain plied to a handful of universities across Southwestern, to study the role of FXR, of the receptors that had already been the United States, Mangelsdorf had never or the bile acid receptor, in metab- cloned. The effort yielded more than considered going to Dallas. However, he olism. “Steve came to the department as a dozen potential candidates for receptors knew Dallas was home to two Nobel a full professor, already renowned for his of mysterious function. Because the bind- Prize-winning pioneers in lipid biology, work on nuclear receptors, without a sin- ing partners for these receptors were un- Michael Brown and Joseph Goldstein, gle research tool because he was return- known at the time, Mangelsdorf called whose work on cholesterol ing from industry. I opened up my lab to them “X-Rs,” a name that later morphed partly overlapped with his own research on him, and we started collaborating,” into “orphan receptors.”“This was a rich nuclear receptors. “When I saw Dallas— Mangelsdorf says. area of exploration, a golden age for re- the city and the university—it went from The collaboration helped researchers ceptor discovery. We cloned and stock- not even being on my radar to the top of understand how FXR and LXR use piled the receptors, calling them X-R 1, 2, my list. The environment for fostering a byzantine signaling network to control 3, and so on,” Mangelsdorf says. “At that scientific potential was astounding,” lipid metabolism immediately after we eat time, having just the sequence for one Mangelsdorf says. a meal. During a meal, cholesterol acti- of these receptors gave you a Nature or vates LXR, which drives the activity of Science paper,” he adds. Mangelsdorf Receptors Aplenty genes that regulate two metabolic path- picked one of the orphan receptor can- At UT Southwestern, Mangelsdorf con- ways—one that turns and sugars didates for further study. tinued to mine the mother lode of into stored fat, and another that removes Mangelsdorf says serendipity, perspi- receptors he had cloned in Evans’s labo- cholesterol by helping excrete most of it ration, and inspiration provide the nar- ratory. He picked one, called LXR, which and turning the rest into bile acids. After rative for much of what followed. “In he later found was activated by choles- the meal, most of the bile acids, which retrospect, of all the candidates I found, terol metabolites called oxysterols (8). help digest food, are recycled to the liver. I was lucky to have picked what turned To Mangelsdorf, the finding seemed During this process, some bile acids latch out to be the grand prize, the one we a mixed blessing: Although he realized he onto FXR in intestinal cells. The binding called RXR, or retinoid X receptor,” he was in a suitable place to study a receptor of bile acids to FXR triggers the synthesis says. Using a seminal assay developed in triggered by a sterol—UT Southwestern of a hormone, called fibroblast growth Evans’s laboratory to identify ligands for was a veritable mecca for aficionados factor 15, which turns off both bile acid orphan receptors, Mangelsdorf found of lipid metabolism—he recalls, “It was synthesis and the LXR target genes in the that the vitamin A metabolite, 9-cis reti- a goldmine, but I was nervous because liver, thus closing a complex regulatory noic acid, was RXR’s natural ligand (6); Brown and Goldstein were working on loop and resetting the system for the next the study was carried out together with similar things.” meal (11). researchers from California-based Ligand Part of what propels Mangelsdorf is his Mangelsdorf’s findings on this tortuous Pharmaceuticals, a spin-off from Evans’s drive, discipline, and doggedness. How- feedback loop won him the 2004 Gerald studies that Mangelsdorf named. “That ever, it was his knack for turning stumbling D. Aurbach Award from the Endocrine was the first demonstration that a com- blocks into stepping stones that helped Society—not least because the findings pound that was not known to work him broker a partnership with Brown and pointed to a seemingly endless array through one of these receptors indeed did Goldstein instead of competing with them. of therapeutic possibilities. First, com- so,” Mangelsdorf says. “It truly opened up That partnership, in turn, led to the dis- pounds activating LXR could help pre- the field of orphan receptors.” covery that LXR is the master regulator of vent and treat atherosclerosis by has- The discovery of RXR’s ligand meant a transcription factor called SREBP1, tening the removal of cholesterol from an array of therapeutic applications for uncovering an unknown regulatory in- the body (10, 12, 13). Next, Mangelsdorf the receptor. The finding suggested that terplay between cholesterol and fatty acid and others showed that an experimental vitamin A, which was then being tested as metabolism (9). The discovery also hel- compound that activated RXR, the re- an experimental cancer drug, likely acted ped vault LXR to the vanguard of investi- ceptor he had characterized as a postdoc through RXR, rendering the receptor gational drug treatment for cholesterol- in Evans’s laboratory, could help treat a therapeutic target for cancer. Further, related diseases. Because LXR helps metabolic syndrome by stimulating FXR, Mangelsdorf’s collaborators found that removes cholesterol from macrophages LXR, and PPARs, all of which are di- RXR paired up with other nuclear re- by turning on the gene for a cholesterol merization partners of RXR (10, 14, 15). ceptors to control many endocrine path- transporter protein (10), the reasoning Further, Mangelsdorf published a 2004 ways, pointing to the receptor’s role in goes, compounds stimulating the receptor Nature Medicine report showing that diabetes and metabolic syndrome (7). could help slow the progression of coro- a compound that stimulated FXR could Mangelsdorf’s trailblazing findings on nary heart disease, which is caused by an help curb cholesterol gallstone disease, orphan receptors established his reputa- inflammatory reaction to cholesterol- a painful condition caused by cholesterol tion and earned him a faculty position at laden macrophages in the arteries. crystals in the gall bladder (16). In addi- the University of Texas Southwestern Mangelsdorf’s contributions to orphan tion, his work on the vitamin D receptor Medical Center in Dallas. At a 1991 receptor research earned him the coveted showed that compounds that activate pharmacology conference organized by 1997 John J. Abel Award from the the receptor could help neutralize po- Johnson & Johnson, Mangelsdorf met American Society for Pharmacology and tentially cancer-causing bile acids, such as Alfred Gilman, then chairman of the Experimental Therapeutics, an accolade lithocholic acid, providing a likely expla- university’s pharmacology department, historically recognized as a harbinger of nation for the protective effect of vitamin who discovered G protein-mediated sig- higher honors. D against colon cancer (17). Add to these naling in cells. That meeting paved the Yet another receptor from Man- therapeutic targets a slew of cellular pro- way to Mangelsdorf’s independent aca- gelsdorf’s repertory became the focus cesses that could be modulated by directly demic career. “Gilman came to me and of the next few months of his research. targeting PPAR, which controls aspects said, ‘The only reason I’m at this meeting Mangelsdorf teamed up with his erstwhile of cell division and metabolism (18, 19). is to invite you to come to UT South- competitor Steven Kliewer, a former In 2000, Mangelsdorf cofounded a western to give a talk for a job,’” postdoc of Evans whom Mangelsdorf California-based biotechnology firm, X-

2of3 | www.pnas.org/cgi/doi/10.1073/pnas.1012718107 Nair Downloaded by guest on September 29, 2021 Ceptor Therapeutics Inc., now a part of through a phase of dormancy in its life odes are estimated to infect nearly one Exelixis, to discover compounds modulat- cycle called dauer diapause, suggesting third of the human population, and there ing nuclear receptors. Whereas a few of X- the involvement of a nuclear receptor is no known drug that attacks their in- Ceptor’s experimental compounds failed triggered by a steroid. What was more, fectious stage,” Mangelsdorf says. Be- to result in drugs because of side effects, the DAF-12 gene showed telltale se- cause DAF-12 controls both entry into others are being tested in clinical trials. quence similarities with LXR and FXR. and exit from diapause, parasitic worms “In general, the problem with nuclear re- In a 2006 Cell paper, Mangelsdorf and would likely need more than one re- ceptors is that potent activators of the re- his graduate students described how ste- sistance-conferring mutation to survive ceptors can do both good and bad. What roid ligands of DAF-12, called dafach- drugs targeting DAF-12. “That’s why we want are modulators to tickle the re- ronic acids, help the worm resume me- I think it’s a huge therapeutic target,” ceptors just enough to do the good but not tabolism and reach reproductive maturity he says. the bad,” Mangelsdorf says. “That concept after diapause; overcrowding, food scar- The long list of physiological roles for is just beginning to be appreciated.” city, and harsh drive the nuclear receptors bolsters Mangelsdorf’s worm toward diapause (20). “Dauer dia- belief that building profiles of their syn- The Parasite Puzzle pause is one of the reasons for the lon- thesis and activity for individual patients Another concept just being appreciated gevity of these worms,” Mangelsdorf says. could have therapeutic benefits. “Our is the role of orphan nuclear receptors Mangelsdorf’s findings on the regula- work on orphan receptors has demon- in parasitic infections. Although it was tion of the worm’s fasting response by strated that they work as a group, not known that invertebrates had the recep- DAF-12 harkens back to the roles of individually, to regulate physiology. They tors, their function in this group of animals LXR and FXR in controlling dietary seem to work as a hierarchical transcrip- had long remained a mystery. Man- cholesterol metabolism in people, under- tional network that controls metabolism,” gelsdorf identified the hormonal ligand for scoring the evolutionary conservation of he says. Profiling this network in cancer a receptor dubbed DAF-12 in the free- this hormonal pathway among animals. patients, for example, could provide bio- living roundworm Caenorhabditis elegans, More importantly, the findings paved the markers that could not only help diagnose a finding that not only shed light on the way for research that identified DAF-12 cancer but also direct treatment. evolution of hormonal pathways in ani- as a drug target in parasitic nematode Mangelsdorf says the high point of his mals but unearthed a potential drug infection, a worldwide scourge that af- career was his election in 2008 to the target for parasitic diseases, such as flicts more than a billion people. “The National Academy of Sciences. “The hookworm and threadworm. “Of all the infectious stage of many parasitic nemat- election is an award that was given for my things I’ve done, I find this to be one of odes resembles the C. elegans diapause— entire career, which is shaped by all the the most exciting—if not the most excit- nonreproductive, nonfeeding, and long- people who stand behind me. I am most ing,” Mangelsdorf says. Whereas mam- lived. Something in the nematodes’ hosts grateful for the election because it ac- mals have 48 different nuclear receptors, helps the worms exit this stage and reach knowledges the importance of the work,” and fruit flies have about 20, C. elegans reproductive maturity. Our hunch was he says. harbors 284 such receptors, a bewilder- that it was the activation of DAF-12,” Over nearly three decades, Mangelsdorf ingly large number for a tiny worm. When Mangelsdorf says. has illuminated the once-obscure world Mangelsdorf first learned of the worm In his PNAS inaugural article, pub- of orphan nuclear hormone receptors. receptors, not a single one had a known lished in June 2009, Mangelsdorf proved However, lofty goals, he says, lie ahead: ligand, let alone well-defined functions. his hunch correct: he demonstrated that “Al Gilman always said one of his great- “That was too tempting a target to go administering dafachronic acid to the est desires was for the pharmacology de- after especially because C. elegans is an threadworm Strongyloides stercoralis partment at UT Southwestern to discover experimental system used by most life noticeably reduced the number of patho- a drug. My goal is to be the first to dis- scientists. Because I was a ligand hunter, genic worms; the ligand activated DAF- cover a widely used drug that goes from I wanted one of those as a notch in my 12, nudged the slumbering worms out of the department into the clinic.” belt,” he says. Mangelsdorf knew that diapause, and disrupted the worms’ nor- the worm needed cholesterol to pass mal development (21). “Parasitic nemat- Prashant Nair, Science Writer

1. Eastell R, Riggs BL (2005) Vitamin D and osteoporosis. ceptors in retinoic acid, thyroid hormone and vitamin 15. Mukherjee R, et al. (1997) Sensitization of diabetic and Vitamin D, eds Feldman D, Pike JW, Glorieux FH (Elsevier D3 signalling. Nature 355:446–449. obese mice to insulin by retinoid X receptor agonists. Academic, Burlington, MA), 2nd Ed., pp 1101–1121. 8. Janowski BA, Willy PJ, Devi TR, Falck JR, Mangelsdorf DJ Nature 386:407–410. 2. Malloy PJ, Pike JW, Feldman D (2005) Hereditary 1,25- (1996) An oxysterol signalling pathway mediated by 16. Moschetta A, Bookout AL, Mangelsdorf DJ (2004) dihydroxyvitamin D-resistant rickets. Vitamin D, eds the nuclear receptor LXR α. Nature 383:728–731. Prevention of cholesterol gallstone disease by FXR Feldman D, Pike JW, Glorieux FH (Elsevier Academic, 9. Repa JJ, et al. (2000) Regulation of mouse sterol regula- agonists in a mouse model. Nat Med 10:1352–1358. Burlington, MA), 2nd Ed., pp 1207–1239. tory element-binding protein-1c gene (SREBP-1c) by oxy- 17. Makishima M, et al. (2002) Vitamin D receptor as an 3. Young RA, Davis RW (1983) Efficient isolation of genes sterol receptors, LXRα and LXRβ. Genes Dev 14:2819–2830. intestinal bile acid sensor. Science 296:1313–1316. by using antibody probes. Proc Natl Acad Sci USA 80: 10. Repa JJ, et al. (2000) Regulation of absorption and 18. Sporn MB, Suh N, Mangelsdorf DJ (2001) Prospects for 1194–1198. ABC1-mediated efflux of cholesterol by RXR hetero- prevention and treatment of cancer with selective 4. McDonnell DP, Mangelsdorf DJ, Pike JW, Haussler MR, dimers. Science 289:1524–1529. PPARγ modulators (SPARMs). Trends Mol Med 7: O’Malley BW (1987) Molecular cloning of cDNA en- 11. Inagaki T, et al. (2005) Fibroblast growth factor 15 395–400. coding the chicken 1,25-dihydroxyvitamin D3 receptor. functions as an enterohepatic signal to regulate bile 19. Inagaki T, et al. (2007) Endocrine regulation of the Science 235:1214–1217. acid homeostasis. Cell Metab 2:217–225. fasting response by PPARα-mediated induction of 5. Ruggiero M, Pacini S, Amato M, Aterini S, Chiarugi V 12. Repa JJ, et al. (2002) Regulation of ATP-binding cassette fibroblast growth factor 21. Cell Metab 5:415–425. (1999) Association between vitamin D receptor gene sterol transporters ABCG5 and ABCG8 by the liver X 20. Motola DL, et al. (2006) Identification of ligands for polymorphism and nephrolithiasis. Miner Electrolyte receptors α and β. JBiolChem277:18793–18800. DAF-12 that govern dauer formation and repro- Metab 25:185–190. 13. Tangirala RK, et al. (2002) Identification of macro- duction in C. elegans. Cell 124:1209–1223. 6. Heyman RA, et al. (1992) 9-cis retinoic acid is a high phage liver X receptors as inhibitors of atherosclerosis. 21. Wang Z, et al. (2009) Identification of the nuclear affinity ligand for the retinoid X receptor. Cell 68: Proc Natl Acad Sci USA 99:11896–11901. receptor DAF-12 as a therapeutic target in parasitic 397–406. 14. Shulman AI, Mangelsdorf DJ (2005) Retinoid X re- nematodes. Proc Natl Acad Sci USA 106:9138–9143. 7. Kliewer SA, Umesono K, Mangelsdorf DJ, Evans RM ceptor heterodimers in the metabolic syndrome. (1992) Retinoid X receptor interacts with nuclear re- N Engl J Med 353:604–615.

Nair PNAS Early Edition | 3of3 Downloaded by guest on September 29, 2021