Adipose triglyceride lipase contributes to cancer-associated cachexia

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Adipose Triglyceride Lipase Contributes to Cancer-Associated Cachexia Suman K. Das, et al. Science 333, 233 (2011); DOI: 10.1126/science.1198973

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References and Notes 1. H. Nakatogawa, K. Suzuki, Y. Kamada, Y. Ohsumi, Nat. Rev. Mol. Cell Biol. 10, 458 (2009). 2. Z. Yang, D. J. Klionsky, Curr. Opin. Cell Biol. 22, 124 (2010). 3. B. Levine, N. Mizushima, H. W. Virgin, Nature 469, 323 (2011). 4. V. Deretic, Curr. Opin. Cell Biol. 22, 252 (2010). 5. V. Kirkin, D. G. McEwan, I. Novak, I. Dikic, Mol. Cell 34, 259 (2009). 6. C. Kraft, M. Peter, K. Hofmann, Nat. Cell Biol. 12, 836 (2010). 7. D. G. McEwan, I. Dikic, Trends Cell Biol. 21, 195 (2011). 8. I. Novak et al., EMBO Rep. 11, 45 (2010). 9. V. Kirkin et al., Mol. Cell 33, 505 (2009).

10. Materials and methods are available as supporting material on Science Online. 11. S. Pankiv et al., J. Biol. Chem. 282, 24131 (2007). 12. C. Behrends, M. E. Sowa, S. P. Gygi, J. W. Harper, Nature 466, 68 (2010). 13. Single-letter abbreviations for the amino acid residues are as follows: A, Ala; D, Asp; E, Glu; F, Phe; G, Gly; I, Ile; and S, Ser. 14. S. Wagner et al., Oncogene 27, 3739 (2008). 15. S. Morton, L. Hesson, M. Peggie, P. Cohen, FEBS Lett. 582, 997 (2008). 16. K. Clark, L. Plater, M. Peggie, P. Cohen, J. Biol. Chem. 284, 14136 (2009). 17. A. L. Radtke, L. M. Delbridge, S. Balachandran, G. N. Barber, M. X. O’Riordan, PLoS Pathog. 3, e29 (2007). 18. T. L. Thurston, G. Ryzhakov, S. Bloor, N. von Muhlinen, F. Randow, Nat. Immunol. 10, 1215 (2009). 19. L. A. Knodler et al., Proc. Natl. Acad. Sci. U.S.A. 107, 17733 (2010). 20. A. J. Perrin, X. Jiang, C. L. Birmingham, N. S. So, J. H. Brumell, Curr. Biol. 14, 806 (2004). 21. C. R. Beuzón et al., EMBO J. 19, 3235 (2000). 22. Y. T. Zheng et al., J. Immunol. 183, 5909 (2009). 23. M. Cemma, P. K. Kim, J. H. Brumell, Autophagy 7, 341 (2011). 24. P. Stehmeier, S. Muller, Mol. Cell 33, 400 (2009). 25. H. Jiang, D. Cheng, W. Liu, J. Peng, J. Feng, Biochem. Biophys. Res. Commun. 395, 471 (2010). 26. S. J. Cherra 3rd et al., J. Cell Biol. 190, 533 (2010). 27. F. Ikeda, N. Crosetto, I. Dikic, Cell 143, 677 (2010). Acknowledgments: We thank P. Cohen, S. Mueller, K. Rajalingam, C. Behrends, and the members of

Adipose Triglyceride Lipase Contributes to Cancer-Associated Cachexia Suman K. Das,1 Sandra Eder,2 Silvia Schauer,1 Clemens Diwoky,3 Hannes Temmel,1 Barbara Guertl,1 Gregor Gorkiewicz,1 Kuppusamy P. Tamilarasan,1 Pooja Kumari,1,4 Michael Trauner,4 Robert Zimmermann,2 Paul Vesely,1 Guenter Haemmerle,2 Rudolf Zechner,2* Gerald Hoefler1* Cachexia is a multifactorial wasting syndrome most common in patients with cancer that is characterized by the uncontrolled loss of adipose and muscle mass. We show that the inhibition of lipolysis through genetic ablation of adipose triglyceride lipase (Atgl) or hormone-sensitive lipase (Hsl) ameliorates certain features of cancer-associated cachexia (CAC). In wild-type C57BL/6 mice, the injection of Lewis lung carcinoma or B16 melanoma cells causes tumor growth, loss of white adipose tissue (WAT), and a marked reduction of gastrocnemius muscle. In contrast, Atgl-deficient mice with tumors resisted increased WAT lipolysis, myocyte apoptosis, and proteasomal muscle degradation and maintained normal adipose and gastrocnemius muscle mass. Hsl-deficient mice with tumors were also protected although to a lesser degree. Thus, functional lipolysis is essential in the pathogenesis of CAC. Pharmacological inhibition of metabolic lipases may help prevent cachexia. achexia (kakos hexis, Greek for “bad condition”) is a devastating syndrome that frequently occurs in patients suffering from chronic infection, such as tuberculosis or AIDS,

C

1 Institute of Pathology, Medical University of Graz, 8036 Graz, Austria. 2Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria. 3Institute of Medical Engineering, Graz University of Technology, 8010 Graz, Austria. 4Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.

*To whom correspondence should be addressed. E-mail: [email protected] (R.Z.); gerald.hoefler@medunigraz. at (G.H.)

and other diseases, including chronic obstructive pulmonary disease, chronic kidney disease, and chronic heart failure. Most commonly, however, cachexia is observed in cancer. The highest frequency of cancer-associated cachexia (CAC) occurs in pancreatic and gastric cancer (1–3). CAC is an important adverse prognostic factor and the immediate cause of death in an estimated 15% of all cancer patients (3–5). Wasting results from depletion of both adipose tissue and skeletal muscle (6, 7). In contrast to starvation, the nonmuscle protein compartment of the body is relatively unaffected in CAC patients (7), implying a

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Dikic laboratory for constructive comments and critical reading of the manuscript; P. Cohen for OPTN and TBK1 reagents; and V. Kirkin for the initial yeast two-hybrid screens. This work was supported by grants from Deutsche Forschungsgemeinschaft, the Cluster of Excellence “Macromolecular Complexes” of the Goethe University Frankfurt (EXC115), the Landes-Offensive zur Entwicklung Wissentschaftlich-ökonomischer Exzellenz–funded Onkogene Signaltransduktion Frankfurt network, and the European Research Council (ERC) under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement no. (250241-LineUb) to I.D. and partly by Swiss National Fonds (3100A0-121834/1) to D.B. The Center for Protein Research is funded by a generous grant from the Novo Nordisk Foundation. J.K. is supported by a scholarship from the Split, Croatia, government, S.W. by a postdoctoral fellowship from the Danish Council for Independent Research (FSS: 10-085134), N.R.B. by the Initiative and Networking Fund of the Helmholtz Association, and H.F. by Swiss National Science Foundation (31003A-121834).

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SUMO-interacting motif also enhances binding affinity (24), similar to LIR modification. Notably, a number of known autophagy receptors contain conserved serine residues adjacent to their LIRs, including NIX and NBR1, indicating a potentially broader impact of phosphorylation of autophagy processes. Interestingly, LC3A and LC3B have phosphorylated serine/threonine residues in their N-terminal extensions that are crucial for the interaction with LIR motifs (25, 26). Taken together, phosphorylation of ubiquitin-like modifiers and their binding domains brings another layer of complexity in controlling ubiquitin and autophagy signaling networks (27).

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Supporting Online Material www.sciencemag.org/cgi/content/full/science.1205405/DC1 Materials and Methods Figs. S1 to S9 Table 1 References 10 March 2011; accepted 17 May 2011 Published online 26 May 2011; 10.1126/science.1205405

tumor-associated metabolic condition that specifically targets adipose tissue and muscle. Thus, anorexia is unlikely to be solely responsible for the loss of skeletal muscle in patients with CAC. Indeed, nutritional supplementation has largely failed to reverse the wasting process (8). The pathogenesis of CAC is multifactorial (9). Central mechanisms regulate appetite, food intake, and energy consumption. Contributing peripheral mechanisms control lipid and carbohydrate metabolism in various tissues. Severe lipid loss in CAC is driven by changes in lipid catabolism (10–15) and, possibly, lipogenesis (16). The concept that increased triacylglycerol (TG) degradation may contribute decisively to CAC is strongly underscored by increased plasma levels of fatty acids (FAs) and glycerol; increased lipolytic rates upon epinephrine stimulation; and increased expression of lipid-mobilizing factors, such as zinc-a2 glycoprotein-1 (AZGP1), tumor necrosis factor a (TNF-a), and interleukins (IL)-1 and -6 (17, 18). The breakdown of fat requires lipolysis of TG stored in cellular lipid droplets and is mediated by adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) (19). This led to our hypothesis that disruption of fat catabolism may prevent the initiation and/or progression of CAC. In vertebrates, lipolysis is most active in adipose tissue, with ATGL predominantly responsible for the initial step of TG hydrolysis (formation of diacylglycerol) and HSL for the hydrolysis of diacylglycerol. We investigated whether one or both of these lipases are essential for CAC. To assess the role of lipases in CAC, we used two different cachexia models in mice lacking

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either Atgl or Hsl. Cachexia was induced in wildtype C57BL/6 (WT) mice, Atgl-deficient (Atgl −/− ) mice (20), and Hsl-deficient (Hsl −/− ) mice (21) by subcutaneous injection of Lewis lung carcinoma (LLC) cells (22) or B16 melanoma cells (23). Tumor growth was observed in 100% of treated animals. Tumor weights tended to be lower in nonfasted (Fig. 1, A to C) and overnight (o/n)fasted (fig. S1, A and B) (24) Atgl −/− and Hsl −/− mice than in WT mice. However, none of the differences reached statistical significance. Next we analyzed body weight, plasma metabolite concentrations, and fat mass in mice of all genotypes with or without tumors. Because all of these parameters strongly depend on the feeding status of the mice and to account for any nutritional bias, they were determined in nonfasted and o/n-fasted animals. Total body weight (after subtraction of tumor weight) differed dras-

tically in lipase-deficient mouse models compared with WT mice in response to LLC and B16 (Fig. 1, D to F). Whereas non–tumor-bearing WT mice on normal chow diet gained weight over a period of 3 weeks, WT mice with LLC started to lose weight 14 days after tumor injection, resulting in an average weight loss of 1.8 g after 21 days. In contrast, body weight in Atgl −/− mice with LLC was identical to Atgl −/− without tumors at all times. Hsl −/− mice exhibited an intermediate phenotype. Compared to non–tumor-bearing Hsl −/− mice, body weight was reduced. However, the loss was less extreme than in WT mice carrying the tumor. Similar results were obtained in B16treated mice (Fig. 1 F). Compared with WT mice without tumors, B16-treated mice weighed 3.3 g less 16 days after tumor injection. In contrast, B16-treated Atgl −/− mice maintained weights similar to those of untreated Atgl −/− mice. Hsl −/− ani-

mals were less protected than Atgl −/− mice and lost on average 2.7 g of body weight. The differences were even more pronounced in o/n-fasted mice, a condition when lipolysis is physiologically induced (fig. S2). Whereas WT mice with LLC weighed 2.1 g (after 14 days) and 5.5 g (after 21 days) less than WT mice without tumors, Atgl −/− mice were totally resistant to weight loss and Hsl −/− animals reached intermediate values. Differences in weight loss in response to the tumors were not explained by variable food intake (fig. S3, A and B), because it was similar in all animals during the initial phase of the experiment and decreased uniformly in all tumor-carrying mice during the final 2 to 4 days. Thus, in the mouse, protection from CACassociated weight loss can be entirely conferred by the lack of ATGL and partially by the absence of HSL.

Fig. 1. Ablation of Atgl protects mice from cancerassociated weight loss and cancer-associated loss of adipose tissue. (A to C) Tumor weights 14 days (d) and 21 days after injecting LLC and 16 days after injecting B16 melanoma (B16) cells were slightly lower in lipasedeficient mice compared with WT. (D to F) WT mice significantly lost weight with tumor progression after injection of LLC and B16 tumor cells, whereas Atgl −/− animals did not develop cachexia. Hsl −/− mice also lost weight but less than WT mice did. (G) Normalized gonadal and epididymal WAT was reduced by about 55% in nonfasted tumor-bearing WT mice 21 days after LLC tumor implantation, whereas lipase-deficient mice were protected from WAT loss. (H to J) No or minimal gonadal and epididymal WAT was detected upon dissection of nonfasted WT B16 tumorbearing mice after 16 days and fasted WT LLC tumor-bearing mice after 21 days compared to saline injected control mice. Atgl −/− tumor-bearing mice retained gonadal and epididymal WAT, whereas partial loss of gonadal and epididymal WAT was observed in Hsl −/− tumor-bearing mice. WAT was dissected, and its mass normalized to tibia length as described in (24). Black bars indicate control (saline-injected) animals; white bars, tumor-bearing animals. To allow direct comparison, values were determined after removal of the respective tumor. ***P < 0.001, **P < 0.01, *P < 0.05, n = 5 to 7 except for (A) to (E) and (G) LLC, Hsl −/−, n = 3 and (D) LLC, 14 days, normal, n = 2. (J) Scale bars represent a length of 1 mm.

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REPORTS mice when compared to mice of the same genotype without tumors (fig. S4B). These differences in glucose levels in LLC-treated WT and Hsl −/− mice were not observed in nonfasted animals (fig. S4C). Similarly, plasma glucose and FA levels of nonfasted B16-treated mice matched those in untreated animals (fig. S4D). Presence of LLC caused an increase in FA levels in WT (fasted: +24.0% at 14 days and +9.9% at 21 days; nonfasted: +54.5% at 21 days) and Hsl −/− mice (fasted: +23.4% at 14 days and +25.0% at 21 days) (fig. S5). In contrast, FA levels in tumor-bearing Atgl −/− mice remained unchanged compared with those

of Atgl −/− mice without tumors independent of the feeding status. Increased FA levels were also observed in nonfasted B16-tumor-bearing WT mice (+27%) (fig. S5D). Serum TG levels were not significantly different in o/n-fasted animals with or without tumors (fig. S6). To assess the contribution of adipose tissue loss to the tumor-induced weight loss, we determined white adipose tissue (WAT) mass by visual inspection, weighing of surgically removed adipose depots (gonadal and epididymal adipose tissue), and in vivo nuclear magnetic resonance (NMR) WAT quantitation. In nonfasted

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Consistent with our previous findings (20, 21), plasma glucose, FA, and TG levels were reduced in o/n-fasted Atgl −/− versus WT mice (figs. S4 to S6). In o/n-fasted Hsl −/− mice, FA and TG levels were also reduced (although less than in Atgl −/− mice), whereas plasma glucose concentrations were unchanged compared with those of WT mice (figs. S4 to S6). The presence of LLC for 14 days did not affect plasma glucose levels in o/nfasted mice of any genotype (fig. S4A). After 21 days, plasma glucose levels were decreased in tumor-bearing, o/n-fasted WT (–43.2%) and Hsl −/− mice (–27.3%) but remained unchanged in Atgl −/−

Fig. 2. Loss of WAT in tumor-bearing animals is mainly attributable to lipolysis. Both LLC and B16 tumors significantly increased FAs (A and C) and glycerol (B and D) release from WAT explants in nonfasted tumor-bearing WT mice. LLC-bearing lipase-deficient mice did not exhibit increased FA or glycerol release from WAT explants, whereas increased FA and glycerol release was observed from WAT explants of B16-tumor-bearing Hsl −/− mice. www.sciencemag.org

WAT explants from B16-tumor-bearing Atgl −/− mice did not show increased FA or glycerol release. (E to J) Lipolytic agonists (TNF-a, IL-6, and AZGP1) were increased in both LLC- and B16-tumor–bearing mice from all genotypes. Black bars indicate control (saline-injected) animals; white bars, tumorbearing animals. ***P < 0.001, **P < 0.01, *P < 0.05, n = 7 except for (A) and (B), n = 3 to 5.

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Fig. 3. Atgl−/− mice were protected from tumorassociated skeletal muscle loss. (A and D) Muscle mass of gastrocnemius (normalized to tibia length) of surgically prepared gastrocnemius illustrate skeletal muscle loss in tumor-bearing WT and Hsl−/− mice but not in Atgl−/− mice. (B and E) Proteasome activity in gastrocnemius muscle homogenates is significantly increased in tumor-bearing WT and Hsl−/− mice but not in Atgl−/− mice. (C and F) Increased caspase 3 and 7 activity in gastrocnemius muscle homogenates demonstrates activation of apoptosis in tumor-bearing WT and Hsl −/− mice. Caspase 3 and 7 activity in gastrocnemius muscle of Atgl −/− mice was not affected by tumor growth. Black bars indicate control (saline-injected) animals, white bars, tumor-bearing animals. ***P < 0.001, **P < 0.01, *P < 0.05, n = 7.

Fig. 4. CAC patients show increased TG hydrolase activity compared with noncachectic patients. Total lipase activity (A), specifically inhibited (HSL, 76-0079) lipase activity (mainly ATGL activity) (B), and HSL activity (determined by subtraction of HSL-inhibited lipase activity from total lipase activity) (C) in visceral WAT of cancer patients compared with those of

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noncancer patients. Lipase activities in WAT of cachectic cancer patients are significantly higher than in noncachectic cancer patients. Ranges indicate mean T standard deviation. (D to F) Total, HSL-inhibited, and HSL lipase activities show negative correlation with BMI of cancer patients. FFA, free fatty acid.

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REPORTS This induction of lipolysis is not observed in the absence of ATGL and significantly reduced in the absence of HSL. Thus, lipase deficiency blocks tumor-induced WAT loss. Several reports have shown that the induction of lipolysis during CAC is mediated by inflammatory cytokines (17), AZGP1 (also designated lipid mobilizing factor, LMF) (18), or cytotoxininduced death executor proteins (CIDE), such as CIDE-A (25). To investigate whether these lipolytic agonists are increased in cachexia models lacking specific lipases, we assessed their plasma levels. In response to LLC, TNF-a and IL-6 levels were increased (between 2- to 3.2fold) in all genotypes (Fig. 2, E and F). Similarly, quantitative Western blot analysis revealed that plasma AZGP1 levels were higher in LLCbearing animals of all genotypes (Fig. 2G). In response to B16, the induction of cytokine release was even more pronounced (Fig. 2, H and I). Plasma levels of TNF-a and IL-6 increased about five- to ninefold and 18- to 21-fold, respectively. Plasma AZGP1 levels were also consistently higher in B16-treated mice of all genotypes compared with untreated mice (Fig. 2J). This suggests that in WT mice the increased concentration of inflammatory and lipolytic agonists induce lipolysis via ATGL and HSL leading to the uncontrolled loss of WAT and cachexia. In the absence of lipases, particularly in the absence of ATGL, this process is disrupted and WAT is retained. In cancer patients, CAC not only emaciates adipose tissue but also consumes skeletal muscle and cardiac muscle (9, 22, 26, 27). Similarly, we observed that LLC and B16 melanoma in mice lowers skeletal muscle mass and heart weight. Surgically removed gastrocnemius muscle of WT mice injected with LLC (21 days) and B-16 (16 days) weighed 36% and 25% less than that of WT mice, respectively (Fig. 3, A and D), suggesting that muscle loss was less pronounced than the loss of adipose mass. Remarkably, Atgl −/− mice suffered no significant loss of gastrocnemius muscle weight in response to the tumors (Fig. 3, A and D). Similarly as in WT mice, LLC and B16 in Hsl −/− mice diminished gastrocnemius muscle weight (Fig. 3, A and D), albeit to a lesser degree (–27% and –18%, respectively). Wasting of gastrocnemius muscle was also reflected by a reduction of total muscle protein in WT (–36%) and Hsl −/− mice (–22%) in response to B16, whereas Atgl −/− mice with B16 melanoma were resistant to the loss of muscle protein (fig. S9). The weight of soleus muscle also decreased in LLCinjected WT mice after 21 days (33%, not statistically significant) and B16-injected WT mice (–27%) (fig. S10). Both LLC and B16 caused a moderate decrease in heart weight (–7.4% and –9.9%, respectively) and total cardiac protein content (–20.1% and –24.9%, respectively) in WT mice but not in Atgl −/− or Hsl −/− mice (fig. S11). Consistent with our previous observations (20), Atgl −/− mice exhibited a twofold increased TG content in gastrocnemius muscle and a 12- to

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15-fold increased TG content in cardiac muscle (fig. S12) compared with WT animals. Muscle atrophy may originate from a decrease in protein synthesis (28) or an increase in protein degradation (9, 22). Studies in a number of experimental models of cachexia suggest that both processes occur simultaneously (9). Animal models of cancer cachexia as well as studies in cancer patients provided evidence that the ubiquitin-proteasome pathway mainly degrades myofibrillar proteins, particularly at later stages of cachexia when patients lost more than 10% of their body weight (29). Additionally, apoptotic cell death characterized by increased activity of caspases contributes to the loss of gastrocnemius muscle in mice bearing the cachexia-inducing MAC16 tumor (30). Consistent with these observations, we detected a marked increase in proteasome activity (Fig. 3, B and E) and an increase in caspase 3 and 7 activity (Fig. 3, C and F) in gastrocnemius muscle of WT mice and Hsl −/− mice 21 days after LLC injection and 16 days after B16 injection. In contrast, no significant change in proteasome or caspase 3 and 7 activity was observed in gastrocnemius muscle of Atgl −/− mice in response to both tumors (Fig. 3 B, C, E, and F). Changes in the weight of gastrocnemius muscle, caspase 3 and 7 activity, and proteasome activity were not observed in WT and Hsl −/− mice, 2 weeks after LLC injection (fig. S13), suggesting that loss of WAT precedes the loss of muscle mass, which is consistent with earlier observations (10). Previous work showed that cachexia is associated with increased FA oxidation in gastrocnemius muscle (9). Our data confirm these findings, showing 1.8- to 2.5-fold increased mRNA expression levels of genes involved in the regulation of cellular FA uptake (CD36 and fatty acid transport protein 1, Fatp-1), FA transport into mitochondria (carnitin palmitoyltransferase-1b, Cpt-1b), and mitochondrial function (peroxisome proliferator-activated receptor-g coactivator-1a, Pgc-1a) in gastrocnemius muscle samples of WT mice with LLC (fig. S14). mRNA levels in muscle samples of Atgl −/− mice were not affected in response to LLC. In Hsl −/− mice, mRNA levels increased in the presence of the tumor, although to a lesser extent than in WT mice. This suggests that the catabolic state in CAC mobilizes FA from adipose tissue, leading to an energy substrate switch from glucose to FA use in skeletal muscle. To test whether the activity of metabolic lipases in WAT also associates with CAC in humans, we determined ATGL- and HSL-mediated TG hydrolase activities of visceral WAT from autopsy samples of 27 patients. Twelve of these individuals had been diagnosed with various forms of malignancies (two adenocarcinomas of the lung, two adenocarcinomas of the colon, two ductal adenocarcinomas of the breast, two adenocarcinomas of the prostate, one hepatocellular carcinoma, one clear cell carcinoma of the kidney, one squamous cell carcinoma of the esophagus,

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LLC-bearing WT mice, WAT weight decreased by 55% after 21 days of tumor growth (Fig. 1G), which corresponded to a loss of 1.7 g of WAT in NMR analysis (fig. S7A). Nonfasted B16bearing WT mice lost 85% of WAT weight after 16 days of tumor growth (Fig. 1H) (–2.0 g of adipose tissue mass in NMR analysis, fig. S7B). In contrast, none of the tumors affected WAT mass of Atgl −/− mice. In fact, weight of body fat depots and total body fat was increased in Atgl −/− mice independent of the presence or absence of tumors when compared to non–tumor-bearing WT mice (Fig. 1, G and H, and fig. S7). This confirms our earlier observation that Atgl deficiency causes obesity in mice kept on a normal chow diet (20) and shows that WAT mass is independent of the presence of the tumor. In nonfasted Hsl −/− mice, LLC did not affect the weight of WAT depots. However, NMR analyses revealed a total WAT reduction by 0.7 g in (Fig. 1G and fig. S7A). B16 in Hsl −/− mice caused a 32% reduction of adipose tissue weight and a 0.9 g WAT loss in NMR analysis (Fig. 1H and fig. S7B). In o/n-fasted animals, the differences were even more striking (Fig. 1, I and J, and fig. S7C). After 21 days, LLC tumors caused the loss of more than 95% of WAT weight (2 g in NMR analysis) in WT mice, whereas adipose mass was again completely retained in LLC-treated Atgl −/− mice. Hsl −/− mice exhibited an intermediate loss of 37% of WAT weight. Results for LLC-bearing animals were substantiated by magnetic resonance imaging analysis. Taken together, these results show that, independently of feeding status and tumor type, ATGL deficiency completely and HSL deficiency partially protects mice from the loss of WAT. Tumor-associated loss of adipose tissue in animal models has been mostly attributed to an increase in WAT lipolysis (10–16). Consistent with these reports, the release of FAs and glycerol from WAT explants was increased in WT mice with LLC (38% and 31%, respectively) and B16 (39% and 21%, respectively) compared with mice without tumors (Fig. 2, A to D). This increase in lipolysis did not occur in LLC- or B16tumor–bearing Atgl −/− mice. WAT lipolysis was also attenuated in tumor-bearing Hsl −/− mice. Whereas FA and glycerol release from WAT was similar in Hsl −/− mice with or without LLC, B16 melanoma formation caused 28% and 19% increases, respectively. To investigate whether changes in TG hydrolase activities underlie the observed differences in lipolytic rates, we measured ATGL and HSL enzyme activities in WAT in response to tumor growth (fig. S8). LLC in o/n-fasted WT mice caused a twofold increase in total lipase activity because of increased ATGL and HSL activity. No tumor-induced increase in WAT lipase activity was observed in Atgl −/− mice, whereas in Hsl −/− mice total TG lipase activity increased by 2.1-fold because of increased ATGL activity. Thus, LLC and B16 cause an induction of WAT TG hydrolase activity, leading to an increased release of FAs and glycerol from WAT.

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and one malignant germ cell tumor). Six out of the 12 patients were designated as cachectic according to the definition of Evans et al. (31). Total lipase, ATGL, and HSL activities were significantly higher in visceral WAT of cancer patients compared with individuals without cancer and significantly higher in cancer patients with cachexia compared with cancer patients without cachexia (Fig. 4, A to C). Lipase activities in cancer patients without cachexia were similar to those of noncancer patients. A significant inverse correlation was found between total lipase, ATGL, and HSL activities in WAT of cancer patients and their body mass index (BMI) (Fig. 4, D to F). In contrast, lipolytic activities in WAT of noncancer patients showed no correlation with their BMI (fig. S15). Thus, our study provides compelling evidence that the previously observed increase in FA and glycerol release from WATof patients with CAC (9, 10) is due to up-regulation of ATGL and HSL activities and that increased lipase activities strongly correlate with cachexia. In summary, our data are consistent with the view that lipolysis plays an instrumental role in the pathogenesis of CAC. The increased catabolism of adipose lipid stores leads to the complete loss of WAT followed by a reduction in muscle mass. The absence of ATGL and, to a lesser degree, HSL reduces FA mobilization, retains WAT and muscle mass, and prevents CAC. Whether the protection of adipose and muscle loss in lipase-deficient mice is a consequence of defective tissue autonomous lipolysis or due to endo-

crine signaling from the tumor or WAT remains to be elucidated. However, pharmacological inhibition of lipases may represent a powerful strategy to avoid the devastating condition of cachexia in response to cancer or other chronic diseases. References and Notes 1. M. J. Tisdale, Nat. Rev. Cancer 2, 862 (2002). 2. J. E. Morley, D. R. Thomas, M. M. Wilson, Am. J. Clin. Nutr. 83, 735 (2006). 3. W. D. Dewys et al., Am. J. Med. 69, 491 (1980). 4. C. Deans, S. J. Wigmore, Curr. Opin. Clin. Nutr. Metab. Care 8, 265 (2005). 5. K. C. Fearon, A. G. Moses, Int. J. Cardiol. 85, 73 (2002). 6. M. Fouladiun et al., Cancer 103, 2189 (2005). 7. K. C. Fearon, Proc. Nutr. Soc. 51, 251 (1992). 8. M. Lainscak, G. S. Filippatos, M. Gheorghiade, G. C. Fonarow, S. D. Anker, Am. J. Cardiol. 101, 8E (2008). 9. M. J. Tisdale, Physiol. Rev. 89, 381 (2009). 10. T. Agustsson et al., Cancer Res. 67, 5531 (2007). 11. A. Hyltander, P. Daneryd, R. Sandström, U. Körner, K. Lundholm, Eur. J. Cancer 36, 330 (2000). 12. S. Klein, R. R. Wolfe, J. Clin. Invest. 86, 1403 (1990). 13. A. Legaspi, M. Jeevanandam, H. F. Starnes Jr., M. F. Brennan, Metabolism 36, 958 (1987). 14. M. Rydén et al., Cancer 113, 1695 (2008). 15. J. H. Shaw, R. R. Wolfe, Ann. Surg. 205, 368 (1987). 16. M. Jeevanandam, G. D. Horowitz, S. F. Lowry, M. F. Brennan, Metabolism 35, 304 (1986). 17. J. M. Argilés, S. Busquets, M. Toledo, F. J. López-Soriano, Curr. Opin. Support. Palliat. Care 3, 263 (2009). 18. C. Bing et al., Proc. Natl. Acad. Sci. U.S.A. 101, 2500 (2004). 19. R. Zechner, P. C. Kienesberger, G. Haemmerle, R. Zimmermann, A. Lass, J. Lipid Res. 50, 3 (2009).

A Pericyte Origin of Spinal Cord Scar Tissue Christian Göritz,1 David O. Dias,1 Nikolay Tomilin,2 Mariano Barbacid,3 Oleg Shupliakov,2 Jonas Frisén1* There is limited regeneration of lost tissue after central nervous system injury, and the lesion is sealed with a scar. The role of the scar, which often is referred to as the glial scar because of its abundance of astrocytes, is complex and has been discussed for more than a century. Here we show that a specific pericyte subtype gives rise to scar-forming stromal cells, which outnumber astrocytes, in the injured spinal cord. Blocking the generation of progeny by this pericyte subtype results in failure to seal the injured tissue. The formation of connective tissue is common to many injuries and pathologies, and here we demonstrate a cellular origin of fibrosis. ost studies on the scar tissue that forms at injuries in the central nervous system (CNS) have focused on astrocytes, and it is often referred to as the glial scar (1–5).

M

1 Department of Cell and Molecular Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden. 2Department of Neuroscience, Karolinska Institute, SE-171 77 Stockholm, Sweden. 3 Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas, 28029 Madrid, Spain.

*To whom correspondence should be addressed. E-mail: [email protected]

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There is also a connective tissue or stromal, nonglial, component of the scar (6–10), but it has received much less attention. The generation of connective tissue, with large numbers of fibroblasts depositing extracellular matrix (ECM) proteins, is a general feature of scarring and fibrosis in all organs and in diverse types of pathology (11). In spite of being a major clinical problem that has been extensively studied, the origin of scar-forming fibroblasts has been difficult to establish. Most studies have suggested that they may derive from

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20. G. Haemmerle et al., Science 312, 734 (2006). 21. G. Haemmerle et al., J. Biol. Chem. 277, 4806 (2002). 22. M. van Royen et al., Biochem. Biophys. Res. Commun. 270, 533 (2000). 23. I. Kawamura et al., Anticancer Res. 19, 341 (1999). 24. Materials and methods are available as supporting material on Science Online. 25. J. Laurencikiene et al., Cancer Res. 68, 9247 (2008). 26. X. Zhou et al., Cell 142, 531 (2010). 27. S. Busquets et al., Clin. Nutr. 26, 239 (2007). 28. M. J. Rennie et al., Clin. Physiol. 3, 387 (1983). 29. J. Khal, A. V. Hine, K. C. Fearon, C. H. Dejong, M. J. Tisdale, Int. J. Biochem. Cell Biol. 37, 2196 (2005). 30. J. E. Belizário, M. J. Lorite, M. J. Tisdale, Br. J. Cancer 84, 1135 (2001). 31. W. J. Evans et al., Clin. Nutr. 27, 793 (2008). Acknowledgments: We thank E. Zechner and C. SchoberTrummler for reviewing the manuscript. The research was supported by the doctoral program Molecular Medicine of the Medical University of Graz (S.D.); GOLD, Genomics of Lipid-Associated Disorders as part of the Austrian Genome Project GEN-AU funded by Forschungsförderungsgesellschaft and Bundesministerium für Wissenschaft und Forschung (Ru.Ze.); SFB LIPOTOX grant no. F30 (Ru.Ze., G.H.), the Wittgenstein Award 2007 grant no. Z136 funded by the Austrian Fonds zur Förderung der Wissenschaftlichen Forschung (Ru.Ze.). S.K.D., Ro.Zi., G.H., and Ru.Ze. hold a patent related to the modulation of ATGL for prevention and treatment of cachexia.

Supporting Online Material www.sciencemag.org/cgi/content/full/science.1198973/DC1 Materials and Methods Figs. S1 to S15 References 12 October 2010; accepted 27 May 2011 Published online 16 June 2011; 10.1126/science.1198973

circulating cells, proliferating resident fibroblasts, endothelial cells, or epithelial cells (12–14). There are also data indicating that pericytes, perivascular cells enwrapping the endothelial cells of capillaries, may differentiate into collagen-producing cells in models of dermal scarring and in kidney fibrosis (15–17). We have explored the role of pericytes in scar formation after spinal cord injury. We found that Glast-CreER transgenic mice (18) enabled recombination of the R26R-yellow f luorescent protein (R26R-YFP) reporter allele (19) in a subset of pericytes lining blood vessels in the spinal cord parenchyma, which allowed us to stably and heritably label these cells (20) (Fig. 1 and figs. S1 to S5). The recombined cells had the typical ultrastructural features of pericytes (21), including being encased in the vascular basal lamina, which separates them from endothelial cells and astrocytes (Fig. 1, A to D). The recombined cells represent a distinct pericyte subpopulation that constitutes ~10% of all pericytes in the adult spinal cord [assessed by electron microscopy (EM)]. At positions where processes intersect, the Glast-CreER–expressing pericytes were invariably located abluminal to the other pericyte subtype (Fig. 1A and fig. S6). We refer to the pericyte subclass that is recombined in GlastCreER mice as type A pericytes and the other

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REPORTS

Corrections & CLarifications

Erratum

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Reports: “Adipose triglyceride lipase contributes to cancer-associated cachexia” by S. K. Das et al. (8 July, p. 233). Fig. 1G shows normalized white adipose tissue (WAT) weight of gonadal, retroperitoneal, and visceral WAT. In Fig. 1, G to J, descriptions of “epididymal WAT” actually refer to retroperitoneal WAT. In addition, the last complete sentence on p. 235 should read, “To assess the contribution of adipose tissue loss to the tumor-induced weight loss, we determined white adipose tissue (WAT) mass by visual inspection, weighing surgically removed adipose depots (gonadal, retroperitoneal, and visceral adipose tissue) and in vivo nuclear magnetic resonance (NMR) WAT quantitation.”

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COMMENTARY How we got our heads

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LETTERS I BOOKS I POLICY FORUM I EDUCATION FORUM I PERSPECTIVES

LETTERS edited by Jennifer Sills

Trade-Secret Model: Potential Pitfalls IN THEIR POLICY FORUM “GENOMICS, BIObanks, and the trade-secret model” (15 April, p. 309), R. Mitchell et al. submit that donating genetic samples for medical research is like selling a confidential commodity of potentially lucrative value, warranting individual licensing arrangements to secure acceptable benefit outcomes. We disagree with this approach to building cancer research biorepositories. Trade secrets derive value from being unknown and not readily ascertainable (1). By contrast, the value of human subject biospecimens contributed for cancer research

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JEFFREY H. MATSUURA Alliance Law Group, 7700 Leesburg Pike, Falls Church, VA 22043, USA. E-mail: jmatsuura@ alliancelawgroup.com

References

1. California Civil Code, Section 3344. 2. Massachusetts General Laws, Chapter 214, Section 1B. 3. California State Constitution, Article I, Section 1B and Florida State Constitution, Article I, Section 23.

increases with widespread dissemination for use in approved studies, accompanied by open sharing of data. (2–5). Whereas trade-secret doctrine recognizes the necessity of preserving confidential information to further personal gain, research participants contributing samples and associated data are primarily motivated by altruistic, not compensatory, desires (2, 3, 6, 7). Moreover, the trade-secret model is not practical from the perspective of biobanking operations and governance. How might cancer biorepositories accurately track and implement the diverse licensing preferences of multiple research participants with respect to such issues as determining future research uses of biospecimens, or returning research

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IN THEIR POLICY FORUM “GENOMICS, BIOBANKS, AND THE TRADEsecret model” (15 April, p. 309), R. Mitchell and his colleagues suggest that trade-secret law could be applied effectively to manage the use of human genomic information. It would be productive to assess the potential application of two other legal models as well: the individual’s right to control his or her name and likeness, and the right to control public disclosure of private facts. Jurisdictions that recognize a right of personal privacy commonly include within that right the ability of an individual to control the use of his/her name and likeness for commercial advantage (1). An individual’s name and visual image are deemed to be unique and highly personal qualities that each person should have the right to control. This right is viewed by the law as part of the individual’s ability to protect the key aspects of his/her personality. Name and likeness have been interpreted to include other characteristics of an individual’s personality, including the sound of his or

her voice (2). It seems reasonable that the legal framework designed to help the individual to protect the integrity of his/her personality should also include the most intimate aspect of an individual’s personality—personal genomic information. Personal privacy rights also frequently include the ability to control public disclosure of private facts about an individual (3). Arguably, genomic information includes the most private and personal facts associated with any individual. The right to control public disclosure of private facts appears to provide another legal vehicle for management of use of personal genomic information. Application of these traditional privacy rights can supplement legal approaches such as the trade-secret model proposed by Mitchell et al. There may also be circumstances in which the tradesecret model would not be appropriate but the traditional privacy rights could be applied. For example, it is unclear whether an individual can effectively assert a trade-secret claim when the secret he or she possesses is not actually understood by the individual asserting the protection. No such complications arise when a traditional personal privacy right is applied.

results? What if participants wanted to negotiate profit distributions for successful products developed in part based on their contributions? How can the numerous, incremental research advances that precede product development be quantified in order to determine a fair distribution of commercial profits among research participants? Progress in scientific research, particularly in the accelerating world of cancer genomics, is not typically attributed to single biospecimen contributors [Henrietta Lacks (8) notwithstanding]. Heralded by the authors as furthering individual autonomy, the trade-secret model has the potential to foment suspicion and distrust among research participants as they compete for the highest-profit dividends.

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In lieu of evaluating the biospecimen contributions of cancer research participants under a trade-secret model, we advocate a custodianship model as set forth in the National Cancer Institute’s Best Practices for Biospecimen Resources (9). The custodianship model supposes that biorepositories accept responsibility for ensuring the long-term quality and security of contributed biospecimens and protect the confidentiality of participant data. This model promotes equitable and continuous access to biospecimens for research in accordance with scientifically vetted public priorities, maintaining trust through accountability, transparency, and justice (10).

CAROL J. WEIL AND CAROLYN COMPTON

Office of Biorepositories and Biospecimen Research, Center for Strategic Scientific Initiatives, The National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. *To whom correspondence should be addressed. E-mail: [email protected]

References and Notes

1. U.S. National Conference of Commissioners on Uniform State Laws, Uniform Trade Secrets Act, §1(4). 2. C. Galbraith, Miss. Law J. 78, 705 (2009). 3. J. Drazen, A. Wood, N. Engl. J. Med. 353, 2809 (2005). 4. NIH, Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies (GWAS) (http://grants.nih.gov/grants/guide/notice-files/ NOT-OD-07-088.html). 5. International Network of Cancer Genome Projects, Nature 464, 993 (2010). 6. J. Thornton, Int. J. Surg. 7, 501 (2009). 7. L. Beskow, E. Dean, Cancer Epidemiol. Biomarkers Prev. 17, 1440 (2008). 8. R. Skloot, The Immortal Life of Henrietta Lacks (Crown, New York, 2010). 9. National Cancer Institute, Office of Biorepositories and Biospecimen, 2010 Revised NCI Best Practices (http:// biospecimens.cancer.gov/practices/2010bp.asp). 10. Custodianship and Ownership Issues in Biospecimen Research Symposium/Workshop, Rockville, MD, 4 to 5 October 2007; http://biospecimens.cancer.gov/global/ pdfs/CaOSumm.pdf.

Letters to the Editor Letters (~300 words) discuss material published in Science in the past 3 months or matters of general interest. Letters are not acknowledged upon receipt. Whether published in full or in part, Letters are subject to editing for clarity and space. Letters submitted, published, or posted elsewhere, in print or online, will be disqualified. To submit a Letter, go to www.submit2science.org.

Trade-Secret Model: Legal Limitations THE POLICY FORUM “GENOMICS, BIOBANKS, and the trade-secret model” (R. Mitchell et al., 15 April, p. 309) introduces a new way to promote the autonomy of research participants in genomic biobanks. However, the proposed trade-secret model suffers from socio-ethical and legal flaws. First, Mitchell et al. conflate the “value” of an individual’s genetic information with a “secret.” Rather than articulating a case for such a link, the authors simply posit that “information encoded by an individual’s DNA” is “something of unique value for a certain kind of ‘business’ (biomedical research).” However, unique values do not necessarily have to be secrets. Second, the trade-secret model will diminish, not enhance, the autonomy of research participants. Enabling biobank contributors to obtain legal ownership (not mere possession) of their genetic information and set the parameters of its use will not permit them greater self-control, free from external interference. Rather, participants will be subjected to contractual negotiations with biobankers. Because the biobankers will unilaterally draft the “limited menu of options,” the trade-secret model could increase the possibility of a power imbalance (1). Third, the model contains legal and policy flaws. Trade-secret information, by definition, must confer an economic benefit on the holder, deriving specifically from the fact that the information is not generally known (2, 3). Genetic information is financially worthless absent outsourced scientific interpretation and technological application (and even then, there is no guarantee of its financial worth). Trade secrets presuppose that the holder knows the confidential information; here, individuals do not know most of their own genetic information, but the researcher will (4). Also, trade secrets do not ameliorate power balance, autonomy, or compensation issues. They are not instrumental legal tools to serve (bio)ethical ends. They are solely means to obtain an eco-

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nomic advantage over others. Do we want to foster a research environment in which biobankers and contributors compete against each other to obtain the most favorable economic terms? Ultimately, to reap the promised medical benefits of genomic research for all of society, we must eschew the individualistic, procedural vision of research that falsely assumes all actors possess conflicting agendas irrevocably irreconcilable outside a legal forum. We should focus instead on developing robust, transparent, and collaborative research models that will truly benefit humanity (5). EDWARD S. DOVE, YANN JOLY,* BARTHA M. KNOPPERS

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Centre of Genomics and Policy, Department of Human Genetics, McGill University, Montreal, QC, H3A 1A4, Canada. *To whom correspondence should be addressed. E-mail: [email protected]

References

1. L. Mulcahy, J. Tillotson, Contract Law in Perspective (Cavendish, London, ed. 4, 2004). 2. U.S. National Conference of Commissioners on Uniform State Laws, Uniform Trade Secrets Act, § 1(4). 3. American Law Institute, Restatement of the Law (Third), Unfair Competition, § 39. 4. J. Couzin-Frankel, Science 331, 662 (2011). 5. B. M. Knoppers, Y. Joly, Trends Biotechnol. 25, 284 (2007).

Response

IN OUR POLICY FORUM, WE PROPOSED A trade-secret model that would enable greater autonomy for individuals who contribute to genomic biobanks by contesting elements of the informed consent regime. We thank Matsuura, Weil and Compton, and Dove, Joly, and Knoppers for their thoughts on the potential of this model. Matsuura proposes that personal privacy rights could strengthen recognition of research participant autonomy. Personal privacy rights enable individuals to control public use of personal or private information or characteristics, and are thus a solution to the problem of unwanted public disclosure. Yet whether guided by current human subjects research protections or recent exemption guidelines, researchers generally promise not to make public any link between individuals and their DNA. Our proposal aims to enhance participant autonomy whether or not unwanted public disclosure becomes an issue. Our model does not require that individuals understand their secret, as both Matsuura and Dove, Joly, and Knoppers suggest. The information qualifies as long as it “derives economic value, actual or potential, from not being generally known” (1).

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two distinct elements of the legal definition of a trade secret: It must have economic value to its proprietor, and it must not be generally known. The avid interest of medical science in obtaining DNA samples seems to be conclusive evidence that a person’s genetic information has economic value. Likewise, it seems self-evident that DNA information cannot be generally known unless and until the person chooses to make it available. We do not see why a menu of options would in principle promote a power imbalance, as Dove, Joly, and Knoppers suggest, given that a menu could be developed in cooperation with likely participants. Such an imbalance seems more likely in the present system of informed consent. Currently, the prospective participant has two choices— take it or leave it—and all terms are dictated by the researcher, and are probably legally unenforceable by the participant (3). The fact that “genetic information is financially worthless absent outsourced scientific interpretation” is not relevant. Many trade secrets cannot be exploited without third-party expertise and resources—that is why their proprietors license them out. Finally, Dove, Joly, and Knoppers suggest that increasing contributor autonomy may run counter to “robust, transparent, and collaborative research models.” We disagree that autonomy and collaboration are opposed, given that true collaboration seems to require that each participant retain autonomy. The idea that the trade-secret model necessarily facilitates rampant individualism is a misunderstanding of the concept of intellectual property. Contrary to what Dove, Joly, and Knoppers contend, trade secrets—and intellectual property generally—can indeed be “instrumental legal tools to serve (bio)ethical ends.” Intellectual property owners use their rights to promote the public interest all the time; for example, PXE International holds and uses a patent (which could just as well be a trade secret) not for profit but to promote its health agenda. If our proposal were given a trial among healthy volunteers, we suspect that many if not most of them would seek the same eleemosynary ends for which Dove, Joly, and Knoppers argue. However, our proposal would let participants make that choice, rather than deferring to scientific and academic elites who speak for them.

School of Law, Department of Social Medicine, and Center for Genomics and Society, University of North Carolina, Chapel Hill, NC 27599–3380, USA. 2

*To whom correspondence should be addressed. E-mail: [email protected]

References

1. U.S. National Conference of Commissioners on Uniform State Laws, Uniform Trade Secrets Act, § 1(4). 2. R. J. Cadigan, A. M. Davis, in Governing Biobanks, J. Kaye, M. Stranger, Eds. (Ashgate Publishing, Farnham, UK, 2009), pp. 117–133. 3. Greenberg v. Miami Children’s Hospital Research Institute, 264 F. Supp. 2d 1064 (S.D. Fla. 2003).

CORRECTIONS AND CLARIFICATIONS Reports: “Adipose triglyceride lipase contributes to cancerassociated cachexia” by S. K. Das et al. (8 July, p. 233). Fig. 1G shows normalized white adipose tissue (WAT) weight of gonadal, retroperitoneal, and visceral WAT. In Fig. 1, G to J, descriptions of “epididymal WAT” actually refer to retroperitoneal WAT. In addition, the last complete sentence on p. 235 should read, “To assess the contribution of adipose tissue loss to the tumor-induced weight loss, we determined white adipose tissue (WAT) mass by visual inspection, weighing surgically removed adipose depots (gonadal, retroperitoneal, and visceral adipose tissue) and in vivo nuclear magnetic resonance (NMR) WAT quantitation.” Research Articles: “Scale for the phase diagram of quantum chromodynamics” by S. Gupta et al. (24 June, p. 1525). The corresponding author’s e-mail address was incorrect. It should be [email protected]. The address has been corrected in the HTML version online.

TECHNICAL COMMENT ABSTRACTS

Comment on “A Test of the Snowball Theory for the Rate of Evolution of Hybrid Incompatibilities” Daniel A. Barbash Matute et al. (Reports, 17 September 2010, p. 1518) tested the theory that the number of genes involved in hybrid incompatibility increases faster than linearly. However, the method they used is inappropriate because it detects genes that are haploinsufficient in a hybrid background but that would not contribute to lethality in wild-type hybrids, thus overestimating the frequency of hybrid inviability. Full text at www.sciencemag.org/cgi/content/full/333/ 6049/1576-b

Response to Comment on “A Test of the Snowball Theory for the Rate of Evolution of Hybrid Incompatibilities” Daniel R. Matute, David A. Turissini, Jerry A. Coyne

ROBERT MITCHELL,1 JOHN M. CONLEY,2 ARLENE M. DAVIS,2 R. JEAN CADIGAN,2 ALLISON W. DOBSON,2 RYAN Q. GLADDEN2

Barbash claims that deficiency mapping of inviability regions cannot distinguish hybrid lethality from haploinsufficiency, the phenomenon whereby a single functional copy of a gene cannot maintain normal function in a hybrid genetic background. Although we acknowledge that his hypothesis deserves careful experimental testing, we argue against his conclusions and provide evidence that our methodology is suitable to study the evolution of Dobzhansky-Muller incompatibilities.

Institute for Genome Sciences and Policy and English Department, Duke University, Durham, NC 27708, USA.

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We do not oppose the custodianship model advocated by Weil and Compton, although we find it legally complex and indeterminate. We do disagree, however, with several of their claims. We do not “submit that donating genetic samples for medical research is like selling a confidential commodity of potentially lucrative value.” Rather, we believe that prospective participants view their DNA as confidential property, and often consider the terms and conditions—which may include financial compensation—upon which they might permit its use. Likening a participant’s DNA to a trade secret does not imply that its primary value is personal gain, nor does it preclude “widespread dissemination for use.” On the contrary, the licensing of trade secrets often encourages widespread dissemination. Researchers working on “approved studies” can, if inclined, include in their menu options a provision for open sharing. With respect to practicalities, we do not propose recognizing the “diverse licensing preferences” of participants. We propose that biobanks offer participants a limited menu of licenses that differ, for example, in the nature of the compensation and the extent of the permitted use. Just as sharing biospecimens motivated creation of material transfer agreements, licensing needs can drive creative approaches to track permitted options. We also wish to clarify that although Weil and Compton (understandably) refer frequently to cancer research, we think that our model should be tested first among healthy volunteers. Weil and Compton’s claim that our model may “foment suspicion and distrust among research participants” seems inconsistent with their claim that research participants “are primarily motivated by altruistic, not compensatory, desires.” Our research suggests that participants are motivated by both altruism and money, with the respective contributions varying among individuals (2)—a reality that our model recognizes. We feel that the current interpretation of human subjects regulation is more likely than our proposal to alienate many among the large populations necessary for biobanking, given that informed consent often serves as a quasilegal device to ensure that an institution retains rights to whatever is derived from a biospecimen yet absolves itself of liability. Our model, by contrast, offers a way for individuals to be actual partners, rather than simply “subjects,” in biobank research. Dove, Joly, and Knoppers are concerned that we conflated “value” with “secret.” However, we described these terms as the

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