November 01, 2007

Top 10 Genetic Enhancements

I recently got asked for my list of top genetic enhancements that have already been done in mammals (and hence could presumbaly be done in humans). Here is my list:

1. The Doogie Mouse. Better memory through overexpression of NMR2B. A very simple, yet good demonstration of how plastic our memory system is. Since then several other ways of enhancing memory genetically have been found, with slightly different effects on different types of memory, forgetting and side effects.

Tang, Y. P., E. Shimizu, et al. (1999). "Genetic enhancement of learning and memory in mice." Nature 401(6748): 63-69.

Tang Y, Wang H, Feng R, Kyin M, Tsien J (2001). "Differential effects of enrichment on learning and memory function in NR2B transgenic mice". Neuropharmacology 41 (6): 779–90. PMID 11640933

Wei, F., G. D. Wang, et al. (2001). "Genetic enhancement of inflammatory pain by forebrain NR2B overexpression." Nature Neuroscience 4(2): 164-169.

Wang, H. B., G. D. Ferguson, et al. (2004). "Overexpression of type-1 adenylyl cyclase in mouse forebrain enhances recognition memory and LTP." Nature Neuroscience 7(6): 635-642.

Routtenberg, A., I. Cantallops, et al. (2000). "Enhanced learning after genetic overexpression of a brain growth protein." Proceedings of the National Academy of Sciences of the United States of America 97(13): 7657-7662.

Tan, D. P., Q. Y. Liu, et al. (2006). "Enhancement of long-term memory retention and short-term synaptic plasticity in cbl-b null mice." Proceedings of the National Academy of Sciences of the United States of America 103(13): 5125-5130.

2. Color vision mice. Adding human photopigment allows (at least females) to see new colors. This is extra interesting since it shows the brain can adapt to the signals from a new sense, at least when growing up with it.

Gerald H. Jacobs, Gary A. Williams, Hugh Cahill, Jeremy Nathans, Emergence of Novel Color Vision in Mice Engineered to Express a Human Cone Photopigment, Science 23 March 2007: Vol. 315. no. 5819, pp. 1723 - 1725

3. Methuselah mice. By reducing growth hormone levels long-lived dwarf mice can be produced. The current record holder survived 4 years 11 months and 3 weeks, while normal mice have a two year lifespan.

A. Bartke, H. Brown-Borg, J. Mattison, B. Kinney, S. Hauck, C. Wright, Prolonged longevity of hypopituitary dwarf mice. Exp. Gerontol. 36, 21-28 (2001)

Bartke A, Brown-Borg H. Life extension in the dwarf mouse. Curr Top Dev Biol. 2004;63:189-225.

4. Monogamous voles. Normally non-monogamous voles can be turned monogamous (and more social) by changing the vassopressin V1a receptor.

Young L. J., Nilsen R., Waymire K. G., MacGregor G. R. and Insel T. R. 1999 Increased affiliative response to vasopressin in mice expressing the V1a receptor from a monogamous vole. Nature 400, 766–768.

Landgraf R., Frank E., Aldag J. M., Neumann I. D., Sharer C. A., Ren X. et al. 2003 Viral vector-mediated gene transfer of the vole V1a vasopressin receptor in the rat septum: improved social discrimination and active social behaviour. Eur. J. Neurosci. 18, 403–411.

Pitkow L. J., Sharer C. A., Ren X., Insel T. R., Terwilliger E. F. and Young L. J. 2001 Facilitation of affiliation and pair-bond formation by vasopressin receptor gene transfer into the ventral forebrain of a monogamous vole. J. Neurosci. 21, 7392–7396

Lim M. M., Wang Z., Olazábal D. E., Ren X., Terwilliger E. F. and Young L. J. 2004 Enhanced partner preference in a promiscuous species by manipulating the expression of a single gene. Nature 429, 754–757.

5 Regenerating MRL mice (OK, a case of accidental breeding rather than genetic engineering, and it involves at least 20 genes). These mice regenerate holes punched in their ears as well as some injuries to heart muscle.

Heber-Katz, E. 1999. The regenerating mouse ear. Seminars in Cell & Develop. Biol. 10:415-420.

Heber-Katz E, Leferovich J, Bedelbaeva K, Gourevitch D, and Clark L (2004) The scarless heart and the MRL mouse. Phil. Trans. R. Soc. Lond. B 359:785-793.

John M. Leferovich, Khamilia Bedelbaeva, Stefan Samulewicz, Xiang-Ming Zhang, Donna Zwasdagger , Edward B. Lankforddagger , and Ellen Heber-Katz, Heart regeneration in adult MRL mice, PNAS August 14, 2001 vol. 98 no. 17 9830-9835

6. Schwarzenegger mice and Belgian blue cows. Strength through myostatin knockout. This has occasionally happened naturally in humans and cattle.

Lee SJ, McPherron AC. Regulation of myostatin activity and muscle growth. Proc Natl Acad Sci USA 2001: 98: 9306–9311

Whittemore LA, Song K, Li X, Aghajanian J, Davies M, Girgenrath S, Hill JJ, Jalenak M, Kelley P, Knight A, Maylor R, O'Hara D, Pearson A, Quazi A, Ryerson S, Tan XY, Tomkinson KN, Veldman GM, Widom A, Wright JF, Wudyka S, Zhao L, Wolfman NM, Inhibition of myostatin in adult mice increases skeletal muscle mass and strength. Biochem Biophys Res Commun. 2003 Jan 24;300(4):965-71.

McPherron, AC, SJ Lee. Double muscling in cattle due to mutations in the myostatin gene. Proc Natl Acad Sci USA 1997, 94:12457

Grobet, L, LJR Martin, D Poncelet, et al. A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle. Nature Genet 1997, 17:71.

Schuelke M, Wagner KR, Stolz LE, Hubner C, Riebel T, Komen W, Braun T., Tobin JF, Lee SJ. Myostatin mutation associated with gross muscle hypertrophy in a child. N Engl J Med 2004: 350: 2682–2688.

Lee SJ (2007) Quadrupling Muscle Mass in Mice by Targeting TGF-ß Signaling Pathways. PLoS ONE 2(8)

7 The hard working monkeys. Work discipline through a blocked dopamine D2 gene? Monkeys tend to slack off until they get close to a reward they have to work for. If injected with a DNA construct that blocks the D2 receptor they worked at an even rate. This is likely less a case of workaholism and more a case of specific memory impairment for how rewarding situations look. Still, adjusting the dopamine system is likely to enable boosts of motivation.

Zheng Liu, Barry J. Richmond, Elisabeth A. Murray, Richard C. Saunders, Sara Steenrod, Barbara K. Stubblefield, Deidra M. Montague, and Edward I. Ginns, DNA targeting of rhinal cortex D2 receptor protein reversibly blocks learning of cues that predict reward, PNAS  August 17, 2004  vol. 101  no. 33, 12336–12341 

8 Anticancer mice. These mice (the result of a lucky mutation) have immune systems that kill cancer cells efficiently and can even help other mice through blood transfusions.

Cui Z, Willingham MC, Hicks AM, Alexander-Miller MA, Howard TD, Hawkins GA, Miller MS, Weir HM, Du W, DeLong CJ. Spontaneous regression of advanced cancer: identification of a unique genetically determined, age-dependent trait in mice. Proc Natl Acad Sci U S A. 2003 May 27;100(11):6682-7.

Hicks AM, Riedlinger G, Willingham MC, Alexander-Miller MA, Von Kap-Herr C, Pettenati MJ, Sanders AM, Weir HM, Du W, Kim J, Simpson AJG, Old LG, Cui Z. Transferable anticancer innate immunity in spontaneous regression/complete resistance mice. PNAS E-published May 8, 2006.

9 Antiobesity mice. These mice are protected from getting obese and diabetic from their diet by their lack of acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1). Their fat tissue can even reduce obesity and glucose buildup in other mice if transplanted. There are other strains protected from obesity by lack of other proteins, and a strain that have more adiponectin that put all excess fat into their blubber, remaining healthy despite turning very obese.

Smith SJ, et al. Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking DGAT. Nat. Genet. 2000;25:87–90

Chen HC, et al. Increased insulin and leptin sensitivity in mice lacking acyl CoA:diacylglylcerol acyltransferase 1. J. Clin. Invest. 2002;109:1049–1055. doi:10.1172/JCI200214672.

Chen HC, Jensen DR, Myers HM, Eckel RH, Farese RV Jr. Obesity resistance and enhanced glucose metabolism in mice transplanted with white adipose tissue lacking acyl CoA:diacylglycerol acyltransferase 1. J Clin Invest. 2003 Jun;111(11):1715-22.

Li-Jun Ma, Su-Li Mao, Kevin L. Taylor, Talerngsak Kanjanabuch, YouFei Guan, YaHua Zhang, Nancy J. Brown, Larry L. Swift, Owen P. McGuinness, David H. Wasserman, Douglas E. Vaughan, and Agnes B. Fogo, Prevention of Obesity and Insulin Resistance in Mice Lacking Plasminogen Activator Inhibitor 1, Diabetes 53:336-346, 2004

Mounib Elchebly, Paul Payette, Eva Michaliszyn, Wanda Cromlish, Susan Collins, Ailsa Lee Loy, Denis Normandin, Alan Cheng, Jean Himms-Hagen, Chi-Chung Chan, Chidambaram Ramachandran, Michael J. Gresser, Michel L. Tremblay, Brian P. Kennedy, Increased Insulin Sensitivity and Obesity Resistance in Mice Lacking the Protein Tyrosine Phosphatase-1B Gene, Science 5 March 1999: Vol. 283. no. 5407, pp. 1544 - 1548

Ja-Young Kim, Esther van de Wall, Mathieu Laplante, Anthony Azzara, Maria E. Trujillo, Susanna M. Hofmann, Todd Schraw, Jorge L. Durand, Hua Li, Guangyu Li, Linda A. Jelicks, Mark F. Mehler, David Y. Hui, Yves Deshaies, Gerald I. Shulman, Gary J. Schwartz and Philipp E. Scherer. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. Journal of Clinical Investigation 117(Sept. 4):2621-2637. 2007

10 Marathon mice. These mice have more expression of PPARδ in their muscles, which makes them turn into type I (slow twitch) fibers that work well for long-distance running. The miche have more endurance and - even when not training - increased resistance to obesity.

Wang YX, Zhang CL, Yu RT, Cho HK, Nelson MC, et al. (2004) Regulation of Muscle Fiber Type and Running Endurance by PPARδ. PLoS Biol 2(10): e294

Some other runner-ups are IGF-1 gene therapy to slow age-related loss of muscle function, mice with calorie-restriction like metabolism improving longevity and heart condition, green fluorescent mice, mice with increased cerebral cortex size and the high EPO levels found in the family of Eero Mäntyranta, giving them extra blood hemoglobin.

Barton-Davis, E.R., Shoturma, D.I., Musaro, A., Rosenthal, N. and Sweeney, H.L. Viral mediated expression of IGF-I blocks the aging-related loss of skeletal muscle function, Proc. Natl. Acad. Sci. USA 95: 15603-15607, 1998.

Anthony M. Payne, Zhenlin Zheng, María Laura Messi, Carol E. Milligan, Estela González and Osvaldo Delbono, Motor neurone targeting of IGF-1 prevents specific force decline in ageing mouse muscle, J. Physiol. 2006;570;283-294 2005

Lin Yan, Dorothy E. Vatner, J. Patrick O'Connor, Andreas Ivessa, Hui Ge, Wei Chen, Shinichi Hirotani, Yoshihiro Ishikawa, Junichi Sadoshima,, and Stephen F. Vatner, Type 5 Adenylyl Cyclase Disruption Increases Longevity and Protects Against Stress, Cell, Vol 130, 247-258, 27 July 2007

Hadjantonakis AK, Gertsenstein M, Ikawa M, Okabe M, Nagy A. Generating green fluorescent mice by germline transmission of green fluorescent ES cells. Mech Dev. 1998 Aug;76(1-2):79-90.

Anjen Chenn and Christopher A. Walsh, Regulation of Cerebral Cortical Size by Control of Cell Cycle Exit in Neural Precursors, Science 297 (5580): 365-369

de la Chapelle A, Traskelin AL, Juvonen E. (1993). "Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis." Proc Natl Acad Sci U S A. 90(10):4495-9.

I, for one, welcome our new rodent overlords.

Addendum November 1 2007: The "brainbow" mouse that expresses several fluoroscent proteins at random in neurons is another impressive modification, although it (like the other fluoroscent animals) is not an enhancement per se - at least not until it starts to be used for aesthetic purposes.

Jean Livet, Tamily A. Weissman, Hyuno Kang, Ryan W. Draft, Ju Lu, Robyn A. Bennis, Joshua R. Sanes1 & Jeff W. Lichtman, Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system, Nature 450, 56-62

Addendum November 2 2007: Mice overexpressing a carboxykinase in muscle have a different energy metablism, making them both marathon mice, more physically active and longer lived.

Parvin Hakimi, Jianqi Yang, Gemma Casadesus, Duna Massillon, Fatima Tolentino-Silva, Colleen K. Nye, Marco E. Cabrera, David R. Hagen, Christopher B. Utter, Yacoub Baghdy, David H. Johnson, David L. Wilson, John P. Kirwan, Satish C. Kalhan, and Richard W. Hanson, Over-expression of the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) in skeletal muscle repatterns energy metabolism in the mouse, Journal of Biological Chemistry, online November 9, 2007.
Posted by Anders3 at November 1, 2007 05:24 PM