Chapter Five: GNR: Three Overlapping Revolutions.

1. 1. Samuel Butler (18351902), "Darwin Among the Machines," Christ Church Press, June 13, 1863 (republished by Festing Jones in 1912 in Samuel Butler (18351902), "Darwin Among the Machines," Christ Church Press, June 13, 1863 (republished by Festing Jones in 1912 in The Notebooks of Samuel Butler The Notebooks of Samuel Butler).

2. 2. Peter Weibel, "Virtual Worlds: The Emperor's New Bodies," in Peter Weibel, "Virtual Worlds: The Emperor's New Bodies," in Ars Electronica: Facing the Future Ars Electronica: Facing the Future, ed. Timothy Druckery (Cambridge, Ma.s.s.: MIT Press, 1999), pp. 20723; available online at http://www.aec.atlen/archiv_files/19902/ EI990b_009.pdf.

3. 3. James Watson and Francis Crick, "Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid," James Watson and Francis Crick, "Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid," Nature Nature 171.4356 (April 23, 1953): 73738, http://www.nature.comlnature/dna50/watsoncrick.pdf. 171.4356 (April 23, 1953): 73738, http://www.nature.comlnature/dna50/watsoncrick.pdf.

4. 4. Robert Waterston quoted in "Scientists Reveal Complete Sequence of Human Genome," CBC News, April 14, 2003, http://www.cbc.ca/story/science/national/2003/04/14/genome030414.html. Robert Waterston quoted in "Scientists Reveal Complete Sequence of Human Genome," CBC News, April 14, 2003, http://www.cbc.ca/story/science/national/2003/04/14/genome030414.html.

5. 5. See chapter 2, note 57. See chapter 2, note 57.

6. 6. The original reports of Crick and Watson, which still make compelling reading today, may be found in James A. Peters, ed., The original reports of Crick and Watson, which still make compelling reading today, may be found in James A. Peters, ed., Cla.s.sic Papers in Genetics Cla.s.sic Papers in Genetics (Englewood Cliffs, N.J.: Prentice-Hall, 1959). An exciting account of the successes and failures that led to the double helix is given in J. D. Watson, (Englewood Cliffs, N.J.: Prentice-Hall, 1959). An exciting account of the successes and failures that led to the double helix is given in J. D. Watson, The Double Helix: A Personal Account of the Discovery of the Structure of DNA The Double Helix: A Personal Account of the Discovery of the Structure of DNA (New York: Atheneum, 1968). Nature.com has a collection of Crick's papers available online at http://www.nature.com/nature/focus/crick/index.html. (New York: Atheneum, 1968). Nature.com has a collection of Crick's papers available online at http://www.nature.com/nature/focus/crick/index.html.

7. 7. Morislav Radman and Richard Wagner, "The High Fidelity of DNA Duplication," Morislav Radman and Richard Wagner, "The High Fidelity of DNA Duplication," Scientific American Scientific American 259.2 (August 1988): 4046. 259.2 (August 1988): 4046.

8. 8. The structure and behavior of DNA and RNA are described in Gary Felsenfeld, "DNA," and James Darnell, "RNA," both in The structure and behavior of DNA and RNA are described in Gary Felsenfeld, "DNA," and James Darnell, "RNA," both in Scientific American Scientific American 253.4 (October 1985), p. 5867 and 6878 respectively. 253.4 (October 1985), p. 5867 and 6878 respectively.

9. 9. Mark A. Iobling and Chris Tyler-Smith, "The Human Y Chromosome: An Evolutionary Marker Comes of Age," Mark A. Iobling and Chris Tyler-Smith, "The Human Y Chromosome: An Evolutionary Marker Comes of Age," Nature Reviews Genetics Nature Reviews Genetics 4 (August 2003): 598612; Helen Skaletsky et al., "The Male-Specific Region of the Human Y Chromosome Is a Mosaic of Discrete Sequence Cla.s.ses," 4 (August 2003): 598612; Helen Skaletsky et al., "The Male-Specific Region of the Human Y Chromosome Is a Mosaic of Discrete Sequence Cla.s.ses," Nature Nature 423 (June 19, 2003): 82537. 423 (June 19, 2003): 82537.

10. 10. Misformed proteins are perhaps the most dangerous toxin of all. Research suggests that misfolded proteins may be at the heart of numerous disease processes in the body. Such diverse diseases as Alzheimer's disease, Parkinson's disease, the human form of mad-cow disease, cystic fibrosis, cataracts, and diabetes are all thought to result from the inability of the body to adequately eliminate misfolded proteins. Misformed proteins are perhaps the most dangerous toxin of all. Research suggests that misfolded proteins may be at the heart of numerous disease processes in the body. Such diverse diseases as Alzheimer's disease, Parkinson's disease, the human form of mad-cow disease, cystic fibrosis, cataracts, and diabetes are all thought to result from the inability of the body to adequately eliminate misfolded proteins.

Protein molecules perform the lion's share of cellular work. Proteins are made within each cell according to DNA blueprints. They begin as long strings of amino acids, which must then be folded into precise three-dimensional configurations in order to function as enzymes, transport proteins, et cetera. Heavy-metal toxins interfere with normal function of these enzymes, further exacerbating the problem. There are also genetic mutations that predispose individuals to misformed-protein buildup.When protofibrils begin to stick together, they form filaments, fibrils, and ultimately larger globular structures called amyloid plaque. Until recently these acc.u.mulations of insoluble plaque were regarded as the pathologic agents for these diseases, but it is now known that the proto fibrils themselves are the real problem. The speed with which a proto fibril is turned into insoluble amyloid plaque is inversely related to disease progression. This explains why some individuals are found to have extensive acc.u.mulation of plaque in their brains but no evidence of Alzheimer's disease, while others have little visible plaque yet extensive manifestations of the disease. Some people form amyloid plaque quickly, which protects them from further protofibril damage. Other individuals turn proto fibrils into amyloid plaque less rapidly, allowing more extensive damage. These people also have little visible amyloid plaque. See Per Hammarstrom, Frank Schneider, and Jeffrey W. Kelly, "Trans-Suppression of Misfolding in an Amyloid Disease," Science Science 293.5539 (September 28, 2001): 245962. 293.5539 (September 28, 2001): 245962.

11. 11. A fascinating account of the new biology is given in Horace F. Judson, A fascinating account of the new biology is given in Horace F. Judson, The Eighth Day of Creation: The Makers of the Revolution in Biology The Eighth Day of Creation: The Makers of the Revolution in Biology (Woodbury, N.Y.: CSHL Press, 1996). (Woodbury, N.Y.: CSHL Press, 1996).

12. 12. Raymond Kurzweil and Terry Grossman, M.D., Raymond Kurzweil and Terry Grossman, M.D., Fantastic Voyage: Live Long Enough to Live Forever Fantastic Voyage: Live Long Enough to Live Forever (New York: Rodale, 2004). See http://www.Fantastic-Voyage.net and http://www.RayandTerry.com. (New York: Rodale, 2004). See http://www.Fantastic-Voyage.net and http://www.RayandTerry.com.

13. 13. Raymond Kurzweil, Raymond Kurzweil, The 10% Solution for a Healthy Life: How to Eliminate Virtually All Risk of Heart Disease and Cancer The 10% Solution for a Healthy Life: How to Eliminate Virtually All Risk of Heart Disease and Cancer (New York: Crown Books, 1993). (New York: Crown Books, 1993).

14. 14. Kurzweil and Grossman, Kurzweil and Grossman, Fantastic Voyage Fantastic Voyage. "Ray & Terry's Longevity Program" is articulated throughout the book.

15. 15. The test for "biological age," called the H-scan test, includes tests for auditoryreaction time, highest audible pitch, vibrotactile sensitivity, visual-reaction time, muscle-movement time, lung (forced expiratory) volume, visual-reaction time with decision, muscle-movement time with decision, memory (length of sequence), alternative b.u.t.ton-tapping time, and visual accommodation. The author had this test done at Frontier Medical Inst.i.tute (Grossman's health and longevity clinic), http://www.FMIClinic.com.For information on the H-scan test, see Diagnostic and Lab Testing, Longevity Inst.i.tute, Dallas, http://www.lidhealth.com/diagnostic.html. The test for "biological age," called the H-scan test, includes tests for auditoryreaction time, highest audible pitch, vibrotactile sensitivity, visual-reaction time, muscle-movement time, lung (forced expiratory) volume, visual-reaction time with decision, muscle-movement time with decision, memory (length of sequence), alternative b.u.t.ton-tapping time, and visual accommodation. The author had this test done at Frontier Medical Inst.i.tute (Grossman's health and longevity clinic), http://www.FMIClinic.com.For information on the H-scan test, see Diagnostic and Lab Testing, Longevity Inst.i.tute, Dallas, http://www.lidhealth.com/diagnostic.html.

16. 16. Kurzweil and Grossman, Kurzweil and Grossman, Fantastic Voyage Fantastic Voyage, chapter 10: "Ray's Personal Program."

17. 17. Ibid. Ibid.

18. 18. Aubrey D. N. J. de Grey, "The Foreseeability of Real Anti-Aging Medicine: Focusing the Debate," Aubrey D. N. J. de Grey, "The Foreseeability of Real Anti-Aging Medicine: Focusing the Debate," Experimental Gerontology Experimental Gerontology 38.9 (September 2003): 92734; Aubrey D. N. J. de Grey, "An Engineer's Approach to the Development of Real Anti-Aging Medicine," 38.9 (September 2003): 92734; Aubrey D. N. J. de Grey, "An Engineer's Approach to the Development of Real Anti-Aging Medicine," Science of Aging, Knowledge, Environment Science of Aging, Knowledge, Environment 1 (2003): Aubrey D. N. J. de Grey et al., "Is Human Aging Still Mysterious Enough to Be Left Only to Scientists?" 1 (2003): Aubrey D. N. J. de Grey et al., "Is Human Aging Still Mysterious Enough to Be Left Only to Scientists?" BioEssays BioEssays 24.7 (July 2002): 66776. 24.7 (July 2002): 66776.

19. 19. Aubrey D. N. J. de Grey, ed., Aubrey D. N. J. de Grey, ed., Strategies for Engineered Negligible Senescence: Why Genuine Control of Aging May Be Foreseeable Strategies for Engineered Negligible Senescence: Why Genuine Control of Aging May Be Foreseeable, Annals of the New YorkAcademy of Sciences, vol. 1019 (New York: New York Academy of Sciences, June 2004).

20. 20. In addition to providing the functions of different types of cells, two other reasons for cells to control the expression of genes are environmental cues and developmental processes. Even simple organisms such as bacteria can turn on and off the synthesis of proteins depending on environmental cues. In addition to providing the functions of different types of cells, two other reasons for cells to control the expression of genes are environmental cues and developmental processes. Even simple organisms such as bacteria can turn on and off the synthesis of proteins depending on environmental cues. E. coli E. coli, for example, can turn off the synthesis of proteins that allow it to control the level of nitrogen gas from the air when there are other, less energy-intensive sources of nitrogen in its environment. A recent study of 1,800 strawberry genes found that the expression of 200 of those genes varied during different stages of development. E. Marshall, "An Array of Uses: Expression Patterns in Strawberries, Ebola, TB, and Mouse Cells," Science Science 286.5439 (1999): 445. 286.5439 (1999): 445.

21. 21. Along with a protein-encoding region, genes include regulatory sequences called promoters and enhancers that control where and when that gene is expressed. Promoters of genes that encode proteins are typically located immediately "upstream" on the DNA. An enhancer activates the use of a promoter, thereby controlling the rate of gene expression. Most genes require enhancers to be expressed. Enhancers have been called "the major determinant of differential transcription in s.p.a.ce (cell type) and time"; and any given gene can have several different enhancer sites linked to it (S. F. Gilbert, Along with a protein-encoding region, genes include regulatory sequences called promoters and enhancers that control where and when that gene is expressed. Promoters of genes that encode proteins are typically located immediately "upstream" on the DNA. An enhancer activates the use of a promoter, thereby controlling the rate of gene expression. Most genes require enhancers to be expressed. Enhancers have been called "the major determinant of differential transcription in s.p.a.ce (cell type) and time"; and any given gene can have several different enhancer sites linked to it (S. F. Gilbert, Developmental Biology Developmental Biology, 6th ed. [Sunderland, Ma.s.s.: Sinauer a.s.sociates, 2000]; available online at www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=.0BpKYEB-SPfx18nm8QOxH).

By binding to enhancer or promoter regions, transcription factors start or repress the expression of a gene. New knowledge of transcription factors has transformed our understanding of gene expression. Per Gilbert in the chapter "The Genetic Core of Development: Differential Gene Expression": "The gene itself is no longer seen as an independent ent.i.ty controlling the synthesis of proteins. Rather, the gene both directs and is directed by protein synthesis. Natalie Anger (1992) has written, 'A series of discoveries suggests that DNA is more like a certain type of politician, surrounded by a flock of protein handlers and advisors that must vigorously ma.s.sage it, twist it and, on occasion, reinvent it before the grand blueprint of the body can make any sense at all.' "

22. 22. Bob Holmes, "Gene Therapy May Switch Off Huntington's," March 13, 2003, http://www.newscientist.com/news/news.jsp?id=ns99993493. "Emerging as a powerful tool for reverse genetic a.n.a.lysis, RNAi is rapidly being applied to study the function of many genes a.s.sociated with human disease, in particular those a.s.sociated with oncogenesis and infectious disease." J. C. Cheng, T. B. Moore, and K. M. Sakamoto, "RNA Interference and Human Disease," Bob Holmes, "Gene Therapy May Switch Off Huntington's," March 13, 2003, http://www.newscientist.com/news/news.jsp?id=ns99993493. "Emerging as a powerful tool for reverse genetic a.n.a.lysis, RNAi is rapidly being applied to study the function of many genes a.s.sociated with human disease, in particular those a.s.sociated with oncogenesis and infectious disease." J. C. Cheng, T. B. Moore, and K. M. Sakamoto, "RNA Interference and Human Disease," Molecular Genetics and Metabolism Molecular Genetics and Metabolism 80.12 (October 2003): 12128. RNAi is a "potent and highly sequence-specific mechanism," 1. Zhang, D. K. Fogg, and D. M. Waisman, "RNA Interference-Mediated Silencing of the S100A10 Gene Attenuates Plasmin Generation and Invasiveness of Colo 222 Colorecta Cancer Cells," 80.12 (October 2003): 12128. RNAi is a "potent and highly sequence-specific mechanism," 1. Zhang, D. K. Fogg, and D. M. Waisman, "RNA Interference-Mediated Silencing of the S100A10 Gene Attenuates Plasmin Generation and Invasiveness of Colo 222 Colorecta Cancer Cells," Journal of Biological Chemistry Journal of Biological Chemistry 279.3 (January 16,2004): 205362. 279.3 (January 16,2004): 205362.

23. 23. Each chip contains synthetic oligonucleotides that replicate sequences that identify specific genes. "To determine which genes have been expressed in a sample, researchers isolate messenger RNA from test samples, convert it to complementary DNA (cDNA), tag it with fluorescent dye, and run the sample over the wafer. Each tagged cDNA will stick to an oligo with a matching sequence, lighting up a spot on the wafer where the sequence is known. An automated scanner then determines which oligos have bound, and hence which genes were expressed...." E. Marshall, "Do-It-Yourself Gene Watching," Each chip contains synthetic oligonucleotides that replicate sequences that identify specific genes. "To determine which genes have been expressed in a sample, researchers isolate messenger RNA from test samples, convert it to complementary DNA (cDNA), tag it with fluorescent dye, and run the sample over the wafer. Each tagged cDNA will stick to an oligo with a matching sequence, lighting up a spot on the wafer where the sequence is known. An automated scanner then determines which oligos have bound, and hence which genes were expressed...." E. Marshall, "Do-It-Yourself Gene Watching," Science Science 286.5439 (October 15, 1999): 44447. 286.5439 (October 15, 1999): 44447.

24. 24. Ibid. Ibid.

25. 25. J. Rosamond and A. Allsop, "Harnessing the Power of the Genome in the Search for New Antibiotics," J. Rosamond and A. Allsop, "Harnessing the Power of the Genome in the Search for New Antibiotics," Science Science 287.5460 (March 17,2000): 197376. 287.5460 (March 17,2000): 197376.

26. 26. T. R. Golub et al., "Molecular Cla.s.sification of Cancer: Cla.s.s Discovery and Cla.s.s Prediction by Gene Expression Monitoring," T. R. Golub et al., "Molecular Cla.s.sification of Cancer: Cla.s.s Discovery and Cla.s.s Prediction by Gene Expression Monitoring," Science Science 286.5439 (October 15, 1999): 53137. 286.5439 (October 15, 1999): 53137.

27. 27. Ibid., as reported in A. Berns, "Cancer: Gene Expression in Diagnosis," Ibid., as reported in A. Berns, "Cancer: Gene Expression in Diagnosis," Nature Nature 403 (February 3, 2000): 49192. In another study, 1 percent of the genes studied showed reduced expression in aged muscles. These genes produced proteins a.s.sociated with energy production and cell building, so a reduction makes sense given the weakening a.s.sociated with age. Genes with increased expression produced stress proteins, which are used to repair damaged DNA or proteins. J. Marx, "Chipping Away at the Causes of Aging," 403 (February 3, 2000): 49192. In another study, 1 percent of the genes studied showed reduced expression in aged muscles. These genes produced proteins a.s.sociated with energy production and cell building, so a reduction makes sense given the weakening a.s.sociated with age. Genes with increased expression produced stress proteins, which are used to repair damaged DNA or proteins. J. Marx, "Chipping Away at the Causes of Aging," Science Science 287.5462 (March 31, 2000): 2390. 287.5462 (March 31, 2000): 2390.

As another example, liver metastases are a common cause of colorectal cancer. These metastases respond differently to treatment depending on their genetic profile. Expression profiling is an excellent way to determine an appropriate mode of treatment. J. C. Sung et al. "Genetic Heterogeneity of Colorectal Cancer Liver Metastases," Journal of Surgical Research Journal of Surgical Research 114.2 (October 2003): 251. 114.2 (October 2003): 251.As a final example, researchers have had difficulty a.n.a.lyzing the Reed-Sternberg cell of Hodgkin's disease because of its extreme rarity in diseased tissue. Expression profiling is now providing a clue regarding the heritage of this cell. J. Cossman et al., "Reed-Sternberg Cell Genome Expression Supports a B-Cell Lineage," Blood Blood 94.2 (July 15, 1999): 41116. 94.2 (July 15, 1999): 41116.

28. 28. T. Ueland et al., "Growth Hormone Subst.i.tution Increases Gene Expression of Members of the IGF Family in Cortical Bone from Women with Adult Onset Growth Hormone Deficiency-Relationship with Bone Turn-Over," T. Ueland et al., "Growth Hormone Subst.i.tution Increases Gene Expression of Members of the IGF Family in Cortical Bone from Women with Adult Onset Growth Hormone Deficiency-Relationship with Bone Turn-Over," Bone Bone 33.4 (October 2003): 63845. 33.4 (October 2003): 63845.

29. 29. R. Lovett, "Toxicologists Brace for Genomics Revolution," R. Lovett, "Toxicologists Brace for Genomics Revolution," Science Science 289.5479 (July 28, 2000): 53637. 289.5479 (July 28, 2000): 53637.

30. 30. Gene transfer to somatic cells affects a subset of cells in the body for a period of time. It is theoretically possible also to alter genetic information in egg and sperm (germ-line) cells, for the purpose of pa.s.sing on those changes to the next generations. Such therapy poses many ethical concerns and has not yet been attempted. "Gene Therapy," Wikipedia, http://en.wikipedia.org/wiki/Gene_therapy. Gene transfer to somatic cells affects a subset of cells in the body for a period of time. It is theoretically possible also to alter genetic information in egg and sperm (germ-line) cells, for the purpose of pa.s.sing on those changes to the next generations. Such therapy poses many ethical concerns and has not yet been attempted. "Gene Therapy," Wikipedia, http://en.wikipedia.org/wiki/Gene_therapy.

31. 31. Genes encode proteins, which perform vital functions in the human body. Abnormal or mutated genes encode proteins that are unable to perform those functions, resulting in genetic disorders and diseases. The goal of gene therapy is to replace the defective genes so that normal proteins are produced. This can be done in a number of ways, but the most typical way is to insert a therapeutic replacement gene into the patient's target cells using a carrier molecule called a vector. "Currently, the most common vector is a virus that has been genetically altered to carry normal human DNA. Viruses have evolved a way of encapsulating and delivering their genes to human cells in a pathogenic manner. Scientists have tried to take advantage of this capability and manipulate the virus genome to remove the disease-causing genes and insert therapeutic genes" (Human Genome Project, "Gene Therapy," http://www.ornl.gov/TechResources/Human_Genome/medicine/genetherapy.html). See the Human Genome Project site for more information about gene therapy and links. Gene therapy is an important enough area of research that there are currently six scientific peer-reviewed gene-therapy journals and four professional a.s.sociations dedicated to this topic. Genes encode proteins, which perform vital functions in the human body. Abnormal or mutated genes encode proteins that are unable to perform those functions, resulting in genetic disorders and diseases. The goal of gene therapy is to replace the defective genes so that normal proteins are produced. This can be done in a number of ways, but the most typical way is to insert a therapeutic replacement gene into the patient's target cells using a carrier molecule called a vector. "Currently, the most common vector is a virus that has been genetically altered to carry normal human DNA. Viruses have evolved a way of encapsulating and delivering their genes to human cells in a pathogenic manner. Scientists have tried to take advantage of this capability and manipulate the virus genome to remove the disease-causing genes and insert therapeutic genes" (Human Genome Project, "Gene Therapy," http://www.ornl.gov/TechResources/Human_Genome/medicine/genetherapy.html). See the Human Genome Project site for more information about gene therapy and links. Gene therapy is an important enough area of research that there are currently six scientific peer-reviewed gene-therapy journals and four professional a.s.sociations dedicated to this topic.

32. 32. K. R. Smith, "Gene Transfer in Higher Animals: Theoretical Considerations and KeyConcepts," K. R. Smith, "Gene Transfer in Higher Animals: Theoretical Considerations and KeyConcepts," Journal of Biotechnology Journal of Biotechnology 99.1 (October 9, 2002): 122. 99.1 (October 9, 2002): 122.

33. 33. Anil Ananthaswamy, "Undercover Genes Slip into the Brain," March 20, 2003, http://www.newscientist.com/news/news.jsp?id=ns99993520. Anil Ananthaswamy, "Undercover Genes Slip into the Brain," March 20, 2003, http://www.newscientist.com/news/news.jsp?id=ns99993520.

34. 34. A. E. Trezise et al., "In Vivo Gene Expression: DNA Electrotransfer," Current Opinion in Molecular Therapeutics 5.4 (August 2003): 397-404. A. E. Trezise et al., "In Vivo Gene Expression: DNA Electrotransfer," Current Opinion in Molecular Therapeutics 5.4 (August 2003): 397-404.

35. 35. Sylvia Westphal, "DNA Nan.o.b.a.l.l.s Boost Gene Therapy," May 12, 2002, http://www.newscientist.com/news/news.jsp?id=ns99992257. Sylvia Westphal, "DNA Nan.o.b.a.l.l.s Boost Gene Therapy," May 12, 2002, http://www.newscientist.com/news/news.jsp?id=ns99992257.

36. 36. L. Wu, M. Johnson, and M. Sato, "Transcriptionally Targeted Gene Therapy to Detect and Treat Cancer," L. Wu, M. Johnson, and M. Sato, "Transcriptionally Targeted Gene Therapy to Detect and Treat Cancer," Trends in Molecular Medicine Trends in Molecular Medicine 9.10 (October 2003): 42129. 9.10 (October 2003): 42129.

37. 37. S. Westphal, "Virus Synthesized in a Fortnight," November 14,2003, http://www.newscientist.com/news/news.jsp?id=ns99994383. S. Westphal, "Virus Synthesized in a Fortnight," November 14,2003, http://www.newscientist.com/news/news.jsp?id=ns99994383.

38. 38. G. Chiesa, "Recombinant Apolipoprotein A-I(Milano) Infusion into Rabbit Carotid Artery Rapidly Removes Lipid from Fatty Streaks," G. Chiesa, "Recombinant Apolipoprotein A-I(Milano) Infusion into Rabbit Carotid Artery Rapidly Removes Lipid from Fatty Streaks," Circulation Research Circulation Research 90.9 (May 17, 2002): 97480; P. K. Shah et al., "High-Dose Recombinant Apolipoprotein A-I(Milano) Mobilizes Tissue Cholesterol and Rapidly Reduces Plaque Lipid and Macrophage Content in Apolipoprotein e-Deficient Mice," 90.9 (May 17, 2002): 97480; P. K. Shah et al., "High-Dose Recombinant Apolipoprotein A-I(Milano) Mobilizes Tissue Cholesterol and Rapidly Reduces Plaque Lipid and Macrophage Content in Apolipoprotein e-Deficient Mice," Circulation Circulation 103.25 (June 26, 2001): 304750. 103.25 (June 26, 2001): 304750.

39. 39. S. E. Nissen et al., "Effect of Recombinant Apo A-I Milano on Coronary Atherosclerosis in Patients with Acute Coronary Syndromes: A Randomized Controlled Trial," S. E. Nissen et al., "Effect of Recombinant Apo A-I Milano on Coronary Atherosclerosis in Patients with Acute Coronary Syndromes: A Randomized Controlled Trial," JAMA JAMA 290.17 (November 5, 2003): 22922300. 290.17 (November 5, 2003): 22922300.

40. 40. A recent phase 2 study reported "markedly increased HDL cholesterol levels and also decreased LDL cholesterol levels," M. E. Brousseau et al., "Effects of an Inhibitor of Cholesteryl Ester Transfer Protein on HDL Cholesterol," A recent phase 2 study reported "markedly increased HDL cholesterol levels and also decreased LDL cholesterol levels," M. E. Brousseau et al., "Effects of an Inhibitor of Cholesteryl Ester Transfer Protein on HDL Cholesterol," New England Journal of Medicine New England Journal of Medicine 350.15 (April 8, 2004): 150515, http://content.nejm.org/cgi/content/abstract/350/15/1505. Global phase 3 trials began in late 2003. Information on Torcetrapib is available on the Pfizer site: http://www.pfizer.com/are/investors_reports/annual_2003/review/p2003ar14_15.htm. 350.15 (April 8, 2004): 150515, http://content.nejm.org/cgi/content/abstract/350/15/1505. Global phase 3 trials began in late 2003. Information on Torcetrapib is available on the Pfizer site: http://www.pfizer.com/are/investors_reports/annual_2003/review/p2003ar14_15.htm.

41. 41. O. J. Finn, "Cancer Vaccines: Between the Idea and the Reality," O. J. Finn, "Cancer Vaccines: Between the Idea and the Reality," Nature Reviews: Immunology Nature Reviews: Immunology 3.8 (August 2003): 63041; R. C. Kennedy and M. H. Shearer, "A Role for Antibodies in Tumor Immunity," 3.8 (August 2003): 63041; R. C. Kennedy and M. H. Shearer, "A Role for Antibodies in Tumor Immunity," International Reviews of Immunology International Reviews of Immunology 22.2 (MarchApril 2003): 14172. 22.2 (MarchApril 2003): 14172.

42. 42. T. F. Greten and E. M. Jaffee, "Cancer Vaccines," T. F. Greten and E. M. Jaffee, "Cancer Vaccines," Journal of Clinical Oncology Journal of Clinical Oncology 17.3 (March 1999): 104760. 17.3 (March 1999): 104760.

43. 43. "Cancer 'Vaccine' Results Encouraging," BBCNews, January 8, 2001, http://news.bbc.co.uk/2/hi/health/1102618.stm, reporting on research by E. M. Jaffee et al., "Novel Allogeneic Granulocyte-Macrophage Colony-Stimulating Factor-Secreting Tumor Vaccine for Pancreatic Cancer: A Phase I Trial of Safety and Immune Activation," "Cancer 'Vaccine' Results Encouraging," BBCNews, January 8, 2001, http://news.bbc.co.uk/2/hi/health/1102618.stm, reporting on research by E. M. Jaffee et al., "Novel Allogeneic Granulocyte-Macrophage Colony-Stimulating Factor-Secreting Tumor Vaccine for Pancreatic Cancer: A Phase I Trial of Safety and Immune Activation," Journal of Clinical Oncology Journal of Clinical Oncology 19.1 (January 1,2001): 14556. 19.1 (January 1,2001): 14556.

44. 44. John Travis, "Fused Cells Hold Promise of Cancer Vaccines," March 4, 2000, http://www.sciencenews.org/articles/20000304/fob3.asp, referring to D. W. Kufe, "Smallpox, Polio and Now a Cancer Vaccine?" John Travis, "Fused Cells Hold Promise of Cancer Vaccines," March 4, 2000, http://www.sciencenews.org/articles/20000304/fob3.asp, referring to D. W. Kufe, "Smallpox, Polio and Now a Cancer Vaccine?" Nature Medicine Nature Medicine 6 (March 2000): 25253. 6 (March 2000): 25253.

45. 45. J. D. Lewis, B. D. Reilly, and R. K. Bright, "Tumor-a.s.sociated Antigens: From Discovery to Immunity," J. D. Lewis, B. D. Reilly, and R. K. Bright, "Tumor-a.s.sociated Antigens: From Discovery to Immunity," International Reviews of Immunology International Reviews of Immunology 22.2 (MarchApril 2003): 81112. 22.2 (MarchApril 2003): 81112.

46. 46. T. Boehm et al., "Antiangiogenic Therapy of Experimental Cancer Does Not Induce Acquired Drug Resistance," T. Boehm et al., "Antiangiogenic Therapy of Experimental Cancer Does Not Induce Acquired Drug Resistance," Nature Nature 390.6658 (November 27,1997): 4047. 390.6658 (November 27,1997): 4047.

47. 47. Angiogenesis Foundation, "Understanding Angiogenesis," http://www.angio.org/understanding/content_understanding.html; L. K. La.s.siter and M. A. Carducci, "Endothelin Receptor Antagonists in the Treatment of Prostate Cancer," Angiogenesis Foundation, "Understanding Angiogenesis," http://www.angio.org/understanding/content_understanding.html; L. K. La.s.siter and M. A. Carducci, "Endothelin Receptor Antagonists in the Treatment of Prostate Cancer," Seminars in Oncology Seminars in Oncology 30.5 (October 2003): 67888. For an explanation of the process, see the National Cancer Inst.i.tute Web site, "Understanding Angiogenesis," http://press2.nci.nih.gov/sciencebehind/angiogenesis/angio02.htm. 30.5 (October 2003): 67888. For an explanation of the process, see the National Cancer Inst.i.tute Web site, "Understanding Angiogenesis," http://press2.nci.nih.gov/sciencebehind/angiogenesis/angio02.htm.

48. 48. I. B. Roninson, "Tumor Cell Senescence in Cancer Treatment," I. B. Roninson, "Tumor Cell Senescence in Cancer Treatment," Cancer Research Cancer Research 63.11 (June 1, 2003): 270515; B. R. Davies et al., "Immortalization of Human Ovarian Surface Epithelium with Telomerase and Temperature-Sensitive SV40 Large T Antigen," 63.11 (June 1, 2003): 270515; B. R. Davies et al., "Immortalization of Human Ovarian Surface Epithelium with Telomerase and Temperature-Sensitive SV40 Large T Antigen," Experimental Cell Research Experimental Cell Research 288.2 (August 15, 2003): 390402. 288.2 (August 15, 2003): 390402.

49. 49. See also R. C. Woodruff and J. N. Thompson Jr., "The Role of Somatic and Germline Mutations in Aging and a Mutation Interaction Model of Aging," See also R. C. Woodruff and J. N. Thompson Jr., "The Role of Somatic and Germline Mutations in Aging and a Mutation Interaction Model of Aging," Journal of Anti-Aging Medicine Journal of Anti-Aging Medicine 6.1 (Spring 2003): 2939. See also notes 18 and 19. 6.1 (Spring 2003): 2939. See also notes 18 and 19.

50. 50. Aubrey D. N. J. de Grey, "The Reductive Hotspot Hypothesis of Mammalian Aging: Membrane Metabolism Magnifies Mutant Mitochondrial Mischief," Aubrey D. N. J. de Grey, "The Reductive Hotspot Hypothesis of Mammalian Aging: Membrane Metabolism Magnifies Mutant Mitochondrial Mischief," European Journal of Biochemistry European Journal of Biochemistry 269.8 (April 2002): 20039; P. F. Chinnery et al., "Acc.u.mulation of Mitochondrial DNA Mutations in Ageing, Cancer, and Mitochondrial Disease: Is There a Common Mechanism?" 269.8 (April 2002): 20039; P. F. Chinnery et al., "Acc.u.mulation of Mitochondrial DNA Mutations in Ageing, Cancer, and Mitochondrial Disease: Is There a Common Mechanism?" Lancet Lancet 360.9342 (October 26, 2002): 132325; A. D. de Grey, "Mitochondrial Gene Therapy: An Arena for the Biomedical Use of Inteins," 360.9342 (October 26, 2002): 132325; A. D. de Grey, "Mitochondrial Gene Therapy: An Arena for the Biomedical Use of Inteins," Trends in Biotechnology Trends in Biotechnology 18.9 (September 2000): 39499. 18.9 (September 2000): 39499.

51. 51. "The notion of 'vaccinating' individuals against a neurodegenerative disorder such as Alzheimer's disease is a marked departure from cla.s.sical thinking about mechanism and treatment, and yet therapeutic vaccines for both Alzheimer's disease and multiple sclerosis have been validated in animal models and are in the clinic. Such approaches, however, have the potential to induce unwanted inflammatory responses as well as to provide benefit" (H. L. Weiner and D. J. Selkoe, "Inflammation and Therapeutic Vaccination in CNS Diseases," "The notion of 'vaccinating' individuals against a neurodegenerative disorder such as Alzheimer's disease is a marked departure from cla.s.sical thinking about mechanism and treatment, and yet therapeutic vaccines for both Alzheimer's disease and multiple sclerosis have been validated in animal models and are in the clinic. Such approaches, however, have the potential to induce unwanted inflammatory responses as well as to provide benefit" (H. L. Weiner and D. J. Selkoe, "Inflammation and Therapeutic Vaccination in CNS Diseases," Nature Nature 420.6917 [December 1926, 2002]: 879-84). These researchers showed that a vaccine in the form of nose drops could slow the brain deterioration of Alzheimer's. H. L.Weiner et al., "Nasal Administration of Amyloid-beta Peptide Decreases Cerebral Amyloid Burden in a Mouse Model of Alzheimer's Disease," 420.6917 [December 1926, 2002]: 879-84). These researchers showed that a vaccine in the form of nose drops could slow the brain deterioration of Alzheimer's. H. L.Weiner et al., "Nasal Administration of Amyloid-beta Peptide Decreases Cerebral Amyloid Burden in a Mouse Model of Alzheimer's Disease," Annals of Neurology Annals of Neurology 48.4 (October 2000): 56779. 48.4 (October 2000): 56779.

52. 52. S. Vasan, P. Foiles, and H. Founds, "Therapeutic Potential of Breakers of Advanced Glycation End Product-Protein Crosslinks," S. Vasan, P. Foiles, and H. Founds, "Therapeutic Potential of Breakers of Advanced Glycation End Product-Protein Crosslinks," Archives of Biochemistry and Biophysics Archives of Biochemistry and Biophysics 419.1 (November 1, 2003): 8996; D. A. Ka.s.s, "Getting Better Without AGE: New Insights into the Diabetic Heart," 419.1 (November 1, 2003): 8996; D. A. Ka.s.s, "Getting Better Without AGE: New Insights into the Diabetic Heart," Circulation Research Circulation Research 92.7 (April 18,2003): 7046. 92.7 (April 18,2003): 7046.

53. 53. S. Graham, "Methuselah Worm Remains Energetic for Life," October 27, 2003, www.sciam.com/article.cfm?chanID=sa003&articleID=000C601F-8711-1F99-86FB83414B7F0156. S. Graham, "Methuselah Worm Remains Energetic for Life," October 27, 2003, www.sciam.com/article.cfm?chanID=sa003&articleID=000C601F-8711-1F99-86FB83414B7F0156.

54. 54. Ron Weiss's home page at Princeton University (http://www.princeton.edu/~rweiss) lists his publications, such as "Genetic Circuit Building Blocks for Cellular Computation, Communications, and Signal Processing," Ron Weiss's home page at Princeton University (http://www.princeton.edu/~rweiss) lists his publications, such as "Genetic Circuit Building Blocks for Cellular Computation, Communications, and Signal Processing," Natural Computing, an International Journal Natural Computing, an International Journal 2.1 (January 2003): 4784. 2.1 (January 2003): 4784.

55. 55. S. L. Garfinkel, "Biological Computing," S. L. Garfinkel, "Biological Computing," Technology Review Technology Review (MayJune 2000), http://static.highbeam.com/t/technologyreview/may012000/biologicalcomputing. (MayJune 2000), http://static.highbeam.com/t/technologyreview/may012000/biologicalcomputing.

56. 56. Ibid. See also the list of current research on the MIT Media Lab Web site, http://www.media.mit.edu/research/index.html. Ibid. See also the list of current research on the MIT Media Lab Web site, http://www.media.mit.edu/research/index.html.

57. 57. Here is one possible explanation: "In mammals, female embryos have two X-chromosomes and males have one. During early development in females, one of the X's and most of its genes are normally silenced or inactivated. That way, the amount of gene expression in males and females is the same. But in cloned animals, one X-chromosome is already inactivated in the donated nucleus. It must be reprogrammed and then later inactivated again, which introduces the possibility of errors." CBC News online staff, "Genetic Defects May Explain Cloning Failures," May 27, 2002, http://www.cbc.ca/stories/2002/05/27/cloning_errors020527. That story reports on F. Xue et al., "Aberrant Patterns of X Chromosome Inactivation in Bovine Clones," Here is one possible explanation: "In mammals, female embryos have two X-chromosomes and males have one. During early development in females, one of the X's and most of its genes are normally silenced or inactivated. That way, the amount of gene expression in males and females is the same. But in cloned animals, one X-chromosome is already inactivated in the donated nucleus. It must be reprogrammed and then later inactivated again, which introduces the possibility of errors." CBC News online staff, "Genetic Defects May Explain Cloning Failures," May 27, 2002, http://www.cbc.ca/stories/2002/05/27/cloning_errors020527. That story reports on F. Xue et al., "Aberrant Patterns of X Chromosome Inactivation in Bovine Clones," Nature Genetics Nature Genetics 31.2 (June 2002): 21620. 31.2 (June 2002): 21620.

58. 58. Rick Weiss, "Clone Defects Point to Need for 2 Genetic Parents," Rick Weiss, "Clone Defects Point to Need for 2 Genetic Parents," Washington Post Washington Post, May 10,1999, http://www.gene.ch/genet/1999/Jun/msg00004.html.

59. 59. A. Baguisi et al., "Production of Goats by Somatic Cell Nuclear Transfer," A. Baguisi et al., "Production of Goats by Somatic Cell Nuclear Transfer," Nature Biotechnology Nature Biotechnology 5 (May 1999): 45661. For more information on the partnership between Genzyme Transgenics Corporation, Louisiana State University, and Tufts University School of Medicine that produced this work, see the April 27, 1999, press release, "Genzyme Transgenics Corporation Announces First Successful Cloning of Transgenic Goat," http://www.transgenics.com/pressreleases/pr042799.html. 5 (May 1999): 45661. For more information on the partnership between Genzyme Transgenics Corporation, Louisiana State University, and Tufts University School of Medicine that produced this work, see the April 27, 1999, press release, "Genzyme Transgenics Corporation Announces First Successful Cloning of Transgenic Goat," http://www.transgenics.com/pressreleases/pr042799.html.

60. 60. Luba Vangelova, "True or False? Extinction Is Forever," Luba Vangelova, "True or False? Extinction Is Forever," Smithsonian Smithsonian, June 2003, http://www.smithsonianmag.com/smithsonian/issues03/jun03/phenomena.html.

61. 61. J. B. Gurdon and A. Colman, "The Future of Cloning," J. B. Gurdon and A. Colman, "The Future of Cloning," Nature Nature 402.6763 (December 16, 1999): 74346; Gregory Stock and John Campbell, eds., 402.6763 (December 16, 1999): 74346; Gregory Stock and John Campbell, eds., Engineering the Human Germline: An Exploration of the Science and Ethics of Altering the Genes We Pa.s.s to Our Children Engineering the Human Germline: An Exploration of the Science and Ethics of Altering the Genes We Pa.s.s to Our Children (New York: Oxford University Press, 2000). (New York: Oxford University Press, 2000).

62. 62. As the Scripps Research Inst.i.tute points out, "The ability to dedifferentiate or reverse lineage-committed cells to multipotent progenitor cells might overcome many of the obstacles a.s.sociated with using ESCs and adult stem cells in clinical applications (inefficient differentiation, rejection of allogenic cells, efficient isolation and expansion, etc.). With an efficient dedifferentiation process, it is conceivable that healthy, abundant and easily accessible adult cells could be used to generate different types of functional cells for the repair of damaged tissues and organs" (http://www.scripps.edu/chem/ding/sciences.htm) . As the Scripps Research Inst.i.tute points out, "The ability to dedifferentiate or reverse lineage-committed cells to multipotent progenitor cells might overcome many of the obstacles a.s.sociated with using ESCs and adult stem cells in clinical applications (inefficient differentiation, rejection of allogenic cells, efficient isolation and expansion, etc.). With an efficient dedifferentiation process, it is conceivable that healthy, abundant and easily accessible adult cells could be used to generate different types of functional cells for the repair of damaged tissues and organs" (http://www.scripps.edu/chem/ding/sciences.htm) .

The direct conversion of one differentiated cell type into another-a process referred to as transdifferentiation-would be beneficial for producing isogenic [patient's own] cells to replace sick or damaged cells or tissue. Adult stem cells display a broader differentiation potential than antic.i.p.ated and might contribute to tissues other than those in which they reside. As such, they could be worthy therapeutic agents. Recent advances in transdifferentiation involve nuclear transplantation, manipulation of cell culture conditions, induction of ectopic gene expression and uptake of molecules from cellular extracts. These approaches open the doors to new avenues for engineering isogenic replacement cells. To avoid unpredictable tissue transformation, nuclear reprogramming requires controlled and heritable epigenetic modifications. Considerable efforts remain to unravel the molecular processes NOTES 557 underlying nuclear reprogramming and evaluate stability of the changes in reprogrammed cells.Quoted from P. Collas and Anne-Marl Hakelien, "Teaching Cells New Tricks," Trends in Biotechnology Trends in Biotechnology 21.8 (August 2003): 35461; P. Collas, "Nuclear Reprogramming in Cell-Free Extracts," 21.8 (August 2003): 35461; P. Collas, "Nuclear Reprogramming in Cell-Free Extracts," Philosophical Transactions of the Royal Society of London Philosophical Transactions of the Royal Society of London, B 358.1436 (August 29, 2003): 138995.

63. 63. Researchers have converted human liver cells to pancreas cells in the laboratory: Jonathan Slack et al., "Experimental Conversion of Liver to Pancreas," Researchers have converted human liver cells to pancreas cells in the laboratory: Jonathan Slack et al., "Experimental Conversion of Liver to Pancreas," Current Biology Current Biology 13.2 (January 2003): 10515. Researchers reprogrammed cells to behave like other cells using cell extracts; for example, skin cells were reprogrammed to exhibit T-cell characteristics. Anne-Mari Hakelien et al., "Reprogramming Fibroblasts to Express T-Cell Functions Using Cell Extracts," 13.2 (January 2003): 10515. Researchers reprogrammed cells to behave like other cells using cell extracts; for example, skin cells were reprogrammed to exhibit T-cell characteristics. Anne-Mari Hakelien et al., "Reprogramming Fibroblasts to Express T-Cell Functions Using Cell Extracts," Nature Biotechnology Nature Biotechnology 20.5 (May 2002): 46066; Anne-Mari Hakelien and P. Collas, "Novel Approaches to Transdifferentiation," 20.5 (May 2002): 46066; Anne-Mari Hakelien and P. Collas, "Novel Approaches to Transdifferentiation," Cloning Stem Cells Cloning Stem Cells 4.4 (2002): 37987. See also David Tosh and Jonathan M. W. Slack, "How Cells Change Their Phenotype," 4.4 (2002): 37987. See also David Tosh and Jonathan M. W. Slack, "How Cells Change Their Phenotype," Nature Reviews Molecular Cell Biology Nature Reviews Molecular Cell Biology 3.3 (March 2002): 18794. 3.3 (March 2002): 18794.

64. 64. See the description of transcription factors in note 21, above. See the description of transcription factors in note 21, above.

65. 65. R. P. Lanza et al., "Extension of Cell Life-Span and Telomere Length in Animals Cloned from Senescent Somatic Cells," R. P. Lanza et al., "Extension of Cell Life-Span and Telomere Length in Animals Cloned from Senescent Somatic Cells," Science Science 288.5466 (April 28, 2000): 669. See also J. C. Ameisen, "On the Origin, Evolution, and Nature of Programmed Cell Death: A Timeline of Four Billion Years," 288.5466 (April 28, 2000): 669. See also J. C. Ameisen, "On the Origin, Evolution, and Nature of Programmed Cell Death: A Timeline of Four Billion Years," Cell Death and Differentiation Cell Death and Differentiation 9.4 (April 2002): 36793; Mary-Ellen Shay, "Transplantation Without a Donor," 9.4 (April 2002): 36793; Mary-Ellen Shay, "Transplantation Without a Donor," Dream: The Magazine of Possibilities Dream: The Magazine of Possibilities (Children's Hospital, Boston), Fall 2001. (Children's Hospital, Boston), Fall 2001.

66. 66. In 2000 the Immune Tolerance Network (http://www.immunetolerance.org), a project of the National Inst.i.tutes of Health (NIH) and the Juvenile Diabetes Foundation, announced a multicenter clinical trial to a.s.sess the effectiveness of islet transplantation. In 2000 the Immune Tolerance Network (http://www.immunetolerance.org), a project of the National Inst.i.tutes of Health (NIH) and the Juvenile Diabetes Foundation, announced a multicenter clinical trial to a.s.sess the effectiveness of islet transplantation.

According to a clinical-trial research summary (James Shapiro, "Campath-Ifi and One-Year Temporary Sirolimus Maintenance Monotherapy in Clinical Islet Transplantation," http://www.immunetolerance.org/public/clinical/islet/trials/shapiro2.html), "This therapy is not suitable for all patients with Type I diabetes, even if there were no limitation in islet supply, because of the potential long-term risks of cancer, life-threatening infections and drug side-effects related to the antirejection therapy. If tolerance [indefinite graft function without a need for long-term drugs to prevent rejection] could be achieved at minimal up-front risk, then islet transplant could be used safely earlier in the course of diabetes, and eventually in children at the time of diagnosis."

67. 67. "Lab Grown Steaks Nearing Menu," http://www.newscientist.com/news/news.jsp?id=ns99993208, includes discussion of technical issues. "Lab Grown Steaks Nearing Menu," http://www.newscientist.com/news/news.jsp?id=ns99993208, includes discussion of technical issues.

68. 68. The halving time for feature sizes is five years in each dimension. See discussion in chapter 2. The halving time for feature sizes is five years in each dimension. See discussion in chapter 2.

69. 69. An a.n.a.lysis by Robert A. Freitas Jr. indicates that replacing 10 percent of a person's red blood cells with robotic respirocytes would enable holding one's breath for about four hours, which is about 240 times longer than one minute (about the length of time feasible with all biological red blood cells). Since this increase derives from replacing only 10 percent of the red blood cells, the respirocytes are thousands of times more effective. An a.n.a.lysis by Robert A. Freitas Jr. indicates that replacing 10 percent of a person's red blood cells with robotic respirocytes would enable holding one's breath for about four hours, which is about 240 times longer than one minute (about the length of time feasible with all biological red blood cells). Since this increase derives from replacing only 10 percent of the red blood cells, the respirocytes are thousands of times more effective.

70. 70. Nanotechnology is "thorough, inexpensive control of the structure of matter based on molecule-by-molecule control of products and byproducts; the products and processes of molecular manufacturing, including molecular machinery" (Eric Drexler and Chris Peterson, Nanotechnology is "thorough, inexpensive control of the structure of matter based on molecule-by-molecule control of products and byproducts; the products and processes of molecular manufacturing, including molecular machinery" (Eric Drexler and Chris Peterson, Unbounding the Future: The Nanotechnology Revolution Unbounding the Future: The Nanotechnology Revolution [New York: William Morrow, 1991]). According to the authors: [New York: William Morrow, 1991]). According to the authors: Technology has been moving toward greater control of the structure of matter for millennia....[P]ast advanced technologies-microwave tubes, lasers, superconductors, satellites, robots, and the like-have come trickling out of factories, at first with high price tags and narrow applications. Molecular manufacturing, though, will be more like computers: a flexible technology with a huge range of applications. And molecular manufacturing won't come trickling out of conventional factories as computers did; it will replace factories and replace or upgrade their products. This is something new and basic, not just another twentieth-century gadget. It will arise out of twentieth-century trends in science, but it will break the trend-lines in technology, economics, and environmental affairs. [chap. 1]Drexler and Peterson outline the possible scope of the effects of the revolution: efficient solar cells "as cheap as newspaper and as tough as asphalt," molecular mechanisms that can kill cold viruses in six hours before biodegrading, immune machines that destroy malignant cells in the body at the push of a b.u.t.ton, pocket supercomputers, the end of the use of fossil fuels, s.p.a.ce travel, and restoration of lost species. Also see E. Drexler, Engines of Creation Engines of Creation (New York: Anchor Books, 1986). The Foresight Inst.i.tute has a useful list of nanotechnology FAQs (http://www.foresight.org/NanoRev/FIFAQ1.html) and other information. Other Web resources include the National Nanotechnology Initiative (http://www.nano.gov), http://nanotechweb.org, Dr. Ralph Merkle's nanotechnology page (http://www.zyvex.com/nano). and (New York: Anchor Books, 1986). The Foresight Inst.i.tute has a useful list of nanotechnology FAQs (http://www.foresight.org/NanoRev/FIFAQ1.html) and other information. Other Web resources include the National Nanotechnology Initiative (http://www.nano.gov), http://nanotechweb.org, Dr. Ralph Merkle's nanotechnology page (http://www.zyvex.com/nano). and Nanotechnology Nanotechnology, an online journal (http://www.iop.org/EJ/journal/0957-4484). Extensive material on nanotechnology can be found on the author's Web site at http://www.kurzweilAI.net/meme/frame.html?m=18.

71. 71. Richard P. Feynman, "There's Plenty of Room at the Bottom," American Physical Society annual meeting, Pasadena, California, 1959; transcript at http://www.zyvex.com/nanotech/feynman.html. Richard P. Feynman, "There's Plenty of Room at the Bottom," American Physical Society annual meeting, Pasadena, California, 1959; transcript at http://www.zyvex.com/nanotech/feynman.html.

72. 72. John von Neumann, John von Neumann, Theory of Self-Reproducing Automata Theory of Self-Reproducing Automata, A. W. Burks, ed. (Urbana: University of Illinois Press, 1966).

73. 73. The most comprehensive survey of kinematic machine replication is Robert A. Freitas Jr. and Ralph C. Merkle, The most comprehensive survey of kinematic machine replication is Robert A. Freitas Jr. and Ralph C. Merkle, Kinematic Self-Replicating Machines Kinematic Self-Replicating Machines (Georgetown, Tex.: Landes Bioscience, 2004), http://www.Moleculara.s.sembler.com/KSRM.htm. (Georgetown, Tex.: Landes Bioscience, 2004), http://www.Moleculara.s.sembler.com/KSRM.htm.

74. 74. K. Eric Drexler, K. Eric Drexler, Engines of Creation Engines of Creation, and K. Eric Drexler, Nanosystems: Molecular Machinery, Manufacturing, and Computation Nanosystems: Molecular Machinery, Manufacturing, and Computation (New York: Wiley Interscience, 1992). (New York: Wiley Interscience, 1992).

75. 75. See the discussion of nanotube circuitry in chapter 3, including the a.n.a.lysis of the potential of nanotube circuitry in note 9 of that chapter. See the discussion of nanotube circuitry in chapter 3, including the a.n.a.lysis of the potential of nanotube circuitry in note 9 of that chapter.

76. 76. K. Eric Drexler and Richard E. Smalley, "Nanotechnology: Drexler and Smalley Make the Case for and Against 'Molecular a.s.semblers,' " K. Eric Drexler and Richard E. Smalley, "Nanotechnology: Drexler and Smalley Make the Case for and Against 'Molecular a.s.semblers,' " Chemical and Engineering News Chemical and Engineering News, November 30, 2003, http://pubs.acs.org/cen/coverstory/8148/8148counterpoint.html.

77. 77. Ralph C. Merkle, "A Proposed 'Metabolism' for a Hydrocarbon a.s.sembler," Ralph C. Merkle, "A Proposed 'Metabolism' for a Hydrocarbon a.s.sembler," Nanotechnology Nanotechnology 8 (December 1997): 14962, http://www.iop.org/EJ/abstract/0957-4484/8/4/001 or http://www.zyvex.com/nanotech/hydroCarbonMetabolism.html. See also Ralph C. Merkle, "Binding Sites for Use in a Simple a.s.sembler," 8 (December 1997): 14962, http://www.iop.org/EJ/abstract/0957-4484/8/4/001 or http://www.zyvex.com/nanotech/hydroCarbonMetabolism.html. See also Ralph C. Merkle, "Binding Sites for Use in a Simple a.s.sembler," Nanotechnology Nanotechnology 8 (1997): 2328, http://www.zyvex.com/nanotech/bindingSites.html; Ralph C. Merkle, "A New Family of Six Degree of Freedom Positional Devices," 8 (1997): 2328, http://www.zyvex.com/nanotech/bindingSites.html; Ralph C. Merkle, "A New Family of Six Degree of Freedom Positional Devices," Nanotechnology Nanotechnology 8 (1997): 4752, http://www.zyvex.com/nanotech/6dof.html; Ralph C. Merkle, "Casing an a.s.sembler," 8 (1997): 4752, http://www.zyvex.com/nanotech/6dof.html; Ralph C. Merkle, "Casing an a.s.sembler," Nanotechnology Nanotechnology 10 (1999): 31522, http://www.zyvex.com/nanotech/casing; Robert A. Freitas Jr., "A Simple Tool for Positional Diamond Mechanosynthesis, and Its Method of Manufacture," U.S. Provisional Patent Application No. 60/543,802, filed February 11, 2004, process described in lecture at http://www.Moleculara.s.sembler.com/Papers/PathDiamMolMfg.htm; Ralph C. Merkle and Robert A. Freitas Jr., "Theoretical a.n.a.lysis of a Carbon-Carbon Dimer Placement Tool for Diamond Mechanosynthesis," 10 (1999): 31522, http://www.zyvex.com/nanotech/casing; Robert A. Freitas Jr., "A Simple Tool for Positional Diamond Mechanosynthesis, and Its Method of Manufacture," U.S. Provisional Patent Application No. 60/543,802, filed February 11, 2004, process described in lecture at http://www.Moleculara.s.sembler.com/Papers/PathDiamMolMfg.htm; Ralph C. Merkle and Robert A. Freitas Jr., "Theoretical a.n.a.lysis of a Carbon-Carbon Dimer Placement Tool for Diamond Mechanosynthesis," Journal of Nanoscience and Nanotechnology Journal of Nanoscience and Nanotechnology 3 (August 2003): 31924, http://www.rfreitas.com/Nano/JNNDimerTool.pdf; Robert A. Freitas Jr. and Ralph C. Merkle, "Merkle-Freitas Hydrocarbon Molecular a.s.sembler; in 3 (August 2003): 31924, http://www.rfreitas.com/Nano/JNNDimerTool.pdf; Robert A. Freitas Jr. and Ralph C. Merkle, "Merkle-Freitas Hydrocarbon Molecular a.s.sembler; in Kinematic Self-Replicating Machines Kinematic Self-Replicating Machines, section 4.11.3 (Georgetown, Tex.: Landes Bioscience, 2004), pp. 13035, http://www.Moleculara.s.sembler.com/KSRM/4.11.3.htm.

78. 78. Robert A. Freitas Jr., Robert A. Freitas Jr., Nanomedicine Nanomedicine, vol. 1, Basic Capabilities Basic Capabilities, section 6.3.4.5, "Chemoelectric Cells" (Georgetown, Tex.: Landes Bioscience, 1999), pp. 15254, http://www.nanomedicine.com/NMI/6.3.4.5.htm; Robert A. Freitas Jr., Nanomedicine Nanomedicine, vol. 1, Basic Capabilities Basic Capabilities, section 6.3.4.4, "Glucose Engines" (Georgetown, Tex.: Landes Bioscience, 1999), pp. 149-52, http://www.nanomedicine.com/NMI/6.3.4.4.htm; K. Eric Drexler, Nanosystems: Molecular Machinery, Manufacturing, and Computation Nanosystems: Molecular Machinery, Manufacturing, and Computation, section 16.3.2, "Acoustic Power and Control" (New York: Wiley Interscience, 1992), pp. 47276. See also Robert A. Freitas Jr. and Ralph C. Merkle, Kinematic Self-Replicating Machines Kinematic Self-Replicating Machines, appendix B.4, "Acoustic Transducer for Power and Control" (Georgetown, Tex.: Landes Bioscience, 2004), pp. 22533, http://www.Moleculara.s.sembler.com/KSRM/AppB.4.htm.

79. 79. The most comprehensive survey of these proposals may be found in Robert A. Freitas Jr. and Ralph C. Merkle, The most comprehensive survey of these proposals may be found in Robert A. Freitas Jr. and Ralph C. Merkle, Kinematic Self-Replicating Machines Kinematic Self-Replicating Machines, chapter 4, "Microscale and Molecular Kinematic Machine Replicators" (Georgetown, Tex.: Landes Bioscience, 2004), pp. 89144, http://www.Moleculara.s.sembler.com/KSRM/4.htm.

80. 80. Drexler, Drexler, Nanosystems Nanosystems, p. 441.

81. 81. The most comprehensive survey of these proposals may be found in Robert A. Freitas Jr. and Ralph C. Merkle, The most comprehensive survey of these proposals may be found in Robert A. Freitas Jr. and Ralph C. Merkle, Kinematic Self-Replicating Machines Kinematic Self-Replicating Machines, chapter 4, "Microscale and Molecular Kinematic Machine Replicators" (Georgetown, Tex.: Landes Bioscience, 2004), pp. 89144, http://www.Moleculara.s.sembler.com/KSRM/4.htm.

82. 82. T. R. Kelly, H. De Silva, and R. A. Silva, "Unidirectional Rotary Motion in a Molecular System," T. R. Kelly, H. De Silva, and R. A. Silva, "Unidirectional Rotary Motion in a Molecular System," Nature Nature 401.6749 (September 9, 1999): 15052. 401.6749 (September 9, 1999): 15052.

83. 83. Carlo Montemagno and George Bachand, "Constructing Nanomechanical Devices Powered by Biomolecular Motors," Carlo Montemagno and George Bachand, "Constructing Nanomechanical Devices Powered by Biomolecular Motors," Nanotechnology Nanotechnology 10 (1999): 22531; George D. Bachand and Carlo D. Montemagno, "Constructing Organic/Inorganic NEMS Devices Powered by Biomolecular Motors," 10 (1999): 22531; George D. Bachand and Carlo D. Montemagno, "Constructing Organic/Inorganic NEMS Devices Powered by Biomolecular Motors," Biomedical Microdevices Biomedical Microdevices 2.3 (June 2000): 17984. 2.3 (June 2000): 17984.

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85. 85. Berkeley Lab, "A Conveyor Belt for the Nano-Age," April 28, 2004, http://www.lbl.gov/Science-Articles/Archive/MSD-conveyor-belt-for-nanoage.html. Berkeley Lab, "A Conveyor Belt for the Nano-Age," April 28, 2004, http://www.lbl.gov/Science-Articles/Archive/MSD-conveyor-belt-for-nanoage.html.

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