Part 33 (1/2)

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 lnature/dna50/watsoncrick.pdf. 171.4356 (April 23, 1953): 73738, lnature/dna50/watsoncrick.pdf.

4. 4. Robert Waterston quoted in ”Scientists Reveal Complete Sequence of Human Genome,” CBC News, April 14, 2003, Robert Waterston quoted in ”Scientists Reveal Complete Sequence of Human Genome,” CBC News, April 14, 2003,

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 /nature/focus/crick/index.html. (New York: Atheneum, 1968). Nature.com has a collection of Crick's papers available online at /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 . (New York: Rodale, 2004). See .

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), .For information on the H-scan test, see Diagnostic and Lab Testing, Longevity Inst.i.tute, Dallas, /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), .For information on the H-scan test, see Diagnostic and Lab Testing, Longevity Inst.i.tute, Dallas, /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 /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, /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-Relations.h.i.+p 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-Relations.h.i.+p 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, 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, 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,” mon 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,” /news/news.jsp?id=ns99993520. Anil Ananthaswamy, ”Undercover Genes Slip into the Brain,” March 20, 2003, /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.