The Singularity Is Near: When Humans Transcend Biology (105 page)

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 analysis, RNAi is rapidly being applied to study the function of many genes associated with human disease, in particular those associated with oncogenesis and infectious disease.” J. C. Cheng, T. B. Moore, and K. M. Sakamoto, “RNA Interference and Human Disease,”
Molecular Genetics and Metabolism
80.1–2 (October 2003): 121–28. RNAi is a “potent and highly sequence-specific mechanism.” L. Zhang, D. K. Fogg, and D. M. Waisman, “RNA Interference-Mediated Silencing of the S100A10 Gene Attenuates Plasmin Generation and Invasiveness of Colo 222 Colorectal Cancer Cells,”
Journal of Biological Chemistry
279.3 (January 16, 2004): 2053–62.

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,”
Science
286.5439 (October 15, 1999): 444–47.

24.
Ibid.

25.
J. Rosamond and A. Allsop, “Harnessing the Power of the Genome in the Search for New Antibiotics,”
Science
287.5460 (March 17, 2000): 1973–76.

26.
T. R. Golub et al., “Molecular Classification of Cancer: Class Discovery and Class Prediction by Gene Expression Monitoring,”
Science
286.5439 (October 15, 1999): 531–37.

27.
Ibid., as reported in A. Berns, “Cancer: Gene Expression in Diagnosis,”
Nature
403 (February 3, 2000): 491–92. In another study, 1 percent of the genes studied showed reduced expression in aged muscles. These genes produced proteins associated with energy production and cell building, so a reduction makes sense given the weakening associated 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
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
114.2 (October 2003): 251.

As a final example, researchers have had difficulty analyzing 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
94.2 (July 15, 1999): 411–16.

28.
T. Ueland et al., “Growth Hormone Substitution 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
33.4 (October 2003): 638–45.

29.
R. Lovett, “Toxicologists Brace for Genomics Revolution,”
Science
289.5479 (July 28, 2000): 536–37.

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 passing 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.
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/gene therapy.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 associations dedicated to this topic.

32.
K. R. Smith, “Gene Transfer in Higher Animals: Theoretical Considerations and Key Concepts,”
Journal of Biotechnology
99.1 (October 9, 2002): 1–22.

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

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

35.
Sylvia Westphal, “DNA Nanoballs Boost Gene Therapy,” May 12, 2002,
http://www.newscientist.com/news/news.jsp?id=ns99992257
.

36.
L. Wu, M. Johnson, and M. Sato, “Transcriptionally Targeted Gene Therapy to Detect and Treat Cancer,”
Trends in Molecular Medicine
9.10 (October 2003): 421–29.

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

38.
G. Chiesa, “Recombinant Apolipoprotein A-I(Milano) Infusion into Rabbit Carotid Artery Rapidly Removes Lipid from Fatty Streaks,”
Circulation Research
90.9 (May 17, 2002): 974–80; 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
103.25 (June 26, 2001): 3047–50.

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,”
JAMA
290.17 (November 5, 2003): 2292–2300.

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,”
New England Journal of Medicine
350.15 (April 8, 2004): 1505–15,
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.
O. J. Finn, “Cancer Vaccines: Between the Idea and the Reality,”
Nature Reviews: Immunology
3.8 (August 2003): 630–41; R. C. Kennedy and M. H. Shearer, “A Role for Antibodies in Tumor Immunity,”
International Reviews of Immunology
22.2 (March–April 2003): 141–72.

42.
T. F. Greten and E. M. Jaffee, “Cancer Vaccines,”
Journal of Clinical Oncology
17.3 (March 1999): 1047–60.

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,”
Journal of Clinical Oncology
19.1 (January 1, 2001): 145–56.

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?”
Nature Medicine
6 (March 2000): 252–53.

45.
J. D. Lewis, B. D. Reilly, and R. K. Bright, “Tumor-Associated Antigens: From Discovery to Immunity,”
International Reviews of Immunology
22.2 (March–April 2003): 81–112.

46.
T. Boehm et al., “Antiangiogenic Therapy of Experimental Cancer Does Not Induce Acquired Drug Resistance,”
Nature
390.6658 (November 27, 1997): 404–7.

47.
Angiogenesis Foundation, “Understanding Angiogenesis,”
http://www.angio.org/understanding/content_understanding.html
; L. K. Lassiter and M. A. Carducci, “Endothelin Receptor Antagonists in the Treatment of Prostate Cancer,”
Seminars in Oncology
30.5 (October 2003): 678–88. For an explanation of the process, see the National Cancer Institute Web site, “Understanding Angiogenesis,”
http:// press2.nci.nih.gov/sciencebehind/angiogenesis/angio02.htm
.

48.
I. B. Roninson, “Tumor Cell Senescence in Cancer Treatment,”
Cancer Research
63.11 (June 1, 2003): 2705–15; B. R. Davies et al., “Immortalization of Human Ovarian Surface Epithelium with Telomerase and Temperature-Sensitive
SV40 Large T Antigen,”
Experimental Cell Research
288.2 (August 15, 2003): 390–402.

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,”
Journal of Anti-Aging Medicine
6.1 (Spring 2003): 29–39. See also notes 18 and 19.

50.
Aubrey D. N. J. de Grey, “The Reductive Hotspot Hypothesis of Mammalian Aging: Membrane Metabolism Magnifies Mutant Mitochondrial Mischief,”
European Journal of Biochemistry
269.8 (April 2002): 2003–9; P. F. Chinnery et al., “Accumulation of Mitochondrial DNA Mutations in Ageing, Cancer, and Mitochondrial Disease: Is There a Common Mechanism?”
Lancet
360.9342 (October 26, 2002): 1323–25; A. D. de Grey, “Mitochondrial Gene Therapy: An Arena for the Biomedical Use of Inteins,”
Trends in Biotechnology
18.9 (September 2000): 394–99.

51.
“The notion of ‘vaccinating’ individuals against a neurodegenerative disorder such as Alzheimer’s disease is a marked departure from classical 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
420.6917 [December 19–26, 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
48.4 (October 2000): 567–79.

52.
S. Vasan, P. Foiles, and H. Founds, “Therapeutic Potential of Breakers of Advanced Glycation End Product-Protein Crosslinks,”
Archives of Biochemistry and Biophysics
419.1 (November 1, 2003): 89–96; D. A. Kass, “Getting Better Without AGE: New Insights into the Diabetic Heart,”
Circulation Research
92.7 (April 18, 2003): 704–6.

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

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,”
Natural Computing, an International Journal
2.1 (January 2003): 47–84.

55.
S. L. Garfinkel, “Biological Computing,”
Technology Review
(May–June 2000),
http://static.highbeam.com/t/technologyreview/may012000/
biologicalcomputing
.

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

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,”
Nature Genetics
31.2 (June 2002): 216–20.