Endnotes Chapters 1,2,3,4,5

Chapter 1
1 A. M. Cunningham. 2003. “BioBots.” ScienCentralNews; www.sciencentral.com/articles/view.php3?
article_id5218391960&language5English; A. Moore. 2001. “Of silicon and submarines.” EMBO Reports. 2(5): 367–370; www.nature.com/cgi-taf/DynaPage.taf?file5/embor/journal/v2/n5/full/embor411.html.
2 “Purdue researchers connect life’s blueprints with its energy source.” Purdue News, February 4, 2003; http://news.uns.purdue.edu/html4ever/030204.Guo.ATP.html.
3 “Today at UCI.” May 8, 2003; http://today.uci.edu/news/release_detail.asp?key5995.
4 R. Kurzweil. “The Law of Accelerating Returns.” KurzweilAI.net. www.kurzweilai.net/
meme/frame.html?main5/articles/art0134.html; R. Kurzweil. 2005 (upcoming). The Singularity Is Near: When Humans Transcend Biology. New York: Viking Press.
5 Ray Kurzweil’s theory of the “law of accelerating returns,” and its social and economic impact, was introduced in The Age of Spiritual Machines (Viking, 1999) and will be further explored in his upcoming book The Singularity Is Near: When Humans Transcend Biology (Viking, 2005).
6 R. N. Anderson. The Ten Leading Causes of Death in the U.S., Final 2000 Data. Heart Disease: 710,760, Cancer: 553,091, Stroke: 167661, Chronic Lower Respiratory Disease: 122,009, Accidents: 97,900, Diabetes: 69,301, Pneumonia/Influenza: 65,313, Alzheimer’s Disease: 49,558, Nephritis, nephrotic syndrome, and nephrosis: 37,251, Septicemia: 31,224.
7 J. C. Riley. 2001. Rising Life Expectancy: A Global History. Cambridge: Cambridge University Press.
8 F. Fukuyama. 2002. Our Posthuman Future: Consequences of the Biotechnology Revolution. New York: Farrar Straus.
9 The U.S. Department of Agriculture’s “Food Pyramid” can be viewed at www.nal.usda.gov:
8001/py/pmap.htm. The emphasis on starches and grains at the base of the pyramid has been linked with the current “epidemic” of obesity plaguing our country.
10 R. N. Anderson. National Vital Statistics Report, 2002 (Sept 16);50:16: 1–86. Also, according to the Minneapolis Heart Institute Foundation, “Approximately two-thirds of heart attacks are first heart attacks and one-third of all heart attacks are fatal. The first symptom of heart attack is often sudden death.” See www.mplsheartfoundation.org.
11 L. A. Ries et al., eds. SEER Cancer Statistics Review, 1973–1999, National Cancer Institute, Bethesda, Maryland. For example, the Alliance for Lung Cancer Fact Sheet states that, due to a lack
of screening, lung cancer is diagnosed in the late stages up to 85 percent of the time; www.alcase.org/factsabout_lungcancer.html. Late-stage diagnosis occurs in close to half of all cervical cancer occurrences. J. M. Ferrante et al. 2000. “Clinical and Demographic Predictors of Late-Stage Cervical Cancer, Arch Fam Med. 9: 439–445. And, over 50 percent of all cases of ovarian cancer are diagnosed in late stages. A. Srikameswaran. “Experts discuss promising new test for ovarian cancer.” Pittsburgh Post-Gazette. May 7, 2002.
12 The Recommended Dietary Allowances were first issued in 1968 by the National Academy of Sciences and were last revised in 1989. These standards vary depending on age, gender, and whether a woman is pregnant or lactating. They are not designed to be “optimal” but rather to avoid specific nutritional deficiency diseases. They are expressed as average daily intakes over time. They rely on dietary sources rather than vitamin or mineral supplementation, and do not account for unusual requirements due to
disease or environmental stress. See www.blionline.com/HDB/NutritionalStandardsRDAUSRDAAnd
RDIAntioxidantsBooklet.htm.
13 O. W. Rasmussen et al. 1993. “Effects on blood pressure, glucose and lipid levels of a high-monounsaturated fat diet compared with a high-carbohydrate diet in NIDDM subjects.” Diabetes Care. 16: 1565–1571.
14 On the Web site for the American Diabetes Association is found the “Diabetic Food Pyramid.” Interestingly, it is essentially identical to the Department of Agriculture’s Food Pyramid recommended for the general public. The same reliance on a starch- and grain-based diet with 30 percent of calories coming from fat is recommended. See www.diabetes.org/main/health/nutrition/article031799.jsp.
15 D. Ornish. “Can lifestyle changes reverse coronary heart disease?” 1990. Lancet. 336: 129–133.
16 E. G. Vermeulen et al. 2000. “Effect of homocysteine-lowering treatment with folic acid plus vitamin B6 on progression of sub clinical atherosclerosis: a randomized, placebo-controlled trial.” Lancet. Feb 12;355(9203): 517–522. Also, in an editorial accompanying A. D. Korczyn. 2002. “Homocysteine, Stroke, and Dementia,” Stroke. 33: 2343–2344, Dr. Korczyn of Tel-Aviv University Medical School in Ramat-Aviv, Israel, says, “Since dietary habits are so different among people, it may be appropriate to recommend 2 to 5 mg folic acid and a similar dose of vitamin B12 daily. This recommendation is based on the known safety of both vitamins, which do not have side effects even if used in excessive amounts, and their low cost.”

Chapter 2
1 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.” (E. Drexler and C. Peterson. 1991. Unbounding the Future: The Nanotechnology Revolution. New York: William Morrow and Company.) According to the authors (chapter 1): “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.”
Drexler and Peterson outline the following possible scenarios to explain the scope 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 button, pocket supercomputers, the end of the use of fossil fuels, space travel, and restoration of lost species. Also see another book by K. E. Drexler, Engines of Creation (Anchor Books, 1986). Foresight Institute has a useful list of nanotechnology FAQs (www.foresight.org/NanoRev/FIFAQ1.html) and other information. Other Web resources include the National Nanotechnology Initiative (www.nano.gov), www.
nanotechweb.org, Dr. Ralph Merkle’s Nanotechnology page (www.zyvex.com/nano/), and Nanotechnology (an online journal: www.iop.org/EJ/journal/0957-4484).
Extensive material on nanotechnology can be found on Ray Kurzweil’s Web site, www.kurzweilai.net.
2 Nanotechnology is technology in which objects are built from individual atoms or molecules, or where one or more dimensions are on a scale of nanometers (billionths of meter). For further information, see K. E. Drexler’s 1986 classic Engines of Creation; www.kurzweilai.net/meme/frame.html?m58.
3 Besides the functions of different types of cells, two other causes 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, for example, can turn off the synthesis of proteins that allow it to fix 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. 1999. “An array of uses: expression patterns in strawberries, Ebola, TB, and mouse cells.” Science. 286(5439): 445).
4 Along with a protein-encoding region, genes include regulatory sequences called promoters and enhancers that control where and when that gene is expressed. Promoters are located “upstream” (on base pairs nearby the transcription site) on the DNA molecule. An enhancer activates a promoter, thereby controlling the rate of gene expression. To be expressed, most genes require enhancers; enhancers determine when genes are expressed and for which target protein cell type. Each gene can have several different enhancer sites linked to it (S. F. Gilbert. 2000. Developmental Biology, 6th ed. Sunderland, Massachusetts: Sinauer Associates; searchable online at www.ncbi.nlm.nih.gov/books/bv.fcgi?call5bv.View..ShowTOC&rid5dbio.TOC&depth52.
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 S. F. Gilbert in the chapter “The Genetic Core of Development: Differential Gene Expression,” “The gene itself is no longer seen as an independent entity 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 massage it, twist it and, on occasion, reinvent it before the grand blueprint of the body can make any sense at all.’”
5 Many antisense RNAs “have shown convincing in vitro reduction in target gene expression and promising activity against a wide variety of tumors.” A. Biroccio, C. Leonetti, and G. Zupi. 2003. “The future of antisense therapy: combination with anticancer treatments.” Oncogene. Sep 29;22(42): 6579–6588. See also “Subtle gene therapy tackles blood disorder.” October 11, 2002, NewScientist.com; www.
newscientist.com/news/news.jsp?id-ns99992915; X. Jiang et al. 2003. “Inhibition of MMP-1 expression by antisense RNA decreases invasiveness of human chrondrosarcoma.” J Orthop Res. Nov;21(6): 1063–1070.
6 B. Holmes. “Gene therapy may switch off Huntington’s.” NewScientist.com, March 13, 2003; www.newscientist.com/news/news.jsp?id5ns99993493.
“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. 2003. “RNA interference and human disease.” Mol Genet Metab. Oct;80(1–2): 121–128. RNAi is a “potent and highly sequence-specific mechanism” (L. Zhang, D. K. Fogg, and D. M. Waisman. 2003. “RNA interference-mediated silencing of the S100A10 gene attenuates plasmin generation and invasiveness of Colo 222 colorectal cancer cells.” J Biol Chem. Oct 21 [e-pub ahead of print]).
7 Gene transfer to somatic cells affects a subset of cells in the body for a period of time. It is theoretically possible to also 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.
8 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,” 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 associations dedicated to this topic.
9 K. Smith. 2002. “Gene transfer in higher animals: theoretical considerations and key concepts.” J Biotechnol. Oct 9;99(1): 1–22.
10 “‘Miracle’ gene therapy trial halted.” NewScientist.com, October 3, 2003; www.newscientist.
com/news/news.jsp?id5ns99992878; Human Genome Project. “Gene therapy,” www.ornl.gov/
TechResources/Human_Genome/medicine/genetherapy.html.
11 L. Wu, M. Johnson, and M. Sato. 2003. “Transcriptionally targeted gene therapy to detect and treat cancer.” Trends Mol Med. Oct;9(10): 421–429.
12 S. Westphal. “Virus synthesized in a fortnight.” NewScientist.com, November 14, 2003; www.
newscientist.com/news/news.jsp?id5ns99994383.
13 A. Ananthaswamy. “Undercover genes slip into the brain.” NewScientist.com, March 20, 2003; www.newscientist.com/news/news.jsp?id5ns99993520.
14 A. E. Trezise et al. 2003. “In vivo gene expression: DNA electrotransfer.” Curr Opin Mol Ther. Aug;5(4): 397–404.
15 S. Westphal. “DNA nanoballs boost gene therapy.” NewScientist.com, May 12, 2002; www.
newscientist.com/news/news.jsp?id5ns99992257.
16 B. Dekel et al. 2003. “Human and porcine early kidney precursors as a new source for transplantation.” Nature Med. Jan 1;(9): 53–60.
17 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.” “Genetic defects may
explain cloning failures.” CBCNews, May 27, 2002; www.cbc.ca/storview/CBC/2002/05/27/
cloning_errors020527. That story reports on F. Xue et al. 2002. “Aberrant patterns of X chromosome inactivation in bovine clones.” Nat Genet. Jun;31(2): 216–220.
18 J. B. Gurdon and A. Colman. 1999. “The future of cloning.” Nature. 402: 743–746; G. Stock and J. Campbell, eds. 2000. Engineering the Human Germline: An Exploration of the Science and Ethics of Altering the Genes We Pass to Our Children. New York: Oxford University Press.
19 W. S. Hwang. 2004. “Evidence of a Pluripotent Human Embryonic Stem Cell Line Derived from a Cloned Blastocyst.” Science. Mar 12;303(5664): 1669–1674.
20 G. Vince. “Nanotechnology may create new organs.” NewScientist.com, July 8, 2003; www.
newscientist.com/news/news.jsp?id5ns99993916.
21 S. Westphal. “‘Virgin birth’ method promises ethical stem cells.” NewScientist.com, April 3, 2003; www.newscientist.com/news/news.jsp?id5ns99993654.
22 Liver stem cells have been transformed into pancreatic cells (L. Yang et al. 2002. “In vitro trans-differentiation of adult hepatic stem cells into pancreatic endocrine hormone-producing cells.” Proc Natl Acad Sci USA. Jun 11;99(12): 8078–8083). Adult muscle stem cells can be transformed into muscle, neural tissue, and blood vessels. Z. Qu-Petersen et al. 2002. “Identification of a novel population of muscle stem cells in mice: potential for muscle regeneration.” J Cell Biol. May;157: 851–864.
23 A. M. Hakelien et al. 2002. “Reprogramming fibroblasts to express T-cell functions using cell extracts.” Nature Biotechnology. May;20: 460–466.
24 See the description of transcription factors in note 3, page 380.
25 R. P. Lanza et al. 2000. “Extension of cell life-span and telomere length in animals cloned from senescent somatic cells.” Science. Apr 28;288(5466): 665–669. See also J. C. Ameisen. 2002. “On the origin, evolution, and nature of programmed cell death: a timeline of four billion years.” Cell Death & Differentiation. Apr;9(4): 367–393; M. E. Shay. “Transplantation without a donor.” Dream: The magazine of possibilities, Children’s Hospital Boston, Fall 2001; www.childrenshospital.org/about/dreamfall01.pdf.
26 S. Bhattacharya. “Stem cell ‘immortality’ gene found.” NewScientist.com, May 30, 2003; www.
newscientist.com/news/news.jsp?id5ns99993786.
27 A. D. de Grey. 2003. “The foreseeability of real anti-aging medicine: focusing the debate.” Exp Gerontol. Sep;38(9): 927–934; A. D. de Grey. 2003. “An engineer’s approach to the development of real anti-aging medicine.” Sci SAGE KE. Jan 8;2003(1): VP1; A. D. de Grey et al. 2002. “Is human aging still mysterious enough to be left only to scientists?” Bioessays. Jul;24(7): 667–676.
28 A. D. de Grey. “Engineering negligible senescence: rational design of feasible, comprehensive rejuvenation biotechnology,” at www.gen.cam.ac.uk/sens/sensov.ppt.
29 A. D. de Grey et al. 2004. “Total deletion of in vivo telomere elongation capacity: an ambitious but possibly ultimate cure for all age-related human cancers.” Annals NY Acad Sci. 1019: 147–170.
30 O. J. Finn. 2003. “Cancer vaccines: between the idea and the reality.” Nat Rev Immunol. Aug;3(8): 630–641; R. C. Kennedy and M. H. Shearer. 2003. “A role for antibodies in tumor immunity.” Int Rev Immunol. Mar–Apr;22(2): 141–172.
31 A. D. de Grey. 2002. “The reductive hotspot hypothesis of mammalian aging: membrane metabolism magnifies mutant mitochondrial mischief.” Eur J Biochem. Apr;269(8): 2003–2009; P. F. Chinnery et al. 2002. “Accumulation of mitochondrial DNA mutations in ageing, cancer, and mitochondrial disease: is there a common mechanism?” Lancet. Oct 26;360(9342): 1323–1235; A. D. de Grey. 2000. “Mitochondrial gene therapy: an arena for the biomedical use of inteins.” Trends Biotechnol. Sep;18(9): 394–399.
32 S. Graham. “Methuselah worm remains energetic for life.” ScientificAmerican.com, October 27, 2003; www.sciam.com/article.cfm?chanID5sa003&articleID5000C601F-8711-1F99-86FB83414B7F0156.
33 P. Ball and H. Pearson. “Drug may give cells a fresh start.” Nature Science Update, January 30, 2004; www.nature.com/nsu/040126/040126-14.html.
34 H. Pearson. “Instant stem cells—just add water.” Nature Science Update, December 19, 2003; www.nature.com/nsu/031215/031215-11.html.
35 R. A. Freitas Jr. Nanomedicine, Volume I: Basic Capabilities, first in an anticipated four-volume Nanomedicine technical book series. Freitas offers a pioneering and fascinating glimpse into a molecular-nanotechnology future with far-reaching implications for the medical profession—and ultimately for the radical improvement and extension of natural human biological structure and function.
36 Sensors and diagnostic tools are important applications of nanotechnology because the devices can be placed in direct contact with cells and the molecules in it. Another option is nanoimaging, in which nanocrystals would seek out different types of molecules, such as cancer cells. When stimulated by a laser, the crystals would emit light. These applications are just the “tip of the nano-iceberg” (P. Balasubramanian and S. Japa. 2003. “Nanosensing,” Stanford Biomedicine Quarterly. Spring, p. 13).
37 For activities of the International Society for BioMEMS and Biomedical Nanotechnology, see its site (www.bme.ohio-state.edu/isb/). You can also find BioMEMS conferences listed on the SPIE site (www.spie.org/Conferences).
38 As reported in the Stanford Biomedicine Quarterly article in note 36 above, researchers used a gold nanoparticle to monitor blood sugar in diabetics. Y. Xiao et al. 2003. “‘Plugging into enzymes’: Nanowiring of redox enzymes by a gold nanoparticle.” Science. Mar 21;299(5614): 1877–1881. “One might even speculate on the design of an ‘artificial pancreas,’ an implant that would release appropriate levels of insulin into the blood from moment to moment according to the blood sugar readings provided by this nanosensor system” (p. 12).
39 Dr. Michael Cima at MIT is one researcher examining in vivo drug release from implantable MEMS arrays. He is one of the authors on G. Voskerician et al. 2002. “Biocompatibility and biofouling of MEMS drug delivery devices.” Biomaterials. 24: 1959–1967.
40 According to Wise, one reason for relatively slow advances over the past thirty years is because of the “aggressive saltwater environment” of living tissue. (Quoted in D. Lammers. “Micro medical devices could transform health care.” EE Times, June 21, 2002; www.eetimes.com/at/news/OEG20020620S0060.) See also the discussion of Wise’s work in J. DeGaspari. “Tiny, tuned, and unattached.” Mechanical Engineering, July 1, 2001; www.memagazine.org/backissues/july01/features/tinytune/tinytune.html.
41 “A team of scientists from Japan have developed tiny spinning screws that can swim along veins. The screws could then be used to ferry drugs to infected tissues or even burrow into tumours to kill them off with a hot lance.” “‘Microbots’ hunt down disease.” BBC News, June 13, 2001; http://news.bbc.co.uk/1/hi/health/1386440.stm. The micromachines are based on cylindrical magnets. (K. Ishiyama, M. Sendoh, and K. I. Arai. 2002. “Magnetic micromachines for medical applications.” J Magnetism Magnetic Materials. 242–245(P1): 41–46.)
42 See the Sandia National Laboratories August 15, 2001, press release “Pac-Man-like microstructure interacts with red blood cells,” www.sandia.gov/media/NewsRel/NR2001/gobbler.htm. For an industry trade article in response, see D. Wilson. “Microteeth have a big bite.” August 17, 2001; www.
e4engineering.com/item.asp?ch5e4_home&type5Features&id542543.
43 P. Ball. “Chemists build body fluid battery.” Nature Science Update, November 12, 2002; www.
nature.com/nsu/021111/021111-1.html.
44 M. Bernstein. “Tiny nanowire could be next big diagnostic tool for doctors.” EurekAlert, December 16, 2003; www.eurekalert.org/pub_releases/2003-12/acs-nc121603.php.
45 J. Sliwa. Researchers envision intelligent implants.” EurekAlert, July 8, 2003; www.eurekalert.org/pub_releases/2003-07/asfm-rei070303.php.
46 J. Whitfield. “Lasers operate inside single cells,” Nature Science Update, October 6, 2003; www.
nature.com/nsu/030929/030929-12.html.
47 Ron Weiss’s home page at Princeton University (www.ee.princeton.edu/~rweiss/) lists his publications, such as 2003. “Genetic circuit building blocks for cellular computation, communications, and signal processing.” Natural Computing, an International Journal. (2): 47–84.
48 S. L. Garfinkel. “Biological computing.” Technology Review, May/June 2000; www.simson.net/
clips/2000.TR.BiologicalComputing.htm.
49 Ibid. See also the list of current research on the MIT Media Lab Web site; www.media.mit.edu/
research/index.html.

Chapter 3
1 Great Smokies Diagnostic Laboratory. “Integrative Medicine,” at www.gsdl.com/gsdl/
functional_med.html.
2 Terry Grossman’s personal experience is by no means unique. In a recent article in JAMA, the official journal of the American Medical Association, 46.3 percent of American people consulted a practitioner of alternative medicine in 1997. (D. M. Eisenberg et al. “Trends in alternative medicine use in the United States, 1990–1997: results of a follow-up national survey.” 1998. JAMA. Nov 11;280(18): 1569–75.)
3 N. M. Bressler et al. 2003. “Potential public health impact of Age-Related Eye Disease Study results: AREDS report no. 11.” Arch Ophthalmol. Nov;121(11): 1621–1624.
4 Approximately 70 percent of Terry Grossman’s macular-degeneration patients have experienced some degree of visual improvement with his treatment protocol, which also includes electrical stimulation of the eyes, while 25 percent stabilized their existing vision. See also E. L. Paul. 2002. “The Treatment of Retinal Diseases with Micro Current Stimulation and Nutritional Supplementation.” Presentation to the International Society for Low-Vision Research and Rehabilitation (ISLRR), Göteborg University, Faculty of Medicine, Göteborg, Sweden; and also L. D. Michael and M. J. Allen. 1993. “Nutritional Supplementation, Electrical Stimulation and Age-Related Macular Degeneration.” J Orthomol Med. 8: 168–171.
5 For further information on the nutritional treatment of autistic disorders, see the DAN! (Defeat Autism Now!) protocols, available through the Autism Research Institute; www.autism.com/ari/
contents.html.

Chapter 4
1 Charles Darwin recognized that one of the primary factors in the size of an animal population is food, which all species require to survive. Species are linked in food chains, starting with producers, which create their own food by converting inorganic compounds into organic compounds. When plants (producers) create organic compounds through photosynthesis, they are storing energy that will then be passed up the food chain as those plants are eaten and then the eaters of those plants are eaten, and so on. Decomposers break down the complex organic compounds created by energy conversion and return the nutrients to the soil, where producers use them once again.
2 Plant cultivation began much sooner than originally thought: there are signs that squash was cultivated in Ecuador and rice in China 10,000 to 11,000 years ago (H. Pringle. 1998. “Neolithic agriculture: the slow birth of agriculture.” Science. 282(5393): 1446–1449). Since then, humans have spread into almost every ecosystem on earth, eating widely ranging diets. Until recently, the maintenance energy required to acquire food was a high proportion of all humans’ energy budgets. One reason may be our brains, which require 20 to 25 percent of our energy needs, compared with 8 to 10 percent for nonhuman primates and 3 to 5 percent for other mammals. Animals with larger brains typically seek richer diets (W. Leonard. 2002. “Food for thought: dietary change was a driving force in human evolution.” Sci Am. Nov 13: 106–115).
Many researchers see a link between obesity in developed countries and the amount of energy that humans have, until recently, spent on food acquisition. “It’s only been maybe the last 30 years, certainly after the Industrial Revolution, since food stopped being scarce,” says Ann Kelley, a neuroscientist at the University of Wisconsin at Madison. “No way have the brain and the physiological systems that regulate body weight had a chance to catch up.” (C. T. Hall. “Caveman history blamed for U.S. obesity.” San Francisco Chronicle, January 12, 2003.)
3 According to the U.S. Department of Agriculture (“A history of American agriculture 1776–1990,” www.usda.gov/history2/text3.htm), in 1790, farmers made up 90 percent of the labor force in a population of almost 4 million. By 1840, that percentage dropped to 69 percent. By 1900, out of a population of 76 million, 38 percent of the labor force worked on farms, which averaged 147 acres in size. By 1990, only 2.6 percent of the labor force worked on farms, which averaged 460 acres in size, out of a total U.S. population of 246 million.
4 In 2000, the Centers for Disease Control (CDC) defined poor nutrition and lack of exercise as the second leading “actual” cause of death in the United States, behind tobacco. “Actual causes of death are defined as lifestyle and behavioral factors such as smoking and physical inactivity that contribute to this nation’s leading killers including heart disease, cancer and stroke” (“Physical Inactivity and Poor Nutrition Catching up to Tobacco as Actual Cause of Death.” March 9, 2004; www.cdc.gov/od/oc/media/pressrel/fs040309.htm). In that same year, “fewer than one-fourth of U.S. adults reported eating recommended amounts of fruits and vegetables daily.” (“Chronic disease prevention: the burden of chronic diseases and their risk factors.” National Center for Chronic Disease Prevention and Health Promotion; www.cdc.gov/nccdphp/burdenbook2002/
03_nutriadult.htm.)
5 The producers at the bottom of a food chain build complex energy-rich compounds from four atoms (carbon, nitrogen, oxygen, and hydrogen). For example, proteins are chains of amino acids, each of which contains an amino group (NH2) and a carboxyl group (COOH). Proteins are broken down into their amino acids during digestion, and these amino acids pass into your bloodstream, from which they are absorbed by cells. Your body uses 20 out of the approximately 100 amino acids in nature as building blocks.
Plants also produce carbohydrates, which your cells absorb and convert into energy to drive all your bodily functions. Glucose, composed of six carbon atoms and six water molecules, is one of the simplest carbohydrates so it can pass directly into the bloodstream. More complex carbohydrates, made up of chains of glucose molecules, need to be broken down into glucose molecules before they can be absorbed. Hydrolysis is the enzymatic reaction that breaks chemical bonds in food through the addition of water.
6 “The apparent simplicity of the water molecule belies the enormous complexity of its interactions with other molecules, including other water molecules” (A. Soper. 2002. “Water and ice.” Science. 297: 1288–1289). There is much that is still up for debate, as shown by the numerous articles still being published about this most basic of molecules, H2O. For example, D. Klug. 2001. “Glassy water.” Science. 294: 2305–2306; P. Geissler et al. 2001. “Autoionization in liquid water.” Science 291(5511): 2121–2124; J. K. Gregory et al. 1997. “The water dipole moment in water clusters.” Science. 275: 814–817; K. Liu et al. 1996. “Water clusters.” Science. 271: 929–933.
A water molecule has slightly negative and slightly positive ends, which means water molecules interact with other water molecules to form networks. The partially positive hydrogen atom on one molecule is attracted to the partially negative oxygen on a neighboring molecule (hydrogen bonding). Three-dimensional hexamers involving six molecules are thought to be particularly stable, though none of these clusters lasts longer than a few picoseconds.
The polarity of water results in a number of anomalous properties. One of the best known is that the solid phase (ice) is less dense than the liquid phase. This is because the volume of water varies with the temperature, and the volume increases by about 9 percent on freezing. Due to hydrogen bonding, water also has a higher-than-expected boiling point.
7 M. S. Jhon. 1989. “Water and health.” Korea Applied Science Research Center for Water, Seoul, Korea. Other articles include M. S. Jhon and J. D. Andrade. 1973. “Water and hydrogels.” J Biomed Mater Res. Nov;7(6): 509–522; and J. D. Andrade et al. 1973. “Water as a biomaterial.” Trans. Am Soc. Artif. Intern Organs. 19: 1–7.
8 The following study cites many benefits from an alkalinizing diet. L. A. Frassetto et al. 1998. “Estimation of net endogenous noncarbonic acid production in humans from diet potassium and protein contents.” Am J Clinical Nutrition. 68: 576–83. “Normal adult humans eating Western diets have chronic, low-grade metabolic acidosis, the severity of which is determined in part by the net rate of endogenous noncarbonic acid production (NEAP), which varies with diet. . . . Normal adult humans eating typical American diets characteristically have chronic, low-grade metabolic acidosis. . . . With advancing age, the severity of diet-dependent acidosis increases independently of diet. That occurs because kidney function ordinarily declines substantially with age, resulting in a condition similar to that of chronic renal insufficiency. Renal insufficiency induces metabolic acidosis by reducing conservation of filtered bicarbonate and excretion of acid. Failure to recognize the respective and independent roles of age-related impaired renal acid-base regulatory capacity and diet net acid load has until recently prevented the recognition that low-grade metabolic acidosis is characteristically present and worsens with age in otherwise healthy adults. . . . Potassium bicarbonate is a natural base that the body generates from the metabolism of organic acid salts of potassium (e.g. potassium citrate) (8), whose density (i.e., mmol K/kJ food item) is greatest in fruit and vegetables. Long-term supplementation of the diet with potassium bicarbonate has numerous anabolic effects. In postmenopausal women, for example, calcium and phosphorus balances improve (1), bone resorption markers decrease (1), bone formation markers increase (1), nitrogen balance improves (9), and serum growth hormone concentrations increase (10). These findings suggest that the adverse effects of chronic, low-grade, diet-dependent acidosis are not inconsequential and may contribute to such age-related disturbances as bone mass decline, osteoporosis, and muscle wasting. One way to reduce or eliminate diet-dependent metabolic acidosis is by eating diets that impose little or no net acid load.”
9 The body maintains the pH of blood at around 7.4. pH. The pH measure, first used by the Danish biochemist S. P. L. Sorensen (1868–1939), expresses the concentration of the hydrogen ion as a number between 1 and 14. A solution with a pH less than 7 is considered acidic, while a solution with a pH of 7 is considered basic, or alkaline. Thus, human blood is slightly alkaline.
“The concentration of H+ in blood plasma and various other body solutions is among the most tightly regulated variables in human physiology. . . . Acute changes in blood pH induce powerful regulatory effects at the level of the cell, organ, and organism” (J. Kellum. 2000. “Determinants of blood pH in health and disease.” Crit. Care. 4: 6–14). In other words, if the pH level changes by even a few tenths of a pH unit, serious problems can result.
Disturbances in the acid-base balance in the blood can cause either acidosis (too much acid, resulting in a decrease in blood pH) or alkalosis (too much base, resulting in an increase in blood pH). There is still much debate regarding how to treat the metabolic disorders that cause these imbalances (see, for example, M. A. Shafiee et al. 2002. “A conceptual approach to the patient with metabolic acidosis.” Nephron. 92 Suppl 1: 46–55).
10 CH3COOH. Acetic acid, one of the carboxylic acids, is a metabolic intermediate in the body. Vinegar is a dilute solution of acetic acid produced by fermenting and oxidizing carbohydrates. See, for example, S. Weinhouse. 1995. “The acetyl group in fatty acid metabolism.” FASEB J. Jun;9(9): 820–821; L. R. Empey et al. 1991. “Fish oil-enriched diet is mucosal protective against acetic acid-induced colitis in rats.” Can J Physiol Pharmacol. Apr;69(4): 480–487.
11 CH3CHOHCOOH. Lactic acid, one of the carboxylic acids, is found in the blood as a salt (lactate). The body creates lactic acid by exercising muscles. This acid is also found in fermented milk products such as sour milk, cheese, and buttermilk. Certain bacteria create lactates during fermentation. For more information, see J. S. Pringle and A. M. Jones. 2002. “Maximal lactate steady state, critical power and EMG during cycling.” Eur J Appl Physiol. Dec;88(3): 214–216; B. S. Dien et al. 2002. “Fermentation of sugar mixtures using Escherichia coli catabolite repression mutants engineered for production of L-lactic acid.” J Ind Microbiol Biotechnol. Nov;29(5): 221–227; H. Pitkanen et al. 2002. “Serum amino acid responses to three different exercise sessions in male power athletes.” J Sports Med Phys Fitness. Dec;42(4): 472–480.
12 H2CO3. The carbonic acid–bicarbonate buffering system helps maintain blood pH (see note 11 above). Two types of salt created from carbonic acid are hydrogen carbonate, which contains HCO3-, and carbonates, which contain CO32-. For more information, see, for example, S. Kimura et al. 2003. “Enzymatic assay for determination of bicarbonate ion in plasma using urea amidolyase.” Clin Chim Acta. Feb;328(1–2): 179–184; A. Vesela and J. Wilhelm. 2002. “The role of carbon dioxide in free radical reactions of the organism.” Physiol Res. 2002;51(4): 335–339; D. A. Bushinsky et al. 2002. “Acute acidosis-induced alteration in bone bicarbonate and phosphate.” Am J Physiol Renal Physiol. Nov;283(5): F1091–1097.
13 C5H4N4O3. In the purine group, uric acid is created as the body digests proteins. As with other acidic by-products of digestion, uric acid must be excreted at sufficient levels to avoid health problems such as gout. For more information, see T. Nakamura et al. 2003. “Serum fatty acid levels, dietary style and coronary heart disease in three neighboring areas in Japan: the Kumihama study.” Br J. Nutr. Feb;89(2): 267–272; F. Perez-Ruiz et al. 2002. “Renal underexcretion of uric acid is present in patients with apparent high urinary uric acid output.” Arthritis Rheum. Dec 15;47(6): 610–613.
14 CnH2nO2. Fatty acids are components of lipids and composed of chains of carbon and hydrogen atoms. The carboxyl group (-COOH) at one end of a fatty acid makes it a carboxylic acid. Single carbon-to-carbon bonds make the acid saturated, while double and triple bonds make it unsaturated. Oleic acid is the most common fatty acid; you can find it in vegetable oils such as olive, palm, and peanut oil. Oleic acid also makes up 46 percent of human fat. See, for example, M. Nydahl et al. 2003. “Achievement of dietary fatty acid intakes in long-term controlled intervention studies: approach and methodology.” Public Health Nutr. Feb;6(1):31-40; G. R. Hynes et al. 2003. “Effects of dietary fat type and energy restriction on adipose tissue fatty acid composition and leptin production in rats.” J Lipid Res. May;44(5): 893–901; S. F. Knutsen et al. 2003. “Comparison of adipose tissue fatty acids with dietary fatty acids as measured by 24-hour recall and food frequency questionnaire in black and white adventists.” Ann Epidemiol. Feb;13(2): 119–127.
15 H3PO4. Phosphoric acid is used in fertilizers, in dental cements, and in the sugar and textile industries; it is also used in food products to provide a fruitlike flavoring. Most of the peer-reviewed literature focuses on the effects of phosphoric acid on tooth enamel (see, for example, B. Dincer et al. 2002. “Scanning electron microscope study of the effects of soft drinks on etched and sealed enamel.” Am J Orthod Dentofacial Orthop. Aug:122(2): 135–141) and on bone density, particularly in girls. (See, for example, J. Fisher et al. 2001. “Maternal milk consumption predicts the tradeoff between milk and soft drinks in young girls’ diets.” J Nutr. Feb:131(2): 246–250; F. Carcia-Contreras et al. 2000. “Cola beverage consumption induces bone mineralization reduction in ovariectomized rats.” Arch Med Res. Jul–Aug 31(4): 360–365.)
16 NaHCO3. Sodium bicarbonate is often called the most important pH blood buffer. Typically, the concentration of bicarbonate in the blood plasma is 25 millimoles per liter. This level is called the bicarbonate threshold. The body produces sodium bicarbonate from the carbon dioxide (CO2) formed in the cells as a by-product of chemical reactions.
After the carbon dioxide filters into the capillaries, it combines with an enzyme of red blood cells called carbonic anhydrase to form carbonic acid (H2CO3). This acid quickly separates into hydrogen ions (H+) and bicarbonate ions (HC3-). The reaction can also reverse, yielding carbon dioxide and water from bicarbonate and hydrogen ions, with the carbon dioxide eliminated through the lungs.
Sodium bicarbonate is used as a medicine to relieve heartburn, sour stomach, or acid indigestion by neutralizing excess stomach acid.
17 Na2HPO4. Sodium phosphate is an important nonbicarbonate base in the renal system. Monobasic phosphate (NaH2PO4) forms when this base accepts hydrogen ions.
18 The balance of bases to hydrogen ions is key to how the renal system eliminates wastes from the metabolism of our food. The kidneys regulate the blood by filtering 20 percent of the plasma and noncell elements from the blood, reabsorbing key components (fluid, ions, small molecules) as needed, and secreting unwanted components in the urine. The entire blood volume of an adult is typically filtered 20 to 25 times a day.
Bicarbonate is one of the components filtered from the blood and then reabsorbed. When the concentration of bicarbonate falls below the threshold of 25 millimoles per liter, no bicarbonate is excreted, which means all of it is reabsorbed into the blood. When the concentration is higher than the threshold, bicarbonate is passed into the urine.
19 H2SO4. Sulfuric acid is a strong acid that ionizes to form hydronium ions (H3O+) and hydrogen sulfate ions (HSO4–). See, for example, T. Ubuka. 2002. “Assay methods and biological roles of labile sulfur in animal tissues.” J Chromatogr B Analyt Technol Biomed Life Sci. Dec 5;781(1-2): 227–249.
20 H3PO4. See note 15 on page 387 on H3PO4 for more detail.
21 The kidneys are an effective mechanism for maintaining the blood pH. To control the concentration of hydrogen ions, for example, the kidneys can excrete 2,500 times more ions in the urine than are found in the blood. Likewise, the kidneys can excrete more or less bicarbonate.
The human body, however, creates many organic and inorganic acids as it breaks down food; and the more acidic the diet, the more time it takes for the kidneys to restore the pH balance in the blood. When you eat an acidic diet, the bicarbonate concentration in the blood is reduced (as is the pH). The kidneys compensate by secreting more hydrogen ions in the urine and secreting more bicarbonate back to the blood than it filtered out. This process continues until the concentrations of hydrogen and bicarbonate ions
are returned to normal. For more detail, see C. Freudenrich. “How your kidneys work” (http://science.
howstuffworks.com/kidney.htm).
Western diets rich in meats and other acid sources, such as colas, produce a heavy acid load. An increasing level of attention is being paid to the resulting health effects. See, for example, M. Maurer et al. 2003. “Neutralization of Western diet inhibits bone resorption independently of K intake and reduces cortisol secretion in humans.” Am J Physiol Renal Physiol. Jan;284(1): F32–40; U. S. Barzel. 1995. “The skeleton as an ion exchange system: implications for the role of acid-base imbalance in the genesis of osteoporosis.” J Bone Miner Res. Oct;10(10): 1431–1436; L. A. Frassetto et al. 2001. “Diet, evolution and aging—the pathophysiologic effects of the post-agricultural inversion of the potassium-to-sodium and base-to-
chloride ratios in the human diet.” Eur J Nutr. Oct;40(5): 200–213.
22 J. Shuster et al. 1992. “Soft drink consumption and urinary stone recurrence: a randomized prevention trial.” Journal Clinical Epidemiology, Aug;45(8): 911–6. This study demonstrated a significant increase in the risk of stone formation for those who consumed phosophoric acid (found in colas): “those who reported at the time of the index stone that their most consumed drink was acidified by phosphoric acid but not citric acid, the experimental group had a 15 percent higher 3 yr recurrence-free rate than the controls, p 5 0.002.” For those who consumed primarily citric acid, no increase was found in risk.
Similar results were found in J. Shuster et al. 1985. “Primary liquid intake and urinary stone disease.” Journal Chronic Disease. 38(11): 907–14. “This investigation indicates that there are important associations between urinary stone disease and a person’s primary liquid intake. . . . an important (p less than 0.01) positive association was found between urinary stone disease and soda (carbonated beverage) consumption. . . . no important associations exist between urinary stone disease and any of milk, water, or tea, when these beverages represent a person’s primary liquid intake. Moreover, soda can be viewed almost synonymously as sugared cola, since few subjects had diet sodas or sugared non-cola soda as primary fluid.”
The following study concludes with a warning to avoid cola consumption: A. Rodgers. 1999. “Effect of cola consumption on urinary biochemical and physiocochemical risk factors associated with calcium oxalate urolithiasis.” Urology Research. 27(1): 77–81. “Since stone formers are advised to increase their intake of fluid, the present study was undertaken to determine the effect of cola beverage consumption on calcium oxalate kidney stone risk factors. . . . Several risk factors changed unfavourably following consumption of cola. In males, oxalate excretion, the Tiselius risk index and modified activity product increased significantly (P , 0.05). In females, oxalate excretion increased significantly while magnesium excretion and pH decreased significantly (P , 0.05). Scanning electron microscopy showed that urines obtained from both sexes after cola consumption supported calcium oxalate crystallization to a greater extent than the control urines. It is concluded that consumption of cola causes unfavourable changes in the risk factors associated with calcium oxalate stone formation and that therefore patients should possibly avoid this soft drink in their efforts to increase their fluid intake.”
The following study demonstrated benefit in avoiding urinary stones from a high fluid intake. R. Siener and A. Hesse. 2003. “Fluid intake and epidemiology or utolithiasis.” Eur J Clin Nutr, Dec;57 Suppl 2: S47–51. “A review of the literature shows that an increased urine volume achieved by a high fluid intake exerts an efficacious preventive effective on the onset and recurrence of urinary stones.” The following study demonstrated the value of consumption of alkalinizing mineral water: T. Kessler and A. Hesse. 2000. “Cross-over study of the influence of bicarbonate-rich mineral water on urinary composition in comparison with sodium potassium citrate in healthy male subjects.” Br J Nutr. 84(6): 865–87. “The aim of the present study on healthy male subjects aged 23–38 years was to evaluate the influence of bicarbonate-rich mineral water (1715 mg bicarbonate/l) on urinary-stone risk factors in comparison with sodium potassium citrate, a well-established treatment in that case. The results showed that the effect of the bicarbonate-rich mineral water was similar to that of the sodium potassium citrate, which suggests that it could be useful in the prevention of the recurrence of calcium oxalate and uric acid stones.”
The following study concludes that people with a history of calcium-containing kidney stones should not avoid calcium and should drink adequate liquids: G. C. Curhan and S. G. Curhan. 1994. “Dietary factors and kidney stone formation.” Compr. Ther. 20(9): 485–9. “Specifically, for individuals who have a history of a calcium-containing kidney stone, important dietary recommendations should include the following: Achieve adequate fluid intake to produce at least 2 liters of urine per day. Avoid calcium restriction (except in the rare instances of excessive intake of greater than several grams per day). A dietary intake of elemental calcium of at least 800 mg/day (the current RDA for adults) is recommended to prevent a negative calcium balance, bone mineral loss, and increased intestinal absorption of oxalate. At present, there is no evidence to support the belief that calcium restriction is beneficial and current data suggest that it may in fact be harmful.”
See also P. M. Hall. 2002. “Preventing kidney stones: calcium restriction not warranted.” Cleve Clin J Med. Nov;69(11): 885–888; B. Shekarraiz and M. L. Stoller. 2002. “Uric acid nephrolithiasis: current concepts and controversies.” J Urol. Oct;168(4 Pt 1): 1307–1314; S. T. Reddy et al. 2002. “Effect of low-carbohydrate high-protein diets on acid-base balance, stone-forming propensity, and calcium metabolism.” Am J Kidney Dis. Aug;40(2): 265–274; N. A. Breslau et al. 1988. “Relationship of animal protein-rich diet to kidney stone formation and calcium metabolism.” J Clin Endocrinol Metab. Jan;66(1): 140–146; F. Grases et al. 1998. “Biopathological crystallization: a general view about the mechanisms of renal stone formation.” Adv Colloid Interface Sci. Feb;74: 169–194; J. M. Aguado and J. M. Morales. 1993. “The pathogenesis and treatment of kidney stones.” N Engl J Med. Feb 11;328(6): 444.
23 NIH. “Kidney Stones in Adults.” http://kidney.niddk.nih.gov/kudiseases/pubs/stonesadults/
index.htm.
24 V. Radosavljevic, S. Jankovic, J. Marinkovic, and M. Djokic. 2003. “Fluid intake and bladder cancer. A case control study.” Neoplasma. 50(3): 234–8. The study states, “Multivariate logistic regression model showed consumption of: soda (OR58.32; 95%CI53.18-21.76), coffee (OR51.46; 95%CI51.05-2.01) and spirits (OR51.15; 95%CI51.04-1.28) as statistically significant risk factors, while mineral water (OR50.52; 95%CI50.34-0.79), skim milk (OR50.38; 95%CI50.16-0.91), yogurt (OR50.34; 95%CI50.12-0.97) and frequency of daily urination (OR50.27; 95%CI50.18-0.41) were statistically significant protective variables. In our study no statistically significant association was observed for total fluid intake. The findings suggest consumption of soda, coffee and spirits were indicated as risk factors for bladder cancer, while mineral water, skim milk, yogurt and frequency of urination as protective factors for bladder cancer.”
25 That is the conclusion of G. R. Fernando, R. M. Martha, and R. Evangelina. 1999. “Consumption of soft drinks with phosphoric acid as a risk factor for the development of hypocalcemia in postmenopausal women.” Journal Clin Epidemiol. Oct;52(10): 1007–10. “The objective of this study was to determine the relationship between the consumption of phosphoric acid-containing soft drinks and hypocalcemia in postmenopausal women . . . In the multivariate regression analysis consumption of one or more bottles per day of cola soft drinks showed association with hypocalcemia (1.28, CI 95% 1.06-1.53). The consumption of soft drinks with phosphoric acid should be considered as an independent risk factor for hypocalcemia in postmenopausal women.”
The following study compared diets with primarily “acid precursors” to diets with primarily “base precursors” and concluded that diets that promote an alkaline body environment reduce “the rate of bone loss and the risk of fracture in postmenopausal women.” D. E. Sellmeyer et al. 2001. “A high ratio of dietary animal to vegetable protein increases the rate of bone loss and the risk of fracture in postmenopausal women.” Am J Clin Nutr. Jan;73(1): 118–122. “Different sources of dietary protein may have different effects on bone metabolism. Animal foods provide predominantly acid precursors, whereas protein in vegetable foods is accompanied by base precursors not found in animal foods. Imbalance between dietary acid and base precursors leads to a chronic net dietary acid load that may have adverse consequences on bone. . . . Elderly women with a high dietary ratio of animal to vegetable protein intake have more rapid femoral neck bone loss and a greater risk of hip fracture than do those with a low ratio. This suggests that an increase in vegetable protein intake and a decrease in animal protein intake may decrease bone loss and the risk of hip fracture.”
26 M. Bertoni et al. 2002 “Effects of a bicarbonate-alkaline mineral water on gastric functions and functional dyspepsia: a preclinical and clinical study.” Pharmacol Res. Dec;46(6): 525–31. “The present study was performed in order to evaluate: (1) the influence of a bicarbonate-alkaline mineral water (Uliveto) on digestive symptoms in patients with functional dyspepsia; (2) the effects of Uliveto on preclinical models of gastric functions. . . . These findings indicate that a regular intake of Uliveto favors an improvement of dyspeptic symptoms.” The preclinical study suggests that the clinical actions of Uliveto water depend mainly on its ability to enhance gastric motor and secretory functions.
27 L. A. Frassetto et al., ibid. See note 8 on page 386.
28 Water can dissociate into hydroxide (OH-) ions, which makes it alkaline (basic), and hydrogen ions (H+). As a result, water can act as a base or an acid. Drinking alkaline water has been claimed to help with constipation, diarrhea, high or low blood pressure, and diabetes.
29 C. L. Wabner and C. Y. Pak. 1993. “Effect of orange juice consumption on urinary stone risk factors.” Journal Urology. Jun;149(6): 1405–8. The study demonstrates the alkalinizing effect of orange juice: “Compared to potassium citrate, orange juice delivered an equivalent alkali load and caused a similar increase in urinary pH (6.48 versus 6.75 from 5.71) and urinary citrate (952 versus 944 from 571 mg. per day).” The study concludes that orange juice reduces two underlying processes in urinary stone formation: “Overall, orange juice should be beneficial in the control of calcareous and uric acid nephrolithiasis.”
A similar protective effect was found for grapefruit juice and apple juice in R. Honow et al. 2003. “Influence of grapefruit, orange, and apple juice consumption on urinary variables and risk of crystallization.” Br J Nutrition. Aug;90(2): 295–300. “Alkalizing beverages are highly effective in preventing the recurrence of calcium oxalate (Ox), uric acid and cystine lithiasis. The aim of the present study was to evaluate the influence of grapefruit-juice and apple-juice consumption on the excretion of urinary variables and the risk of crystallization in comparison with orange juice. . . . We showed that both grapefruit juice and apple juice reduce the risk of CaOx stone formation at a magnitude comparable with the effects obtained from orange juice.”
30 A free radical is a molecule that, in contrast to most molecules, contains at least one unpaired electron and as a result is usually highly reactive. A considerable body of literature explores the role of oxygen free radicals in aging as well as in disease processes such as heart disease and cancer. According to some theories, mitochondrial DNA is a major target of free radical attack. See, for example, A. Ishchenko et al. 2003. “Age-dependent increase of 8-oxoguanine-, hypoxanthine-, and uracil-DNA glycosylase activities in liver extracts from OXYS rats with inherited overgeneration of free radicals and Wistar rats.” Med Sci Monit. Jan;9(1): BR16–24; Y. Okatani et al. 2003. “Acutely administred melatonin restores hepatic mitochondrial physiology in old mice.” Int J Biochem Cell Biol. Mar;35(3): 367–375; J. Sastre. 2002. “Ginkgo biloba extract EGb 761 protects against mitochondrial aging in the brain and in the liver.” Cell Mol Biol. Sep;48(6): 685–692; A. Anantharaju. 2002. “Aging Liver: A review.” Gerontology. Nov–Dec;48(6): 343–353.
31 H. Valtin. 2004. Upcoming article in Journal of Physiology: Regulatory, Integrative and Comparative Physiology. See American Physiological Society press release at www.the-aps.org/press/journal/release8-13-02.htm.

Chapter 5
1 Glucose, fructose, and galactose are isomers (molecules with the same number and types of atoms as another molecule, but with different properties). The different arrangement of atoms gives these sugars different properties.
2 M. Bloomfield and L. Stephens. 1996. Chemistry and the Living Organism, 6th ed. New York: John Wiley and Sons; W. Tamborlane et al., eds. 1997. The Yale Guide to Children’s Nutrition. New Haven and London: Yale University Press.
3 E. Westman. 2002. “Is dietary carbohydrate essential for human nutrition?” Am J Clin Nutr. 75(5): 951–953. The established human nutrients are water, energy, amino acids, essential fatty acids, vitamins, minerals, trace minerals, electrolytes, and ultratrace minerals. (A. E. Harper. “Defining the essentiality of nutrients.” In M. D. Shils et al., eds. 1993. Modern Nutrition in Health and Disease, 9th ed. Boston: William and Wilkins, pp. 3–10.)
4 Lactose intolerance varies by age and by race. The activity of the enzyme lactase declines after babies are weaned, so most of the human adult population is lactose-intolerant (J. L. Vilotte. 2002. “Lowering the milk lactose content in vivo.” Reprod Nutr Dev. Mar–Apr 42: 127–132). Depending on race, the deficiency occurs in 50–90 percent of most populations. “White, western Europeans are the exception.” A. Ferguson. 1995. “Mechanisms in adverse reactions to food.” Allergy. 50: 32–38.
5 W. Willett and M. Stampfer. 2003. “Rebuilding the food pyramid.” Sci Amer. Jan: 64–71; “The basics of good nutrition: Essential nutrients and their functions.” In D. Tapley et al., eds. 1995. Columbia University College of Physicians and Surgeons Complete Home Medical Guide. New York: Crown Publishers (or available online at http://cpmcnet.columbia.edu/texts/guide).
6 Our primate ancestors also could not digest fiber (K. Milton. 1993. “Diet and primate evolution.” Sci Amer. Aug: 86–93). See also “The basics of good nutrition: Essential nutrients and their functions.” In D. Tapley et al., eds. 1995. Columbia University College of Physicians and Surgeons Complete Home Medical Guide. New York: Crown Publishers (or available online at http://cpmcnet.columbia.edu/texts/guide).
7 Fructose has a glycemic index in the 30s. Glucose and sucrose, along with white bread and potatoes, have index values over 85. In fact, glucose is sometimes used as the reference food for the scale, with an index of 100. For more information, see K. Foster-Powell et al. 2002. “International table of glycemic index and glycemic load values: 2002.” Am J Clin Nutr. 76(1): 5–56.
8 Insulin surges lead to overeating and also foster the deposition of fat. D. S. Ludwig et al. 1999. “High glycemic index foods, overeating, and obesity.” Pediatrics. Mar;103: E26; D. S. Ludwig. 2001. “Relation between consumption of sugar-sweetened drinks and childhood obesity: a prospective, observational analysis.” Lancet. Feb 17;357: 505–508. This last study found that “each additional sugar-sweetened drink consumed” per day significantly increased a child’s chance of developing obesity later.
9 F. S. Facchini et al. 2001. “Insulin resistance as a predictor of age-related diseases.” J Clin Endocrinol Metab. Aug;86(8): 3574–3578; J. Salmeron et al. 1997. “Dietary fiber, glycemic load, and risk of non-insulin-dependent diabetes mellitus in women.” JAMA. Feb 12; 277(6): 472–477.
10 The bulk provided by insoluble fiber increases stool size and shortens stool transit time through the intestine. Shorter transit times are better for bowel function. There is less time, for example, for “bad” bacteria to proliferate and produce toxins. In addition, insoluble fiber may inhibit the metabolism of carcinogens in the gut. In ascertaining the contribution of insoluble fiber to preventing colon cancer, it has been difficult to distinguish between the potential benefits of the fiber and the benefits of other cancer-inhibiting nutrients found in fiber-rich foods such as vegetables. S. A. Bingham et al. 2003. “Dietary fibre in food and protection against colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC): an observational study.” Lancet. May 3;361(9368) :1496–1501; U. Peters et al. 2003. “Dietary fibre and colorectal adenoma in a colorectal cancer early detection programme.” Lancet. May 3;361(9368): 1491–1495; S. Gråsten et al. 2000. “Rye bread improves bowel function and decreases the concentrations of some compounds that are putative colon cancer risk markers in middle-aged women and men.” J Nutr. 130: 2215–2221.
11 N. M. Avena and B. G. Hoebel. 2003. “Amphetamine-sensitized rats show sugar-induced hyperactivity (cross-sensitization) and sugar hyperphagia.” Pharmacol Biochem Behav. Feb;74(3): 635–639; C. Colantuoni et al. 2002. “Evidence that intermittent, excessive sugar intake causes endogenous opioid dependence.” Obes Res. Jun;10(6): 478–488; C. Colantuoni et al. 2001. “Excessive sugar intake alters binding to dopamine and muopioid receptors in the brain.” Neuroreport. Nov 16;12(16): 3549–3552.
12 C. B. Ebbeling and D. S. Ludwig. 2001. “Treating obesity in youth: should dietary glycemic load be a consideration?” Adv Pediatr. 48: 179–212; S. B. Roberts. 2000. “High-glycemic index foods, hunger, and obesity: is there a connection?” Nutr Rev. 58: 163–169.
13 S. Higgenbotham et al. 2004. Dietary glycemic load and risk of colorectal cancer in the Women’s Health Study. J Natl Cancer Inst. Feb 4; 96(3): 229–233.
14 K. Foster-Powell et al. 2002. “International table of glycemic index and glycemic load values: 2002.” Am J Clin Nutr. Jul;76(1): 5–56.
15 For more complete lists, see www.lifelonghealth.us/mhc_home/pdf_docs/GLYCEMIC_INDEX.pdf;
C. T. Netzer. 2000. The Complete Book of Food Counts. New York: Dell.
16 These findings were especially pronounced in overweight women. S. Liu et al. 2001. “Dietary glycemic load assessed by food-frequency questionnaire in relation to plasma high-density-lipoprotein cholesterol and fasting plasma triacylglycerols in postmenopausal women.” Am J Clin Nutr. Mar;73(3): 560–566.
17 G. M. Reaven. 2003. “Age and glucose intolerance.” Diabetes Care. 26: 539–540; G. M. Reaven. 1998. “Insulin resistance and human disease: a short history.” Basic Clin Physiol Pharmacol. 9(2–4): 387–406. “The number of adults in the United States with diabetes increased by 49 percent between 1991 and 2000 . . . and Type II diabetes accounts for practically all of that increase” (J. Marx. 2002. “Unraveling the causes of diabetes.” Science. 296(5568): 686–689, summarizing Centers for Disease Control and Prevention data).
18 M. Blüher et al. 2003. “Extended longevity in mice lacking the insulin receptor in adipose tissue.” Science. Jan 24;299(5606): 572–574; S. H. Golden et al. 2002. “Risk factor groupings related to insulin resistance and their synergistic effects on subclinical atherosclerosis: the atherosclerosis risk in communities study.” Diabetes. Oct;51: 3069–3076; F. Wollesen et al. 2002. “Insulin resistance and atherosclerosis in diabetes mellitus.” Metabolism. Aug;51: 941–948.
19 J. Marx. 2002. “Unraveling the causes of diabetes.” Science. 296(5568): 686–689; R. K. Campbell and J. R. White. 2002. “Insulin therapy in type 2 diabetes.” J Am Pharm Assoc. Jul–Aug;42: 602–611; G. M. Reaven. 1999. “Insulin resistance: a chicken that has come to roost.” Ann NY Acad Sci. Nov 18;892: 45–57.
20 F. Abbasi et al. 2002. “Relationship between obesity, insulin resistance, and coronary heart disease risk.” J Am Coll Cardiol. Sep 4;40(5): 944–945; S. Liu and W. C. Willett. 2002. “Dietary glycemic load and atherothrombotic risk.” Curr Atheroscler Rep. Nov 4: 454–461; G. M. Reaven. 2000. “Diet and Syndrome X.” Curr Atheroscler Rep. Nov;2(6): 503–507; S. Liu et al. 2000. “A prospective study of dietary glycemic load, carbohydrate intake, and risk of coronary heart disease in U.S. women.” Am J Clin Nutr. 71(6):1455–1461; J. Yip et al. 1998. “Resistance to insulin-mediated glucose disposal as a predictor of cardiovascular disease.” J Clin Endocrinol Metab. Aug;83(8): 2773–2776.
21 High glycemic load has been noted as a risk factor for pancreatic, breast, and colon cancers. See, for example, D. S. Michaud. 2002. “Dietary sugar, glycemic load, and pancreatic cancer risk in a prospective study.” J Natl Cancer Inst. 94(17): 1293–1300; L. S. Augustin et al. 2001. “Dietary glycemic index and glycemic load, and breast cancer risk: a case-control study.” Ann Oncol. 12(11): 1533–1538; E. Giovannucci. 2001. “Insulin, insulin-like growth factors and colon cancer: a review of the evidence.” J Nutr. Nov;131(11): 3109S–20S.
22 Discovered in 1879, saccharin is 300 times sweeter than sugar. In 1977, when the Food and Drug Administration (FDA) proposed to ban saccharin, it was the only alternative sweetener. The public outcry prompted Congress to pass the Saccharin Study and Labeling Act, which required foods containing saccharin to display a warning label. That requirement remained in place for more than two decades. Even though the government now claims to have exonerated saccharine through the Saccharin Warning Elimination via Environmental Testing Employing Science and Technology Act of 2000, many scientists remain concerned about the tens of millions of people consuming the sweetener and evidence of carcinogenesis. See, for example, W. Bell et al. 2002. “Carcinogenicity of saccharin in laboratory animals and humans.” Int J Occup Environ Health. Oct–Dec;8: 387–393; Y. Sasaki et al. 2002. “The comet assay with 8 mouse organs: results with 39 currently used food additives.” Mutation Research. 519(1–2): 103–119.
23 H. J. Roberts. 1992. Aspartame (Nutrasweet): Is It Safe? New York: The Charles Press. As with saccharin, controversy continues to rage over the safety of aspartame. The FDA defends the sweetener, although research shows a variety of possible heath effects (see, for example, S. K. van den Eeden et al. 1994. “Aspartame ingestion and headaches: a randomized crossover trial.” Neurology. Oct;44(10): 1787–1793).
24 R. J. Wurtman. 1983. “Neurochemical changes following high-dose aspartame with dietary carbohydrates.” N Engl J Med. Aug 18;309(7): 429–30; “Migraine provoked by aspartame.” 1986. N Engl J Med. Aug 14;315(7): 456; S. E. Moller. 1991. “Effect of aspartame and protein, administered in phenylalanine-equivalent doses, on plasma neutral amino acids, aspartate, insulin and glucose in man.” Pharmacol Toxicol. 68(5): 408–412.
25 Soluble fiber can be digested by the body as opposed to insoluble fiber, which cannot. D. L Sprecher and G. L. Pearce. 2002. “Fiber-multivitamin combination therapy: a beneficial influence on low-density lipoprotein and homocysteine.” Metabolism. Sep;51(9): 1166–1170; B. M. Davy et al. 2002. “High-fiber oat cereal compared with wheat cereal consumption favorably alters LDL-cholesterol subclass and particle numbers in middle-aged and older men.” Am J Clin Nutr. Aug;76(2): 351–358.
Eating soluble fiber may also be beneficial for individuals with syndrome X. (B. M. Davy and C. L. Melby. 2003. “The effect of fiber-rich carbohydrates on features of Syndrome X.” J Am Diet Assoc. Jan;103(1): 86–96.)
26 Insoluble fiber cannot be digested by humans and is found in foods such as wheat bran, vegetables, and whole grains. M. Hill. 2003. “Dietary fibre and colon cancer: where do we go from here?” Proc Nutr Soc. Feb;62(1): 63–65; American Dietetic Association and Dietitians of Canada. 2003. “Position of the American Dietetic Association and Dieticians of Canada: Vegetarian Diets.” Can J Diet Pract Res. Summer;64(2): 62–81.
27 A. Mukherjee and J. Chakrabarti. 1997. “In vivo cytogenetic studies on mice exposed to acesulfame-K-a non-nutritive sweetener.” Food Chem. Toxicol. Dec;35(12): 1177–1179.
28 See www.ffcr.or.jp/zaidan/FFCRHOME.nsf/pages/e-kousei-sucra for Japanese studies on the safety of sucralose.
29 Stevia is a Paraguayan plant. Each leaf of stevia “contains 9 to 13 percent stevioside, which is 300 times sweeter than sugar.” Stevia has been used as a sweetener in Japan for over three decades; this may be a reason for the number of Japanese studies on the plant. (See, for example, E. Koyama et al. 2003. “In vitro metabolism of the glycosidic sweeteners, stevia mixture and enzymatically modified stevia in human intestinal microflora.” Food and Chem Toxicol. 41(3): 359–374; M. Matsui et al. 1996. “Evaluation of the genotoxicity of stevioside and steviol using six in vitro and one in vivo mutagenicity assays.” Mutagenesis. Nov;11(6): 573–579.)

Chapters: 6-10, 11-15, 16-20, 21-23