Further reading: Medical topics.

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Further reading: Medical topics (includes some web sites)

Introduction
Web sites
Articles Other sources of Further reading at this web site

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Introduction

This page was originally intended as a supplement for the course Introduction to Organic and Biochemistry. That may help to explain the choice of topics here.

Chapter handouts contain a section of "Further reading", for those who want to explore more. For some chapters (especially Lipids & Metabolism), there is quite a range of related medical topics, many dealing with nutrition. Because those reference lists have become rather long, I have decided to split off this page, listing many medical topics here. The distinction is not clear-cut; some medical articles will continue to be in Chapter handouts, when they are very closely related to class material. However, this page will be for a range of general medical (nutritional) topics, loosely related to class material.

Caution. The papers I present here and my comments should not be taken as medical advice. I present them because I think they are interesting scientific papers, somewhat related to material for a current class, and of possible medical relevance. Controversies are common in many of these fields, and I make no attempt to resolve them -- I do not have the medical expertise to do so.

Links to some articles are shown, when I am fairly sure that they are freely available online. Many of the other articles are available with subscription access, certainly from UC computers.

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Web sites

Pharmacogenetics (pharmacogenomics) is an emerging science of choosing "the right drug for the right person", based on the patient's individual metabolic characteristics. Nutrigenomics is the analogous field of choosing the right nutrition for each person.

The following two items are major nutrigenomics sites:
* The Center of Excellence for Nutritional Genomics at UC Davis, supported by the NCMHD (National Center for Minority Health and Health Disparities, part of the NIH) : http://nutrigenomics.ucdavis.edu.
* The European Nutrigenomics Organisation (NuGO): http://www.nugo.org/everyone/. In particular, see their page http://www.nugo.org/nip/ for the Nutrigenomics Information Portal, then choose Research. Also, they have an electronic newsletter. You can read it online, or sign up to receive it by email; choose NutriAlerts from the "NuGO sites" menu at the left (of either of those pages).

The two sites above are also listed for Biotechnology in the News (BITN), under DNA and the genome - Examples of how genome information is useful. More about nutrigenomics and related topics is on that page. A specific page of the NuGO site, on Adipose Tissue, is listed for Organic/Biochemistry Internet resources, under Lipids.

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Articles (listed by publication date, oldest first)

M Gladwell, Annals of medicine: John Rock's error. New Yorker 3/13/00, p 52. Sex hormones -- including birth control pills -- are steroids. This article, which received much attention, reviews some of the history of the birth control pill cycle. The underlying focus is whether modern women (with earlier puberty, fewer pregnancies, and less time lactating) menstruate "too many times", possibly leading to breast cancer. I am not in a position to evaluate this, so I suggest that you take it as a provocative theory (and some interesting history in any case).

P J Houghton, Products of Chemistry: Old yet new -- Pharmaceuticals from plants. J Chem Educ 78:175, 2/01. Delightful article, with lots of biology and chemistry; lots of structures (nice pictures!). Good browsing, and good for more serious reading about drug development if you are so inclined.

G Taubes, Nutrition: The soft science of dietary fat. Science 291:2536, 3/30/01. News. Major discussion of the story of effect of fats on health. The big message is how little evidence there is for much of what you hear. Good general reading, but controversial. For some follow-up correspondence, see Science 293:801, 8/3/01 and 295:1464, 2/22/02.

P W Sherman & S M Flaxman, Protecting ourselves from food. Amer Sci 89:142, 3/01. The main part of this article discusses the argument that, historically, spices were used because of their antimicrobial activity. More speculatively (I think), they then suggest that pregnancy-related nausea and vomiting (commonly called morning sickness) serves to protect the developing fetus from food problems. Very readable!

J L Goldstein & M S Brown, Molecular medicine: The cholesterol quartet. Science 292:1310, 5/18/01. News. Ouellette discusses the role of cholesterol carrier proteins in the p 442 Essay (not assigned). A high level of LDL is considered a risk factor for heart disease. The title of this news article refers to four genes that have been found to be mutated in one or another form of elevated LDL disease. The newest of them is reported in this issue. By the way, the authors of this item are the pioneers in the area of cholesterol-carrying proteins, work for which they received the Nobel prize in 1985. For more developments, not entirely consistent with the basic notions, see Brown & Goldstein (2006) and Couzin (2008).

Feature section on Obesity. Science 299:845 ff, 2/7/03. Includes articles on the molecular and cellular controls of obesity, on possible drugs, and on the social issues.

Feature section on Testing Human Limits, published just before the 2004 Olympic games in Athens. Science 305:631 ff, 7/30/04. Includes issues of physiology, genetics, technology and pharmacology that affect athletic performance.

P A Kiberstis, A surfeit of suspects. Science 307:369, 1/21/05. Introduction to special issue on type 2 diabetes. Topics include genetic factors, obesity, adipokines (hormones from fat cells), insulin, mitochondrial functions, role of brain.

E Ravussin, Physiology: A NEAT way to control weight? Science 307:530, 1/28/05. News. NEAT = non-exercise activity thermogenesis. The work discussed here shows that people who fidget more are less likely to be obese. It also suggests that the degree of fidgeting is a "natural" behavior, not easily altered. This was a big news story; its significance is not entirely clear, but the basic idea is that fidgeting does burn calories.

D Butler & H Pearson, Flash in the pan. Nature 433:794, 2/24/05. First of a series of three articles in a news feature "Dietary advice special", stimulated by the new US dietary guidelines. Together, the three articles are a useful mix of science and politics.

S Simpson et al, The gut: Inside out. Science 307:1895, 3/25/05. Introduction to special feature section on The Gut: Inner Tube of Life. Topics include the role of microbes in the gut, inflammation, and energy balance.

G Nagendrappa, An appreciation of free radical chemistry. 3. Free radicals in diseases and health. Resonance, April 2005 (Vol 10 #4), p 65. A good overview of free radicals in biology. Includes discussion of the role of anti-oxidants. Free online: http://www.ias.ac.in/resonance/Apr2005/Apr2005Classroom.html. (This is part of a series on various aspects of free radicals. The paper refers to Parts 1 and 2, in the February and March 2005 issues. Part 1, a general introduction, may be particularly useful here. Later parts of the series are in the July, August, and September 2005 issues, which you can access through their Back issues button.)

R Nogueiras & M Tschop, Biomedicine: Separation of conjoined hormones yields appetite rivals. Science 310:985, 11/11/05. News. A single gene codes for two peptide hormones (ghrelin & obestatin) -- with opposite effects on appetite.

J M Ordovas, Diet-heart hypothesis: will diversity bring reconciliation? Amer J Clinical Nutrition 82(5):919-920, 11/05. Editorial, focusing on an article in this issue. Connections between diet -- especially dietary fat -- and heart disease are often noted, but the evidence behind them is actually rather weak. One reason is the variability between individuals. Online at http://www.ajcn.org/cgi/content/full/82/5/919.

M Wang et al, Fat storage in adipocytes requires inactivation of leptin's paracrine activity: Implications for treatment of human obesity. PNAS 102:18011, 12/13/05. The discovery of the hormone leptin was the start of a new era in understanding fat storage. Fat cells make leptin, which -- by the simple view -- feeds back and reduces fat production. Leptin-deficient mice are obese, and giving them leptin cures their obesity. Indeed, a few human families have been shown to have a genetic defect in leptin production. However, most obese humans have normal or even high levels of this hormone. Thus leptin is only a part of the story. The paper here explores some of the complexity of the leptin signaling pathway. Free online at: http://www.pnas.org/content/102/50/18011.abstract.

J D Baxter & P Webb, Metabolism: Bile acids heat things up. Nature 439:402, 1/26/06. News. From the journal summary: "Thyroid hormone causes fat loss, but harnessing this action to treat obesity is difficult because it is associated with harmful side effects. However, bile acids generate active thyroid hormone just where it is needed." The work was done in mice; they discuss the possible relevance to humans, which remains to be tested.

M S Brown & J L Goldstein, Biomedicine: Lowering LDL -- Not only how low, but how long? Science 311:1721, 3/24/06. News. The discussion of Goldstein & Brown (2001) notes that a high level of LDL is considered a risk factor for heart disease. Similarly, a high level of HDL is generally considered good. Now, another piece of the cholesterol story. They discuss work showing that people with a particular mutant protease, due to a mutation, have low LDL and very low incidence of heart disease. The protease role may well be to destroy LDL, though one cannot exclude that it has other functions, too. They suggest that the very low heart disease is due to lifelong low level of LDL -- and suggest earlier treatment with statins to achieve this. For more suggesting that the basic story of LDL and HDL is over-simplified, see Couzin (2008).

A Herbert et al, A common genetic variant is associated with adult and childhood obesity. Science 312:279, 4/14/06. They find evidence for a gene that may contribute to a propensity to be obese. The function of the gene is not known at this point, but it is located near some genes known to be involved in fat metabolism.

The April 21, 2006, issue of Science contains a Feature section on Influenza. Topics include patterns of flu virus spread, issues of host specificity, drugs, and vaccines. Many of the articles should be readable by the general audience. This reference is also listed on my page for Biotechnology in the News (BITN): Influenza, which has more about bird flu.

J S Flier, Neuroscience: Regulating energy balance: The substrate strikes back. Science 312:861, 5/12/06. News. A picture is emerging of how appetite is regulated by a complex network of signals, from both hormones and metabolites. This news story focuses on neuronal integration of the signals.

E P Zorrilla et al, Vaccination against weight gain. PNAS 103:13226, 8/29/06. + Commentary, by Zigman & Elmquist, p 12961. Ghrelin is a peptide hormone that is part of the complex regulatory cycles involved in obesity. Here they show that a vaccine against the hormone leads to weight loss -- in rats. Both the article and the Commentary discuss the implications -- and limitations -- of the finding. It is likely that the finding will be followed up in humans, probably starting with those with extreme conditions not amenable to other treatments. An interesting organic chemistry point is that the active form of this hormone has an octanoyl group attached to it; this is thought to be unique in biochemistry. The Commentary (with link to the article) is online at: http://www.pnas.org/content/103/35/12961.extract.

H Pearson, Medicine: Sleep it off. Nature 443:261, 9/21/06. News Feature. There are fragments of evidence linking sleep deficiency and obesity. The causal connection is unclear. If there is something to it, it might, of course, be through hormones. A readable overview -- of an interesting but quite inconclusive story.

G J Morton et al, Central nervous system control of food intake and body weight. Nature 443:289, 9/21/06. Review. Fairly heavy reading, but a good status report on what we know about control of food intake.

D J Graham, COX-2 inhibitors, other NSAIDs, and cardiovascular risk: The seduction of common sense. JAMA 296:1653, 10/4/06. Editorial. + Accompanying articles, pp 1619 & 1633. An item listed in the Ch 13 Further reading raised the point that aspirin and other drugs vary in how they inhibit various forms of the COX enzymes. This finding led to the development of COX-2 inhibitors, such as Vioxx. Subsequent experience has shown that that story is more complicated than originally thought. In particular, risks associated with use of COX-2 inhibitors became apparent. Major analyses of these risks were reported in this JAMA issue, and Graham comments on these studies. I should stress that the basic biochemical idea that there are multiple forms of COX and different drugs inhibit those forms differently is still valid. Perhaps most importantly, the effects of the multiple COX enzymes are more complex than thought.

S G Waxman, Neurobiology: A channel sets the gain on pain. Nature 444:831, 12/14/06. News. "Nerve impulses that convey pain signals to the brain are produced by sodium channels in the neuronal membrane. Studies on people who are unable to feel pain identify one specific sodium channel as essential to the process." One idea that follows from this work is that drugs targeted to this specific channel protein might be useful for treatment of pain.

D Nath et al, Obesity and diabetes. Nature 444:839, 12/14/06. Introduction to a Nature Insight feature section. A superb collection of review articles on multiple aspects of energy metabolism. The articles include: Mechanisms linking obesity to insulin resistance and type 2 diabetes; Adipocytes as regulators of energy balance and glucose homeostasis; Gut hormones and the regulation of energy homeostasis; Inflammation and metabolic disorders; Sirtuins as potential targets for metabolic syndrome; Mechanisms linking obesity with cardiovascular disease; Abdominal obesity and metabolic syndrome

K Powell, Obesity: The two faces of fat. Nature 447:525, 5/31/07. News feature. An emerging story is that fat cells are metabolically active, making hormonal signals that affect glucose and fat metabolism. Thus the overall amount of body fat is not the entire story; how much fat individual fat cells have is an issue. Good overview.

R A Forshee et al, A critical examination of the evidence relating high fructose corn syrup and weight gain. Crit Rev Food Sci Nutr 47(6):561-82, 8/07. Is HFCS (high fructose corn syrup) a major contributor to the obesity epidemic? This article reviews the literature, and concludes that evidence does not support that hypothesis. Is this the last word? The authors are associated with the food industry; does that taint their story? Well, the main thing they have done here is to lay out information -- a lot of it. We can be open to others criticizing parts of this paper, and to bringing in new data. In fact, they note that evidence is lacking on some points, and call for further work. But for now this paper probably stands as about as good a summary there is. Free online, at http://www.informaworld.com/smpp/content?content=10.1080/10408390600846457.

J M Suh et al, Adipose is a conserved dosage-sensitive antiobesity gene. Cell Metabolism 6:195-207, 9/07. They show that a conserved gene, called adipose, inhibits fat formation in a wide range of organisms, including worms, flies and mice. Mutants lacking the functional protein are obese. And transient stimulation of the gene leads to transient inhibition of fat formation, in flies. Relevance to humans? Well, we have the gene. Stay tuned. A news story about this work: Gene 'controls body fat levels', http://news.bbc.co.uk/2/hi/health/6977423.stm.

N Combe et al, Trans fatty acids, conjugated linoleic acids, and cardiovascular diseases. European Journal of Lipid Science and Technology 109(9):945-953, 9/07. Review. The common unsaturated fatty acids have cis double bonds; if there are multiple double bonds, they are three carbons apart. Trans fatty acids have trans double bonds, and conjugated fatty acids have double bonds that are two carbons apart (alternating single and double bonds). Both such classes occur naturally, in limited situations; trans fatty acids are also produced when unsaturated fatty acids are partially hydrogenated, in order to produce more saturated (more solid) fats. This article reviews what is known about the effects of these two types of fatty acids, from both human and animal data. The general conclusion is that trans fatty acids are harmful -- about as harmful as saturated fats, perhaps worse. The data for conjugated fatty acids is less clear, and may even be different for different members of the family. This is a good readable overview. It also serves as a good introduction to the types of data that are brought to bear on these issues -- and the limitations. One limitation is noted in the title: the focus here is cardiovascular disease. There is no information about what other effects these fats may have -- for better or worse.

P Hakimi et al, Overexpression of the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) in skeletal muscle repatterns energy metabolism in the mouse. J Biol Chem 282(45):32844-55, 11/9/07. By genetic engineering they develop mice that over-express a particular enzyme of carbon metabolism in the skeletal muscle. Compared to the control mice, the resulting mice eat more, exercise more, run faster, weigh less and have less fat, and live longer. A striking set of results. The reason for these effects is not at all clear, but it will undoubtedly open up some new areas of work.

J Xu et al, Dandruff-associated Malassezia genomes reveal convergent and divergent virulence traits shared with plant and human fungal pathogens. PNAS 104:18730-5, 11/20/07. Fungi of the genus Malassezia grow on the human scalp, and are probably involved in dandruff formation. The relationship between the fungus and the skin condition is not clear; the fungus seems to be a necessary but not sufficient factor. Some anti-dandruff shampoos target these fungi. An interesting characteristic of these fungi is their inability to make fatty acids; they do make extracellular lipases -- and presumably feed off scalp oils. The genome analysis reported here shows that they lack a typical fatty acid synthase system -- and have many genes for lipases. This paper is basic genome analysis -- of organisms of practical interest. Where it leads, time will tell. The paper is, in part, from Procter & Gamble. It is free online: http://www.pnas.org/content/104/47/18730.abstract.

A Caspi et al, Moderation of breastfeeding effects on the IQ by genetic variation in fatty acid metabolism. PNAS 104:18860-5, 11/20/07. Breastfeeding is known to correlate with higher IQ. It is considered likely that this is due to the fatty acid composition of human breast milk; certain long-chain polyunsaturated fatty acids are characteristic of the human milk. Here they show that this effect varies with the genetics of the child. The gene that is implicated has to do with fatty acid metabolism. However, the precise effect of the genetic variants studied here is not known. This is an intriguing report on "nature vs nurture" -- showing how they interact. However, I'm inclined to take it as a rather preliminary report for now. Free online at: http://www.pnas.org/content/104/47/18860.abstract.

N S Bryan et al, Dietary nitrite supplementation protects against myocardial ischemia-reperfusion injury. PNAS 104:19144, 11/27/07. Whether consumption of nitrite or nitrate is good for you or bad seems to be rather murky. The complex chemistry -- and biochemistry -- of these species is part of the problem; many things are going on. There is concern that they might be carcinogenic, but there is little data to support that it is actually a problem. Here, they show that nitrite is cardioprotective, because it serves as a source of NO. This is in mice. Free online at: http://www.pnas.org/content/104/48/19144.abstract.

J C Milne et al, Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450:712, 11/29/07. This is part of a set of complex and fascinating stories -- with no clear conclusions. One idea is that "SIR" proteins may be involved in aging; this was originally found in yeast. Another story is that a polyphenol in red wine, called resveratrol, seems to delay aging. And another is that extreme caloric restriction seems to delay aging -- in a quite wide range of organisms. These three stories turn out to be related. It is now understood that SIR proteins modify chromatin, that caloric restriction acts through SIR, and that resveratrol activates SIR. Resveratrol itself is probably not a useful drug, because the levels needed for benefit are too high to be practical. But it has stimulated much work to look for alternatives that may act similarly. This paper reports some progress. From the journal's summery: "This work describes the identification and characterization of novel small molecule activators of SIRT1, an NAD⁺-dependent deacetylase that mediates the beneficial effects of caloric restriction. These small molecules are structurally unrelated to, and much more potent than, resveratrol, and improve metabolic function in animal models of diabetes and obesity."

Q-L Ma et al, Omega-3 fatty acid docosahexaenoic acid increases SorLA/LR11, a sorting protein with reduced expression in sporadic Alzheimer's Disease (AD): Relevance to AD prevention. J Neurosci 27:14299-14307, 12/26/07. This paper brings together some pieces of the story for a possible dietary effect on AD. There is evidence that higher intake of the long chain omega-3 fatty acid DHA, found in fish oils, correlates with reduced risk of AD. Here they show that this fatty acid may work by increasing the activity of a protein that tends to help a precursor be eliminated rather than converted to the Alzheimer plaque peptide. At the end of the paper they note that clinical trials of DHA as a treatment for existing AD are in progress. The very preliminary evidence available at that time suggests that it is not effective at treatment except possibly for early cases. There is a good news story about this paper: Why fish oil is good for you -- UCLA researchers find anti-Alzheimer's mechanism in omega-3 fatty acids. http://www.eurekalert.org/pub_releases/2007-12/uoc--wfo122107.php.

P Ocaranza et al, Gene therapy reduces ethanol intake in an animal model of alcohol dependence. Alcoholism: Clinical and Experimental Research 32(1):52, 1/08. Some people lack the enzyme aldehyde dehydrogenase, which catalyses the second step in the breakdown of ethanol. Therefore, they accumulate acetaldehyde, which is quite toxic. Such people quickly learn to avoid alcohol, and therefore the incidence of alcoholism among these people is low. A drug, disulfiram, is based on the same idea; it inhibits the aldehyde dehydrogenase, but it has its own problems. Here, using a rat model, they show that administering a virus coding for an antisense RNA to reduce expression of the aldehyde dehydrogenase leads to reduced alcohol usage.

L Rajendran et al, Efficient inhibition of the Alzheimer's disease β-secretase by membrane targeting. Science 320:520-523, 4/23/08. Alzheimer's disease involves the conversion of a normal cellular protein to a toxic form. One step in this conversion is carried out by a protease called β-secretase, which is associated with cellular membranes. This protease is considered a possible target for drugs to combat Alzheimer's disease. Here, they show that targeting such a drug to the membrane improves its effectiveness. They achieve the targeting by combining the drug with a sterol.

K L Spalding et al, Dynamics of fat cell turnover in humans. Nature 453:783, 6/5/08. The number of adipocytes (fat cells) in a person seems to be set during adolescence; it varies little during adulthood. Even major changes in the amount of fat stored are accommodated almost entirely by changes in the size of adipocytes, not in their number. However, this paper shows that about 10% of the adipocytes are turned over each year. Thus there is regulated renewal of adipocytes, but the regulation is not by energy balance. Intriguing implications. The paper also involves some interesting methodology. They date the adipocytes by measuring their content of the isotope C-14. The amount of this isotope in the atmosphere was increased by the nuclear bomb tests of the 1950s. Thus the amount of C-14 in cells can be used to estimate when they were made.

B Brodsky & J Baum, Structural biology: Modelling collagen diseases. Nature 453:998, 6/19/08. News. Collagen is the major structural protein in the human body. There are diseases that are known to be due to mutations in collagen genes. Here they discuss work on a model system, exploring how specific amino acid changes affect collagen. The primary focus is osteogenesis imperfecta, commonly known as brittle-bone disease.

J Couzin, Cholesterol veers off script. Science 322:220, 10/10/08. News. Over the years, the idea has developed that low LDL levels and high HDL levels are desirable. However, not all data are consistent with these simple ideas. Predictions made from those ideas do not always work well. This news story discusses recent information, including failed drugs. The genetic work (of the Hobbs group) discussed by Brown & Goldstein (2006) is included here. Somehow, all this will lead to reevaluation, and to better models.

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