ScienceWeek

SCIENCEWEEK

November 10, 2006

Vol. 10 - Number 45

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If you are a scientist you believe that it is good to find out how the world works, that it is good to find out what the realities are, that it is good to turn over to mankind at large the greatest possible power to control the world... It is not possible to be a scientist unless you believe that the knowledge of the world, and the power which this gives, is a thing which is of intrinsic value to humanity, and that you are using it to help in the spread of knowledge, and are willing to take the consequences.

-- J. Robert Oppenheimer (1904-1967)

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Contents (full reports below):

1. Medical Biology: On Alzheimer's Disease. One hundred years ago, on 3 November 1906, at the 37th meeting of the Society of Southwest German Psychiatrists in Tübingen, Germany, Alois Alzheimer presented the clinical and neuropathological characteristics of the disease that Emil Kraepelin subsequently named after him. Alzheimer's disease (AD) is now the most common neurodegenerative disease...


2. Neurophysiology: On Life, the Universe, and Body Temperature. In his book Life, the Universe, and Everything, Douglas Adams describes an advanced civilization that asks a supercomputer to calculate an answer to the Ultimate Question of "life, the universe, and everything". After several million years of calculation, the computer answers: "42". A similarly inscrutable constant that we face in everyday life is 37...


3. Neuroscience: On Crossed circuits. The rapidly growing field of neural engineering has led to the development of electronic devices that interact directly with neurons with the aim of examining fundamental neural operations and of replacing damaged brain functions. New work uses a self-contained electronic circuit implanted in the brains of monkeys to demonstrate a basic feature of learning...


4. Physical Chemistry: On the Organization of Porous Solids. Although the era of empirical chemistry is seemingly long gone, many chemical processes are still poorly understood. The formation of crystalline porous solids with nanoscale cavities is a case in point. These materials are extremely useful catalysts for many industrial chemical reactions, but we have little understanding of how they crystallize from...


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Also Noted:

Biotech. The Countercultural Origins of an Industry. Eric J. Vettel. University of Pennsylvania Press, Philadelphia, 2006. Hardback: 289 pp., illus. $39.95, £26. ISBN 0812239474. More information at: http://www.amazon.com/exec/obidos/ASIN/0812239474/scienceweek

A Brief History of Modern Psychology. Ludy T. Benjamin Jr. Blackwell, Malden, MA, 2006. Paperback: 264 pp., illus. $29.95, £17.99, AU$59.95. ISBN 140513206X. More information at: http://www.amazon.com/exec/obidos/ASIN/140513206X/scienceweek

Complex Systems in Biomedicine. A. Quarteroni, L. Formaggia, and A. Veneziani, Eds. Springer, Milan, 2006. Hardback: 306 pp., illus. $79.95. ISBN 8847003946. More information at: http://www.amazon.com/exec/obidos/ASIN/8847003946/scienceweek

Earth Cycles. A Historical Perspective. David Oldroyd. Greenwood Guides to Great Ideas in Science. Greenwood, New York, 2006. Hardback: 248 pp., illus. $65, £36.99. ISBN 0313332290. More information at: http://www.amazon.com/exec/obidos/ASIN/0313332290/scienceweek

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Special Note: A New Book by the Editor of ScienceWeek:

JUNK SCIENCE. How Politicians, Corporations, and Other Hucksters Betray Us. Dan Agin. Thomas Dunne Books/St. Martin's Press, New York, 2006. Hardback: 336 pp., $24.95. ISBN 0312352417.

From NEW SCIENTIST (UK) (issue of 4 November 2006):

Dan Agin, an emeritus biologist at the University of Chicago, is passionate in defence of science. In JUNK SCIENCE he targets those who abuse or distort it, starting with scientists who fake results. This is neither rare nor easily uncovered, he warns. Agin lambasts the Bush administration, Big Tobacco, the pharmaceutical industry, mainstream and alternative medicine, psychotherapy, the religious right and others who deny or attack inconvenient research. Anyone who values good science will appreciate finding all this together in a cogent, powerfully argued book.

More information about JUNK SCIENCE at: http://www.amazon.com/exec/obidos/ASIN/0312352417/scienceweek

A recent long review of this book appeared in the San Diego Union-Tribune, October 22, 2006. The review can be accessed at:

http://www.signonsandiego.com/uniontrib/20061022/news_lz1v22junk.html

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1. MEDICAL BIOLOGY: ON ALZHEIMER'S DISEASE

The following points are made by M. Goedert and M.G. Spillantini (Science 2006 314:777):

1) One hundred years ago, on 3 November 1906, at the 37th meeting of the Society of Southwest German Psychiatrists in Tübingen, Germany, Alois Alzheimer presented the clinical and neuropathological characteristics of the disease (1,2) that Emil Kraepelin subsequently named after him (3). Alzheimer's disease (AD) is now the most common neurodegenerative disease, with more than 20 million cases worldwide. At the time of his lecture, Alzheimer was head of the Anatomical Laboratory at the Royal Psychiatric Clinic of the University of Munich. He had moved there in 1903 after having spent 14 years at the Municipal Institution for the Mentally Ill and Epileptics in Frankfurt, where Franz Nissl had introduced him to brain histopathology. In November 1901, Alzheimer admitted Auguste D., a 51-year-old patient, to the Frankfurt hospital because of progressive memory loss, focal symptoms, delusions, and hallucinations. After the death of Auguste D. in April 1906, her brain was sent to Munich for analysis. Alzheimer's use of the silver staining method developed by Max Bielschowsky 4 years earlier (4) was crucial for the identification of neuritic plaques and neurofibrillary tangles, the defining neuropathological characteristics of the disease. Whereas plaques had been reported before, first by Blocq and Marinesco in an elderly patient with epilepsy (5), Alzheimer was the first to describe the tangle pathology. In 1911, he found a different type of nerve cell inclusion in two cases with focal degeneration of the cerebral cortex (2). This is now known as the Pick body (even though it was first described by Alzheimer) and the clinicopathological entity is known as Pick's disease, after Arnold Pick, who first described it in 1892. Pick's disease belongs to the spectrum of frontotemporal lobar degeneration (FTLD).

2) The presence of abnormal deposits helped greatly with disease classification. However, their molecular composition and role in the pathological process remained unknown. Over the past 25 years, a basic understanding has emerged from the coming together of two independent lines of research. First, the molecular study of the deposits led to the identification of their major components. Second, the study of rare, inherited forms of disease resulted in the discovery of the causative gene defects. In most cases, the defective genes encode the major components of the pathological lesions or factors that change their levels. It follows that a toxic property of the proteins that make up the filamentous lesions underlies the inherited disease cases. A similar toxic property may also cause the much more common sporadic forms of disease.

3) In the electron microscope, plaques and tangles contain abnormal filaments. Plaque filaments are extracellular and have the molecular fine structure of amyloid. This term refers to filaments with a diameter of around 10 nm that have a cross-beta structure and characteristic dye-binding properties. Most tangle filaments have a paired helical morphology and are also amyloid-like. Paired helical filaments are present in nerve cell bodies, as well as in neurites in the neuropil and at the periphery of neuritic plaques. After the identification of filaments, it took another 20 years before their major components were known. The identification of amyloid-beta as the major plaque component and tau as the major tangle component ushered in the modern era of research on AD. Filamentous tau deposits are also present in a number of other neurodegenerative disorders, including Pick's disease.

4) Amyloid-beta is 40 to 42 amino acids in length and is generated by proteolytic cleavage of the much larger amyloid precursor protein (APP), a transmembrane protein of unknown function with a single membrane-spanning domain. The N terminus of amyloid-beta is located in the extracellular domain of APP, 28 amino acids from the transmembrane region, and its C terminus is in the transmembrane region. The enzymes whose activity gives rise to the N and C termini are called beta-secretase and gamma-secretase, respectively. A third enzyme, alpha-secretase, cleaves between residues 16 and 17, precluding amyloid-beta formation. The major species of amyloid-beta are 40 or 42 amino acids long, and it is the more amyloidogenic 42–amino acid form (with its two additional hydrophobic amino acids) that is deposited first. In the three-dimensional structure of the amyloid-beta fibril, residues 1 to 17 are disordered, with residues 18 to 42 forming a beta-strand–turn–beta-strand motif that contains two parallel beta sheets formed by residues 18 to 26 and 31 to 42.

References (abridged):

1. A. Alzheimer, Allg. Z. Psychiatr. 64, 146 (1907).

2. A. Alzheimer, Z. Ges. Neurol. Psychiat. 4, 356 (1911).

3. E. Kraepelin, Psychiatrie. Ein Lehrbuch fur Studierende undärzte. II. Band (Barth Verlag, Leipzig, 1910).

4. M. Bielschowsky, Neurol. Centralbl. 21, 579 (1902).

5. P. Blocq, G. Marinesco, Sem. Méd. 12, 445 (1892).

Science http://www.sciencemag.org

ScienceWeek http://scienceweek.com

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2. NEUROPHYSIOLOGY: ON LIFE, THE UNIVERSE, AND BODY TEMPERATURE

The following points are made by Clifford B. Saper (Science 2006 314:773):

1) In his book Life, the Universe, and Everything, Douglas Adams describes an advanced civilization that asks a supercomputer to calculate an answer to the Ultimate Question of "life, the universe, and everything". After several million years of calculation, the computer answers: "42". A similarly inscrutable constant that we face in everyday life is 37, the mean body temperature measured in degrees Celsius of humans and most other mammals. We tend to take this number for granted, as it is always in the same, narrow range, until, of course, we become ill with a fever. We then take medications, usually inhibitors of prostaglandin synthesis (aspirin, ibuprofen, etc.), which typically brings our body temperature back to normal. But why is 37 °C "normal", and is this truly the optimal operating temperature for our bodies?

2) New work (1) questions this dogma. Surprisingly, their results suggest that our usual body temperature may not be optimal, at least in determining our life span. The work is based on a growing revolution in our understanding of how the brain controls body temperature. Although it has been known for decades that the preoptic area -- the most rostral tip of the hypothalamus -- is both thermosensitive and necessary for maintaining normal body temperature, the details of the neural circuits that control body temperature have only recently begun to be elucidated (2). It is now understood that neurons in the medial preoptic region have an intense inhibitory effect on thermogenic responses. Other neurons in the middle part of the hypothalamus, including the paraventricular and dorsomedial nuclei, have an excitatory effect on thermogenesis, but are normally held in check by the preoptic neurons. The interplay between the thermogenic neurons and those in the medial preoptic nucleus that hold them in check is critical in controlling body temperature under a wide range of conditions. The hypothalamic sites, furthermore, have descending inputs to brainstem and spinal areas that control autonomic thermoregulatory responses. By shifting blood flow to cutaneous blood vessels, heat can be exhausted, whereas heat retention is promoted by shifting blood flow to deep blood vessels (hence fingers and toes turn blue in the cold).

3) Thermogenesis is subserved by neural inputs to brown adipose tissue, at least in small mammals, where ?3 adrenergic receptors mediate production of uncoupling protein 1 (UCP-1). UCP-1 allows mitochondria in brown adipose tissue to convert adenosine 5'-triphosphate (ATP) to heat, rather than to energy for performing work. Thus, small mammals that lack sufficient mass for heat retention carry portable heaters in the form of brown adipose tissue that allow them to avoid hypothermia.

4) Here is where the intervention engineered by Conti et al (1) comes in. They produced transgenic mice in which expression of the UCP-2 gene (closely related to UCP-1) is placed under the control of the promoter for hypocretins (also called orexins). Hypocretins are peptides that are produced only by cells in the lateral hypothalamus (3). By placing UCP-2 expression under the control of this promoter, the investigators effectively placed a small heater into the hypothalamus. As their data show, this caused heating of the preoptic area, a region in which previous work had shown that insertion of heat probes would cause a reduction in body temperature. The result is that the transgenic animals expressing the UCP-2 gene had a continuous reduction in body temperature by 0.3° to 0.5°C. (4,5)

References (abridged):

1. B. Conti et al., Science 314, 825 (2006).

2. S. F. Morrison, News Physiol. Sci. 19, 67 (2004).

3. J. T. Willie, R. M. Chemelli, C. M. Sinton, M. Yanagisawa, Annu. Rev. Neurosci. 24, 429 (2001).

4. G. A. Bray, T. Bellanger, Endocrine 29, 109 (2006).

5. R. K. Liu, R. L. Walford, J. Gerontol. 30, 129 (1975).

Science http://www.sciencemag.org

ScienceWeek http://scienceweek.com

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3. NEUROSCIENCE: ON CROSSED CIRCUITS

The following points are made by Andrew B. Schwartz (Nature 2006 444:47):

1) The rapidly growing field of neural engineering has led to the development of electronic devices that interact directly with neurons with the aim of examining fundamental neural operations and of replacing damaged brain functions. New work (1) uses a self-contained electronic circuit implanted in the brains of monkeys to demonstrate a basic feature of learning -- the ability to change the routing of neural information -- that could prove useful in rehabilitative therapy.

2) The authors used off-the-shelf components to build what they call a "neurochip". Neurons in the brain's motor cortex fire impulses during voluntary movements, and the neurochip picks up these impulses, or "spikes", by means of a recording microelectrode placed near the neurons. Through the neurochip, the spikes trigger an electric-stimulus pulse through a second, stimulating electrode at an adjacent site in the motor cortex. Because the circuit is self-contained, this spike-stimulus sequence could be carried out continuously for 24 hours while the animal went about its normal activities in its cage (termed the conditioning period). The idea behind the neurochip was that by picking up the signals from one neuronal circuit and transferring them to another repeatedly over a 24-hour period, a new information route might be formed. This would have obvious potential with regard to rehabilitation after neural injury, but it would also give insight into learning, which is thought to occur as neural circuits and connections are strengthened through use.

3) The authors also used a technique called intracortical microstimulation (ICMS), which provides a measure of neural connectivity (2,3) between the cortical neurons and muscles, to assess whether the neural circuit had been rerouted by the neurochip during the conditioning period. In ICMS, high-frequency bursts -- or trains -- of electrical pulses (in the range 10-100 microamps) are passed through microelectrodes in the cortex, activating a large network of neuronal connections spanning the cortex, subcortical structures, and the spinal cord to generate muscle twitches.

4) Cortical neurons that project to different muscles are in fact intermixed in the part of the motor cortex that is likely to be activated by ICMS (4). Because of the extent of this network, it is not possible to delineate a specific functional route between the stimulation site and the observed muscle twitch using ICMS by itself, and it is difficult to ascribe a specific causal role to any cortical neuron. But although ICMS is only a rough measure of connectivity, it can indicate when the pathways change in response to external stimuli. For instance, activation of the muscles by ICMS changes rapidly with peripheral-nerve injury (5), or even when a limb is placed in a splint for just a few hours.

References (abridged):

1. Jackson, A., Mavoori, J. & Fetz, E. E. Nature 444, 56-60 (2006).

2. Asanuma, H. & Sakata, H. J. Neurophysiol. 30, 35-54 (1967).

3. Stoney, S. D., Thompson, W. D. & Asanuma, H. J. Neurophysiol. 31, 659-669 (1968).

4. Rathelot, J. A. & Strick, P. L. Proc. Natl Acad. Sci. USA 103, 8257-8262 (2006).

5. Donoghue, J. P., Suner, S. & Sanes, J. N. Exp. Brain Res. 79, 492-503 (1990).

Nature http://www.nature.com/nature

ScienceWeek http://scienceweek.com

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4. PHYSICAL CHEMISTRY: ON THE ORGANIZATION OF POROUS SOLIDS

The following points are made by Rutger A. van Santen (Nature 2006 444:46):

1) Although the era of empirical chemistry is seemingly long gone, many chemical processes are still poorly understood. The formation of crystalline porous solids with nanoscale cavities is a case in point. These materials are extremely useful catalysts for many industrial chemical reactions, but we have little understanding of how they crystallize from their disordered precursors. Such insight could enable better catalysts to be designed. A novel combination of spectroscopic tools has now been used to unravel the mechanistic details of the synthesis of complex nanoporous solids, as reported in two papers in the Journal of the American Chemical Society (1,2). The results suggest that molecular complexes in the synthetic mixture "recognize" template molecules, so forming clusters from which ordered structures may grow.

2) Zeolites are porous solids that contain channels up to 1 nanometer long. The building-blocks of these solids are tetrahedra of oxygen atoms, with a cation at the centre of each tetrahedron. Three-dimensional networks are formed through corner-sharing of the tetrahedra. From the infinite number of theoretical frameworks that can be constructed from these building-blocks, only about 150 different zeolites are found experimentally. Archetypal zeolites have a lattice framework that is electrostatically neutral, such as is seen in silicalite, which is constructed from SiO4 tetrahedra. Similar structures, known as aluminophosphates, can be constructed from combinations of aluminium-based tetrahedra (AlO4) and phosphorus-based tetrahedra (PO4) (3). A good example of this is the zeolite known as AlPO4-5, which contains one-dimensional channels.

3) Zeolites become catalysts only when reactive complexes are incorporated into the structure. This can be done in two ways. First, one can replace cations in the lattice framework with cations that have a lower positive charge. For example, when cobalt ions (Co2+) substitute for some of the aluminium ions (Al3+) in aluminophosphates, a porous solid is generated that catalyzes oxidations (4). Such cation substitutions result in a framework that has an overall negative charge. This can be balanced by placing cations in the nanoporous channels. If reactive cations are used, this is a second way to activate catalytic behavior. A breakthrough in zeolite science came with the discovery that previously unknown structures could be made by adding organic bases to the chemical reactions used to prepare zeolites (5). These organic bases seem to act as a template for the formation of micropores and are now commonly used in zeolite synthesis, although the molecular details of their role are poorly understood.

4) Now, Weckhuysen and colleagues (1,2) have advanced our understanding of the molecular mechanism for the organic-base-mediated synthesis of zeolites. Zeolites usually form as gels, which then crystallize into the desired microporous solids. The authors used a combination of in situ techniques to examine this crystallization process. They applied X-ray scattering methods (1) previously also used to study silicalite synthesis from solution to probe the dimensions of particle aggregates and the presence of crystals. They combined this with spectroscopy (2) to investigate the local environment of the atoms.

References (abridged):

1. Beale, A. M. et al. J. Am. Chem. Soc. 128, 12386-12387 (2006).

2. O'Brien, M. G., Beale, A. M., Catlow, C. R. A. & Weckhuysen, B. M. J. Am. Chem. Soc. 128, 11744-11745 (2006)

3. Flanigan, E. M., Lok, B. M., Patton, R. L. & Wilson, S. T. in New Developments in Zeolite Science and Technology Vol. 28 (eds Murakami, Y., Ijima, A. & Ward, J. W.) 103-112 (Elsevier, Amsterdam, 1986).

4. Raja, R., Sankar, G. & Thomas, J. M. J. Am. Chem. Soc. 123, 8153-8154 (2001).

5. Barrer, R. M. & Denny, P. J. J. Chem. Soc. 971-982 (1961).

Nature http://www.nature.com/nature

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