ScienceWeek

SCIENCEWEEK

December 1, 2006

Vol. 10 - Number 47

--------------------------------

Humanity is far from perfect in its understanding, abilities, or intentions. We must not imagine, however, that we and our civilization are less than precious. We have the gift of intelligence, and that is the finest thing this planet has ever produced.

-- Michael A. Seeds

--------------------------------

Contents (full text below):

1. Neuroscience: On the Brain's "Dark Energy"

2. Climate Science: How Fast Are the Ice Sheets Melting?

3. Medicine: On Blastomeres and Stem Cells

4. Human genomics: On Human Genome Variation in Disease

--------------------------------

Also Noted:

Probabilities. The Little Numbers that Rule Our Lives. Peter Olofsson. Wiley-Interscience, Hoboken, NJ, 2006. Hardback: 277 pp., illus. ISBN 0470040017. More information at: http://www.amazon.com/exec/obidos/ASIN/0470040017/scienceweek

The Neuroscience of Human Relationships. Attachment and the Developing Social Brain. Louis Cozolino. Norton, New York, 2006. Hardback: 459 pp., illus. ISBN 0393704548. More information at: http://www.amazon.com/exec/obidos/ASIN/0393704548/scienceweek

Good and Real. Demystifying Paradoxes from Physics to Ethics. Gary I. Drescher. MIT Press, Cambridge, MA, 2006. Hardback: 363 pp., illus. ISBN 0262042339. More information at: http://www.amazon.com/exec/obidos/ASIN/0262042339/scienceweek

Dark Cosmos. In Search of Our Universe's Missing Mass and Energy. Dan Hooper. Smithsonian Books (HarperCollins), New York, 2006. Hardback: 256 pp., illus. ISBN 006113032X. More information at: http://www.amazon.com/exec/obidos/ASIN/006113032X/scienceweek

The Artist and the Mathematician. The Story of Nicholas Bourbaki, the Genius Mathematician Who Never Existed. Amir D. Aczel. Thunder's Mouth (Avalon Publishing Group), New York, 2006. Hardback: 251 pp. ISBN 1560259310. More information at: http://www.amazon.com/exec/obidos/ASIN/1560259310/scienceweek

=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=

Search or browse thousands of ScienceWeek reports at the ScienceWeek website: http://scienceweek.com

=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=

1. NEUROSCIENCE: ON THE BRAIN'S "DARK ENERGY"

The following points are made by Marcus E. Raichle (Science 2006 314:1249):

1) Since the 19th century, and possibly longer, two perspectives on brain functions have existed (1). One view posits that the brain is primarily reflexive, driven by the momentary demands of the environment; the other, that the brain's operations are mainly intrinsic, involving the maintenance of information for interpreting, responding to, and even predicting environmental demands. While neither view is dominant, the former has motivated most neuroscience research. But technological advances, particularly in neuroimaging, have provoked a reassessment of these two perspectives.

2) Human functional neuroimaging, first with positron emission tomography (PET) and now largely with functional magnetic resonance imaging (fMRI), allows the brain's responses to controlled stimuli to be studied by measuring changes in brain circulation and metabolism (energy consumption). These studies have revealed that the additional energy required for such brain responses is extremely small compared to the ongoing amount of energy that the brain normally and continuously expends (2). The brain apparently uses most of its energy for functions unaccounted for -- "dark energy", in astronomical terms. What do we know about this dark energy?

3) The adult human brain represents about 2% of the body weight, yet accounts for about 20% of the body's total energy consumption, 10 times that predicted by its weight alone. What fraction of this energy is directly related to brain function? Depending on the approach used, it is estimated that 60 to 80% of the energy budget of the brain supports communication among neurons and their supporting cells (2). The additional energy burden associated with momentary demands of the environment may be as little as 0.5 to 1.0% of the total energy budget (2). This cost-based analysis implies that intrinsic activity may be far more significant than evoked activity in terms of overall brain function.

4) Consideration of brain energy may thus provide new insights into questions that have long puzzled neuroscientists. For example, researchers have sought to explain the relative disproportion of connections (i.e., synapses) among neurons that appear to perform functions intrinsically within the cerebral cortex. Take the visual cortex, whose primary function is to respond to external input to the retina. Less than 10% of all synapses carry incoming information from the external world (3) -- a surprisingly small number. From a brain energy perspective, however, the cortex may simply be more involved in intrinsic activities.(3-5)

References (abridged):

1. R. Llinas, I of the Vortex: From Neurons to Self (MIT Press, Cambridge, MA, 2001).

2. M. E. Raichle, M. Mintun, Annu. Rev. Neurosci. 29, 449 (2006).

3. A. Peters, B. R. Payne, J. Budd, Cereb. Cortex 4, 215 (1994).

4. B. Haider, A. Duque, A. R. Hasenstaub, D. A. McCormick, J. Neurosci. 26, 4535 (2006).

5. B. A. Olshausen, in The Visual Neurosciences, L. M. Chalupa, J. S. Werner, Eds. (MIT Press, Cambridge, MA, 2003), pp. 1603-1615.

Science http://www.sciencemag.org

ScienceWeek http://scienceweek.com

=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=

2. CLIMATE SCIENCE: HOW FAST ARE THE ICE SHEETS MELTING?

The following points are made by Anny Cazenave (Science 2006 314:1250):

1) If the ice sheets covering Greenland and Antarctica were to melt completely, they would raise sea level by about 65 m. But even a small loss of ice mass from the ice sheets would have a great impact on sea level, particularly on low-lying islands and coastal regions. New satellite observations, including those reported by Luthcke et al (1), now allow estimates of the mass balances of the ice sheets and their evolution through time.

2) For the past 3000 years, global sea level has remained stable, but since the end of the 19th century, tide gauges have detected global sea-level rises [~1.8 mm/year on average over the past 50 years (2,3)]. Satellite altimetry data document a rate of ~3 mm/year since 1993 (4). However, it remains unclear whether the recent rate increase reflects an acceleration in sea-level rise or a natural fluctuation on a decadal time scale.

3) Present-day sea-level rise has several causes. During the past decade, ocean warming has contributed roughly half of the observed rate of sea-level rise (5), leaving the other half for ocean-mass increase caused by water exchange with continents, glaciers, and ice sheets. The contribution of mountain glaciers and small ice caps to sea-level rise in the past decade is estimated to be ~0.8 mm/year. These figures constrain the contribution from ice sheets to less than 1 mm/year in the past decade.

4) Since the early 1990s, remote-sensing data based on airborne laser and satellite radar altimetry, as well as the space-borne Synthetic Aperture Radar Interferometry (InSAR) technique, have provided the first observations of ice sheet mass balance. These observations indicate accelerated ice-mass loss in recent years in the coastal regions of southern Greenland. In contrast, slight mass gain is reported in central high-elevation regions. Over Antarctica, remote sensing indicates accelerated mass loss in the western part of the continent, whereas the eastern part is gaining some mass as a result of increased precipitation. Because of these contrasting behaviors -- mass loss in coastal regions and mass gain in elevated central regions -- ice-sheet mass loss exceeds mass gain only slightly. Thus, according to the recent mass-balance estimates, the ice sheets presently contribute little to sea-level rise. However, great uncertainty remains, mainly because of incomplete coverage by remote-sensing surveys, spatial and temporal undersampling, measurement errors, and perturbation from unrelated signals.

References (abridged):

1. S. B. Luthcke et al., Science 314, 1286 (2006).

2. J. A. Church et al., J. Climate 17, 2609 (2004).

3. S. Holgate, P. Woodworth, Geophys. Res. Lett. 31, L07305 (2004).

4. A. Cazenave, R. S. Nerem, Rev. Geophys. 42, RG3001 (2004).

5. S. Levitus, J. I. Antonov, T. P. Boyer, Geophys. Res. Lett. 32, L02604, (2005).

Science http://www.sciencemag.org

ScienceWeek http://scienceweek.com

=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=

3. MEDICINE: ON BLASTOMERES AND STEM CELLS

The following points are made by Joe Leigh Simpson (Nature 2006 444:432):

1) Generating human stem cells from a single cell recovered during preimplantation genetic diagnosis does not, in principle, harm the embryo. Can the approach be used in assisted reproductive technology programmes? Klimanskaya et al (1) report an advance for the field of human embryonic stem (hES) cell biology. Readers may have a sense of déjà vu, however, for this paper first appeared as an online publication (2) on 23 August. It was the subject of controversy, partly because of confusion over certain points. It now appears both in print and on the Nature website with an explanatory addendum.

2) The promise of regenerative medicine through stem-cell therapy is intoxicating. Stem-cell lines are pluripotent (that is, they can develop into various cell types); they are self-renewable; and they can differentiate into functional cells. Scientific hurdles remain, principally in inducing nascent stem cells into the desired differentiation pathway. But the potential for treating intractable human disease, by using stem cells to repair damaged tissue, is real. This, however, is a topic that is as much about ethics and politics as about science.

3) The approach of Klimanskaya et al (1) offers a possible route around the objection that the creation of hES cells involves destroying the embryo from which they arise. The authors propose that it could be applied as part of the established technique of preimplantation genetic diagnosis (PGD), which is used to identify genetic defects in embryos created through in vitro fertilization before they are implanted in the uterus. Their procedure1 was as follows. During the early stages of embryo development, the fertilized egg starts to divide into cells called blastomeres. Klimanskaya et al separated individual blastomeres from human embryos at the 8-cell stage, using a micromanipulation method widely used in PGD. Multiple blastomeres from a given embryo were singly placed in individual wells within a flask and allowed to divide. Approximately half did so, and were subject to further culture, as described in the paper. The original cohort of 91 blastomeres yielded 19 ES-cell-like outgrowths and two stable hES cell lines.

4) This work with human blastomeres follows a demonstration by the same group that ES cells can be derived from single mouse blastomeres. In these earlier mouse experiments, an intact viable embryo developed that consisted of the seven remaining blastomeres; by contrast, in the work with human cells, multiple blastomeres were taken from the 8-cell stage and no embryos were allowed to remain in culture. This was a source of confusion in the earlier online publication (2). The main question raised by Klimanskaya et al (1) is whether a single human blastomere, already required for PGD, could be allowed to divide prior to genetic analysis: one daughter cell would then be used for clinical diagnosis, whereas the other would be used to derive an hES cell line. The remaining 7-cell ball of blastomeres would be implanted in the uterus to develop normally, as is PGD practice. The advantage of this procedure would be in creating additional hES cell lines. Parents could possibly bank hES cells from the child from which the blastomere came, so their child could benefit from patient-derived hES-cell therapies if they come to fruition. Furthermore, banking of large numbers of hES cells could be a way of providing immunologically compatible cell lines for a large proportion of the population.(3-5)

References (abridged):

1. Klimanskaya, I., Chung, Y., Becker, S., Lu, S.-J. & Lanza, R. Nature 444, 481–485 (2006).

2. Klimanskaya, I., Chung, Y., Becker, S., Lu, S.-J. & Lanza, R. Nature doi: 10.1038/nature05142 (2006).

3. Chung, Y. et al. Nature 439, 216–219 (2006).

4. Verlinsky, Y. & Kuliev, A. Practical Preimplantation Genetic Diagnosis (Springer, New York, 2005).

5. Munné, S. et al. Reprod. BioMed. Online 7, 91–97 (2003)

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

ScienceWeek http://scienceweek.com

=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=

4. HUMAN GENOMICS: ON HUMAN GENOME VARIATION IN DISEASE

The following points are made by K.V. Shianna and H.F. Willard (Nature 2006 444:428):

1) The human genome contains many forms of genetic variation. The most plentiful are the millions of single base-pair changes in the DNA code that were identified in the course of determining the human genome sequence, and then more systematically through the International HapMap Project (1). These so-called single nucleotide polymorphisms (SNPs) distinguish any two unrelated copies of the genome. They account for the long-hypothesized, evolutionarily "neutral" forms of widespread genetic variation that mark diversity within our species, as well as mutations, both rare and common, that account for or contribute to disease.

2) Less expected have been variations in the copy number of sequence elements -- that is, variation in the number of deleted or duplicated versions of segments of the genome that result in a range of the number of copies (instead of the usual two) among apparently "normal" members of the population (2). Several studies have described the prevalence of common deletion polymorphisms in the human genome (3,4). New work (5) now presents results of a global genome-wide screen looking for all types of copy-number variants (CNVs) using several hundred reference samples from four human populations. The researchers document nearly 1500 variable regions, covering 12% of the human genome and including hundreds of genes and other functional elements whose copy number differs, sometimes dramatically, among us. The data suggest that the greatest source of genetic diversity in our species lies not in millions of SNPs, but rather in larger segments of the genome whose presence or absence calls into question what exactly is a "normal" human genome.

3) To detect CNVs, Redon et al (5) used two complementary genome-wide technologies. The first was a genotyping approach in which some 500,000 SNPs were assayed, looking for stretches of adjacent SNPs that displayed atypical ratios of the expected two versions (called alleles) of a given SNP. The second involved comparing each sample with a reference standard, and looking for systematic differences in intensity among a set of more than 26,000 large-insert cloned segments that span nearly all of the currently sequenced portion of the genome. Combining these approaches provided coverage adequate to detect most forms of CNVs. In total, 1447 CNVs were identified across the 270 HapMap samples. The estimated average length of CNV regions per genome analysed was more than 20 million base pairs, representing some 5- to 10-fold more variation between any two randomly chosen genomes than suggested previously by studying SNPs alone. More than half of the CNVs that were identified overlap known annotated genes in the genome. So it is likely that CNVs play a role in so-called complex diseases, in which multiple genes and/or gene-environment interactions are involved.

4) Mechanistically, how might copy-number variation be involved with complex disease? When deletions or duplications are present within a gene or its regulatory region, there is a reasonable chance that there will be an imbalance in the appropriate level of RNA and thus protein production from that gene. For genes and pathways in which the amount of a functional product produced is critical, it seems likely that CNVs could underscore variation in susceptibility to disease. Classically, variation in the copy number of the globin genes was shown to be responsible for various disorders of haemoglobin, such as the alpha-thalassaemias6. More recently, variable copy number of the CCL3L1 gene was reported to be associated with increased resistance to infection by HIV.

References (abridged):

1. International HapMap Consortium Nature 437, 1299-1320 (2005).

2. Feuk, L. et al. Nature Rev. Genet. 7, 85-97 (2006).

3. Hinds, D. A. et al. Nature Genet. 38, 82-85 (2005).

4. McCarroll, S. A. et al. Nature Genet. 38, 86-92 (2005).

5. Redon, R. et al. Nature 444, 444-454 (2006).

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

ScienceWeek http://scienceweek.com

=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=