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ScienceWeek
SCIENCEWEEK
March 2, 2007
Vol. 11 - Number 9
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If the Lord Almighty had consulted me before embarking on the Creation, I should have recommended something simpler.
-- Alfonso X, King of Castile (1226-1284)
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Contents (full text below):
1. Chemistry: Water from First Principles
2. Stem Cells: Data on Adult Stem Cells Questioned
3. Physics: Gravity Passes a Little Test
4. Cell Biology: Aneuploidy and Cancer
5. Seizure Prediction: The Long and Winding Road
6. The Politics of Uncertainty: The AIDS Debate, Thabo Mbeki and the South African Government Response
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1. Science 2 March 2007:
Vol. 315. no. 5816, pp. 1228 - 1229
DOI: 10.1126/science.1140758
Perspectives
Chemistry: Water from First Principles
Anthony J. Stone
The water molecule is very simple, yet water in its various forms is one of the most complicated substances. Its anomalous behavior, such as its expansion on freezing and other more subtle properties, is related to the detailed form of the interaction between its molecules, which is still imperfectly understood. For more than 70 years, scientists have been trying to understand the behavior of water in its different forms from first principles--that is, based on the fundamental properties of the water molecule. Much progress has been made in this task in recent years, and the report by Bukowski et al. on page 1249 of this issue (1) marks an important step.
For some substances, the properties of the bulk solid, liquid, or gas can be deduced with reasonable accuracy once one knows the pair potential--that is, the function that describes how the energy of a pair of molecules depends on their relative geometry. For molecules like water, this function depends on six coordinates: the position (three coordinates) and orientation (three more) of either molecule relative to the other. The energy of an assembly of molecules is then taken to be a sum of all pair interactions in the assembly.
For water, and for many other substances, however, the pair potential is not enough. The energy of an assembly of water molecules cannot be described adequately as a sum of pair potentials. The interaction between any two molecules leads to a distortion of both molecules, which in turn modifies their interactions with a third molecule (see the figure). A three-body function is needed to take such effects into account. The three-body correction is a function of 12 coordinates: the position and orientation of two molecules relative to the third. Even this is not enough: In principle, there are four-body and five-body corrections, and so on. These are smaller, but are thought to be important for the tetrahedral structure of liquid water (2). Most of these many-body corrections can be accounted for by a careful description of the polarization of each molecule by its neighbors (3). There are other many-body effects that are not included in this way--for example, the three-body correction to the van der Waals attraction (4)--but they are smaller and can often be ignored.
For simulations of liquid water and of biological systems in the presence of water, very simple descriptions are needed because of computational constraints. They usually approximate the many-body effects by modifying the pair potential, typically by enhancing the molecular dipole moment. These models are quite successful in modeling liquid water at ambient temperature and pressure, but give a very poor account of the water dimer, because the modified pair potential is incorrect.
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2. Science 2 March 2007:
Vol. 315. no. 5816, p. 1207
DOI: 10.1126/science.315.5816.1207a
News of the Week
Stem Cells: Data on Adult Stem Cells Questioned
Constance Holden
Just as her team is preparing some long-awaited follow-up papers on multipotent adult progenitor (MAP) cells, stem cell researcher Catherine Verfaillie is dealing with accusations that her landmark study, published in Nature in 2002, contains "flaws" that could jeopardize its conclusions. Nature has decided to rereview the work. Verfaillie, now at the Catholic University of Leuven, Belgium, says that although some data are puzzling, the problems do not affect her findings.
The accusations were raised last summer but became widely known only last week following an article in New Scientist. They've received a flurry of attention because of the big splash Verfaillie made when she originally reported that her team had cultivated a new type of cell that appeared to have the potential to grow into most cell types in the body (Science, 9 February, p. 760).
Last year, two New Scientist reporters noticed that the Nature paper and another the team published at the same time in the Journal of Experimental Hematology contained identical data on flow cytometry--a technique for identifying cells--even though the two papers described different cell populations. They notified Verfaillie, who in turn notified the journal editors and the University of Minnesota (UMN), Twin Cities, where she did the research.
At Verfaillie's request, UMN convened three experts to review the flow-cytometry data. They concluded last August that the duplication was an "honest error." Verfaillie subsequently had an erratum published in the hematology journal.
However, the panel also said it had reservations about the "validity" of the flow-cytometric analysis data in the Nature paper. Flow cytometry involves the use of antibodies to recognize proteins on cell membranes. Some of the fluorescent signatures generated by antibodies showed a variability "far outside what would be expected for this kind of experiment," said the panel. If those data are unreliable, it could mean that the MAP cells do not have all the characteristics described in the paper.
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3. Nature 446, 31-32 (1 March 2007) | doi:10.1038/446031a; Published online 28 February 2007
Physics: Gravity Passes a Little Test
Clive Speake
Isaac Newton's inverse-square law of gravity has given faultless service ever since that infamous encounter with an apple in the late seventeenth century. It might seem surprising, therefore, that physicists still feel compelled to verify it. But they do: writing in Physical Review Letters1, Kapner et al. detail the latest high-precision test, showing that the gravitational forces between laboratory masses separated by as little as 55 mum — a scale at which there are good reasons to believe that the inverse-square law will break down — are consistent with Newton's law. But why should we prick up our ears at the news, "Gravity doesn't fail again"?
Of course, it could be argued that Newton's law is so fundamental that it should be subject to the most stringent tests on offer at any time. But the true significance of Kapner and colleagues' result lies in its implications for resolving the 'cosmological constant problem'. This problem, in turn, brings into sharp focus a conflict at the heart of efforts to develop a 'theory of everything', a theoretical framework that would treat gravitation and the other forces of nature on an equal footing. The incompatibility of gravitation with quantum mechanics is central to this conflict.
To illustrate where Kapner and colleagues' study fits in, let us work backwards from this impasse. One promising approach to breaking it is string theory, which endows fundamental matter and field particles with internal degrees of freedom that can be likened to the harmonics of a string. A well-known result of quantum mechanics is that a harmonic oscillator (or, to give another example, a mass on a spring) has a finite amount of energy even at a temperature of absolute zero, at which its thermal vibrations would have ceased entirely. This idea of a non-zero 'ground state' energy can also be applied to electromagnetic radiation contained in, say, a metal box. Here, each resonant mode (like the resonances of a drum head) carries the zero-point energy. The total energy density is the sum of the contributions from all the modes, and the magnitude of the sum is determined largely by the highest (or cut-off) frequency.
If this picture is applied to the vibrating quantum fields that suffuse the vacuum of the cosmos, a surprising result emerges. Simple thermodynamics shows that the vacuum must produce a negative pressure to balance out its non-zero, positive energy density. Furthermore, relativity theory suggests that negative pressure — the 'sucking' of the vacuum — creates a repulsive component to gravity. We therefore expect the zero-point energy of all the quantum fields at large in the Universe to act against the mutual attraction of ordinary matter. If this effect were big enough, it could create a Universe in which the recession speeds of distant galaxies would increase with time.
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4. Nature 446, 38-39 (1 March 2007) | doi:10.1038/446038a; Published online 28 February 2007
Cell Biology: Aneuploidy and Cancer
David Pellman
Aneuploid cancers are like Tolstoy's unhappy families: each aneuploid cancer has its own particular abnormal chromosome content, and thus its own abnormal characteristics. This variability has long frustrated biologists trying to establish whether aneuploidy is a cause or a consequence of malignant transformation. Two papers in Cancer Cell1, 2 advance the argument for 'cause', but with qualifications.
There are two ways in which cells can become aneuploid: they can develop alterations in the number of intact chromosomes, which is known as whole-chromosome aneuploidy and originates from errors in cell division (mitosis); and they can undergo rearrangements in chromosome structure — deletions, amplifications or translocations — that arise from breaks in DNA. Such rearrangement is a well-established cause of tumour development. By contrast, the contribution of whole-chromosome aneuploidy to cancer is the subject of controversy.
Weaver et al.2 studied a line of genetically engineered mice that tend to gain or lose whole chromosomes with each cell division because of a defect in mitosis. These mice are heterozygous for the Cenp-e (centromere protein E) gene — that is, they have only one functional copy. This gene encodes a motor protein that is involved in aligning chromosomes normally on the mitotic spindle3, 4, and complete loss of the gene is lethal. Heterozygous cells, however, have only partly defective mitotic spindles and are viable, but develop whole-chromosome aneuploidy more frequently than normal cells (Fig. 1a). The CENP-E protein has roles not only in chromosome segregation, but also in modulating the spindle checkpoint4, which is a signalling system that senses spindle defects and delays mitosis to prevent errors in chromosome segregation. Thus, loss of CENP-E is a double whammy: cells make more mistakes and fail to respond to them properly.
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5. Brain 2007 130(2):314-333; doi:10.1093/brain/awl241
Seizure Prediction: The Long and Winding Road
Florian Mormann1, Ralph G. Andrzejak3, Christian E. Elger1 and Klaus Lehnertz1,2
1 Department of Epileptology, University of Bonn Bonn, Germany 2 Helmholtz-Institute for Radiation and Nuclear Physics, University of Bonn Bonn, Germany 3 Department of Technology, University Pompeu Fabra Barcelona, Spain
The sudden and apparently unpredictable nature of seizures is one of the most disabling aspects of the disease epilepsy. A method capable of predicting the occurrence of seizures from the electroencephalogram (EEG) of epilepsy patients would open new therapeutic possibilities. Since the 1970s investigations on the predictability of seizures have advanced from preliminary descriptions of seizure precursors to controlled studies applying prediction algorithms to continuous multi-day EEG recordings. While most of the studies published in the 1990s and around the turn of the millennium yielded rather promising results, more recent evaluations could not reproduce these optimistic findings, thus raising a debate about the validity and reliability of previous investigations. In this review, we will critically discuss the literature on seizure prediction and address some of the problems and pitfalls involved in the designing and testing of seizure-prediction algorithms. We will give an account of the current state of this research field, point towards possible future developments and propose methodological guidelines for future studies on seizure prediction.
Epilepsy is one of the most common neurological disorders, second only to stroke, with a prevalence of 0.6–0.8% of the world's population (Annegers, 1996Go). Two-thirds of the patients achieve sufficient seizure control from anticonvulsive medication, and another 8–10% could benefit from resective surgery. For the remaining 25% of patients, no sufficient treatment is currently available.
For epilepsy patients who do not achieve complete seizure control, it is the sudden, unforeseen way in which seizures strike ‘like a bolt from the blue’ that represents one of the most disabling aspects of the disease. Apart from the risk of serious injury, there is often an intense feeling of helplessness that has a strong impact on the everyday life of a patient. A method capable of predicting the occurrence of seizures could significantly improve the therapeutic possibilities (Elger, 2001Go) and thereby the quality of life for epilepsy patients.
A question of particular interest is whether apart from clinical prodromi, which are found only in some patients (Hughes et al., 1993Go; Rajna et al., 1997Go; Schulze-Bonhage et al., 2006Go), characteristic features can be extracted from the continuous EEG that are predictive of an impending seizure. If it were possible to reliably predict seizure occurrence from dynamical changes in the EEG of epilepsy patients, fully automated closed-loop seizure-prevention systems could be envisioned. Treatment concepts could move from preventive strategies (e.g. long-term medication with anti-epileptic drugs) towards an EEG-triggered on-demand therapy [e.g. by excretion of fast-acting anticonvulsant substances (e.g. Stein et al., 2000Go) or by electrical or other stimulation in an attempt to reset brain dynamics to a state that will no longer develop into a seizure (e.g. Theodore and Fisher, 2004Go; Morrell, 2006Go)].
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6. Social History of Medicine 2006 19(3):521-538; doi:10.1093/shm/hkl077
The Politics of Uncertainty: The AIDS Debate, Thabo Mbeki and the South African Government Response
Kiran van Rijn
Shortly after becoming President of South Africa in 1999, Thabo Mbeki began to seek non-mainstream advice about his nation's AIDS epidemic; a number of those consulted were outspoken in denying the causal link between HIV and AIDS. In response to Mbeki's actions, over 5,000 scientists signed the ‘Durban Declaration’, which declared HIV to be the cause of AIDS, and which appeared in Nature shortly before the thirteenth AIDS conference, held in Durban, South Africa, in July 2000. The government position and strategy were not completely resolved until July 2002, when the Constitutional Court effectively compelled the government to provide anti-retroviral medication to all HIV-infected pregnant women. Mbeki's public remarks, in essence, can be interpreted as seeking to promote an understanding of AIDS in Africa in terms of epidemiology, rather than virology. Throughout this episode, different interpretations of AIDS served to advance different moral and political courses of action. The ability of medical science to compel political action depended on whether that science was understood to be conclusive or uncertain, objective or value-laden, disinterested or tied to vested interests. Mbeki (along with AIDS sceptics) tested conventional AIDS science for these qualities. By examining the politics of uncertainty, we learn about the politics that sustain certainty.
This is the paradox: the more a body of knowledge is understood to be objective and disinterested, the more valuable it is as a tool in moral and political action. Conversely, the capacity of a body of knowledge to make valuable contributions to moral and political problems flows from an understanding that it was not produced and evaluated to further particular human interests.
Dr Art Amman, a paediatrician and head of the US-based Global Strategies for HIV Prevention, said in a group e-mail to international colleagues: ‘After reviewing the volumes of communication having to do with the Duesberg disciples, personally listening in court for two days to these individuals, and surveying the damage they are invoking, I am trying to reach some conclusions and think about a rational approach to limiting their future damage and influence.’
Amman's e-mail said the scientific community should publish ‘a denunciation of these individuals and their theories as not credible, dangerous and analogous to other pseudo-scientific theories in the past which are taken up by despots for nefarious intent’, such as theories of eugenics and racial superiority.
News item: A. Sulcas, ‘Mbeki's AIDS Call Alarms Scientists’, Sunday Independent, 18 March 2000.
As I listened and heard the whole story told about our own country, it seemed to me that we could not blame everything on a single virus.
Thabo Mbeki, ‘Speech by President Mbeki at the Opening Session of the 13th International AIDS Conference’, Unwembi's Resource of South African Government Information, July 9, 2000.
When Thabo Mbeki, shortly after assuming the Presidency of South Africa in 1999, began to seek non-mainstream advice about the AIDS epidemic sweeping across his nation, howls of protest filled the scientific and lay press. Not to be deterred, he summoned a panel of experts, a significant number of whom were outspoken in rejecting the causal link between HIV and AIDS. In response, over 5,000 scientists signed the so-called Durban Declaration, which declared HIV to be the cause of AIDS, and which appeared in Nature shortly before the thirteenth AIDS conference, held in Durban, South Africa, in July 2000. For two years, Mbeki and his African National Congress-led government wavered on the issue of the cause of AIDS and how to deal with it. In April 2002, the South African government finally decided to offer anti-retroviral medications to victims of rape. In July 2002, a Constitutional Court ruling denied the government appeal of a Pretoria High Court decision of December 2001 that had compelled the government to provide such medications to all HIV-infected pregnant women.
Medicine has long tended to take its stand upon the authority of science. But what happens when this authority comes under attack? This essay explores the implications of treating science—and medical science, in particular—as conclusive, objective and disinterested, and the implications of treating it as uncertain, value-laden, and tied to vested interests. Proponents of the causal link between HIV and AIDS present this link in the first way; on these grounds they designate a moral path that demands specific actions from politicians such as Mbeki. Those who question this link emphasise the uncertainties in the science, the vested interests of those who defend the link, and the social, economic and historical context in which the science has developed. Such sceptics challenge the very nature of science, asking what constitutes a ‘hard’ fact; what roles consensus, peer review, publication and funding should and do play; and how particular kinds of expertise and assumptions shape the content of science.
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