Subject: [SciPol 613] ScienceWeek May 25, 2007

From: "Dan Agin" <[email-masked]>
Date: Fri, 25 May 2007 11:50:21 -0500

SCIENCEWEEK

May 25, 2007

Vol. 11 - Number 20

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This fright, this night of the mind, must be dispelled
not by the rays of the sun, nor day's bright spears,
but by the face of nature and her laws.

-- Lucretius (95-55 B.C.)

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Contents (full text below):

1.Astronomy: Dark Matter in Galactic Collisional Debris

2.Physiology: Proteasomes Keep the Circadian Clock Ticking

3.Genetics: Gene Count Numbers: Finally a Firm Answer?

4.Genetics: Perceptions of Epigenetics

5.Neuroscience: The Molecular Wake-Up Call

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1.

Science 25 May 2007: Vol. 316. no. 5828, pp. 1132 - 1133 DOI:
10.1126/science.1143506

Astronomy: Dark Matter in Galactic Collisional Debris

Bruce G. Elmegreen

Galaxies that are born in clusters occasionally get so close to
each other that material from their outer regions, which is only
weakly bound by gravity, gets flung into space, producing long
tidal tails. Other material can fall from one galaxy to the
other, making a bridge. When these tails and bridges disperse,
they can leave behind clumps that may become independent
galaxies. Small galaxies can also collide with and travel through
large galaxies, producing giant circular wakes and more clumps.
As the colliding galaxies eventually lose their orbital energy
and merge, some of the debris falls back in. These are the
processes that are thought to have built up most of today's
galaxies from the small clumps produced in the early universe. An
important question that goes back 50 years (1) is whether the
smallest of today's galaxies, the dwarfs, are old surviving
remnants from early times, or young debris from recent
collisions. On page 1166 of this issue, Bournaud et al. (2)
report the presence of dark matter in tidal dwarfs. This is
contrary to most theoretical predictions, providing new details
about galaxy formation and about the nature of dark matter.

The formation of dwarf galaxies has been difficult to understand
because essentially all small galaxies have relatively large
amounts of dark matter, usually 10 times the visible matter
evident with optical and radio telescopes. However, collisional
debris is not supposed to have dark matter. Galaxies should be
born with their dark matter in equilibrium, having an orbital
energy comparable to the gravitational potential energy. Giant
spirals should therefore have dark-matter particles moving at
high speeds. This means that small, weakly bound collisional
debris cannot hold onto the dark matter from their former
galaxies. The dwarfs just get the cold gas and whatever slow-
moving stars are in the part of the disk they came from

The discovery of collisional debris with dark matter comes as a
welcome surprise: It begins to clarify the origin of some dwarf
galaxies, but it also implies a new kind of dark matter,
something that cools like baryons (e.g., neutrons and protons) or
stays cool from birth and ends up in galaxy disks. Bournaud et
al. observed neutral hydrogen at high resolution in several dwarf
galaxies that formed in the ringlike debris of a collision
involving the galaxy NGC 5291. These dwarfs show rotation curves
(which plot orbital velocity of stars versus their distance from
the galactic center) indicating that the total mass exceeds the
visible mass by a factor of 2. This is not the factor of 10
commonly observed in other dwarf galaxies, but it is good
evidence for dark matter, anyway.

One can imagine four possibilities for this new dark matter: (i)
exotic particles that dissipate energy yet give off no detectable
light; (ii) normal dark matter that stays cool even in deep
potential wells; (iii) dim stars or stellar remnants that give
off too little light to see; or (iv) gas that gives off too
little light to see. Bournaud et al. favor interpretation (iv).
They suggest that because the most abundant gas is hydrogen, and
molecular hydrogen (H2) at ultralow temperature does not radiate
well, a likely source of unseen disk mass is H2.

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2.

Science 25 May 2007: Vol. 316. no. 5828, pp. 1135 - 1136 DOI:
10.1126/science.1144165

Physiology: Proteasomes Keep the Circadian Clock Ticking

David Gatfield and Ueli Schibler

The accumulation of a protein within a cell is determined by the
rates of its synthesis and decay. Because only a minor fraction
of all proteins actually executes rate-limiting functions,
organisms are quite resilient to moderate changes in the
concentrations of most proteins. However, some proteins must be
regulated in a particularly precise manner, and this applies to
components of the circadian clock, a biological device that
regulates a range of physiological processes in many organisms,
over a roughly 24-hour cycle. Two papers in a recent issue of
Science, by Godinho et al. (1) and Busino et al. (2), and a
recent study in Cell by Siepka et al. (3), exemplify the
necessity of this precision by showing that mistimed degradation
of two circadian clock proteins (cryptochromes) in the mouse
causes their accumulation throughout the day. Their presence at
the wrong time dampens the expression of other clock proteins and
as a result, lengthens the period of the circadian cycle.

In mammals, most physiological processes such as sleep-wake
cycles, heart rate, blood pressure, and metabolism oscillate in a
daily cycle, influenced by the circadian clock (4). The rhythm-
generating molecular circuitry in hypothalamic neurons and
peripheral cells (5) relies on a negative-feedback loop involving
the Cryptochrome (Cry1 and Cry2) and Period (Per1 and Per2)
proteins. Cry and Per proteins are transcriptional repressors,
and their expression is activated by a heterodimer containing the
transcription factor Bmal1 and either of two other transcription
factors, Clock or Npas2 (see the figure) (6). Once Per and Cry
proteins reach critical concentrations, they form heterotypic
complexes that bind to the Bmal1-Clock/Npas2 heterodimers and
thereby annul their transcriptional activation potential.
Consequently, Cry and Per transcription is reduced, Cry and Per
protein accumulation falls below the concentrations required for
autorepression, and a new cycle of Cry and Per expression can
ensue. Although both Per and Cry proteins are indispensable in
establishing the negative-feedback loop, the latter are the rate-
limiting repressors of the molecular oscillator (7). Hence, the
cyclic accumulation of Cry proteins must be controlled in a
particularly rigorous manner.

Most short-lived proteins are degraded by the proteasome, a
multisubunit molecular shredding machine. To be recognized by the
proteasome, proteins must be tagged with multiple ubiquitin
polypeptides on particular lysine residues. However, mammals
express thousands of unstable proteins, and the question arises
of how specificity of degradation by the proteasome is
accomplished. This has now been solved for Cry proteins through
biochemical and genetic experiments.

Busino et al. used mass spectrometry to identify Cry1 and Cry2 in
a complex with Fbxl3, as revealed by coimmunoprecipitation of the
proteins from cell lysates. Fbxl3 (which contains a motif called
an F-box that mediates protein interactions) is a subunit of one
of the more than 70 mammalian ubiquitin ligase complexes that
recognizes targets for degradation by proteasomes. Specificity of
the Fbxl3-Cry interaction was confirmed by showing that nine
other F-box proteins did not associate with Cry proteins. Of
these F-box proteins, only the overexpression of Fbxl3 reduced
the stability of Cry2 in cultured cells. Perhaps more
importantly, reduction of endogenous Fbxl3 messenger RNA (mRNA)
by RNA interference (and the consequential decrease in Fbxl3
protein) abolished the cyclic expression of Cry and Per genes,
supposedly due to the continually high expression of the
repressor proteins Cry1 and Cry2. Fbxl3 appears to influence
clock gene expression specifically through its interaction with
Cry proteins, because reducing Fbxl3 expression in mouse
fibroblasts lacking Cry1 and Cry2 genes did not alter the
constitutively high accumulation of Per1 and Per2mRNAs in these
cells.

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3.

Science 25 May 2007: Vol. 316. no. 5828, p. 1113 DOI:
10.1126/science.316.5828.1113a

Genetics: Working the (Gene Count) Numbers: Finally, a Firm
Answer?

Elizabeth Pennisi

COLD SPRING HARBOR, NEW YORK--How many genes are in the human
genome? Seven years ago, researchers were predicting that our
genetic code was anywhere from 28,000 to 150,000 genes strong.
Those were the outliers in a betting pool organized by Ewan
Birney of the European Bioinformatics Institute in Hinxton, U.K.
Birney predicted the answer would be in by 2003, when the human
genome was due to be finished (Science, 19 May 2000, p. 1146).

He was wrong--and so was everybody who bet.

Today, the gene number is still "a mess," according to Michele
Clamp, a computational biologist at the Broad Institute of the
Massachusetts Institute of Technology and Harvard in Cambridge,
Massachusetts, who spoke at the Biology of Genomes meeting here
earlier this month. The three databases that track protein-coding
genes can't seem to agree, giving totals of 23,000, 19,000, and
18,000 genes. The real answer is 20,488--well below the lowest
guess--with perhaps 100 more yet to be discovered, Clamp
reported.

This count may hold up. "I've looked at her data very carefully,"
says Francis Collins, director of the U.S. National Human Genome
Research Institute in Bethesda, Maryland. "It's a pretty good
number."

In the classical sense, a gene is a sequence of DNA that codes
for a particular protein. For proteins to be produced, a gene
must first be transcribed, a process in which the cell makes a
matching RNA molecule that carries the gene's instructions to the
centers of protein production. Gene-prediction programs rely
heavily on identifying the so-called open reading frames between
the three-base codes that start and stop transcription. But
there's been an explosion of discoveries of confusing RNA
"genes": transcribed sequences that have a biological function
but don't produce a protein. And at the meeting, Birney and his
colleagues reported finding several thousand other genes that
also don't code for proteins, but researchers have no clues as to
what they do.

Thus an open reading frame "is not enough" to identify a gene
that codes for a protein, said Clamp: "It's time to produce an
integrated catalog of protein-coding genes based on the
comparative evidence."

Clamp compared all the human genes in a database called Ensembl
with those cataloged for dog and mouse. In all, 19,209 were the
real, protein-coding McCoy, 3009 had been erroneously put on the
gene list, and 1177 remained ambiguous, she reported.

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4.

Nature 447, 396-398 (24 May 2007) | doi:10.1038/nature05913;
Published online 23 May 2007

Genetics: Perceptions of Epigenetics

Adrian Bird

Geneticists study the gene; however, for epigeneticists, there is
no obvious 'epigene'. Nevertheless, during the past year, more
than 2,500 articles, numerous scientific meetings and a new
journal were devoted to the subject of epigenetics. It
encompasses some of the most exciting contemporary biology and is
portrayed by the popular press as a revolutionary new science -
an antidote to the idea that we are hard-wired by our genes. So
what is epigenetics?

There has always been a place in biology for words that have
different meanings for different people. Epigenetics is an
extreme case, because it has several meanings with independent
roots. To Conrad Waddington, it was the study of epigenesis: that
is, how genotypes give rise to phenotypes during development1. By
contrast, Arthur Riggs and colleagues defined epigenetics as "the
study of mitotically and/or meiotically heritable changes in gene
function that cannot be explained by changes in DNA sequence"2:
in other words, inheritance, but not as we know it. These
definitions differ markedly, although they are often conflated as
though they refer to a single phenomenon. Waddington's term
encompasses the activity of all developmental biologists who
study how gene activity during development causes the phenotype
to emerge, but it suffers from the disadvantage that
developmental biologists themselves rarely, if ever, use this
word to describe their field. In this sense, the usage is
obsolete. The definition put forward by Riggs and colleagues
tells us what epigenetics is not (inheritance of mutational
changes), leaving open what kinds of mechanism are at work. In
this article, I give examples of how epigenetic phenomena are
studied and interpreted, and I propose a revised definition that
embodies contemporary usage of the word.

The molecular basis of heritable epigenetics has been studied in
a variety of organisms. The DNA methylation system and the
Polycomb/Trithorax systems come closest to the ideal, because
alterations in these systems are often inherited by subsequent
generations of cells and sometimes organisms (Box 1). A classic
case of what Robin Holliday named epimutation3 is the peloric
variant of toadflax (Linaria) flowers (Fig. 1), first described
by Linnaeus. In this variant, heritable silencing of the gene
Lcyc, which controls flower symmetry, is due not to a
conventional mutation (that is, a mutation in the nucleotide
sequence) but to the stable transmission of DNA methylation at
this locus from generation to generation4. Although most variants
arising in laboratory plants are due to conventional mutations
rather than epimutations of this kind, examples of
transgenerational epigenetics are now well documented in plants
(see page 418) and fungi. In animals, however, the transmission
of epigenetic traits between organismal generations has, so far,
been detectable only by using highly sensitive genetic assays5.
The mouse agouti locus (also known as nonagouti), which affects
coat colour, is the best-studied example, being affected by the
extent of DNA methylation at an upstream transposon. Genetically
identical parents whose agouti genes are in different epigenetic
states tend to produce offspring with different coat colours,
although the effect is variable.

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5.

Nature 447, 368-370 (24 May 2007) | doi:10.1038/447368a;
Published online 23 May 2007

Neuroscience: The Molecular Wake-Up Call

Alison Abbott

It is 50 years since Arvid Carlsson showed dopamine to be a
neurotransmitter. Alison Abbott profiles a chemical and its
champion.

They were conscious but you wouldn't know it: able to perceive
the world around them but powerless to look around, sniff the air
or to cry out. So when the young scientist injected them with a
chemical called L-dopa, he witnessed what seemed to be a miracle.
They stirred, opened their eyes and began roaming around as if
nothing had happened.

This may sound familiar from the book Awakenings1 - the true
story of how, in 1963, the neurologist Oliver Sacks used L-dopa
to spectacularly revive patients with sleeping sickness who had
been 'frozen', speechless and motionless, for more than 40 years.
But the unwritten and equally startling prequel took place in
Lund, Sweden, several years earlier. The protagonists were
rabbits; their saviour a young Swedish pharmacologist called
Arvid Carlsson.

In his experiment, Carlsson showed that dopamine - the chemical
manufactured from levodopa, or L-dopa - acts as a
neurotransmitter in the brain, passing signals between
neighbouring neurons. Injection of L-dopa restored the
propagation of electrical signals in the brains of rabbits that
had been rendered catatonic, allowing the animals to move. But
the pharmacological establishment was scornful of Carlsson's
claim. At a London meeting in 1960, the foremost experts in
neural transmission made it clear that they didn't believe him -
dopamine was thought to be the metabolite of another
neurotransmitter rather than one in its own right.

Within years the critics were silenced. Dopamine was shown to be
a pivotal chemical in the neural circuits that drive pleasure and
addiction, as well as in illnesses such as Parkinson's disease,
for which L-dopa quickly became a first-line treatment. It
remains so today. In 2000, Carlsson shared the Nobel Prize in
Physiology and Medicine for his discovery. And next week
neuroscientists will gather at a meeting in Carlsson's home town
of Gothenburg, Sweden, to celebrate the 50th anniversary of his
formative paper on the awakened rabbits2.

During the past half century, Carlsson and dopamine have followed
intertwined paths. Researchers now understand that the way
dopamine works is subtle and complex, and its mechanisms of
action are central to the function of many neurological and
psychiatric drugs. And Carlsson, now a sprightly 84-year-old,
still spends hours pondering the mysteries of brain chemistry.
But he feels marginalized in Gothenburg and, last year, the
institute established in his name closed prematurely after bitter
feuds about funding.

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