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Chemical physics

Molecules are cool

John M. Doyle and Bretislav Friedrich
nder ordinary conditions, atoms and
molecules of a gas zigzag in all directions and have a wide distribution
of speeds related to temperature. At room
temperature, for instance, gaseous atoms
or molecules are most likely to move at the
speed of rifle bullets. Such restlessness puts a
limit on the level of detail at which atomic
and molecular properties can be studied.
The emergence of methods for slowing
and trapping gaseous species has led to a
renaissance in atomic physics, which is now
progressing into molecular/chemical physics
as well. The latest developments come from
Bethlem et al.1 and Maddi et al.2 they have
independently devised kindred techniques
for slowing molecules that potentially provide new approaches to subsequent trapping
and spectroscopy in particular.
Control of atomic behaviour has already
become pretty sophisticated. For instance, a
class of atoms, best represented by the alkali
metals, can now be routinely slowed with
light and loaded into traps (constructed
from light or magnetic fields)3. This laser
cooling relies on the rapid absorption and
emission of photons by an atom placed in
light tuned near the atoms resonant frequency. With a careful arrangement of the
laser beams, the atoms can preferentially
absorb photons from a single direction. Due
to the momentum of the photon, the atom
gets small velocity kicks opposite to its
direction of travel. This can be used to slow a
beam of atoms so they can be caught in traps
and cooled to very low temperatures (for
example, evaporative cooling is applied to
magnetically trapped atoms to attain
BoseEinstein condensation at temperatures below 1 mK). Unfortunately, the energy-level structure of molecules prevents the
maintenance of the requisite simple absorptionemission cycle and so makes laser slowing impractical. In consequence, molecules
(and many complex atoms) were relegated to
the sidelines.
Last year, however, two very different
approaches to cooling and trapping of molecules were successfully implemented. In
one, CaH molecules were cooled with a cryogenically refrigerated helium buffer gas and
loaded into a magnetic trap4. In the other, Cs2
molecules were formed from laser-cooled
Cs atoms and then confined in a light trap5.
Now we have the techniques devised by
Bethlem et al.1 and Maddi et al.2. Like laser
slowing of a beam, they produce velocity
kicks opposite to the direction of travel.
They work with bunches of atoms or molecules all travelling in one direction, and make

NATURE | VOL 401 | 21 OCTOBER 1999 | www.nature.com

no recourse to lasers or cryogenics. Instead

these new methods use time-varying inhomogeneous electric fields to provide the
kicks and the resultant slowing.
Inhomogeneous electric fields that can
be turned on or off quickly are produced by
pairs of electrodes. The potential energy of
an atom or a molecule varies in a characteristic way with the strength of the electric field.
Depending on whether the electric dipoles
are on average antiparallel or parallel to the
electric field, the particles energy either
increases (these are low-field seekers) or
decreases (these are high-field seekers) with
increasing field strength. The energy of
low-field seekers is lowest at minimum field
strength and, therefore, in an inhomogeneous field they seek these low-field regions.
In contrast, high-field seekers are forced
towards the maximum field strength.
Polar molecules possess both high- and

low-field-seeking states in an electric field.

Atoms, on the other hand, become polarized
only in the presence of an electric field and so
their electric dipoles are always parallel to the
field; they can only be high-field seekers in an
electric field. The technique of Bethlem et al.
relies on low-field seekers and, therefore, is
well suited for slowing polar molecules; that
of Maddi et al. relies on high-field-seeking
states and so is potentially suitable for slowing both atoms and molecules.
Figure 1 illustrates the two approaches. In
the scheme of Bethlem et al. (Fig. 1a), molecules enter an inhomogeneous electric field
from a field-free region. As they approach the
region of maximum field strength between
the electrodes, the potential energy of lowfield seekers is increasing. This occurs at the
expense of their translational energy which
is being correspondingly reduced (a consequence of energy conservation). To prevent
the molecules from regaining the translational energy as they leave the field, the field is
quickly switched off. The molecules thus end
up in a homogeneous, field-free region where
their potential (and thus translational) energy remains constant. To maximize the loss
of translational energy, the field has to be

a
Pulse of
polar molecules

Time

High voltage

High voltage

Pulse of
Cs
atoms

Time

Figure 1 Principle of molecular and atomic slowing by time-varying inhomogeneous fields. Length of
orange arrows indicates speed. a, One of the 63 stages used by Bethlem et al.1 to decelerate a pulsed
beam of CO(a3P) molecules from 225 m s11 to 98 m s11. The two opposing rods are simultaneously
switched by two independent high-voltage switches. The decelerating stages are stacked in
alternating vertical and horizontal configurations, keeping the molecules focused. They gain
potential energy as they approach the field maximum, and so lose kinetic energy. When the field is
switched off, the molecules are left with reduced velocity. b, A deceleration stage used by Maddi et al.2
to slow a pulse of Cs atoms (released from a magneto-optic trap) from 2 m s11 to 0.2 m s11. The two
opposing condenser plates are simultaneously energized by two independent high-voltage power
supplies. The electric field is turned on when the Cs pulse reaches the uniform field region, thereby
inducing an electric dipole in the atoms. As the pulse leaves the plates it passes through an area of
decreasing field strength. Its potential energy increases at the expense of kinetic energy, resulting in
pulse deceleration.
1999 Macmillan Magazines Ltd

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switched off just at the point where the
molecules reach the fields maximum.
Maddi et al. (Fig. 1b) used atoms in their
experiments, but their scheme could, in
principle, be applied to molecules. The atoms
enter an inhomogeneous electric field from a
region of a large homogeneous electric field.
The homogeneous field is formed by two
condenser electrodes that are energized after
the atoms entry. Atoms in their high-fieldseeking states then gain potential energy as
they pass through the inhomogeneous field
at the exit of the condenser, again at the
expense of their translational energy.
In both versions, the atoms or molecules
arrive in pulses: a pulsed beam of metastable
molecules is created from a supersonic beam
expansion (Bethlem et al.), or a pulsed beam
of ground-state atoms is launched from a
magneto-optic trap (Maddi et al.). The pulsing is crucial, because the switching of the
fields must be accurately synchronized with
the arrival of the atoms or molecules. These
techniques may enable atoms or molecules
to be slowed enough for capture in traps.
Yet another new approach6 to slowing
beams of atoms and molecules is based on
supersonic expansion from a nozzle placed
at the end of a spinning armature. The nozzle
is oriented so that it moves in the opposite
direction to the discharging gas, and its
speed roughly equals the speed of the
expanding atoms or molecules. As a result, it
cancels the particles speed in the laboratory
frame, leaving the atoms or molecules essentially at rest.
Cold molecules should prove useful in
spectroscopy and the study of molecular
structure, especially in ultra-high-resolution
spectroscopy, which requires cold (slow) and
trapped (long-interaction-time) samples.
An especially promising area for study is
collisions of ultra-cold molecules, when the
molecules behave like waves, perhaps giving
rise to a new chemistry. The technique may
also enable the study of collective quantum
effects in molecular systems, including Bose
Einstein condensation. Just as atom cooling is
opening up new avenues of research, it is likely that the same will happen with molecular
cooling with repercussions for chemistry
and even, perhaps, biology.

John M. Doyle is in the Department of Physics, and

Bretislav Friedrich is in the Department of
Chemistry and Chemical Biology, and the
Department of Physics, Harvard University,
Cambridge, Massachusetts 02138, USA.
e-mails: jd@jsbach.harvard.edu
brich@chemistry.harvard.edu
1. Bethlem, H. L., Berden, G. & Meijer, G. Phys. Rev. Lett. 83,
15581561 (1999).
2. Maddi, J. A., Dinneen, T. P. & Gould, H. Phys. Rev. A (in the
press). http://xxx.lanl.gov/abs/physics/9909027
3. Wieman, C. E., Pritchard, D. E. & Wineland, D. J. Rev. Mod.
Phys. 71, S253S262 (1999).
4. Weinstein, J. D. et al. Nature 395, 148150 (1998).
5. Takekoshi, T., Patterson, B. M. & Knize, R. J. Phys. Rev. Lett. 81,
51055108 (1998).
6. Herschbach, D. Rev. Mod. Phys. 71, S411S418 (1999).

NATURE | VOL 401 | 21 OCTOBER 1999 | www.nature.com

Pharmacology

Towards better benzodiazepines

William Wisden and David N. Stephens
leeplessness and anxiety afflict us all
sometimes to the point of breakdown.
The usual treatment is drugs of the benzodiazepine family, such as diazepam (Valium), which have helped millions of patients
since they were introduced in the late 1950s.
Benzodiazepines induce relaxation, but they
can also play tricks on memory (hence their
association with date rape), reduce concentration, cause physical clumsiness and intensify the effects of alcohol. They can also be
addictive. In an exciting study on page 796 of
this issue, Rudolph et al.1 report the use of
mouse molecular genetics to study the target
for benzodiazepine action. This work sets
the foundations for developing Valium-like
drugs that ease anxiety or help the onset of
sleep, but without the destructive side
effects.
To function properly, brain circuits need
balanced positive and negative signals. The
negative inhibitory signals come from the

H
101

R
101
C

Out
In

Valium-sensitive
1 (His)

Valium-insensitive
1 (Arg)

H/R
1

Cl

Figure 1 Structure of the GABAA receptor. The

receptor is made up of five subunits, and one of
these, the a1 subunit, is shown from the side (a).
In a complete receptor, the subunits form a ring
with the chloride (Cl1) ion-channel at the centre
(shown from above, b). The neurotransmitter
GABA binds at the interface between the a and b
subunits (green circles), causing the chloride
channel to open. The interface between an a1
and a g subunit creates the binding site (red
triangle) for benzodiazepine drugs such as
Valium. If a key histidine residue (H101) in the
extracellular amino-terminal domain of the a1
subunit is changed to arginine, the
benzodiazepine-binding site is inactivated
although the receptor still responds to GABA4,7.
1999 Macmillan Magazines Ltd

chemical neurotransmitter GABA (gaminobutyric acid). When GABA binds to

its target protein complex the GABAA
receptor a chloride ion-channel opens,
allowing chloride ions to move into neurons
and damp down their electrical activity. Benzodiazepines bind to a specific site on the
GABAA receptor and induce a subtle change
in its shape. This change causes GABA to
work more efficiently at the receptor, so the
movement of chloride ions into the neuron
increases2,3. But because GABAA receptors
are found throughout the brain, benzodiazepine treatments often affect those circuits
that control, say, attention or balance, as
strongly as they influence the circuits that
regulate anxiety; hence the side effects.
The situation is further complicated
because there are many types of GABAA
receptor2,3. Most are made of a, b and g
subunits arranged in a pentamer, with the
chloride ion-channel at the centre. Benzodiazepines bind at the interface between the a
and g subunits4 (Fig. 1). There are six types
of a subunit, a1a6, distributed in various
brain circuits to make an overlapping mosaic
of receptor subtypes. So it is difficult to
understand what each subtype does. Available drugs are not selective enough, and
genetic studies in mice where the gene for
a particular subunit is inactivated often
cause death5 or severe neurological illness6.
This is because the brain circuitry has no
brakes on its activity, so it spirals into
dysfunction.
In an alternative approach, Rudolph et
al.1 have exploited a variable amino acid in
the a subunit known as the R/H site7. The a1,
a2, a3 and a5 subunits all have histidine (H)
at position 101 of their polypeptide chain,
whereas a4 and a6 have arginine (R)7. The
histidine contributes to the binding pocket
for benzodiazepines, and in vitro studies7
show that only GABAA receptors with this
amino acid at position 101 of their a subunits are sensitive to these drugs. If histidine
is mutated to arginine, drugs such as
diazepam no longer improve the action of
GABA at the GABAA receptor. However,
the receptors sensitivity to GABA and its
function stay unchanged8.
Rudolph et al. now put this discovery into
a physiological setting. Using the technique
of homologous recombination, they engineered mice in which residue 101 in the a1
subunit is mutated from histidine to arginine. (The a1 protein is a good first choice
for this experiment because it contributes
to over 60% of GABAA receptors in the
brain.) The authors found that drug-free
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