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Custodian of the Two Holy Mosques
King Abd Allah Ibn Abd al-Aziz Al-Saud
Patron of the King Faisal Foundation
HRH Prince Salman Ibn Abd Al-Aziz Al-Saud
Crown Prince, Deputy Premier and Minister of Defence
HRH Prince Muqrin bin Abd Al-Aziz Al-Saud
Second Deputy Premier
Content
Introduction 1
2013 King Faisal International Prize
Award in
Medicine (The Genetics of Obesity) 3
............................................................
The Genetics of Obesity: Early Studies
By Professor Douglas L. Coleman 5
............................................................
Leptin at Twenty
By Professor Jeffrey M. Friedman 7
2013 King Faisal International Prize
Award in
Science (Physics) 9
............................................................
Breaking the Attosecond Barrier - and
Beyond
By Professor Paul B. Corkum 12
............................................................
Real-time Observation and Control of
Electron Motion
By Professor Ferenc Krausz 18
INTRODUCTION
The King Faisal Foundation continues the traditions of Arabic and Islamic
philanthropy, as they were revitalized in modern times by King Faisal. The
life and work of the late King Faisal bin Abd Al-Aziz, son of Saudi Arabia’s
founder and the Kingdom’s third monarch, were commemorated by his
eight sons through the establishment of the Foundation in 1976, the year
following his death. Of the many philanthropic activities of the Foundation,
the inception of King Faisal International Prizes for Medicine in 1981 and
for Science in 1982 will be of particular interest to the reader of this book.
These prizes were modeled on prizes for Service to Islam, Islamic Studies
and Arabic Literature which were established in 1977. At present, the Prize in
each of the five categories consists of a certificate summarizing the laureate’s
work that is hand-written in Diwani calligraphy; a commemorative 24-carat,
200 gram gold medal, uniquely cast for each Prize and bearing the likeness
of the late King Faisal; and a cash endowment of SR750,000 (US$200,000).
Co-winners in any category share the monetary award. The Prizes are
awarded during a ceremony in Riyadh, Saudi Arabia, under the auspices of
the Custodian of the Two Holy Mosques, the King of Saudi Arabia.
Nominations for the Prizes are accepted from academic institutions, research
centers, professional organizations and other learned circles worldwide, as
well as from previous laureatues. After preselection by expert reviewers, the
short-listed works are submitted for further, detailed evaluation by carefully
selected international referees. Autonomous, international specialist
selection committees are then convened at the headquarters of the King Faisal
Foundation in Riyadh each year in January to make the final decisions. The
selections are based solely on merit, earning the King Faisal International
Prize the distinction of being among the most prestigious of international
awards to physicians and scientists who have made exceptionally outstanding
advances which benefit all of humanity.
(Excerpt from Introduction to ‘Articles in Medicine and Science 1”
by H.R.H. Khaled Al Faisal, Chairman of the Prize Board and Director
General of King Faisal Foundation)
WINNERS OF THE 2013
KING FAISAL INTERNATIONAL
PRIZE
FOR MEDICINE
The King Faisal International Prize for Medicine (The Genetics of Obesity)
for the year 1434H - 2013G has been awarded jointly to: Professor Jeffrey
M. Friedman (USA) and Professor Douglas L. Coleman (USA).
The research findings of Professor Friedman and Professor Coleman led to
the identification and characterization of the leptin pathway. This seminal
discovery has had a major impact on our understanding of the biology
of obesity, describing some of the key afferent pathways in body weight
regulation active in man. Their fundamental discoveries have also helped
in the recognition of more illuminating views of the endocrine system.
Because of their major contribution to the field of the genetics of obesity
they have been awarded King Faisal International Prize in Medicine for the
year 1434H. (2013).
The Genetics of Obesity: Early Studies
Douglas L. Coleman
Professor Emeritus The
Jackson Laboratory Bar
Harbor,Main 04609
USA
Upon receiving my PhD in biochemistry from the University of Wisconsin
in 1958, the prospects of returning to employment in Canada were poor and
I was offered a position at The Jackson Laboratory in Bar Harbor, Maine.
When I accepted this position, my plan was to remain at The Jackson
Laboratory one or two years to further my education in biology, especially
genetics and immunology. As things turned out, however, the Jackson
Laboratory provided a very fertile environment – with excellent colleagues
and world-class mouse models of disease – and I spent my entire career in
Bar Harbor. I never dreamed that I would get involved with diabetes-obesity
mutants or that my research would one day be deemed important enough to
be considered for a major scientific award.
In 1958, only one obese mutant (ob/ob) was known.1 It had been discovered in
1950 and characterized as a model for mild diabetes but was not the subject of
any ongoing studies by other investigators at the Jackson Laboratory. The obese
mutation is located on chromosome 6 and the mouse is characterized by massive
obesity, marked hyperphagia and mild transient diabetes. In 1965, a new obesity
mutant (db/db) was discovered and I was asked to assist in characterizing this
new mutant and, in particular, compare it to the obese mutant. We found that this
mutation is on chromosome 4 and, like the obese mutant, the mouse develops
marked obesity and hyperphagia but, unlike the obese mutant, develops a severe
life-shortening diabetes.2 Figure 1 illustrates the striking obesity of the diabetes
mutant (right) compared with a normal littermate (left) at 8 weeks of age. The
diabetes mouse is nearly twice the size (30 vs. 20g.) of the normal mouse and
the extra weight is all adipose tissue. Since both the ob/ob and db/db mice
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become morbidly obese with similar kinetics, the diabetes mutant shown in
this figure could equally represent the obese mouse, since at this age they are
phenotypically identical in all visual aspects.2
When I began characterizing this new mutation, I wondered if some circulating
factor might control the diabetes-obesity syndrome. For example, could a
factor produced in the normal mouse prevent or mediate the diabetes-obesity
condition? Conversely, might a factor produced by the diabetes mutant
elicit obesity in a normal mouse? If this hypothetical factor was carried
through the blood, I reasoned I could test for its presence by linking the
blood supplies of the various mouse strains. Parabiosis requires the surgical
joining of two mice by skin-to-skin anastomosis from the shoulder to the
pelvic girdle. Wound healing and cross circulation is established in two to
three days. To avoid a vigorous immune-mediated rejection, this technique
requires that the mice be on the same genetic background, an issue that
would delay some desired pairings e.g., db/db with ob/ob). Most parabiosis
experiments fail either because there is no factor or there is insufficient
factor exchanged because no major blood vessels are involved and cross-
circulation via the skin is limited (0.5-1%).
Because the obese and diabetes mutants were on different background
strains, my first parabiosis experiment involved the joining of the diabetes
mutant to a normal mouse.3 After what appeared to be good wound healing
and a healthy-looking parabiont pair, I was surprised to observe that the
normal mouse died. My immediate thought was that I was a pretty poor
surgeon but repeated attempts consistently yielded the same outcome:
only the normal mouse in the pair died. Encouraged by this stereotypic
pattern, I initiated a more detailed characterization of the normal partners
and found that, after about one week, their blood sugar concentrations
declined to starvation levels. Moreover, at necropsy the normal mice not
only consistently lacked food in their stomachs and food remnants in their
intestines but also had no detectable glycogen in their livers. In marked
contrast, the diabetes partners consistently retained elevated blood sugar
concentrations and their stomachs and intestines were distended with food
and food residues. This was my Eureka moment! These results led me to
conclude that the diabetes mouse produced a blood-borne satiety factor so
powerful that it could induce the normal partner to starve to death, even in
the face of the limited cross-circulation inherent
between paribiotic pairs. Despite my excitement, my colleagues and most
of the scientific community remained largely unconvinced.
16
At about the same time as these first parabiosis studies were done, a new
spontaneous diabetes mutant was discovered.4 This mutant did not manifest
severe life-shortening diabetes and, therefore, appeared identical to the
syndrome seen in the ob/ob mutant but, like the db/db mutant, it mapped
to chromosome 4. This new diabetes mutation was discovered on the
C57Bl/Ks inbred background whereas the ob/ob mutation was maintained
on the related C57Bl6/J background – leading me to wonder whether the
inbred background could mediate the severity of the disease. To answer
this question, I placed the diabetes gene on the C57Bl/6 background and
the obese gene on the C57Bl/Ks background by five cycles of cross-
intercross breeding, thereby producing two new congenic lines.5,6 I
found that both the obese and diabetes mutations, when maintained on
the C57Bl/Ks inbred background, produced identical syndromes: marked
obesity with severe life-shortening diabetes. In contrast, when maintained
on the C57Bl/6 background, both mutations produced obesity but with
only mild and transient diabetes. These studies clearly established that
the severity of the diabetes was dependant on modifying genes in the
inbred background. Interestingly, the gene or genes responsible for these
profound changes remain unknown to this day, although a great deal of
effort has gone into attempts at identifying them. Knowing that two genes
on separate chromosomes produce identical syndromes strongly suggested
that these genes mediate a common metabolic pathway.
Having both mutants on both inbred backgrounds permitted the parabiosis
of the obese mutants with the diabetes mutants without fear of rejection.
This experiment would allow me to answer a question that always nagged
me: was the normal parabiont starving because it was continually being
dragged around by the larger diabetes partner and never had a chance
to eat? Parabiosis of the mutants of the same weight would address
this issue. These additional parabiosis experiments revealed that the
obese and diabetes mutants responded the same regardless of inbred
background.7 After collateral circulation developed, blood sugar levels
in the obese mutant declined, eventually reaching starvation levels.
Survival time ranged from 20 to 30 days. At necropsy, it was clear that
the adipose tissue mass in the obese parabiont had decreased and neither
food nor food residue could be found in the stomachs or intestinal tracts
of the obese partner. In contrast, the diabetes mutant was gorged with
food and gaining weight. Consistent with the lack of food in the obese
partner, food consumption of the pair was decreased to about that typical
of a single diabetes mutant. These striking results clearly indicated that
the obese mutant, like the normal mouse, recognized and responded to
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the factor provided by the diabetes partner.
Several additional parabiosis and lesion experiments tied up loose ends.
Parabiosis of the obese mutants with normal mice not only slowed the
weight gain in the obese mutant and decreased food consumption of the pair
to that seen in normal with normal parabionts but also resulted in a pair of
animals that survived for months, until sacrifice.8 This study demonstrated
that the factor produced by the normal mouse was probably the same as that
produced by the diabetes mutant but in insufficient amounts to be lethal. My
overall conclusions from the parabiosis studies were that the diabetes mutant
over-produced a satiety factor but could not respond to it – perhaps due
to a defective receptor, while the obese mutant recognized and responded
normally to the factor but could not produce it. Further studies with diabetes
mutants lesioned in the ventromedial nucleus and/or the arcuate nucleus
region of the hypothalamus suggested that the receptor resided in these areas
of the brain.8 Additional support for a satiety factor acting on a receptor
in the brain came from a study in which rats lesioned in the ventromedial
nucleus of the brain produced hyperphagia and obesity.8 Moreover, when
lesioned rats were parabiosed with normal rats, the normal rat lost weight,
became unthrifty but did not die.8 Despite these clear results, many of my
colleagues and many in the obesity field maintained the dogma that obesity
was entirely behavioral not physiological.
Based on these experiments, however, some investigators did accept a
physiological basis as an underlying cause contributing to obesity and the
hunt for the satiety factor became a race. All of these early satiety factor
candidates (e.g., cholecystokinin, somatostatin, pancreatic polypeptide) did
not stand up to rigorous experimentation and I continued my own attempts at
identifying the factor. In control studies using normal by normal parabionts,
I had observed that the pairs remained active and healthy for four months
(when they were sacrificed) but on necropsy did display one abnormality:
the size of the fat pads was smaller than those isolated from unparabiosed
normal mice. This suggested to me that the factor might be a component
of adipose tissue. Although the factor was produced by adipose tissue, my
time-consuming attempts at isolating it proved futile as I concentrated my
efforts on individual fatty acids or lipid extracts of adipose tissue.
Following a tour-de-force positional cloning exercise carried out over
many years, the long-sought satiety factor was definitively identified by
my colleague and co-King Faisal Awardee, Jeffery Friedman9. This satiety
factor was named “leptin” and with the subsequent cloning of the leptin
18
receptor, the field exploded. Essentially all of the predictions made from
the parabiosis experiments were verified: the obese gene encodes a blood
borne hormone (leptin) that functions in a negative feedback loop to control
adipose tissue mass through modulating appetite; the diabetes gene encodes
the leptin receptor; leptin is produced in adipose tissue; and the leptin
receptor is expressed primarily in the hypothalamus. These discoveries
not only changed our thinking of obesity from being caused by a lack of
willpower to an imbalance of hormone signaling but also demonstrated that
adipose tissue is not just a useless and unwanted fat storage site but rather
an important and essential endocrine organ.
In humans, many leptin deficiency syndromes are responsive to leptin
replacement. Given that leptin plays a role in numerous pathways, the
effects of too little leptin are widespread (infertility, impaired immune
function, decreased insulin response, altered homeostasis). While leptin
mutations are not common in humans, leptin therapy in the few people
who lack an active form of this hormone is a Godsend, transforming them
from morbidly obese individuals living in a state of perceived starvation
into much leaner individuals with a more normal lifestyle. Leptin therapy
has also successfully treated patients with reduced adipose tissue mass,
like lipodystrophy and amenorrhea. Leptin therapy, however, is not the
panacea for curing obesity since ordinary obese humans, who have normal
genes for leptin and its receptor, are leptin resistant. Despite extensive
efforts in many laboratories, it remains unclear why ordinary obese
people become resistant to their own leptin. As we learn more about the
molecular mechanisms governing this critical hormone, however, it is
likely that combination therapies involving leptin will prove efficacious
in other diseases. Indeed, the exciting preclinical work from Roger
Unger’s laboratory raises
the possibility that leptin
supplementation therapy
may prove beneficial in
the treatment of type 1
diabetes.10
Most aspects of life depend
on luck and I certainly was
lucky throughout my career.
In an often repeated quote,
Louis Pasteur said luck favors
the prepared mind and I had
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the good fortune of interacting with many mentors who helped prepare my
mind. I thank them all.
References
1. Ingalls AM, Dickie MM, and Snell GD. 1950. Obese, a new mutation in the
house mouse. J. Heredity 41:317-319.
2. Hummel KP, Dickie MM, Coleman DL 1966. Diabetes, a new mutation in the
mouse. Science 153:1127-1128.
3. Coleman DL and Hummel KP. 1969. Effects of parabiosis of normal with
genetically diabetic mice. Am. J. Physiol. 217:1298-1304.
4. Hummel KP, Coleman DL, Lane PW. 1972. The influence of genetic background
on the expression of mutations at the diabetes locus in the mouse 1. C57Bl/KsJ
andC57Bl/6J strains. Biochem. Genet. 7:1-13.
5. Coleman DL. Hummel KP. 1973. The influence of genetic background on the
expression of the obese (ob) gene in the mouse. Diabetologia 9:287-293.
6. Coleman DL. 1973. Effects of parabiosis of obese with diabetes and normal
mice .Diabetologia 9:1298-1304.
7. Coleman DL. Hummel KP. 1970. The effects of hypothalamic lesions in
genetically diabetic mice.Diabetologia 6:263-267.
8. Hervey GR.1959. The effects of lesions in the hypothalamus in parabiotic rats.
J. Physiol., London 145:336-352.
9. Zhang Y. Procenca R. Maffei M. Barone M. Leopold L. Friedman JM. 1994.
Positional cloning of the mouse obese gene and its human homologue, Nature
372:425-32
10. Wang M. Chen L. Clark GO. Lee Y. Stevens RD. Ikayeura OR. Wenner BR.
Bain JR. Charon MJ. Newgard CB. Unger RH. 2010. Leptin therapy in insulin-
deficient type 1 diabetes. PNAS 107:4813-4819.
20
Leptin at Twenty
By Jeffrey M. Friedman Investigator, Howard
Hughes Medical Institute Professor, The
Rockefeller University Investigator, Howard
Hughes Medical Institute
1230 York Avenue,New York, NY 10065
Tel: 2128800-327-
Fax: 2127420-327-
E-mail: [email protected]
USA
Abstract
The cloning of the ob gene and hormone leptin has led to many new insights.
The identification of leptin has uncovered a new endocrine system regulating
body weight. This system provides a means by which changes in nutritional
state regulate most, perhaps all, physiologic systems as part of the adaptive
response to starvation. A number of leptin deficiency syndromes that are
treatable with leptin replacement have been identified. The majority of
obese subjects are leptin resistant, which establishes that obesity is the result
of hormone resistance. Leptin treatment results in weight loss in a subset
of obese patients and can also synergize with other anti-obesity agents to
reduce weight raising the possibility that leptin could in time emerge as
part of a combination therapy for obesity. Leptin provides an entry point
for studying the basic science of a complex human behavior. Finally, the
identification of leptin and the neural circuit that it activates has established
that there is a powerful biological basis for obesity, a fact that is (correctly)
changing public perception about this medical condition.
The ob gene was cloned in 1994, and leptin was identified in 1995 as the
product of the ob gene and a hormonal signal that regulates energy balance
[1-4]. The passage of nearly twenty years of research with more than 100,000
articles on leptin (S Korres, personal communication, 2013), now provides
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an opportunity to assess, with some hindsight, what has been learned in the
interim. Some of the relevant concepts that have emerged are discussed below.
The cloning of the ob gene and its gene product leptin has led to the
elucidation of a robust physiologic system that maintains fat stores at a
relatively constant level. Leptin is a peptide hormone secreted by adipose
tissue in proportion to its mass. Recessive mutations in the leptin gene are
associated with massive obesity in mice and some humans establishing a
genetic basis for obesity. Leptin circulates in blood and acts on the brain to
regulate food intake and energy expenditure. When fat mass falls, plasma
leptin levels fall stimulating appetite and suppressing energy expenditure
until fat mass is restored. When fat mass increases, leptin levels increase,
suppressing appetite until weight is lost. This system maintains homeostatic
control of adipose tissue mass and links changes in nutritional state to
adaptive alterations in other physiologic systems.
The Identification of Leptin and a New Endocrine System Regulating Body
Weight:
Several lines of evidence have previously suggested that body weight is
regulated by a robust homeostatic system. First, body weight is remarkably
stable in humans over long intervals, in individuals who are healthy
and not actively trying to change their weight [5]. Since the first law of
thermodynamics applies similarly to inanimate and biological systems, as
shown by the Prussian surgeon Hermann von Helmholtz, the striking stability
of weight in living organisms in a stable environment strongly suggested
that body weight is physiologically regulated. The stability of weight has
been noted in patients monitored over long periods of times and the imputed
precision of this system is remarkable considering the numbers of calories
consumed in that interval [6]. In addition, a precise balance between energy
intake and energy expenditure has also been noted over even a 2-week time
frame, which tended to average out day to day fluctuations in intake [7].
Second, the weight of animals that were either overfed or starved returned
to that of a control group once the stimulus to alter weight was removed
[2, 8-12]. Finally, when animals are fed nutrient in varying dilutions, they
adjust their intake to maintain constancy of the number of calories that are
consumed, not the volume [13].
All these data suggested that there must be a biologic system that regulates
food intake and maintains homeostatic control of body weight and fat mass
22
[13]. This premise was articulated often during the first half of the 20th
century and was further advanced by the demonstration that body weight
could be altered, in either direction, by introducing specific lesions in the
hypothalamus. Thus lesions of the ventromedial hypothalamic lesions cause
obesity while lesions of the lateral hypothalamus cause leanness [14]. These
data were correctly interpreted by a number of prescient scientists to mean
that brain centers in the hypothalamus receive peripheral signals that reflect
an organism’s nutritional state as part of a feedback loop or loops that acts
to maintain homeostatic control of body weight [15, 16].
A key question concerned the identity of these putative signals. It was
proposed that glucose, fat and protein stores were in some way sensed, as
were core temperature, recent food intake and other variables [15, 16]. The
possibility that one of these signals might be derived from adipose tissue
was first proposed by Kennedy although neither the nature of this factor nor
the mechanism by which it acted was clear [17]. Later Hervey invoked a
mechanism whereby a fat derived factor, perhaps a steroid hormone that
increased appetite, was partitioned in both the adipose tissue and aqueous
compartments and was thus diluted as adipose mass increased [18]. That
this factor might be hormonal was first suggested by data from parabiosis
(cross circulation) experiments between rats made obese by ventromedial
hypothalamic (VMH) lesions and control rats [19]. Hervey observed that the
normal rats paired to those with a VMH lesion ate less and lost weight and he
proposed that the lesioned rats overproduced an appetite-suppressing factor
secondary to a lesion at its site of action (i.e.; the hypothalamus). Although
the existence of this factor could be inferred from this and later studies by
Coleman, the intrinsic difficulty of implementing a biochemical purification
using a behavioral assay of feeding behavior impeded successful efforts to
identify it. In retrospect, with the identification of this factor as leptin, it is clear
how challenging such a purification would be, even using modern methods,
in part because leptin does not reduce food intake acurely and needs to be
delivered chronically to elicit an anorectic effect. A biochemical approach for
identifying endogenous appetite suppressants is also complicated by frequent
false positives that result from the observation that many compounds exert
aversive effects, which nonspecifically reduce appetite.
A clue to the identity of this circulating factor was provided by data from
parabiosis experiments performed by Dr. Douglas Coleman who paired
ob/ob and db/db mice to wild-type mice or to each other; ob and db are
recessive mouse mutations that cause massive obesity in mice as a result of
profound hyperphagia and reduced energy expenditure [20, 21]. In addition,
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both mutants manifest a pleiotropic set of numerous other physiologic
abnormalities (see below and) [22]. The phenotypes of both mutations are
strikingly similar, which suggested that the encoded genes functioned in
the same physiologic pathway. Results from parabiosis experiments were
consistent with this possibility and further suggested that the ob gene
encoded a circulating factor that suppressed food intake and body weight
and that the db gene encoded its receptor. The aforementioned studies using
the parabiotic union of mice with lesions of the ventromedial hypothalamus
to normal rats further suggested that this receptor was localized in the
hypothalamus. In aggregate, these studies were consistent with the
parsimonious hypothesis that a circulating factor produced in adipose tissue
and encoded by the ob gene acted on a receptor in the hypothalamus that
was encoded by the db locus. Parabiosis experiments from genetically obese
fa rats further suggested that the rat fa gene also encoded the receptor [23].
Thus, the available evidence suggested that food intake and body weight—
or, more precisely, adipose tissue mass—were regulated by an endocrine
system. In retrospect, this conclusion seems obvious, but at the time many
dismissed this hypothesis. The reasons for this pervasive skepticism are not
entirely clear, but among them undoubtedly was the protracted time between
the formulation of this hypothesis and the identification of the putative factor.
As mentioned, the use of biochemistry to identify the putative circulating
factor that was described by Hervey and Coleman would have been at best
difficult and potentially impossible. Purification of protein factors from
plasma using an in vivo bioassay is extremely difficult especially using food
intake as an assay owing to the frequency with which “toxic” agents can
induce nausea or other aversive stimuli. In addition, we know now that leptin
does not acutely reduce food intake and needs to be administered in several
doses to elicit an effect [2, 24]. However, the introduction of a positional
cloning in the 1980s provided an alternative approach for identifying mutant
genes. This approach allows one to isolate mutant genes based solely on
a detailed knowledge of their position on a genetic map (hence the name
positional cloning).
It was this methodology that was used to identify the ob and db genes
and that ultimately allowed our group to formally test the aforementioned
hypothesis. In 1994 the ob gene was identified by positional cloning as a
4.5 kb RNA that was expressed exclusively in adipose tissue [1]. This RNA
encoded a predicted 167–amino acid polypeptide with a signal sequence,
which indicated that it was secreted and likely to circulate in plasma. The
gene is disrupted in the two available mutant alleles of ob; in the original
24
C57/Bl6J ob/ob mutation, a nonsense mutation disrupts protein function,
whereas in the second coisogenic ob 2j mutation, a retroviral insertion
abrogates expression of the coding sequence altogether [2, 25].
The available data at the time suggested the hypothesis that this polypeptide,
that we named leptin from the Greek root leptos, meaning “thin”, functioned
as the afferent signal in a negative feedback loop that maintained stability
of adipose tissue mass [1-4]. If true, the following criteria needed to be
satisfied: leptin should circulate in plasma, its concentrations should change
proportionately with increases or decreases of fat mass, and the recombinant
protein should reduce food intake and body weight in lean and ob but not
db mice. Finally, the db gene should encode the receptor for leptin and be
localized in the hypothalamus (and possibly elsewhere).
All these criteria were satisfied. Leptin circulates in the plasma of all
mammals tested including humans and rodents as an ~ 16 kD protein with a
single disulfide bond that is required for bioactivity [2]. Leptin levels increase
with increases of adipose tissue mass and decrease when adipose mass is lost
[26]. Injections or infusions of leptin reduce food intake and body weight of
wild type and ob mice but have no effect on db mice [2-4, 24]. The failure
of recombinant leptin to alter food intake or weight in db mice established
specificity of the effect and essentially excluded the possibility that the protein
reduced weight as a result of an aversive effect [2].
The leptin receptor was first identified biochemically and shown to be a
cytokine family receptor that is expressed broadly [27]. It was subsequently
shown that leptin receptor RNA was alternatively spliced and that in
C57Bl/Ks db/db mice, the first db mutant to be identified by Coleman,
only one of the splice variants, referred to as ObRb (also known as LepR-l)
was defective and that all of the other splice variants are normal in these
animals. These mutant mice show an identical phenotype to animals with
null mutations of the leptin receptor or leptin itself [28, 29]. This genetic
evidence established the critical importance of this receptor isoform in leptin
signaling. ObRb is the only receptor isoform that expresses all the protein
motifs required for cytokine receptor signaling. More importantly, while the
other receptor isoforms were expressed broadly, ObRb is highly enriched
in the hypothalamus in precisely those nuclei that alter body weight when
lesioned [28, 30]. This genetic evidence suggested that leptin acted directly
on the hypothalamus to regulate food intake and body weight. Consistent
with a CNS site of action, infusions of low dose leptin centrally replicate all
the effects of peripheral leptin even at intracerebroventricular doses that do
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not alter plasma leptin levels [2]. It is now known the leptin receptor also
signals at other CNS sites outside the hypothalamus as well as in immune
cells and that its expression at these sites contributes to the broad panoply of
leptin’s effects (see below).
In aggregate, these data establish that leptin is a novel hormonal signal in a
negative feedback loop that maintains homeostatic control of adipose tissue
mass by modulating the activity of neural circuits that regulate food intake
and energy expenditure. These conclusions are important not only because
key elements of the homeostatic system regulating weight were identified
but also because the identification of leptin and its receptor confirmed the
existence of this homeostatic system, the existence of which was often
debated. Although centuries of earlier work dating to Antoine Laviosier
suggested that energy balance in living organisms was likely to be under
homeostatic control, at the time that leptin was identified this hypothesis had
become controversial in part because of the intrinsic difficulty of identifying
its molecular elements. In the decades leading up to the identification of
leptin, the failure to identify the molecular elements of the physiologic system
regulating energy balance left a void that was filled by innumerable, largely
incorrect theories about how or even if weight was regulated biologically.
Changes in Nutritional State Regulate Other Physiologic Systems:
Leptin deficient ob mice develop a complex phenotype that includes
abnormalities in most, perhaps all, physiologic systems[31]. These pervasive
abnormalities are distinct from those typically manifest in human obesity.
This important difference originally raised questions about whether the ob
gene product would be play a role in regulating body weight in human. We
now know that leptin does play a role in humans because leptin mutations
result in profound obesity in obese humans [32]
In retrospect, it has been appreciated that all of the abnormalities evident
in massively obese ob/ob mice (paradoxically) resemble those that develop
during starvation of normal animals and humans. This apparent paradox can
be most easily understood if one considers the normal response to starvation.
With weight loss, fat mass is lost and leptin levels fall [26]. This low leptin
level is sensed and induces a state of positive energy balance by increasing
appetite and food intake and also reducing energy expenditure as part of a
biologic response aimed at restoring fat mass. This same starvation signal
(i.e.; low leptin) also modulates the function of other biologic systems as
part of the adaptive response to starvation. These responses include (but are
not limited to) cessation of female ovulation, reduced immune function, a
26
decrement in insulin signaling, and the development of a sick euthyroid state
[33-35]. A role for leptin in ovulation was consistent with the suggestion by
Rose Frisch that an adipose tissue derived factor was required to develop and
maintain reproductive capacity in females. As described below in studies
of patients with hypothalamic amenorrhea, we now know that this adipose
factor is leptin [36].
Similar to the case for animals or humans that have lost weight and develop
a decreased plasma leptin, the absence of leptin production as a result of
a genetic mutation, leads to a state of perceived starvation. In this state,
a potent signal in the form of low plasma leptin triggers a set of biologic
responses that are normally activated in the starved state. Despite the fact
that leptin deficient organisms become obese, the leptin mutation prevents
the generation of a leptin mediated signal that normally suppresses these
responses.
A key result in support of this conclusion was provided by injecting fasted
animals with recombinant leptin [33]. In this experiment, leptin was able
to suppress the effect of starvation on ovulation, thyroid function and
other neuroendocrine responses. Analogous studies have also shown that
recombinant leptin can also suppress the immune abnormalities that develop
in fasted animals [34].
The role of low leptin in inducing a pleiotropic set of effects in humans
has been further confirmed by the proven efficacy of leptin for treating a
number of diseases that are caused by leptin deficiency in humans (see
below). Overall, these human and animal data confirm that leptin plays a
key role in the adaptive response to starvation by modulating the function of
other physiologic systems. It is widely accepted (correctly so) that changes
in nutritional state alter the function of other physiologic systems. It is now
clear that leptin is a key means by which such changes in nutritional state
are communicated.
Many Leptin Deficiency Syndromes Are Treatable With Leptin Replacement:
Leptin mutations in human are associated with massive obesity that is
remediable by leptin treatment [32]. While leptin mutations are rare, the
demonstration of a profound phenotype in these patients confirms the role
of this hormone in human physiology. Note, the low incidence of leptin
mutations is similar to that observed for other key hormones such as insulin
as a complete loss of hormone function is catastrophic in an evolutionary
context (for example, leptin deficient humans and animals are infertile and
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leptin deficient animals are likely to be more susceptible to predation) and
thus strongly selected against.
Leptin deficient patients, as mentioned above, also show a set of abnormalities
in other physiologic systems and these too are remediated by leptin
treatment [32, 37]. The realization that leptin deficiency is associated with
alterations in the function of other organ systems suggested the possibility
that low leptin levels associated with other conditions might have pathologic
consequences. Several such conditions have been identified, the first of
which was lipodystrophy.
Lipodystrophy (LD) comprises a set of conditions that are associated with the
absence or a profound reduction in adipose tissue mass [38]. Lipodystrophy
can be complete or partial and is often the result of mutations in genes
normally required for adipose tissue development. Lipodystrophy can also
be acquired as a result of autoimmunity and also can develop in chronic HIV
patients [39, 40]. Indeed a substantial number of HIV patients, generally
those on HAART triple therapy, develop lipodystrophy
In this condition, a reduction of adipose tissue results in the secondary
deposition of lipid in other organs, in particular the liver, and a severe,
potentially intractable insulin resistance. Because of the loss of the secreting
organ (adipose tissue), leptin levels are pathologically low in lipodystrophic
patients. The contribution of the low leptin level to the consequences of this
disease has been clearly established by the proven clinical benefit of leptin
treatment to correct the hepatic steatosis and insulin resistance these patients
develop [38, 41, 42]. The response to leptin therapy was most pronounced
in patients with complete lipodystrophy but beneficial effects were also
evident in some patients with partial and HIV lipodystrophy. Finally,
leptin also ameliorated the neuroendocrine abnormalities that develop in
LD patients despite the fact that a significant loss of adipose tissue mass
was observed [38]. This finding, and an analogous finding in patients with
hypothalamic amennorhea, uncouple the normal relationship between fat
mass and the response to starvation and thus confirm that it is a low leptin
level that conveys the information that an organism is pathologically thin
(not the fat mass itself).
Hypothalamic amenorrhea (HA) is another condition associated with low
leptin levels. Female patients who are extremely thin showed delayed
puberty or sometimes fail to enter puberty at all. In addition, adult females
who develop extreme leanness, (often associated with extreme exercise)
frequently stop menstruating [36]. Women with this condition show a
28
prepubertal pattern of gonadotrophin secretion and also manifest other
neuroendocrine and metabolic abnormalities including premature, severe
osteoporosis that in most cases cannot be treated adequately with hormone
replacement therapy [43]. This condition is not uncommon affecting
4-8% of women of reproductive age and accounting for as many as one
in three visits by women to an infertility clinic (personal communication,
Chris Mantzoros). The contribution of hypoleptinemia to this condition
was confirmed by the demonstration that leptin replacement therapy can
restore reproductive function in women with HA some of whom had not
menstruated for years [43]. HA patients also develop a set of neuroendocrine
abnormalities typically associated with starvation, which are also ameliorated
by leptin treatment. In addition, there is evidence from serum markers that
leptin might also improve the bone pathology and that recent findings show
a dramatic effect of leptin to improve bone mineral density in these patients
[44]. Similar to the results for lipodystrophy, these patients lose adipose
mass thus confirming the key role of hypoleptinemia in the activation of a
set of physiologic responses to starvation [45].
These data further suggest that leptin might have beneficial effects in other
conditions associated with extremely low leptin levels. As noted by Frisch,
delayed puberty is often associated with extreme leanness and the failure to
enter puberty in the correct temporal window can have significant, life-long
consequences [36]. Females with leptin mutations typically do not enter
puberty even when showing an appropriate bone age; leptin therapy rapidly
induces a peri-pubertal pattern of gonadotrophin secretion which reverts when
leptin therapy is stopped [32]. In this setting leptin is permissive for the onset
of puberty, as leptin treatment does not induce puberty in young women who
have not reached the appropriate bone age. Thus, it is conceivable that in
some cases leptin therapy might be of benefit for inducing puberty.
Women with anorexia nervosa and with cachexia resulting from cancer or
severe chronic infections also show many of the same abnormalities observed
in malnourished individuals including prominent immune abnormalities.
These immune alterations often contribute to the high mortality rate of
these conditions. Consistent with this, patients with leptin mutations show
abnormalities in immune function and in one extended pedigree segregating
leptin mutations, there was a high incidence of premature death from infectious
disease [37, 46]. While leptin would have the undesirable effect of inducing
weight loss in the setting of cachexia, there is evidence from animals that
leptin administration can suppress these abnormalities at lower doses than are
required to suppress food intake or body weight [47]. Thus it is conceivable
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that very low dose carefully titrated leptin treatment could have beneficial
effects on immune function and other systems in cachectic patients.
Finally, patients with insulin deficiency and Type 1 Diabetes are often thin
and show low leptin levels. Recent studies in animals have shown that leptin
administration to groups of Type 1 diabetic animals can normalize blood
glucose in groups of animals that otherwise die of ketoacidosis [48]. The
possibility that leptin might have similar effects in human is now being
tested. It has been suggested that the mechanism by which leptin elicits this
effect is by reducing glucagon secretion however other mechanisms may be
relevant [48].
Most Obese Patients are Leptin Resistant.
Plasma leptin levels in human are highly correlated with adipose tissue mass
and most obese patients have high leptin levels [26]. The presence of a high
endogenous hormone level in the absence of an evident hormone effect (in
this instance, leanness) suggests that there is resistance to that hormone.
Thus, the initial data indicating that endogenous leptin levels are elevated in
animal and human obesity suggested that the response of obese subjects to
exogenous leptin was likely to be variable [24]. Leptin’s efficacy was first
shown to be variable in rodents that showed a spectrum of leptin sensitivity
with leptin deficient states having extreme leptin sensitivity and animals
with leptin receptor mutations being the most resistant [24]. Animals with
diet induced obesity induced by a cafeteria or highly palatable diet, often
a reliable predictor of responses in human, showed a minimal response to
leptin administration.
A similar variability in the response to leptin has been seen in obese humans.
Thus while a statistically significant effect of leptin to reduce weight was
observed in a small cohort of obese patients, only a subset of obese humans
(~ 1/3) showed a clinically significant degree of weight loss on leptin therapy
(personal communication, Alex DePaoli) [49]. These data indicated that the
utility of leptin as a monotherapy for the treatment of obesity was likely to
limited to a subset of patients. It is yet unclear whether the individuals that
respond to leptin have lower starting leptin levels than non-responders. At
a given body mass index or percent fat, there is substantial variability of
leptin and ~ 10-15 % of obese subjects have endogenous levels of leptin that
are indistinguishable from lean patients [26]. The demonstration that leptin
can have therapeutic effects in some patients with low leptin levels in other
settings (see above), has suggested there could potentially be efficacy for
leptin in obese patients with low plasma leptin levels [47]. While leptin has
30
been shown to have potent weight reducing effects in obese animals with
low leptin levels, this possibility has not been directly tested in humans [47].
A key issue for future studies will be to elucidate the molecular mechanisms
responsible for leptin resistance. Leptin activates signal transduction in
specific neural populations in the hypothalamus and other brain regions [50].
The leptin receptor signals via the JAK-Stat signal transduction pathway,
which depends in part on phosphorylation of tyrosine residues of specific
protein substrates including Stat3[50]. Signaling by this class of receptors is
generally time limited as a consequence of the secondary activation of SOCS
proteins which inhibit the JAK kinase, and specific tyrosine phosphatases
which shut off cytokine signaling after the signal transduction pathway is
initially activated. Consistent with this, the cellular effects of leptin have
been amplified in cells lacking either SOCS3 or PT1b, a phosphotyrosine
phosphatase. Importantly, mice with haploinsufficiency for either of these
genes are resistant to obesity and remain lean on a high fat diet and retain
leptin sensitivity [51, 52]. While these studies do not establish whether
these proteins directly contribute to the development of leptin resistance,
these data do show that the enhancement of leptin sensitivity can protect
against obesity. These results also suggest that chemical inhibitors of
SOCS3 or PT1b could have potential as anti-obesity agents either alone or
in combination with leptin.
Recently, the hormone amylin has been shown to ameliorate leptin resistance
though the molecular mechanism has not been fully established [53]. Amylin
is a peptide hormone secreted from pancreatic cells that has a number of
effects on plasma glucose that are synergistic with insulin. This agent is
approved for the treatment of diabetes as an adjunct to insulin treatment.
Amylin reduces glucose absorption, suppresses glucagon secretion and
reduces food intake [53].
Amylin mono-therapy is associated with a durable weight loss of ~ 5 % in
human establishing it as one of a number of gastrointestinal signals that regulate
nutrient intake and disposition. The possibility that amylin could interact with
leptin to achieve even greater weight loss was first assessed in diet induced
rats where it was shown that doses of leptin that had no discernible effect
as a monotherapy in this setting, could significantly enhance the response to
amylin [53]. The data further suggested that there was true synergy between
leptin and amylin and that amylin could restore leptin signal transduction in
the hypothalamus of DIO rats. The clinical significance of these findings was
also assessed in human where the combination of leptin and amylin resulted
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in substantial weight loss of 12.9 % that was significantly greater than either
agent alone [53]. Further studies will reveal whether this combination is safe
and efficacious for the treatment of obesity.
Evolutionary Implications
Overall, these data confirm that adipose tissue mass is under homeostatic
control in mammals. This suggests that there is an optimal amount of adipose
tissue, and that there is a selective advantage for animals and humans to
maintain a constant level of adiposity. This further suggests that there might
be a selective disadvantage for mammals to have either too much or too little
adipose tissue. A reduced adipose tissue mass increases the relative risk of
starvation especially in an environment where stored food is not available
(such as for most mammals as well as humans living a hunter gatherer
lifestyle) [54]. Conversely, excess adipose tissue is known to increase the
risk of predation and also limit hunting capacity and is thus disadvantageous
for most mammalian species including our ancestors who depended on
hunting to survive and who were often victims of predators [55]. Therefore
it is likely that a homeostatic system evolved to balance the relative risks
of starvation vs. predation in populations that were vulnerable to both. The
level at which adipose tissue mass is “set” in each populations depends on
what the prevailing risk is (starvation vs. predation). Thus the environmental
condition strongly influences which populations are most likely to become
obese. For example, it has been observed that those populations at greatest
risk for starvation historically are most likely to become most obese in
modern times when food becomes readily available.
Leptin Provides an Entry Point for Studying a Complex Human
Behavior
Leptin treatment of leptin deficient animals or humans has extremely potent
effects on food intake. In one instance, the food intake of a leptin deficient
child was monitored before and after the first series of leptin injections.
Prior to the first injection, this then three-year-old child ate at least 2000
KCal at a single test meal (personal communication, Stephen O’Rahilly).
This is the approximate number of calories a fully-grown adult might eat
in an entire day. After a short period of leptin treatment, this child ate 180
KCal at an identical test meal. Marked effects of leptin to reduce food
intake in lipodystrophic patients and others have also been noted [38].
The mechanism by which leptin reduces food intake has been partially
elucidated. Leptin acts by modulating the activity of a set of neural
32
pathways and, in general, activates pathways that inhibit food intake and
inhibits pathways that activate food intake. A portion of leptin’s actions
appear to result from inhibition of NPY/AGRP expressing neurons in the
arcuate nucleus of the hypothalamus which stimulate appetite and activation
of POMC neurons which reduce appetite by activating the MC4 receptor in
other parts of the brain [56]. However it is likely that other neural pathways
also play a role and it is not clear what the aggregate set pathways are that
can account for the full effect of leptin treatment. Moreover it is also not
clear whether leptin resistance abrogates leptin signaling by the NPY or
POMC neurons or as yet unknown neural circuits. The identification of
those circuits that are altered in the leptin resistant state would provide key
entry points for delineating the molecular mechanisms.
It is also unknown which of the sites to which these and other
hypothalamic neurons project are responsible for the reduction of food
intake. It has recently become clear however that leptin signaling has
important modulatory effects on dopaminergic neurons that are part of
reward pathways that provide input to the nucleus accumbens [57, 58]. Other
studies have shown that leptin acts in part by reducing the reward value of
food confirming that pathways regulating homeostatic eating intersect with
pathways that confer the hedonic (i.e.; pleasurable) value of nutrient [59].
Consistent with this, fMRI imaging of leptin deficient subjects has revealed
a marked increase in activity in the nucleus accumbens in response to images
of food even in the fed state [60-62]. Normal individuals typically show
this activity only in the starved state and do not show this response in the
fed state. The activity that is seen in the accumbens in fed leptin deficient
patients was normalized by leptin therapy [60-62]. In addition, leptin
deficient patients show markedly different food preferences and perception
of food than do normal individuals [60-62]. These data establish that leptin
plays an important role to regulate feeding, a typical complex motivational
behavior. Further studies of the components of the neural circuit activated
by leptin may provide a means for elucidating the process by which complex,
behavioral decisions are generated.
Biologic Basis for Obesity
The importance of the aforementioned neural circuits for human obesity has
been established in a series of genetic studies in which it has been shown
that single gene, Mendelian defects account for ~ 15 % of cases of morbid
human obesity, perhaps more [63-71]. (In one cohort 15% of individuals
with severe, early onset obesity were members of consanguineous
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pedigrees, personal communication, Stephen O’Rahilly). Thus in addition
to mutations in the leptin and leptin receptor genes, significant obesity
is also demonstrable in patients with POMC and MC4R mutations. This
level of Mendelian inheritance exceeds that for most, perhaps all, other
complex traits all of which are commonly accepted to have a genetic basis.
Consistent with this, twin studies and other approaches have established a
substantial genetic basis for obesity with a hereditability of .7-.9, a level
exceeded only by height [72]. While a subset of these individuals show
Mendelian inheritance, the majority of these cases are likely to be the result
of polygenes interacting with environmental factors. It is likely the use of
whole genome sequencing will lead to the identification of additional genetic
loci that cause obesity [73].
The identification of genetic factors that cause obesity is beginning to
have an impact on public perception of the obese. In the US, the obese are
too often held to be responsible for their condition. Obese individuals on
average make less money than their no better-qualified lean counterparts
and are promoted less readily [74, 75]. In addition, the obese are often the
object of ridicule to an extent that would be unacceptable for any other trait.
The identification of human mutations that cause obesity requires that we
modify the explanation that is often invoked to explain the pathogenesis of
obesity, “The obese eat too much and exercise too little”. Although this is
undoubtedly true, the deeper question is, “Why do the obese eat more and
exercise less? The answer appears to be less about the conscious choices that
the obese make and more about their biologic makeup. The identification of
leptin and other components in a physiologic system that maintains energy
balance has established that feeding is at its core a basic biologic drive
analogous to thirst, breathing and reproduction [74]. Although one can
consciously override a basic drive over the short term, over time the basic
drive to eat dominates. There are innumerable instances in our common
experience that basic drives typically trump a conscious desire. The world
would be a better place if people who deride the obese kept this in mind.
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WINNERS OF THE 2012
KING FAISAL INTERNATIONAL
PRIZE
FOR SCIENCE
The King Faisal International Prize for Science (Physics) for the year 1434H
- 2013G has been awarded jointly to: Professor Paul B. Corkum (Canada)
and Professor Ferenc Krausz (Hungary/Austria).
The prize winners are recognized for their independent pioneering work
which has made it possible to capture the incredibly fast motion of electrons
in atoms and molecules in a “movie” with a time resolution down to
attoseconds. An attosecond is a vanishingly short time. One attosecond
compared to one second is like one second compared to the age of the
Universe.
When intense ultra-short laser pulses are focused into a gas, a laser-like
beam of attosecond pulses of ultraviolet light is produced.
Professor Corkum was the first to explain this phenomenon with a
conceptually simple model. He has harnessed this process for pioneering
studies in collision physics, plasma physics, and molecular science. He has
even been able to produce tomographic images of the movement of electrons
in molecules.
42
Breaking the Attosecond Barrier
- and Beyond
Paul Corkum
Joint Attosecond Science laboratory University of
Ottawa and National Research Council of Canada
The origins of ultrashort pulse
science
How can scientists probe the fastest
phenomena that occur in nature?
How, for example, can they monitor
the vibration and their relaxation
in a solid? How can they track a
chemical reaction that might occur
in only 30 femtoseconds?
Before 1960, scientists had to
rely on electronic technologies to
probe the mysteries of the fastest
accessible phenomena in nature at
that time – a speeding bullet for
example. Then in 1960 came the
laser – a revolutionary tool that
gave optical scientists the ability to produce light pulses as short as a few
picoseconds.
With the laser’s invention, optics (which studies the behaviour and application
of light) displaced electronics as the best means to systematically probe
nature’s fastest phenomena.
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By 1964, optical researchers
had discovered how lasers
could be used to produce
light pulses as short as a few
picoseconds. To observe
important processes such as
sound waves relaxing in a
solid, a typical experiment
could use a beam splitter to
divide a single pulse into two
replica pulses. One pulse
excites the process of interest.
Since light travels 0.3 mm in
a picosecond, a delay can be
imposed on the other pulse
by sending it over a slightly
longer path. By varying the
path difference, the delayed pulse probes the evolving system excited by the
first pulse. In the case of a vibrating solid, we would see how a vibration,
started by the pump-pulse, evolved with time.
Ultrashort pulse technology has changed our lives. It has enabled us to
encode information onto short light pulses and use them for high-speed
communication. It has allowed us to excite solids to see how quickly they
respond ─ information critical for modern electronics. We have also learned
to trace the path of chemical reactions in “real time.” Each new application
has encouraged laser scientists to improve short-pulse laser sources, and
each advance in sources has opened new areas of research. This history is
encapsulated in Figure 1.
A new barrier to overcome
As we entered the 1980s, an apparently fundamental limit approached. Figure
1 shows that by 1986, the shortest pulse was only 6 femtoseconds: three
periods of the then-used 600 nm wavelength of light. The only way forward
would be to use shorter-wavelength light, but that looked like a daunting task
─ daunting because in 1917, long before the first laser was created, Einstein
had derived an equation [1] showing that the shorter the wavelength of light,
the harder it would be to create a tool such as a laser. How could we ever reach
the attosecond time scale while struggling against Einstein’s prediction?
Thus, throughout the 1980s and 1990s, scientists largely abandoned the drive
44
to shorten pulses. Instead, they explored new laser materials and created many
engineering advances. Furthermore, better pump-probe methods emerged,
enabling us to learn more about the systems we were studying. Most important,
however, was the intensity frontier. It was by studying high-intensity light
that we would break the log-jam. To understand how, we need to consider
plasma physics – the physics of ionized gases.
Plasma physics and the next breakthrough
A plasma is a gas in which some or all of the atoms are ionized, so plasma physicists
are always concerned with atomic ionization and recombination. Therefore, they
were very aware of the work of L. V. Keldysh [2] and others showing that we can
treat ionization in an intense light pulse as if the electron tunnelled — the simplest
of quantum mechanical processes. Furthermore, since plasmas are usually very
hot they usually treat the electrons as classical particles. When classical electrons
interact with intense light to a reasonable approximation, they oscillate (much like
a cork bobbing up and down on a water wave).
Plasma physicists also knew that electrons that collide with ions can convert
some or all of their kinetic energy into light by recombining or by scattering.
But oscillating electrons can gain kinetic energy, thereby absorbing photons
from the light beam that oscillates them. So three concepts that would turn out
to be critical for producing shorter pulses (and therefore faster measurements)
were already in place, waiting to be applied to atomic and laser problems.
These concepts were:
(1) the probability of ionization;
(2) how to treat the electron once it was formed; and
(3) how radiation could be produced by an electron interacting with an ion.
A plasma perspective on atomic ionization and vice versa
The first two plasma ideas that laser scientists focussed on were the tunnelling
approximation for the probability of ionization, and the oscillating motion of
an electron in intense light. The resulting model’s predictions were rapidly
verified [3]. The first important implication was immediately apparent: that it
might be possible to excite media that could support X-ray lasers by ionizing
an atomic gas. Let me explain:
Atomic ionization forms plasmas. The electrons created by atomic ionization
become the plasma’s electrons. Therefore the characteristics imposed by
ionization determine the plasma parameters. The new model showed that the
temperature of a plasma’s electrons could be controlled over a very wide range.
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If so, it would be possible to design plasmas that would contain just the right
conditions for X-ray lasing. Soon however, X-ray lasers were overwhelmed
by a second advance.
Barely had the dream of X-ray lasers been proposed when the third plasma
idea (how radiation is produced during the interaction between an electron
and an ion) was imported into the model. With that third concept, we had a
comprehensive and intuitive model of atomic ionization. We could now use
that model to guide us towards producing attosecond pulses and also very
short wavelength radiation.
Figure 2 illustrates the model’s three steps [4]:
1. An electron is released near a crest of the light wave.
2. The electron is carried by the force of the light wave. First it moves away
from its parent ion, but as the field reverses, it is driven back towards its point
of origin, where it has a significant probability of re-encountering its parent
ion.
3. The re-encounter offers three possibilities — all of which can happen:
a) The electron can elastically scatter, gaining kinetic energy from the light
wave. In plasma physics, this process is known as inverse Bhremsstrahlung.
In atomic and molecular physics, it is known as above-threshold-ionization.
b) The electron can in-elastically scatter with its parent ion, exciting another
electron or knocking it free. This process is related to collisional ionization in
a plasma, and as non-sequential double ionization in atomic physics.
c) The electron can also recombine to its initial ground state, transferring
its kinetic energy into
photon energy. Since the
electron began and ended
in the same state, the light
from different atoms can
add coherently to create
intense light. This process
is known as high harmonic
generation if multiple
recollisions are possible, or
attosecond pulse generation
if only one collision takes
place. By showing us
how transferring long-
46
wavelength light into shorter-wavelength light occurs, the model showed how
we can produce much shorter pulses.
Making attosecond pulses
In solving the challenges we faced in 1986 of how to shorten photon pulses
to less than approximately 6 femtoseconds, we developed concepts that were
new for optics. Based on the resulting insights we have learned how to produce
and control an ionizing electron — from the parent ion’s point of view, the
recolliding electron looks like an attosecond electron pulse. Furthermore,
from the moment of ionization, each electron “beamlet” is shorter than the
shortest optical pulse that we could achieve by conventional means.
To create a single attosecond pulse, we had to engineer the waveform of the
guiding infrared light field so that only one electron beamlet can recollide
with its parent [5]. Today, we can draw on a number of approaches to ensure
a single recollision. For example, we can make the duration of the light pulse
that powers the recollision so short that one electron beamlet recollides with
sufficient energy to produce high-energy photons. Then, if we look through a
filter, we see only one pulse.
Using this and related approaches, we have reached the current record pulse
duration, which is shorter than 70 attoseconds and almost 100 times shorter
than the record 6 fs from 1986 to 2000. As we hone the technology, it should
be possible to reach pulses of only a few attosecond in duration, although we
have much to learn before we achieve that in practice.
In addition to producing attosecond pulses, we have also created a new
nonlinear optical technology. This new approach enables an electron born from
an atom or molecule to return to its parent with attosecond timing precision.
In fact, it can hardly miss! With this particle, we can simultaneously resolve
Ångstrom-scale structure and attosecond-scale dynamics. The attosecond
photon pulse can even “report” this information to us.
How can we measure anything so fast?
A process fast enough to produce an attosecond pulse is also fast enough
to measure the pulse itself. This fundamental concept, and how it could be
implemented, was already clear from the same plasma perspective that led to
attosecond pulses in the first place. The general technique was first called the
“Sub-femtosecond Streak Camera” [6], now replaced by “attosecond streak
camera”. (“Streak camera” refers to the very early history of short-pulse
measurement when a streak camera was the only method of measurement.)
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In a conventional streak camera, an electron is photo-excited by the pulse to be
measured in a photocathode that rapidly emits it. In the attosecond streak camera
the photocathode is an atom and an intense infrared light pulse is also present
at the electron’s birth. As soon as the electron is released, it is accelerated by
the light pulse much as we described earlier. The range of moments of birth of
the electron – that is, the duration of the attosecond pulses – is encoded in the
final momentum of the photo-electrons. Measuring the momentum distribution
as a function of delay between the attosecond and infrared pulse gives us all the
information that we need to reconstruct the pulse duration.
In-situ and ex-situ measurement
Having created a new technology, it is essential to apply it to important
problems in science. We have three key tools at our disposal:
• The new method that created the attosecond pulses in the first place.
• The recollision electron.
• The attosecond pulse.
Each tool is important and they suggest two basic approaches to experiments
that are sometimes referred to as in-situ and ex-situ measurement. For ex-
situ measurement, we adapt the previous methods of ultrafast pump-probe
spectroscopy. The attosecond pulse pumps or probes those dynamics that
we wish to study. For in-situ measurement, we exploit the attosecond
recollision electron, either directly or indirectly. Consequently, for in-
situ measurement the unknown sample must be the system that creates
the attosecond pulse. Before we comment further on this direction of
research, it is useful to understand the recollision process from a quantum
mechanical perspective.
Attosecond pulse production as an electron interferometer:
For more than a century, science has known that classical physics does not
provide us with a complete description of nature at the atomic level. Our
plasma perspective was useful only because many photons are involved
in creating any attosecond pulse. It is more precise, however, to think of
an electron wavefunction rather than a particle-like electron and to think
of ionization as splitting the electron wavefunction rather than having
the electron emerge intact from the tunnel. In the quantum mechanical
description, one part of the electron wavefunction remains with the atom
and the other part is launched as a wave packet (like a ripple, propagating
in space). When the wave packet returns to its parent, these two parts of the
same wavefunction overlap and interfere with each other. In the foregoing
48
quantum mechanical description
[7], attosecond pulse generation
arises from the charge oscillation
the interference creates. Thus,
attosecond pulse generation is a
form of electron interferometry.
The characteristics of the
attosecond pulse encode details
of the interferometer.
This interferometric interpretation
is even more powerful than
the classical model, because
science has learned a lot about
interferometers that we can adapt
to attosecond technology. We know from optics, for example, that by using
interferometry we can determine almost everything about an optical beam.
If this is true for an optical
interferometer, it must also be true
for the electron interferometer.
In other words, by manipulating
this interferometer, we should be
able to measure both the bound
state wavefunction and the
characteristics of the recollision
electron (and therefore the
attosecond pulse itself).
In fact, that is exactly what we do.
The orbital image that we have
measured for the valence electron
of a nitrogen molecule (shown in
Figure 4) is obtained in this way
[8]. But to obtain this image, we
need to seize control of a molecule
that is tumbling freely in space.
High intensity light and attosecond technology – a powerful combination
Attosecond pulses arose while we were studying how matter interacts with
intense, ultrashort light pulses. Even at intensities lower than those needed
for ionization, the system is still strongly influenced by a light pulse. Under
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such circumstances, both the system and the light share responsibility for the
spectrum. This sharing provides a tool by which a light pulse can control
molecules. With an intense infrared light pulse, we can align them in space or
orient polar molecules — and much more.
To obtain the image in Figure 4, we used an intense infrared pulse to align
N2. For each alignment, we created high harmonics that reported on the
aligned recollision — an in-situ measurement. We then used this harmonic
spectrum as a function of alignment to reconstruct the orbital image following
tomographic methods.
For some molecules and some alignments, a single electron disrupts the
remaining electrons. Their resulting oscillation (the oscillation of the
hole) can also be measured by the recolliding electron. Thus, experiments
are launching us along new paths in which we image electrons and study
their dynamics.
What is next?
As we look ahead, the developments of attosecond science have placed us at
the forefront of four major sub-fields of science: Ultrafast Science; Nonlinear
Optics; Collision Physics; and X-ray Science.
Ultrafast science has retained its freshness for 50 years because time is a
natural frontier in all of the physical sciences. As attosecond methods are
developed to measure shorter and shorter time intervals, we will inevitably
find unexplored science, opening new processes for inspection. From the
perspective of where we sit today, we are still a very long way from any
natural boundary. We can expect technology to drive the production of even
shorter pulses, motivated by the demand to study ever faster phenomena. The
current forefront? Measuring and controlling electronic dynamics in atoms,
molecules and solids.
Nonlinear optics is also a 50-year-old sub-field of optical science. Recollision
physics, from which attosecond pulses emerged, is a forefront of nonlinear
optics and a second tradition on which we can build. In fact, all ultrafast
measurements are of necessity nonlinear. Since nonlinear optics is so
fundamental to time-resolved measurements, we should expect that the
development of non-perturbative nonlinear optics will open new measurement
paradigms. At present, it already allows attosecond pulses to be measured as
they are being formed.
Collision physics is one of the oldest fields of physics. It was through collisions
50
that science first learned about the structure of matter. Therefore, through the
collision aspect of a recollision, optics gains systematic access to this kind of
structural information. Already this includes atomic and molecular structure.
But the influence goes both ways. Attosecond science offers important tools
to collision physics that were previously lacking. For example, it offers
the opportunity to time-resolve collision events, something that was not
systematically available previously. Time resolution could be particularly
helpful for ultrafast studies of the dynamics in the atomic nucleus. In addition,
since re-collisions can be timed with respect to optical pulses, an optical
pulse could prepare the sample to be probed by the collision. It will be very
interesting to probe optically-aligned, oriented or dissociating molecules with
the well-developed methods of collision physics.
The role of the X-ray region of the spectrum was greatly enhanced about 30
years ago by the development of the synchrotron. The mathematics of short-
pulse formation and the technology of their generation require that attosecond
pulses lie in the XUV or soft X-ray spectral region. With attosecond and
high harmonic generation opening this spectral region to laser-like sources
and ultrafast pulses, the unique diagnostic capabilities of X-rays can be turned
to time-dependent issues.
But attosecond science is not the only new “game-in-town”. Just as femtosecond
technology has given birth to attosecond technology, synchrotron technology
has spawned a new free-electron laser technology. These lasers produce
very bright femtosecond X-ray beams, thereby providing a different route to
some of the same features that we have described above. Looked at from
an overview, these two rapidly developing and closely related technologies
represent a truly historic technological advance. Together they will power
important discoveries in the next decades.
Acknowledgements:
It is my pleasant duty to acknowledge the contribution of the National Research
Council of Canada to the birth and growth of attosecond science. Their
continual support over many years has been essential. I also acknowledge
important support from Canadian’s other funding agencies, particularly the
Natural Sciences and Engineering Research Council, the Canada Foundation
for Innovation and the Canada Research Chairs program. Ontario’s
contribution through the Premier’s Discovery Fund and the Ontario Centres
of Excellence has also been very helpful. In addition, I wish to highlight the
support of the US AFOSR and the US ARMY MURI program.
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References:
[1] A. Einstein, “On the Quantum Theory of Radiation”, Phys. Zs. 18, 21
(1917)
[2] L. V. Keldysh, Eksp. Teor. Fiz. 47 1945 (1964); [Sov. Phys. JETP 20,
1307 (1965)]
[3] P. B. Corkum, N.H. Burnett and F. Brunel, “Above Threshold Ionization
in the Long Wavelength Limit”, Phys. Rev. Lett. 62, 1259 (1989)
[4] P. B. Corkum, “A Plasma Perspective on Strong Field Multiphoton
Ionization”, Phys. Rev. Lett. 71, 1994 (1993)
[5] P. B. Corkum, M. Y. Ivanov and N. H. Burnett, “Sub Femtosecond Pulses”,
Opt. Lett. 19, 1870 (1994)
[6] M. Ivanov et al, “Routes to Control of Intense Field Atomic Polarizability”,
Phys. Rev. Lett. 74, 2933, (1995); E. Constant et al. “Methods for the
Measurement of the Duration of High-Harmonic Pulses”, Phys. Rev. A
56, 3870 (1997)
[7] M. Lewenstein et al, “Theory of High Harmonic Generation by Low
Frequency Laser Fields”, Phys. Rev. A 49, 2117 (1994)
[8] J. Itatani et al. “Tomographic Imaging of Molecular Orbitals”, Nature 432,
867 (2004)
Further reading
• H. Niikura et al, “Sub-laser-cycle electron pulses for probing molecular
dynamics”, Nature, 417, 197 (2002)
• J. Levesque and P. B. Corkum, “Attosecond Science and Technology” Can.
J Phys, 84, 1 (2006).
• P. B. Corkum and Ferenc Krausz, “Attosecond Science”, Nature Physics,
3, 381 (2007).
• P. B. Corkum, “Recollision Physics”, Physics Today, 64, 36, (2011)
52
Real-time Observation and Control of
Electron Motion
Ferenc Krausz
Professor of Physics, LMU Muenchen
Director, MPQ, Garching, Germany
100 Sussex Drive, Ottawa, Canada K1A 0R6
Brief historical overview: from milliseconds to attoseconds
Attosecond science is the culmination of a long-standing evolution of the study
of fast-evolving phenomena in nature. It was already known in the XIXth century
that short flashes of light permit recording rapid phenomena and uncover truths
that the eye is incapable of perceiving. By recording freeze-frame snapshots of a
galloping horse via spark photography, Muybridge (1878) was able to show that
at certain instants all four legs of the horse were off the ground simultaneously1
. In the same century, Toepler (1864) extended spark photography to studying
microscopic dynamics by initiating the motion with a trigger spark (pump flash)
and subsequently photographing it with a second spark (probe flash) that was
delayed electronically with respect to the first2 . Pump-probe spectroscopy
was born. Abraham and Lemoine (1899) refined the technique by deriving the
pump and the probe flash from the same spark with a variable optical path
length in between . The resultant optical synchronism between3 . the
triggering and photographing flash opened the way to improving the resolution
of pump-probe spectroscopy to the limit set by the flash duration.
With these milestones the conceptual framework for studying transient
microscopic phenomena was complete. Subsequent progress in time-resolved
1- E. Muybridge, Animals in Motion, ed. by L. S. Brown (Dover Publ. Co., New York, 1957).
2- P. Krehl and S. Engemann, ”August Toepler - the first who visualized shock waves,” Shock
Waves 5, 1 (1995).
3- H. Abraham and T. Lemoine, Compt. Rend. (Paris) 129, 206 (1899).
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measurements was driven and dictated by the development of sources of ever
shorter flashes of light and techniques for their measurement. Motivation for these
developments came from quantum mechanics. It predicts the characteristic
time
scale for the rapidity of microscopic dynamics as Δt ~ h / ΔW , where ΔW is
the spacing between the relevant energy levels of the microscopic system and is
Planck’s constant. Applying this simple rule to the millielectronvolt and several-
to-multi-electronvolt energy spacing of vibrational and electronic energy
levels, respectively, suggest that structural dynamics of molecules and solids as
well as related chemical reactions and phase transitions evolve on a
femtosecond time scale, whereas electronic motion on the atomic scale is to be
clocked in attoseconds.
The resolution of time-resolved spectroscopy was limited by the nanosecond
duration of pulses of incoherent light for more than half a century (Fig. 1). A
revolution in technology was required to end this standstill. The invention of the
laser by Basov, Maiman, Prokhorov and Townes4 and (perturbative)
nonlinear optics by Bloembergen and coworkers5 provided the
technological basis for the generation and measurement of picosecond and
femtosecond light pulses, which improved the resolving power of pump-probe
spectroscopy by six orders of magnitude within merely two and a half decades6 .
Four decades after the first observation of intermediates of chemical reactions
by Eigen, Norrish and Potter in the 1940’s7 , femtosecond metrology
permitted real-time observation of molecular dynamics, the breakage and
formation of chemical bonds by Zewail and co-workers, leading to the birth of
femtosecond chemistry 8
Fig. 1 Evolution of techniques for real-time observation and control of
microscopic processes. Discontinuities in the slope of briefest measured events
versus years indicate revolutions in technology: #1, laser (Basov, Maiman,
Prokhorov, Townes and coworkers) permitting generation and amplification of
coherent broadband light, and nonlinear optics (Bloembergen and coworkers)
4- A. L. Schawlow and C. H. Townes, Phys. Rev. 112, 1940 (1958); T. H. Maiman, Nature 187,
493 (1960).
5- J. A. Armstrong, N. Bloembergen, J. Ducuing, and P. S. Pershan, Phys. Rev. 127,
1918 (1962).
6- For a review, see T. Brabec and F. Krausz, Rev. Mod. Phys. 72, 545 (2000) and references
therein.
7- R. G. W. Norrish and G. Porter, Nature 164, 658 (1949); M. Eigen, Discuss. Faraday Soc.
17, 194 (1954).
8- For a review, see A. H. Zewail, J. Phys. Chem. A 104, 5660 (2000).
54
allowing the generation of ultrashort light pulses and their measurement; #2,
attosecond control and metrology based on concepts pioneered by Corkum and
laser techniques (controlled few-cycle light fields) developed by our group.
While changes in molecular structure occurs on a femtosecond time scale,
the quantum states of electrons in atomic systems undergo changes typically
within tens to thousands of attoseconds. Hence, real-time-access to atomic-
scale electron dynamics required yet another revolution in time-resolved
science. Concepts for strong-field control of ionization and comcomitant
atomic processes, put forward by Paul Corkum and coworkers9 , along with
controlled few-cycle light fields and their use for sub-femtosecond strong-
field control, demonstrated by our group, paved the way to this revolution.
In what follows we shall review the basic technological developments and
P. B. Corkum, Phys. Rev. Lett. 71, 1994 (1993). P. B. Corkum, et al., Opt. Lett. 19, 1870 (1994).
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proof-of-principle experiments that brought about the capability of accessing
atomic-scale electron motion in real time.
Advancing femtosecond technology to its ultimate frontier
As a first step towards attosecond technology, we advanced femtosecond
technology to its ultimate limit set by the oscillation period of light in the red/
near-infrared spectral range (2-3 fs), where low material dispersion favours
ultrashort pulse generation. In a series of experimental and theoretical papers
published in the first half of the 1990’s and reviewed in [1], we gained insight
into the mechanisms of few-cycle pulse formation in femtosecond solid-
state lasers and identified imperfect dispersion control as a major limitation.
This latter finding made us to invent (in cooperation with Róbert Szipöcs
and Kárpát Ferencz) a device capable of providing dispersion control with
unprecedented precision over previously inaccessible bandwidths: aperiodic
(chirped) multilayer dielectric mirrors, briefly: chirped mirrors [2]. Chirped
mirrors have been capable of providing group-delay dispersion control over
ultra-broad optical bandwidths to arbitrary order with low loss and constitute
up to the present day the only optical devices with this unique combination
of properties. They have been the key to pushing the frontier of femtosecond
technology towards its ultimate limit set by the light wave period [3],[4]. They
are meanwhile in widespread use in thousands of femtosecond laser systems
all over the world.
Breaking the 1-femtosecond barrier
Our intense few-cycle (few-femtosecond) laser pulses first demonstrated
in collaboration with Orazio Svelto and coworkers [4],[5] have enabled us,
in cooperation with Paul Corkum and Ulrich Heinzmann, to generate and
measure the first light pulse with a duration of less than one femtosecond, i.e.
on the attosecond scale [6]. The most intense field oscillation cycle of such
a laser pulse rips an electron off the atom, pulls it away from the core and
– during its subsequent half cycle, with its field direction reversed – pushes
the electron back to the vicinity of the core where it can recombine back
into its original bound state. Upon doing so, an extreme ultraviolet or soft-
X-ray burst is emitted at photon energies more energetic than any emission
resulting at other instants during the laser-atom interaction. We isolated this
emission by spectral filtering and measured the duration of the emerging burst
as 650-attosecond (Fig. 2). Our experiment also provided direct time-domain
access to field oscillations of visible light and has been recognized as “the first
56
attosecond measurement”10 . First applications to capturing electrons leaving
the atom or undergoing inner-shell transitions [7] have been acknowledged
as “the first genuine application of attosecond pulses for time-resolved
attosecond spectroscopy”11 and as studies “heralding a new field of research:
attophysics”12 . In 2002, the birth of attosecond science was selected by the
world’s premier scientific journals as one of the 10 greatest breakthroughs in
all areas of science13 .
Fig. 2 The first source of light flashes shorter than 1 femtosecond, heralding
the birth of attosecond science, see Ref. [6].
Controlled light waveforms steering electrons on the attosecond scale
However, the toolbox for attosecond technology was yet to be completed.
Theoretical studies predicted a sensitive dependence of the characteristics of
the generated attosecond pulse on the electric field waveform of their few-
10- Y. Silberberg, “Physics at the attosecond frontier”, Nature 414, 494 (2001).
11- M. Lewenstein, “Resolving processes on the attosecond time scale”, Science 297, 1131 (2002).
12- L. F. DiMauro, “Atomic photography”, Nature 419, 789 (2002).
13- Nature 420, 737 (2002); Science 298, 2299 (2002).
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cycle driver laser pulse [5]. In the mid 1990’s, our group discovered that
the field oscillations of light become accessible to measurement in the few-
cycle regime [3]. With the help of the Nobel-Prize-winning frequency comb14
technique drawing on the femtosecond solid-state laser technology reviewed
in [1], in collaboration with Theodor Hänsch and co we succeeded in producing
intense few-cycle light pulses with a controlled evolution of their oscillating
electric field. We also demonstrated the utility of waveform-controlled light
for controlling strong-field/electron interactions on the attosecond scale [8].
This has opened the door for the generation of isolated attosecond pulses
with well reproducible characteristics and their use for precision attosecond
measurements.
These results reveal how advancing femtosecond technology to its ultimate
frontier almost naturally led to the next revolution in time-resolved metrology.
In pulses comprising merely a few wave cycles, the oscillating light field
becomes experimentally accessible, allowing the control of the shape of light
waves. Intense, waveform-controlled few-cycle light, in turn, provides an
electric field variable on the electronic (i.e. attosecond) timescale and rivalling
in strength intra-atomic fields binding the electrons to the atomic core. It is this
strong, controlled, attosecond force exerted by the electric field of waveform-
controlled few-cycle light on electrons that has brought about the attosecond
revolution (#2 in Fig. 1) in ultrafast science.
Attosecond control, metrology, and spectroscopy
Waveform-controlled light and isolated attosecond pulses coming in
synchrony with them have led to a number of breakthroughs in time-
resolved metrology and spectroscopy. By implementing the basic concept
of high-speed streak camera imaging with electrons steered by light fields,
as proposed by Paul Corkum15 , the controlled light fields permit not only
the reproducible generation of isolated attosecond pulses but also their
precision measurement [9] and – with the help of the latter – their own
full temporal characterization [10] (Fig. 3). These completely controlled and
characterized attosecond tools have meanwhile allowed to render electronic
motion observable and controllable on the atomic and sub-atomic scales in
real time, just as femtosecond technology permits observation and control of
the motion of whole atoms in molecules and solids.
14- T. W. Hänsch, Rev. Mod. Phys. 78, 1297 (2006).
15- J. F. Itatani et al., Phys. Rev. Lett. 88, 173903 (2002).
58
Fig. 3 The first picture of a light wave, recorded with attosecond pulses, see
Ref. [10].
Beyond the reproducible generation of isolated sub-100-attosecond pulses
[11] (in cooperation with Dave Attwood), attosecond light-field control of
electrons has meanwhile also resulted in first demonstrations of controlling
molecular structure and reactions [12], in collaboration with Marc Vrakking,
Joachim Ullrich, and Abdallah Azzeer. Sculpting few-cycle light waveforms
within the wave cycle [13] is further expanding the experimental opportunities
to control the motion of electrons in atomic systems with the engineered
attosecond force of light.
In a series of collaborative projects, we have applied these attosecond tools
for gaining direct real-time insight into fundamental electron phenomena. In
a joint effort with Marc Vrakking and coworkers, we observed how electrons
tunnel out of their atomic binding potential under the influence of a strong
light field in subsequent steps lasting several hundred attoseconds each [14].
In cooperation with Pedro Echenique, Ulrich Heinzmann, Dietrich Menzel,
Johannes Barth and coworkers, we succeeded in tracing electron charge
transport through atomic layers in crystals and layered structures on time scales
of tens to hundreds of attoseconds [15]. Supported by the theory of Joachim
Burgdörfer and Costas Nicolaidis, we discovered a small but significant ( as)
delay in the photoelectric effect [16]. A multilateral cooperation with Stephen
Leone, Robin Santra, and Abdallah Azzeer gave rise to real-time observation
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of valence electron wavepacket motion inside atoms [17]. Last but not least,
the extension of attosecond control and metrology to the scrutiny of strong-
field processes in dielectrics led, in cooperation with Mark Stockman and
Johannes Barth, to the discovery of the feasibility of switch on and off electric
current in dielectrics on a sub-femtosecond scale [18],[19].
Outlook
Attosecond technology provides – for the first time in the history of science
– real-time access to the motion of electrons on atomic and sub-atomic
scales. The potential scale of impact of this technical capability can be hardly
overestimated. Insight into and control over microscopic electron motion are
likely to be important for developing brilliant sources of X-rays as well as for
understanding molecular processes relevant to the curing effects of drugs, the
transport of bioinformation, or the damage and repair mechanisms of DNA,
at the most fundamental level, where the borders between physics, chemistry
and biology disappear. Attosecond technology may also become instrumental
in advancing electronics and electron-based information technologies to
their ultimate speed: from microwave towards lightwave frequencies. These
prospects suggest that the new discipline affords promise for advancing
science, technology and medicine likewise.
Acknowledgement
Attosecond science is the result of a truly international effort. The advances
reviewed in this article could not have been achieved without the cooperation
of groups from three continents, whose leaders are acknowledged in the main
text, and the dedicated work of number of coworkers and colleagues of the
author, who appear as co-authors in the list of references below. The author is
deeply indebted to all of them for their invaluable contributions.
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