A SHOT AT MIGRAINE
`
`Drug companies are racing to prove antibody treatments
`can prevent the ·debilitating headaches
`By Emily Underwood
`
`long as she can remember,
`s
`53-year-old Rosa Sundquist has tal(cid:173)
`lied' the number of days per month
`when her head explodes with pain.
`The migraines started in childhood
`and . have gotten worse as she's
`grown older. Since 2008, they have
`incapacitated her at least 15 days
`per month, year-round.
`Head-splitting pain isn't the worst of
`Sundquist's symptoms. Nausea, vomiting,
`and an intense sensitivity to light, sound, and
`smell make it impossible for her to work -she
`
`116
`
`8 JA NUARY 2016 • VOL 351 ISSUE 6269
`
`used to be an office manager-or often even
`to leave her light-proofed home in Dumfries,
`Virginia. On the rare occasions when she
`does go out to dinner or a movie with her
`husband and two college-aged children, she
`·wears sunglasses and noise-canceling head(cid:173)
`phones. A short trip to the grocery store can
`turn into a full-blown at\:3.ck "on a
`dime:' she says.
`Every 10 weeks, Sundquist gets
`32 bee sting-like injections of the
`nerve-numbing botulism
`toxin
`into her face and neck. She also
`
`PODCAST
`
`To hear a podcast
`wit h author Emily
`Underwood, go
`to http://scim.ag/
`pod_6269
`
`visits a neurologist in Philadelphia, Penn(cid:173)
`sylvania, who gives her a continuous intra(cid:173)
`venous infusion of the anesthetic lidocaine
`over 7 days. The lidocaine makes "Sundquist
`hallucinate, but it can reduce her attacks,
`. she says-she recently counted 20 migraine
`days permonth instead of 30. Sundquist
`can also sometimes ward off an
`attack with triptans, the only
`drugs specifically designed to in(cid:173)
`terrupt migraines after they start.
`Millions of others similarly
`dread the onset of a migraine,
`
`sciencemag.org SCIENCE
`
`1
`
`EX2167
`Eli Lilly & Co. v. Teva Pharms. Int'l GMBH
`IPR2018-01426
`
`

`

`although many are not afflicted as severely
`as Sundquist. Worldwide, migraines strike
`roughly 12% of people at least once per
`year, with women roughly three times as
`likely as men to have an attack. The Mi(cid:173)
`graine Research Foundation estimates that
`u.s. employees take 113 million sick days
`per year because of migraines, creating an
`annual loss of $13 billion. The toll under(cid:173)
`scores how little current treatments-not
`just drugs, but nerve-numbing injections,
`behavioral therapies, and special diets-can
`h.elp many people.
`On the horizon, however, is a new class of
`drugs that many scientists believe can stop
`migraines at their root. The drugs block
`the activity of a molecule called calcitonin
`gene-related peptide, or CGRP, which spikes
`during migraine attacks. CGRP is "the best
`validated target for migraine, ever;' says
`David Dodick, a neurologist at the Mayo
`Clinic in Phoenix. It may also help finally
`solve the centuries-old puzzle of what trig(cid:173)
`gers the complex events of a migraine attack,
`which can cause brain activity to be "com(cid:173)
`pletely disregulated" for several days, similar
`to epilepsy and other recurrent, seiZurelike
`disorders, says Michel Ferrari, a neurologist
`at Leiden University in the Netherlands.
`Four pharmaceutical companies are rac(cid:173)
`ing to complete advanced clinical-trials of
`antibodies that either neutralize CGRP by
`binding to it, or block its receptor. So far,
`Dodick says, the data suggest the drugs work
`faster, for 'longer, and better than anything
`currently available. Most striking, he notes,
`is a subset of "superresponders;' whose at(cid:173)
`tacks appear to cease entirely for 6 months
`after a single injection of a CGRP-blocking
`antibody. "I've been in this field now for
`21 years, and this is the most exciting thing
`we've seen so far;' says Dodick, who has con(cid:173)
`sulted for several of the companies develop(cid:173)
`ing CGRP blockers.
`Others are more restrained. Given that the
`frequency of migraines can wax -and wane,
`at least some people in these initial trials
`may simply be getting better on their own,.
`. Ferrari says. "For me, it's still too early to
`judge the efficacY:'
`
`GREEK PHYSICIAN HIPPOCRATES de(cid:173)
`Scribed migraines in detail in the 5th century
`B.C.E., including the shining, scintillating
`"auras" that roughly a fifth of sufferers see a
`few minutes before an attack. Because vom(cid:173)
`iting seemed to relieve some migraineurs'
`symptoms, Hippocrates believed that the
`headaches resulted from an excess of ''yel(cid:173)
`low bile." But by the mid-20th century, most
`Physicians thought that dilated arteries and
`Veins in the head were key to the disorder
`because many patients describe feeling
`those blood vessels throb during an attack.
`
`NEWS
`
`ute, says Michael Moskowitz, a migraine re(cid:173)
`searcher at Harvard University. In its wa:ke,
`neuronal activity is temporarily depressed.
`Genetic studies of people with inherited
`forms of migraine and some animal stud- _
`ies suggest that CSD plays a central role in
`many, if not all, migraines, Moskowitz says.
`Of the 41 gene variants ·the studies have
`linked to migraine risk, many are in genes
`that modulate electrical activity in neurons
`and are thought to make carriers more
`susceptible to CSD.
`rodents,
`in
`Based on experiments
`Moskowitz believes CSD can trigger mi(cid:173)
`graines by irritating a network of neurons,
`the trigeminovascular system, which inner(cid:173)
`vates cerebral blood vessels. Moskowitz's
`lab discovered the system at the Massachu(cid:173)
`setts Institute of Technology in Cambridge
`in the 1980s, when they traced a group of
`fine nerve fibers radiating from blood ves(cid:173)
`sels in the meninges-delicate membranes
`that envelop the brain and spinal cord-to
`the trigeminal nerve, which innervates the
`
`14°/o face, head, and jaw. Moskowitz
`
`Americans affected
`by migraine or
`·severe headache
`
`"Look at any portrait of a person having a
`migraine, and they are pressing their hands
`to their temples;' says neurologist Marcelo
`Bigal at the Frazer, Pennsylvania, location of -
`· Israel-based Teva Pharmaceutical Industries,
`one of the companies developing a CGRP(cid:173)
`blocking drug.
`Many of the early remedies constricted
`blood vessels, adding to the misperception
`that abnormal blood flow was key to the dis(cid:173)
`order, Bigal says. The first such drugs, called
`ergotamines, were powerful vasoconstrictors
`derived from the ergot fungus, which grows
`on rye and other grains and led to mass
`poisonings in the Middle Ages. Large· doses
`of the fungus can cause seizures, psychosis,
`and gangrene in the limbs-a syll.drome
`some called St. Anthony's fire-but doctors
`found that small doses could help prevent
`women from hemorrhaging after childbirth,
`and they sometimes relieved migraines.
`Yet even refined, synthetic versions of
`ergotamine can dangerously narrow blood
`vessels, so doctors and patients welcomed
`the triptans, which selectively
`constrict the blood vessels of the
`brain. Introduced in the 1990s
`and still the most widely pre(cid:173)
`scribed migraine-specific drugs,
`triptans can head off a migraine
`attack in roughly 50% to 60% of
`people. who take them. They don't
`work for everyone, however, and
`they share an unpleasant side
`effect with ergots and many pain
`medications: If a person takes
`them frequently,
`their head(cid:173)
`aches may become more fre(cid:173)
`quent and severe.
`Although both ergotamine
`and triptans act on blood vessels,
`studies that began in the 1990s
`"torpedoed" the idea that dilated
`vessels actually cause migraines,
`says neurologist Jes Olesen of
`the University of Copenhagen.
`Particularly important, he notes,
`have been a series of detailed
`functional magnetic resonance
`imaging
`(fMRI)-based blood
`vessel studies showing no relationship be(cid:173)
`tween abnormal blood flow in the brain and
`the pain of migraine attacks.
`As the blood vessel theory of migraines
`unraveled, researchers looked to other po(cid:173)
`tential triggers. One was a disruption of
`normal electrical activity in the brain: a
`seizurelike phenomenon called cortical
`spreading depression (CSD). Strongly asso(cid:173)
`ciated with the aura many migraineurs get,
`this slow wave of abnormal neuronal exci(cid:173)
`tation usually begins in the occipital lobe at
`the back of the brain, and spreads over it at
`a rate of roughly 2 mm to 3 mm per min-
`
`3:1
`
`Ratio of women
`to men suffering
`migraine
`
`$20
`billion
`
`Estimated annual
`U.S. cost of migraine
`in treatments and
`lost productivity
`
`proposed
`that migraine pain
`arises when these fine nerves are
`irritated or stimulated by CSD or
`other factors. He also suggested
`that blocking the release of Sub(cid:173)
`stance P-the only pain-signaling
`neurotransmitter known at the
`time-in these nerves might ease
`migraineurs' symptoms.
`the
`Although many found
`hypothesis compelling, multiple
`trials of drugs designed to block
`the activity of Substance P failed
`to head off acute attacks in mi(cid:173)
`graine patients. Today, although
`most researchers agree that a
`hypersensitive trigeminovascular
`system is likely the source of
`pain in migraines, few would ar(cid:173)
`gue -that CSD is the only or most
`important factor in inflaming it,
`Moskowitz says. For one thing,
`most people who get the head(cid:173)
`aches don't experience the visual
`aura thought to be a conse(cid:173)
`quence of CSD. And only a handful of brain
`imaging studies have actually shown hints
`of CSD in human migraineurs. These ex(cid:173)
`periments, however, are difficult to conduct
`because they require deliberately sparking
`a migraine right before putting a person in
`an fMRI scanner. In 2001, Moskowitz per(cid:173)
`formed what many in the field describe as
`the most compelling demonstration of CSD's
`link to migraines, in an engineer who was
`able to trigger his own migraines through
`exercise-in this case, playing basketball for
`80 minutes before Moskowitz and colleagues
`recorded his brain activity.
`
`SCIENCE sciencemag.org
`
`8 JANUARY 2016 • VOL 351 ISSUE 62 69 117
`
`2
`
`

`

`NEWS I 'FEATURES
`
`:I
`- - - - - - - -1
`
`THE FAILURE of the Substance P-blocking
`drugs opened the door for CGRP, an ob(cid:173)
`scure, 37-amino a~id peptide, discovered
`largely by accident by neuroscientists
`Susan Amara and Michael Rosenfeld of the
`University of California, San Diego. While
`studying a thyroid hormone called calcito(cid:173)
`nin, which helps regulate the body's sodium
`and calcium levels, Amara and Rosenfeld
`found that the same gene that encodes
`calcitonin in the tqyroid gland produces a
`slightly different peptide in another part of
`the brain. As one of the earliest examples
`of alternative gene splicing, which enables
`a single gene to produce multiple proteins,
`the discovery made a splash when it was
`published in Nature in 1982.
`After finding CGRP is plentiful in brain
`pathways that process pain and in brain re(cid:173)
`gions that regulate blood flow, neurologist
`Lars Edvinsson, of Lund University in
`Sweden, wondered whether CGRP is in(cid:173)
`volved in migraines. His group soon found
`that CGRP. can trigger what was then
`considered a hallmark sign of migraines:
`When released from the trigeminovascu(cid:173)
`lar nerves, it is a powerful vasodilator of
`cerebral blood vessels. In 1990, he paired
`up with neurologist Peter Goadsby, now at
`King's College London, to further explore
`CGRP's role in migraine patients. After get(cid:173)
`ting permission to take blood samples from
`the jugular veins of people who had come
`to the emergency room for a severe mi(cid:173)
`graine, the researchers measured the
`amounts of a range of different pep(cid:173)
`tides, including Substance P, during
`and after attacks. "The amazing
`thing was that CGRP' was the
`only peptide that was signifi(cid:173)
`cantly released;' Edvinsson says.
`At first, Edvinsson and oth(cid:173)
`ers
`thought CGRP
`triggered
`migraines by expanding blood
`vessels in the brain. Instead,
`a growing pile of studies
`suggested that CGRP was
`not· just a vasodilator, but a
`previously unknown, pain(cid:173)
`signaling neurotransmitter.
`Other groups found that ris(cid:173)
`ing levels of CGRP in jugular
`blood-not patterns of ab(cid:173)
`normal blood flow-signaled
`a migraine · attack. Then,
`in a pivotal 2002 study,
`and
`colleagues
`Oleson
`injected CGRP
`into the
`blood of migraineurs and
`found that they developed
`migrainelike
`headaches
`within
`hours, whereas
`nonmigraineurs got at most
`a mild headache. That sug-
`
`118
`
`8 JAN UARY 2016 • VOL 351 IS SUE 6269
`
`gested migraineurs are unusually sensitive
`to the peptide's effects, Oleson says.
`By the early 2000s, the biology around
`CGRP and migraine was strong enough to
`inspire a few companies to attempt drug ·
`development. German
`pharmaceutical
`company Boehringer Ingelheim designed
`a small molecule called bibn4096bs to
`block CGRP's receptor. The drug could stop
`acute migraine attacks in some people,
`but produced adverse side effects. Another
`company, Merck, tried to block the CGRP
`receptor with a different small compound.
`It, too, seemed to work modestly well, but
`its trial also had to stop because it showed
`signs of liver toxicity. But the glimmers of
`efficacy-were encouraging, says Jaume Pons
`in San Francisco, California, who was at that
`time head of protein engineering at Rinat,
`a spinoff of Genentech that specialized in
`antibodies to treat cancer.
`Pons . and others ·began to explore other
`approaches. Perhaps antibodies were worth
`a shot, he thought, because they can last a
`
`long time in the body and can be exception(cid:173)
`ally specific, reducing the frequency With
`which people need injections. But because
`most researchers thought it necessary to tar(cid:173)
`get migraines in the brain and antibodies are
`generally too large to pass through the blood(cid:173)
`brain barrier, they tended to dismiss the op(cid:173)
`tion, Pons says. Back then, "most people were
`not considering the use of antibodies for
`pain;' but Ririat had already begun clinical
`trials of a different antibody pain treatment
`with promising initial results, he says.
`In 2004, Rinat launched an antibody pro(cid:173)
`gram targeting CGRP. If it worked, the team
`reasoned, it would show that it was possible
`to treat migraines from outside the brain,
`by blocking CGRP only in the peripheral
`nervous system. That would lower the risk
`of the side effects often provoked by drugs
`that act in the brain, Pons says. In a few
`months, the firm developed the peptide(cid:173)
`blocking antibody now being tested by Teva
`under the name TEV-48125. The antibody
`faced plenty of roadblocks. The Rinat team
`
`Migraine's tangled roots
`Once considered a disorder of blood vessels, neuroscientists have pinpointed a new mechanism for migraines:
`the release of a substance called calcitonin gene-related peptide (CGRP, below), which sensitizes nerves (yellow)
`in the face, head, and jaw, and alongside blood vessels (red) surrounding the brain. Antibodies that block inter(cid:173)
`actions between CGRP and its receptors on cells could become the next generation of migraine drugs.
`
`Trigeminal nerves
`The trigeminal nerves relay sensations
`of pain and touch from the face. head,
`and jaw to a central hub, or ganglion, ·
`inside the brainstem.
`
`Trigeminal
`· ganglion
`
`Trigeminovascular system
`Another set of nerves
`innervates blood vessels in the
`meninges-membranes that ,
`protect the brain and include
`the dura and pia mater. Like
`trigeminal nerves, these fibers
`produce CGRP.
`
`sciencemag.org SCIENCE
`
`3
`
`

`

`managed to launch a phase I study testing
`TEV-48125's safety, but Pfizer acquired the
`company in 2006, and by 2011, the firm
`"decided that migraine was not an area it
`wanted to pursue;' Pons says.
`Other big companies had made similar
`decisions at the time, Pons says. The Food
`and Drug Administration (FDA) has espe(cid:173)
`cially stringent safety standards for pain
`treatments, and estimates for the market
`value of a new migraine drug are uncertain,
`ranging wildly from roughly $200 mil(cid:173)
`lion several years ago to $5 billion, making
`it hard for companies to commit a large
`amount of money to drug development.
`Despite the risk, in 2013 a venture capi(cid:173)
`tal company called venBio bought the
`rjghts to TEV-48125 and launched a new
`company called Labrys Biologics and con(cid:173)
`tinued the antibody's clinical development.
`Neuroscientist Corey Goodman, a managing
`pattner of venBio in San Francisco, Califor(cid:173)
`nia, had until 2009 been president of the
`biotherapeutics division at Pfizer, where he
`oversaw Rinat and Pons's team. Goodman
`remembered TEV-48125 was a ''very good
`antibody," and after recruiting more inves(cid:173)
`tors, Labrys kicked off two phase II trials in
`people with frequent migraines. The trials
`produced "the most beautiful phase II data
`I've ever seen;' Goodman says, with signifi(cid:173)
`cant reductions in number of headache days
`over placebo, even for the most severe cases.
`Teva bought Labrys in 2014 and is now
`racing with Alder Biopharmaceuticals, Eli
`Lilly, and Amgen to win FDA approval for
`the first migraine antibody drug. So far, the
`four phase II clinical trials, at least one from
`each firm, have produced similarly encour(cid:173)
`aging results, with up to 15% of participants
`experiencing complete relief, Goodman
`says: "I don't think it's too early to start talk(cid:173)
`ing about a cure for some patients suffering
`from this debilitating disease!'
`One of the superresponders is 26-year-old
`Julia Berner, who has been getting a mi(cid:173)
`graine every day since she was a little girl.
`Over the years, she's tried epilepsy medica(cid:173)
`tions, Chinese remedies, and nerve blocks,
`among countless other treatments, with
`no success. Within a few days of receiving
`four shots of Teva's thick, viscous, antibody(cid:173)
`containing solution in the back of her arms
`and the skin around her hips, however, the
`migraines disappeared.
`The difference was
`"mind-blowing;'
`she says. Berner usually spends her days
`avoiding any small disturbance that could
`make her constant, low-grade migraines
`more severe. After getting the antibody in(cid:173)
`jections, that burden lifted. "I hadn't real(cid:173)
`ized how tired they make me;' she says.
`"Everyone around me noticed the change in
`my demeanor."
`
`SCIENCE sciencemag.org
`
`DESPITE SUCH ANECDOTAL SUCCESSES,
`some migraine researchers don't think it's
`time to celebrate yet. If CGRP "really is a
`fundamental mechanism, you would expect
`a much higher proportion of patients to
`be completely free of attacks;' Ferrari says.
`Safety also concerns him because of CGRP's
`natural role in dilating atteries and main(cid:173)
`taining blood supply to the heart and brain.
`"Theoretically, if you block CGRP you could
`translate a minor stroke or cardiac isch(cid:173)
`emia ... into a full blown stroke or heart at(cid:173)
`tack;' he says. So far, the companies say they
`haven't seen that or other significant side
`effects in the several thousand people who
`have completed phase I and II trials, but the
`drugs have only been administered for up to
`6 months-not long enough to judge long(cid:173)
`term effects, Bigal says.
`Still, the fact that CGRP antibodies can
`prevent migraines in some fraction of pa(cid:173)
`tients is a "really cool finding" from a re(cid:173)
`search perspective, says Andrew Russo, a
`molecular physiologist and neurologist at
`
`"I've been in this field
`now for 21 years, and this
`is the most exciting thing
`we've seen so far."
`David Dodick, Mayo Clinic
`
`the University of Iowa in Iowa City, who
`consults for Alder.
`The trial results confirm that CGRP is a
`major new player in migraines-and perhaps
`even the fundamental trigger-even though
`the chain of events remains murky. "We don't
`really know what's going on, but we have
`some ideas;' Russo says. One view is that the
`increased amounts of CGRP released at the
`start of a migraine sensitize the trigeminal
`nerve to what are normally innocuous sig(cid:173)
`nals, resulting in inflammation in the nerves
`that is relayed to the brain as a pain signal.
`In that scenario, Dodick says, a mi(cid:173)
`graineur's brain is like a car with a height(cid:173)
`ened alarm system that "goes off simply
`because you walked close to it!' In the end,
`the brain reaches what Sigal describes as a
`"permissive" state, in which normal light be(cid:173)
`comes very bright, normal sounds very loud,
`"and you can smell a perfume two blocks
`away from Bloomingdale's!' CGRP-binding
`antibodies help turn down the volume in the
`trigeminal · nerve, by "mopping up" excess
`peptide or preventing it from binding to and
`activating cells, Dodick proposes.
`But why are migraineurs more sensitive
`to CGRP-or produce too much of it-in
`the first place? Some researchers loop back
`
`to CSD, which cettain animal studies sug(cid:173)
`gest can trigger a surge of CGRP, Russo
`says. In that case, genetic predisposition to
`the abnormal brain activity could lead to
`many migraines.
`A growing number of studies point to an(cid:173)
`other important factor: stress. Even minor in(cid:173)
`sults, such as missing a few hours' sleep, can
`often "push the migraine brain over the line
`into having an attack;' Sigal says. And experi(cid:173)
`ments in rats and cultured cells show that
`corticotropin-releasing hormone, which the
`body releases in response to stress, also in(cid:173)
`creases neuronal production of CGRP, Russo
`says. Strikingly, many migraine medications
`also boost CGRP in animal models, possibly
`explaining why people who use drugs like
`triptans too frequently end up with more se(cid:173)
`vere migraines, he says.
`That the relatively large CGRP-blocking
`antibodies can prevent migraines in some
`people have convinced most in the field that
`it is indeed possible to stop the headache
`from outside the central nervous system,
`even though it is clearly a brain disorder, ac(cid:173)
`cording to Moskowitz. "The evidence is favor(cid:173)
`ing that [the dJ;ugs are] working somewhere
`on the trigeminal connections into the brain,
`not in the brain itself, unless there's some
`massive change" in the permeability of the
`blood-brain barrier during an attack, he says.
`Some . researchers, however, still argue
`that the CGRP-blocking antibodies must be
`getting past the blood-brain barrier into the
`brainstem-even in trace amounts-to beef(cid:173)
`fective. Goadsby favors this view, and notes
`that some sections of the brainstem are not
`very well protected by the barrier.
`Whatever the resolution to that debate,
`the discovery of CGRP's migraine connection
`underscores the value of carefully dissecting
`the neural pathways that lead to pain and
`searching for a linchpin mo.lecule, Moskowitz
`says. If CGRP fulfills its promise as a block(cid:173)
`buster pain target, that success could signal
`to drug developers that effective treatments
`for other complex and seemingly intractable
`pain disorders, such as fibromyalgia, are also
`within reach, Moskowitz says. Eli Lilly is al(cid:173)
`ready testing its CGRP-antibody in people
`with cluster headaches, which occur in regu(cid:173)
`lar, cyclical patterns and can be even more
`painful than migraines.
`As for Sundquist, she's well aware of the
`clinical trials for the various CGRP-related
`drugs, and she is hopeful. But the random
`assortment of failed remedies that fills her
`closet-antidepressants, nutritional supple(cid:173)
`ments, a headband that transmits painful
`electric zaps to her scalp and "looks like
`something from StaT Trek"-makes her
`wary as well. "I'm just waiting for more
`information, and praying that I will be
`healthy again." •
`
`8 JANUARY 2016 • VOL 351 ISSUE 6269 119
`
`4
`
`

`

`180
`
`Machinery to insert
`membrane proteins
`
`158
`
`Life after death
`
`RESEARCH
`
`IN BRIEF
`134 From Science and other journals
`
`REVIEW
`137 EARTH HISTORY
`The Anthropocene is functionally and
`stratigraphically distinct from the
`Holocene C. N. Wate·rs et al.
`REV IEW. SUMMARY; FOR FULL TEXT:
`d x.doi.org(10.1126/science.aad2622
`
`RESEARCH ARTICLES
`138 BRAIN CIRCUITS
`Gating of hippocampal activity, plasticity,
`and memory by entorhinal cortex .
`long-range inhibition J B= et al.
`RESEARCH ARTICLE SUMMARY; FOR FULL TEXT:
`dx.doi.org/10.1126/science.aaa5694
`
`139 HEMATOPOIESIS
`Distinct routes of lineage development
`reshape the human blood hierarchy
`across ontogeny F. Notta et al.
`RESEARCH ART ICLE SUMMARY; FOR FULL TEXT:
`d x.doi .org/10.1126/science.aab2116
`~ PERSPECTIVE P. 126; REPORT P. 176
`
`140 GEOMORPHOLOGY
`Geomorphic and ·geologic controls of
`geohazards induced by Nepal's 2015
`Gorkha earthquake J S. Kargel et al.
`RESEARCH ART ICLE SUMMARY; FOR FULL TEXT:
`dx.doi.org/10.1126/science.aac8353
`~ REPORT P. 147
`
`REPORTS
`141 THERMOELECTRIC$
`illtralligh power factor and thermoelectric
`performance in hole-doped single-crystal
`SnSe L.-D. Zhao et al.
`~ PERSPECTIVE P. 124
`
`144 GEOPHYSICS
`Shear deformation of bridgmanite and
`magnesiowiistite aggregates at lower
`mantle conditions J Girard et al.
`~ PERSPECTIVE P. 122
`
`147 GEOMORPHOLOGY
`Repeated catastrophic valley infill
`following medieval earthquakes in the
`Nepal Himalaya W Schwanghart et al.
`~ RESEARCH ARTICLE P. 140
`
`151 SOLAR CELLS
`A mixed-cation lead mixed-halide
`perovskite absorber for tandem solar cells
`D. P. McMeekin et al.
`~.NEWS STORY P. 113
`
`155 FOREST ECOLOGY
`Dominance of the suppressed: Power-law
`size structure in tropical forests
`C. E. Farrior et al.
`
`186 CHEMOTAXIS
`Polysialylation controls dendritic cell
`trafficking by regulating chemokine
`recognition E. Kiermaier et al.
`
`158 MICROBIOME
`Microbial community assembly and
`metabolic function during mammalian
`corpse decomposition J L. Metcalf et·al.
`~ PODCAST ·
`
`162 ANCIENT MICROBIOME
`The 5300-year-old Helicobacter pylori
`genome of the Iceman F. Maircner et al.
`
`165 PALEOCLIMATE
`Reconciliation of the Devils Hole climate
`record with orbital forcing
`G. E. Moseley et al.
`
`169 CELL BIOLOGY
`Accurate concentration control of
`mitochondria and nucleoids R. Jajoo et al.
`
`173 PROTEIN AGGREGATES
`Cytoplasmic protein aggregates
`interfere with nucleocytoplasmic
`transport of protein and RNA
`A. C. Woerner et al.
`~ PERSPECTIVE P. 125
`
`176 STEM CELL NICHE
`Fetal liver hematopoietic stem cell niches
`associate with portal vessels
`J A . Khan et al.
`~. PERSPECTIVE P. 126: RESEARCH ART ICLE P. i39
`
`180 PROTEIN STRUCTURE
`The structure of the ~-barrel assembly
`machinery complex J Bakelar et al.
`
`DEPARTMENTS
`107 EDITORIAL
`Biggest opportunity of our age
`By Sir David King
`
`198 WORKING LIFE
`Want a letter? You write it for me
`By RogerS. Day
`
`ON THE COVER
`Tree of portal blood
`vessels in the m~rine
`fetal liver at embryonic
`days 12 (bottom left), 13
`(bottom right), and 14.5
`(top), reconstructed
`in three dimensions
`from serial cryosections
`of portal vasculature.
`Branch 'surface area is scaled according
`to fractal geometries, together with the
`number of hematopoietic stem cells (HSCs;
`yellow spheres), suggesting that HSC niche
`expansion is related to portal vessel surface
`area. See pages 126, 139, and 176.
`Data visualization: Valerie Altounianj
`Science; base meshes created by Jalal Khan
`(Icahn School of Medicine at Mount Sinai)
`using MeshLab
`
`Science Staff ............................. ................. 106
`New Products .............................. ................ l91
`Science Careers ................ ...................... ... 192
`
`SCIENCE (ISSN 0036·8075) is published weekly on Friday, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue, NW, Washington, DC 20005. Periodicals
`mail postage (publication No. 484460) paid at Washington. DC. and additional mailing offices. CopYright © 2016 by the American Association for the Advancement of Science. The title SCIENCE is a registered trademark of the AAAS.
`Domestic individual membership and subscription (51 issues): $165 ($74 allocated to subscription). Domestic institutional subscription (51 issues): $1522; Foreign postage extra: Mexico. Caribbean (surface mail) $55: other countries (air
`assist delivery) $89. First class, airmail. student. and emeritus rates on request. canadian rates with GST available upon request. GST #1254 88122. Publications Mail Agreement Number 1069624. Printed in the U.S.A.
`Change of address: Allow 4 weeks. giving old and new addresses and B·digit account number. Postmaster: Send change of address to AAAS. P.O. Box % 178. Washington. DC 20090-6178. Single·copy sales: $15.00 current issue.
`$20.00 back issue prepaid includes surface postage: bulk rates on request. Authorization to photocopy material for internal or personal use under circumstances not falling within the fair use provisions of the Copyright Act is granted by
`AAAS to libraries and other users registered with the Copyright Clearance Center (CCC) Transactional Reporting Service. provided that $35.00 per article is paid directly to CCC. 222 Rosewood Drive. Danvers. MA01923. The identification
`code for Science is 0036·8075. Science is indexed in the Reader's Guide to Periodical Literature and in several specialized indexes.
`
`SCIENCE. sciencemag.org
`
`8 JANUARY 2016 • VOL 351 ISSUE 6269 105
`
`5
`
`

`

`l‘he molecule at the
`heart of migraine p. 116
`
`Thermoelectric performance
`gets a boost pp. 124 & 141
`
`Prehistoric pathogen
`genome p. 162
`
`
`
`.
`
`5
`
`.
`
`I
`
`pr"
`-
`
`'c
`
`"ii
`
`8 JANUARY 2016
`sciencemagorg
`
`.
`
`Q. )
`
`-
`
`c5
`
`.
`
`'3“
`
`(g:
`
`[Iii
`
`'16-;
`
`"’
`
`2
`
`'
`
`4
`
`DO NOT REMOVE FROM
`CURRENT PERIODICALS
`ROOM
`
`Vascular dynamics
`Branching promotes stem cell
`expansion in the developing liver
`9b. 126, 139, &176
`
`~ ;
`
`-:
`
`:..
`-:
`
`
`
`***5-DIGIT53706
`
`n:
`
`#041
`
`628/1511
`
`P929 2133 8939
`
`
`
`11/20/156269
`
`
`
`
`LIBRARYUNIVOFWISCONSINMADISON728STATESTREET330MEMORIAL
`
`
`
`
`MADISONWI53706
`
`
`
`
`6
`
`