`
`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
`
`EX2167
`Eli Lilly & Co. v. Teva Pharms. Int'l GMBH
`IPR2018-01710
`
`1
`
`
`
`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
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`4
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`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
`
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`SCIENCE. sciencemag.org
`
`8 JANUARY 2016 • VOL 351 ISSUE 6269 105
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`5
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`l‘he molecule at the
`heart of migraine p. 116
`
`Thermoelectric performance
`gets a boost pp. 124 & 141
`
`Prehistoric pathogen
`genome p. 162
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`Vascular dynamics
`Branching promotes stem cell
`expansion in the developing liver
`9b. 126, 139, &176
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