Constance Scharff

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Constance Scharffworking group was unavailable andso Constance Scharff and her newlyacquired team were forced to “jointhe queue”. Making a virtue out ofnecessity, the team opted for “space-saving” experiments, starting withseveral molecular genetic experi-ments. Their hospitable colleaguesfrom the neighbouring researchgroup were able to provide themeach with fifty centimetres of labo-ratory bench space for the necessarypipette work. Fortunately, in themeantime, the team has moved intoits own laboratory space.

NEW CELLS

FOR NEW TUNES

Mice with genes that have beenmodified or switched off, that is tosay mice that have been “recreated”so to speak, are currently definingthe nature of biomedical research. Sohow come Constance Scharff is de-voting herself to bird research? “Ofcourse, mice, flies, or threadwormsoffer the power of genetics and havetherefore brought us a multitude ofelegant methods and valuable find-ings. Unfortunately, none of theseorganisms have the ability to learnacoustic forms of communication. Incontrast to this, a whole range ofparallels exist between song learningin birds and the acquisition of hu-man speech”, says Scharff. EvenCharles Darwin observed that thefirst rudimentary attempts of youngsongbirds to produce sound hadsomething in common with the at-tempts made by young children tospeak. It is also becoming increas-ingly clear that certain aspects ofthese processes are controlled bysimilar neuronal mechanisms.

It is above all the experiments car-ried out by Fernando Nottebohmfrom the Rockefeller University, Con-stance Scharff’s PhD mentor, that areresponsible for revolutionizing our

thinking about brains. In a series ofelegant experiments, Nottebohm andhis team showed that, in the case ofcanaries and zebra finches, new neu-rons are constantly being createdduring adulthood and that these neu-rons migrate to specific song control-ling regions and become integratedthere into the existing neuronal cir-cuits. A long-standing neurobiologi-cal dogma that the number of neu-rons in the brain of vertebrates wasunalterably fixed on the day of birthwas thereby upturned. Today weknow that the production and suc-cessful integration of neurons intoadult brains takes place not only inthe case of songbirds but also ro-dents, apes, and even humans.

In 1984 Constance Scharff comesto work in Fernando Nottebohm’slaboratory. Prior to this, she hasspent two years at the Adelphi Uni-versity in Garden City, New York.Overseas she had managed to escapethe somewhat theoretical and there-fore often boring basic studies inGermany. “All my friends applied toan American organisation for a stayin the USA. I decided to jump on thebandwagon, almost at the lastminute”, she explains. Courses at-tended by no more than 10 to 15students, and the opportunity in al-most every laboratory of taking partin projects, not only teaches studentshow “the business of science is reallydone”, but also awakens in them asense of curiosity which inspiresthem to design and carry out theirown tests. It is Carol Diakow, thenAssistant Professor in Adelphi, whois responsible for steering ConstanceScharff’s long-term fascination forbehavioural neurobiology towardsexperimental research. She thereforestays on Long Island and does notreturn to Germany as originallyplanned. She applies to severalAmerican universities: the Rocke-

Eighty percent of married female academics in Germany have academic spouses. The problem

of “coupled careers” is one that affects women in particular. The fact that it is possible for both

partners to successfully pursue their separate careers is demonstrated by the achievements of

CONSTANCE SCHARFF: whilst she is leader of the C3 Research Group at the MAX PLANCK

INSTITUTE FOR MOLECULAR GENETICS, her husband, ARTURO ZYCHLINSKY, is director of the

Cellular Microbiology Department at the MAX PLANCK INSTITUTE FOR INFECTION BIOLOGY. PHO

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Birds are cosmopolitans and cantherefore be found all over the

world. As migratory birds, whichspend the summer in the North andwinter in the warmer southernclimes, they can also be described asbeing “travellers between twoworlds”. In this sense, ConstanceScharff can also be regarded as acosmopolitan: born in Northern Ger-many, she moved to Marburg in1979 to study biology and threeyears later left Marburg to travel toManhattan. What was originally on-ly meant to be a student exchangeextended into a visit lasting almostten years. At the beginning of the1990s she returned to Europe forthree years – this time to Paris –thereafter spending a further sevenyears in Manhattan. She has nowtouched down in Berlin – bringingher birds with her; for these havebeen the focus of her scientific re-search for more than ten years.

Eight pairs of small zebra fincheshave taken up residence in the for-mer caretaker’s apartment at theMax Planck Institute for MolecularGenetics in Berlin. But this is just thebeginning: in mid-May ConstanceScharff is expecting a further deliv-ery of birds to join the rest of theflock. The institute will then have aproper stock of birds. “But we had tostart somewhere”, she says. SinceSeptember of last year ConstanceScharff has been working as a C3scientist at the institute and her SFBgrant application was already ap-proved a long time ago. She joinedthe Molecular Human Genetic De-partment led by Hans-Hilger Ropers,within the framework of the C3 Pro-gramme launched by the MaxPlanck Society. Ropers has shownthat he is open to new concepts andmodel systems. However, up until afew weeks ago, the laboratory spacethat had been allocated to the new

Fixing her sights on thebirds – Constance Scharffbelongs to the young generation of neuro birdresearchers who have conquered new researchground in the USA.

Fixing her sights on thebirds – Constance Scharffbelongs to the young generation of neuro birdresearchers who have conquered new researchground in the USA.

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feller University in New York, theUniversity of Madison in Wisconsinand the University of California inBerkeley. “I was already getting a lit-tle homesick and wanted to return toGermany, but on the other hand Iwas determined to find out how far Icould get.”

The Rockefeller University takeson around 20 new students everyyear. Only a few students from thevast number of applicants are select-ed and invited to attend a personalinterview. Constance Scharff has toundergo six or seven interviews at

all three universities. Hardly any ofthe questions asked relate to factualknowledge. Most professors were in-terested in sounding out the scientif-ic curiosity of their potential stu-dents, the diversity of their interests,and their open-mindedness. Con-stance Scharff passes the “test” withflying colours and is accepted by allthree universities. And at this point,she becomes so captivated withManhattan that her desire to returnto Germany becomes secondary.Scharff therefore enrols at theRockefeller University and in 1991completes her PhD with FernandoNottebohm on the neuronal basis ofsong learning in birds.

Yet, Constance Scharff does be-lieve that there is more to life thanscience alone. At the end of theeighties she meets Arturo Zychlin-sky, a fellow Rockefeller student,who is later to become her husband.And she is sure that she does notwant to sacrifice her desire to havechildren in favour of a scientific ca-reer. The couple marry in New Yorkand decide to move to France bothas postdocs.

However, as she works on her am-bitious project at the Institut d’Em-bryology Cellulaire et Moléculaire inParis, she is confronted with morethan enough challenges – not leastwhen her daughter Anna is born inFebruary 1992. “This did slow downmy career”, she says. “But after Ar-turo had published his first NATURE

article at the same time as ourdaughter was born, it was clear that he would be the first to look for a job.”

FAMILY AND

CAREER UNITED

Two years later, Arturo Zychlinskyis actually offered a position at theSkirball Institute of Molecular Medi-cine at the New York UniversityMedical School. By sheer coinci-dence, Fernando Nottebohm contactsConstance Scharff also at this time.A project that she had initiated threeyears before has received research

funding and he asks her to lead thisproject as Postdoctoral Associate inhis laboratory. This is how Scharffand Zychlinsky, as a husband andwife team, actually succeed in fur-ther pursuing their separate profes-sional careers. Their second daughterMilena is born is in June 1995. Inview of the excellent “Child andFamily Center” day care facilities onthe campus at the Rockefeller Uni-versity and the fact that “workingscience moms” are the order of theday, Constance Scharff has no prob-lem combining family and career.

She therefore starts her experi-ments again into how and wheresong learning takes place in thebrain of zebra finches. Her main fo-cus of interest is centred on one ofthe key regions, the “high vocal cen-tre”, or HVC, without which song-birds cannot sing. Two differentneuronal pathways have their originhere: the motor pathway is essentialfor song production; the relevantHVC neurons send their axons, i.e.their nerve fibres, into the so-calledRA region which monitors the mus-cles of the vocal organ in the throat.The second pathway controls thelearning of the song. The corre-sponding HVC neurons project intothe “Area X”. In contrast to the othercells, these cells are created exclu-sively during embryogenesis and areno longer renewed at a later date.

Neurons in the brain can be selec-tively eliminated using a method de-veloped by Jeff Macklis at Harvardwhich Constance Scharff has adapt-ed to suit her own object of study,the zebra finch: when the substancechlorine e6 is microinjected into theRA region, it will find its way bymeans of retrograde transport (in thedirection of the cell body) into theHVC>RA projection neurons. Thisdrug can be photoactivated bymeans of a laser, causing neuronaldeath of all cells that contain thesubstance. As a result, the birds losttheir ability to sing complexmelodies. If the birds are injectedwith a radioactive substance which

incorporates itself into the DNA ofdividing cells, it is possible to deter-mine whether new cells have beencreated to replace the dead cells. Inthe experiments carried out by Con-stance Scharff, the birds treated inthis way displayed three times asmany new neurons in this regionthan the control birds. And the ex-tent of this neuronal replacementwas mirrored by the birds’ ability toregain their ability to sing. One ofthe test birds even mastered its exactpre-operative repertoire after threemonths. However, neurons, whichproject from HVC into the “Area X”,are not replaced following selectiveelimination.

As a result of these experimentsConstance Scharff has gained newinsight into the regenerative abilityof the brain: she was able to showthat neuronal death triggers the pro-duction of new cells and that thisprocess can be stimulated by the se-lective elimination of cells. The good

news: cell death is followed by theproduction of new cells and a func-tional disruption in behaviour couldbe rectified. The bad news: not alltypes of neurons possess this abilityto regenerate.

WHAT DOES A SPEECH

GENE DO IN BIRD’S BRAINS?

One of the greatest surprises toscientists in recent years was the dis-covery that the majority of geneshave been preserved across species.In fact, more than 98 percent of thehuman genome is identical to that ofour closest relative, the chimpanzee.So what makes humans differentfrom apes? Firstly, their communica-tive abilities. In the search for thegenetic foundations of speech, scien-tists last year came across the Foxp2gene in their study of a large familyin which several members havespeech difficulties. In the case ofthose family members who have asignificant speech deficiency the

gene is mutated, whilst those mem-bers with normal speech ability carryan intact Foxp2 gene.

Under normal circumstances,Foxp2 carries the building instruc-tions for a transcription factor, i.e. aprotein which switches on specificgenes. One hypothesis about thefunction of Foxp2 suggests that itcontrols the development of the neu-ronal pathways necessary for acquir-ing speech. In order to test this theresearchers rely on an animal modelwhich will allow them to track theneuronal processes that lead to ab-normal development and conse-quently to impairment of the cogni-tive functions. The subject of Foxp2mouse mutations is therefore hotlydisputed. The breakthroughs couldpossibly be achieved in a completelydifferent area than expected – name-ly in the field of bird research. Thescientists working in ConstanceScharff’s research group in Berlinhave now discovered that zebrafinches also have a Foxp2 genewhich is 98 percent identical to thehuman Foxp2. This reinforces thehope that under certain conditionsthis animal model can provide moreinformation than the laboratorymouse living in a plexiglas box. Thisis because songbirds, with theiracoustic communicative ability, arecloser to humans than mice. “Onemust always keep in sight the brain’send product, as it were, namely theproduction of species-specific be-haviour”, says Constance Scharff.Perhaps the Berlin neurobiologistswill succeed in demonstrating howFoxp2 contributes towards song andtherefore indirectly to speech. In theUSA in the meantime, a whole newgeneration of young neurobiologistsusing songbirds as a model hasemerged and, as a result of theirwork, new chapters are being writteninto the established textbooks. Andwhat about Germany? One enthusi-astic researcher and a hundred zebrafinches are in full flight across the“neurolandscape” in Berlin.

CHRISTINA BECK

The other side of “couple careers”: whilst Constance Scharff is still in the laboratory testing tissue under the microscope, …

… Arturo Zychlinsky is at home keeping their two daughters Milena and Anna occupied.

Zebra finches are suitable test objects in

many respects, not leastbecause they are relatively

easy to keep and breed in an aviary.