FUTURA 28 | 2.2013 CONTENTS FUTURA PUBLISHING … · And as the famous German poet Bertolt Brecht once penned in Stories of Mr Keuner, a changing face need not be feared. The type

2

Published by Boehringer Ingelheim Fonds

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forschung

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55116 Mainz

Germany

Tel. +49 6131 27508-0

Fax +49 6131 27508-11

E-mail: [email protected]

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Editor-in-Chief Dr Claudia Walther

Editors Kirsten Achenbach (BIF executive

editor), Karsten Fiehe (muehlhausmoers

corporate communications gmbh)

Authors in this issue Kirsten Achenbach, Claire

Ainsworth, Karsten Fiehe, Michael Mennig,

Michael Simm, Volker Stollorz, Dr Claudia

Walther

Translating, copy-editing and proofreading Adam

Blauhut, Dr Caroline Hadley, Dr Caroline M.

Taylor, Dr Susan Simpson

Production muehlhausmoers corporate

communications gmbh,

www.muehlhausmoers.com

Project management Karsten Fiehe, Michael

Mennig

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Images Boehringer Ingelheim Fonds, unless

stated otherwise

Cover photos Owen Smith/cultura/Corbis (bottom

left); Eva Kowalinski (bottom right)

Publication date of current issue December 2013

BIF FUTURA is the journal of the Boehringer Ingelheim Fonds, a

non-profit organization supporting basic research in biomedicine.

Opinions expressed in BIF FUTURA cannot automatically be assumed

to be the official standpoint of the Boehringer Ingelheim Fonds. This is

particularly the case when the article is accompanied by the name of

the author. Reproduction of articles or parts of the journal only with

reference to and the permission of the foundation.

PUBLISHING INFORMATION

C O N T E N T S

The cover illustration shows a stylized view of erythrocytes and

T cells as they flow inside a blood vessel. T cells are the main

target of HIV, the retrovirus that causes AIDS. Since the discovery

of HIV in 1983, about 35 million people have died of AIDS. But

today, better treatments have made the disease more manage-

able. For more information see the article on page 8.

FUTURA 28 | 2.2013

A Virus like no Other HIV: one of the world’s greatest ever public health challenges.

Projects and Results

BIF fellows present their PhD projects and completed theses.

A True BIF Success Story

BIF fellows join forces – and publish groundbreaking paper in Nature.

THE JOURNAL OF THE BOEHRINGER INGELHEIM FONDS VOL. 28 | 2.2013

FUTURA BIF

Y E A R S

30

BOEHRINGER INGELHEIM FONDS

News from 1983 4

A VIRUS LIKE NO OTHER

From deadly disease to preventable illness: HIV 30 years on 8

4 OUT OF 1,260

BIF and its alumni: an exceptional relationship 13

PROJECTS

In March 2013, 12 applications for fellowhips were approved and all 12 were taken up.

In July 18 applications for fellowships were approved, 17 of which were taken up. 19

RESULTS

Twenty-one former fellowship holders give brief accounts of their results 50

BIF’s 30th anniversary celebration: science, networking and fun 58

BIF guide to ... Mainz 63

BIF numbers and graphics 64

A stimulating weekend at Gracht 68

News, profiles, upcoming events 71

CREATING FREEDOM Interview with Dr Claudia Walther, BIF’s managing director 60

WHO’S WHO AT BIF Introducing the BIF team 66

A TRUE BIF SUCCESS STORY

BIF fellow Maria Hondele is first author of a groundbreaking Nature paper 70

F A C T S

F E L L O W S

F O U N D A T I O N

3

A man who had not seen Mr. K for a long time greeted him with the words: ‘You haven’t

changed a bit.’ ‘Oh!’ said Mr. K. and turned pale.

The training of junior scientists has changed greatly in the 30 years since the Boehringer In-

gelheim Fonds (BIF) was founded. And as the famous German poet Bertolt Brecht once

penned in Stories of Mr Keuner, a changing face need not be feared. The type of partnership

that is customary between professors and graduate students, at least in Germany, is now com-

peting with a plethora of graduate and PhD programmes that provide ‘structured training’.

A doctoral student needs to learn much: expertise in his or her field, its approaches and

schools of thought, how to handle a long-term project, overcome problems and motivation-

al lows and adopt ‘good scientific practice’. Most importantly, the student must – as the Uni-

versity of Cambridge puts it – acquire ‘critical, analytic and interpretative skills’. On top of

that, there are the soft skills, e.g., how to communicate one’s research to peers, funding agen-

cies and the public. Some of these aspects are now offered by PhD programmes, relieving the

supervisor. Thesis advisory committees help by providing checks and balances. The pro-

grammes also greatly facilitate the exchange of knowledge within and beyond an institute by

bringing PhD students together. And very importantly, graduate programmes have also en-

abled Germany to integrate students from abroad with different educational backgrounds

into its research system. On a more cautionary note, many of their selection processes seem

to run the risk of losing the quiet and shy, albeit no less brilliant, students. A set time frame

for PhD projects as customary in the programmes certainly has its benefits for the students.

However, a strict limitation to three years as seen at some institutions in Europe will do basic

research no favour. It bears the risk of selecting against particluarly explorative, ambitious,

risky projects. And from our many interviews with BIF candidates, we still find that the

most mature junior scientists did not choose a PhD programme, but a particular topic and

the best laboratory for it. For them, being part of a programme is an additional bonus.

Since the early 1980s, the general financial situation surrounding PhDs has also greatly

improved. This is certainly good news. However, in some countries there seems to be a trend

towards perceiving doctoral students (also apparent among the students themselves) as em-

ployees rather than budding scientists. More and more doctoral students seem to expect de-

cent working hours and salaries, as well as holidays and all the social benefits countries such

as Switzerland and Germany offer. A crucial change in approach? The doctoral phase used

to be considered a part of higher education, a training in research and scientific thinking

and an investment phase in one’s career. And while fair conditions are mandatory, isn’t this

a more fruitful approach to this formative phase in life in which one can and should explore

to the fullest extent one’s talent and abilities?

Dr Claudia Walther, managing director

FROM TWOSOMES TO PROGRAMMES

FUTURA 28 | 2.2013BOEHRINGER INGELHEIM FONDS E D I T O R I A L

»Many selection

processes seem to

run the risk of los-

ing the quiet and

shy, albeit no less

brilliant, students.«

F A C T S

5

WHAT HAPPENED IN 1983?The Boehringer Ingelheim Fonds was established 30 years ago in 1983. On these pages we

revisit discoveries and innovations of this eventful year, which saw major advances in science

and technology and many memorable moments in entertainment.

FUTURA 28 | 2.2013BOEHRINGER INGELHEIM FONDS

A DIFFERENT TYPE OF RNA

Although enzymes are normally proteins, RNA can also act as one,

as the Canadian scientist Sidney Altman ob-

served aft er 10 years of intensive research,

published in the journal Cell. Altman

discovered the ribo zyme RNase P,

which is a combination of RNA and

protein. Until then, RNA was

seen as a medium for infor-

mation storage. In 1989, Alt-

man received the Nobel

Prize for his discovery.

Sidney Altman re-

ceived the 1989 Nobel

Prize for Chemistry.

Th e Motorola DynaTAC 8000X

was the fi rst cell phone approved

for commercial distribution in

the US. Th e phone weighed 800

grams, was about 33 centimetres

long and off ered only 30 min-

utes of talk time. Resembling a

thick gray brick, it cost around

3,995 US dollars.

With the publication of

Molecu lar Biology of the Cell,

the standard work in cell biol-

ogy made its fi rst appearance

on the market. Th e most re-

cent fi ft h edition is around

1,400 pages long and contains

more than 1,500 illustrations.

FIRST CELL PHONE ON THE

US MARKET

THE MOTHER OF ALL TEXTBOOKS

Pho

tos:

Garl

and

Sci

ence

(to

p left

); M

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rola

(to

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; p

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); A

FP/G

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due to copyright

limitations.

6

BOEHRINGER INGELHEIM FONDSFUTURA 28 | 2.2013 F A C T S

Driving to his cabin in the Mendocino Woods on a cool

spring night in 1983, Dr Kary B. Mullis hit on the idea of

polymerase chain reaction (PCR) and changed the face

of biology. PCR allows reseachers to rapidly copy minute

amounts of DNA. Without it, most work with DNA to-

day, from medical diagnosis to catching villains, would

be unimaginable. Th e New York Times said it ‘divides

biology in two epochs’ – one before and one aft er PCR.

A NIGHT THAT CHANGED THE

FACE OF BIOLOGY

Long before the rise of modern day consoles, the Japanese

company Nintendo launched a device called the Famicom

on its home market. Resembling a grey box, it later became

world famous as the Nintendo Entertainment System (NES) and

helped to make game consoles enor-

mously popular. Game classics

such as Super Mario Bros.

entered popular culture

and took the genre to en-

tirely new levels. Inci-

dentally, Mario

the Plumber is

still available on

the latest console!

With PCR even minute amounts of DNA can be rapidly copied.

Pho

tos:

Myl

ène H

am

el, 2

010 (le

ft); W

ikim

ed

ia C

om

mo

ns

(Pla

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n); s

hutt

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tock

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Surf

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)

THE START OF NINTENDO’S SUCCESS

IN THE BEGINNING WAS ‘WORD’

Two types of programmes burst onto the scene and still

cause frustration today: the fi rst ver-

sion of Microsoft Word and the fi rst

computer virus, which was tested in a

university course in Los Angeles.


due to copyright

limitations.


due to copyright

limitations.

FUTURA 28 | 2.2013BOEHRINGER INGELHEIM FONDS F A C T S

7

The top US hits from 1983 are still being

played on the radio today.

Exultant: Barry Marshall (left) and Robin Warren

(right) accepting the Nobel Prize.

TopHits

1983

EVERY BREATH YOU TAKEThe Police1BILLIE JEANMichael Jackson2FLASHDANCE (WHAT A...)Irene Cara3

An article published in the med-

ical journal Th e Lancet in 1983

wrote medical history: in it Barry

Marshall and Robin Warren ar-

gued that a previously unknown

bac terium (Helicobacter pylori)

caused most stomach ulcers. As it

turned out, they were right, and in

2005 they won the Nobel Prize for

their discovery.

DISCOVERY OF THE STOMACH BUG

AN ANCIENT DNA SEQUENCE

Th e homeobox was discovered by two separate teams of scientists – one from

Basel, the other from Indianapolis. Th is DNA sequence is a characteristic fea-

ture of a crucial class of genes that regulate the embryonic development of body

segments from fl ies to man. It typically consists of around 180 base pairs and

encodes a protein domain capable of

binding to DNA. Th e homeobox is

extremely old in evolutionary terms

and probably emerged early in the

development of eukaryotes.

Th e 55th Academy Awards were dom-

inated by Gandhi: the fi lm received

awards in eleven categories, including

Best Picture, Best Director and Best

Actor (Ben Kingsley, photo). Th e

Oscar for Best Actress went to Meryl

Streep (photo) for her role in Sophie’s

Choice.

AND THE OSCAR GOES TO ...

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limitations.


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limitations.

9

FUTURA 28 | 2.2013BOEHRINGER INGELHEIM FONDS F A C T SPho

to: O

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/Co

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Somewhere in West Africa at the beginning of the 20th century,

the acquired immunodeficiency syndrome (AIDS) claimed its

first human victim. There were few witnesses, if any. What we

know, we owe to researchers such as Jacques Pepin, a physician

specializing in infectious diseases and an epidemiologist who

heads the Center for International Health at the Université de

Sherbrooke, Canada. To find out where the human immunodefi-

ciency virus (HIV), the deadly virus causing AIDS, originally

came from, Pepin literally followed its tracks across 16 African

countries during the 1980s.

In his book The Origins of AIDS, Pepin describes how the dis-

ease was first transmitted from chimpanzees to men: someone

may have been bitten or more likely a bush meat hunter was in-

fected while slaughtering an ape. Thus an ancestor of HIV – the

simian immunodeficiency virus (SIV) – jumped the species bar-

rier. The transfection from apes or monkeys to humans seems to

have occurred at least six different times.

The genealogy of HIV relies on a small number of biopsies

and blood samples dating back as far as 1959, and on evolutionary

theory that allowed scientists to estimate the relatedness of viral

strains from differences in their gene sequence. There are two

major classes, HIV-1 and HIV-2, the latter being less aggressive

and largely restricted to West Africa. HIV-1 is divided into three

A VIRUS LIKE NO OTHER

groups that arose from different cross-species infections. The

main M group causes more than 90 percent of infections world-

wide and currently has nine subtypes that are distributed un-

equally in different parts of the world, with varying degrees of vir-

ulence and ways of transmission. Genetic recombination, which

occurs when different viral subtypes present in the same host ex-

change their genetic material, has also given rise to new HIV var-

ieties that differ in their biomedical properties.

At the beginning, the disease went virtually unnoticed for

more than half a century. Based on the population density, the

prevalence of SIV in chimpanzees and the likelihood of transmis-

sion, Pepin has estimated that by 1921 almost certainly less than

ten individuals had been infected. Eventually, the virus managed

to multiply and spread, favoured by urbanization, prostitution

and commerce, but also through the frequent use of reusable syr-

inges and needles during medical campaigns intended to eradi-

cate tropical diseases. Sterilization of equipment was often not

possible because of power outages and lack of fuel for generators.

It took decades for HIV to journey from West Africa via Haiti

to the USA. There, the first cases of AIDS were described in June

1981 by the Centers for Disease Control’s Morbidity and Mortality

Weekly Report: a cluster of five cases of Pneumocystis carinii pneu-

monia among unrelated gay men living in Los Angeles, a disease

When French virologists Françoise Barré-Sinoussi and Luc Montagnier published their land-

mark paper on the discovery of HIV 30 years ago, not many people would have guessed that

this insidious virus would soon become one of the greatest challenges ever to public health.

With unparalleled speed, however, an unlikely alliance of scientists, doctors, activists and

politicians succeeded in curbing the pandemic. Learning fast and spreading knowledge effec-

tively, these people turned AIDS from a once deadly disease into a preventable illness – and

for those already infected, into a condition that can be lived with.

By Michael Simm

10

BOEHRINGER INGELHEIM FONDSF A C T SFUTURA 28 | 2.2013

that up to then had been almost exclusively limited to severely im-

munosuppressed patients. In New York, other gay men had suc-

cumbed to Kaposi’s sarcoma, a rare cancer that is also associated

with immunosuppression. In Western countries some 20,000 peo-

ple – most of them haemophiliacs – became infected through

contaminated blood products long before a serological test be-

came widely available in 1985.

The speed at which HIV was established as the causative agent of

AIDS was impressive. The puzzle was solved within just two years,

when French immunologists Françoise Barré-Sinoussi from the

Pasteur Institute in Paris and Luc Montagnier reported the isola-

tion of HIV from a patient’s lymph node in the journal Science.

‘We tentatively conclude that this virus … belong(s) to a family of

T-lymphotropic retroviruses that are horizontally transmitted in

humans and may be involved in … AIDS,’ they wrote. At the Na-

tional Cancer Institute in the USA, Robert Gallo isolated the same

virus in 1984, but only Barré-Sinoussi and Montagnier later re-

ceived the 2008 Nobel Prize for Physiology or Medicine for their

discovery. It is now common knowledge that HIV is the causative

agent of AIDS and can be transmitted by sex, blood and contam-

inated blood products, as well as by the placenta and by breast-

feeding. HIV has claimed more than 25 million lives over the last

three decades, and approximately 34 million people were living

with the virus in 2011, according to the World Health Organiza-

tion (WHO). More than 300,000 scientific articles have now been

published on HIV/AIDS.

Just a handful of proteins are specified in the 9,173 base pairs of

the HIV genome. Yet this virus wreaks havoc like no other. One rea-

son is HIV’s ability to specifically attack helper T cells (CD4+ T cells),

which have a crucial part in initiating the human immune response

to infections. Without them, antibody responses become stifled and

other T cells simply won’t be activated. The body is now extremely

vulnerable to pathogens and cancerous cells that it would normally

dispose of. Appropriately, the resulting disease was termed ‘acquired

immune deficiency syndrome’, or AIDS for short.

A second characteristic that makes HIV so dangerous is its ca-

pacity to generate mutations at an extraordinary rate. HIV’s gen-

etic material consists of only one strand of ribonucleic acid (RNA),

which is about one million times more susceptible to errors in rep-

Despite AIDS being one of the

most deadly pandemics in hu-

man history, it has also taught us

many lessons that have improved

healthcare across the planet –

particularly in Africa. Thus argues

Peter Piot, director of the London

School of Hygiene and Tropical

Medicine and former executive di-

rector of the Joint United Nations

Programme on HIV/AIDS (UN-

AIDS). ‘The unified and integrat-

ed response to AIDS, though far

from perfect, can serve as a mod-

el for society’s future response to

the growing epidemic of chronic

diseases.’ That sentiment is also

shared by Elisabeth Girrbach, who

has promoted several projects on

behalf of GIZ, a federal enterprise

that supports the German govern-

ment in achieving its objectives in

the field of international cooper-

ation for sustainable develop-

ment. ‘The epidemic has brought

about unprecedented internation-

al cooperation, such as the cre-

ation of UNAIDS and the Global

Fund to Fight AIDS, Tuberculosis

and Malaria,’ she says.

The Global Fund was originally set

up to finance anti-AIDS activities

only, but later broadened its man-

date. AIDS was recognized as pre-

ceding most cases of tuberculosis

in developing countries, leading

to a broader perspective. Tiered

pricing for medicines in different

countries became commonplace,

and both the fight against malar-

ia and tuberculosis was helped by

the strengthening of services for

maternal and child health in coun-

tries such as Ethiopia and Malawi,

argues Piot.

Educational strategies and infra-

structures that were developed

within the context of the AIDS

epidemic can also be adapted to

new challenges. GIZ, for instance,

has developed an approach for

managing HIV in the workplace

that could be copied for other dis-

eases. Through brochures and

posters for specific target groups,

within a decade close to two mil-

lion employees were reached

through public–private partner-

ships. Counselling and education

to peers was also provided, who

then spread the messages about

how to prevent HIV infections

and treat the disease, sometimes

supported by singers, storytellers

or drama groups.

One of the most important in-

sights gained during the fight

against AIDS, according to Girr-

bach, was the need to reach

out beyond the health sector it-

self to other parts of society, so

that every one could see how they

would be affected by the pan-

demic. The crisis is not over yet,

but it has taught the world a les-

son that it’s unlikely to ever for-

get: you cannot tackle a glob-

al crisis successfully unless you’re

ready to think – and act – beyond

your own borders.

WHAT HIV HAS TAUGHT US – IMPROVING HEALTHCARE ACROSS THE PLANET

Pho

to: sh

utt

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tock

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In the course of the AIDS pandemic healthcare in Africa has improved.


due to copyright

limitations.

11


lication than double-stranded DNA, the ‘standard genetic equip-

ment’ of all living beings. Hence the virus mutates rapidly and – if

treated with single drugs – can quickly become resistant.

In 1985, the first antibody test was licensed, enabling the

screening of blood supplies. In 1987, the first antiretroviral drug

azidothymidine (AZT) became available for the treatment of

AIDS just one year after the beginning of clinical trials. Hans

Jäger, a physician who has treated several thousand AIDS patients

at Schwabing Hospital in Munich and at the Sloan Kettering Can-

cer Center in New York, witnessed the breakthrough. ‘Hardly ever

have we learned so much about a disease in such a short time’, re-

counts Jäger. Originally intended as an anticancer drug and syn-

thesized in 1964, AZT interferes with the virus’ replication – with

dramatic effect: ‘Twenty-two patients had died the year before.

Now, in 1987, we were down to two deaths’, says Jäger.

Other drugs targeted different structures of the virus: scientists

developed more than a dozen ‘cousins’ of AZT from two chemical

classes, all inhibiting the enzyme reverse transcriptase. They

found two substances that interfere with binding, fusion and en-

try of HIV-1 into the host cell. Another half a dozen agents were

developed that block the viral protease enzyme necessary for the

exit of mature virions after they have been assembled in the host

cell. Yet another class of drugs with currently two approved sub-

stances inhibit the integration of the virus’s genetic material into

the DNA of the host.

With so many weapons to choose from, the development of

highly active antiretroviral therapy (HAART) became possible in

the mid-1990s. It combined three or four drugs from different

classes, thus simultaneously increasing treatment efficiency and

targeting the problem of viral resistance. A person infected with

HIV produces on average ten billion virions per day. By applying

HAART, however, doctors were able to prevent replication almost

completely and sometimes even suppress the virus below the level

of detection. At the same time, many of the side effects that pa-

tients suffered when taking relatively high doses of single drugs

were also reduced, because every component of their ‘cocktail’

could now be given at lower concentrations. ‘HAART, in essence,

has turned AIDS into a disease that one can live with’, says Jäger.

‘The life expectancy and quality of life for our patients is now

comparable to someone with diabetes or hypertonia’, he adds. By

June 2013, a total of 26 antiretroviral drugs have been licensed for

the treatment of HIV infection. Regrettably, though, discrimina-

tion and stigma are still issues.

Much to their credit, the international community readily

engaged with controlling the spread of AIDS in the Western

hemi sphere. Making HIV a manageable disease has been greatly

helped by research and health programmes such as the Joint Unit-

ed Nations Programme on HIV and AIDS (UNAIDS), which was

launched in 1996 to serve as the main advocate for accelerated,

comprehensive and coordinated global action on the pandemic.

The Global Fund to Fight AIDS, Tuberculosis and Malaria began

work in 2002 with seed money from Microsoft founder Bill

Gates and within a decade has approved close to 23 billion US

dollars for more than 1,000 programmes in 151 countries. In the

USA, President George W. Bush established his Emergency Plan

for AIDS Relief (PEPFAR) in 2003 and set aside 15 billion US

dollars to fight the pandemic over the next five years by provid-

ing drugs and counselling to 12 African countries. The pro-

gramme, reinforced with 48 billion US dollars for the next five

years in 2008 is still by far the largest investment ever against any

infectious disease.

Gradually, the tide seems to have turned. Progress has been

facilitated by a willingness of Western companies to make their

inventions and technology available at low cost by expiring pat-

ents that allow countries such as Brazil, India and South Africa to

produce antiretroviral drugs comparatively cheaply, plus the will-

ingness of both international organizations and private founda-

tions to pick up at least part of the bill for drugs.

The Bill and Melinda Gates Foundation alone has contributed

close to 4 billion US dollars to these efforts. ‘A year’s supply of

antiretroviral drugs that would cost 12,000 euros in Germany is

less than 100 euros in developing countries now and hence no

longer out of reach for most poor patients’, reports Hans Jäger. Ac-

cess is still by no means universal, Jäger adds, ‘but the progress is

impressive.’

Revised therapy guidelines now recommend starting antiret-

roviral therapy as early as possible. Male circumcision has been

Just a handful of proteins are

specified in the 9,173 building

blocks of the HIV genome.

Yet this virus wreaks havoc

like no other.

12


Pho

to: C

DC

- N

ati

onal C

ente

r fo

r H

IV, ST

D a

nd

TB

Pre

venti

on

marrow transplant from a donor whose CD4+ cells were resistant to

viral infection due to a mutation that crippled the surface receptor

CCR5, thereby preventing the virus from binding. Brown no longer

takes any medication. Even though traces of the virus can still be de-

tected, most of his immune cells are ‘off limits’ now for HIV, so most

experts consider him ‘functionally cured’. In order to achieve the

same goal in other patients, one strategy applied to six HIV-positive

men has involved specifically removing the genetic code for the

CCR5 receptor from patients’ isolated T cells and then re-infusing

those cells. Ninety days later, seven percent of CD4+ cells were found

to have the desired mutation. Mutations that modify an immune re-

ceptor also benefit about one in 300 HIV-infected individuals. These

so-called ‘elite-controllers’ do mount an immune response to HIV-

infected cells. Their cytotoxic T cells kill infected cells so fast that the

virus has little chance to multiply.

In France, a small number of patients from the so-called Vis-

conti cohort have also been able to live well without medication

for several years – most likely because they received antiretroviral

drugs shortly after they were infected, when the viral load was still

low. New combinations of as many as five drugs that are currently

being tested may be able to do the same for most patients by elim-

inating even the few remaining latently infected cells that are not

reached by standard therapy. It won’t take another 30 years to fi-

nally defeat the plague called AIDS, hopes Anthony Fauci, who

contributed massively to early research and is now head of the US

National Institute of Allergy and Infectious Diseases: ‘With collec-

tive and resolute action now and a steadfast commitment for years

to come, an AIDS-free generation is indeed within reach.’

found to reduce susceptibility to infection by 50–70 percent in

three African trials and both WHO and UNAIDS now say it

should be considered for HIV prevention. The use of antiretro-

viral therapy before sex or as pre-exposure prophylaxis has also

recently been shown to be effective in high-risk individuals. It re-

duced HIV rates in homosexual men with multiple partners by

nearly half, and in discordant couples – where only one partner is

infected – by two-thirds.

The fact that viral load is the greatest risk factor for transmis-

sion has given rise to the new concept of ‘treatment as prevention’,

a principle first proved in mother-to-child transmission. Drug

combinations given to pregnant and breast-feeding women can

drastically reduce transmission, as shown by Robert Shapiro from

Harvard University in a large field trial in Botswana. Making

HAART available from pregnancy through to six months postpar-

tum resulted in high rates of virus suppression, with an overall rate

of mother-to-child transmission of 1.1 percent. Given these fig-

ures, paediatric HIV could now be eliminated almost completely.

Hopes for controlling the HIV-1 pandemic through vaccines

have been foiled repeatedly by the virus’s diversity and rapid mu-

tation rates, though. Despite advanced new approaches, no break-

through is in sight. The most recent major trial was aborted in the

USA in April 2013 when infections were found to occur more fre-

quently among the 2,500 participants receiving the vaccine than

amongst the control group.

Much better news was presented by several prominent re-

searchers at the 19th World AIDS Conference, held in Washington

in late 2012: curing AIDS is no longer a remote possibility, stated

HIV co-discoverer Barré-Sinoussi. Eleven pilot studies with the aim

of verifying this are ongoing. Some are based on the case of Timothy

Ray Brown, better known as the ‘Berlin patient’. Brown had devel-

oped leukaemia on top of his HIV infection and had received a bone

Scanning electron micrograph of HIV-1 virions

(green) on the surface of a human lymphocyte.

Further information:

Jacques Pepin: The Origins of AIDS

Randy Shilts: And the Band Played On

13

Pho

tos:

St

eff

en H

art

mann, K

linik

um

Uni M

ünch

en (to

p left

); E

MB

L-Euro

pean B

ioin

form

ati

cs Inst

itute

(to

p r

ight)

; M

GH

Pho

tog

rap

hy;

Ho

op

er

(bo

tto

m left

); F

ried

rich

Mie

scher

Inst

itute

(b

ott

om

rig

ht)

F A C T SBOEHRINGER INGELHEIM FONDS FUTURA 28 | 2.2013

4 OUT OF 1,260Fostering excellent scientists is what BIF does. Its fellows are selected with great care and given

extensive and very personal support. Out of 1,260 fellows in all programmes to date, about 165

have already gone on to become professors and about 90 are group leaders in their own right.

14


Pho

to:

Sylv

ia W

illax

(to

p r

ight)

; M

ela

nie

Fla

ch,

Pri

yanke

Sahasr

ab

ud

he,

So

nya

Sach

se,

Isar

Starn

berg

(to

p left

, fr

om

to

p left

clo

ckw

ise)

With BIF, people always were and always will be at the centre

of its funding programmes. Over the years, this approach

has created an exceptional bond between BIF and its alumni. Th is

also means that alumni are willing to give back to others within

the network.

Each summer for nearly 30 years, a group of young scientists

has headed to the mountains of Austria, for a week of hiking, sci-

ence and networking. Th ey are BIF PhD and nowadays also MD

fellows, outstanding young researchers who have been funded for

up to three years to undertake fascinating research in internation-

ally renowned laboratories. At this year’s Hirschegg retreat, the fel-

lows clubbed together and made a quilt-like wall of images as a

thank you for the BIF team. ‘A wonderful present for the walls of

our new premises,’ says Claudia Walther, managing director of BIF,

‘and a colourful example of the enthusiasm and creativity of our

fellows.’

Th is personal approach is a big part of what makes BIF diff er-

ent from other funding bodies, says Claudia. ‘We are more than just

a chequebook,’ she says. ‘We try to help whenever problems arise.’

As well as off ering pastoral support via the offi ce team, BIF also

runs a number of week-long seminars and other meetings off ering

enough time for learning, exchange – and networking. Many fel-

lows form long-lasting collaborations and friendships as a result –

some have even tied the marriage knot.

Th is support is in place because BIF thinks that the positive ef-

fects of the stimulating exchange with like-minded fellows cannot

be overestimated. Furthermore, success in science demands more

than just academic excellence, particularly in today’s highly com-

petitive environment. But it goes without saying that academic ex-

cellence was and is central to BIF’s funding approach. All fellow-

ship applicants are judged on three criteria: their academic achieve-

ments to date, the originality, creativity and scientifi c quality of

their proposed projects and the labs in which the projects are pur-

sued.

Over the past 30 years, this strategy has paid off , as many BIF

fellows have gone on to head world-leading biomedical research

teams. Futura caught up with four of them (see below) to ask them

about their work and what role BIF played in shaping their careers.

It’s a telling fact that nine out of ten fellows stay in touch with BIF

long aft er their original stipend has expired: a fi tting testament to

the liveliness of the resulting network.

THE BIF TIMELINE

Squares of the quilt made by the Hirschegg 2013 participants as a pre-

sent for BIF’s new premises.

No matter what weather – in Hirschegg hiking it is. Here participants have

time to discuss the presented work and get to know each other better.

BIF’s founding

The fi rst four fellows

50th ITC500th application

(PhD and postdoc)

Move within Stuttgart1st Summer seminar in Oberjoch, later Hirschegg

100th BIF fellow

1st Communication training

in Blaubeuren, later Lautrach

1 9 8 3 1 9 8 4 1 9 8 5 1 9 8 6 1 9 8 7 1 9 8 8 1 9 8 9

15

FUTURA 28 | 2.2013BOEHRINGER INGELHEIM FONDS F A C T SPho

to:

Chri

stia

n H

aas

(pub

lished

in N

atur

e)

Christian Haass, Alzheimer Research

One of the most important discoveries in Alzheimer research start-

ed with a bet during Harvard Medical School’s Friday aft ernoon

happy hour. Christian Haass, then a BIF fellow, suggested to a PhD

student that the protein fragments known to form tangled clumps

in the brains of Alzheimer’s patients might not be confi ned to

people who have the disease. What if healthy people also produced

the fragment, as part of their normal physiology? Th e student

scoff ed at the idea. ‘He was outright laughing,’ says Christian. ‘So I

said, “You can laugh, I will just try it”.’

At the time, in the early 1990s, scientists believed that only the

cells of Alzheimer’s patients produced this protein fragment, called

β-amyloid. But the fact that the β-amyloid was made by snipping

the end off a normal cellular protein made Christian question the

dogma. On the weekend aft er the bet, he went into his lab and

found β-amyloid in the tissue culture fl uid surrounding healthy

lab-grown cells.

As well as disproving the dogma, Christian’s discovery meant

that scientists did not have to create new model systems to screen

for anti-Alzheimer’s drugs. Th ey could use existing cell lines, saving

time and money. Many of the resulting potential drugs are already

in clinical trials. Christian, who now heads a research team at

Ludwig Maximilian University in Munich (LMU), continues to

lead the way in dementia research, pioneering new methods for

studying the problem in humans and model animals.

His interest in Alzheimer’s and β-amyloid began in the late

1980s while he was a PhD student at the Centre for Molecular Biol-

ogy (ZMBH) in Heidelberg, Germany. He became inspired by the

work of ZMBH scientist Konrad Beyreuther, who had recently

identifi ed β-amyloid. ‘I followed his work closely, went to the meet-

ings, and became very interested in this fi eld,’ says Christian. Th e

fact that very little was known about β-amyloid protein and how it

formed the mysterious fi bres in the brain intrigued him.

In 1990, this fascination led him to apply for a postdoc posi-

tion under the tutelage of neurologist Dennis Selkoe at Harvard

Medical School, where he was supported by a BIF fellowship. ‘Th at

was the key thing: to go to the best lab in America without having

to ask them for funding,’ says Christian. ‘For me, this was really the

jumpstart for my career.’ Following his discovery of β-amyloid in

normal cells, Christian stayed in Selkoe’s group to work on the

mechanism cells use to produce the protein fragment. Th e result

was a fl urry of infl uential papers that allowed him to progress to

become assistant professor at Harvard, where he remained until

1995, when he got a full professorship at LMU and returned to

Germany. Since then, Christian has branched out to look at the

role of abnormally tangled proteins in other neuro degenerative

diseases, such as Parkinson’s disease, amyotrophic lateral sclerosis

(ALS — also known as Lou Gehrig’s disease), and frontotemporal

lobar degeneration (FTLD), the second most common form of de-

mentia in people aged under 65. FTLD is of particular interest,

says Christian, because the faulty protein causing the condition is

relatively easy to target with drugs, opening up the possibility that

it could become the fi rst truly treatable neurodegenerative condi-

tion.

It is also possible to detect FTLD with a simple blood test in

patients who are not yet symptomatic. Th is has important implica-

tions for diseases such as Alzheimer’s, says Christian, where early

detection is vital. ‘We now believe the disease starts 20 years before

we see symptoms,’ he says. Given the rate at which the populations

of developed nations are ageing, the need for accurate, early diag-

nosis and eff ective treatments for dementia has never been more

pressing.

This gel proved that normal cells produce amyloid -peptids and thus

allowed researchers to use simple cell cultures for drug development.

Aβ

Hermann Fröhlich takes over as managing director from Hasso Schroeder

1,000th application (PhD and postdoc)

1st alumni meetingin the USA

1,000th travel grant1st alumni seminar in Gracht

End of postdoc funding, concentration on PhDs

1 9 9 0 1 9 9 1 1 9 9 2 1 9 9 3 1 9 9 4 1 9 9 5

16


Ask a scientist what fi rst got him or her interested in science, and

many will recall childhood memories of gazing at the night sky

or marvelling at the patterning of a butterfl y’s wing. For Sarah

Teichmann, it was the beautiful colours of the autumn leaves.

‘I was interested in thinking about molecules in life when I was

at school,’ says Sarah. ‘Th at’s how I became motivated to study biol-

ogy.’ Fast forward 20 years, and Sarah, now a senior group leader at

the Wellcome Trust Sanger Institute and research group leader at the

European Bioinformatics Institute in the UK, has translated her fas-

cination into a highly successful academic career. She is at the fore-

front of systems biology, an emerging discipline that aims to explain

how individual molecules within a cell co-operate to aff ect the cell’s

overall behaviour. Sarah’s research gives a global view of what is hap-

pening in cells, and off ers new insights into how proteins behave. Her

work could help scientists predict how proteins interact with each

other, so they may design drugs that can interrupt disease processes.

‘For me, it was always clear that having a holistic view of the cell is the

way forward,’ says Sarah. ‘Th e big picture is just as important as the

atomic details.’

Aft er achieving a fi rst-class degree in Natural Sciences at the

University of Cambridge, Sarah applied for a PhD project at the UK’s

Medical Research Council Laboratory of Molecular Biology (MRC-

LMB). As a dual US-German citizen she was ineligible for UK gov-

ernment funding; however, with a BIF PhD fellowship, which funds

research internationally, she was able to pursue her PhD, exploring

the brand-new fi eld of computational biology.

‘Th is was in the really early days, in the mid-1990s,’ says Sarah.

‘Th e word “bioinformatics” had only just been coined.’ Working with

Cyrus Chothia, a pioneer in bioinformatics, Sarah looked for new

ways to make sense of the vast datasets being produced in genome-

sequencing projects. She and her colleagues developed new methods

that made it possible to compare the sequences of proteins encoded

in an organism’s genome. Proteins with similar sequences are likely

to have similar structures and functions, so comparing unknown

proteins with familiar ones allows scientists to predict what an un-

known protein might do.

In 1999, Sarah moved to University College London, where she

was once again at the forefront of a new fi eld: network biology. Th is

discipline aims to understand how the myriad interactions of a cell’s

constituent molecules give rise to its behaviour. Sarah’s work demon-

strated how proteins form networks of interactions, and how they

club together to form larger ‘machines’, or complexes. Th is led to a

burst of highly infl uential publications, and Sarah returned to the

LMB to set up her own group. She turned her focus to transcription

factors, proteins that help to control the activity of genes. Th e tran-

scription-factor database her group created (http://www.transcrip-

tionfactor.org/) allows researchers to search for genes that are pre-

dicted to encode for transcription factors.

On the Genome Campus since February 2013, Sarah continues

to innovate. She co-founded the state-of-the-art Single Cell Genom-

ics Centre, a joint initiative between the Sanger Institute and EMBL-

EBI that explores how gene activity is controlled in single cells.

Having supervised two BIF PhD students, Sarah says she con-

tinues to see the benefi ts of her early association with the founda-

tion, particularly of the support and networking the BIF continues

to provide.

‘Th e BIF has supported me in many diff erent ways, beyond

my PhD,’ says Sarah. ‘You can never underestimate the ongoing

impact of a fellowship like this, and I feel very lucky to have been a

part of it.’

The interfaces between proteins in complexes (left) can be represented

using graph theory (right) to allow large-scale analysis of interfaces

across protein databases.

Sarah Teichmann, Systems Biology

Pho

to:

Em

manuel Le

vy

1 9 9 6 1 9 9 7 1 9 9 8 1 9 9 9 2 0 0 0 2 0 0 11st Hirschegg

seminar

1st alumni meet-

ing in Woods Hole

500th BIF fellow Leibniz Prize for Regine Hengge

Start of three-year evalu-ation study (Bornemann study)

Move from Degerloch to Stuttgart

17


Konrad Hochedlinger looked at the baby mice with a mixture of

euphoria and relief. It was 2001, and for the previous two years he

had struggled to do what many biologists had long considered im-

possible: to prove one could ‘reprogramme’ a fully specialized

adult cell and use it to create a whole new animal. ‘Th at was really

a very gratifying moment,’ says Konrad, ‘aft er two years of not be-

ing sure whether this would work at all, or whether my PhD would

ever work out, or whether I would have a future in science!’

He need not have worried. Konrad, now at the Center for Re-

generative Medicine at Massachusetts General Hospital (MGH) in

Boston, is one of the world’s leading stem cell researchers. Th anks

to his work and to that of other scientists, the once science-fi ction-

al prospect of growing replacement tissues that are compatible

with a patient’s body is now becoming reality. His work has also

shed new light on the fundamental biology of how cells develop

their specialized functions, how this goes wrong in cancer, and

even whether it might be possible one day to reprogramme cancer-

ous cells to behave more like healthy ones.

Back in the mid-1990s, biologists believed that fully special-

ized adult mammalian cells could not revert to an immature state

from which they could give rise to any cell type in the body. Th en,

in 1997, UK scientists announced that they had removed the nu-

cleus from an adult sheep cell and transplanted it into an egg

whose own nucleus had been removed. Th e contents of the egg had

caused the nucleus to become immature again, resulting in the

birth of a clone, a lamb called Dolly. However, there was some

doubt as to whether Dolly had come from the nucleus of a fully

specialized adult cell, or from one of the rare, more immature stem

cells that replenish adult tissues.

Dolly was a turning point for Konrad. ‘I was immediately

hooked,’ he says. He secured a PhD post in the lab of renowned

stem cell biologist Rudolf Jaenisch at the Whitehead Institute at

MIT, where he was supported by a BIF PhD fellowship. ‘Th is was

the most prestigious and supportive of all the fellowships on off er

and I was very glad to get it,’ he says.

Konrad boldly set out to prove beyond doubt that it is possible

to reprogramme fully specialized adult cells. ‘Th e project was quite

risky and almost prone to fail,’ he says. His success caused a big stir

among biomedical researchers – and BIF immediately fl ew Konrad

to the yearly alumni meeting at Gracht castle near Cologne, where

he presented his work as the fi rst current fellow.

Konrad went on to use his technique to correct a genetic fault

that caused immune defi ciency in mice. ‘Th is led to the fi rst proof-

of-principle experiment for therapeutic cloning,’ he says. To com-

plete his hattrick, he then showed that it was possible to repro-

gramme cancer cells to behave like normal cells.

But reprogramming nuclei by transplanting them into eggs is

tricky and ineffi cient. In 2006, researchers in Japan revealed they

had reprogrammed adult cells genetically, without using eggs.

Konrad, who had just set up is own lab at MGH, improved the

method for producing these cells, known as induced pluripotent

stem cells, or iPS cells, which are now the focus of his research.

Konrad stays in touch with BIF via the friends he made as a

fellow, and through his PhD student Marti Borkent, who is also

supported by BIF. Konrad himself has fond memories of the indi-

vidual support he received from the foundation staff , especially

Monika Beutelsbacher and Hermann Fröhlich. ‘Th e personal char-

acter of Boehringer Ingelheim Fonds is something that I really ap-

preciated and still appreciate a lot,’ says Konrad. ‘Th ey were – and

still are – always there for us.’

Induced pluripotent stem cell under UV light (top), which activates the

green fl uorescent marker present in these cells, and bright light.

Konrad Hochedlinger, Stem Cells

Pho

to:

K.

Ho

ched

ling

er

2 0 0 2 2 0 0 3 2 0 0 4 2 0 0 5 2 0 0 6 2 0 0 7Leibniz Prize for Christian Haass

Leibniz Prize for

Stefanie Dimmeler

Move from Stuttgart to

Heidesheim

External evaluation of fellow-

ship programme published

Start of MD fellowships

Leibniz Prize for Detlev Weigel

18


Pho

to: A

. W

anner, C

. G

eno

ud

, R

. Fr

ied

rich

It seems that whatever path he takes, Rainer Friedrich’s research

keeps leading him back to a small, stripy tropical fi sh. ‘I tried to es-

cape at one point,’ he says. ‘I worked a little bit with worms and

mice. Th en I was thinking about insects, such as fruit fl ies. But I al-

ways came back.’ It’s just as well that he did. Th anks to Rainer, this

little fi sh, the zebrafi sh, has become a rising star in the fi eld of

neuro science, where its small size and amenable physiology have

allowed researchers to probe the biology of the brain in unprece-

dented detail. Rainer and other scientists in the fi eld are applying a

range of new techniques to the fi sh to tackle some of the big ques-

tions in neuroscience. For example, they want to understand how

circuits of neurons in the brain process complex information, al-

lowing us to perform sophisticated tasks such as identifying smells

or navigating our environment. ‘Th e zebrafi sh is booming as a

model system in neuroscience,’ says Rainer. ‘We now have a huge

arsenal of tools that did not exist 20 years ago.’

It was just under 20 years ago that Rainer began his PhD stud-

ies at the Max Planck Institute for Developmental Biology in

Tübingen, Germany. He was drawn to a project that involved im-

aging patterns of neuronal activity in a part of the zebrafi sh brain

known as the olfactory bulb, which processes information about

odours detected by the nose. At that time, scientists had a good un-

derstanding of how the brain interpreted information about cer-

tain other senses, such as vision, but the data coming out of the ol-

factory system was not making much sense.

Th e issue lay in how neuroscientists were approaching the

problem: studying the behaviour of individual neurons rather than

groups. ‘Some people, including me, had the idea that the informa-

tion must somehow be in the combination of the activity of many

cells together,’ says Rainer. At around this time, new techniques

emerged that fi nally allowed researchers to study multiple neurons

simultaneously. Th ese included calcium imaging, which let scien-

tists watch the activity of living neurons in real time.

Rainer was tasked with applying these methods to the zebra-

fi sh, which was used as a model for studying development at his

institute. Th ere was a slight complication, however. Rainer’s ori-

ginal supervisor had moved to another university. Th anks to his

BIF PhD fellowship, however, he was able to stay in Tübingen.

‘Th is gave me the freedom to get on with this project,’ says Rainer.

Th e project was a success, introducing the fi sh as a model system

for neurobiology. Rainer eventually went on to head his own lab

fi rst at the Max Planck Institute for Medical Research and then at

the Friedrich Miescher Institute for Biomedical Research in Basel,

Switzerland. Here he continues to study neuronal circuits with

state-of-the-art technologies such as multi-photon imaging, which

allows scientists to visualize dynamic neuronal activity patterns in

living tissue. His recent contributions to the fi eld include showing

how the brain distinguishes one similar odour from another, or

how it exploits timing between neuronal fi ring to transmit diff er-

ent messages to diff erent parts of the brain simultaneously. Under-

standing the basic biology of circuits, he says, is vital to working

out what goes wrong in neurological diseases such as autism. He

and his team have now begun to model some of these diseases in

zebrafi sh.

Rainer says he greatly values his continuing contact with BIF,

attending its seminars not just for the science, but also for the valu-

able support and networking opportunities it aff ords. By now, a

number of his students have also been BIF PhD fellows, including

one who has set up his own lab, and in turn recruited a BIF PhD.

‘Th at’s now three generations that have stayed in touch,’ says Rain-

er, ‘forming a small BIF dynasty.’

Reconstructions of 137 neurons from large-volume 3D electron micros-

copy data in the zebrafi sh brain.

Rainer Friedrich, Neurobiology

2 0 0 8 2 0 0 9 2 0 1 0 2 0 1 1 2 0 1 2 2 0 1 3Claudia Walther takes over as managing director

1,000th BIF fellow

165th professor among alumniLeibniz Prize for Ivan Dikic

50 years ITC Move from Heidesheim to Mainz

19

FUTURA BOEHRINGER INGELHEIM FONDS F E L L O W S

Please understand that in the interest

of our fellows, we publish only results

online, not descriptions of ongoing

projects.

Therefore, this pdf continues with the

section Results.

BOEHRINGER INGELHEIM FONDSF E L L O W SFUTURA 28 | 2.2013

50

RESULTS The Boehringer

Ingelheim Fonds funds excel-

lent PhD students who are

selected as much for their

aca demic record as for their

ambitious projects and the

scientific quality of the lab-

oratories in which they wish

to work. Here they present

a synopsis of their findings,

which aim to push the bound-

aries of our knowledge of the

fundamental phenom ena

of human life.

SERAP ERKEKMolecular determinants of nucleosome retention in mouse sperm 51

SEBASTIAN HOGLAnalysis of regulated intramembrane proteolysis using mass spectrometry 51

ANNA-CARINA JUNGKAMP

Identifying target sites of RNA-binding proteins in the nematode transcriptome 51

SUSANNE A. KASSUBETranscription regulation by non-coding RNAs and the DNA helicase RECL5 52

THAIS LAVAGNOLLI Cohesin regulates early steps of cellular reprogramming 52

MICHAL LUBAS3’-5’ RNA degradation pathways in human cells 52

JULIA LUDWIGThe role of Dickkopf-3 in the adaptive immune system 53

SIGRID MILLES

Structure and dynamics of the highly flexible nucleoporin 153 53

STEPHANIE PANIERRNF168-mediated control of the ubiquitin-dependent DNA double-strand break response 53

TATJANA PETOJEVIC

Activation of the Mcm2-7 helicase by ancillary replication factors GINS and Cdc45 54

INES PINHEIROIdentification and characterization of H3K9 monomethylases 54

AHMED RATTANIRegulation of anaphase in mammalian meiosis 54

SARAH RIEUBLANDStructured connectivity in inhibitory cerebellar circuits 55

MATTHIAS ROSENWALDTransdifferentiation of brown and white adipocytes 55

MATTHIAS SIEBERTStructure, function and transport of the cytomatrix at the active zone in Drosophila 55

KATHARINA SONNENHuman Cep192 and Cep152 co-operate in Plk4 recruitment and centriole duplication 56

SYLVIA TIPPMANNRegulation of gene expression: a quantitative assessment 56

TONGTONG ZHAO

Mechanisms of oocyte polarization and axis formation in Drosophila 56

51

FUTURA 28 | 2.2013BOEHRINGER INGELHEIM FONDS F E L L O W S

Eukaryotic gene expression is extensively

regulated by hundreds of RNA-binding pro-

teins (RBPs), the biological functions of

which are mostly unknown. Each RBP can

bind and regulate many mRNAs and so a

fi rst step to understanding their function is

to identify their target sites at a transcrip-

tome-wide level. A recently developed

method known as PAR-CLIP uses photore-

active nucleosides to crosslink RBPs to their

target RNAs prior to immunoprecipitation. I

have established in vivo PAR-CLIP (iPAR-

CLIP) to determine, at nucleotide resolution,

transcriptome-wide binding sites of GLD-1,

a conserved, germline-specifi c translational

repressor in Caenorhabditis elegans. To-

gether with my colleagues, I identifi ed 439

reproducible target mRNAs that are mostly,

as expected, expressed in the C. elegans ger-

mline. Upon GLD-1 knockdown, protein –

but not mRNA – expression of the 439 tar-

gets was upregulated, indicating that GLD-1

indeed has a functional role in the post-tran-

scriptional regulation of these genes. Finally,

we discovered strongly conserved GLD-

1-binding sites that are located directly up-

stream of start codons for translation. Th ese

sites are functional in vitro and confer strong

repression in vivo. Our results thus suggest

that GLD-1 interacts with the translation

machinery near the start codon, which is a

novel mode of gene regulation in eukaryotes.

PUBLICATIONS

Jungkamp AC, Stoeckius M, Mecenas D, Grün D,

Mastrobuoni G, Kempa S, Rajewsky N (2011) In vivo and

transcriptome-wide identifi cation of RNA binding protein

target sites. Mol Cell 44: 828–840

ANNA-CARINA JUNGKAMP

Discipline: Molecular Medic, Diploma

Institute: Berlin Institute for Medical

Systems Biology, Max Delbrück Cen-

ter for Molecular Medicine, Germany

Supervisor: Prof. Nikolaus Rajewsky

IDENTIFYING TARGET SITES OF RNA-BINDING PROTEINS IN THE NEMATODE TRANSCRIPTOME

cf. BIF FUTURA, VOL. 25 | 3.2010

In eukaryotic cells, DNA is packaged with

histone proteins to form nucleosomes,

which are involved in the regulation of both

gene expression and genome stability. In

sperm cells of some animals, however, only

a small proportion of the genome is pack-

aged in this way. In human sperm, the nu-

cleosomes are known to be enriched at loci

that are important for development and

signalling. Th e goals of my PhD project

were to determine if the genome-wide lo-

calization of nucleosomes is similar in

mouse sperm and to identify the principles

of nucleosome retention. I used high-

throughput genome sequencing to show

that DNA sequence, histone variants, his-

tone modifi cations and gene expression

have a combined eff ect on how mouse

sperm retains nucleosomes. My work dem-

onstrated that of the 3 histone H3 variants,

H3.3 is most predominant in sperm, where-

as H3.1 and H3.2 are present in lower

amounts. I also found that the histone

methylation state in sperm is directly relat-

ed to gene expression in the early embryo,

suggesting a function for retained nucleo-

somes in gene regulation.

PUBLICATIONS

Erkek S, Hisano M, Liang C-Y, Gill M, Murr R, Dieker J et

al (2013) Molecular determinants of nucleosome retention

at CpG-rich sequences in mouse spermatozoa. Nat Struct

Mol Biol 20: 868–875

Brykczynska U, Hisano M, Erkek S, Ramos L, Oakeley

EJ, Roloff TC et al (2010) Repressive and active histone

methy lation mark distinct promoters in human and mouse

sperm atozoa. Nat Struct Mol Biol 6: 679–687

SERAP ERKEK

Discipline: Molecular Biologist, MSc

Institute: Friedrich Miescher

Institute for Biomedical Research

(FMI), Basel, Switzerland

Supervisor: Prof. Antoine Peters

MOLECULAR DETERMINANTS OF NUCLEOSOME RETENTION IN MOUSE SPERM


Th e cleavage of transmembrane proteins by

regulated intramembrane proteolysis (RIP)

is a key process in cellular signalling but it

can also have pathological consequences.

Alzheimer’s disease (AD) is supposedly ini-

tiated by the RIP-dependent liberation of a

short peptide from the amyloid precursor

protein (APP) into the interneuronal space.

Th e aim of my PhD was to analyse the RIP

of the APP homologue APLP2, and to iden-

tify novel targets of the AD RIP-protease

BACE1. Using mass spectrometry, I deter-

mined the exact APLP2 cleavage sites and

mapped APLP2 processing in neurons.

Furthermore, I established a quantitative

proteomic workfl ow that enabled me to

identify 24 candidate substrates of BACE1

that accumulated in the brains of Bace1-

knockout zebrafi sh. My results will be use-

ful for unravelling BACE1 function and

evaluating the side-eff ects of BACE1 inhibi-

tion, a potential therapy for AD.

PUBLICATIONS

Hogl S, van Bebber F, Dislich B, Kuhn PH, Haass C,

Schmid B et al (2013) Label-free quantitative analysis of the

membrane proteome of Bace1 protease knock-out zebra-

fi sh brains. Proteomics 13: 1519–1527

Schmid B, Hruscha A, Hogl S, Banzhaf-Strathmann J,

Strecker K, van der Zee J et al (2013) Loss of ALS-associated

TDP-43 in zebrafi sh causes muscle degeneration, vascular

dysfunction, and reduced motor neuron axon outgrowth.

Proc Natl Acad Sci USA 110: 4986–4991

Hogl S, Kuhn PH, Colombo A, Lichtenthaler SF (2011) De-

termination of the proteolytic cleavage sites of the amyloid

precursor-like protein 2 by the proteases ADAM10, BACE1

and γ-secretase. PLoS One 6: e21337

SEBASTIAN HOGL

Discipline: Biochemist, MSc

Institute: German Center for

Neurodegenerative Diseases

(DZNE), Munich, Germany

Supervisor: Prof. Christian

Haas

ANALYSIS OF REGULATED INTRAMEMBRANE PROTEOLYSIS USING MASS SPECTROMETRY


52


RNA synthesis and degradation are key

steps in the regulation of gene expression in

all organisms. In eukaryotes, 3'-5' RNA de-

cay is driven primarily by the RNA exo-

some complex, the functions of which are

regulated by various auxiliary proteins. Th e

goal of my PhD research was to investigate

the nuclear exosome interaction network in

humans by combining metabolic labelling,

affi nity purifi cation and mass spectrometry.

One of my key fi ndings was the discovery

and characterization of the nuclear exo-

some targeting (NEXT) complex, which di-

rects the rapid decay of nuclear exosome

substrates. By shift ing my focus to cytoplas-

mic RNA metabolism, I also identifi ed a

new player in RNA decay – the 3'-5' exo-

ribonuclease hDIS3L2. Using fl uorescence

microscopy, in-vitro RNAse assays and sev-

eral low- and high-throughput RNA and

protein techniques, I demonstrated the role

of hDIS3L2 in an exosome-independent

degradation pathway of human cytoplas-

mic mRNA.

PUBLICATIONS

Lubas M, Damgaard C, Tomecki R, Cysewski D, Jensen

TH, Dziembowski A (2013) Th e hDIS3L2 exonuclease

specifi es a parallel 3'-5' degradation pathway of human

cytoplasmic mRNA. EMBO J 32: 1855–1868

Lubas M, Chlebowski A, Dziembowski A, Jensen TH

(2012) Chapter one: Biochemistry and function of RNA

exosomes. Th e Enzymes 31: 1–30

Lubas M, Christensen MS, Kristiansen MS, Domanski M,

Falkenby LG, Lykke-Andersen S et al (2011) Interaction

profi ling identifi es the human nuclear exosome targeting

complex. Mol Cell 43: 624–637

MICHAL LUBAS

Discipline: Molecular Biologist, MSc

Institute: Department of Molecular

Biology and Genetics, Aarhus

University, Aarhus, Denmark

Supervisor: Prof. Torben H. Jensen

3’-5’ RNA DEGRADATION PATH-WAYS IN HUMAN CELLS


Cohesin is critical for sister chromatid co-

hesion and chromosome segregation in di-

viding cells. It also has roles in chromatin

organization and in regulating gene expres-

sion across several developmental pro-

cesses and cell types. In my PhD project, I

asked whether cohesin regulates gene ex-

pression during the re-establishment of

pluripotency in somatic cells upon repro-

gramming. To dissociate this role from its

essential functions during the cell cycle, I

established genetic approaches to condi-

tionally delete cohesin in embryonic stem

(ES) cells and somatic cells. For my repro-

gramming system, I chose heterokaryons –

cells formed by fusing ES cells and somatic

cells, in which reprogramming occurs

without cell division, making it simpler to

isolate cohe sin’s other functions. Cohesin

depletion enhanced the ability of ES cells to

induce reprogramming in somatic cells by

reactivating the expression of pluripotency

markers, possibly by a mechanism involv-

ing up-regulation of the reprogramming

factor c-Myc. In contrast, cohesin-depleted

somatic cells could not re-activate their

own pluripotency markers and failed to si-

lence their lineage-specifi c genes aft er fu-

sion with ES cells. Th is study provides im-

portant insights into the mechanisms by

which cohesin regulates gene expression in

reprogramming.

PUBLICATIONS

Seitan VC, Hao B, Tachibana-Konwalski K, Lavagnolli T,

Mira-Bontenbal H, Brown KE et al (2011) A role for cohesin

in T-cell-receptor rearrangement and thymocyte diff erentia-

tion. Nature 476: 467–471

THAIS LAVAGNOLLI

Discipline: Biologist, MSc

Institute: Imperial College

London, London, UK

Supervisor: Dr Matthias

Merkenschlager

COHESIN REGULATES EARLY STEPS OF CELLULAR REPROGRAMMING


Gene transcription by RNA polymerase II

(Pol II) is controlled by both protein and

RNA factors. Th e aim of my PhD was to

under stand transcription regulation by

studying 2 regulators: stress-induced non-

coding RNAs (ncRNAs) and RECQL5, a

helicase involved in repressing transcrip-

tion during DNA repair. Using cryo-elec-

tron micros copy (cryo-EM), I found a con-

served docking site for ncRNAs in the cleft

of Pol II. My crystal structure of part of

RECQL5’s Pol II-binding domain showed

similarity to a domain in the transcription

elongation factor TFIIS, which promotes

transcription of arrested elongation com-

plexes. Binding of RECQL5 and TFIIS to

Pol II is indeed competitive, and I con-

fi rmed with a transcription assay that REC-

QL5 binding hinders TFIIS function. My

cryo-EM reconstruction of RECQL5 bound

to Pol II revealed a novel regulatory mecha-

nism: while the Pol II-binding domain oc-

cludes TFIIS binding, the helicase domain

blocks Pol II movement along DNA. Th is

molecular mech anism might be used by

other factors that co-ordinate transcription

with DNA replication, repair or recombina-

tion.

PUBLICATIONS

Kassube SA, Fang J, Grob P, Yakovchuk P, Goodrich A,

Nogales E (2013) Structural insights into transcriptional

repression by non-coding RNAs that bind to human Pol II.

J Mol Biol 425: 3639–3648

Kassube SA, Jinek M, Fang J, Tsutakawa S, Nogales E

(2013) Structural mimicry in transcription regulation of

human RNA polymerase II by the DNA helicase RECQL5.

Nat Struct Mol Biol 20: 892–899

SUSANNE A. KASSUBE

Discipline: Biologist, Diploma

Institute: University of

California, Berkeley,

CA, USA

Supervisor: Dr Eva Nogales

TRANSCRIPTION REGULATION BY NON-CODING RNAS AND THE DNA HELICASE RECQL5


53


Nuclear pore complexes (NPCs) are vital

transport conduits between the nucleoplasm

and cytoplasm in eukaryotic cells, through

which large molecules can only pass with the

help of nuclear transport receptors (NTRs).

Th is selectivity is ensured by a permeability

barrier in the centre of the NPC, which is

formed by intrinsically disordered and

phenyl alanine-glycine rich nucleoporins

(FG-Nups). To investigate how the fl exible

FG-Nups with their heterogeneous but non-

random primary sequences mediate this

function, I have developed an integrated

chemical biology–fl uorescence approach to

study their plasticity at the single-molecule

level using time- and polarization-resolved

multi-parameter spectroscopy. I could show

that the FG-domain of Nup153 adopts a col-

lapsed coil that can lead to the formation of

amyloid fi bres. Th ese can then interlace into

networks resulting in macroscopic hydrogels.

Mimicking the crowded conditions inside the

cell enhances Nup153 association into amyl-

oids, which can be inhibited by NTRs. My re-

sults therefore have implications for NPC

transport models and NPC assembly.

PUBLICATIONS

Milles S, Lemke EA (2011) Single molecule study of the intrin-

sically disordered FG-repeat nucleoporin 153. Biophys J 101:

1710–1719

Milles S, Tyagi S, Banterle N, Koehler C, Vandelinder V, Plass T

et al (2012) Click strategies for single-molecule protein fl uores-

cence. J Am Chem Soc 134: 5187–5195

Milles S, Huy Bui K, Koehler C, Eltsov M, Beck M, Lemke EA

(2013) Facilitated aggregation of FG nucleoporins under mo-

lecular crowding conditions. EMBO Rep 14: 178–183

SIGRID MILLES

Discipline: Biophysicist, Diploma

Institute: European Molecular

Biology Laboratory,

Heidelberg, Germany

Supervisor: Dr Edward A. Lemke

STRUCTURE AND DYNAMICS OF THE HIGHLY FLEXIBLE NUCLEO-PORIN 153


Dickkopf-3 (Dkk3) is a secreted protein with

known functions in tumour biology and a

suspected role in the immune system. Dkk3

has been shown to be important in a trans-

genic model of peripheral T-cell tolerance,

which is crucial for avoiding autoimmune

reactions. To further understand its immune

function, I studied the eff ects of Dkk3 on T

and B cells in mice by comparing Dkk3-defi -

cient mice with wild-type mice. I confi rmed

that Dkk3-defi cient mice develop more per-

sistent symptoms of experimental autoim-

mune encephalomyelitis, a T-cell-mediated

disease that mirrors human multiple scler-

osis. My work revealed that the disease path-

ology of these mice was linked to more

brain-infi ltrating leukocytes and an altered

profi le of local cytokines. Furthermore, the

knock-out mice had enhanced functions re-

lated to a subset of B cells: they secreted

more of the B1-specifi c cytokine IL-10 and

exhibited a greater B1-specifi c antibody re-

sponse. To analyse the eff ect of Dkk3 on a B-

cell-mediated autoimmune disease, I used a

mouse strain modelling human systemic

lupus erythematosus. Treating these mice

with a Dkk3-neutralizing antibody led to

more B1 cells and increased infl ammation of

organs. In conclusion, I identifi ed Dkk3 as a

novel immune modulator limiting T- and B-

cell-mediated autoimmunity.

PUBLICATIONS

Papatriantafyllou M, Moldenhauer G, Ludwig J, Tafuri A,

Garbi N, Hollmann G et al (2012) Dickkopf-3, an immune

modulator in peripheral CD8 T-cell tolerance. Proc Natl Acad

Sci USA 109: 1631–1636

JULIA LUDWIG

Discipline: Immunologist, Diploma

Institute: Department of Molecular

Immunology, German Cancer

Research Center (DKFZ),

Heidelberg, Germany

Supervisor: Prof. Bernd Arnold

THE ROLE OF DICKKOPF-3 IN THE ADAPTIVE IMMUNE SYSTEM


In response to highly toxic DNA double-

strand breaks (DSBs), cells initiate a com-

plex signalling-based response that activates

cell-cycle checkpoints and co-ordinates

DNA repair. Control of this pathway relies

on numerous post-translational modifi ca-

tions, including phosphorylation and ubiq-

uitylation. During my PhD project, I identi-

fi ed the E3 ubiquitin ligase RNF168 as a cru-

cial component of the human response to

DSBs. Using immunofl uorescence assays

and in vitro biochemical analyses, I found

that RNF168 co-operates with the upstream

E3 ubiquitin lig ase RNF8 to form a cascade

of regulatory ubiquitylation at DSBs. Th is

then generates a molecular landing platform

for the ubiqui tin-dependent accumulation

of checkpoint and DNA-repair proteins such

as the breast cancer-associated protein BR-

CA1. Th e importance of this response is fur-

ther underscored by our fi nding that RID-

DLE syndrome, an immunodefi ciency and

radiosensitivity disorder, is caused by muta-

tions in the RNF168 gene. Collectively, my

results demonstrate that RNF168-mediated

chromatin ubiquitylation is crucial for the

physio logical response to DSBs in humans.

PUBLICATIONS

Stewart GS, Panier S, Townsend K, Al-Hakim AK, Kolas NK,

Miller ES et al (2009) Th e RIDDLE syndrome protein medi-

ates a ubiquitin-dependent signaling cascade at sites of DNA

damage. Cell 136: 420–434

Panier S, Ichijima Y, Fradet-Turcotte A, Leung CC, Kaustov

L, Arrowsmith CH, Durocher D (2012) Tandem protein

interaction modules organize the ubiquitin-dependent re-

sponse to DNA double-strand breaks. Mol Cell 47: 383–395

STEPHANIE PANIER

Discipline: Molecular Biologist,

Diploma

Institute: University of Toronto,

Toronto, Canada

Supervisor: Dr Daniel Durocher

RNF168-MEDIATED CONTROL OF THE UBIQUITIN-DEPENDENT DNA DOUBLE-STRAND BREAK RESPONSE


54


During eukaryotic DNA replication, heli-

cases separate the DNA double helix into

single strands that are then exposed to poly-

merases for the synthesis of new strands.

One such helicase comprises 6 minichromo-

some maintenance (Mcm) proteins, num-

bered 2–7, which are pre-assembled onto the

DNA as a hexameric ring. Th e Mcm com-

plex is inactive in G1 but the association of 2

auxiliary factors Cdc45 and GINS – forming

the stable ‘CMG’ – leads to the activation of

the Mcm motor and the switch into S phase.

Th e aim of my PhD project was to study this

activation process in more detail. We recon-

stituted the CMG using a baculovirus over-

expression system and identifi ed a key role

for Cdc45/GINS in inducing structural re-

arrangements in the complex by single-par-

ticle electron microscopy. Th ese modifi ca-

tions close a gap in the ring upon nucleotide

binding and increase the unwinding effi -

ciency of the ATPase motor. We also found

that as the CMG moves along the DNA, both

strands contact the helicase and are guided

in specifi c, but opposite, directions around

the Mcm subunits. Altogether, these results

suggest a specifi c entry site for DNA into the

CMG, and point to a discrete start position

for the strand separation step.

PUBLICATIONS

Costa A, Ilves I, Tamberg N, Petojevic T, Nogales E,

Botchan MR, Berger JM (2011) Th e structural basis for

MCM2-7 helicase activation by GINS and Cdc45. Nat

Struct Mol Biol 18: 471–477

Ilves I, Petojevic T, Pesavento JJ, Botchan MR (2010) Acti-

vation of the MCM2-7 helicase by association with Cdc45

and GINS proteins. Mol Cell 37: 247–258

TATJANA PETOJEVIC

Discipline: Biotechnologist, Diploma

Institute: Free University of Berlin,

Berlin, Germany

Supervisors: Prof. Michael Botchan

and Prof. Petra Knaus

ACTIVATION OF THE MCM2-7 HELI-CASE BY ANCILLARY REPLICATION FACTORS GINS AND CDC45


During the anaphase stage of meiosis,

accurate chromosome segregation depends

on the co-ordination of 2 key processes.

Cohesin, a protein complex that connects

replicated chromosomes, is cleaved, and

homologous kinetochores are pulled by

microtubules to opposite poles of the cell.

Th e spindle assembly checkpoint (SAC)

monitors the microtubule–kinetochore at-

tachments and prevents the cohesin com-

plexes from separating until aberrant

connections have been fi xed by an aurora

kin ase-dependent error correction machin-

ery. Although these processes work together

seamlessly, it was not known how this co-

ordination is achieved in mammalian

oocytes. In my PhD project, I found that

Shugoshin-like protein 2 (Sgol2) has several

roles in add ition to protecting cohesin. Sgol2

is involved in silencing the SAC, promoting

the congression and bi-orientation of bi-

valent chromosomes on spindles, limiting

chromosome stretching, and facilitating the

attachment of microtubules to kinetochores.

Th e ability of Sgol2 to protect cohesin and to

silence the SAC depends on its interaction

with protein phosphatase 2A (PP2A). In

contrast, its eff ects on stretching and attach-

ment formation are mediated by recruiting a

motor protein, MCAK, and by inhibiting

Aurora B/C kinase activity, respectively. By

interacting with diff erent regulatory pro-

teins, Sgol2 links processes that are essential

for faithful chromosome segregation.

PUBLICATIONS

Th e results of this project have not yet been published.

AHMED RATTANI

Discipline: Biochemist, MPhil

Institute: University of Oxford,

Oxford, UK

Supervisor: Prof. Kim Nasmyth

REGULATION OF ANAPHASE IN MAMMALIAN MEIOSIS


Pericentric heterochromatin, a large chroma-

tin domain adjacent to the centromere, is im-

portant for overall chromosome organization

and genomic stability. Methylation of this do-

main is associated with gene repression, in

particular the histone modifi cation marks

H3K9me3 and H4K20me3 (trimethylation

on lysine 9 of histone H3 and on lysine 20 of

histone H4). Th ere are indications that his-

tone trimethylation is a 2-stage process that

begins with histone monomethylation, but

the mechanisms underlying this fi rst step re-

main unknown. In my PhD project, we devel-

oped a biochemical assay to follow H3K9

monomethylation in the cytoplasm of mouse

embryonic fi broblasts. We used mass spec-

trometry to analyse fractions containing

H3K9 monomethylase activity and identifi ed

4 proteins with the conspicuous SET domain

for histone lysine methylation. In vivo knock-

down of these candidates revealed that the

proteins Prdm3 and Prdm16 are indeed

H3K9 monomethylases. Depletion of both

enzymes resulted in a reduction of cytoplas-

mic H3K9me1 and prevented H3K9me3 at

the pericentric heterochromatin, which sub-

sequently led to the disintegration of this do-

main. Our results therefore show that

H3K9me1 is essential for heterochromatin

integrity, and reveal Prdm3 and Prdm16 as

H3K9 monomethylases necessary for the es-

tablishment of pericentric heterochromatin.

PUBLICATIONS

Pinheiro I, Margueron R, Shukeir N, Eisold M, Fritzsch C,

Richter FM et al (2012) Prdm3 and Prdm16 are H3K9me1

methyltransferases required for mammalian heterochro-

matin integrity. Cell 150: 948–960

INES PINHEIRO

Discipline: Biochemist, Diploma

Institute: Max Planck Institute

of Immunobiology and Epigen-

etics, Freiburg, Germany

Supervisor: Dr Thomas Jenuwein

IDENTIFICATION AND CHARACTERIZATION OF H3K9 MONOMETHYLASES


55


White adipocytes are fat-storage cells

whereas brown adipocytes metabolize

lipids and carbohydrates to generate heat

and maintain body temperature. Brown-in-

white (brite) adipocytes are brown adipo-

cytes that can be found in predominantly

white adipose tissue of mammals aft er cold

stimulation but their origin has been a mat-

ter of debate. Th e aim of my PhD project

was to evaluate the transdiff erentiation the-

ory, which proposes that there is a direct in-

terconversion between mature brite and

white adipocytes in response to changes in

environmental temperature. I generated

transgenic mice for transient, as well as per-

manent, fl uorescent labelling of brite adi-

pocytes to trace these cells at diff erent tem-

peratures. I showed that cold-induced brite

adipocytes disappeared within several

weeks of warm adaptation. Interestingly,

rather than being eliminated, these cells

transformed into typical white adipocytes.

Furthermore, these white adipocytes could

transdiff erentiate into brite adipocytes

upon cold stimulation. My results support

the proposed pharmacological conversion

of adipocytes from a lipid-storing into a li-

pid-burning phenotype, which may consti-

tute a novel approach to counteracting obe-

sity and its secondary metabolic disorders.

PUBLICATIONS

Rosenwald M, Perdikari A, Rülicke T, Wolfrum C (2013)

Bi-directional interconversion of brite and white adipo-

cytes. Nat Cell Biol 15: 659–667

Rosenwald M, Wolfrum C (2013) Th e origin and defi nition

of brite versus white and classical brown adipocytes. Adipo-

cyte (in press)

MATTHIAS ROSENWALD


Institute: Swiss Federal Institute

of Technology (ETH), Zurich,

Switzerland

Supervisor: Prof. Christian Wolfrum

TRANSDIFFERENTIATION OF BROWN AND WHITEADIPOCYTES


Neurons form complex networks, com-

monly called neural circuits, which are the

information processing units in the brain.

Despite their crucial role in signal process-

ing, little is known about the connection

patterns within these networks or the rules

that govern their formation. Interneurons

in the mammalian brain are connected by

both electrical synapses and inhibitory

chemical synapses, forming 2 types of net-

works. By in-vitro patch-clamp recording

from multiple interneurons of mammalian

cerebellar slices, I found that the connectiv-

ity of interneuron networks is highly struc-

tured and cannot be adequately described

by simple random connectivity rules. Th e

electrical and chemical networks overlap,

and they both contain patterns in which

connections are clustered. I also found that

the chemical network appears to follow a

transitive rule: if cell A connects to cell B

and cell B connects to cell C, then cell A

also connects to cell C. I showed that this

rule is supported by a characteristic spatial

organization of the neurons along the sagit-

tal planes of the cerebellar cortex. My re-

sults represent the fi rst report of structured

connectivity between inhibitory neurons in

the mammalian cerebellum and have im-

portant implications for the functional

properties of the cerebellar circuit.

PUBLICATIONS

Th e results of this project have not yet been published.

SARAH RIEUBLAND

Discipline: Neuroscientist, MSc

Institute: University College

London, London, UK

Supervisor: Prof. Michael

Häusser

STRUCTURED CONNECTIVITY IN INHIBITORY CEREBELLAR CIRCUITS


Th e cytomatrix at the active zone (CAZ)

regulates the release of synaptic vesicles

(SVs) from neuronal pre-synapses. In my

PhD project, I investigated the structure,

function and axonal transport of evolution-

arily conserved CAZ proteins in Drosophila

melanogaster. I discovered a role for RIM-

binding protein (RBP) as a CAZ compo-

nent that is essential for SV release. Using

super-resolution microscopy, I found that

RBP surrounds and clusters Ca2+ channels

in the pre-synaptic membrane, which are

responsible for triggering SV release. More-

over, I used isoform-specifi c mutants and

fl uorescently tagged constructs of the CAZ

protein Bruchpilot to show that proper

CAZ formation requires an alternating pat-

tern of its 2 major isoforms. Th is organiza-

tion also regulates the number of readily re-

leasable SVs. Further investigation of the

axonal transport of Bruchpilot and RBP

uncovered a link to a transport adaptor. My

work has revealed new components and or-

ganization principles of the CAZ that are

essential for regulating SV release and

neur onal function.

PUBLICATIONS

Matkovic T, Siebert M, Knoche E, Depner D, Mertel S,

Owald D et al (2013) Th e Bruchpilot cytomatrix regulates

the readily-releasable pool of synaptic vesicles. J Cell Biol

202: 667–683

Liu KS, Siebert M, Mertel S, Knoche E, Wegener S,

Wichmann C et al (2011) RIM-binding protein, a central

part of the active zone, is essential for neurotransmitter re-

lease. Science 334: 1565–1569

MATTHIAS SIEBERT

Discipline: Molecular

Neuroscientist, MSc

Institute: NeuroCure Cluster of

Excellence,Free University

of Berlin, Berlin, Germany

Supervisor: Prof. Stephan Sigrist

STRUCTURE, FUNCTION AND TRANS-PORT OF THE CYTOMATRIX AT THE ACTIVE ZONE IN DROSOPHILA


56


Th e back-belly dorsal-ventral (DV) axis of

Drosophila is set up in the egg when the oo-

cyte nucleus migrates from the posterior of

the cell to a point at its anterior margin. For

the past decade, it had been assumed that

dynein pulls the nucleus to the anterior

along the polarized microtubule cytoskel-

eton that defi nes the head-to-tail anterior-

posterior (AP) axis, making DV dependent

on AP. However, by imaging nuclear migra-

tion in living oocytes, I have shown that dy-

nein is required to anchor the nucleus aft er

migration, but not for migration itself. Th e

nucleus is instead pushed across the oocyte

by centrosomal microtubules that grow

against its posterior side, leading to the for-

mation of a large posterior indentation. In-

hibition of microtubule growth by drugs or

laser ablation of the centrosomes abolish

the nuclear indentation and migration. I

also performed biophysical calculations to

show that microtubule polymerization can

provide suffi cient force to move the nucleus

through the viscous cytoplasm, confi rming

the feasibility of the pushing model. My re-

sults therefore reveal that, contrary to the

conventional view, the AP and DV axes are

established independently. Th ey also de-

scribe a novel mechanism for nuclear mi-

gration, which may provide a model for

understanding how subcellular organelles

are moved in other contexts.

PUBLICATIONS

Zhao T, Graham OS, Raposo A, St Johnston D (2012)

Growing microtubules push the oocyte nucleus to polarize

the Drosophila dorsal-ventral axis. Science 366: 999–1003

TONGTONG ZHAO

Discipline: Developmental Biologist, BSc

Institute: The Gurdon Institute,

University of Cambridge,

Cambridge, UK

Supervisor: Prof. Daniel St Johnston

MECHANISMS OF OOCYTE POLAR-IZATION AND AXIS FORMATION IN DROSOPHILA


Centrioles are cellular structures that act as

assembly platforms for centrosomes and

cilia. Th eir single duplication per cell cycle

is regulated by polo-like kinase 4 (Plk4),

and dysregulation can lead to cancer. In

nematodes, recruitment of Plk4 to the cen-

triole requires Spd-2. To understand how

this process works in mammals, I studied

the homologous human protein Cep192. I

showed that Cep192 depletion reduces but

does not completely remove centriolar

Plk4. Using a small-scale screen, I discov-

ered that Cep192 and another centrosomal

protein, Cep152, interact with Plk4. Double

depletion of Cep192 and Cep152 complete-

ly abolished both Plk4 binding to centrioles

and centriole duplication. My work re-

vealed that the Plk4-binding regions of

Cep152 and Cep192 are rich in negatively

charged residues, which may mediate elec-

trostatic interactions with positive residues

in the binding region of the kinase. Co-

operation between Cep192 and Cep152 is

therefore crucial for Plk4 recruitment and

centriole duplication. My results shed light

on how Plk4 is guided to centrioles to allow

correct cell function.

PUBLICATIONS

Sonnen KF, Gabryjonczyk AM, Anselm E, Stierhof YD,

Nigg EA (2013) Human Cep192 and Cep152 cooperate in

Plk4 recruitment and centriole duplication. J Cell Sci 126:

3223–3233

Sonnen KF, Schermelleh L, Leonhardt H, Nigg EA (2012)

3D-structured illumination microscopy provides novel in-

sight into architecture of human centrosomes. Biol Open 1:

965–976

KATHARINA SONNEN


Institute: Biocenter,

University of Basel,

Basel, Switzerland

Supervisor: Prof. Erich A. Nigg

HUMAN CEP192 AND CEP152 CO-OPERATE IN PLK4 RECRUITMENT AND CENTRIOLE DUPLICATION


For transcription to proceed, RNA polymer-

ase must bind to DNA. Th e accessibility of

DNA can change depending on chromatin

modifi cations. Th e regulation of this step,

and of gene expression in general, is typically

analysed by measuring changes to mRNA

levels in the cell. Th e aim of my PhD project

was to study the relative contribution of

transcriptional and post-transcriptional

regu lation to steady-state levels of mRNA. I

used genome-wide data from mouse embry-

onic stem cells on histone modifi cations and

the extent of RNA polymerase II binding. By

computationally modelling initial transcrip-

tion, I showed that these 2 chromatin-based

properties explain 84% of the observed vari-

ance in mRNA levels. Th en I studied the

eff ect of post-transcriptional regulation by

measuring RNA half-life and predicting the

impact of microRNAs, which bind to mRNA

and lead to RNA degradation. Decay pro-

cesses explain only 1% more – the 85th per-

centile – of the variance in mRNA levels,

suggesting that post-transcriptional regula-

tion has a minor impact. My work is among

the fi rst to show a quantitative analysis of the

regulation of gene expression on a genome-

wide scale and contributes to our under-

standing of the balance between transcrip-

tional and post-transcriptional processes.

PUBLICATIONS

Tippmann SC, Ivanek R, Gaidatzis D, Schöler A, Hoerner

L, Van Nimwegen E et al (2012) Chromatin measurements

reveal contributions of synthesis and decay to steady-state

mRNA levels. Mol Syst Biol 8: 593

SYLVIA TIPPMANN

Discipline: Bioinformatician, BSc

Institute: Friedrich Miescher In-

stitute for Biomedical Research

(FMI), Basel, Switzerland

Supervisor: Prof. Dirk Schübeler

REGULATION OF GENE EXPRESSION: A QUANTITATIVE ASSESSMENT


BOEHRINGER INGELHEIM FONDS FUTURA 28 | 2.2013F O U N D A T I O N

57

SCIENCE, NETWORKING AND FUN On 16 March, BIF celebrated its 30th anniversary in Mainz 58

CREATING FREEDOM An interview with BIF’s managing director 60

A BIF GUIDE TO ... MAINZ The BIF team presents its new home on the shores of the River Rhine 63

BIF NUMBERS AND GRAPHICS Where do BIF fellows come from? Where do they work? 64

WHO’S WHO AT BIF? A portrait of the BIF team 66

A STIMULATING WEEKEND The annual alumni meeting at Gracht castle was coloured by BIF’s 30th anniversary 68

A TRUE BIF SUCCESS STORY Breakthrough paper by BIF fellows: Maria Hondele’s paper on the histone chaperone

FACT was recently published in Nature 70

NEW TEAM MEMBER Kirsten Achenbach is now in charge of all press and public relations activities at BIF 71

THREE BIF ALUMNI AMONG NEW EMBO MEMBERS BIF alumni Anne Eichmann, Herwig Baier and Michael Boutros elected 71

PROFILES What are they doing now? In this issue: Prof. Michael Rape 71

UPCOMING EVENTS BIF Christmas party, 109th International Titisee Conference, meeting of BIF’s Board of

Trustees in Mainz, Germany 71

THE FOUNDATION The

Boehringer Ingelheim Fonds

(BIF) is a public foundation –

an independent, non-profit

institution for the exclusive

and direct promotion of basic

research in biomedicine. The

foundation pays particular

attention to fostering jun-

ior scientists. From the start

it has provided its fellow-

ship holders with more than

just monthly bank transfers:

seminars, events and per-

sonal support have nurtured

the development of a world-

wide network of current and

former fellows.


58

F O U N D A T I O NFUTURA 28 | 2.2013

Pho

tos:

cxc

xcxc

xccx

cx

By Kirsten Achenbach

1

2

3

9

16

12

6

SCIENCE, NETWORKING AND FUN 4

15

Thirty years of BIF called for a celebration – and

BIF being BIF it was a fine mix of high-profile sci-

entific talks, the chance to make and renew con-

tacts, as well as good food and entertainment.

11

14

13

710

59


On 16 March, BIF celebrated its 30th

anniversary with a scientifi c sympo-

sium and gala dinner in the country inn

‘Laubenheimer Höhe’ near Mainz. Th e

talks covered vascular development, pain

and temperature perception, chromatin

modifi cations and DNA damage as

well as Alzheimer’s disease, malaria

and a student talk on nuclear pore

transport proteins. Th e speakers

hailed from as far away as Paris,

France and Texas, USA. During the

coff ee breaks current BIF fellows pre-

sented their posters. Th e gala dinner

in the evening included short talks

by Prof. Andreas Barner, chairman

of the executive committee of BIF,

and Hubertus von Baumbach,

chairman of the board of the found-

ing family. Th e food was superb –

as food at BIF usually is – and

the entertainment scientifi c: Th e

‘Physikanten’ blew giant smoke

rings through the hall, unleashed

a two-metre high fi re tornado and

crushed metal barrels with a watering

can. But Prof. Herbert

Jäckle, former board

member and vice

president of the Max

Planck Society, gar-

nered the most ap-

plause. With his sharp

eye and insider know-

ledge he set the audience

laughing with a zoologist’s

description of the four

different BIF sub-

species: fellows, alumni,

board members, and

administrators.

An abridged version

of Prof. Jäckle’s talk

can be found on the

BIF website under

news > fellows >

photo gallery (Ger-

man only, sorry).

1 Celebrating 30 years of BIF called for a

bottle of wine or two.

2 Carmelina Petrungaro and Sebastian

Virreira Winter, two current BIF fellows.

3 Prof. Herbert Jäckle describing the dif-

ferent BIF subspecies.

4 The evening saw a more festive mood

with a seated dinner and more formal attire.

5 The show by the ‘Physikanten’ presented

science in a most entertaining way.

6 Several guests literally formed a con-

nection, playing music by conducting elec-

tricity through their joined hands.

7 Jenny Pestel was one of the 20 current

BIF fellows who presented a poster during

the symposium.

8 Sigrid Milles (right) gave the student talk

on nuclear pore proteins, here with Kirsten

Achenbach, the new communications offi -

cer at BIF.

9 Prof. Benjamin U. Kaupp, member of

BIF’s Board of Trustees, and Dr Claudia

Walther thanked all speakers and guests.

10 Prof. Andreas Ladurner and Dr Silke

Thomas

11 Even senior scientists need to concen-

trate before giving a presentation: Prof.

Joachim Hertz from Texas seeking a quiet

corner before his talk.

12 Prof. Anne Eichmann from Yale gave a

talk on vascular development.

13 The Forseti Quartet

14 Prof. Andreas Barner, chairman of the

Executive Committee of BIF.

15 At the time a doctor, now a professor,

Jan Siemes talked about pain and tempera-

ture perception.

16 Prof. Ivan Dikic, one of BIF’s post-doc-

toral research awardees and recent Leibniz

Prize recipient.

F O U N D A T I O N FUTURA 28 | 2.2013

5

15

16

12

8

Pho

tos:

Erik

Sch

rader;

Jan-M

ichael Pete

rs (no

. 5)

BOEHRINGER INGELHEIM FONDSFUTURA 28 | 2.2013 F O U N D A T I O N

60

You award fellowships to gifted researchers

and meet with renowned scientists twice a

year at the famous conference by Lake Titi-

see. Aren’t programmes of this type outdat-

ed in an age teeming with fellowships and

conferences?

Not at all. It is true that the number of fund-

ing programmes and conferences has in-

creased. That said, there are still too few

genuine research scholarships that offer

young scientists a chance to pursue their

own ideas independently. Another point is

that although science is international, many

funding bodies have a distinctly national

slant. The UK primarily supports British

citizens, the USA primarily American citi-

zens. We, by contrast, also promote, for ex-

ample, the outstanding Iran ian who has

studied in the USA but wants to conduct re-

search in the UK.

How has the number of these international

applicants grown in recent years?

The proportion of non-German citizens

amongst our applicants has been rising for

many years. At present, about 50 percent of

our fellows do not hold a German passport,

and some 60 percent work abroad. There

has been a marked increase in applicants

from overseas, especially China and India,

but they are still faring below average in the

selection process.

Exactly what kind of support do the chosen

few receive?

Those candidates who pass the strict selec-

tion procedure are given an all-round sup-

port package in addition to the monthly

stipend: our international network, sem-

inars and personal support. Our experi-

ence shows that especially talented junior

researchers want more than just a cheque.

CREATING FREEDOM

For 30 years, the Boehringer Ingelheim Fonds has been helping scientists to undertake research in the

fields they find most exciting. Here is a summary of talent promotion on the frontiers of disciplines.

INTERVIEW WITH BIF’S MANAGING DIRECTOR DR CLAUDIA WALTHER BY VOLKER STOLLORZ

FUTURA 28 | 2.2013BOEHRINGER INGELHEIM FONDS F O U N D A T I O N

61

Pho

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Cars

ten C

ost

ard

We are there for our fellows when prob-

lems arise, and at our regular seminars the

fellows can exchange views, give moral and

scientific support to each other and learn –

all in a pleasant atmosphere. At the first

seminar, they get to know each other and

take away inspiration. At the second sem-

inar, trust and confidence build and the fel-

lows are even more enthusiastic and may

even start collaborations. These meetings

usually last about a week. The seminars are

a gift of time to the fellows. We aim to

create an atmosphere in which trust devel-

ops, exchange becomes more lively and rel-

evant and critical issues may also be dis-

cussed. And sometimes lifelong friend-

ships form.

In the heated race to publish the findings of

the latest experiment, investing a week’s

time may be difficult.

Yes, this pressure has increased greatly.

We now hear this comment more fre-

quently the first time we invite our fel-

lows. When they leave, however, it’s no

longer an issue. The participants have

seen how they personally benefit from the

network and how much they can learn on

every level.

How do you gauge the success of your

fellows?

Thanks to our personal support, nine out of

ten alumni maintain contact with us. This is

probably unique in the world. We thus

know what has become of the young people

we promote. So far, over 98 percent of them

have completed their doctorates. Looking

only at the last decade, that number was

over 99.3 percent. We also had an academic

evaluation by social scientists from ETH

Zurich. We wanted to know if our selection

is fair and reliable and whether we really

pick the most talented minds. The study

confirmed this. It also gauged the success of

our fellows in terms of their scientific pub-

lications: their work is published in leading

journals such as the Proceedings of the Na-

tional Academy of Sciences, Journal of Bio-

logical Chemistry, EMBO Journal, Nature,

Development, Cell and Science. In addition,

on average their publications are cited far

more often than those of other authors in

the same media.

How many fellows manage to win professor-

ships?

About 60 percent of the people we promote

remain in academia, a relatively high per-

centage. Of the 1,200 or so alumni who have

passed through our programme, over 165

have become professors and just under an

additional 90 have become group leaders.

But a professorship does not necessarily

make for a top researcher. A key indicator of

success is how many ‘rising stars’ a funding

programme can identify. Can you give an ex-

ample of these genuine ‘highlights’?

Certainly. I could mention Konrad

Hochedlinger, whom we supported during

his doctoral thesis in Rudolf Jaenisch’s lab

at the Whitehead Institute in the USA.

Today, he is one of the world’s leading

stem cell researchers. Then there’s Chris-

tian Haass, the well-known Alzheimer’s re-

searcher from Munich, and Detlef Weigel

from Tübingen, who today is working with

plants. I could continue this list for some

time. We now have five recipients of the

Gottfried Wilhelm Leibniz Prize in our

ranks: new this year is Ivan Dikic, who is

currently working at Frankfurt University.

You’re still waiting for the first Nobel

laureate.

Yes, but when Venkatraman Ramakrishnan

was awarded the Nobel Prize in Chemistry


62

for his work on unravelling the structures

of ribosomes in 2009, two publications by

BIF fellow James Ogle as first author were

mentioned by the Nobel Committee in

their explanation for awarding the prize.1)

What feedback do you receive from your

fellows, apart from their gratitude, that is?

The fellowship holders most value sharing

ideas with kindred spirits, with inquisitive-

minded young people who want to get

ahead and who motivate one another, and

who are passionate about science and their

individual topics. I think being surrounded

by many other talented people is seen as

hugely enriching by our fellows.

Are genuine cooperative research projects

born that otherwise wouldn’t exist?

Yes, this is due to the style of our seminars,

at which researchers from different subdis-

ciplines come together. We see this particu-

larly at the summer seminars. To put it sim-

ply, they meet, discuss and back home at

the lab win over their supervisors and get

going with their collaboration right away. A

few years later and the publication lies on

our table here in Mainz. At the moment, we

are delighted to see a paper in Nature writ-

ten by three BIF fellows: two doctoral stu-

dents whose cooperation started at the

summer seminar in Hirschegg, and the su-

pervisor of one of the students, who is also

an alumnus of the foundation (see page 70).

Let’s talk about the key committee at BIF, the

Board of Trustees. Their core task is to select

the fellows. To whom do you entrust this

function?

BIF supports basic research in biomedicine.

On the Board of Trustees, therefore, we

have to cover as many disciplines as possi-

ble and take account of changes in various

fields. We need a good mixture of institu-

tions, i.e. researchers from Max Planck In-1) http://www.nobelprize.org/nobel_prizes/chemistry/

laureates/2009/ advanced-chemistryprize2009.pdf

stitutes as well as from universities, and be-

cause we work internationally, from top in-

stitutions abroad, too.

That sounds like trying to square the circle.

Yes, especially since scientific excellence,

the key criterion, also applies to the trus-

tees themselves. For 30 years, our doctoral

programme has promoted excellence: we

seek out the top 5 percent of candidates

with the most exciting projects in the best

laborator ies. The Board of Trustees must

be accordingly structured to do justice to

these three criteria. The trustees must also

have a reputation for fairness and integrity

in their own scientific communities. For

example, in the event of doubt they must

have the impartiality to say ‘I don’t agree

with this hypothesis at all, but it is formu-

lated in a sound and valid way, the experi-

ments have been developed accordingly, so

we will promote the candidate and his or

her project.’

How do you identify talent in disciplines that

lie within fields beyond the expertise of your

trustees? Let’s say, for example, computation-

al biology, where mathematicians and com-

puter scientists can form a better judgement

than cell biologists.

It’s clear that seven trustees cannot cover

the entire biomedical research field and

every development within it. That’s why we

have project proposals additionally ap-

praised by an external evaluator.

In modern research, there is the increasing di-

lemma that genuine breakthroughs occur in

the no man’s land between the established

disciplines. How do you prevent disciplinary

limitations?

The disciplines do not just convene in our

doctoral programme but also at the Inter-

national Titisee Conferences. We want to

create the freedom talented minds need in-

stead of having them follow programmes

devised by us.

I always thought that was the role of spon-

sors. But taking great risks is often at variance

with the sponsor’s desire for recognition.

It’s a delicate balance. But at BIF we look for

talented researchers who genuinely push

frontiers and propose exciting projects.

Promoting doctoral students and excellent

basic research is a risky venture. You need

to have personalities on the Board of Trus-

tees who not only identify potential but are

also willing to take risks. We thus create a

solid basis in a double sense – with fresh

know ledge and by promoting young peo-

ple. These are two key bridges to the future.

By the way, what is your budget?

At the present time, we have an annual

budget of about five million euros.

Where do you see the future of BIF?

Basic research, basic research, basic re-

search. It is becoming ever more important

to give scientists the freedom needed to de-

velop original ideas, to do what they find

most exciting themselves. Secondly, we

want to provide young scientists with ideal

support and help them to find their place in

cutting-edge research. I think our way of

doing this is highly sustainable. Founda-

tions and the public sector must also offer

long-term programmes with time horizons

that allow basic research to flourish.


63

Pho

tos:

BIF

(1), L

and

esh

aup

tsta

dt

Main

z (2

,3,4

)

1

A BIF GUIDE TO ...

MAINZ

SPRING

SUMMER

AUTUMN

WINTER

Dip your feet in the Rhine and relax on the

beach – depending on the time of day either

on the Mainz side (morning sun) or on the

Kastel side (afternoon and evening sun). It

is the most chilled place you can be with

drinks, music and a great atmosphere. 3

Take a stroll through the wineries in thecountryside and taste the fantastic regionalwine in the ‘Straußenwirtschaften’ or sit inone of the many cafes in Mainz, drink cof-fee, meet friends, admire the old buildingsand enjoy the still warm days. 2

Unterhaus – actually a terrific place year

round for watching up-and-coming come-

dy stars.

Gutenberg Museum: Take a look at an

original Gutenberg bible.

CINEMA

Capitol and Palatin: Off the beaten track,with an old-school cinema feeling, modern technology, many different events and low prices.

Choir windows in St. Stephan’s Church:The only stained glass windows by re-nowned Russian-Jewish artist Marc Chagall.Try to book a tour with Monsignore Meyer.Roman ruins aplenty, for example, the Ro-man theatre: the largest amphitheatrenorth of the Alps held up to 10,000 people.St. Martin’s Cathedral: More than a 1,000years of city and ecclesiastic history.Mainz 05: Everybody loves the team, if notnecessarily the new stadium.

BEST SIGHTS

NIGHTLIFE

In this anniversary issue of FUTURA, the BIF team shows you its new home: Mainz. The many

vineyards, the Rhine, the carnival festivities and the BIF office are all good reasons for a visit.

Top-end: Hyatt Regency Mainz and

Favorite Parkhotel

Mid-end: Hotel Königshof

Low-end: Youth hostel or after BIF’s Christ-

mas party on the floor of the BIF office 1

WHERE TO STAY

Country: Germany

Population: About 200,000

Area: 97.75 km2

Students: About 36,000

Famous for Mainz carnival, St. Martin’s

Cathedral, Johannes Gutenberg and the

invention of printing

Websites: www.mainz.de

FACTS & FIGURES

Contributors wanted! If you would like

to introduce your city to the readers of

FUTURA, send an e-mail to

[email protected].

Fastnacht in Mainz 4 is a ‘must’. Do not

wear your best tie on ‘Weiberfastnacht’,

though – it will be cut off!

Heiliggeist: Medieval alms house withhigh vaulted ceilings turned restaurant,bar and beer garden – a unique atmo-sphere with bird song where you least expect it.

Schon Schön: Mostly students, differentmusic styles, central location.Red Cat: Drinking, dancing, lounging inthis bar is an unforgettable experience. Allmusic styles are represented, Thursdaysfree entry, student flair.Rockkeller Alexander the Great: Forthose who like it hard and dark.Eisgrub: Quaint atmosphere, top-qualityself-brewed beer, but the food quality isvariable.

KUZ: Music, partying, dancing, open-aircinema, theatre, exhibitions, concerts,family fun – you name it, they’ve got it.

2

4

3


Gra

phic

s: K

atr

in K

reft

When BIF started out in 1983, the first four fellows were selected from just seven applicants, all

of them German. This has long since changed. In 2013, BIF has received more than 700 applica-

tions for its PhD programme. About 50 of them will be approved – a success rate of only about 7

percent. Today, almost 60 percent of our current fellows are working outside Germany, with the

three leading destinations being the USA, Switzerland and the UK.

BIF NUMBERS AND GRAPHICS...

Fin

lan

d

Portugal

Greece

Turkey

Estonia

Lithuania

Poland Slovakia

HungarySlovenia Romania

Bulgaria

Former Yugoslavia

Serbia

Cro

atia

Ru

ssia

Ukrain

e

Israel

Switzerla

nd

France

Italy

Spain Ir

elan

d G

reat

Brit

ain

Germ

any

No

rway

De

nm

ark

Net

her

lan

ds

Bel

giu

m

Austria

So

uth

Ko

rea

Ho

ng

Ko

ng

Tai

wan

New

Zea

land

Can

ada

USA

Colom

bia B

razil Chile

Argentina

Tunisia

Egypt

South Africa

Pa

kis

tan

Ind

ia

Ch

ina

EURO

PE

AF

RIC

A

AM

ERICA

ASIA/AUSTRALIA

BIF FELLOWSBY NATIONALITY

BIF is getting more and more international: by the end of 2013, about 1,260 junior scientists from nearly 50 nations had received BIF

fellowships. Th e number of non-Germans has been growing steadily. Currently, the ratio among the 120 current fellows is 50 percent

Germans to 50 percent non-Germans. At the last deadline, BIF received applications from 60 nations.

64

PROFESSORS PPPPP FFEEESSSSSSSOOOOORRRRPPRR FEEE SSOOOOORRRRPPRRR S RRRRPPRRR FE ORPRRR E SSS SSSS AMONG ALUMNIAAAMMMOONNGG AAALAMMOONNGG AM

Boston

Francisco

Berlin

Munich

Zurich

London

Paris

BerlinLondon

Melbourne

Singapore

Today, BIF counts among its alumni

165 professors, around 90 group

leaders and fi ve recipients of Ger-

many’s most prestigious science

award – the Gottfried Wilhelm

Leibniz Prize.

PHD FELLOWSEEEEFEEEFEEELFEEELFFEEELLFFEEELLL CURRENT, BY INSTITUTE

Boston

Berlin

London

Barcelona

Vienna

Berlin

Munich

Zurich

London

Paris

BOEHRINGER INGELHEIM FONDS F O U N D A T I O N FUTURA 28 | 2.2013

Th e distribution of the current fellows also refl ects where leading la-

boratories in the life sciences are located. Th is is to be expected, since

one of our three selection criteria is the quality of the laboratory in

which the fellow wishes to work.

65


66

FUTURA 28 | 2.2013

1 Dr Claudia Walther is the managing

director of the Boehringer Ingelheim

Fonds (BIF). Her work includes strategic

planning, budgeting and fi nances, per-

sonnel, management and development of

funding programmes and representation

of the foundation. She communicates

BIF’s activities to its Board of Trustees,

the founding family and other stakehold-

ers. On top of that, she is involved in the

selection process of new BIF fellows, in-

terviewing a third of the candidates. In

an honorary capacity, Claudia also serves

as managing director of BIF’s two inde-

pendent sister foundations: the Boehring-

er Ingelheim Foundation (BIS) and the

Siblings Boehringer Foundation for the

Humanities, the smallest of the three

foundations.

2 Dr Carsten Lambert heads the selection

process for PhD fellowships, BIF’s largest

programme. His work involves scrutiniz-

ing all applications, identifying the right

external peer reviewers, organizing peer-

review and evaluation processes, and

communicating with applicants. He trav-

els a lot since he interviews most of the

candidates personally. Carsten is also re-

sponsible for the travel grant programme

for non-BIF fellows and runs its selection

process.

3 Vera Schlick takes care of all incoming

applications for PhD and MD fellowships as

well as for travel grants. In this capacity, Vera

answers the plethora of questions from

young scientists from all over the world. She

checks the formal criteria of the applications

and transfers the data ino the database. She

supports the peer-review process and also

informs applicants of BIF’s decisions. Vera

organizes all the board meetings and the in-

terviews for PhD candidates, including

travel arrangements for the BIF team, and

prepares statistics for internal use.

4 Sandra Schedler and 5 Dr Anja

Hoffmann Working as a well-honed team,

WHO’S WHO AT BIF?

In this anniversary issue we’re taking the opportu-

nity to introduce all the members of the BIF team

and describe their areas of responsibility.

F O U N D A T I O N

1

2

5

6

3

4

FUTURA 28 | 2.2013

67

Pho

tos:

Cars

ten C

ost

ard

, A

ng

elik

a S

tehle

Anja and Sandra provide the person-

al support to fellows and alumni that is

one of the hallmarks of BIF. Sandra works

part-time and is more involved in the ad-

ministrative and organizational processes.

For example, she organ izes nearly all of

BIF’s seminars and takes care of the fellows’

applications for travel allowances and fel-

lowship extensions. Sandra also manages

the Klatschmail mailing list and Where-to-

Find-Whom – the networking portals of

BIF. Anja, on the other hand, travels more

and attends most sem inars, mentoring the

fellows on site. In addition, she heads BIF’s

most recent programme, the MD fellow-

ships, including promotion of the pro-

gramme, the entire selection process and

supporting the selected fellows in the usual

BIF style. She not only evalu ates applica-

tions for BIF’s travel grant programme, but

is also responsible for running the Heinrich

Wieland Prize programme for the BIS.

6 Kirsten Achenbach is in charge of all

press and public relations activities at BIF

as well as the communication seminars for

BIF fellows. Th is includes BIF’s interna-

tional journal FUTURA, the websites, bro-

chures and fl yers, the programmes for

alumni seminars, training and honing fel-

lows’ writing and presenta-

tion skills, as well as all the

press relations, e.g. for the International

Titisee Conferences. Kirsten is also re-

sponsible for the communications for BIS

and the Siblings Boehringer Foundation for

the Humanities.

7 Iris Bodenbender is BIF’s offi ce man-

ager as well as Claudia Walther’s assistant

and responsible for IT. She organizes two

International Titisee Conferences per year

as a ‘full-service’ package for the scientifi c

chairs of the conferences, including the

programme and travel arrangements. For

the BIS, Iris also manages its accounts and

administers its scientifi c meeting pro-

gramme.

8 Beate Kant is responsible for account-

ing and administrative tasks at BIF. She

ensures, for example, that fellows and

travel grant holders all over the world re-

ceive their stipends and grants securely

and on time. She also works for the Sib-

lings Boehringer Ingelheim Foundation

for the Humanities, taking care of the ap-

plications for grants for publication costs.

Th is involves answering a multitude of

questions from applicants, ensuring that

applicants’ documentation is complete, or-

ganizing all the correspondence and main-

taining the database.

9 Genia Rosellen-Meckel, also part-time,

works for BIS. She administers the Explora-

tion Grants, the PLUS 3 programme, as well

as the Heinrich Wieland Prize and the

Boehringer Ingelheim Prize. She prepares

the statistics and also organizes the scien-

tifi c advisory board meetings.

10 Süleyman Tangüler keeps the offi ce run-

ning. Süleyman works part-time and is in

charge of the main tenance of all equipment,

technical and otherwise, and provides tech-

nical support for all seminars and confer-

ences. He assists in secretarial matters as

well, in particular at the deadlines for appli-

cations, and organ izes documents for the

archive. He is also BIF’s safety offi cer.

BIF relocated in September 2012:

Boehringer Ingelheim Fonds

Schusterstr. 46-48

55116 Mainz, Germany

Tel. +49 (0)6131 27 50 8-0

Fax: +49 (0)6131 2750 8-11

[email protected]

www.bifonds.de

F O U N D A T I O N

7

10

9


8

Pho

tos:

Ays

e T

asc

i-St

ein

eb

ach

A STIMULATING WEEKENDBy Kirsten Achenbach

68

BOEHRINGER INGELHEIM FONDSF O U N D A T I O NFUTURA 28 | 2.2013

Sunny weather, a congenial setting and the usual perfect ser-

vice at Gracht Castle meant that all 110 guests enjoyed a stimu-

lating and entertaining alumni meeting. The speakers covered

RNAs, the dark matter in our genomes, neurobiology 2.0 and

systems biology, as well as methods for observing molecules

at the nano scale. Due to BIF’s 30th anniversary this year, the

programme also included improvisational theatre, a mind-bend-

ing talk on time tilting, as well as a highly amusing lecture by

Michael Gloschewski on how to improve your memory.

1

2

5

6

7

8

3

4

1

2

69

FUTURA 28 | 2.2013F O U N D A T I O NBOEHRINGER INGELHEIM FONDS

1 Christine Selhuber-Unkel gave a detailed

talk about biophysics at the nanoscale.

2 The Forseti Quartett played at the recep-

tion on Friday.

3 The Rittersaal was fi lled to capacity.

4 Werner Große introducing “time tilting”.

5 Oliver Weidenrieder in discussion with

Stephanie Miller.

6 An actor from the ‘Gorillas’ theatre

group being brought into position by Jörg

Ruppert.

7 Stefan Isenmann and Rainer Friedrich

discussing Rainer’s overview of 30 years of

neurobiology.

8 The weather made for very relaxing

coff ee breaks on the beautiful castle

grounds.

9 The obligatory group photograph –

this time at the spot where all the wed-

ding group photos are taken.

10 Otto Boehringer is declared an hon-

orary BIF fellow by Claudia Walther

and given one of the new lapel pins with

the BIF logo.

11 Michael Boutros explaining RNA –

‘the dark matter’ in our genomes.

9

10

11


70

Pho

tos:

Mari

a H

ond

ele

(b

ott

om

); E

va K

ow

alin

ski (t

op

left

)

In July 2013 Nature published a true BIF

paper in which four current BIF fellows

and one BIF alumnus participated: fi rst au-

thor Maria Hondele, Ludwig Maximilian

University Munich (LMU), fourth author

Felix Halbach, Max Planck Institute for Bio-

chemistry, corresponding author Andreas

Ladurner (LMU), as well as Nadja Fenn and

Martin Seizl (both LMU).

In the paper, the authors unravel the

fi rst crystal structure of a protein bound to

the histone H2A-H2B dimer. Based on their

fi ndings, they suggest a mechanism for how

DNA can be transcribed while staying

wrapped around the nucleosome. Andreas,

Maria’s group leader at the Butenandt Insti-

tute and LMU Biomedical Centre, says that

‘with this paper Maria has

managed a breakthrough

that has defi ed structural

biologists for over 15 years.’

In her PhD project, Maria took a close look at

the histone chaperone FACT. As its full name

(facilitates chromatin transcription) implies,

FACT reorganizes nucleosomes during DNA

transcription, replication and repair. Using

high-resolution X-ray crystallography, the

team analysed the structure of the FACT

chaperone domain bound to histones H2A–

H2B. It turned out that FACT binds the his-

tone dimer in a way that blocks the site of

strongest interaction between H2B and

DNA. Th ey therefore suggest that DNA is

partially displaced from the H2A–H2B dimer

during nucleosome reorganization. Th is pro-

cess opens up the nucleosome suffi ciently for

access of DNA and RNA polymerases during

replication and transcription. But in contrast

to the conventional view, ‘this mechanism

works without disassembling the histone

core or unwrapping the DNA completely

from histones, therefore helping to preserve

chromatin integrity’, explains Andreas.

Besides being exciting science and an

important milestone in the chromatin

fi eld, the paper also highlights an impor-

tant aspect of BIF’s seminars: Maria and

Felix met in 2009 during the week-long

summer sem inar in Hirschegg and stayed

in touch. ‘When my lab moved from the

EMBL in Heidelberg to Munich, Felix’s

help made everything just so much easier.

First, he helped me fi nd a place to stay,’ says

Maria. ‘But more importantly, he support-

ed me in getting access to equipment and

guided me through the computational

analysis.’ Nadja and Martin opened doors

to further important facilities. So, next

time you get an invitation to one of BIF’s

seminars, jump at the chance – who knows

what it might lead to. Aft er all, meeting

and networking with other alumni is part

of the BIF experience.

REFERENCE

Hondele, M, Stuwe T, Hassler M, Halbach F, Bowman A,

Zhang, E et al (2013) Structural basis of histone H2A–H2B

recognition by the essential chaperone FACT. Nature 499:

111–14

A TRUE BIF SUCCESS STORY

Breakthrough paper by BIF fellows: Maria Hondele and Felix Halbach are authors of a ground-

breaking Nature paper on the histone chaperone FACT.

By Kirsten Achenbach

Maria Hondele and Felix Halbach met at

one of BIF’s traditional summer seminars.

Crystal structure of the complex between

C. thermophilum Spt16M (red and bronze),

histone H2A (turquoise) and histone H2B (blue).


71

20 DECEMBER 2013

BIF Christmas party

Christmas is coming again – and with it

BIF’s Christmas party. It starts at 6pm. All

fellows and alumni are invited to come to

our new premises in downtown Mainz

and greet, meet and celebrate with us.

Come and take a look at our new office at

Schusterstrasse 46–48 with its rooftop

terrace. Food and drink will be provided,

and floor space for people wanting to stay

overnight is available.

14–15 MARCH 2014

Meeting of BIF’s Board of Trustees in

Mainz, Germany

Our foundation’s Board of Trustees con-

sists of six internationally renowned sci-

entists, the chairman of the Board of

Managing Directors at the company

Boehringer Ingelheim and – as a perma-

nent guest – a representative of the Ger-

man Research Foundation (DFG). The

trustees work in an honorary capacity.

They decide on all matters of fundamen-

tal importance, scrutinize applications

for BIF’s fellowship programmes and se-

lect topics and chairs for the Internation-

al Titisee Conferences.

9–13 APRIL 2014

109th International Titisee Conference

‘Microbiome-host mutualism in the shap-

ing of host immunity is the topic of the

109th ITC at Lake Titisee’, Germany. It is

chaired by Dan R. Littman (Skirball Insti-

tute, New York University, NY, USA),

Samuel I. Miller (University of Washing-

ton, Seattle, WA, USA), and Phillipp J.

Sansonetti (Institute Pasteur, Paris,

France). The participants will focus on

how the immune system is shaped by the

microbiome and, conversely, how indi-

vidual constituents and communities of

microbiota are influenced by host factors.

Participation is by invitation only

Need an update on upcoming events?

Check our website at www.bifonds.de!

71

UPCOMING EVENTS

NEW TEAM MEMBER

Pho

tos:

Cars

ten C

ost

ard

(b

ott

om

left

), H

HM

I (t

op

rig

ht)

THREE BIF ALUMNI ELECTED AS NEW

EMBO MEMBERS

In May 2013, EMBO announced its newly elected ‘outstanding researchers in the

life sciences’, among them three of our alumni. We congratulate Anne Eichmann

(Center for Interdisciplinary Research in Biology, France, and Yale School of Med-

icine, US, fellow from 1990 to 1992), Herwig Baier (Max Planck Institute of Neuro-

biology, Munich, Germany, fellow from 1991 to 1994) and Michael Boutros (Ger-

man Cancer Research Center DKFZ, and University of Heidelberg, Germany, fel-

low from 1997 to 1999). EMBO members are expected to give suggestions and

feedback on EMBO activities, to serve on selection committees for EMBO’s fund-

ing programmes and to mentor young scientists. According to EMBO’s director,

Maria Leptin, ‘Our members are the basis for the international reputation of our

organization.’

Science communica-

tions expert Kirsten

Achenbach is now

in charge of all press

and public relati–

ons activities at BIF.

Her responsibilities

include communi-

cation sem inars for

the fellows, the journal FUTURA, press re-

lations for the International Titisee Confer-

ences as well as the website, the programme

for the alumni meetings in Gracht, etc., etc.

Trained as a mar ine biologist and a special-

ist editor, Kirsten has a 12-year track record

in press relations and editing in English and

German. Kirsten has worked for the Max

Planck Institute for Chemistry in Mainz,

Germany, as well as for MARUM – the

Centre for Mar ine Environmental Sciences

in Bremen, Germany. ‘I am looking for-

ward to sharing my passion for science

communication with the fellows,’ says

Kirsten. ‘I am already very impressed by the

BIF fellows I met in Lautrach and Cold

Spring Harbor.’ Kirsten studied marine

biol ogy in Bremen, Germany, and College

Park, Maryland, USA. For her master’s the-

sis she investigated learning behaviour in

PROFILES

Prof. Michael Rape,

a BIF fellow from

2001 to 2002 and

now at the Univer-

sity of California,

Berkeley, USA, has

been selected as a

Howard Hughes

Medical Institute

(HHMI) investigator. The HHMI aims to

‘find the best original-thinking scientists

and give them the resources to follow their

instincts’. He was also awarded the Vilcek

Prize for Creative Promise, which is en-

dowed with 35,000 US dollars and is pre-

sented to the three most influential immi-

grants to the USA in the biomedical sci-

ences under the age of 38.

octopods. Her first engagement as a science

communicator took her to icy realms: she

worked as a lecturer on an expedition cruise

ship in the Antarctic and the Arctic. In her

spare time, Kirsten takes along her camera

when hunting for insects, plays disc golf or

goes ballroom dancing with her husband.

So, Kirsten, welcome to BIF!

Schusterstr. 46-4855116 MainzGermanyTel. +49 6131 27508-0Fax +49 6131 27508-11E-mail: [email protected] 0179-6372

Documents

FUTURA 28 | 2.2013 CONTENTS FUTURA PUBLISHING … · And as the famous German poet Bertolt Brecht once penned in Stories of Mr Keuner, a changing face need not be feared. The type