futura 28 | 2.2013 contents futura publishing … · and as the famous german poet bertolt brecht...
TRANSCRIPT
2
Published by Boehringer Ingelheim Fonds
Stiftung für medizinische Grundlagen-
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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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
Art direction Britta Siebert
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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
oto
rola
(to
p r
ight)
; p
nas.
org
(b
ott
om
left
); A
FP/G
ett
y Im
ag
es
(bo
tto
m r
ight)
Sorry, image not available
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
ysta
tio
n); s
hutt
ers
tock
/anya
ivano
va (to
p); T
ech
Surf
ace
.co
m (b
ott
om
)
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.
Sorry, image not available
due to copyright
limitations.
Sorry, image not available
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 ...
Pho
tos:
Am
eri
can A
cad
em
y o
f A
chie
vem
ent
(to
p r
ight)
; hig
hfi ve
.me.u
k (t
op
); O
pab
inia
reg
alis
(b
ott
om
left
);
Los
Ang
ele
s Tim
es
(bo
tto
m r
ight)
Sorry, image not available
due to copyright
limitations.
Sorry, image not available
due to copyright
limitations.
Sorry, image not available
due to copyright
limitations.
9
FUTURA 28 | 2.2013BOEHRINGER INGELHEIM FONDS F A C T SPho
to: O
wen S
mit
h/c
ult
ura
/Co
rbis
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
ers
tock
/sp
irit
of
am
eri
ca
In the course of the AIDS pandemic healthcare in Africa has improved.
Sorry, image not available
due to copyright
limitations.
11
FUTURA 28 | 2.2013BOEHRINGER INGELHEIM FONDS F A C T S
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
BOEHRINGER INGELHEIM FONDSF A C T SFUTURA 28 | 2.2013
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
BOEHRINGER INGELHEIM FONDSF A C T SFUTURA 28 | 2.2013
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
BOEHRINGER INGELHEIM FONDSF A C T SFUTURA 28 | 2.2013
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
FUTURA 28 | 2.2013BOEHRINGER INGELHEIM FONDS F A C T S
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
BOEHRINGER INGELHEIM FONDSF A C T SFUTURA 28 | 2.2013
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
cf. BIF FUTURA, VOL. 25 | 2.2010
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
cf. BIF FUTURA, VOL. 25 | 3.2010
52
BOEHRINGER INGELHEIM FONDSF E L L O W SFUTURA 28 | 2.2013
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
cf. BIF FUTURA, VOL. 25 | 3.2010
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
cf. BIF FUTURA, VOL. 25 | 2.2010
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
cf. BIF FUTURA, VOL. 25 | 3.2010
53
FUTURA 28 | 2.2013BOEHRINGER INGELHEIM FONDS F E L L O W S
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
cf. BIF FUTURA, VOL. 25 | 3.2010
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
cf. BIF FUTURA, VOL. 25 | 1.2010
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
cf. BIF FUTURA, VOL. 23 | 2.2008
54
BOEHRINGER INGELHEIM FONDSF E L L O W SFUTURA 28 | 2.2013
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
cf. BIF FUTURA, VOL. 25 | 1.2010
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
cf. BIF FUTURA, VOL. 25 | 1.2010
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
cf. BIF FUTURA, VOL. 23 | 1.2008
55
FUTURA 28 | 2.2013BOEHRINGER INGELHEIM FONDS F E L L O W S
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
Discipline: Biochemist, Diploma
Institute: Swiss Federal Institute
of Technology (ETH), Zurich,
Switzerland
Supervisor: Prof. Christian Wolfrum
TRANSDIFFERENTIATION OF BROWN AND WHITEADIPOCYTES
cf. BIF FUTURA, VOL. 25 | 3.2010
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
cf. BIF FUTURA, VOL. 24 | 2.2009
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
cf. BIF FUTURA, VOL. 25 | 3.2010
56
BOEHRINGER INGELHEIM FONDSF E L L O W SFUTURA 28 | 2.2013
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
cf. BIF FUTURA, VOL. 23 | 2.2008
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
Discipline: Biochemist, Diploma
Institute: Biocenter,
University of Basel,
Basel, Switzerland
Supervisor: Prof. Erich A. Nigg
HUMAN CEP192 AND CEP152 CO-OPERATE IN PLK4 RECRUITMENT AND CENTRIOLE DUPLICATION
cf. BIF FUTURA, VOL. 24 | 1.2009
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
cf. BIF FUTURA, VOL. 24 | 2.2009
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.
BOEHRINGER INGELHEIM FONDS
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
BOEHRINGER INGELHEIM FONDS
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
tos:
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
BOEHRINGER INGELHEIM FONDSFUTURA 28 | 2.2013 F O U N D A T I O N
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.
FUTURA 28 | 2.2013BOEHRINGER INGELHEIM FONDS F O U N D A T I O N
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
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
BOEHRINGER INGELHEIM FONDSFUTURA 28 | 2.2013 F O U N D A T I O N
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
BOEHRINGER INGELHEIM FONDS
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
www.bifonds.de
F O U N D A T I O N
7
10
9
BOEHRINGER INGELHEIM FONDS
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
BOEHRINGER INGELHEIM FONDSFUTURA 28 | 2.2013 F O U N D A T I O N
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).
FUTURA 28 | 2.2013BOEHRINGER INGELHEIM FONDS F O U N D A T I O N
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