A whole new arena of questions
Jennifer Lippincott-Schwartz is a tenured investigator at the National Institutes of Health in Bethesda, United States. Her research focuses on visualisation, tracking and quantification of organelle pathways and dynamics within living cells and whole organisms. In an interview with EMBOencounters she talks about her new job as President of the American Society for Cell Biology (ASCB) for 2014 and evolving topics in cell biology.
Professor Lippincott-Schwartz, how exciting is the task of guiding such a large organisation as ASCB?
It is thrilling. I have been part of the ASCB throughout my whole career, going to the annual meeting every year since I was a graduate student and participating in many of its activities, from programming planning to serving as President. I have seen ASCB grow as a society. Being at the helm of the organisation this year is very gratifying but intimidating given its size. Fortunately, I am helped by a terrific professional staff at ASCB, including Executive Director Stefano Bertuzzi.
The ASCB president is changed every year. How would you like to set yourself apart?
I see that cell biology is changing. For the first time, we have the tools to interface with physical science in a big way. This is mainly due to the improved computational capabilities for predictive modelling of data. Another factor is the advanced microscopy techniques that allow us to look at cells and tissues at higher resolution and in a dynamic fashion. These new computational and imaging techniques are revealing aspects of biology that have never been seen or described before. This is opening up a whole new arena of questions for cell biologists. Since answering many of these questions will require bridging biological concepts with physical science principles, I am trying to provide ways to better build this bridge.
One of the things that I have initiated this year is a special issue of our flagship journal Molecular Biology of the Cell, which will be devoted to papers at the interface of cell biology and physics, as well as papers that incorporate modelling and predictive aspects of modelling involving big data analysis.
In addition to bridging with the physical sciences, we also need to integrate cell biology with the translational sciences. For this, we have designed several symposia at our annual meeting that will focus on the cell biology underlying different diseases – from infectious diseases to cancer.
What does your job look like?
My job is to run the ASCB together with Stefano Bertuzzi and his excellent staff. We work on initiatives that range from improving our journals – Molecular Biology of the Cell and Life Sciences Education – to interfacing with our large number of committees, including education, international affairs, women’s issues, and public policy. The biggest job so far has been organizing the programme of the annual meeting, held this year in December (www.ascb.org/2014meeting), which I have done together with my Program Chair Wallace Marshall. ASCB will be partnering this year with the International Federation of Cell Biology. I also had to recently select biology artwork from our members to be displayed at Dulles International Airport in Washington, D.C.
How do you define the role of ASCB?
Its main role is to facilitate interactions between cell biologists and to help them position themselves for opportunities in the wider field of biomedical and biophysical sciences. The society acts as a way for cell biologists to learn about other scientist’s work and to communicate their own research. The annual meeting also hosts a huge group of vendors, who themselves play an important role in providing the technological developments for doing our science.
How much time remains to pursue your research?
I still find time to run my lab and continue research. That said, there are times when the job is full time. For example, several weeks ago we had our biannual two-day Council meeting, discussing new projects and goals of the society.
Does your position also involve political lobbying?
One day each year, the ASCB Council spends a day on Capitol Hill to talk to congressmen and senators to encourage them to support legislation and give greater financial support to the biomedical profession. I have to recuse myself for some of these activities because I am a government employee and I am not allowed to lobby. But council members and committee heads go out and meet individual senators.
Political lobbying is something that ASCB has been doing for at least fifteen years. For a good reason: it is important for the politicians to be aware of what is happening in cell biology. Most of our scientists believe that the big crisis and the budget cuts are major problems facing all of biomedical research right now in the United States, impacting our science in a very big way.
What is your current research project?
I use live cell imaging to address fundamental processes within cells including cell compartmentalization, cell motility, protein trafficking and organelle inheritance at different scales in space and time. My lab has introduced new approaches for visualizing and analyzing these processes, including the use of photoactivatable fluorescent proteins for photohighlighting and superresolution imaging of single molecules at high density. While I have spent much of my career focused on understanding secretory organelles like the Golgi apparatus and the endoplasmic reticulum (ER). More recently, I have also studied more obscure organelles, like lipid droplets, peroxisomes, primary cilia and autophagosomes, and I am now fascinated with mitochondria and their relationship to other organelles. This has caused me to begin thinking hard about cell metabolism – how it relates to the behaviour and dynamics of organelles, in particular mitochondria, and the cytoskeleton, and how this all might be studied using microscopy.
Which were the key factors that contributed to your successful career?
I like to focus on questions that are simple but take a topic to a new level or direction. I also have a philosophical penchant for studying process and relationships between things. This explains why I am so attracted to fluorescence imaging, since a whole world of dynamics and relationships is revealed every time one looks down a microscope. I was an early user of the Green Fluorescent Protein (GFP) – and helped develop some new imaging approaches using it, including confocal photobleaching, photoactivation and photoactivated localization microscopy (PALM). These new techniques help us image more dynamically and with higher resolution. Everything I am well known for came from being able to visualise at a better level.
How do you help people understand your research?
Science is about communication. All successful scientists that I know are excellent communicators. Before I went into science, I spent three years teaching at the high school level: one year in Africa, two years in California. In 2013, I co-organized the EMBO | EMBL Symposium Seeing is Believing. It was absolutely fantastic. I am also speaking in a concurrent session on Membrane organization & super resolution at the FEBS | EMBO 2014 meeting in Paris this year.
We all have different ways of thinking. When I talk about my research, I try to understand the perspective of the listener and be as simple as possible. I also try and use analogies and relate my findings to other fields and viewpoints.
Darwin in the desert
DARWIN21 – a project in Saudi Arabia to engineer plants and to secure world food production
Five years ago, a 36-square-kilometer university opened its gates in the desert sands of Saudi Arabia – the King Abdullah University of Science and Technology (KAUST). KAUST is not only a university – it is an experiment and a dream made reality by King Abdullah Bin Abdulaziz Al Saud, who aims to stem the exodus of young, talented students from the kingdom and promote Saudi Arabia as a business hub. The 12.5 billion US dollar campus at the Red Sea coast close to Jeddah was completed within two years. Thanks to a generous donation, the university can afford competitive salaries, grants, state-of-the-art equipment and ambitious research projects.
One of these is DARWIN21 – a project shaped by EMBO Member Heribert Hirt. At the end of last year, he decided to move from France to Saudi Arabia to give his research a head start and fulfil a long-standing wish. “KAUST promised to get my idea rolling and get the community on board.” The scale of his undertaking shows parallels to the great voyage of Charles Darwin in the nineteenth century only DARWIN21 explores life in deserts. The aim of the project is to visit arid regions to collect and analyse rhizosphere microbes. Why in deserts? Because deserts exhibit the harshest conditions of drought, salt and heat that plants are exposed to. Here, selection has shaped the interactions between plants and microbes for thousands of years.
Previous studies have shown that the ability of a variety of plants to adapt to stress conditions appears to depend on the association with rhisophere microbes. But can all plants improve stress tolerance when associated with their appropriate rhizosphere microbial partners? To answer this question, the Austrian scientist and his team launched a worldwide network of desert researchers and plan to build the world’s first heritage stock centre for desert microbes. The next step is to create a molecular database on rhisophere microbial genomes and their gene functions using the latest genomic analysis methods.
Hirt’s research results could be of major importance to agriculture as they provide a basis for the engineering of plants that produce higher yields or are more resistant to drought. If all goes well, the scientists could eventually help replant arid areas and thereby secure future world food production.
His laboratory has already set up collaborations with groups in Jordan, the United Arab Emirates, Pakistan, Namibia and Argentina. From several expeditions to Saudi Arabia and Jordan, the scientists have gathered a collection of more than 700 endophyte strains. They started screening those on Arabidopsis and found several that help these plants to survive under stress conditions. Daniele Daffonchio, a new microbiology professor at KAUST, explores the properties of these microbes. Specialists from the Center for Bioinformatics at KAUST produce publicly accessible databases. Additional field trials with some microbial strains that passed the test with Arabidopsis are planned for autumn 2014 with wheat and barley.
“KAUST is an exceptional place to work,” concludes the 58-year-old after his first six months at the new institute. “It reminds me of a monastery where about 120 top researchers are concentrated with their teams in a small village of about four thousand people.” For Hirt, what counts even more is the intensive interaction between researchers, ample funding and the most modern technology that allows realization of projects that are impossible to do elsewhere.
INFO: International conference on “Root desert rhizosphere microbes for sustainable agriculture” will be held at KAUST from 3-5 November 2014.
Science meets policy and politics
Highlights from the EMBO | EMBL Anniversary Science and Policy Meeting
2014 marks the 50th anniversary of EMBO, the 45th anniversary of the European Molecular Biology Conference (EMBC), the organization of member states who fund EMBO, and the 40th anniversary of the European Molecular Biology Laboratory (EMBL). EMBO, EMBC, and EMBL recently combined their efforts to put together a joint event at the EMBL Advanced Training Centre in Heidelberg, Germany, on 2 and 3 July 2014. The anniversary celebration recognized the science that has contributed to the success of the organizations over the years and acknowledged the roles of EMBO, EMBC, and EMBL in policy, politics, and society.
The meeting featured the participation of European ministerial representatives, scientific talks from researchers, and presentations on policy issues focused on excellence and inclusion. It was also an opportunity to bring togethercurrent and former directors of EMBO and EMBL as well as former committee and council members who shaped the direction of both organizations over the last decades.
Maria Leptin, Director of EMBO, and Iain Mattaj, Director General of EMBL, opened the meeting and welcomed more than 250 scientists, politicians, policy makers, supporters of science, and friends of EMBO from across the world. In their presentations, they summarized the past, present and future roles of each organization. “EMBO’s achievements have been possible due to cross-country cooperation,” said Leptin. “The foundation of EMBC in 1969 had a dual aim: To secure a source of funds for the activities of EMBO and to provide a framework to establish the European Molecular Biology Laboratory. It is a remarkable testament that both goals have been achieved.”
Georg Schütte, State Secretary of the German Federal Ministry of Education and Research, emphasized how EMBO and EMBL have been trendsetters in the life sciences. “Many former EMBL researchers are now directors of internationally renowned research institutions in Europe and have dispersed this philosophy of EMBL and EMBO across Europe,” said Schütte. He also discussed the crucial early roles EMBO and EMBL played in helping molecular biology become a major, if not one of the most important, forces in influencing the life sciences over the last several decades.
The importance of the scientific workforce as a whole and the individual scientists contributing to research was discussed in several contexts. “EMBO and EMBL have shown that when Europe combines its forces by bringing together its best talents, it can lead the world in science and innovation,” remarked Robert-Jan Smits, Director-General, Research & Innovation, for the European Commission. The development and implementation of key infrastructures and the provision of training have been important contributions to the European life science community.
The ability to bring highly trained individuals together, either within a physical infrastructure like EMBL, or in transnational research projects, will be a key contributor to advancing science and research in Europe over the next several decades.
In a scientific talk, Elizabeth Murchison of the University of Cambridge described her groundbreaking work to investigate two types of transmissible cancer: the Tasmanian devil facial tumour disease and the canine transmissible venereal tumour. After a ceremony to unveil the ScienceTree (see box), an oak tree planted in soil obtained from countries throughout the European Union to symbolize the importance of European integration, representatives from the governments of France, Luxembourg, Malta, Spain and Switzerland took part in a panel discussion moderated by Marja Makarow, Vice President for Research of the Academy of Finland. Mauro Dell'Ambrogio, State Secretary for Education, Research and Innovation in Switzerland, stressed that science policy, to be effective, must not only invest in knowledge but also in people. Carmen Vela, Spain’s Secretary of State for Research, Development and Innovation, outlined how participation in EMBL had been essential for the development of science in her country. Evarist Bartolo, the Minister of Education and Employment of Malta, outlined the state of life science research in his country. Malta’s application to become a member of both EMBL and the European Molecular Biology Conference was endorsed in the same week as the anniversary meeting, an excellent illustration of the roles of EMBO, EMBC, and EMBL in contributing to the cohesiveness of European research.
The second day of the meeting focused on concerns about excellence and inclusion in scientific research. Bruno Strasser, a science historian at the University of Geneva, opened by recounting the origins of EMBO and the European Molecular Biology Conference. “The history of the European Molecular Biology Conference illustrates how molecular biologists succeeded in bringing their discipline to national and international political agendas and gained broad intergovernmental backing.” The journey was not straightforward and many of the barriers appear familiar for transnational cooperation projects. The scientists active in the early years of EMBO and the EMBC learned quickly and were remarkably astute in ascertaining what was needed in the context of science policy. The foundation of the EMBC was an essential step for the sustainable funding of the activities of EMBO, and of the laboratory that was established in 1974.
Marc Heppener of the European Space Agency explained how the ESA works as a platform for the inclusion of nations with emerging interests in space science and space exploration. He described some of the many successful projects that have been concluded or are in progress.
The meeting concluded with a talk and discussion specifically on the relationship between excellence and inclusion by Helga Nowotny, ERA Council Forum, Austria. The promotion of excellence is essential and well established in the European scientific landscape but challenges exist in ensuring that everyone benefits. “We are all striving to support and promote excellence in the life sciences but we have to be acutely aware that it must be inclusive and take into consideration diversity,” said Nowotny. This precise concern, how to recognize and reward excellence while promoting the development of new entrants to research, is exactly the intersection where EMBO, EMBC, and EMBL will continue to work in the years ahead.
Michael N. Hall, Professor of Biochemistry at the Biozentrum of the University of Basel, is one of the winners of the 2014 Breakthrough Prize in Life Sciences. He received the prize for his discovery of the protein kinase target of rapamycin (TOR) and its role in cell growth control. In the same week in December, Hall’s laboratory was announced as a co-recipient of an 11.2 million Euros Synergy Grant from the European Research Council (ERC). In an interview with EMBOencounters, Hall recalls the award ceremony in California and the highlights of 2013.
What were the factors that made 2013 such a success?
The support from the ERC came after several years of applying to different agencies. We submitted the project a number of times before finally succeeding. We learned from our failures. For example, initially we underestimated the importance of pathology. By the time the successful application rolled around, we had proof of concept. It also took time to recruit patients with hepatocellular carcinoma for the study. With regard to the prize, I suppose the story had matured to a point where the significance of the original discovery was clear.
What makes the TOR protein so special? It has kept your research going for more than two decades.
TOR is a highly conserved protein that controls the fundamentally important processes of growth and aging. It is found in all eukaryotes – all the way from yeast to humans, including flies, plants and worms. TOR is a validated drug target, implicated in several diseases such as diabetes, cardiovascular disease and cancer. As a result, several communities are interested in TOR – the pharmaceutical industry, clinical researchers and basic scientists. The positive side is that we have an immediate audience for whatever we do. The downside is that it is extremely competitive.
You mentioned that the protein offers a promising target for a wide range of diseases. Which one would you like to focus on in the future?
For us it is clearly cancer. We do some research that relates to obesity and diabetes, but the main focus is going to be liver cancer. This is the focus of the 11 million Euro Synergy grant that Niko Beerenwinkel, Gerhard Christofori, Markus Heim and I just received.
How will the Synergy Grant change your research and your set-up?
It will help me expand my basic research into translational research areas and increase my team by a few people. Our laboratory received the grant together with colleagues in the Department of Biomedicine of the University of Basel and the Department of Biosystems Science and Engineering at the ETH Zurich to explore how tumours become resistant to targeted therapies. It is a translational project that takes us into the operating room. In fact, I have visited the operating room to see how the tumour samples are collected. This helped me to understand that there are people behind our research – something I knew of course but did not fully appreciate. It makes a huge difference for someone who started out as a yeast geneticist.
The project takes my laboratory in a direction it has been going for a few years. We want to ramp it up now. In the eighties and nineties, my laboratory focused on yeast genetics but we have now moved on to mammalian cells. More recently we started working on mice to better understand the process of cell growth in the context of whole body growth. To find out what happens when this process is not functioning properly, we decided to start working on human tumours. It is a logical conclusion to how my laboratory has been evolving since the eighties.
Were you surprised to hear that your past discovery earned you the Breakthrough Prize?
I was very surprised. In fact, it took me a while to believe it.
A declared goal of the prize is “to celebrate scientists and generate excitement about the pursuit of science as a career”. Do you believe this will happen?
The prize certainly celebrates scientists as individuals. At least I and the other laureates felt very celebrated. I am sceptical that the prize itself is going to encourage a young person to go into science. You do not go into science to win prizes. But, hopefully the prize will generate excitement about science, which will then lead young people to pursue a scientific career. We need more people and funding in science. There are many problems that still need to be solved, for example, cancer and climate change. Who will solve these problems if not scientists? Who will make the next technological breakthrough that will lead to something as important and useful as the internet?
What was the award ceremony like?
The gala was a unique experience. It was a glitzy Oscar-type ceremony at NASA’s Ames Research Center in California that brought together very different types of people. A genuine mix of Hollywood celebrities, Silicon Valley bigshots and scientists. Movie stars and scientists do not often have the chance to mix. Yet everybody seemed to enjoy each other’s company and have a good time.
How are you going to use the money?
I am not exactly sure yet, but I probably will not use it for my research. However, I would like to give back to science, most likely by helping young scientists.
You were born in Puerto Rico, grew up in South America and have lived in Switzerland for almost thirty years. Are you planning to move continents again?
I feel very lucky that I ended up in Basel, and in particular at the Biozentrum. It is a scientific paradise. And I am still happy here and do not plan to move. In addition to my American citizenship I am a Swiss citizen now. I could however go back to the United States once I retire as my mandatory retirement approaches here. I like being a scientist and I do not see myself stopping, at least not yet.
Life Sciences in India – on the right track
The past twenty years have seen tremendous changes in the life science sector in India. New initiatives have helped to build basic science, establish laboratories, set up funding and recruitment programmes for postdoctoral researchers and faculty. India’s challenge now is to improve the flow of funds, to retain or bring back their best brains and to become more competitive internationally.
As in many other fields, India has become a worldwide hub for science and technology. It participates in mega-projects such as the International Rice Genome Project, Large Hadron Collider and ITER – one of the biggest international collaborations to produce electricity from nuclear fusion. Indian government spending on research and development (R&D) has grown by seven per cent each year between 2007 and 2012. By contrast, in Europe it fell by 0.5 per cent and in the United States by 2 per cent a year. 
The focus of research in India traditionally lies on engineering and IT – sectors that are easy to commercialise. The country also hugely invested in nuclear R&D and the national space programme. “Astronomers and physicists made excellent cases for investments of large sums of money in major intellectual quests that may have collateral practical benefits,” says EMBO Associate Member VijayRaghavan, who is a professor at the National Centre for Biological Sciences (NCBS) in Bangalore and head of the Department of Biotechnology (DBT) under the Ministry of Science and Technology.
Science – a historical effort
The quest for knowledge is deeply rooted in India’s identity as a nation. The country began to build a strong foundation in modern science during the first days of its independence. In the 1950s, India’s first Prime Minister Jawaharlal Nehru expanded support of the nation’s institutes of science and technology. In the sixties, India led the “green revolution,” which served as the basis for its efforts to feed its citizens and which set the stage for economic growth. Traditionally, there is a deep appreciation for learning. Academics who spend their time in research and teaching are highly valued.
The life science sector is gaining ground. Innovative national research centres have been founded, including five new Indian Institutes of Education and Research, nine new Indian Institutes of Technology, a new National Institute of Science Education and Research and 28 new Central Universities. Several career-development and recruitment schemes for postdoctoral researchers have been set up. The rapid growth of India’s economy makes for a dynamic job market with many new job openings. New research projects help to understand how the immune system works against disease, and how nutrition and brain development are linked. Clinical, agricultural and biotechology research is steadily gaining momentum.
The government support for creating new research centres, for funding and science infrastructure has been tremendous. “India is much better endowed in terms of research support than it was twenty years ago,” says VijayRaghavan. NCBS, where he still has a laboratory, was set up in 1988 and gave new impetus to the development of modern biology in India. In a partnership with the UK-based Wellcome Trust, DBT offers fellowship schemes to basic biomedical scientists, clinicians and public health researchers who wish to pursue academic research in India. The aim of the schemes is to provide flexible and generous funding to allow for internationally competitive science.
IndiaBioscience (IBS) is another example of an initiative created to help the life science sector get out of its niche existence. IBS functions as a catalyst organization to strengthen recruitment, networks, collaborations, research-oriented education and science communication. The initiative grew out of the annual Young Investigator Meeting that started in 2009. The meeting brings together India’s best young life science researchers, senior faculty, representatives of grant-funding agencies and science policy makers.
EMBO is a regular participant at the annual Young Investigator Meeting. The organization has contributed to the life sciences in India in many ways. A number of scientific meetings, lecture series and keynote lectures were funded by EMBO in recent years. In November 2013, an EMBO–India Young Scientists Networking meeting in Bangalore brought together thirty European and Indian young group leaders to discuss joint collaborations and funding options. Further lectures and a workshop are planned for 2014.
The opportunities for doing research are tremendous. Yet there are several challenges. “While our foundations in modern biology are good, we will slip back rapidly if we do not keep pace with the changing world,” warns VijayRaghavan.
How to bring back the best brains?
According to EMBO Associate Member Inder M. Verma, professor at the Salk Institute in La Jolla, United States, India has not succeeded in attracting its diaspora as effectively as China. Chinese politicians have made it much easier for their researchers to come back. Their salaries at home are internationally competitive and they receive a strong personal support.
The Indian government needs to make its top scientists feel they are in the same advantageous position as their colleagues abroad. “Scientists do not want to take a chance to go back to a system where they are afraid they will not succeed. And I do not blame them, I did not do that myself,” says Professor Verma, who left India in 1967 to pursue his scientific career, first in Israel and then, in 1971, in the United States. Since 1983, he has been involved in improving the country’s basic science infrastructure. He visits India regularly and was also one of the founding fathers of DBT.
The good news is that this structural problem is slowly reversing. The younger generation of scientists is especially eager to return to India. For a reason: The Wellcome Trust-DBT Indian Alliance gives up to 200,000 thousand US dollars per year to outstanding returning scientists to help them set up their own laboratories. Other prestigious schemes include the Ramalignaswami Re-entry Fellowship also run by DBT.
A critical mass of scientific leaders
The Indian government has just announced more than twenty new research centres. Most of them are lacking scientific leadership. Large grants of up to millions of dollars are available for people who decide to take the helm. Yet there have not been many takers. The country does not have a sufficient number of science leaders who are willing to go to these new places and mentor young faculty. The Indian system of family, close colleagues and of being established in one place is difficult to break. “In the United States, people go where the best science is done. In India, family seems to be the strongest magnet,” explains Verma.
A huge challenge is institutional support for scientists. Decent housing and unlimited access to the laboratory are required to keep scientists happy. There is a need for more flexible support for international travel. The flow of funds has to improve. Indian science still suffers from excessive bureaucracy. The purchasing system for supplies is full of problems created by distance, customs and duties. At every level, a small percentage of time and quality is lost. Resources per se are often not a problem, yet their distribution is one.
The same is true for other practicalities. India does not have proper animal facilities. There has hardly been any development of transgenic or knock-out mice – an essential component of modern biology. The country is still suffering from lack of substantial equipment, which elsewhere is taken for granted.
“These are serious problems and we are all working together to push changes. There is tremendous enthusiasm here,” summarizes VijayRaghavan. “The foundation and very strong competence we have in clinical and agricultural research and in ecology can be brought to basic biology in a wonderful way. If we manage to piece all the components together, great things can happen.”
“I think the government is on the right track,” adds Inder Verma. “It is tremendous compared to what used to be twenty years ago. They have a reasonably good idea that basic science is still the fundamental path along which the clinical and translational research will stand. The government has realized that you need to invest a lot initially in order to have a lot of gains much later.”
 Source: J. Chakma et al. (2014) 370: 3-6 New England Journal of Medicine
From targeted to multitargeted cancer treatments
EMBO Member Alexander Levitzki, Professor of Biochemistry at the Hebrew University of Jerusalem, Israel, pioneered the generation of tyrosine phosphorylation inhibitors (tyrphostins) in the late 1980s to the mid-1990s. Work in his group focused on the development of “tyrphostins”, or “tyrosine kinase inhibitors” (TKI), directed against epidermal growth factor receptor (EGFR), Her-2, Bcr-Abl, Jak-2, vascular endothelial growth factor receptor 2 and platelet-derived growth factor receptor. These findings led to the development of 15 tyrosine kinase inhibitors that are currently used in cancer therapy. Dramatic effects have been achieved in the treatment of early chronic myelogenous leukemia with Gleevec. Nevertheless, despite the increasing use of tyrosine kinase inhibitors in the clinic, their performance has been modest against solid tumours.
Most targeted therapies are aimed at one critical oncogenic marker, so it is easy for tumours to develop resistance, especially as tumours are constantly evolving. “We sought strategies that would hit tumours at many targets, since malignant tumours exhibit ever-changing heterogeneity,” says Levitzki. “We began with tumours that overexpress EGFR, which is currently targeted in the clinic by the tyrosine kinase inhibitors Gefitinib, Erlotinib, Lapatinib and by two antibodies, Cetuximab and Panitumumab. These targeted agents exhibit weak efficacies against tumours that overexpress EGFR.” In these tumours, although EGFR is overexpressed, it apparently is not an essential survival factor. Therefore, in the clinic, only a small subset of EGFR-overexpressing tumours responds to EGFR inhibition, and these tumours often acquire resistance rapidly.
“We have converted the overexpression of EGFR, rather than its activity, into the Achilles heel of the tumour,” says Levitzki. This was achieved by using the EGFR as an entry point into the tumour. Levitzki’s group uses an EGFR-targeting vector to specifically deliver synthetic double-stranded RNA, PolyInosine-PolyCytosine (PolyIC), into tumours that overexpress the EGFR. This results in tumour-specific internalization of large amounts of PolyIC. The internalized PolyIC activates several signaling pathways, including protein kinase R and other double-stranded RNA-dependent factors, leading to cell death. In addition, PolyIC induces a “bystander effect,” due to the production of interferon-alpha, interferon-beta and cytokines that recruit immune cells, such as NK and T cells. These immune cells attack all of the tumour cells, including cells that do not overexpress EGFR (Figure 1). Thus, the internalized PolyIC induces the rapid demise of the targeted cell as well as neighboring tumour cells, but spares the more robust non-tumour cells. Indeed, this vector led to the complete regression of disseminated EGFR-overexpressing tumours in mice (1). “This new strategy tackles an important deficiency of targeted therapy, namely its inability to contend with the heterogeneity of malignant tumours,” says Levitzki.
The vector for delivery of PolyIC consists of polyethyleneimine-polyethyleneglycol–ligand, where the ligand can be epidermal growth factor, as in the initial experiments, or any other suitable ligand. “In our most recent studies, we have replaced the homing epidermal growth factor moiety by a ligand that zeros in on Her-2, destroying Her-2 overexpressing breast cancer cells (2), even ones that are resistant to Trastuzumab (Herceptin).” Similar vectors have been generated to target metastatic prostate cancer using a vector targeting prostate surface membrane antigen (PSMA), and metastatic melanoma using a vector targeting protease activated receptor 1 (Par1).
Another approach to enhance targeted therapy was discovered by serendipity. “We began looking for insulin-like growth factor 1 receptor kinase inhibitors in 1997. After developing a number of generations of such inhibitors, we came across a family of tyrphostins that act as allosteric kinase inhibitors of these receptors,” says Levitzki. An unexpected property of this particular family of novel tyrphostins, which include NT157, was the ability to induce the irreversible proteolytic destruction of Irs1 and Irs2, the signal transducers of insulin-like growth factor 1 receptor. This results in dramatic anti-tumour effects in experimental animals harboring prostate cancer, ovarian cancer or metastatic melanoma (3). Recently, B-Raf inhibitors have been hailed as effective therapy against metastatic melanoma, but resistance develops rapidly. NT157 is effective even against tumours that carry B-Raf activating mutations that are resistant to Vemurafenib (Zelboraf). “Our laboratory is currently developing strategies to induce the irreversible destruction of other signaling molecules, such as mutated K-Ras,” adds Levitzki. The focus of Levitzki’s laboratory is finding ways to target specific tumour markers, while invoking a holistic anti-tumour response.
EMBO Press launches
More than 230 guests attended the launch of EMBO Press held concurrently with the American Society of Cell Biology meeting on 15 December 2013. The event took place at the Audubon Aquarium of the Americas overlooking the Mississippi.
“We are proud to announce EMBO Press to such a wonderful crowd of people,” said Bernd Pulverer, Head of Scientific Publications at EMBO, speaking at the launch event. EMBO Press affords us the independence to lead in implementing innovations to ensure that journals continue to aid scientists and to encourage scientific research. The striking new designs of the four scientific journals on the platform, with new functionality and forward-looking policies, should speak for themselves,” added Pulverer. “EMBO Press is founded on the themes of transparency and accountability of the editorial process and on innovation to allow us to publish high quality research in a way that is more accessible and useful. We hope to contribute to a reliable, quality literature and to encourage others to share in this vision,”
EMBO Press went public online early in the New Year. The new publishing platform delivers enhanced functionality, an innovative design, as well as constructive editorial policies, processes and quality standards across the four EMBO publications.
“It is one of our goals to add maximal value to published research through the optimized presentation of research data and to provide a more flexible and customizable interface to allow the reader to drill down as deep into a paper as they see fit,” added Pulverer. “It is our aim to transform the research paper from a written record of a research project with illustrations to a fully fledged research tool without loosing sight of accessibility to our broad readership. The four EMBO Press journals will achieve wider global reach through collaboration with our publishing partners HighWire Press and Wiley.”
Also at the American Society of Cell Biology, EMBO Director Maria Leptin chaired a panel discussion focused on whether peer review is under threat. The panel included contributions from Bruce Alberts, Professor Emeritus in the Department of Biochemistry and Biophysics at the University of California, San Francisco, Anthony Hyman, Research Group Leader and Director at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany, Jon Lorsch, Director of the National Institute of General Medical Sciences, Emilie Marcus, Chief Executive Officer of Cell Press, and Melina Schuh, Group Leader at the MRC Laboratory of Molecular Biology in Cambridge, England. The speakers addressed concerns about peer review and research assessment from the perspective of funders, institutions, journals, and scientists.
Bernd Pulverer also took part in a panel discussion on DORA, the San Francisco Declaration on Research Assessment, which has attracted more than 10,500 signatures, including 437 organizations, across all the sciences. The declaration highlights the problem of using journal- based metrics as a proxy for quality in the assessment of individual scientists, highlighting that all the stakeholders – journals, funders, research institutions and importantly researchers – have to work together to bring about change.
More than 5000 people attended the American Society of Cell Biology meeting from 50 countries.
The new EMBO Press platform is online at embopress.org.
Meet the scientist: Lord Robert May
EMBO Members for 2014 - Anniversary election
Professor May, how did you become interested in ecology?
After returning to Australia from my postdoctoral research at Harvard in 1961, I spent twelve years in the physics department at Sydney University. At that time, ecology was moving beyond being purely descriptive to acquire a more theoretical foundation for the phenomena in the natural world. Ecology is a young subject. The word is only about a hundred years old. The head of the biology department at Sydney – a distinguished ecologist – established an organisation called Social Responsibility in Science and I thought I should learn more about what I was being socially responsible about. I developed interest in animal population dynamics and the relationship between complexity and stability in natural communities.
You have degrees in chemical engineering and physics, you are an ecologist, zoologist and mathematician. What is your common theme?
I like looking at complicated things and asking what are the essentials of what is happening. I see the mathematical approach as a way of thinking very clearly and expressing your ideas very unambiguously. Mathematics is the central theme in the way I have moved from place to place in pursuit of interesting problems.
You took maths to the banking and finance system. It is a long way from chemical engineering.
That was completely accidental. I was part of the study group put together by the US National Academy of Sciences and the Federal Reserve Bank in 2006, before the banking crisis happened. At that time we had published a paper on modelling the banking system. It opened a new way of making short-term predictions on things that looked random, but were governed by rules. This is how I started working for the Bank of England. It was not done deliberately, but I was drawn into it and took it seriously.
Is it important to be flexible?
I never planned a trajectory for my life. Most of the things that have happened in my life were accidents rather than careful planning. But I have been rather flexible in taking advantage of these accidents.
There is an interesting book Chance and Necessity by Jacques Monod. He emphasises that a nature of a scientific discovery is a mixture of accident and the alertness to take advantage of the accidents. This is something I have been pretty good at.
From your time as Chief Scientific Advisor to the UK government and as President of the Royal Society, what do you think you are particularly well remembered for?
When I took on the job as Chief Scientist in 1995, the public excitement about mad cow disease was at its peak. Shortly after, I produced a formal protocol for science advice in government. This protocol emphasized that science not always tells the government what to do, but reports what the knowledge is. Its aim is to frame a debate – the rest would be a democratic decision.
During my time at the Royal Society, it was not so much my personal influence, but the Society as a whole that recognised that it should widen its membership. The provision was to elect people who had been successful in the application of science in business and industry rather than those who advanced the frontiers of knowledge. Also, we did a better job at electing more women as members. I made a start on much of this and other people have carried it forward very well.
Science live for Russian high-school students
A two-week Summer School in the Russian research centre Pushchino proved to be a life-changing event for some of the eighty high-school students in attendance. Fyodor Kondrashov, group leader at the Centre for Genomic Regulation in Barcelona, Spain, initiated the project two years ago to give young people a realistic experience of what it is like to do scientific research.
Exploring new territory
Vishva Dixit is Vice President of Physiological Chemistry at Genentech. In the 1990s, Dr. Dixit and colleagues made a series of discoveries at the University of Michigan that helped define the molecular events of programmed cell death. More recently, he has been looking at the links between molecular signaling, cancer and inflammation. At The 5th EMBO Meeting in Amsterdam, The Netherlands, he talked to Barry Whyte about his career in academic and industrial research.
Announcing EMBO Press
Previous articles in EMBOencounters explored important topics in scientific publishing related to peer review, editorial processes and the merits of journal impact factors in assessing research. This month we are excited to announce the launch of EMBO Press, a new editorially independent publishing platform that will allow us to develop further EMBO scientific publications and build on the established strong reputation of our journals.
Olivier Voinnet is Professor and Chair of RNA Biology at the Swiss Federal Institute of Technology Zürich as well as Directeur de recherche Détaché du Centre National de la Recherche Scientifique (CNRS), France. In 2009, he was awarded the EMBO Gold Medal for his work on RNA silencing in plants. In EMBOencounters, he talks to Barry Whyte about his career and recent papers in Nature Genetics and Science.
An insatiable curiosity - interview with EMBO Member Cédric Blanpain
Cédric Blanpain is a professor of stem cell and developmental biology at the Free University of Brussels. His original approach to science has earned him a series of awards and resulted in several high-profile papers in 2012. In EMBOencounters, he talks to Yvonne Kaul about his career and his work on stem cells and cancer.
EMBO to celebrate 50th anniversary in 2014
2014 is the 50th anniversary of EMBO and a full programme of events and activities are planned throughout the year. The 50th anniversary is an opportunity to look back on achievements and reflect on progress. It is also a time to celebrate and take a glimpse into the future.
New prize for cancer research
The BEUG FOUNDATION FOR METASTASIS RESEARCH is accepting applications for the METASTASIS PRIZE. Scientists are still trying to understand how cancer spreads from the place where it first arises to other locations in the body, a process that can have dramatic consequences for the health of cancer patients. The Metastasis Prize is meant to encourage and help introduce new approaches to impede cancer metastasis.
Under one roof
The newly founded Berlin Institute of Health is poised to be one of the leading institutes for health research in Europe.
Institute of Functional Genomics, Lyon, moves to new building
Researchers at The Institute of Functional Genomics in Lyon, France, moved into a new state-of-the-art building in October 2012. The new 4500-m2 research facility is located in the biotechnology district of the south of Lyon.
The limits of privacy
Bartha Knoppers is a professor of law from McGill University in Montreal, Canada, and an internationally recognized expert on the ethical aspects of genetics and biotechnology. She is one of the speakers at the upcoming Science & Society Conference on Public and Private Health: Genomics, Medicine and Society which will be held in Heidelberg from 7–8 November and her talk will focus on Large data collections: protecting research participants while allowing useful research. In an interview with EMBOencounters, she talks about the privacy of health information in the digital age.
Life sciences in Portugal
Progress despite recession
Science in Portugal benefits from generous private donations but needs to provide long-term stability for individual researchers. The budget has remained stable, yet has to be distributed to a growing pool of researchers.
Inside scientific publishing
The San Francisco Declaration on Research Assessment
More than 7000 scientists and 250 science organizations have by now put their names to a joint statement called the San Francisco Declaration on Research Assessment (DORA). The declaration calls on the world’s scientific community to avoid misusing the Journal Impact Factor in evaluating research for funding, hiring, promotion, or institutional effectiveness. Here EMBO Director Maria Leptin discusses some of the concerns and also provides her personal perspective about the use of Journal Impact Factors and the significance of the recommendations.
Tom Cech is Director of the University of Colorado BioFrontiers Institute in the United States. In 1989, he and Sidney Altman were awarded the Nobel Prize in Chemistry for the discovery of the catalytic properties of RNA molecules. Cech was President of the Howard Hughes Medical Institute from 2000–2009. Here he discusses science in Europe and activities closer to home in the United States.
EMBO conference takes to the sea
Almost 180 participants embarked on MS Trollfjord last May to learn the latest on molecular mechanisms of autophagy. The focus was on the regulation of autophagosome biogenesis and the role of selective types of autophagy in health and disease.