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Breakthrough research

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. [1]

 

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.

 

Main players

 

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.”

 

[1] Source: J. Chakma et al. (2014) 370: 3-6 New England Journal of Medicine
doi: 10.1056/NEJMp1311068

 

 

 

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.

 Fig.1 The multitargeting of long chain dsRNA

“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.

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