Dermatology Medical News

Cells, like ordinary households, produce “garbage” – debris and dysfunctional elements – that need disposal. When the mechanism for taking out this garbage fails, rare genetic diseases called lysosomal storage disorders (including Tay-Sachs, Batten and Fabry disease) can disable and even kill the children they affect. In adults, such failure leads to neurodegenerative diseases that occur later in life, such as Alzheimer’s and Parkinson’s diseases.

An international partnership between researchers at the Jan and Dan Duncan Neurological Research Institute (NRI) at Texas Children’s Hospita, Baylor College of Medicine and the Telethon Institute of Genetics and Medicine in Naples, Italy, led to the discovery of a master gene that controls not only the lysosomes, which destroy the debris, but also cellular compartments called autophagosomes that encapsulate the material and fuse with the lysosomes to achieve the ultimate clearance of the cell’s “garbage.”

This finding may cast new light on the search for ways to combat these inherited diseases and neurodegenerative diseases that start in adulthood. A report on the research, done in collaboration with scientists from the Cambridge Institute for Medical Research of the University of Cambridge in the United Kingdom, appears online in the current issue Science Express.

“The master gene (transcription factor EB or TEFB) that controls the function of lysosomes (organelles in the cell that break down waste and cellular debris) also controls the function of autophagosomes,” said Dr. Andrea Ballabio, scientific director at the Telethon Institute of Genetics and Medicine in Naples, Italy, and professor of molecular and human genetics at BCM and the Texas Children’s Neurological Research Institute. “Defects in this process are also implicated in neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases.”

Ballabio, who is also on the faculty of the Federico II University in Naples and senior author of the report, describes the autophagosomes as “garbage trucks” that pick up the debris and take it to the lysosomes, which “incinerate” it.

The discovery that a single master gene directs this activity “is one of the few examples of coordinated regulation of two cellular compartments,” he said.

Ballabio and his colleagues had already demonstrated that TEFB regulates the genesis and formation of lysosomes, but they were considering whether they could use the gene as a switch to increase the capacity of the cell to get rid of waste products. They knew that the number of lysosomes would increase, but that would not be helpful without more autophagosomes.

“We thought there would be no point in increasing the incinerators unless we could also increase the garbage trucks,” he said.

They found that TFEB controlled both activities.

“This understanding paves the way to finding drugs to activate the process,” said Dr. Carmine Settembre, postdoctoral fellow at TIGEM, NRI and BCM and first author of the report. The work already done on mice and ongoing work in the laboratory is paving the way to better understanding of the gene and possible applications in human disease.

“This gene is a wonderful tool,” said Ballabio. “By modulating the activity of a single gene, we can induce the activity of a variety of other genes that are involved in the process of degradation.”

“Collaborations are the best way to accelerate discovery and advance the search for ways to impact neurological disorders. This partnership between NRI, BCM and Telethon Institute of Genetics and Medicine is a fine example of the power of collaborations,” said Dr. Huda Zoghbi, director of the NRI at Texas Children’s Hospital, professor of neurology, neuroscience, pediatrics and molecular and human genetics at BCM and an investigator with the Howard Hughes Medical Institute.

Notes:

Others who took part in this research include Chiara Di Malta, Vinicia Assunta Polito, Diego Medina and Pasqualina Colella, all of TIGEM; Francesco Vetrini, postdoctoral associate at BCM; Serkan Erdin, postdoctoral associate, Serpil Uckac Erdin, research technician, Tuong Huynh, research associate and Dr. Marco Sardiello, assistant professor all in the department of molecular and human genetics at BCM and with the NRI; and Dr. David C. Rubinsztein and Moises Garcia Arencibia of Cambridge Institute for Medical Research.

Funding for this work came from the Italian Telethon Foundation, Cherie and James C. Flores, the Beyond Batten Disease Foundation, the European Research Council, the European Molecular Biology Organization, the Wellcome Trust and the Intellectual and Disabilities Research Center at BCM.

The laboratory at the NRI is a joint venture between the Telethon Foundation, the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital and BCM.

Source:
Graciela Gutierrez

Baylor College of Medicine Continue reading →

Researchers have developed a genetic tool in mice to speed the discovery of novel genes involved in cancer. The system – called PiggyBac – has already been used by the team to identify novel candidate cancer-causing genes.

This new development of the PiggyBac system makes it a powerful addition to the armoury of genetic methods available to researchers for picking apart the genetic causes of cancer. It will complement advances in genomics and genetics of cancer, by providing biological validation to human mutations identified by cancer genome sequencing.

The PiggyBac process involves shipping cargos of genetic material – called transposons – around the genome using an engine known as a transposase. The team has incorporated the PiggyBac system into the mouse genome, where the transposons can jump from gene to gene, from chromosome to chromosome, disrupting or altering the activity of the genes where they land.

“Far from being destructive, this process is empowering our search for genes underlying cancer,” says Professor Allan Bradley, from the Wellcome Trust Sanger Institute and senior author on the paper. “Some genes, when disrupted, will push cells along the road to tumour development. When we look at the tumours that develop in our mice, we can search for the molecular fingerprint of the transposons in the genome; this allows us to identify the disrupted genes that are the cause. But what is extraordinary about this new model is its adaptability – with PiggyBac, we can look at specific organs, we can switch genes on and switch genes off, we can look for cancer genes across the whole genome.

“It’s the organism version of whole-genome study.”

The team searched for novel cancer genes in 63 mouse blood cancers. The system opened new doors in the genome: when the researchers inspected 72 distinct locations at which their transposon had entered the genome, they found that a remarkable two-fifths of these genetic sites had never been detected before.

“As well as highlighting the potential of this system to get at genetic regions previously beyond reach, the new genes that we have already identified using PiggyBac open exciting new avenues for future studies,” says Dr Roland Rad, from the Wellcome Trust Sanger Institute and first author on the paper. “For instance, we found that one of the genes, called Spic, was disrupted in nine distinct myeloid leukaemia tumours in our mice. An event of this frequency merits study in human cancer and, when we take into account recent studies that have found this gene has a role in the development of white blood cells, we can be even more optimistic about the potential of this finding.”

Other genes identified include Hdac7, which is known to participate in the creation of white blood cells in the thymus but has, to date, not been studied in the context of blood cancers; and Bcl9, a gene whose human equivalent is thought to be involved in leukaemia.

Researchers can now look in detail at the genetic equivalents in the human genome and ask what role their new genes play. One of the challenges of cancer genetics is that genomes in cancer cells can be ravaged by hundreds or even thousands of mutations. By looking at cancers modelled in the mouse, teams can begin to understand – at a biological level – which, among the thousands of mutations present, is the cause.

Before transposons researchers often used other methods, such as viruses, to cause mutations and generate tumours. Although these have had success in identifying genetic culprits in cancers of the blood and breast, they have not been effective in other cancer types.

It is only in recent years that researchers have been able to activate transposons to mutate genomes of higher organisms, such as mice – starting with a model called Sleeping Beauty. PiggyBac has many advantages over Sleeping Beauty and significantly extends the toolkit available to researchers. But the two systems can also complement one another.

“These transposons have particular preferences, particular ways of working,” says Dr Pentao Liu, from the Wellcome Trust Sanger Institute and an author on the paper. “While Sleeping Beauty transposons slot into the genome most comfortably according to one pattern, PiggyBac follows another. So, naturally, one system will find genes that another might not. What is really exciting is that we have been able to incorporate both systems into our mouse lines so that they can be used together.

“By optimising PiggyBac in this way and by sharing these tools with researchers worldwide, we can hope to drive new discovery in cancer research.”

The team have developed three types of transposons, which can be shipped around the genome to achieve different effects. Some will find genes involved in blood cancers, some in solid tumours, and some can find genes in both. They have also developed novel methods that let researchers activate the transposon only in the specific organ they are studying – be it lung, liver, pancreas or any other tissue in the mouse.

With the PiggyBac model now working to identify genes, the team will extend its reach – looking for further genes underlying a whole range of cancers in different organs of the mouse.

Publication Details:
Rad R et al. (2010) PiggyBac Transposon Mutagenesis: A Tool for Cancer Gene Discovery in Mice. Science.

Funding:
This work was supported by the Wellcome Trust and the German Research Foundation.

Source:
Don Powell

Wellcome Trust Sanger Institute Continue reading →

If a strand of your DNA was stretched out completely, it would be more than six feet long. It’s hard to imagine that it can fit inside the nucleus of one of your cells, but that’s exactly how it works.

For much of the last century, scientists have been busy figuring out how DNA is packaged in cells, and have found strong indications that the packaging is integral to how DNA works. The packaging – comprised mostly of an amino acid molecule called a histone – influences the on and off switches of different genes that regulate cellular function and play a role in human diseases ranging from cancer to genetic disorders. Scientists study histones by using antibodies to specific “flavors” of histones that are only very slightly different from one another. The antibodies help to pinpoint what DNA is being packaged by a certain kind of “flavor” of histone, and how that affects gene regulation. Different flavors affect genes differently.

“And this is where it gets complicated,” says Jason Lieb, PhD, who led the project. “Many companies make these antibodies that we scientists use in our labs – but there are so many different kinds of histones and types of tests we do that it’s just not feasible for the companies to anticipate every single way that a given antibody can be used.”

This is a problem, explains Lieb, who is a professor of biology at UNC-Chapel Hill and member of UNC Lineberger Comprehensive Cancer Center, since scientists can’t be absolutely certain that the antibody is recognizing a specific “flavor” of histone, or one that is very closely related.

“Histones are essentially the key to the DNA library. They tell you which ‘shelves’ of that library – or areas of the genome – are open or closed to information moving in and out. But since the differences between the different ‘flavors’ of histones are often extremely small, and it’s likely that an antibody may react with more than one histone or in different ways depending on the type of test being used in the lab. It makes scientific precision very difficult,” Lieb notes.

In a paper published in the journal Nature Structural and Molecular Biology, Lieb and his colleagues from across the country describe how they tested more than 200 antibodies against 57 histone modifications (or flavors) in three different organisms, using three different tests commonly used in this kind of genetic analysis. They found that about 25 percent of antibodies currently sold have a problem with specificity – targeting the anticipated histone – in a given test. They believe that this proportion is likely to remain steady over time.

“So we thought, ok, we need to help ourselves as scientists. We set up a web-based searchable database. Our results are there and other scientists can also post their results so that we have a self-sustaining, up-to-date source of information that is really important to scientists working to understand a broad range of genetic phenomena,” he said.

The research was funded by the National Human Genome Research Institute (part of the United States National Institutes of Health) and included researchers from the Universities of California at Santa Cruz, Berkeley, and San Diego, the Lawrence Berkeley National Laboratory, the Ludwig Institute for Cancer Research, Harvard Medical School, the University of Cambridge (UK), Washington University in St. Louis, Ontario Institute for Cancer Research (Canada) and Rutgers University.

Source:
Ellen de Graffenreid
University of North Carolina School of Medicine Continue reading →

Contact: Warren Froelich
froelichaacr
215-440-9300
American Association for Cancer Research

Researchers from The Cancer Center at the University of Minnesota have demonstrated that variations in genes may determine the outcome and toxicity of treatments for myeloma cancer patients.

The findings support thinking that physicians may optimize care by adjusting treatment according to a patient’s specific genetic condition. The findings will be presented September 15, 2003 at the American Association for Cancer Research (AACR)-sponsored specialty meeting on ‘SNPs, Haplotype, and Cancer: Application in Molecular Epidemiology.’

Although chemotherapy drugs can be effective against myeloma in many patients, they can be less effective or even lethal in others.

By determining a patient’s toxic susceptibility to drugs through analysis of specific genetic variances, or single nucleotide polymorhphisms (SNPs), in genes known to promote myeloma growth, clinicians can adjust dosage levels or choose alternate, safer drugs to benefit the patient.

Led by Brian Van Ness, Ph.D., professor of genetics and a member of The Cancer Center, researchers analyzed patient samples from an Eastern Cooperative Oncology Group Study on myeloma chemotherapy treatments for 700 patients between 1987-1994.

For this particular investigation, researchers examined 400 patient DNA samples for SNPs in genes that promote myeloma growth. Those patients with the SNPs that result in low production of the growth factor, generally had better outcomes to the chemotherapy and increased survival times.

‘These data confirm that our research on genetic variances and their effect on treatment outcome is headed in the right direction,’ said Van Ness. ‘This important first step means we can start developing clinical trials based on genetic conditions that can lead to more effective treatments and help to evaluate new, targeted therapies.’

Myeloma is a cancer of plasma cells, which are antibody-producing cells normally present in the bone marrow. More than 1,000 new cases or myeloma are diagnosed daily around the world making this the second most common form of blood cancer after lymphoma.

Co-authors of this study are William R. Kiffmeyer, Ph.D., Fangyi Zhao Ph.D. and Martin Oken M.D. of the University of Minnesota, and Emily Blood and Montse Rue, Ph.D. of the Easter Cooperative Oncology Group. The International Myeloma Foundation, through its Bank on a Cure project, will considerably expand this study in the future.

The Cancer Center at the University of Minnesota is a National Cancer Institute-designated Comprehensive Cancer Center. Awarded more than $80 million in peer-reviewed grants during fiscal year 2003, the Cancer Center conducts cancer research that advances knowledge and enhances care. The center also engages community outreach and public education efforts addressing cancer. To learn more about cancer, visit the University of Minnesota Cancer Center Web site at cancer.umn.edu. For cancer questions, call the Cancer Center information line at 1-888-CANCER MN (1-888-226-2376) or 612-624-2620 in the metro area.

Additional Contacts:
John Weiner
USC
323-442-2830

Todd Matthew
The Cancer Center (University of Minnesota)
612-624-6165 Continue reading →

Researchers have identified characteristic patterns of molecules called microRNA (miRNA) in the blood of people with lung cancer that might reveal both the presence and aggressiveness of the disease, and perhaps who is at risk of developing it. These patterns may be detectable up to two years before the tumor is found by computed tomography (CT) scans.

The findings could lead to a blood test for lung cancer, according to a researcher with the Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute who helped lead study.

“We found patterns of abnormal microRNAs in the plasma of people with lung cancer and showed that it might be possible to use these patterns to detect lung cancer in a blood sample,” says principal investigator Dr. Carlo M. Croce, professor of molecular virology, immunology and medical genetics, and director of the Human Cancer Genetics program.

“These abnormal microRNAs were present in blood serum well before the tumors were detected by a sensitive method such as spiral CT scan, suggesting they might have strong predictive, diagnostic and prognostic potential.”

The findings were published in a recent issue of the Proceedings of the National Academy of Sciences.

Croce and his collaborators initially identified the molecular patterns in tissue samples collected from patients participating in a clinical trial examining the use of spiral CT scans to screen for lung cancer. The trial involved 1,035 individuals aged 50 years or older who had smoked at least a pack of cigarettes a day for 20 years or more. All patients underwent a CT scan every year for five years and provided blood, sputum and urine samples.

The researchers initially analyzed 28 tumor samples and 24 samples of normal-lung tissue for their miRNA profiles. They identified miRNAs that could discriminate between lung tumor and normal lung tissue. They also found patterns of miRNAs that distinguished tumors with faster growth rates and that correlated with poor disease-free survival.

Then Croce and his colleagues analyzed blood samples that had been collected more than a year before the individual’s lung cancer was detected by spiral CT. They discovered a signature of 15 miRNAs that could identify 18 of 20 individuals whose cancer was later detected by spiral CT.

To verify that finding, they applied the signature to a second set of blood samples collected during a similar but unrelated lung-cancer trial. Here, the signature correctly identified 12 of 15 patients whose lung tumors were detected more than a year later by spiral CT. The researchers estimated that the signature were detectable in blood up to 28 months prior to spiral CT detection.

The researchers also found miRNA signatures in the blood that were associated with the following:
Lung-cancer diagnosis – a signature identified 16 of 19 patients with lung cancer in set one, and 12 of 16 patients in set two.
Poor prognosis – a signature identified five of five patients with poor prognosis in set one; four of five in set two.
Good prognosis – a signature identified five of 15 patients in set one, and five of 11 patients in set two.

“Our goal was to identify biomarkers that could predict tumor development and prognosis to improve lung-cancer diagnosis and treatment,” Croce says. “Overall, these findings strengthen the observation that circulating miRNA in plasma is detectable well before clinical disease detection by spiral CT, indicating the possibility of identifying high-risk patients on the basis of miRNA profiling.”

Source:
Darrell E. Ward
Ohio State University Medical Center Continue reading →

The Human Genetics team at The University of Queensland Diamantina Institute have successfully used a new gene-mapping approach for patients affected by severe skeletal abnormalities.

Skeletal dysplasias are a group of diseases that cause abnormalities in the skeleton’s growth and function. This can lead to problems such as abnormal height and/or limb length, difficulty with reproduction and decreased life span. Families affected by skeletal dysplasias are usually very small in number, which can make it difficult to find the disease-causing gene for that family.

Associate Professor Andreas Zankl, a clinical geneticist from The University of Queensland Centre for Clinical Research, developed a Bone Dysplasia registry for patients and their families – the first of its kind in Australia. Through the registry, the UQDI team of researchers met a family with two young daughters affected by a severe form of dwarfism.

The team used next-generation sequencing to simultaneously study the four immediate family members and compare their exomes – the coding section of the genes – to each other and against the reference sequence from the international Human Genome Project.

They were able to discover which gene within the family caused the abnormality. Impressively, the mapping process took only a few weeks. The UQDI researchers then successfully determined how the genetic abnormality caused the skeletal disease.

In the past, researchers could only sequence and compare a few genes at a time, which was expensive and time-consuming. For example, UQDI researchers had spent a decade finding the responsible gene for another type of skeletal dysplasia, fibrodysplasia ossificans progressiva.

In contrast, next-generation sequencing technology can provide more rapid results for mapping genes in these particular types of diseases. However, despite this breakthrough in progress, Associate Professor Emma Duncan said it was still an intensive process.

“Typically, we all have a number of small genetic differences – we find approximately 20,000 on average just in our coding regions when compared with the Human Genome sequence – so it’s still a very involved process to work out which one is the disease-causing mutation,” she said.

“For this family, it’s been a huge relief to find out why their little girls have this devastating skeletal disorder, and understanding the genetics has helped them in their planning for any future pregnancies,” said Professor Matthew Brown.

With the success of their next-generation sequencing approach, the team have also researched another skeletal dysplasia case which involved five unrelated individuals, comparing their exomes with each other and with the Human Genome Project.

By examining just this small number of affected people, the responsible gene has been identified. UQDI researchers will continue to map unknown genes for skeletal dysplasias and for other likely single-gene inherited diseases.

The paper has been published in the Public Library of Science (PLoS).

The success of this discovery was due to funding by the Australian Cancer Research Foundation, NAB and NHMRC, The Rebecca L Cooper Foundation, the Royal Children’s Hospital Research Foundation and an ANZ Medical Research Grant. Finally, the team of dedicated UQDI researchers: Professor Brown, Dr Zankl, Dr Evgeny Glazov, Dr Graeme Clark, Dr Gethin Thomas, Dr Tony Kenna and Dr Duncan.

The UQDI would like to thank the patients and their families who generously participated in the project.

Source:

The University of Queensland Diamantina Institute Continue reading →

Therasis Co-Founder, Andrea Califano, Ph.D., and Wei Keat Lim, Ph.D., Head of Computational Systems Biology at Therasis, along with a team of scientists at Columbia University, have reported in the journal Nature the identification of two genes that, when simultaneously activated, cause the most lethal form of glioblastoma, an aggressive brain tumor. The findings were first published in an advanced online edition of Nature on December 23, 2009, see here.

The genes were identified by reverse-engineering a map of the complex molecular interactions that occur within the actual tumor cells, also known as a cellular network, using advanced cancer systems biology algorithms. These computational methods and algorithms were developed in the laboratory of Dr. Califano, who is also the Director of the Joint Centers for Systems Biology and Associate Director of the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center.

The team used one of the algorithms (ARACNe) to reconstruct the cellular network that controls the behavior of these tumors. Then, a second algorithm (MARINa) was used to identify the master regulators of the worst prognosis in glioblastoma from this network. This analysis pinpointed two genes, with no known prior association with brain cancer, as playing a key, synergistic role in determining the most aggressive properties of glioblastoma, including invasion of normal surrounding tissue and angiogenesis. ARACNe and several other algorithms are exclusively licensed to Therasis from Columbia University. Together, they form the computational foundation of the company’s robust drug discovery platform, known as the Therasis Filter™.

The computational findings were confirmed by a follow-up validation study, in which the expression of these genes was found to be strongly correlated with increased mortality. Furthermore, the tumor network and genes’ functions were confirmed both in cell lines and in mouse models. Expression of the two genes in neural stem cells caused them to display all the hallmarks of the most aggressive glioblastoma. Conversely, silencing these genes in aggressive human glioma cells, which are normally highly tumorigenic when transplanted in mice, completely blocked their ability to form tumors.

“This study validates the potential of the Therasis Filter™ to transform oncology drug discovery and development by enabling a comprehensive understanding of the inner regulatory interactions in actual tumor cells to guide target identification,” commented Dr. Califano. “These findings of two new synergistic glioblastoma targets support our technology platform and will guide new approaches to combination therapy and associated diagnosis through targets and biomarkers that are causally, rather than statistically, associated with the tumors.”

Dr. Stefan Catsicas, Chairman of the Tilocor Group, whose Tilocor Life Science arm has invested $12M into Therasis’ Series A financing, added, “This study illustrates that scientific excellence is necessary to develop innovative treatments. The combined expertise of the founders and of the management of Therasis should allow the company to translate this excellence into clinical breakthroughs.”

Rather than identifying therapies based solely on cytotoxicity, or ability to kill cancer cells, the Therasis Filter™ enables a more informed approach to drug development by determining key molecular targets and uncovering synergistic interactions within a cellular network. The subsequent reverse-mapping of the effects of a single agent or combination on these cellular activities affords a better understanding of the mode of action and specific toxicity of new treatments, as well as biomarkers of activity.

Therasis was recently founded by Drs. Riccardo Dalla Favera, Owen O’Connor, and Andrea Califano, leaders in basic, translational, and clinical oncology research. The company is developing an internal pipeline of oncology drug candidates and forming drug discovery partnerships with other pharmaceutical and biotechnology companies.

About the Therasis Filter™

The Therasis Filter™ enables the identification of disease-specific alterations in the networks of molecular interactions that regulate cellular processes, allowing the rapid identification of new chemical entities and synergistic combinations that target these alterations. Beginning with high throughput screening of compound libraries, the Therasis Filter™ first collects a large number of molecular profiles of chemically-perturbed cells. These profiles are used to reconstruct accurate maps of molecular interactions, also known as “interactomes.” The latter are experimentally validated and analyzed to identify disease-specific alterations in tumor-derived tissues, compounds targeting these alterations and biomarkers complementing clinical development. Interactomes are also effective in characterizing drug mechanisms of action, supporting both drug rescuing and drug repositioning efforts.

Source
Therasis Continue reading →

Johnson & Johnson has announced that Axel Ullrich, Ph.D., director of the Department of Molecular Biology at the Max Planck Institute of Biochemistry in Germany, whose discoveries have led to novel cancer therapies including Herceptin® (trastuzumab) , is the winner of the 2009 Dr. Paul Janssen Award for Biomedical Research. An independent committee of world-renowned scientists selected Dr. Ullrich, who on September 8 will receive a $100,000 prize during a ceremony in Beerse, Belgium.

“Dr. Ullrich was chosen for his pioneering work in applying molecular biology and molecular cloning to the discovery of protein therapeutics for the treatment of a wide range of diseases, including diabetes and cancer,” said Solomon Snyder, M.D., distinguished service professor of Neuroscience, Pharmacology and Psychiatry, Johns Hopkins School of Medicine and chairman of The Dr. Paul Janssen Award Selection Committee.

“He is one of few basic scientists whose work not only has influenced academic research, but also has helped millions of patients suffering from major chronic diseases,” Snyder continued. “We received a number of outstanding nominations for this year’s Award and are pleased to acknowledge Dr. Ullrich with this distinction. His work has had a remarkable impact on human health and truly embodies the efforts of the Award’s namesake, ‘Dr. Paul,’ who helped save millions of lives through his contribution to the discovery and development of more than 80 medicines.”

Ullrich has pioneered the translation of genomics-based discoveries into novel approaches for the treatment of major diseases. Working at Genentech, Inc. in the early 1980s, he developed genetically engineered human insulin, the first therapeutic derived from gene cloning. In 1987, Ullrich and collaborators discovered that the neu/HER2 gene is amplified and overexpressed in more than 30 percent of invasive breast cancers. HER2 was chosen for the development of an entirely novel cancer therapy, culminating in the production of an anti-HER2 monoclonal antibody that since 1998 has been used successfully to treat patients with metastatic breast cancer. This was the first targeted therapeutic agent developed on the basis of a newly discovered gene with an oncogenic function in human cancer.

In the early 1990s, Ullrich identified the signaling system involved in regulating tumor angiogenesis, the growth of blood vessels in tumors. He discovered that inhibiting a key player in the signaling system (called vascular endothelial growth factor receptor or VEGFR) suppresses the generation of blood vessels in tumors and slows down cancer cell growth. Years later, a small molecule inhibitor of the VEGFR2 kinase function was developed, from which a derivative was approved in 2006 for the treatment of kidney carcinoma and gastro-intestinal stromal tumors.

“It is an honor to receive an award of this stature and to be recognized among so many outstanding scientists,” said Ullrich. “Dr. Paul is a legend whose work had a tremendous impact on combating some of the world’s most serious diseases. Four of the more than 80 medicines he developed are on the World Health Organization’s list of essential medicines.”

“Johnson & Johnson is pleased the Selection Committee chose Dr. Ullrich as the recipient of the 2009 Dr. Paul Janssen Award, as we believe that his discoveries capture the spirit and legacy of Dr. Paul,” said Paul Stoffels, M.D., global head, Research & Development, Pharmaceuticals, Johnson & Johnson. “Dr. Paul’s passion for his work and dedication to creating life-saving therapies for the individuals most in need should continue to serve as an inspiration to the scientific community as we carry on with our quest to care for the world, one patient at a time.”

Nominations for the 2010 Dr. Paul Janssen Award will open in September and submission details will be announced at that time.

About The Dr. Paul Janssen Award

Established by Johnson & Johnson, The Dr. Paul Janssen Award salutes the most passionate and creative scientists in basic or clinical research whose scientific achievements have made, or have strong potential to make, a measurable impact on human health. The Dr. Paul Janssen Award is named for Dr. Paul Janssen, who founded Janssen Pharmaceutica, N.V. in 1953. Known to his colleagues as “Dr. Paul,” Janssen was one of the 20th century’s most gifted and passionate researchers, a physician-scientist who helped save millions of lives through his contribution to the discovery and development of more than 80 medicines, of which four are on the World Health Organization’s list of essential medicines. In 1961, Janssen Pharmaceutica, N.V. joined the Johnson & Johnson Family of Companies. Janssen’s legacy continues to inspire Johnson & Johnson and its commitment to finding innovative cures for unmet medical needs.

Source:
Seema Kumar, Johnson & Johnson Pharmaceutical Services, L.L.C

Porter Novelli

View drug information on Herceptin. Continue reading →

Researchers at the Department of Biochemistry and Molecular Biology of Universitat Aut??noma de Barcelona (UAB) have revealed the process by which proteins with a tendency to cause conformational diseases such as amyotrophic lateral sclerosis, familial amyloidotic polyneuropathy, familial amyloidotic cardiomyopathy, etc. finally end up causing them. Researchers have carried out an analysis of their 3D structure and studied why these proteins finally become toxic although they are correctly folded, an indicator that they are functioning correctly. The answer can be found in the separation of the proteins, which under normal conditions are found in groups of two or more, caused by a genetic mutation in their composition. Researchers believe this discovery, published recently in the journal PLoS Computational Biology, could also be the cause of other diseases of unknown origins.

Every day cells produce thousands of new proteins which renew themselves every second and which, by obeying the orders prescribed in our genetic code, work towards the proper functioning of our body. However, these proteins occasionally suffer genetic mutations which can cause changes in their composition, thus preventing them from carrying out their functions and the activities they are assigned. In many cases this gives way to the formation of toxic macromolecular aggregates amyloid fibrils – which block our body’s protein quality control system and finally provoke cell death.

Protein aggregation and the misfolding of proteins can be linked to the origin of many conformational diseases which can be either genetic or spontaneous. The proteins involved can either have an unstructured or lineal unfolded form such as in Alzheimer’s and Parkinson’s disease or Type II Diabetes, or can be globular, showing a folded 3D-structure. The former have been widely characterised by scientists and the process by which they unfold is known. The process leaves regions uncovered which are in the risk of becoming aggregated and these eventually form toxic assemblies. Globular proteins are known to be linked to hepatic, cardiac, renal and neurological disorders. However scientists do not know exactly how they manage to aggregate despite the fact that they are correctly folded within the body.

Through computational analysis, researchers Salvador Ventura and Virg?­nia Castillo, from the UAB Department of Biochemistry and Molecular Biology, have discovered that, in non-disease conditions, globular proteins related to conformational diseases are found associated in pairs to other proteins or in complex subunits, in a way that one protein covers the aggregation-prone region of the other and thus prevents the onset of this process. Therefore these regions remain obscured in the interior of the structure and are inoffensive to the organism as long as the two proteins are joined together. Researchers have found that genetic mutations produced in the interaction sites of the protein pair prevents their association, leaving aggregation-prone regions uncovered and favouring the formation of toxic aggregates. According to researchers, this would explain why out of two people with the same globular proteins and the same risk regions, only the one who suffers a genetic mutation would finally develop a disease.

The conclusions obtained have led researchers to contemplate the possibility that dissociation is a general mechanism, which not only affects globular proteins with a clearly defined structure, but also others which have not yet been characterised and which could be the cause of diseases of unknown origin.

As possible strategies to prevent the dissociation of proteins, the authors propose introducing genetic mutations into the proteins to strengthen their association and developing specific molecules to block the risk regions of already dissociated proteins.

The results of the study carried out by UAB researchers coincides with those obtained by researchers at Cambridge University, who also published similar data in the journal Proceedings of the National Academic of Sciences.

In the future UAB researchers are planning to expand their computational analysis to cover the whole set of human proteins with a defined 3D-structure. With this objective they seek to discover the proteins responsible for different genetic diseases of unknown origins and offer a series of new therapeutic targets for these disorders.

Source: Barcelona Universitat Aut??noma Continue reading →

One of the concerns of citizens with the development and use of genetically engineered mosquitoes in the fight against dengue fever and malaria is the fact that most of the current approaches result in released engineered strains remaining in the environment.

We provide a novel approach that enables self-limiting spread of an engineered construct and describe its population genetic and mechanical properties.

Proceedings of the Royal Society B: Biological Sciences

Proceedings B is the Royal Society’s flagship biological research journal, dedicated to the rapid publication and broad dissemination of high-quality research papers, reviews and comment and reply papers. The scope of journal is diverse and is especially strong in organismal biology.

Proceedings of the Royal Society B: Biological Sciences Continue reading →