Genetic insight into plant sex

Monash University

A study of moss has provided insight into how land plants reproduce and could help researchers engineer higher yielding crops. Image: leungchopan/Shutterstock New research has uncovered a mechanism that regulates the reproduction of plants, providing a possible tool for engineering higher yielding crops. In a study published in Science, researchers from Monash University and collaborators in Japan and the US, identified for the first time a particular gene that regulates the transition between stages of the life cycle in land plants. Professor John Bowman, of the Monash School of Biological Sciences said plants, in contrast to animals, take different forms in alternating generations - one with one set of genes and one with two sets. "In animals, the bodies we think of are our diploid bodies - where each cell has two sets of DNA. The haploid phase of our life cycle consists of only eggs if we are female and sperm if we are male. In contrast, plants have large complex bodies in both haploid and diploid generations," Professor Bowman said. These two plant bodies often have such different characteristics that until the mid-1800s, when better microscopes allowed further research, they were sometimes thought to be separate species. Professor Bowman and Dr Keiko Sakakibara, formerly of the Monash School of Biological Sciences and now at Hiroshima University, removed a gene, known as KNOX2 from moss. They found that this caused the diploid generation to develop as if it was a haploid, a phenomenon termed apospory. The equivalent mutations in humans would be if our entire bodies were transformed into either eggs or sperm. "Our study provides insights into how land plants evolved two complex generations, strongly supporting one theory put forward at the beginning of last century proposing that the complex diploid body was a novel evolutionary invention", Professor Bowman said. While Professor Bowman's laboratory in the School of Biological Sciences is focused on basic research exploring the evolution and development of land plants, he said there were possible applications for the results as mutations in the gene cause the plant to skip a generation. One goal in agriculture is apomixis, where a plant produces seeds clonally by skipping the haploid generation and thereby maintaining the characteristics, such as a high yielding hybrid, of the mother plant. Apomixis would mean crops with desirable qualities could be produced more easily and cheaply. "Gaining a better understanding of the molecular basis of plant reproduction and the regulations of the alternation of generations could provide tools to engineer apomixis - a breakthrough that would be highly beneficial, especially in developing countries," Professor Bowman said. Editor's Note: Original news release can be found here.

Study illuminates roles of novel epigenetic chemical in the brain

Researchers from the Centre for Addiction and Mental Health (CAMH) have identified a new role of a chemical involved in controlling the genes underlying memory and learning.

"The brain is a plastic tissue, and we know that learning and memory require various genes to be expressed," says CAMH Senior Scientist Dr. Art Petronis, who is a senior author on the new study. "Our research has identified how the chemical 5-hmC may be involved in the epigenetic processes allowing this plasticity." Dr. Petronis is head of the Krembil Family Epigenetics Laboratory in CAMH's Campbell Family Mental Health Research Institute.

5-hmC is an epigenetic modification of DNA, and was discovered in humans and mice in 2009. DNA modifications are chemical changes to DNA. They flag genes to be turned "on" – signalling the genome to make a protein – or turned "off." As the overwhelming majority of cells in an individual contain the same genetic code, this pattern of flags is what allows a neuron to use the same genome as a blood or liver cell, but create a completely different and specialized cellular environment.

The research, published online in Nature Structural & Molecular Biology, sheds light on the role of 5-hmC. Intriguingly, it is more abundant in the brain than in other tissues in the body, for reasons not clear to date.

The CAMH team of scientists examined DNA from a variety of tissues, including the mouse and human brain, and looked at where 5-hmC was found in the genome. They detected that 5-hmC had a unique distribution in the brain: it was highly enriched in genes related to the synapse, the dynamic tips of brain cells. Growth and change in the synapse allow different brain cells to "wire" together, which enables learning and memory.

"This enrichment of 5-hmC in synapse-related genes suggests a role for this epigenetic modification in learning and memory," says Dr. Petronis.

The team further showed that 5-hmC had a special distribution even within the gene. The code for one gene can be edited and "spliced" to create several different proteins. Dr. Petronis found that 5-hmC is located at "splice junctions," the points where the gene is cut before splicing.

"5-hmC may signal the cell's splicing machinery to generate the diverse proteins that, in turn, give rise to the unprecedented complexity of the brain," he says.

The research team is continuing to investigate the role of 5-hmC in more detail, and to determine whether 5-hmC function is different in people with bipolar disorder and schizophrenia compared to people without these diagnoses.

Provided by Centre for Addiction and Mental Health

"Study illuminates roles of novel epigenetic chemical in the brain." September 17th, 2012. http://medicalxpress.com/news/2012-09-illuminates-roles-epigenetic-chemical-brain.html

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Robert Karl Stonjek

Study Produces Massive Data Set

Science Daily William Noble, professor of genome sciences and computer science, in the data center at the William H. Foege Building. Noble, an expert on machine learning, and his team designed artificial intellience programs to analyze ENCODE data. These computer programs can learn from experience, recognize patterns, and organize information into categories understandable to scientists. The center houses systems for a wide variety of genetic research. The computer center has the capacity to store and analyze a tremendous amount of data, the equivalent of a 670-page autobiography of each person on earth, uncompressed.The computing resources analyze over 4 pentabytes of genomic data a year. (Credit: Clare McLean, Courtesy of University of Washington)

 — The Human Genome Project produced an almost complete order of the 3 billion pairs of chemical letters in the DNA that embodies the human genetic code -- but little about the way this blueprint works. Now, after a multi-year concerted effort by more than 440 researchers in 32 labs around the world, a more dynamic picture gives the first holistic view of how the human genome actually does its job.

During the new study, researchers linked more than 80 percent of the human genome sequence to a specific biological function and mapped more than 4 million regulatory regions where proteins specifically interact with the DNA. These findings represent a significant advance in understanding the precise and complex controls over the expression of genetic information within a cell. The findings bring into much sharper focus the continually active genome in which proteins routinely turn genes on and off using sites that are sometimes at great distances from the genes themselves. They also identify where chemical modifications of DNA influence gene expression and where various functional forms of RNA, a form of nucleic acid related to DNA, help regulate the whole system.

"During the early debates about the Human Genome Project, researchers had predicted that only a few percent of the human genome sequence encoded proteins, the workhorses of the cell, and that the rest was junk. We now know that this conclusion was wrong," said Eric D. Green, M.D., Ph.D., director of the National Human Genome Research Institute (NHGRI), a part of the National Institutes of Health. "ENCODE has revealed that most of the human genome is involved in the complex molecular choreography required for converting genetic information into living cells and organisms."

NHGRI organized the research project producing these results; it is called the Encyclopedia of DNA Elements or ENCODE. Launched in 2003, ENCODE's goal of identifying all of the genome's functional elements seemed just as daunting as sequencing that first human genome. ENCODE was launched as a pilot project to develop the methods and strategies needed to produce results and did so by focusing on only 1 percent of the human genome. By 2007, NHGRI concluded that the technology had sufficiently evolved for a full-scale project, in which the institute invested approximately $123 million over five years. In addition, NHGRI devoted about $40 million to the ENCODE pilot project, plus approximately $125 million to ENCODE-related technology development and model organism research since 2003.

The scale of the effort has been remarkable. Hundreds of researchers across the United States, United Kingdom, Spain, Singapore and Japan performed more than 1,600 sets of experiments on 147 types of tissue with technologies standardized across the consortium. The experiments relied on innovative uses of next-generation DNA sequencing technologies, which had only become available around five years ago, due in large part to advances enabled by NHGRI's DNA sequencing technology development program. In total, ENCODE generated more than 15 trillion bytes of raw data and consumed the equivalent of more than 300 years of computer time to analyze.

"We've come a long way," said Ewan Birney, Ph.D., of the European Bioinformatics Institute, in the United Kingdom, and lead analysis coordinator for the ENCODE project. "By carefully piecing together a simply staggering variety of data, we've shown that the human genome is simply alive with switches, turning our genes on and off and controlling when and where proteins are produced. ENCODE has taken our knowledge of the genome to the next level, and all of that knowledge is being shared openly."

The ENCODE Consortium placed the resulting data sets as soon as they were verified for accuracy, prior to publication, in several databases that can be freely accessed by anyone on the Internet. These data sets can be accessed through the ENCODE project portal (www.encodeproject.org) as well as at the University of California, Santa Cruz genome browser,http://genome.ucsc.edu/ENCODE/, the National Center for Biotechnology Information,http://www.ncbi.nlm.nih.gov/geo/info/ENCODE.html and the European Bioinformatics Institute,http://useast.ensembl.org/Homo_sapiens/encode.html?redirect=mirror;source=www.ensembl.org.

"The ENCODE catalog is like Google Maps for the human genome," said Elise Feingold, Ph.D., an NHGRI program director who helped start the ENCODE Project. "Simply by selecting the magnification in Google Maps, you can see countries, states, cities, streets, even individual intersections, and by selecting different features, you can get directions, see street names and photos, and get information about traffic and even weather. The ENCODE maps allow researchers to inspect the chromosomes, genes, functional elements and individual nucleotides in the human genome in much the same way."

The coordinated publication set includes one main integrative paper and five related papers in the journal Nature; 18 papers inGenome Research; and six papers in Genome Biology. The ENCODE data are so complex that the three journals have developed a pioneering way to present the information in an integrated form that they call threads.

"Because ENCODE has generated so much data, we, together with the ENCODE Consortium, have introduced a new way to enable researchers to navigate through the data," said Magdalena Skipper, Ph.D., senior editor at Nature, which produced the freely available publishing platform on the Internet.

Since the same topics were addressed in different ways in different papers, the new website, www.nature.com/encode, will allow anyone to follow a topic through all of the papers in the ENCODE publication set by clicking on the relevant thread at the Nature ENCODE explorer page. For example, thread number one compiles figures, tables, and text relevant to genetic variation and disease from several papers and displays them all on one page. ENCODE scientists believe this will illuminate many biological themes emerging from the analyses.

In addition to the threaded papers, six review articles are being published in the Journal of Biological Chemistry and two related papers in Science and one in Cell.

The ENCODE data are rapidly becoming a fundamental resource for researchers to help understand human biology and disease. More than 100 papers using ENCODE data have been published by investigators who were not part of the ENCODE Project, but who have used the data in disease research. For example, many regions of the human genome that do not contain protein-coding genes have been associated with disease. Instead, the disease-linked genetic changes appear to occur in vast tracts of sequence between genes where ENCODE has identified many regulatory sites. Further study will be needed to understand how specific variants in these genomic areas contribute to disease.

"We were surprised that disease-linked genetic variants are not in protein-coding regions," said Mike Pazin, Ph.D., an NHGRI program director working on ENCODE. "We expect to find that many genetic changes causing a disorder are within regulatory regions, or switches, that affect how much protein is produced or when the protein is produced, rather than affecting the structure of the protein itself. The medical condition will occur because the gene is aberrantly turned on or turned off or abnormal amounts of the protein are made. Far from being junk DNA, this regulatory DNA clearly makes important contributions to human health and disease."

Identifying regulatory regions will also help researchers explain why different types of cells have different properties. For example why do muscle cells generate force while liver cells break down food? Scientists know that muscle cells turn on some genes that only work in muscle, but it has not been previously possible to examine the regulatory elements that control that process. ENCODE has laid a foundation for these kinds of studies by examining more than 140 of the hundreds of cell types found in the human body and identifying many of the cell type-specific control elements.

Despite the enormity of the dataset described in this historic collection of publications, it does not comprehensively describe all of the functional genomic elements in all of the different types of cells in the human body. NHGRI plans to invest in additional ENCODE-related research for at least another four years. During the next phase, ENCODE will increase the depth of the catalog with respect to the types of functional elements and cell types studied. It will also develop new tools for more sophisticated analyses of the data.

Personal genomics: where science fiction meets reality

EMMA HUANG, CSIRO

Share on print While genes can tell us a lot, they still need to be considered in the context of the environment to improve prediction of disease or particular traits. Image: zmeel/iStockphoto Imagine a future where doctors take a strand of your hair or a drop of your blood and tell you yourDNA predicts a 78% risk of developing heart disease. On the plus side, it also predicts exactly which treatments will work best for you. The genetic code is well enough understood that individual predictions and treatments based ongenomics are universal. In science fiction, this is a “not-too-distant” future. The 1997 film GATTACA, directed by Andrew Niccol, describes a world driven by genomics. At or before birth, doctors calculate your probability of being diagnosed with heart disease, neurological and psychological disorders, and even predict how tall you will be or whether you will need glasses. For better or worse, this decides the course of your life. In this world a genome sequence is not only cheap, fast, and readily available – it’s also easy to interpret. Human Genome Project So let’s compare science fiction with science reality. The Human Genome Project was started in 1990 with aims including sequencing the human genome, identifying and mapping all genes, improving tools for data analysis, and addressing potential ethical, legal and social issues associated with genomics. It took 13 years and US$3 billion to complete. Since then, sequencing has rapidly become both cheaper and faster. Now, sequencing a full human genome costs under US$10,000, and takes only two days. It’s cost-effective enough to be performed in large studies and, within a few years, thousands of human genome sequences will be available. If progress continues at this pace, widespread acquisition of genetic data may indeed be “not-too-distant”. But, translating that data into knowledge through analysis and interpretation will take much longer. Translating DNA into traits How do we translate the 3 billion As, Cs, Ts and Gs of the human genome into a precise description of an individual’s risk for disease? We need to identify which parts of the genome are associated with disease. More than 99.5% of the genome is identical between two humans, but that still leaves 15m positions to search through, which is akin to finding needles in a haystack. Many different methods exist to essentially look for genetic variants which are over-represented in individuals with disease relative to those without. These work well in cases where only one variant causes disease (such as Huntington’s disease). Indeed, more than 3,000 traits already have a causal gene characterised and annotated. This success forms the basis for a public-health funded system in Australasia to screen newborns for about 30 rare diseases, including cystic fibrosis and hypothyroidism . The similarities with newborn testing in GATTACA are clear, but in science reality the testing won’t tell you anything about your child’s risk for heart disease. For this and other more common diseases (such as Alzheimer’s and diabetes) there are many different genetic factors influencing risk. If these act in pairs, the size of the search problem is increased from millions to hundreds of trillions of possibilities. Further, we often need to consider networks of genetic variants, where changes in one pathway have flow-on effects to other regions of the genome. Can we decode the DNA code? There’s been some success in identifying individual variants affecting disease – at the end of 2011 more than 1,600 studies had reported regions of the genome associated with about 250 different traits. But these rarely account for the full spectrum of genetic effects expected for a given disease. For human height, which, unlike many disorders, is easy to measure and highly influenced by genetic factors, the nearly 200 variants discovered account for only a small portion of the overall variation. Improving individual prediction will require researchers in biology, statistics, computational science and many other disciplines to work together for years to come. Even if we completely understood the language of DNA sequence, it’s just the tip of the iceberg. Not only are there many effects of DNA beyond that of the sequence (such asepigenetics) – the fact that DNA is only part of the story can be seen in the fact identical twins are not identical people. Genetics must be considered in the context of environment to improve prediction, as it plays a huge developmental role. A relatively simple example is the disease phenylketonuria, which can cause mental retardation and seizures. This is a disease with a known genetic cause, and is in fact one of the 30 screened for at birth. The environment is critical in the course of the disease, as patients given a strict diet can lead a normal life. For diseases such diabetes and cancer, both genetic and environmental factors, as well as interactions between the two, must be considered in order to produce accurate models. There are certainly success stories in personal genomics, and it has the potential to change medicine and society as a whole. But even if the future is bright, we’re still a long way from making science fiction into science reality. Editor's Note: This article was originally published by The Conversation, here, and is licenced as Public Domain under Creative Commons. See Creative Commons - Attribution Licence.

Explainer: what is the Human Genome Project?

MELISSA SOUTHEY, THE UNIVERSITY OF MELBOURNE

n print The Human Genome Project has already changed the way we think about our health and the world around us, but it is still in its early stages. More complex analysis of our genomes could lead to even more breakthroughs and greater understanding of our bodies and evolution. Image: mevans/iStockphoto For many decades humans have pursued work to characterise the human genome. Today,publicly available references to genome sequences are available and have been instrumental in effecting recent advances in medicine, genetics and technology. But interpretation of the human genome is in its early stages and large initiatives are now embarking on more complex pursuits to characterise the human genome that include understanding individual genome variation. What is the human genome sequence? The human genome sequence is contained in our DNA and is made up of long chains of “base pairs” that form our 23 chromosomes. Along our chromosomes are the base pair sequences that form our 30,000 genes. All humans share a great degree of similarity in their genome sequences – the same genes are ordered in the same manner across the same chromosomes, yet each of us is unique (except for identical twins) in terms of the exact base pair sequence that makes up our genes and thus our DNA/chromosomes. It is this similarity that, in a genetic sense, defines us as “human” and the specific variation that defines us as individuals. Launching the Human Genome Project As early as the 1980s, momentum was gathering behind activities that supported, and would eventually define, the Human Genome Project. Conversations had turned into workshops that likened characterisation of the human genome to characterisation of the human anatomy that had centuries earlier revolutionised the practice of medicine. In 1990, with continued support from the United States Department of Energy, the United States National Institutes of Health (NIH) and widespread international collaboration and cooperation, the $3 billion dollar Human Genome Project was launched. The project aimed to determine the sequence of the human genome within 15 years. By 2000 (well ahead of schedule) a working draft of the human genome was announced. This was followed by regular updates and refinements and today we all have access to a human “reference genome sequence”. This sequence does not represent the exact sequence of the base pairs in every human, it is the combined genome sequence of a few individuals and represents the broad architecture of all human genomes that scaffolds current and future work aiming to characterise individual sequence variation. The detail and stories behind the Human Genome Project are themselves extraordinarily human. This project benefited from our human drive for discovery and advancement and our human response to competition. It forced us as individuals and communities to consider our personal, ethical and social attitudes towards the availability of human genome information, intellectual property protection (especially gene patenting) and public versus private/commercial enterprise in a broad sense. Advancing the project's success In the years after the initiation of the Human Genome Project there were constant and significant advances in key areas that facilitated the enormous DNA sequencing effort. These advances were achieved in all areas key to the efficient processing of DNA into electronic DNA sequence information. They included: improvements in the chemistries and instruments used to decipher the base pair sequences of prepared pieces of DNA significant improvements in the capacity of computing facilities to manage the volume and nature of data generated from the instruments perhaps most importantly, improvements in the analytical tools The then state-of-the-art DNA sequencing chemistry used in the Human Genome Project wasSanger sequencing – capable of sequencing single stretches of several hundred base pairs at a time. Advances in analytical methods of putting these pieces back together into the 3.3 billion base pair human genome was fundamental to the progress of the project. The Human Genome Project was also advanced by competition. In 1998 a privately funded project with similar aims was launched in the United States by Celera Genomics. Using a modification of the DNA sequencing technique and a smaller budget it was partly responsible for the accelerated progress of the Human Genome Project. This competition brought forward other aspects of the project for ethical and legal scrutiny and discussion. Patent wars The issue of patenting genes formed a background to the Human Genome Project and many other similarly focused projects for some time. In the early 1990s it had been a serious issue of contention between James Watson and Bernadine Healy (then Director of NIH). Competition between Celera Genomics and The Human Genome Project now brought the discussion into a different dimension. The publicly-funded Human Genome Project released new data freely and in 2000 released the first working draft of the genome on the web. In contrast, Celera filed preliminary patent applications on more than 6,000 genes and also benefited from the data provided by the publicly-funded project. In March 2000, the US president Bill Clinton announced that the genome could not be patented and should be made freely available. The stock market dipped transiently because this announcement did not reflect the tangible benefits for biological research scientists. Within 24 hours of the release of the first draft of the human genome, the scientific community downloaded half a trillion bytes of information from the University of California, Santa Cruz’sgenome server – a strong indication of the relevance of this information to the biological, biotechnological and medical research communities. Interpretation of the genome sequence is in its early stages but has already improved our ability to offer genetic testing and clinical management of many diseases. We are now embarking on more complex pursuits to characterise the human genome so as to understand individual genome variation. This work is supported by projects related to, and of the same magnitude as, the Human Genome Project, including projects characterising the genomes of other species, among them mice and yeast, the International HapMap Project,The Personal Genome Project and the 1000 Genomes Project. These projects are greatly enhanced by the next generation of sequencing methodologies, which will expedite the characterisation of the human genome at an individual level in coming years. Editor's Note: This article was originally published by The Conversation, here, and is licenced as Public Domain under Creative Commons. See Creative Commons - Attribution Licence.

Genetic clues for type 2 diabetes

THE UNIVERSITY OF WESTERN AUSTRALIA

Share on print The two studies identified 53 loci (regions on the chromosome where genes are located) that are linked to glycemic traits and type 2 diabetes. The research could help scientists develop a tool to detect the risk of developing type 2 diabetes.  Image: fpm/iStockphoto Busselton residents and researchers from The University of Western Australia have contributed to a worldwide scientific collaboration that has identified new genetic links in the quest to map the biological pathways that cause diabetes.  In two papers published online today in Nature Genetics the researchers have identified a substantial number of new loci (the specific place on a chromosome where a gene is located) linked with glycemic traits and type 2 diabetes (T2D) that have not been described in previous research. Diabetes is a condition where there is too much glucose, a type of sugar, in the blood.  Type 2 diabetes is the most common form of diabetes affecting some 90 per cent of all people with diabetes. It is sometimes described as a ‘lifestyle disease' strongly associated with high blood pressure, high cholesterol and obesity. In the study ‘Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes' researchers extended the discovery and characterisation of variants influencing susceptibility to T2D. The study expanded T2D association analysis to almost 150,000 individuals and in so doing added another 10 loci to the list of confirmed variant signals. It also concluded that genetic profiling had the potential to provide a useful risk assessment for developing T2D. The second paper titled "Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways" discovered another 38 new loci with glycemic traits not described in previous research, taking the total number of signals influencing glycemic traits to 53. "This research will provide a better understanding of the genes associated with glycemic control that may interact with environmental factors and trigger diabetes," co-author Dr Jennie Hui from the UWA Schools of Pathology and Laboratory Medicine and Population Health said. The research collaborations also included scientists from The University of Western Australia's Centre for Genetic Epidemiology and Biostatistics, and the UWA School of Medicine and Pharmacology in conjunction with the Busselton Population Medical Research Institute.  The Busselton Health Study (BHS) is one of the world's longest running epidemiological research programs. Since 1966, it has contributed to an understanding of many common diseases and health conditions.  The unique BHS database is compiled and managed by UWA's School of Population Health. Editor's Note: Original news release can be found here.

DNA explains why women live longer

MONASH UNIVERSITY

Share on print Mitochondria (green) exist in almost all animal cells and convert food into the energy that powers the body. The researchers found mutations within mitochondrial DNA affect how long males live and the speed at which they age.  Image: Eraxion/iStockphoto Scientists are beginning to understand one of life's enduring mysteries - why women live, on average, longer than men. Published in Current Biology, research led by Monash University describes how mutations to the DNA of the mitochondria can account for differences in the life expectancy of males and females. Mitochondria, which exist in almost all animal cells, are vital for life because they convert our food into the energy that powers the body. Dr Damian Dowling and PhD student, Florencia Camus, both from the Monash School of Biological Sciences, worked with Dr David Clancy from Lancaster University to uncover differences in longevity and biological ageing across male and female fruit flies that carried mitochondria of different origins. They found that genetic variation across these mitochondria were reliable predictors of life expectancy in males, but not in females. Dr Dowling said the results point to numerous mutations within mitochondrial DNA that affect how long males live, and the speed at which they age. "Intriguingly, these same mutations have no effects on patterns of ageing in females. They only affect males,” Dr Dowling said. “All animals possess mitochondria, and the tendency for females to outlive males is common to many different species. Our results therefore suggest that the mitochondrial mutations we have uncovered will generally cause faster male ageing across the animal kingdom.” The researchers said these mutations can be entirely attributed to a quirk in the way that mitochondrial genes are passed down from parents to offspring. “While children receive copies of most of their genes from both their mothers and fathers, they only receive mitochondrial genes from their mothers. This means that evolution’s quality control process, known as natural selection, only screens the quality of mitochondrial genes in mothers," Dr Dowling said. "If a mitochondrial mutation occurs that harms fathers, but has no effect on mothers, this mutation will slip through the gaze of natural selection, unnoticed. Over thousands of generations, many such mutations have accumulated that harm only males, while leaving females unscathed.” The study builds on previous findings by Dr Dowling and his team that investigated the consequences of maternal inheritance of mitochondria in causing male infertility. “Together, our research shows that the mitochondria are hotspots for mutations affecting male health. What we seek to do now is investigate the genetic mechanisms that males might arm themselves with to nullify the effects of these harmful mutations and remain healthy,” Dr Dowling said. Editor's Note: Original news release can be found here.

The Little Cell That Could

Critics point out that cell therapy has yet to top existing treatments. Biotech companies are setting out to change that—and prove that the technology can revolutionise medicine.

By Megan Scudellari | 

 

NEW SKIN: A scientist at Advanced Tissue Sciences in La Jolla, California, holds up a section of artificial skin—human cells on a biocompatible scaffold—used for treating severe wounds.Corbis, © George Steinmetz

Since Ernest McCulloch and James Till first demonstrated the existence of self-renewing cells in the bone marrow of mice in 1963, stem cells have been hyped every which way: they will cure cancer, make diseased hearts whole, and reverse Alzheimer’s. These breakthroughs have clearly not come to pass. But the effort to use cells to treat disease continues to chug along, and there may finally be light at the end of the tunnel.

Cell therapy—the therapeutic use of somatic cells, stem cells, and cells derived from stem cells to treat various conditions—is not new. The first successful human-to-human blood transfusion occurred in 1818, and the first bone marrow transplant occurred more than half a century ago. But finally, after a 200-year journey punctuated with more failures than successes, cell therapy has become an industry for the first time.

There are currently eight cell-based treatments in the United States, ranging from a prostate cancer vaccine to a wrinkle remedy. Globally, the industry is predicted to rake in $2.7 billion this year and reach $5.1 billion by 2014. Other indicators of a growing industry are visible: there are more than 100 ongoing cell therapy trials in the U.S., with numerous products in the late stages of clinical development; some 30 cell therapy companies are now publicly traded; and large pharmaceutical companies are starting to snatch up promising candidates.

But while the field is beginning to take shape, it has yet to determine its final form. Cell therapies “could be paradigm-shifting for the healthcare field,” says Mahendra Rao, director of the National Institutes of Health’s new Intramural Center for Regenerative Medicine. “The proof will be when we have a whole series of products, not just a couple,” he says.

Cell therapy can potentially be the fourth pillar in health care, together with small molecules, biologics, and devices, agrees Chris Mason, a cell therapy expert at University College London (UCL). “Cell therapies are looking at areas of unmet need”—such as Parkinson’s and multiple sclerosis (MS)—“that have not been addressed using the other modalities,” he says.

But the industry struggles with biological complexity, unexplored regulatory paths, and tentative investors who have become callous after a decade of hype. And there’s one major, missing ingredient—an approved therapy that lives up to all the promises. No cell therapy has cured cancer, fixed heart disease, or stopped neurodegeneration.

“We need a big success,” says Robert Lanza, chief scientific officer at Advanced Cell Technology, a company developing human embryonic stem cell (hESC)-derived cell therapies for eye diseases. “When we finally go into patients and give an injection that stops MS or stops lupus in its tracks, you’re going to see people running toward cell therapies.”

Waiting for Herceptin

Advocates love to compare cell therapies to monoclonal antibodies (mAbs). Discovered in 1975, mAbs didn’t have a major success until 1998, when Genentech’s Herceptin, an mAb for breast cancer treatment, was approved by the US Food and Drug Administration. Herceptin (trastuzumab), called a “breakout drug,” is now one of the best-selling biotech products in history, generating more than $5 billion in annual worldwide sales (the drug costs $70,000 for a full course of treatment). Other mAbs followed Herceptin until monoclonal antibodies became one of the most common drugs in medicine, with an estimated global market of $15.6 billion in 2010, expected to reach $31.7 billion by 2017.

CELL-BASED VACCINE: A close-up of the cell separation process used to manufacture Dendreon’s Provenge, an autologous cellular immunotherapy for prostate cancer.Dendreon Corporation

The cell therapy industry has yet to find its Herceptin. “For those of us who have been in the sector for a long time, we’re still waiting for the big blockbuster,” says Lee Buckler, founder and managing director of the Cell Therapy Group, a cell therapy consulting company. “It’s hard to argue—there’s not much out there, and what’s out there is not hugely impactful yet,” agrees Kevin D’Amour, chief scientific officer of ViaCyte, a California-based biotech that engineers hESCs into insulin-producing islet cells for the treatment of diabetes. Currently marketed cell therapy products focus on dermatology and orthopedics, including Advanced BioHealing’s Dermagraft, a fibroblast-derived cell therapy for diabetic foot sores; Fibrocell Science’s laViv, a cosmetic product to smooth smile lines; and Genzyme’s Carticel, a culture of patients’ own chondrocytes for knee cartilage repair. The sole cell therapy in oncology is Dendreon’s Provenge, a cell-based prostate cancer vaccine. Provenge (sipuleucel-T) has been the object of both praise, for being the first therapeutic cancer vaccine to reach the market, and criticism, for its limited efficacy at a high cost: the vaccine extends life by about 4 months for a price of $93,000 per treatment.

“So far we’ve got some nice products, but nothing paradigm-shifting,” says Buckler. “But these are first-generation products, and unless you are Steve Jobs, first-generation products are rife with commercial and technical challenges, so it’s no surprise that they’re not as effective or commercially viable as we hoped,” he says. “Don’t measure us too strictly by those first few products, but we’d better damn well learn now with the second and third generation.”

Catching Pharma’s eye

A 2010 analysis published in Cell Stem Cell called pharma’s involvement in cell therapies “hesitant,” and found that large pharmaceutical companies sponsored only 3 of 68 cell therapy clinical trials that year (Cell Stem Cell

, 6:517-20, 2010). “The move to true cell-based therapeutics by pharma is still modest,” wrote the authors, all Pfizer employees.

There seems to be two main reasons for the pharmaceutical industry’s reluctance. First, approved cell therapies such as Provenge carry a hefty price tag for a treatment that doesn’t significantly surpass current standards of care. Like antibodies, cell therapies are expensive to make, especially autologous therapies in which a single batch is made per patient, rather than a large batch for hundreds of patients. “It’s never going to be cheap to make cell therapies,” says Jeff Abbey, president and CEO of Durham, North Carolina-based Argos Therapeutics. “It’s clearly a big challenge for everybody in the field.”

Second, cell therapies do not fit into Big Pharma’s traditional reductionist pursuit of drugs. Stem cells are the most “dynamic, complex entities ever proposed for therapies,” says Lanza—a far cry from small molecules like aspirin, for which companies know the exact mechanism and can be assured that every molecule in an aspirin bottle is aspirin, nothing else. In many cases of cell therapy, scientists don’t understand exactly how the cells work. To some, that is a major drawback. “A lot of cell therapies under clinical development . . . are being used with little to no understanding of the mechanism of action,” says ViaCyte’s D’Amour. “If you don’t know how it works, it’s hard to say it’s working at all.”

But others say that black-box complexity is the wave of the future. “It’s important to know enough to produce a robust, safe therapy,” says UCL’s Mason, “but do you have to understand every bit of the mechanism? No, I don’t think you do. The cells are working at many different levels, and that’s what makes them so powerful.”

Despite those challenges, there is some evidence that in the last several years Big Pharma has started to take an interest in the field. In 2008, Genzyme signed an agreement with stem cell company Osiris Therapeutics, committing up to $1.38 billion in development, regulatory, and sales milestone payments for two of the company’s cell therapies. In December 2010, Cephalon bought a 20 percent stake in Mesoblast and the rights to market the Australian company’s adult stem-cell therapies for $350 million—a major attraction for Teva Pharmaceuticals, the world’s largest generic drug maker, which purchased Cephalon 5 months later. Teva is now funding Mesoblast’s late-stage clinical trials for cell-based therapies. And in May 2011, pharmaceutical heavyweight Shire purchased Advanced BioHealing and its approved cell therapy, Dermagraft, for $750 million.

“Pharma has shifted from exploratory mode, to exploitation mode, to actually make profits on cell therapies,” says Mason, who sits on the scientific advisory board of several large pharmaceutical companies. “These companies are finally putting in substantial money.”

The increased commitment may be a sign that Big Pharma is starting to believe that the early hype is finally coming to fruition. “This is going to revolutionize medicine,” says Lanza. “What you’ve been hearing about stem cells—that after 10 years not much has happened—well, now it’s happening. In the next few years, you’re going to see pretty remarkable things.”

Cell Therapies in Development

Today, second and third generation therapies are just reaching late-stage clinical trials. Here are a few noteworthy companies running advanced trials, each hoping to find the field’s first blockbuster product.

Have a Heart

Michigan-based Aastrom Biosciences, specializing in cell therapies for chronic cardiovascular diseases, is one of the few companies with a cell therapy in a Phase III trial. Ixmyelocel-T is a treatment for critical limb ischemia, an obstruction of leg arteries that causes severe pain and can even lead to amputation. In the trial, 600 patients will be treated with their own mesenchymal stem cells and anti-inflammatory macrophages derived from bone marrow. The company expects to unblind the results in the second half of 2014, says Tim Mayleben, CEO of the company. “We want to be among the first to market innovative cell therapy.”

Curing Cancer?

Argos Therapeutics, based in Durham, North Carolina, will soon begin a Phase III trial with a cell therapy for metastatic kidney cancer and its ongoing Phase II trial for a cell-based HIV treatment. Both therapies rely on autologous dendritic cells—bone marrow-derived immune cells taken from a patient and expanded in culture—loaded with tumor antigens to activate the immune system. “We do have patients living an extremely long time, but we haven’t definitively cured anybody yet,” says Jeff Abbey, president and CEO of Argos. He notes that the current kidney cancer trial, like most oncology trials, is conducted in patients with late-stage disease. “I can’t wait to do our next trial with earlier-stage patients,” he adds. “Maybe there we can stop the cancer from ever coming back.”

Eye for an Eye

Advanced Cell Technology is one of just a handful of companies using hESCs to derive cells for treatment. The company is transforming hESCs into retinal pigment epithelium (RPE)—a single layer of cells beneath the retina that nourishes and protects retinal cells—and injecting RPE cells into the eye to treat degenerative blindness diseases. “We almost went out of business three times, but now we’ve figured out how to do it,” says the company’s CSO Robert Lanza. Though the treatment is still only in safety studies, it has made a substantial difference in the lives of two legally blind women in whom it was first tested, says Lanza: they now boast of reading computer screens and recognising colours.

Source: TheScientist

http://the-scientist.com/2012/07/01/the-little-cell-that-could/

Scientists identify gene linked to facial, skull and cognitive impairment

A gene whose mutation results in malformed faces and skulls as well as mental retardation has been found by scientists. Credit: Phil Jones

A gene whose mutation results in malformed faces and skulls as well as mental retardation has been found by scientists.

They looked at patients with Potocki-Shaffer syndrome, a rare disorder that can result in significant abnormalities such as a small head and chin and intellectual disability, and found the gene PHF21A was mutated, said Dr. Hyung-Goo Kim, molecular geneticist at the Medical College of Georgia at Georgia Health Sciences University.

The scientists confirmed PHF21A's role by suppressing it in zebrafish, which developed head and brain abnormalities similar to those in patients. "With less PHF21A, brain cells died, so this gene must play a big role in neuron survival," said Kim, lead and corresponding author of the study published in The American Journal of Human Genetics. They reconfirmed the role by giving the gene back to the malformed fish – studied for their adeptness at regeneration – which then became essentially normal. They also documented the gene's presence in the craniofacial area of normal mice.

While giving the normal gene unfortunately can't cure patients as it does zebrafish, the scientists believe the finding will eventually enable genetic screening and possibly early intervention during fetal development, including therapy to increase PHF21A levels, Kim said. It also provides a compass for learning more about face, skull and brain formation.

The scientists zeroed in on the gene by using a distinctive chromosomal break found in patients with Potocki-Shaffer syndrome as a starting point. Chromosomes – packages of DNA and protein – aren't supposed to break, and when they do, it can damage genes in the vicinity.

"We call this breakpoint mapping and the breakpoint is where the trouble is," said Dr. Lawrence C. Layman, study co-author and Chief of the MCG Section of Reproductive Endocrinology, Infertility and Genetics. Damaged genes may no longer function optimally; in PHF21A's case it's about half the norm.

"When you see the chromosome translocation, you don't know which gene is disrupted," Layman said. "You use the break as a focus then use a bunch of molecular techniques to zoom in on the gene." Causes of chromosomal breaks are essentially unknown but likely are environmental and/or genetic, Kim said.

Little was known about PHF21A other than its role in determining how tightly DNA is wound in a package with proteins called histones. How tightly DNA is wound determines whether proteins called transcription factors have the access needed to regulate gene expression, which is important, for example, when a gene needs to be expressed only at a specific time or tissue. PHF21A is believed to primarily work by suppressing other genes, for example, ensuring that genes that should be expressed only in brain cells don't show up in other cell types, Kim said.

Next steps include using PHF21A as a sort of geographic positioning system to identify other "depressor" genes it regulates then screening patients to look for mutations in those genes as well. "We want to find other people with different genes causing the same problem," Layman said, and they suspect the genes PHF21A interacts with or regulates are the most likely suspects. It's too early to know what percentage of Potocki-Shaffer syndrome patients have the PHF21A mutation, Kim noted. "Now that we know the causative gene, we can sequence the gene in more patients and see if they have a mutation," Layman said.

They also want to look at less-severe forms of mental deficiency, including autism, for potentially milder mutations of PHF21A. More than a dozen of the 25,000 human genes are known to cause craniofacial defects and mental retardation, which often occur together, Kim said.

Provided by Georgia Health Sciences University

"Scientists identify gene linked to facial, skull and cognitive impairment." July 5th, 2012. http://medicalxpress.com/news/2012-07-scientists-gene-linked-facial-skull.html

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Robert Karl Stonjek

Four gene loci predispose people to most common subtype of migraine

An international research group has identified four new gene loci predisposing people to the most common subtype of migraine, migraine without aura. About two-thirds of migraine sufferers belong to this group. The study will be published in Nature Genetics on June 10, 2012.

Researchers studied genetic data of more than 11 000 people and found altogether six genes that predispose to migraine without aura. Four of these genes are new and two of them confirm previous findings.

The new genes identified in this study provide further evidence for the hypothesis that dysregulation of molecules important in transmitting signals between brain neurons contribute to migraine. Two of the genes support the hypothesis of a possible role of blood vessels and thus disturbances in blood flow.

The researchers carried out what is known as a genome-wide association study (GWAS) to zoom in on genome variants that could increase susceptibility to migraine; they compared genomes of 4800 migraine patients with more than 7000 non-migraine individuals. The project was performed by the International Headache Genetics Consortium consisting of leading migraine researches from Europe and Australia.

This was the third report on genes predisposing people to common forms of migraine, but the first one on the most common migraine subtype. "The study establishes for the first time a specific gene that contributes to this common disease" said Professor Aarno Palotie at FIMM and the Wellcome Trust Sanger Institute, the chair of the International Headache Genetics Consortium.

The carefully studied migraine patients collected from specialized headache clinics were provided a strong basis for the success of this study.

Migraine affects approximately one in six women and one in eight men, making it a leading cause of work absence and short-term incapacity: 25 million school or work days are lost for migraine each year. A US report measures its economic costs as similar to those of diabetes and WHO lists it as one of the top twenty diseases with the causes of years lived with disability (YLDs). In up to one third of migraine patients, the headache phase may be preceded or accompanied by transient neurological disturbances, the so-called aura (i.e. migraine with aura), while the majority of patients suffer from migraine without aura.

"Studies of this kind are possible only through large-scale international collaboration - bringing together the wealth of data with the right expertise and resources. The identified genes open new doors to investigate how this type of migraine comes about," said Dr. Arn van den Maagdenberg, one of the senior authors on the paper.

More information: DOI: 10.1038/ng.2307

Provided by University of Helsinki

"Four gene loci predispose people to most common subtype of migraine." June 10th, 2012. http://medicalxpress.com/news/2012-06-gene-loci-predispose-people-common.html

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Robert Karl Stonjek

Handful of genetic changes led to huge changes to human brain

Changes to just three genetic letters among billions led to evolution and development of the mammalian motor sensory network, and laid the groundwork for the defining characteristics of the human brain, Yale University researchers report.

This networks provides the direct synaptic connections between the multi-layered neocortex in the human brain responsible for emotions, perception, and cognition and the neural centers of the brain that make fine motor skills possible.

A description of how a few simple changes during the early development of mammals led to the creation of complex structures such as the human brain was published May 31 in the journal Nature.

"What we found are the genetic zip codes that direct cells to form the motorsensory network of the neocortex," said Nenad Sestan, associate professor of neurobiology, a researcher for the Kavli Institute for Neuroscience, and senior author of the paper

The paper investigated the genetic changes that occur during the early stages of development of an embryo and that direct cells to take on specific functions. Bits of DNA that do not code for proteins, called cis-regulatory elements, have been previously identified as critical drivers of evolution. These elements control the activation of genes that carry out the formation of the basic body plans of all organisms.

Sungbo Shim, the first author, and other members of Sestan's lab identified one such regulatory DNA region, which they named E4, that specifically enhances development of the corticospinal system. E4 is conserved in all mammals, indicating its importance to survival, the scientists explain. The lab also discovered how SOX4, SOX11, and SOX5 – sections of DNA called transcription factors — control the expression of genes and operate cooperatively to shape this network in the developing embryo. The changes in the genetic alphabet needed to trigger these evolutionary changes were tiny, note the researchers.

By manipulating only three genetic letters, scientists were able to functionally "jumpstart" regulatory activity in a zebrafish.

The authors also show that SOX4 and SOX11 are important for the layering of the neocortex, an essential change that led to increased complexity of the brain organization in mammals, including humans.

"Together, our fine motor skills that allow us to manipulate tools, walk, speak, and write, as well as our cognitive and emotional abilities that allow us to think, love, and plan all derive from these changes," Sestan said.

Sestan's lab is also investigating whether other types of changes in these genes and regulatory elements early in development might lead to intellectual disability and autism.

Provided by Yale University

"Handful of genetic changes led to huge changes to human brain." May 30th, 2012. http://medicalxpress.com/news/2012-05-genetic-huge-human-brain.html

Posted by
Robert Karl Stonjek