Although every cell of our bodies contains the same genetic instructions, specific genes typically act only in specific cells at particular times. Other genes are “silenced” in a variety of ways. One mode of gene silencing depends upon the way DNA, the genetic material, is packed in the nucleus of cells.

When packed very tightly around complexes of proteins called histones, the DNA double helix is rendered physically inaccessible to molecules that mediate gene expression. Now, a research team that includes Michael Q. Zhang, Ph.D., a professor at Cold Spring Harbor Laboratory (CSHL), has published a comprehensive analysis of modification patterns in histones.

Using a new technology called ChIP-Seq, the team identified 39 histone modifications, including a “core set” of 17 modifications that tended to occur together and were associated with genes observed to be active.

Modification Patterns With Different “Personalities”

Scientists have long known that chemical changes at particular locations in histone complexes influence how tightly the DNA is wrapped around the histones. “But it is important to know whether particular modifications occur together in characteristic patterns, or if these patterns can predict gene activities,” Dr. Zhang explained.

At the heart of the team’s efforts to determine this, Keji Zhao, Ph.D., of the National Heart, Blood, and Lung Institute of the National Institutes of Health, and his colleagues developed a method to map modifications in human white blood cells known as CD4+ T cells. First they used an enzyme to cut the DNA into short segments, which remained attached to histone “spools.” For each of 39 distinct histone modifications, the scientists used an antibody to extract matching histone-DNA combinations. Finally, they used the ChIP-Seq DNA-sequencing technology to determine which parts of the genome were bound to each type of modified histone.

The team’s most recent research, published in the July 2008 issue of Nature Genetics, maps the DNA locations that bind to histones containing molecular configurations called acetyl groups at 18 different positions in the “tails” of the histone proteins. The scientists combined this information with earlier maps for 19 different changes called methylation modifications, and for replacement of one of the histone proteins with a well-known variant.

The various modifications showed distinctive “personalities,” each preferentially associating with particular regulatory regions of genes.

Looking for Patterns

Mapping many modifications enabled the researchers to explore whether different types tend to appear together in the same type of DNA regulatory regions. They found that some recurring combinations did occur frequently at “promoter” and “enhancer” regions in DNA, which are known to increase the activity of nearby genes. In particular, the team identified one combination of 17 modifications that was present in more than a quarter of the more than 12,000 promoter regions they examined.

On average, the genes corresponding to this “backbone” set were expressed more actively. That is to say, they were activated, setting the cellular machinery in motion to produce specific proteins, the workhorses of most life processes.

The rich relationships detected by the researchers among the various histone modifications suggests that specific combinations might carry specific meanings. Previous researchers have proposed a “histone code” hypothesis, which posits that a particular combination of modifications may be recognized by a particular protein module. Some scientists believe such histone code may determine the activity of a given gene.

But, cautions Dr. Zhang, while there are patterns, like the backbone, that are highly correlated, “none of them has exact predictive value.” He maintains “there must be something else” that also affects gene activity.

Since genes with higher or lower expression levels may have the same patterns of modification, and not all active genes share a common pattern, the reality is likely more complex than a universal histone code that predicts exact gene expression level. Nonetheless, the new research provides a rich data source for understanding how specific combinations of histone modifications modulate the effects of many genes, in turn helping to modify activity within and among cells. “Critical future research should focus on finding proteins that target histone modifications to genetic regions with particular sequences,” Dr. Zhang emphasized.

With more new mothers in the workplace than ever before, there has been a corresponding increase in the number of child-care facilities in the United States.

The current research was supported in part by the Berkowitz Fellowship of the department of nutrition, Harvard School of Public Health; an Early Childhood Longitudinal Study, Birth Cohort training grant from the National Center for Education Statistics; and training grants on statistical analysis for education policy from the American Educational Research Association.

A typical symptom of Parkinson’s disease is tremor in patients. A group of scientists, including Professor Peter Tass from Forschungszentrum Jülich have succeeded in demonstrating the mechanisms which cause the so-called tremor: neuron clusters in the depths of the brain drive the tremor. This discovery supports Tass’ research activities aiming at developing a therapy for Parkinson’s disease. A new deep brain pacemaker is to bring cells out of the diseased mode for good.

Today’s article in the high-impact journal “Europhysics Letters” shows that the scientists from Forschungszentrum Jülich, a member of the Helmholtz Association, are on the right track. Their new deep brain pacemaker is to help Parkinson’s patients on a large scale for the first time in 2009. Communication between the networks of neurons is disturbed in people suffering from Parkinson’s disease. These “fire” their stimuli at the same time thus causing the typical tremor. The frequency measured here is 5 hertz (Hz), i.e. five oscillations per second. In Germany, there are officially around 150,000 Parkinson’s patients, although it is estimated that up to 450,000 people are affected.

To date, scientists have assumed that the 5-Hz rhythm deep in the brain resulted from nerve signals, which are transmitted from muscles in the limbs back to the brain. The scientific term for this response is “proprioceptive feedback”. The prevailing opinion of many scientists to date, however, is that the “cross fire” is not emitted by the brain. The reason for this assumption was that the measured frequency of the “proprioceptive feedback” and the frequency in a specific core region of the brain, in the thalamus and the basal ganglia, were not completely synchronous.

With a combination of several state-of-the-art analytical processes, the team has now succeeded in demonstrating that it is not only nerve signals from the muscles as feedback that drive the diseased 5-Hz rhythm in the brain. Headed by Prof. Volker Sturm, neurosurgeons in Cologne implanted electrodes in patients for the measurements, and scientists in Saratov, Russia, recalculated the obtained data together with scientists from Jülich. “Signals in the frequency domain of 5 Hz from the core region of the brain also drive the tremor”, explained Peter Tass. “The difference: the feedback from the limbs is a fast and easy stimulus transmission. The signals from the thalamus and the basal ganglia are, however, transmitted to certain loop-like neuron pathways of the brain and spinal cord. Therefore, the dynamics are more complicated and the pathway is longer.”

The Jülich medical scientist, mathematician and physicist believes that these new findings reinforce the theoretical basis of “his” deep brain pacemaker. This device influences the disturbed neurons in the core region of the brain and effectively removes their compulsion to “fire” at the same time. Tass’ new development disturbs this compulsory diseased mode by using very mild, targeted and desynchronized stimuli in different places. In this way, the rhythm becomes irregular and breaks down. Compared to conventional devices of this type, the Jülich deep brain pacemaker puts less strain on the patient and needs less energy. Moreover, the nerve tissue is stimulated in such a way that the neurons abandon their diseased strong synaptic networks and thus forget their compulsion to develop diseased rhythms.

The pacemaker consists of two electrodes that are carefully located at the dysregulated parts of the brain. The so-called stimulator provides the electrodes with energy and signals to stimulate the neurons in the brain. This device is implanted below the collarbone under the skin and thin wires also connect it with the electrodes under the skin.

Sounding the chest with a cold stethoscope is probably one of the most commonly used diagnostics in the medical room after peering down the back of the throat while the patient says, “Aaaah”. But, research published in the inaugural issue of the International Journal of Medical Engineering and Informatics looks set to add an information-age approach to diagnosing heart problems. The technique could circumvent the problem of the failing stethoscope skills of medical graduates and reduce errors of judgment

Listening closely to the sound of the beating heart can reveal a lot about its health. Healthcare workers can identify murmurs, palpitations, and other anomalies quickly and then carry out in-depth tests as appropriate. Now, Samit Ari and Goutam Saha of the Indian Institute of Technology in Kharagpur have developed an analytical method that can automatically classify a much wider range of heart sounds than is possible even by the most skilled stethoscope-wielding physician.

Their approach is based on a mathematical analysis of the sound waves produced by the beating heart known as Empirical Mode Decomposition (EMD). This method breaks down the sounds of each heart cycle into its component parts. This allows them to isolate the sound of interest from background noise, such as the movements of the patient, internal body gurgles, and ambient sounds.

The analysis thus produces a signal based on twenty five different sound qualities and variables, which can then be fed into a computer-based classification system. The classification uses an Artificial Neural Network (ANN) and a Grow and Learn (GAL) network. These are trained with standardized sounds associated with a specific diagnosis.

The team then tested the trained networks using more than 100 different recordings of normal heart sounds, sounds from hearts with a variety of valve problems, and different background noises. They found that the EMD system performs more effectively in all cases than conventional electronic, wavelet-based, approaches to heart sound classification.

A disturbing percentage of medical graduates cannot properly diagnose heart conditions using a stethoscope, the researchers explain, and the poor sensitivity of the human ear to low frequency heart sounds makes this task even more difficult. The automatic classification of heart sounds based on Ari and Saha’s technique could remedy these failings.

Using an engineered common cold virus, UCLA researchers delivered a genetic payload to prostate cancer cells that allowed them, using Positron Emission Tomography (PET), to locate the diseased cells as they spread to the lymph nodes, the first place prostate cancer goes before invading other organs.

The tiny cancer metastases in the pelvic lymph nodes are very difficult to find using conventional imaging tools such as CT scanning. This discovery could aid oncologists in finding the cancer’s spread earlier, when it’s more treatable, and before it invades distant organs, said Lily Wu, a researcher at UCLA’s Jonsson Cancer Center and the senior author of the study.

The next step for Wu and her colleagues is linking the non-invasive imaging advance with a treatment component, activating a toxic agent in the genetic payload to kill the spreading cancer cells. Wu hopes one day to be able to find tiny prostate cancer metastases in patients and kill them at the same time, watching it all on a PET scanner. She currently is refining this image-guided therapy in her lab in mouse models.

“I think this is very exciting for many reasons,” said Wu, who also is an associate professor of pharmacology and urology. “We now know we can reach these prostate cancer metastases at an earlier stage than before, and we know we can deliver genes to those cancer cells that produce proteins that can be imaged by PET. Now we will find out how effective this genetic toxic payload is in preventing further spread of the cancer to other vital organs.”

The study appears July 11, 2008 in the early, online edition of the peer-reviewed journal Nature Medicine.

The spread of prostate cancer to the pelvic lymph nodes is the most reliable indicator that the patient will have a poor prognosis, with disease recurrence and progression likely. Accurately assessing pelvic lymph node involvement in patients is critical in planning their treatment, Wu said.

Currently, physicians don’t know if a treatment is attacking cancer cells until, using traditional imaging, they see a decrease in tumor size, an insensitive approach that can take weeks and months. And if the treatment isn’t working, the patient is exposed to a toxic therapy that isn’t helping them. If Wu is successful, an oncologist would know within days if the cancer has spread and whether the treatment is killing the cancer.

Using mouse models, Wu and her team engineered a virus to travel to the lymph nodes, using a prostate cancer-specific vector that dictates s its protein payload be expressed only in prostate cells. The payload in this case is a protein that can be imaged by PET scanning. The virus was introduced into the tumor in the mouse and Wu and her team were able to detect PET signals only from the lymph nodes with cancer cell involvement, indicating the virus reached and infected the prostate cancer cells and produced the imaging protein.

As part of this study, Wu co-developed TSTA, a two-step transcriptional amplification method, which increased the expression of the genetic payload inside the cancer cells – in effect boosting the imaging signals and potential killing activity of the engineered virus.

Wu believes this type of image-guided therapy has the potential to improve the way advanced prostate cancer is treated.

“It would represent a treatment advance in patients for whom outcome is not good,” Wu said. “This would help improve the prognosis for these patients by letting us find and treat these metastases early. If we can catch the cancer before it invades other organs, we have a better chance to change the outcomes for these patients.”

This type of approach was pioneered in the field of breast cancer with testing of the sentinel lymph node, the first place breast cancer goes when it spreads. A biopsy can determine if the cancer is in the sentinel node, therefore spreading, and oncologists base their treatment decisions on that information. In prostate cancer, the lymph nodes are much more difficult to access for biopsy, so Wu’s method provides a much needed, non-invasive alternative.

Smaller, more accurate, higher performance and lower priced that is the formula for success for micro and nanoelectronics.  Miniaturisation plays a crucial economic role to-day and contributes significantly to the key technologies of the 21st century; however, the smaller the structures, the more susceptible they are to minimal contaminations.  Within the scope of ANNA, the European cooperation project, the Physikalisch-Technische Bundesanstalt (PTB) is working in its laboratory at the electron storage ring BESSY II in Berlin for the first time, together with external users, at selected measuring sites for the use of synchrotron radiation.  The international cooperation under the umbrella of ANNA is to concentrate research competence Europe-wide.  In this case, it is a matter of findings on the physical-chemical characteristics of semiconductor surfaces and nanolayers as well as the further development of reference-specimen-free analysis methods for detecting the surface contamination and layer characteristics.

This year, the world and, in particular, developing countries and the poor have been hit by both food and energy crises.  As a consequence, prices for many staple foods have risen by up to 100%.  When we examine the causes of the food crisis, a growing population, changes in trade patterns, urbanization, dietary changes, biofuel production, and climate change and regional droughts are all responsible.  Thus we have a classic increase in prices due to high demand and low supply.  However, few commentators specifically mention the declining availability of water that is needed to grow irrigated and rainfed crops.  According to some, the often mooted solution to the food crisis lies in plant breeding that produces the ultimate high yielding, low waterconsuming crops.  While this solution is important, it will fail unless attention is paid to where the water for all food, fibre and energy crops is going to come from.

A few years ago, IWMI (the International Water Management Institute) demonstrated that many countries are facing severe water scarcity, either as a result of a lack of available fresh water, or due to a lack of investment in water infrastructure such as dams and reservoirs.  What makes matters worse is that this scarcity predominantly affects developing countries where the majority of the world’s under-nourished people-approximately 840 million -live.

The causes of water scarcity are essentially identical to those of the food crisis.  There are serious and extremely worrying factors that indicate water supplies are steadily being used up.  Essentially every calorie of food requires a liter of water to produce it.  Thus those of us on western diets, use about 2500-3000 liters per day.  A further 2.5 billion people by 2030 will mean that we have to find over 2000 more cubic kilometers of fresh water to feed them.  This is not any easy task given that current water usage for food production is 7500 cubic kilometers and supplies are scarce.  According to the recent report “Water for Food, Water for Life” of the Comprehensive Assessment of Water Management in Agriculture, which drew on the work of 700 scientists, unless we change the way we use water and increase “water productivity” (i.e. more crop per drop) we will not have enough water to feed the world’s growing population (This population is estimated to increase from 6 billion now to about 8.5 billion in 25 years.)  Compared with the lengthy agenda to combat climate change, this is a very short time indeed and yet the impacts of water scarcity will be profound.  However, very little is being done about it in most countries.

Since the formulation of the UN Millennium Goals in 2002, much of the water agenda has been focused around the provision of drinking water and sanitation.  This water comes from the same sources as agricultural water and as we urbanize and improve living standards there will be increasing competition for drinking water from domestic and other urban users, putting agriculture under further pressure.  While improving drinking water and sanitation is vital with respect to health and living standards, we cannot afford to neglect the provision and improved productivity of water for agriculture.

There are potential solutions.  Better water storage has to be considered.  Ethiopia, which is typical of many sub-Saharan African countries, has a water storage capacity of 38 cubic meters per person.  Australia has almost 5000 cubic meters per person, an amount that in the face of current climate change impacts may be inadequate.  While there will be a need for new large and medium-sized dams to deal with this critical lack of storage in Africa, other simpler solutions are also part of the equation.  These include the construction of small reservoirs, sustainable use of groundwater systems including artificial groundwater recharge and rainwater harvesting for smallholder vegetable gardens.  Improved yearround access to water will help farmers maintain their own food security using simple supplementary irrigation techniques.  The redesign of both the physical and institutional arrangements of some large and often dysfunctional irrigation schemes will also bring the required productivity increases.  Safe, risk free reuse of wastewater from growing cities will also be needed.  Of course these actions need to be paralleled by development of droughttolerant crops, and the provision of infrastructure and facilities to get fresh food to markets.

Current estimates indicate that we will not have enough water to feed ourselves in 25 years time, by when the current food crisis may turn into a perpetual crisis.  Just as in other areas of agricultural research and development, investment in the provision and better management of water resources has declined steadily since the green revolution.  I and my water science colleagues are raising a warning flag that significant investment in both R&D and water infrastructure development are needed, if dire consequences are to be avoided.

A new NOAA coral bleaching prediction system indicates that there will be some bleaching in the Caribbean later this year, but the event will probably not be severe.  NOAA issued the first-ever seasonal coral bleaching outlook this week at the 11th International Coral Reef Symposium in Ft.  Lauderdale, Fla.

The system also suggests that there is a risk of widespread bleaching in the Northwestern Hawaiian Islands in August, but little bleaching elsewhere during the northern hemisphere summer.

“The ability to predict coral bleaching events and provide advance warning is critically important to sustaining healthy reefs,” said Tim Keeney, deputy assistant secretary of commerce for oceans and atmosphere and co-chair of the United States Coral Reef Task Force.  “When coral reef managers and reef users are alerted, they can mobilize monitoring efforts, develop response strategies, and educate reef users and the public on coral bleaching and possible effects on reef resources.”

The new prediction system uses NOAA experimental sea surface temperature forecasts to develop maps of anticipated coral bleaching severity during the upcoming bleaching season (August to October).  While NOAA’s Coral Reef Watch Program uses satellite sea surface temperature data to alert managers and scientists around the world of the risk of coral bleaching, the new prediction system includes longer range temperature forecasts up to three-months.

Coral bleaching is associated with a variety of stresses, especially increased ocean temperatures.  This causes the coral to expel symbiotic micro-algae living in their tissues – algae that provide corals with food.  Losing their algae leaves coral tissues devoid of color, and thus they appear bleached.  Prolonged coral bleaching of over a week can lead to coral death and the loss of coral reef habitats for a range of marine life.

A major coral bleaching event occurred in the Caribbean in 2005, resulting in significant coral death in much of the region.

“As global temperatures continue to climb, predicting coral bleaching becomes even more critical,” said C. Mark Eakin, Ph.D., coordinator of NOAA’s Coral Reef Watch Program.  “Our goal is to issue bleaching forecasts for coral reefs worldwide.”

Providing preventive treatment for malaria, given once per term, dramatically reduces rates of malaria infection and anaemia among schoolchildren, and significantly improves their cognitive ability, according to new research published today in the Lancet.

Malaria is a major cause of morbidity and mortality in early childhood, but its consequences during the school-age years are less widely acknowledged.  By the time an African child enters school they have generally been repeatedly infected with malaria and have acquired immunity to the parasite making them less likely to die.  However, malaria still accounts for up to 20% of deaths among schoolchildren, is an important cause of school absenteeism, and may hinder educational achievement.  Additionally, many schoolchildren continue to harbour malaria parasites without displaying any symptoms of disease.  These asymptomatic infections frequently go unrecognised and untreated, leading to anaemia and, as demonstrated for the first time in this study, impaired performance in school.

School-based health programs have been shown to work well in combating other diseases, such as worm infections, but less is known about their role in tackling malaria.  Yet more children are now attending school than ever before and governments are increasingly recognising the importance of child health for educational achievement.

A multi-disciplinary team of Kenyan and British researchers investigated the impact of IPT, a new method of tackling malaria which involves the mass administration of a full course of an anti-malarial drug irrespective of whether children are infected.  They assessed whether IPT could reduce the prevalence of anaemia, and improve classroom attention and educational achievement in schoolchildren.  They carried out a randomised, placebo-controlled trial of IPT in 30 primary schools in a rural area of high malaria transmission in western Kenya.  In total, 4916 children, aged 5-18 years, received three treatments (sulfadoxine-pyrimethamine combined with amodiaquine, or a dual placebo) at four-monthly intervals, once each school term.  The impact of treatment was assessed through cross-sectional surveys 12 months later.

IPT dramatically reduced the occurrence of malaria infection in schoolchildren.  The risk of anaemia was halved among those receiving IPT compared with the controls, and significant improvements were also seen in class-based tests of sustained attention among those receiving IPT.  No impact was observed for educational achievement.

Dr. Matthew Jukes, Assistant Professor of International Education at the Harvard Graduate School of Education, worked on the study and comments: ‘Although it has long been suspected that malaria impairs school performance, this is the first study to provide evidence of a direct link between malaria and reduced attention in class.  These results indicate that malaria infection may hinder learning and its prevention could be important to enhance the educational potential of schoolchildren.’

Dr. Siân Clarke, a Lecturer in Malaria Research and Control at the London School of Hygiene & Tropical Medicine, comments: ‘Our findings highlight the neglected burden of malaria in older children, and reveal that malaria infection in schoolchildren may have more profound consequences than previously appreciated.  Preventing malaria could have important health and cognitive benefits for African schoolchildren and deserves more attention.  These results show us that intermittent preventive treatment in schools is a novel and effective means to address this problem.’

The findings of the study have particular relevance for the global ‘Education for All’ initiative which aims to achieve universal school enrolment and enhance schooling.

The intervention could prove a valuable and affordable addition to realising ‘Education for All’ goals through school health and nutrition programmes which already provide treatments against worm infections.  School-age children represent 26% of Africa’s population where 94% of children go to school.  Numerically, this represents up to191 million children who could benefit from a systematic approach to school-based malaria control, which could include IPT.

Dr. Simon Brooker, a Reader in Tropical Epidemiology at the London School of Hygiene & Tropical Medicine adds: ‘For a small financial investment the potential gains from the approach of IPT are extremely attractive.  An important next step will be to work with government and development partners in Africa to investigate further the feasibility and costeffectiveness of scaling up an IPT package within the context of school health programmes’.

T-cell acute lymphoblastic leukemia (T-ALL)

The white blood cells in our body combat foreign intruders, such as viruses and bacteria.  However, in leukemia, the formation of white blood cells is disturbed: the cells that should develop into white blood cells multiply out of control without fully maturing.  This process disrupts the production of normal blood cells, making patients more susceptible to infections.  T-ALL, a particular form of leukemia, is the most prevalent cancer in children under 14 years of age and occurs predominantly between the ages of two and three.  At the moment, with an optimal treatment using chemotherapy, over half of the children are cured.  But scientists hope to be able to develop targeted therapies that are less toxic than chemotherapy, based on knowledge of the biological processes behind T-ALL.

Importance of the location

Oncogenes are often at the root of cancer.  So, scientists around the world are concentrating on identifying oncogenes and their related proteins.  Recent research by Kim De Keersmaecker and colleagues in Jan Cools’ research group (VIB-K.U.Leuven) indicates that the location in the cell where these proteins are found plays an important role in the entire carcinogenic mechanism.  In collaboration with Maarten Fornerod (Nederlands Kanker Instituut, Amsterdam) and Gary Gilliland (Harvard Medical School, Boston), the VIB researchers have demonstrated that NUP214-ABL1, a fusion of two proteins, is carcinogenic only when it is in a protein complex near the nucleus of the cell.  Located at another place in the cell, NUP214-ABL1 does not lead to cancer.  This finding sheds new light on the study of carcinogenic processes.

A new therapeutic approach?

Many forms of cancer are caused by genetic defects in which a certain kinase becomes too active and this is the case with NUP214-ABL1.  The most obvious solution is to make the carcinogenic kinase inactive, and so kinase inhibitors are usually used to combat these kinds of cancers.  However, the carcinogenic kinase often becomes resistant to these inhibitors which is certainly true for T-ALL.  So, scientists are actively seeking alternative approaches.

De Keersmaecker’s recent research results now offer a possibility.  Indeed, the scientists have shown in cells that NUP214-ABL1 is no longer carcinogenic when it cannot bind with the protein complex in the vicinity of the cell nucleus.  On the basis of these results, the researchers want to further investigate the therapeutic possibilities of compounds that render binding between the complex and NUP214-ABL1 impossible.  This study also indicates that the location of proteins can play an important role in other forms of cancer/leukemia as well.

A study published July 11th in the open-access journal PloS Pathogens suggests that herpesviruses use multiple strategies to manipulate important components of the host cell nuclear environment during infection.  The study, conducted by researchers at the University of Toronto in collaboration with Affinium Pharmaceuticals Inc., provides novel insights into the potential functions of over 120 previously uncharacterized viral proteins.

Most people are infected with the three human herpesviruses that were the subject of this study; namely herpes simplex virus (type 1), Epstein-Barr virus, and cytomegalovirus.  Herpesviruses have complex life cycles due to their adept manipulation of the host cell environment.  Although often asymptomatic, herpesviruses can cause life-threatening diseases.  In order to provide a more complete understanding of how these viruses alter host cells, the researchers developed a system to examine each viral protein individually in human cells.

The researchers investigated over 230 individual proteins from the three herpesviruses.  They focused on 93 identified viral proteins that localized to the cell nucleus and altered key cellular components that regulate gene expression, cell growth and death, and antiviral responses.

Cells depend on nuclear structures called PML bodies to control cell proliferation and survival, to ensure damaged DNA is repaired, and to inhibit virus replication.  24 of the nuclear viral proteins, several of which had no previously assigned function, were found to disrupt or reorganize PML bodies, suggesting that herpesviruses employ multiple strategies for manipulating this key regulator of essential cellular processes.

Further studies will be needed to determine how the identified viral proteins function in the context of viral infection, but this research provides a starting point for investigating how these proteins affect important processes of the cell nucleus.

Research involving large Middle Eastern families, sophisticated genetic analysis and groundbreaking neuroscience has implicated a half-dozen new genes in autism.  More importantly, it strongly supports the emerging idea that autism stems from disruptions in the brain’s ability to form new connections in response to experience – consistent with autism’s onset during the first year of life, when many of these connections are normally made.

Interestingly, not all the affected genes were actually deleted, but only prevented from turning on – offering hope that therapies could be developed to reactivate the genes.  The study, led by researchers at Children’s Hospital Boston and members of the Boston-based Autism Consortium, is the cover article in the July 11 issue of Science.

Autism genes have been difficult to identify because the disorder is complex, with a variety of causes stemming from many possible genes or combinations of genes.  In addition, since people with autism tend not to have children, most of the genes identified thus far aren’t inherited from a parent, but instead are mutated during embryonic development, making them hard to track through traditional linkage studies in families.

Christopher Walsh, MD, PhD, chief of genetics at Children’s Hospital Boston, approached the problem by studying Middle Eastern families.  In traditional Arab societies, it is common for cousins to marry, increasing the likelihood that offspring will inherit rare mutations.  Middle Eastern families also tend to have many children, making them ideal for mapping genes.

“To map a gene for autism in American families, averaging two to three kids per family, you would need to pool many families,” says Walsh, who is also a Howard Hughes Medical Institute investigator at Beth Israel Deaconess Medical Center (BIDMC).  “In larger families, one family alone may be enough to definitively localize a gene.”

The Homozygosity Mapping Collaborative for Autism (HMCA) recruited 104 families with a high incidence of autism from the Arabic Middle East, Turkey and Pakistan; 88 of these families have cousin marriages.  Local clinicians were rigorously trained in administering standardized autism research assessments.  Walsh’s team later flew to sites in Turkey, Dubai, Kuwait and Saudi Arabia to confirm the diagnoses.

Using a technique called homozygosity mapping Walsh and colleagues compared the DNA of family members with and without autism, searching for recessive mutations—those that cause disease only when a child inherits two copies.

“We check each set of chromosomes from beginning to end, looking for one place where the child has two identical pieces of DNA on both chromosomes,” Walsh explains.  “Eventually we find a spot where all affected children have two identical chunks of DNA, and where unaffected children have something different.”

Just over 6 percent of the 88 families showed rare, inherited deletions within DNA regions linked to autism.  These affected DNA regions varied among families, further indication of autism’s large variety of genetic causes.  In all, the technique identified five chromosome deletions affecting at least six identifiable genes (C3orf58, NHE9, PCDH10, contactin-3 [CNTN3], RNF8, and genes encoding a cluster of cellular sodium channels).

One of the genes, NHE9, was also found to be mutated in European and American children with autism (particularly those with both autism and seizures).

Experience-dependent learning: A common thread

The genes discovered are diverse in function, but all seem to be part of a fundamental molecular network that orchestrates the refinement and maturation of brain connections, or synapses, in response to input from the outside world.  It is the refinement of these synaptic connections that is the basis of learning and memory, suggesting that autism at its heart may represent molecular defects of learning.

“This network can be disrupted in a myriad of ways, and may be one mechanism that people with a variety of autism-linked mutations share,” says Michael Greenberg, PhD, a coauthor on the paper and director of the Neurobiology Program at Children’s Hospital Boston.

Normally, as a neuron (brain cell) receives an incoming message at the synapse, a network of reactions is sparked that extends all the way to its nucleus.  Greenberg and his colleagues had long been mapping this network, and had previously found that it activates at least 300 genes.  These genes then communicate back to the neuron’s surface, telling the cell to make a new synapse, strengthen the synapse that’s already there, eliminate a synapse, or make a different kind of synapse.  This give-and-take system is how the brain builds its circuitry; neuroscientists call it “experience-dependent learning.”

Working independently of Walsh, Greenberg and his colleagues had already identified three of the same genes found in the Middle Eastern patients (c3orf58, NHE9, and PCDH10) while looking for genes that turn on or off in neurons as part of this network – either in response to synaptic activity or through so-called transcription factors that are activated by synaptic activity.

The work bolsters a growing body of evidence that autism may represent a disruption of the brain’s ability to modify its synaptic connections in response to experience.

“Taken together, our findings suggest that experience-dependent learning could be relevant to autism, and that autism might result from the deregulation of any one of a number of genes that are part of the same signaling pathway,” Greenberg says.

Can normal function be revived?

Interestingly, only one chromosome deletion found in the Middle Eastern families actually removed a gene – in most cases, what was lost was a region adjacent to the gene that contains its “on/off” switches.  This has important implications for therapy, because it suggests that autism mutations don’t always remove a gene altogether, but only inhibit its activity in certain contexts, says Eric Morrow, MD, PhD, of Massachusetts General Hospital, who is co-first author of the paper with Seung-Yun Yoo, PhD.  “This means that we would not need to replace the gene, if we could only figure out how to reactivate it, perhaps with medications,” says Morrow, who also holds appointments at BIDMC and Children’s.

The findings also support the use of behavioral therapies in autism, which expose children to a rich environment and highly repetitive activities that may help turn on the genes and strengthen synaptic connections, Morrow adds.

“This publication a big event in the world of autism research,” says Clarence Schutt, PhD, Scientific Advisor to the Nancy Lurie Marks Family Foundation, which funded work by both the Walsh and Greenberg labs.  “To have discovered a connection between autism and activity-related gene expression at the synapse will put this field at the center of neuroscience.”

Scientists have identified about two dozen genes that control embryonic stem cell fate.  The genes may either prod or restrain stem cells from drifting into a kind of limbo, they suspect.  The limbo lies between the embryonic stage and fully differentiated, or specialized, cells, such as bone, muscle or fat.

By knowing the genes and proteins that control a cell’s progress toward the differentiated form, researchers may be able to accelerate the process – a potential boon for the use of stem cells in therapy or the study of some degenerative diseases, the scientists say.

Their finding comes from the first large-scale search for genes crucial to embryonic stem cells.  The research was carried out by a team at the University of California, San Francisco and is reported in a paper in the July 11, 2008 issue of “Cell.”

“The genes we identified are necessary for embryonic stem cells to maintain a memory of who they are,” says Barbara Panning, PhD, associate professor of biochemistry and biophysics at UCSF, and senior author on the paper.  “Without them the cell doesn’t know whether it should remain a stem cell or differentiate into a specialized cell.”

The scientists used a powerful technique known as RNA interference, or RNAi, to screen more than 1,000 genes for their role in mouse embryonic stem cells.  The technique allows researchers to “knock down” individual genes, reducing their abundance in order to determine the gene’s normal role.

The research focused on proteins that help package DNA.  In the nucleus, DNA normally wraps around protein complexes called nucleosomes, forming a structure known as chromatin.  This is what makes up chromosomes.

They found 22 proteins, each of which is essential for embryonic stem cells to maintain their consistent shape, growth properties, and pattern of gene expression.

Most of the genes code for multi-protein complexes that physically rearrange, or “remodel” nucleosomes, changing the likelihood that the underlying genes will be expressed to make proteins.

The main player they identified is a 17-protein complex called Tip60-p400.  This complex is necessary for the cellular memory that maintains embryonic stem cell identity, Panning explains.  Without it, the embryonic stem cells turned into a different cell type, which had some features of a stem cell but many features of a differentiated cell.

The scientists believe that Tip60-p400 is necessary for embryonic stem cells to correctly read the signals that determine cell type.  These findings are not only important for understanding cellular memory in embryonic stem cells, but will also likely be relevant to other cell types, they say.

Inactivation of other genes disrupted embryonic stem cell proliferation.  These genes were already known to have only slight influence on viability of mature cells in the body.  This suggests that embryonic stem cells are “uniquely sensitive to certain perturbations of chromatin structure,” the scientists report.

If other types of stem cells are also found to be sensitive to these chromatin perturbations, this could lead to novel cancer therapies in the future, Panning says.

Among patients with castration-resistant prostate cancer, the addition of hormone therapy following vaccine treatment improved overall survival compared with either treatment alone or when the vaccine followed hormone treatment, according to recent data published in the July 15 Clinical Cancer Research, a journal of the American Association for Cancer Research.

Philip M. Arlen, M.D., director of the Clinical Research Group for the Laboratory of Tumor Immunology and Biology, Center for Cancer Research, at the National Cancer Institute, said the findings have important implications for guiding treatment decisions for prostate cancer patients.

“Vaccines, if and when they are approved, can be safely and effectively combined with other therapies, including hormones,” said Arlen.  “There appears to be an advantage in overall survival.”

Arlen and colleagues enrolled 42 patients who had castration-resistant prostate cancer.  These patients were randomly assigned to receive either a poxvirus-based prostate-specific antigen vaccine or hormone therapy with nilutamide.  At progression, patients received the other therapy and continued to receive their original therapy.

For all the patients enrolled in the study, the three-year survival probability was 71 percent and the median overall survival was 4.4 years.  Patients randomized to the vaccine had a three-year survival probability of 81 percent and an overall survival of 5.1 years, while patients taking nilutamide had a three-year survival probability of 62 percent and an overall survival of 3.4 years.

Of the 42 patients in the study, 12 patients who were originally assigned to vaccine switched to nilutamide plus vaccine and eight patients who were originally assigned to nilutamide switched to vaccine plus hormone, due to rising levels of prostate-specific antigen with no evidence of metastasis.  For patients who received vaccine and then nilutamide, the three-year survival probability was 100 percent with a median overall survival of 6.2 years.  For patients who switched to the vaccine after hormone, the three-year survival probability was 75 percent with a median overall survival of 3.7 years.

Arlen said the hormone therapy in combination with the vaccine works in two ways.

“By using hormone therapy in prostate cancer you can help enhance your T-cell response to where the cancer is in the prostate gland, and you are also more likely to achieve a better immune response,” said Arlen.

Building on the results of this phase II study, researchers have developed another generation of this vaccine by adding molecules which boost T-cell responses.

Based on the current pace of vaccine research overall, Arlen predicts that men with prostate cancer could potentially see an effective, new treatment vaccine within the next several years.

“Phase II trials such as this one are adding to our knowledge, and other phase III trials are getting ready to publish their data,” said Arlen.  “If the phase II data hold up in phase III trials, we could see a new treatment vaccine within a few years.”

Wei Tong and colleagues, at Children’s Hospital of Philadelphia, have provided new insight into the molecular control of hematopoietic stem cells (HSCs), the cells that give rise to all types of blood cell, by explaining why mice lacking an inhibitory protein known as Lnk have more HSCs than normal mice.

In the study, it was observed that a greater proportion of HSCs in mice lacking Lnk were not undergoing cell division and were said to be quiescent (i.e., in a state of inactivity or in silent mode).  Lnk was found to regulate HSC quiescence by binding a signaling protein known as JAK2 after it was activated following binding of the soluble factor TPO to its receptor Mpl.  The authors therefore hypothesize that in the absence of the inhibitory molecule Lnk, TPO-initiated signaling from Mpl to JAK2 goes unchecked and the number of HSCs produced is increased to a level at which they do not need to undergo cell division as often to maintain their population.