The identification of five genes involve in the metastasis of breast tumours to the lung is the principal finding of a scientific team made up of two bodies from the University of Navarra, the Applied Medical Research Centre (CIMA) and the University Hospital of the University of Navarra.

Doctor Alfonso Calvo, researcher in the area of Oncology at the CIMA, led the work with the special collaboration of Doctor Ignacio Gil Bazo, cancer specialist from the University Hospital.  The study made up a significant part of Mr Raúl Catena’s PhD thesis.

For this research, recently published in the scientific journal Oncogene, a transgenic mouse model which presented a greater tendency for developing metastasis was employed.  The increase in what is known as the Vascular Endothelial Growth Factor (VEGF) in its mammary glands triggered profound changes in the tumoural structure, which enabled the malignant cells to leave the tumour and invade the lungs.

Finally, the pattern of genes responsible for this tumoural migration to the lungs was analysed and this was compared to that shown by women with breast tumours with pulmonary metastatic affectation.  It was shown that five of these genes were common to the animal model and patients with breast cancer.  Most effective ways of treatment

According to the results of this study, of the five genes identified, the Tenascina-C gene seems to be a good therapeutic target for the treatment of metastatic breast cancer.  In fact, the blocking of the expression of this gene in the animal model enabled a significant reduction, both in tumour growth and in the incidence of pulmonary metastasis.

This new discovery in the complex network that is the metastasis process of tumours provides key data on the knowledge of cancer and its spreading, at the same time identifying new targets for which new pharmaceutical medicines that contribute to more efficacious treatment of this disease can be designed.

Researchers at the University of Cincinnati (UC) are looking for ways to reduce or prevent heart damage by starting where the problem often begins: in the genes.

Following a heart attack, cells die, causing lasting damage to the heart.

Keith Jones, PhD, a researcher in the department of pharmacology and cell biophysics, and colleagues are trying to reduce post-heart attack damage by studying the way cells die in the heart—a process controlled by transcription factors.

Transcription factors are proteins that bind to specific parts of DNA and are part of a system that controls the transfer of genetic information from DNA to RNA and then to protein.  Transfer of genetic information also plays a role in controlling the cycle of cells—from cell growth to cell death.

“We call it ‘gene regulatory therapy,’” says Jones.

So far, studies have identified the role for an important group of interacting transcription factors and the genes they regulate to determine whether cells in the heart survive or die after blood flow restriction occurs.

Often, scientists use virus-like mechanisms to transfer DNA and other nucleic acids inside the body.

The “virus” takes over other healthy cells by injecting them with its DNA.  The cells, then transformed, begin reproducing the virus’ DNA.  Eventually they swell and burst, sending multiple replicas of the virus out to conquer other cells and repeat the process.

Now, UC researchers are further investigating new, non-viral delivery mechanisms for this transfer of DNA.

“We can use non-viral delivery vehicles to transfer nucleic acids, including transcription factor decoys, to repress activation of specific transcription factors in the heart,” Jones says, adding that the researchers have made this successfully work within live animal models.  “This means we can block the activity of most transcription factors in the heart without having to make genetically engineered mice.”

Jones will be presenting these results at the International Society for Heart Research in Cincinnati, June 17-20.

He says this delivery mechanism involves flooding the cells with “decoys” which trick the transcription factors into binding to the decoys rather than to target genes, preventing them from activating those genes.

“We can use this technology to identify the target genes and then investigate the action of these genes in the biological process,” Jones says.

He says that this delivery has limitations and advantages.

“It can be used to block a factor at any point in time and is reversible,” he says.  “However, right now, a specific delivery route must be used to target the tissue or cell.”

Jones and other researchers are hoping that this new technology will allow them to directly address the effects of gene regulation in disease, as opposed to using classical drugs that treat symptoms or have significant adverse outcomes.

“So far, this seems to cause no adverse effects in animals,” he says.  “We are hopeful and are working toward pre-clinical studies.”

Researchers have determined that there are hundreds of biological differences between the sexes when it comes to gene expression in the cerebral cortex of humans and other primates.  These findings, published June 20th in the open-access journal PloS Genetics, indicate that some of these differences arose a very long time ago and have been preserved through evolution.  These conserved differences constitute a signature of sex differences in the brain.

Many more obvious gender differences have been preserved throughout primate evolution; examples include average body size and weight, and genitalia design.  This study, believed to be the first of its kind, focuses on gene expression within the cerebral cortex.  The cerebral cortex is involved in many of the more complex functions in both humans and other primates, including memory, attentiveness, thought processes and language.

The researchers measured gene expression in the brains of male and female primates from three species: humans, macaques, and marmosets.  To measure activity of specific genes, the products of genes (RNA) obtained from the brain of each animal were hybridized to microarrays containing thousands of DNA clones coding for thousands of genes.  The authors also investigated DNA sequence differences among primates for genes showing different levels of expression between the sexes.

“Knowledge about gender differences is important for many reasons.  For example, this information may be used in the future to calculate medical dosages, as well as for other treatments of diseases or damage to the brain,” says team leader Professor Elena Jazin, at Uppsala University, Sweden.

In addition to the results mentioned above, the researchers also report on evolutionary speeds in genes that have been identified as male or female-oriented.  This could provide clues about the power of natural selection processes during the evolution of primates.

Lead author Björn Reinius notes that the study does not determine whether these differences in gene expression are in any way functionally significant.  Such questions remain to be answered by future studies.

What makes a human different from a chimp?  Researchers from the European Molecular Biology Laboratory’s European Bioinformatics Institute [EMBL-EBI] have come one important step closer to answering such evolutionary questions correctly.  In the current issue of Science they uncover systematic errors in existing methods that compare genetic sequences of different species to learn about their evolutionary relationships.  They present a new computational tool that avoids these errors and provides accurate insights into the evolution of DNA and protein sequences.  The results challenge our understanding of how evolution happens and suggest that sequence turnover is much more common than assumed.

“Evolution is happening so slowly that we cannot study it by simply watching it.  That’s why we learn about the relationships between species and the course and mechanism of evolution by comparing genetic sequences,” says Nick Goldman, group leader at EMBL-EBI.

The four letter code that constitutes the DNA of all living things changes over time; for example individual or several letters can be copied incorrectly [substitution], lost [deletion] or gained [insertion].  Such changes can lead to functional and structural changes in genes and proteins and ultimately to the formation of new species.  Reconstructing the history of these mutation events reveals the course of evolution.

A comparison of multiple sequences starts with their alignment.  Characters in different sequences that share common ancestry are matched and gains and losses of characters are marked as gaps.  Since this procedure is computationally heavy, multiple alignments are often built progressively from several pairwise alignments.  It is impossible, however, to judge if a length difference between two sequences is a deletion in one or an insertion in the other sequence.  For correct alignment of multiple sequences, distinguishing between these two events is crucial.  Existing methods, that fail to do that, lead to a flawed understanding of the course of evolution.

“Our new method gets around these errors by taking into account what we already know about evolutionary relationships,” says Ari Löytynoja, who developed the tool in Goldman’s lab.  “Say we are comparing the DNA of human and chimp and can’t tell if a deletion or an insertion happened.  To solve this our tool automatically invokes information about the corresponding sequences in closely related species, such as gorilla or macaque.  If they show the same gap as the chimp, this suggests an insertion in humans.”

Findings achieved with the new technique suggest that insertions are much more common than assumed, while the frequency of deletions has been overestimated by existing methods.  A likely reason for these systematic errors of other techniques is that they were originally developed for structural matching of protein sequences.  The focus of molecular biology is shifting, however, and understanding functional changes in genomes requires specifically designed methods that consider sequences’ histories.  Such approaches will likely reveal further bugs in our understanding of evolution in future and might challenge the conventional picture of sequence evolution.

The potentially fatal heart disease LQT-2, which is characterized by the prolongation of a specific interval of time (known as the QT interval) in the heart’s electrical cycle, is caused by mutations in the HERG gene. What triggers the changes in the electrical activity in the heart (and therefore in the beating of the heart) has not been completely determined, although loud noises and emotional stress can be triggers. In a new study, a team of researchers from the Academic Medical Centre, The Netherlands, and the University of Wisconsin, Madison, has revealed that fever can also trigger life-threatening changes in the electrical activity in the heart of patients with LQT-2.

The team, led by Arthur Wilde and Craig January, measured the electrical activity in the heart over time (something that is recorded in an ECG) of two LQT-2 patients with the same HERG mutation (A558P), and found that fever was associated with prolonged QT intervals in these individuals. When this mutation was introduced into a cultured human cell line, the cells exhibited temperature-dependent characteristics, including altered electrical currents across their cell membranes at high temperatures. The authors therefore conclude that similar changes in electrical currents occur in heart cells at the high temperatures associated with fever and that fever is a potential trigger of the potentially lethal changes in the electrical activity in the heart of patients with LQT-2.

New data, generated by Hongbing Shen and colleagues, at the Cancer Center of Nanjing Medical University, People’s Republic of China, has identified a genetic variation that seems to help predict survival in individuals with non–small cell lung cancer (NSCLC).

A systematic screen of the DNA carrying the information for generating regulatory RNA molecules known as a microRNAs identified a specific genetic variant that was associated with decreased survival in individuals with NSCLC.  The specific genetic variation resulted in increased levels of expression of the functional miRNA molecule.  This was not because more of the miRNA was made but because more of the precursor form of the functional molecule was processed to become functional.  The functional miRNA molecule generated by the genetic variation also had different functional properties.  The authors hope that further characterization of genetic variations that modify miRNA expression and/or function will uncover other indicators of survival and opportunities for developing new therapeutics.

In individuals with type 2 diabetes, the way the level of glucose (the sugar molecule that is our main source of energy) in the body while not eating (fasting glucose level) is regulated fails and fasting glucose levels increase dramatically.  New insight into genetic variations that have an impact on the fasting glucose levels of nondiabetic individuals has now been provided by a team of researchers from the Istituto Nazionale Ricovero E Cura Anziari, Italy, and the University of Southern California.  Specifically, an association between one defined genetic variation and increased fasting glucose levels was observed in nondiabetic individuals.  This variation was located between two genes known as G6PC2 and ABCB11.  As G6PC2 carries the information for making a protein expressed by the cells that become dysfunctional in individuals with type 2 diabetes, the authors suggest that the genetic variation probably affects fasting glucose levels by altering the expression of this gene.

Prenatal biochemical screening tests are widely used to look for chromosomal abnormalities in the fetus which can lead to serious handicap, or even death during gestation or in the first few days after birth. But these tests are only able to detect fewer than half of the total chromosomal abnormalities in the fetus, a scientist will tell the annual conference of the European Society of Human Genetics tomorrow (Monday 2 June) Dr. Francesca R. Grati, of the TOMA Laboratory, Busto Arsizio, Italy, says that these findings mean that women should be better informed on the limitations of such diagnostic tests.The researchers studied 115,576 prenatal diagnoses carried out during the last fourteen years. 84,847 were amniocenteses, usually carried out around the 16th week of pregnancy, and 30,729 chorionic villus samplings, which can be undertaken from 12 weeks into the pregnancy. Both these tests carry an increased risk of miscarriage, so the decision on whether or not to undertake them can be difficult to weigh up. “Since our sample included a large number of women aged less than 35 who underwent invasive prenatal diagnosis without any pathological indication to do so, we felt that the results could be useful in helping to inform pre-test counselling of such women”, says Dr. Grati. “Up until now, the information we had came from smaller studies which only looked at the performance of these tests in detecting a limited number of chromosomal abnormalities.”

After analysing the results of the chromosomal abnormalities from their own dataset, the researchers combined them with the official detection rates for these abnormalities published by SURUSS and FASTER consortia. These are multi-centre research groups involved in the investigation of screening and diagnostic tests performed in pregnancy, whose results are being used to optimise prenatal care for pregnant patients. They found that current screening procedures were only able to detect half the total chromosomal abnormalities in women both younger and older than 35.

The TOMA laboratory is particularly suited to carry out this kind of research, says Dr. Grati, because it was among the first in the world to deal with prenatal diagnosis, and has a vast number of prenatal diagnostic samples at its disposal.

Current tests do not detect all fetal chromosomal abnormalities, but only trisomies 21 (Down syndrome), 18 (Edward’s syndrome), and 13 (Patau syndrome), monosomy X (Turner syndrome), and triploids (conceptuses with 69 chromosomes instead of 46). “These are common vital chromosomal abnormalities, but there are many others which are not picked up by these tests”, says Dr. Grati. “And the tests do not even detect 100% of the common abnormalities.”

At conception, 23 chromosomes from each parent combine to create a fetus with 46 chromosomes in all its cells. Trisomy occurs when the fetus has one additional chromosome (47 instead 46). The extra genetic material from the additional chromosome causes a range of problems of varying severity.

In Down syndrome, for example, where the fetus has three copies of chromosome 21, babies are usually born with impaired cognitive ability and physical growth, cardiac defects and a characteristic facial appearance. Unlike many other such abnormalities, however, babies born with Down syndrome are able to lead relatively normal lives and their life expectancy is around 50 years.

Other than trisomy, the fetus can also have the loss of genetic material (deletions) or chromosomal abnormalities in a non-homogeneous form, where there is a mixture of two cell lines, one normal and the other abnormal. “Some of these disorders are relatively common in the fetus, which may have as much chance of surviving as children who are born with Down syndrome, and it is worrying that current biochemical tests are not always able to detect them” says Dr. Grati. “Our research confirms that it is fundamental for doctors to counsel patients about the limitations of current screening methods, so that they can make an informed decision on whether or not to undergo invasive diagnostic testing.”

What are the genes implicated in upright walking of humans? The discovery of four families in which some members only walk on all fours (quadrupedality) may help us understand how humans, unlike other primates, are able to walk for long periods on only two legs, a scientist will tell the annual conference of the European Society of Human Genetics tomorrow (Monday 2 June).The quadrupedal families in Turkey previously attracted attention in 2005, when they were discovered. Now the Turkish team reports that they have found the first gene implicated in quadrupedal locomotion in these families.

Professor Tayfun Ozcelik, of Bilkent University, Ankara, Turkey, and colleagues, studied four unrelated families where some members were affected by the rare quadrupedic condition, Unertan syndrome, which is also associated with imperfect articulation of speech, mental retardation, and defects in the cerebellum, a part of the brain involved in motor control. They found that the affected individuals in two families had mutations in the gene responsible for the expression of very low density lipoprotein receptor (VLDLR), a protein which is known to be critical to the proper functioning of the cerebellum during development.

Although the families lived in isolated villages 200-300 km apart and reported no ancestral relationships, the scientists expected to find a single genetic mutation implicated in the condition. They were surprised to find that this was not the case.

“We carried out genome-wide screening on these families”, said Professor Ozcelik, “and found regions of DNA that were shared by all those family members who walk on all fours. However, we were surprised to find that genes on three different chromosomes are responsible for the condition in four different families.

“In families A and D there were mutations in VLDLR on chromosome 9, and in family B the phenotype maps to chromosome 17 to a region that contains at least 157 genes, and we are still looking for the precise mutation. Neither region appears to be implicated for family C.”

In all cases, the affected individuals were the offspring of consanguineous marriages, which suggests that if they had married outside the family they would not have had the condition. All of them had significant developmental delay in infancy. “Whereas normal infants make the transition to walking on two legs in a relatively short period”, said Professor Ozcelik, “these individuals continued to move on their palms and feet and never walked upright. Although they can stand from a sitting position and maintain this upright position with flexed hips and knees, they virtually never initiate bipedal walking on their own.”

It has been suggested in the past that lack of access to medical care exacerbated the effects of an under-developed cerebellum, and that this led to quadrupedality. “Although it may be true that family B lacked proper medical care, families A and D had consistent access to good medical attention, and both families sought a correction of quadrupedality in their affected children”, said Professor Ozcelik. “Indeed, an unaffected member of family A is a physician, who has been actively involved in the medical interventions. In addition, the parents in family A also discouraged their affected children from walking on all fours, to no avail. We think that social factors are unlikely to be involved in the development of quadrupedal locomotion.”

Mutations causing VLDLR deficiency are also found in Hutterites, a group of Anabaptists who live in colonies of North America. There, however, most of the affected individuals cannot walk at all. The neurological characteristics of the affected members of the Turkish families and the Hutterites seem similar, with the most striking difference being that the Turkish individuals are able to walk on all fours, said the scientists. They hypothesize that the Hutterites may be more profoundly affected due to the deficiency in VLDLR and a neighbouring gene, and therefore lack the motor skills even for quadrupedal locomotion.

Along with brain enlargement, speech, and the ability to make tools, upright walking has long been regarded as one of the key traits that have led to modern humans. Professor Ozcelik’s team have opened a window on how mutations in VLDLR affect brain development and influence gait in humans.

“It will be interesting to see if the VLDLR gene is involved in other types of cerebellar ataxias. In addition, we hope to identify the defective genes associated with quadrupedal locomotion in families B and C”, he says.

Big pharma gave up on soil bacteria as a source of antibiotics too soon, according to research published in the June issue of Microbiology. Scientists have been mining microbial genomes for new natural products that may have applications in the treatment of MRSA and cancer and have made some exciting discoveries.

“Over the last eight years we have been looking for new natural products in the DNA sequence of the antibiotic-producing bacterium Streptomyces coelicolor,” said Professor Gregory Challis from the University of Warwick. “In the last 15 years it became accepted that no new natural products remained to be discovered from these bacteria. Our work shows this widely-held view to be incorrect.”

In 1928 Alexander Fleming discovered penicillin, which was subsequently developed into a medicine by Florey and Chain in the 1940s. The antibiotic was hailed as a ‘miracle cure’ and a golden age of drug discovery followed. However, frequent rediscovery of known natural products and technical challenges forced pharmaceutical companies to retreat and stop looking for new molecules.

Currently the complete genetic sequences of more than 580 microbes are known. It is possible to identify pathways that produce new compounds by looking at the DNA sequences and many gene clusters likely to encode natural products have been analysed. ‘Genome mining’ has become a dynamic and rapidly advancing field.

Professor Challis and his colleagues have discovered the products of two cryptic gene clusters. One of the clusters was found to produce several compounds that inhibit the proliferation of certain bacteria. Three of these compounds were new ones, named isogermicidin A, B and C. “This discovery was quite unexpected,” said Professor Challis. “Our research provides important new methodology for the discovery of new natural products with applications in medicine, such as combating MRSA infections.”

The other product they discovered is called coelichelin. Iron is essential for the growth of nearly all micro-organisms. Although it is the fourth most abundant element in the Earth’s crust it often exists in a ferric form, which microbes are unable to use. “The gene cluster that directs production of coelicehlin was not known to be involved in the production of any known products,” said Professor Challis. “Our research suggests that coelichelin helps S. coelicolor take up iron.”

Many researchers have followed Professor Challis and his colleagues into the exciting field of genome mining. “In the near future, compounds with useful biological activities will be patented and progressed into clinical or agricultural trials, depending on their applications” said Professor Challis.

“From a basic science perspective, the advances being made in genomics are important discoveries, but it’s unrealistic for individuals to believe those advances can yield meaningful information that will improve their health,” said James P. Evans, M.D., Ph.D., professor of genetics and medicine in the UNC School of Medicine. “And even saying ‘It’s not there yet’ is too optimistic. It’s going to be a long time before the potential is realized.”

Evans, who is also the director of the cancer and adult genetics clinics and the Bryson Program in Human Genetics in UNC’s medical genetics department, will talk about how personal genomics will affect human lives at a panel discussion titled “Your Biological Biography” at the World Science Festival being held in New York City, May 28 to June 1. Evans will speak between 1 p.m. and 2:30 p.m. on Saturday, May 31, at the Kimmel Center for University Life at New York University.

“The sequencing of the human genome revealed that in relative terms, humans are 99.9 percent the same,” Evans said. “But in absolute terms, we are very different. For example, a one-thousandth of a difference in their respective DNA profiles translates into more than 3 million differences between any two unrelated individuals.”

Some of these differences are medically relevant, in that they influence disease predisposition and response to drugs, areas Evans studies in his research. And the differences are of interest in non-medical ways, specifically when they address ancestry, behavior traits and the innate curiosity humans have about their genes.

Sequencing of the human genome, which was completed in 2003, also gave rise to commercial entities offering direct-to-consumer genetic testing for a fee, usually between $1,000 and $3,000. Evans worries that individuals may seek such testing with the false hope that they will get meaningful results regarding their risks for disease and actionable medical advice about how to decrease their risks.

“Much of the current excitement about genetics and medical genomics is predicated on the idea that knowing our genomes better will improve our health,” Evans said. “In fact, for the vast majority of such risk assessments, the increased risk of an individual developing the disease in question is modest – one- to two-fold over baseline. And in few such conditions are there specific effective interventions to diminish the risk. Further, there is little evidence that having the specific genetic information would actually induce a change in lifestyle.”

Society has tended to place an almost mystical association on genetic information, Evans said, adding that what to do with this new knowledge and how to interpret the information presents many unanswered challenges.

“Most physicians, by their own admission, are not geneticists and won’t know what to do with the information,” said Evans, who uses family history and genetic testing to evaluate and counsel patients about their risk for cancer. “Many who do understand the technology and how it is generated don’t know what to do with it. So there’s huge potential for patient harm – either for patients to be lulled into a false sense of security by this new genomic information or, in the opposite extreme, to have unnecessarily increased anxiety.”

And Evans said he can see even more extreme measures “where interventions are implemented – for example, a total body scan – that put patients on a road to invasive tests that they are better off not getting.”

Evans believes these challenges say something about how humans value information, but then fail to scrutinize what it really means. “It’s hard for me to over-estimate the beauty and utter significance of sequencing the human genome and other animal genomes,” Evans said. “The technology is very promising for all of us, but there is a big gap between having that knowledge and applying it for the betterment of human health.”

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a rapidly progressive, fatal neurological disease involving the degeneration and death of motor neuron cells.

ALS is one of the most common neuromuscular diseases worldwide, affecting as roughly 25,000 Americans, with an estimated 5,000 new diagnoses each year. The life expectancy of ALS patients is usually 3 to 5 years after diagnosis.

5-10 percent of all ALS cases are inherited. About 20% of these familial ALS cases are the result of an inherited genetic mutation on chromosome 21, in the gene encoding for the superoxide dismutase 1 (SOD1) enzyme. SOD1 is an antioxidant that protects the body from DNA damage caused by the accumulation of free radicals within cells. However, several reports have demonstrated that mutated SOD1 toxicity is not due to decreased antioxidant activity, but rather to a ‘gain of unknown toxic function’.

In their upcoming paper, Dr. Ichijo and colleagues delineate how mutations in SOD1 lead to motor neuron cell death and the progression of ALS. The researchers characterized a molecular pathway by which mutated SOD1 contributes to the accumulation of malformed proteins inside the endoplasmic reticulum (ER) compartment of motor neuron cells. Beyond a certain threshold, this ER stress induces cell death.

Interestingly, Dr. Ichijo’s team found that the inactivation of certain key factors in this pathway could mitigate neurodegeneration and prolong survival in a mouse model of inherited ALS.

Although not all familial ALS cases are due to the SOD1 mutation (and not all persons with a mutated form of SOD1 develop ALS), further insight into mechanism of the disease will undoubtedly aid in the development of an effective treatment for ALS.

While many university students tend to mature out of heavy-drinking behavior by the time they become young adults, some go on to develop alcohol-use disorders (AUDs). Most genetic research on an individual’s family history of alcoholism (FHA) has looked at the parents’  “usually paternal” alcohol use. New findings indicate that looking at the density of FHA  including first-, second- and third-degree relatives is much more telling.Results will be published in the August issue of Alcoholism: Clinical & Experimental Research and are currently available at OnlineEarly.

“Using a density measure of FHA can identify a greater number of individuals who may be at risk for developing an alcohol problem,” said Christy Capone, a postdoctoral research fellow at Brown University’s Center for Alcohol and Addiction Studies and the study’s first author. “The greater number of affected relatives’ the greater the potential risk of developing an AUD. Ours is the first published study to examine this measure among college students.”

Family density appears to be a promising method to identify a higher percentage of at-risk individuals, agreed John Hustad, research associate at Brown University. For example, in this study, approximately 44 percent of the at-risk participants would have been missed if a typical family-history measure had been used instead of the family-history density approach.

The study population for this research consisted of 408 undergraduate students (293 females, 115 males) from a northeastern U.S. university who were asked to complete an anonymous survey for course credit during the 2005-2006 academic year.

“Our use of a density measure identified a large proportion of students, about 29 percent, who are at potentially greater risk for development of AUDs based on their report of alcoholism among first- and second-degree relatives,” said Capone. “Our other key finding was the relationship between FHA and other potential risk factors  behavioral undercontrol, age of onset of drinking (AOD), and cigarette use.”

All of these risks factors are inter-related, added Hustad. First, family-history density was related to AOD, behavioral undercontrol, and current cigarette use which, in turn, are related to alcohol use and/or alcohol-related problems in this sample of college students. Second, behavioral undercontrol was associated with alcohol problems but not the degree of alcohol consumption; this suggests that individuals with a family-history density of AUDs and behavioral undercontrol are more likely to behave irresponsibly when drinking.

“The importance of identifying these risk factors is the idea that they can be useful markers of at-risk status and can help us to develop appropriate intervention strategies,” said Capone. “Although, given the fact that many students come to college already having experience with alcohol, I believe that preventive interventions should begin early in the high-school years or during the transition from middle school to high school.”

Hustad agreed. “Due to the relationship between earlier AOD and more alcohol-related problems during college, it is clear that education and prevention efforts should begin well before the college years,” he said. “Until that happens, the risk factors identified in this research can be easily implemented in any screening and brief intervention for incoming college students. For example, these results suggest that effective interventions addressing tobacco use may have a positive influence on both smoking and alcohol-related consequences.”

“It is important to remember that not everyone with density of familial alcoholism will go on to develop a long-term problem with alcohol themselves,” said Capone. “Alcohol dependence is a very complex disorder and FHA is but one influence on its development. However, college students who are heavy drinkers and have a greater density of familial alcoholism are certainly at higher risk of continuing to drink in a problematic fashion after the college years.”

Researchers at the Burnham Institute for Medical Research, led by Josh Luis Millhn, Ph.D., have demonstrated in mice the first successful use of enzyme replacement therapy to prevent hypophosphatasia (HPP), a primary skeletal disease of genetic origin. This discovery lays the foundation for future clinical trials for HPP patients.

Rickets is a softening of the bones that most commonly results from a lack of vitamin D or calcium and from insufficient exposure to sunlight. Hypophosphatasia is a rare, heritable form of rickets caused by mutations in a gene called TNAP, which is essential for the process that causes minerals such as calcium and phosphorus to be deposited in developing bones and teeth. The physical presentations of this disorder can vary depending on the specific mutation, with more severe symptoms occurring at a younger age of onset. The most severe form of the disease occurs at birth, which can present with absence of bone mineralization in utero, resulting in stillbirth.

Using a mouse model, Josh Luis Millhn, Ph.D. tested the hypothesis that, when administered from birth, a bone-targeted form of the TNAP gene would ease the skeletal defects of HPP. The Millhn laboratory, in collaboration with scientists from Enobia Pharma in Montreal, Canada and from the Shriners Hospitals for Children in St. Louis, Missouri, created a soluble form of human TNAP that had been shown to display a strong attraction to bone tissue. Upon injecting the enzyme into the fat layer under the skin of the mice, the treated mice maintained a healthy rate of growth and apparent well being, as well as normal bone mineral density (BMD) of the skull, femur and spine. In fact, complete preservation of skeletal and dental structures were observed after 15 days, and bone lesions were still not seen after 52 days of treatment.

“While the biochemical mechanism that leads to skeletal and dental defects of HPP is now generally understood,” said Dr. Millhn, “there is currently no established medical treatment.”

Given the success of this therapy in preventing HPP, current efforts in Dr. Millhn’s laboratory are focused on reversing the bone defects in mice once the disease is quite advanced. Future clinical trials may reveal this as the first promising therapy for patients with this genetic disorder.

Viruses are true experts at importing genetic material into the cells of an infected organism. This trait is now being exploited for gene therapy, in which genes are brought into the cells of a patient to treat genetic diseases or genetic defects. Korean researchers have now made an artificial virus. As described in the journal Angewandte Chemie, they have been able to use it to transport both genes and drugs into the interior of cancer cells.

Natural viruses are extremely effective at transporting genes into cells for gene therapy; their disadvantage is that they can initiate an immune response or cause cancer. Artificial viruses do not have these side effects, but are not especially effective because their size and shape are very difficult to control—but crucial to their effectiveness. A research team headed by Myongsoo Lee has now developed a new strategy that allows the artificial viruses to maintain a defined form and size.

The researchers started with a ribbonlike protein structure (β-sheet) as their template. The protein ribbons organized themselves into a defined threadlike double layer that sets the shape and size. Coupled to the outside are “protein arms” that bind short RNA helices and embed them. If this RNA is made complementary to a specific gene sequence, it can very specifically block the reading of this gene. Known as small interfering RNAs (siRNA), these sequences represent a promising approach to gene therapy.

Glucose building blocks on the surfaces of the artificial viruses should improve binding of the artificial virus to the glucose transporters on the surfaces of the target cells. These transporters are present in nearly all mammalian cells. Tumor cells have an especially large number of these transporters.

Trials with a line of human cancer cells demonstrated that the artificial viruses very effectively transport an siRNA and block the target gene.

In addition, the researchers were able to attach hydrophobic (water repellant) molecules—for demonstration purposes a dye—to the artificial viruses. The dye was transported into the nuclei of tumor cells. This result is particularly interesting because the nucleus is the target for many important antitumor agents.