Scientists Identify Key Factor That Controls HIV Latency

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ScienceDaily (June 27, 2009) — Scientists at the Gladstone Institutes of Virology and Immunology (GIVI) have found another clue that may lead to eradication of HIV from infected patients who have been on antiretroviral therapy. A real cure for HIV has been elusive because the virus can "hide" in a latent form in resting CD4-T cells. By understanding this "latency" effect, researchers can identify ways to reactivate the virus and enable complete clearance by current or future therapies.

Researchers in the laboratory of GIVI Associate Director Eric Verdin, MD have found that methylation of cytosine in the DNA of infected cells is associated with HIV latency and that inhibition of DNA methylation causes the reactivation of latent HIV. These observations offer a potential new strategy for inhibiting HIV latency and reactivating the virus. The discovery was reported in the current edition of PLoS Pathogens.
"While HIV-1 latency is likely to be a multifactorial process, we have shown that inhibiting the methylation of the provirus contributes to an almost complete reactivation of latent HIV-1," said lead author Steven E. Kauder.
The research team, which also included scientists from the University of Utah and Stockholm's Karolinska Institute, developed in vitro models of HIV-1 latency in T cells that harbor a full-length HIV genome. The provirus in the cell lines also encoded a fluorescent marker to illuminate HIV-1 transcriptional activity.
In addition to finding that DNA methylation is a mechanism of latency, the scientists also discovered that a host protein, called methlyl-CpG binding domain protein 2 (MBD2) binds to the methylated HIV DNA and is an important mediator of latency.
"Interfering with methylation greatly potentiates the reactivation of HIV," Kauder said. In this study, the researchers found that the drug 5-aza-2'deoxycytidine (aza-CdR) can inhibit HIV methylation and cause the virus to reactivate.
"Combined with other areas of our investigation into HIV latency, this research provides important new knowledge about the process and opens many new pathways for future study," said Dr. Verdin, senior author of the study.
The research team included Alberto Bosque and Vicente Planelles of the University of Utah and Annica Lindqvist of Karolinska University. The study was supported by the National Institutes of Health
Eric Verdin's primary affiliation is with the Gladstone Institute of Virology and Immunology, where his laboratory is located and all his research is conducted. He is also professor of medicine at the University of California, San Francisco.
Adapted from materials provided by Gladstone Institutes, via EurekAlert!, a service of AAAS.

Structural biology scores with protein snapshot.

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Surface-filled representation of diacylglycerol kinase. The "porch-like" structure of the enzyme is highlighted, and the substrate diacylglycerol is depicted bound to the active site. Investigators at the Vanderbilt Center for Structural Biology used NMR methods to determine the structure of diacylglycerol kinase, the largest membrane-spanning protein studied by NMR to date. Credit: Charles Sanders, Ph.D., Vanderbilt University Center for Structural Biology.

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In a landmark technical achievement, investigators in the Vanderbilt Center for Structural Biology have used nuclear magnetic resonance (NMR) methods to determine the structure of the largest membrane-spanning protein to date.

Although NMR methods are routinely used to "take molecular pictures" of small proteins, large proteins - and particularly those that reside within the cell membrane - have been reluctant to smile for the camera.
In the June 26 issue of Science, Charles Sanders, Ph.D., professor of Biochemistry, and colleagues report the NMR structure of the large bacterial protein diacylglycerol kinase (DAGK), a complex of three subunits that each cross the membrane three times (for a total of nine membrane spans).
The group's ability to determine the NMR structure of DAGK suggests that similar methods can now be used to study the structures of other membrane proteins.
"We're taking the methods that we used for diacylglycerol kinase and applying them to high value targets such as G protein-coupled receptors," Sanders said.
G protein-coupled receptors - the largest family of cell signaling proteins - are targets for about half of all pharmaceuticals. Sanders is collaborating with other Vanderbilt investigators to tackle G protein-coupled receptor structure using both NMR and a complementary structural approach, X-ray crystallography.
DAGK may be a therapeutic target for certain types of bacterial infections. It is a virulence factor in the bacteria Streptococcus mutans, which causes tooth decay.
Sanders selected DAGK as a model for studying membrane enzymes when he started his own research lab 17 years ago. DAGK is the smallest known kinase (a protein that adds chemical groups called phosphates onto other molecules), and it is not similar to any other known proteins.
The DAGK structure, Sanders said, "confirmed that this is a really strange kinase." The enzyme has a porch-like structure, with a wide opening for its substrate diacylglycerol and the active site at the top of the porch.
"The active site looks nothing like any other kinase active site - it's a unique architecture," Sanders said.

The researchers also performed exhaustive mutagenesis studies in which they characterized mutations at each amino acid in DAGK and used the data to map the active site of the enzyme onto the structure. They identified two sets of mutations that resulted in non-functional DAGK. One set altered the active site so that it no longer did its job, and the second set caused the protein to fold incorrectly (misfolding).
Sanders said the team was surprised to find that nearly all of the mutations that caused misfolding were in the active site. The expectation, he explained, is that mutations in the active site would cause a loss of function but would not usually affect protein folding, whereas key residues for folding would be located elsewhere in the protein to underpin the scaffold for the active site.
"Our study shows that you can't make that assumption," he said.
Sanders cautions that investigators cannot simply predict the impact of a mutation based on it being located in the active site. The finding has implications for personalized medicine, which aims to use the predicted impact of disease-causing mutations to make therapy decisions.
"The therapeutic strategy for addressing catastrophic misfolding versus simple loss of function may be very different," Sanders said.
Sanders and his team, who got interested in protein folding because of their work with DAGK, are now pursuing structural studies of misfolded membrane proteins that cause diseases including peripheral neuropathy (Charcot-Marie-Tooth Disease), diabetes insipidus and Alzheimer's disease.
"For proteins that misfold because of mutations, we're using NMR tools to understand exactly what the mutations do to the proteins in terms of structure and stability," Sanders said. "We believe that understanding will lead to predictions about how to intervene and avoid misfolding."
Source: Vanderbilt University Medical Center (news : web)

Discovery Of Facial Malformation Gene

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ScienceDaily (June 19, 2009) — The first specific genetic mutation which can cause a potentially serious facial disfigurement has been identified by researchers at Oxford University. The finding, published online in the American Journal of Human Genetics, offers the promise of improved genetic counselling for parents at risk.

Formation of the human face is a complex and exquisitely orchestrated developmental process that occurs between four and eight weeks of embryonic development. Disturbance to this development can lead to malformations of the head and face, including abnormal nasal configuration, cleft lip, and widely spaced eyes.
Most cases of disfigurement are caused by damage to the developing embryo early in pregnancy; genetic causes are thought to be responsible for only a minority of cases, and these usually also involve other parts of the body. No mutation of a single gene has previously been identified that leads specifically to facial malformations.
Researchers, led by Professor Andrew Wilkie from the Weatherall Institute for Molecular Medicine at the University of Oxford and Dr Irene Mathijssen from the Erasmus Medical Centre in the Netherlands and funded by the Wellcome Trust, identified individuals from seven families who shared a similar, distinctive facial appearance, including an abnormally large distance between the eyes and a wide, malformed nose. They termed this condition ‘frontorhiny’.
Genetic analysis showed that each of the individuals carried two copies of a mutation in the gene ALX3. Mouse models have previously highlighted the involvement of the equivalent gene in the production of a protein which regulates other genes involved in facial development – in other words, switching them on and off. However, while the absence of the protein produced by this gene does not disrupt facial development in mice, Professor Wilkie and colleagues found that in humans it leads to frontorhiny.
‘Frontorhiny can be a very distressing condition,’ says Professor Wilkie. ‘It causes facial disfigurement and other health problems, such as breathing difficulties and dermoids (benign cysts under the skin). The cosmetic surgery can be very challenging, requiring multiple operations.’
By identifying and naming the condition, the researchers believe that they will be able to diagnose more cases and provide improved genetic counselling. Because this is a recessive genetic disorder, a parent with the condition is very unlikely to have a similarly affected child. However, where unaffected parents have a child with the condition, they have a one in four chance of each future child being affected.
‘This finding is very important from the point of view of genetic counselling and offers hope to those families considered to be at risk,’ explains Professor Wilkie. ‘For example, by correctly diagnosing the condition in an adult, we can reassure them that their children are unlikely be affected.’
Professor Wilkie believes that the research also highlights the power of genetics to identify the origins of genetic disorders.
‘This study illustrates the tremendous power of genetics to identify the origins of rare disorders such as frontorhiny, even when working with very small numbers of individuals. In this research, just three affected individuals helped us to narrow the search for the particular genetic mutation responsible to around one three thousandth of the human genome. The previous mouse genetic work then helped finish the job for us.’
Adapted from materials provided by University of Oxford.

Silver nanoparticles show 'immense potential' in prevention of blood clots

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Silver nanoparticles (shown) could help prevent blood clots. Credit: The American Chemical Society.
Scientists are reporting discovery of a potential new alternative to aspirin, ReoPro, and other anti-platelet agents used widely to prevent blood clots in coronary artery disease, heart attack and stroke. Their study, scheduled for the June 23 issue of ACS Nano, a monthly journal, involves particles of silver -- 1/50,000th the diameter of a human hair -- that are injected into the bloodstream.

Debabrata Dash and colleagues point out that patients urgently need new anti-thrombotic agents because traditionally prescribed medications too-often cause dangerous bleeding. At the same time, aging of the population, sedentary lifestyle and spiraling rates of certain diseases have increased the use of these drugs. Researchers are seeking treatments that more gently orchestrate activity of platelets, disk-shaped particles in the blood that form clots.
The scientists describe development and lab testing of silver nanoparticles that seem to keep platelets in an inactive state. Low levels of the nanosilver, injected into mice, reduced the ability of platelets to clump together by as much as 40 percent with no apparent harmful side effects.
The nanoparticles “hold immense potential to be promoted as an antiplatelet agent,” the researchers note. “Nanosilver appears to possess dual significant properties critically helpful to the health of mankind — antibacterial and antiplatelet — which together can have unique utilities, for example in coronary stents.”
More information: ACS Nano, Journal Article: “Characterization of Antiplatelet Properties of Silver Nanoparticles”
Provided by American Chemical Society (news : web)

Breakthrough in the treatment of bacterial meningitis

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It can take just hours after the symptoms appear for someone to die from bacterial meningitis. Now, after years of research, experts at The University of Nottingham have finally discovered how the deadly meningococcal bacteria is able to break through the body's natural defence mechanism and attack the brain.

The discovery could lead to better treatment and vaccines for meningitis and could save the lives of hundreds of children.
Bacterial meningitis in childhood is almost exclusively caused by the respiratory tract pathogens Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae. The mechanism used by these lethal germs to break through the blood brain barrier (BBB) has, until now, been unknown.
The team led by Dlawer Ala'Aldeen, Professor of Clinical Microbiology and Head of the Molecular Bacteriology and Immunology Group at the Centre for Biomolecular Sciences, recently discovered that all three pathogens target the same receptor on human cerebrovascular endothelial cells — the specialised filtering system that protects our brain from disease — enabling the organisms to cross the blood-brain barrier.
Their findings, published today in The Journal of Clinical Investigation, suggest that disruption or modulation of this interaction of bacterial adhesins with the receptor might offer unexpectedly broad protection against bacterial meningitis and may provide a therapeutic target for the prevention and treatment of disease.
Professor Ala'Aldeen, who has been studying meningitis and its causes for over 20 years, said: "This is a significant breakthrough which will help us design novel strategies for the prevention and treatment of bacterial meningitis. Identification of the human receptor and bacterial ligands is like identifying a mysterious key and its lock, which will open new doors and pave the way for new discoveries."
The research, carried out in collaboration with the Department of Infectious Diseases at St. Jude Children's Research Hospital in Memphis Tennessee, also involved students from the University who have been regular and willing volunteers in the research programme.
Professor Ala'Aldeen said: "The ultimate aim is to save lives by protecting the healthy and curing the sick. We are one step closer to new breakthroughs that would prevent disease or its complications. There still is a long way to go before we have the ultimate vaccine and the ultimate treatment of bacterial meningitis."
Source: University of Nottingham (news : web)

Developed a human monoclonal antibody that neutralizes the Hepatitis C virus (HCV).

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ScienceDaily (May 11, 2009) — aking aim at a leading cause of liver failure in the United States, a team of scientists at the Massachusetts Biologic Laboratories (MBL) of the University of Massachusetts Medical School (UMMS) has developed a human monoclonal antibody that neutralizes the Hepatitis C virus (HCV). The new antibody effectively neutralized the virus in culture, and then prevented infection by the virus in a pre-clinical animal model of the disease.

Details of the research were presented April 23 in Copenhagen, Denmark at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL). "We are pleased with the progress of this program," said Donna Ambrosino, MD, executive director of the MBL and a professor of pediatrics at the Medical School. "This antibody shows significant efficacy against the virus."
In the current study, MBL scientists injected transgenic mice (HuMAb Mouse® technology, Medarex, Inc.) with elements of HCV and then painstakingly searched for individual human antibodies produced in the mice that would recognize and bind to the HCV's outer coat, known as the glycoprotein. Once they found human antibodies that looked promising, they evaluated in vitro the ability of those antibodies to neutralize the virus and selected a lead candidate antibody for further characterization. Collaborative work with clinical researchers from the Department of Medicine at the Medical School's Worcester campus demonstrated that this antibody, now known as MBL-HCV1, was able to bind tightly with all genotypes of HCV tested from infected patient samples.
MBL-HCV1 was then tested off-site on three non-human primates. In that study, one animal received no antibody, one a low dose of the new antibody, and one a higher dose. Then all three animals were exposed to HCV. The animals with low or no antibody dosages developed HCV infections, but the animal with the higher dose was protected. Subsequently, researchers gave the high-dose of the antibody to the animal that originally received no antibody, and in that case the HCV was cleared from that animal's system. "These results are encouraging as a possible treatment for HCV infected patients, but more work needs to be done before we know how effective it will be in people," Dr. Ambrosino noted.
HCV attacks the liver and can eventually lead to liver failure. According to the U.S. Centers for Disease Control and Prevention, 3.2 million Americans are chronically infected with HCV and some 10,000 die annually of the disease. Globally, as many as 170 million people are estimated to suffer from HCV infection. For the most serious cases of HCV that do not respond to antiviral drugs, liver transplantation is the only option.
Typically 2,000 to 4,000 liver transplants are done each year in the United States (far less than the number of people on the waiting list for available organs). Transplantation can be a life saving treatment; however, in nearly all cases the patient's new liver is eventually infected by HCV because the virus remains in the patient's bloodstream during surgery. The powerful antiviral drugs now used to attack HCV prior to end-stage liver failure are not routinely used during surgery due to the patients' weakened condition and because of the strong medication used to avoid rejection of the new liver. After re-infection with HCV, nearly 40 percent of patients suffer rapid liver failure.
To close that clinical gap, the new antibody developed at MBL is designed to be a therapy shortly before and after transplant surgery. By giving a patient the new antibody before and during the time when the donor liver is implanted, researchers hope the HCV virus left in the bloodstream will be neutralized and rendered unable to infect the new liver. Then, because monoclonal antibodies are highly specific and typically have little or no side-effects, additional dosages of the new antibody could, theoretically, be given immediately after transplant surgery to continue neutralizing any remaining virus.
It is also possible, researchers theorize, that the antibody could be used in combination with new antiviral drugs for treatment in patients with newly diagnosed HCV infection. Use of the new antibody for both liver transplant patients and in newly diagnosed HCV patients will now be further evaluated. A Phase 1 human clinical trial of MBL-HCV1 in healthy subjects is expected to begin later this year.
Adapted from materials provided by University of Massachusetts Medical School, via EurekAlert!, a service of AAAS.

Making Gene Therapy Safer: Delivering Genes Via Polymers

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http://www.sciencedaily.com/releases/2007/09/070907095614.htm

Science Daily — In work that could lead to safe and effective techniques for gene therapy, MIT researchers have found a way to fine-tune the ability of biodegradable polymers to deliver genes.

Gene therapy, which involves inserting new genes into patients' cells to fight diseases like cancer, holds great promise but has yet to realize its full potential, in part because of safety concerns over the conventional technique of using viruses to carry the genes.
The new MIT work, published this week in Advanced Materials, focuses on creating gene carriers from synthetic, non-viral materials. The team is led by Daniel Anderson, research associate in MIT's Center for Cancer Research.
"What we wanted to do is start with something that's very safe-a biocompatible, degradable polymer-and try to make it more effective, instead of starting with a virus and trying to make it safer," said Jordan Green, a graduate student in biological engineering and co-first author of the paper.
Gregory Zugates, a former graduate student in chemical engineering now at WMR Biomedical, Inc., is also a co-first author of the paper.
Gene therapy has been a field of intense research for nearly 20 years. More than 1,000 gene-therapy clinical trials have been conducted, but to date there are no FDA-approved gene therapies. Most trials use viruses as carriers, or vectors, to deliver genes.
However, there are risks associated with using viruses. As a result, many researchers have been working on developing non-viral methods to deliver therapeutic genes.
The MIT scientists focused on three poly(beta-amino esters), or chains of alternating amine and diacrylate groups, which had shown potential as gene carriers. They hoped to make the polymers even more efficient by modifying the very ends of the chains.
When mixed together, these polymers can spontaneously assemble with DNA to form nanoparticles. The polymer-DNA nanoparticle can act in some ways like an artificial virus and deliver functional DNA when injected into or near the targeted tissue.
The researchers developed methods to rapidly optimize and test new polymers for their ability to form DNA nanoparticles and deliver DNA. They then chemically modified the very ends of the degradable polymer chains, using a library of different small molecules.
"Just by changing a couple of atoms at the end of a long polymer, one can dramatically change its performance," said Anderson. "These minor alterations in polymer composition significantly increase the polymers' ability to deliver DNA, and these new materials are now the best non-viral DNA delivery systems we've tested."
The polymers have already been shown to be safe in mice, and the researchers hope to ultimately run clinical trials with their modified polymers, said Anderson.
Non-viral vectors could prove not only safer than viruses but also more effective in some cases. The polymers can carry a larger DNA payload than viruses, and they may avoid the immune system, which could allow multiple therapeutic applications if needed, said Green.
One promising line of research involves ovarian cancer, where the MIT researchers, in conjunction with Janet Sawicki at the Lankenau Institute for Medical Research, have demonstrated that these polymer-DNA nanoparticles can deliver DNA at high levels to ovarian tumors without harming healthy tissue.
Other MIT authors on the paper are Nathan Tedford, a former graduate student in biological engineering now at Epitome Biosystems; Linda Griffith, professor of biological engineering; Douglas Lauffenberger, head of biological engineering, and Institute Professor Robert Langer. Sawicki and Yu-Hung Huang of the Lankenau Institute are also co-authors.
The research was funded by the National Institutes of Health, the Department of Defense and the National Science Foundation.
Note: This story has been adapted from a news release issued by Massachusetts Institute of Technology.

Fausto Intilla

www.oloscience.com

In the Genome Race, the Sequel Is Personal

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http://www.nytimes.com/2007/09/04/science/04vent.html?ref=science

By NICHOLAS WADE
Published: September 4, 2007

The race to decode the human genome may not be entirely over: the loser has come up with a new approach that may let him prevail in the end.

In 2003, a government-financed consortium of academic centers announced it had completed the human genome, fending off a determined challenge from the biologist J. Craig Venter. The consortium’s genome comprised just half the DNA contained in a normal cell, and the DNA used in the project came from a group of people from different racial and ethnic backgrounds.
But the loser in the race, Dr. Venter, could still have the last word. In a paper published today, his research team is announcing that it has decoded a new version of the human genome that some experts believe may be better than the consortium’s.
Called a full, or diploid genome, it consists of the DNA in both sets of chromosomes, one from each parent, and it is the normal genome possessed by almost all the body’s cells. And the genome the team has decoded belongs to just one person: Dr. Venter.
The new genome, Dr. Venter’s team reports, makes clear that the variation in the genetic programming carried by an individual is much greater than expected. In at least 44 percent of Dr. Venter’s genes, the copies inherited from his mother differ from those inherited from his father, according to the analysis published in Tuesday’s issue of PLoS Biology.
Huntington F. Willard, a geneticist at Duke University who has had early access to Dr. Venter’s genome sequence, said that the quality of the new genome was “exceptionally high” and that “until the next genome comes along this is the gold standard right now.”
Dr. Willard said it was “hugely better” than the consortium’s sequence, at least for his particular research interest.
“I don’t want to fan the fires but I like this, it’s a really good genome,” said Edward M. Rubin, a genome expert at the Lawrence Berkeley National Laboratory.
Dr. Venter’s race with the consortium began in 1998 when he spotted a quicker method of decoding the human genome. He tried to wrest this rich scientific prize from his academic rivals by co-founding a genome-decoding company called Celera. By June 2000, the two sides were neck and neck preparing a draft sequence of the genome. But in January 2002, Dr. Venter was abruptly fired as president of Celera. The consortium went on to claim victory when it announced its completion of the genome the next year.
But the consortium’s genome, though immensely useful to biologists, was full of gaps and only complete in the sense that it was the best that could be done with existing technology.
Dr. Venter has spent the last five years and an extra $10 million of his institute’s money in improving the draft genome he prepared at Celera. That genome was based mostly on his own DNA, and the new diploid version is entirely so. His critics may accuse him of an egocentricity of considerable dimension, but by analyzing his own genome he has sidestepped the problems of privacy and consent that could have arisen with other people’s DNA when he made the whole sequence publicly available, as he is doing now.
Like James Watson, the co-discoverer of DNA, whose genome is also being decoded, Dr. Venter believes strongly in making individual DNA sequences public to advance knowledge and hasten the era of personalized genomic medicine.
If other experts find that Dr. Venter’s genome is the best available, could it be said that he won the human genome race after all?
“There is this long history of Craig’s vanity, which for much of the scientific community is irritating,” Dr. Rubin said, declining to give a direct answer.
Asked the same question, Dr. Venter replied: “I’m not sure I’d want to be the one to say that, but we’re not through racing yet. I’ll let you know when we’ve stopped.”
James Shreeve, author of “The Genome War,” said, “I think he already believes he’s the true winner of the genome race for what he did at Celera,” noting that the consortium, too, believed it had won.
Though there are now novel technologies for decoding DNA very cheaply, Dr. Venter’s genome sequence could set a high bar for a long time. It was decoded with an old method, known as Sanger sequencing, that is expensive but analyzes stretches of DNA up to 800 units in length. The cheaper new technologies at present analyze pieces of DNA only 200 units or so long, and the shorter lengths are much harder to assemble into a complete genome.
Dr. Watson’s genome is being decoded with a next-generation machine developed by 454 Life Sciences. But the company’s researchers are putting the pieces in correct order by matching them to the consortium’s genome sequence rather than by doing an independent assembly.

Dr. Venter’s genome could be the gold standard for many years, especially if he continues to improve it. Samuel Levy, who led the J. Craig Venter Institute team that decoded the genome, said that it was a work in progress and that new versions would be published as the remaining gaps were closed. There are 4,500 gaps where the sequence of DNA units is uncertain, and no technology yet exists for decoding the large amounts of DNA at the center and tips of the chromosomes.

Biologists studying variation in the human genome, whether to discover causes of disease or for other reasons, have mostly looked at what are called SNPs or “snips,” which are sites on the genome where a single unit of DNA is changed.
But there are other kinds of variation, all of which can have consequences for a person. One type is called indels, where a single DNA unit has either been inserted or deleted from the genome. Another is copy number variation, in which the same gene can exist in multiple copies. There are also inversions, in which a stretch of DNA has been knocked out of its chromosome and reinserted the wrong way around. Dr. Venter’s genome has four million variations compared with the consortium’s, including three million snips, nearly a million indels and 90 inversions.
“This is the first time that anyone has had an accurate representation of how much variation there is in a human genome,” said Stephen W. Scherer of the University of Toronto, a co-author of the study.
Biologists had estimated that two individuals would be identical in 99.9 percent of their DNA, but the true figure now emerges as much less, around 99.5 percent, Dr. Scherer said.
The genome is being made publicly available on the database operated by the National Center for Biotechnology Information and is free for any use. Dr. Venter said he would add phenotypic information to the version on his own Web site, meaning medical records and other data to help researchers correlate his bodily characteristics with his DNA.
What little is understood about the human genome at present consists mostly of medical variants that put people at risk of disease. So interpreting a genome brings mostly adverse news. Dr. Venter reports that he has variants that increase his risk of alcoholism, coronary artery disease, obesity, Alzheimer’s disease, antisocial behavior and conduct disorder.
But these predictions are far from certain. As more individual genomes are decoded, the information from them will become more valuable, Dr. Venter said, provided that people can overcome “irrational fears of even seeing their genetic code.”
Although Dr. Venter has decoded the DNA sequence inherited from both of his parents, he does not yet know which sequences are from his mother and which from his father. The issue could be resolved by analyzing DNA from his mother, who is alive and well, and the matter is under consideration, Dr. Levy said. Dr. Venter has traced his ancestry for three generations and found that his mother’s and father’s ancestors came from England.
Next month, Dr. Venter will publish an autobiography, “A Life Decoded.” The book describes the twists and turns that led him down the unlikely path into scientific research. “Rebellious and disobedient,” as he describes himself, he dedicated his teenage years to the pursuit of young women and the California surf, to the detriment of his academic career.
He was drafted at the time of the Vietnam war and enlisted in the Navy. Because of a high I.Q. score, he was given a choice of any Navy career, from nuclear engineering to electronics. He chose the hospital corps school, because it was the only course that did not require any further enlistment. Only too late did he discover the reason. Corpsmen in Vietnam did not usually survive long enough to re-enlist — the half-life of medics in the field was six weeks, he writes.
Learning how to manipulate the Navy bureaucracy, he got himself assigned to the Navy hospital in Da Nang, where chances of survival were better. But the work was harrowing. He witnessed several hundred soldiers die on his operating table, mostly when he was massaging their heart or trying to breathe life into them.
“I learned more than any 20-year-old should ever have to about triage, about sorting those you can salvage from those you cannot do anything for except ease their pain as they died,” Dr. Venter writes in the autobiography.
He escaped from Vietnam with his life and an interest in medical research. With his lack of academic skills, this was a hard field for him to break into, but by 1975 he had a Ph.D. By the late 1980s, he was starting to make his mark as one of the few scientists who could get useful results out of the first DNA sequencing machines that were then becoming available.
He was the first to sequence the genome of a bacterium, Hemophilus influenzae, even though his grant application was turned down by the National Institutes of Health on the advice of experts who said his method would not work. With the human genome, an even greater prize, the pace of competition was intense, especially when his approach turned out to be more efficient than the one his rivals had chosen.
In the book, Dr. Venter says that detractors badmouthed his work, pressured other scientists not to cooperate with him and tried strenuously to block publication of his report, of which they had earlier maneuvered to be made co-authors.
“Like most human endeavors, science is driven in no small part by envy,” he writes.
Dr. Venter has never fully lost his youthful disrespect for authority and establishments. His investment in himself — choosing his own genome to sequence, naming his laboratory the J. Craig Venter Institute — may come across as vainglorious, but it can also be seen as a signal of survival, defying the establishments he believes have sought to crush him. However nettlesome he may seem to some of his colleagues, he has the charm and the personal skills to have recruited many highly able researchers to his teams.
Another reason for his success has been his skill at raising private finances to achieve research goals after being denied support from the National Institutes of Health. That a scientist of his ability has been forced to work outside the N.I.H.’s peer-review system puts peer review in a strange light. If his diploid human genome should become a standard, the success is one that he will have earned by perseverance and defiance of long odds.

Fausto Intilla

www.oloscience.com

'Skinny Gene' Exists

Source:

http://www.sciencedaily.com/releases/2007/09/070904122434.htm

Science Daily — Researchers at UT Southwestern Medical Center have found that a single gene might control whether or not individuals tend to pile on fat, a discovery that may point to new ways to fight obesity and diabetes.

"From worms to mammals, this gene controls fat formation," said Dr. Jonathan Graff, associate professor of developmental biology and internal medicine at UT Southwestern and senior author of a study appearing in the Sept. 5 issue of Cell Metabolism. "It could explain why so many people struggle to lose weight and suggests an entirely new direction for developing medical treatments that address the current epidemic of diabetes and obesity.
"People who want to fit in their jeans might someday be able to overcome their genes."
The gene, called adipose, was discovered in fat fruit flies more than 50 years ago by a graduate student at Yale University, but few people knew about it. Its mechanism was unknown, and whether it's important in other genes was a mystery.
In the current study, the UT Southwestern researchers examined how adipose works by analyzing fruit flies, tiny worms called C. elegans, cultured cells, and genetically engineered mice, as well as by exploiting sophisticated molecular techniques. Using several methods, they manipulated adipose in the various animals, turning the gene on and off at different stages in the animals' lives and in various parts of their bodies.
It was discovered that the gene, which is also present in humans, is likely to be a high-level master switch that tells the body whether to accumulate or burn fat.
In the mice, the researchers found that increasing adipose activity improved the animals' health in many ways. Mice with experimentally increased adipose activity ate as much or more than normal mice; however, they were leaner, had diabetes-resistant fat cells, and were better able to control insulin and blood-sugar metabolism.
In contrast, animals with reduced adipose activity were fatter, less healthy and had diabetes.
The researchers' work on flies showed that the gene is "dose-sensitive" -- that is, the various combinations of the gene's variants lead to a range of body types from slim to medium to obese.
"This is good news for potential obesity treatments, because it's like a volume control instead of a light switch; it can be turned up or down, not just on or off," Dr. Graff said. "Eventually, of course, the idea is to develop drugs to target this system, but that's in the years to come."
This genetic mechanism makes survival sense, he said, because if a population has many versions of the gene scattered among many different individuals, at least some will survive in different conditions. For instance, a fat fruit fly may be able to survive famine, but a sleeker model might be better at evading predators.
Dr. Graff said the next step is to understand better the exact mechanisms by which adipose exerts its control.
Although the current study finally identifies the adipose gene's function, the gene was discovered more than 50 years ago when Winifred Doane, now a professor emeritus at Arizona State University, was studying fruit flies and noticed that some contained more fat than others. She linked this trait to a gene she named adipose and hypothesized that this natural variation gave the chubbier flies an evolutionary advantage; they could hoard more fat on the same amount of food as their skinnier counterparts, allowing them to survive times of famine.
But for people in developed countries, this trait has backfired. It's all feast and no famine, so the fat builds and builds.
"Even a pound a year adds up over a lifetime," Dr. Graff said.
Other UT Southwestern researchers involved in the study were Dr. Jae Myoung Suh, postdoctoral researcher in developmental biology; Daniel Zeve, Robert Li and Michael Wang, students in the Medical Scientist Training Program; Dr. Renee McKay, instructor of developmental biology; Dr. Jin Seo, postdoctoral researcher in developmental biology; and Zack Salo, undergraduate at UT Arlington.
The work was supported by the National Institutes of Health.
Note: This story has been adapted from a news release issued by UT Southwestern Medical Center.

Fausto Intilla

www.oloscience.com

Genome Study Shines Light On Genetic Link To Height

Source:

http://www.sciencedaily.com/releases/2007/09/070902193734.htm

Science Daily — It became clear nearly a century ago that many genes likely influence how tall a person grows, though little progress, if any, has followed in defining the myriad genes. Now an international research team brings light to this age-old question by pinpointing a genetic variant associated with human height -- the first consistent genetic link to be reported.

The findings, published in Nature Genetics, stem from a large-scale effort led by scientists at the Broad Institute of Harvard and MIT, Children's Hospital Boston, the University of Oxford and Peninsula Medical School, Exeter.
Using a new "genome-wide association" method, the research team searched the human genome for single letter differences in the genetic code that appear more often in tall individuals compared to shorter individuals. By analyzing DNA from nearly 35,000 people, the researchers zeroed in on a difference in the HMGA2 gene -- a 'C' written in the DNA code instead of a 'T'. Inheriting the 'C'-containing copy of the gene often makes people taller: one copy can add about a half centimeter in height while two copies can add almost a full centimeter.
"This is the first convincing result that explains how DNA can affect normal variation in human height," said co-senior author Joel Hirschhorn, an associate member of the Broad Institute, a pediatric endocrinologist at Children's Hospital Boston, and an associate professor of genetics at Harvard Medical School. "Because height is a complex trait, involving a variety of genetic and non-genetic factors, it can teach us valuable lessons about the genetic framework of other complex traits -- such as diabetes, cancer and other common human diseases."
In addition to being a textbook example of a complex trait, height is a common reason children are referred to medical specialists. Although short stature by itself typically does not signal cause for concern, delayed growth can sometimes reflect a serious underlying health condition. "By defining the genes that normally affect stature, we might someday be able to better reassure parents that their child's height is within the range predicted by DNA, rather than a consequence of disease," said Hirschhorn.
Nearly 90% of the variation in height among most human populations can be attributed to DNA. The remainder is due to environmental and lifestyle factors, such as nutrition. Although a few genes have been uncovered through studies of rare, single-gene stature disorders, most do not seem to be associated with height in the general population. Recent advances, including the completion of the HapMap project and the availability of large-scale research tools, enabled the scientists to take a systematic approach to understand how common genetic differences can impact a person's height.
The results of the research team, which also includes co-senior authors Timothy Frayling of the Peninsula Medical School, Exeter and Mark McCarthy of the University of Oxford, spring from data made available in two recent genome-wide association studies of type 2 diabetes. The studies, one led by the Diabetes Genetics Initiative and the other by the Wellcome Trust Case Control Consortium, involved nearly 5,000 patients who generously volunteered DNA samples as well as pertinent clinical information, such as height and weight.
After scrutinizing the initial data, the scientists identified a single letter change -- known as a single nucleotide polymorphism or SNP -- in the HMGA2 gene as the most promising result. They collaborated with additional researchers to study this SNP through a second phase of analysis that encompassed nearly 30,000 individuals: adults and children from the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Exeter Family Study of Childhood Health (EFSOCH),
European adults taking part in a study of type 2 diabetes risk (UKT2D GCC), Finnish individuals participating in the FINRISK1997 health survey, and a set of tall and short European American and Polish adults assembled for studies of height. This two-pronged approach enabled co-first author Guillaume Lettre, a researcher at the Broad Institute and Children's Hospital Boston, and his colleagues to convincingly prove that the DNA variation in HMGA2 influences height.
The genomic find, though, is not the only indication that HMGA2 affects height. Previous studies in mice and humans revealed that a handful of rare stature disorders result from severe mutations in the gene. Taken together, the findings provide strong evidence for a role for HMGA2 in height. However, the identified SNP accounts for just 0.3% of the normal variability in human stature, which means there are probably many others yet to be found. To do this, researchers will need to study even larger groups of individuals.
"Unlike most other complex traits, height is something that can be easily defined and measured in very large numbers of people," said Hirschhorn. "Soon the scientific community will have access to many more large-scale genomic data sets, making it feasible to identify additional genes involved in height."
While surprisingly little is known about how genes hardwire humans for growth, some initial clues have already surfaced as a result of the HMGA2 discovery. The gene is active in the first months of fetal growth and shuts off shortly before birth, suggesting it orchestrates growth-related events early in human development. Moreover, it appears to influence the overall longitudinal growth of the skeleton, as scientists found that the T-to-C change in the gene's DNA sequence correlates with an increased length of both the limbs and spine in young children. HMGA2 has also been implicated in certain forms of cancer. Thus, further studies may help dissect the relationship between normal growth and the deranged growth central to cancer.
Citation: Weedon MN et al. A common variant of HMGA2 is associated with adult and childhood height in the general population. Nature Genetics; DOI:10.1038/ng2121
Note: This story has been adapted from a news release issued by Broad Institute of MIT and Harvard.

Fausto Intilla

www.oloscience.com