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Mon 20 Aug 2007 12:00 AM

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Research matters

News from the Harvard Medical School research community.

News from the Harvard Medical School research community.

Mental health

Brain Size and Signal Decline with Advance of Schizophrenia.

Dean Salisbury, HMS associate professor of psychiatry at McLean Hospital, and Robert McCarley, HMS professor of psychiatry at the VA Boston Healthcare System, have found both structural and functional evidence that schizophrenia is a progressive disorder, according to their report in the May Archives of General Psychiatry. "This changes our view of the disorder ...and could possibly lead to a therapy that could arrest the course of schizophrenia," said McCarley.


Researchers have debated whether or not schizophrenia is set at birth or develops over time.

Researchers have debated whether or not schizophrenia, which attacks both the frontal and temporal lobes of the brain, is set at birth or develops over time. Previous magnetic resonance imaging (MRI) studies of schizophrenics showed no progressive changes in the brain, but a few studies near first hospitalisation did show a change in brain size. Still, the results were controversial-stronger evidence was needed.

What researchers sought to uncover was a decrease in brain size that corresponded to a loss of brain function. Salisbury and McCarley found just that - a tight correlation between a brain wave called mismatch negativity (MMN) and the volume of the Heschl gyrus, a section of the temporal lobes.

MMN brain waves, caused by auditory cues, are tested by playing a series of identical beeps, with an occasional "oddball" beep thrown in. The brain automatically responds to this difference by producing an MMN, which originates from the Heschl gyrus.

In a series of three experiments spanning 18 months, McCarley and Salisbury found that schizophrenics' MMN waves were initially normal, but quickly diminished over time. In one test group, 14 out of 16 schizophrenia patients displayed an MMN decline over time, and in an additional test, 11 out of 11 test subjects showed a combined decrease in Heschl gyrus volume and MMN response.

While the sample sizes were relatively small, the researchers noted that long-term studies with the psychiatrically ill can be difficult - half of their subjects never returned for further tests. However, McCarley and Salisbury are following up with another study of new patients as a replication sample.

Not only does the study give hope of ending the onslaught of schizophrenia, it provides a tool to monitor the process. "Drugs that try to halt the shrinkage [of the brain] can be developed, and we can use the MMN to track that," said Salisbury.

Gregory Light, an assistant professor of psychiatry at the University of California, San Diego, who is not an author on the study, believes the work is groundbreaking: "It's really a substantial contribution to the science of understanding schizophrenia," he said.


Women aged 50-59 who took oestrogen show a reduced risk of coronary plaque buildup.

A new study from the Women's Health Initiative (WHI) has evaluated, for the first time in a randomised trial, the relationship between oestrogen therapy and coronary artery calcium in young postmenopausal women. JoAnn Manson, MD, from Brigham and Women's Hospital (BWH) and colleagues found that oestrogen therapy in women aged 50-59 is related to lower coronary artery calcium, a marker for plaque blockage in the coronary arteries and a predictor of future risk of heart attack. These findings were published in the June 21, 2007 issue of the New England Journal of Medicine.

"These findings lend further support to the theory that oestrogen may slow early stages of plaque buildup and lead to less hardening of the arteries supplying blood flow to the heart," said Manson, lead author of the study and chief of Preventive Medicine at BWH. "These results, together with previous WHI findings about lower rates of coronary bypass surgery and angioplasty for younger women who take oestrogen, provide reassurance for recently menopausal women who are considering oestrogen therapy for the short-term treatment of menopausal symptoms," added Manson, who is also one of the principal investigators of the WHI.

Coronary artery calcium was measured by cardiac computed tomography (CT scans) in 1064 women who were aged 50-59 years and randomly assigned to oestrogen-alone therapy (conjugated equine estrogens, 0.625 mg/d) or to placebo at the start of the WHI trial. After an average of 7.4 years of treatment, the women receiving oestrogen were 30-40% less likely to have severe coronary artery calcium than women receiving placebo. Among women who were taking their study medications regularly, women receiving oestrogen had a 60% lower risk of severe coronary calcium. These risk reductions were statistically significant.

The authors caution, however, that the new study should not be interpreted to mean that women should take oestrogen to protect their hearts and stress that more research is needed to evaluate the effects of oestrogen in younger women.

"Although these findings indicate that oestrogen therapy in younger menopausal women is related to less plaque in the arteries supplying the heart, this does not mean that oestrogen should be taken for the express purpose of preventing cardiovascular disease," concluded Manson, who is also a professor of medicine at Harvard Medical School and author of Hot Flashes, Hormones & Your Health. "Oestrogen is known to have other risks and should be used only for the treatment of menopausal symptoms at the lowest dose for the shortest duration necessary," she added.

A faster way to recover from chemotherapy and marrow transplant.

Researchers at Children's Hospital Boston report finding a new way to increase stem cells in blood, suggesting a possible treatment to help patients who undergo chemotherapy or bone marrow transplant for leukaemia and other cancers recover their immune function more quickly. In the June 21 issue of Nature, they demonstrated that a stable analogue of prostaglandin can enhance the blood-forming system, both during embryonic development and after it's been damaged.


More research is needed to evaluate the effects of oestrogen in younger women.

The discovery, made possible through high-volume drug screening in zebrafish, marks the first time stem-cell production has been induced by a small-molecule drug, says the study's senior author, Leonard Zon, MD, of the Children's Hospital Boston Stem Cell Program and Division of Hematology/Oncology. Other studies, including one from Zon's own lab, have identified ways of increasing formation of blood stem cells, which give rise to each of the body's various blood cell types. However, the methods are technically complex and haven't lent themselves to broad medical use.

The hospital now hopes to conduct a clinical trial of the drug, a long-active derivative of prostaglandin E2 known as dmPGE2. This compound was originally tested more than 20 years ago for patients with gastritis, but was never marketed as a drug.

Currently, patients undergoing bone marrow transplant must wait for marrow from a matched donor to replenish their stem cells and reproduce the full array of blood cell types, including all the cells of the immune system. When there's no suitable donor for a marrow match, patients can receive umbilical cord blood, which also contains blood stem cells. But the number of stem cells in one cord of blood is often not adequate for older children and adults, leaving them with diminished immune function and high risk for infections.

Zon and colleagues Trista North, PhD, and Wolfram Goessling, MD, PhD, both also of Children's Stem Cell Program, zeroed in on dmPGE2 by screening more than 2,500 chemicals in zebrafish. Knowing that two genes, runx1 and cmyb, are required for blood stem cells to develop in vertebrate embryos, they looked for compounds that altered the expression (activation) of these genes. North spent six months placing 15,000+ tiny embryos in wells, each containing a different chemical -- five embryos to a well, 48 wells to a plate -- then checking each embryo 24 hours later to monitor its development and count its blood stem cells.

The screen identified 82 chemicals that markedly increased or decreased gene activity. Of these, 10 turned out to affect the prostaglandin pathway: five increased the formation of blood stem cells, and five decreased it. "We weren't specifically looking for prostaglandins," says Zon, a Howard Hughes Medical Institute investigator who is also a member of the Harvard Stem Cell Institute. "This was a surprise finding."

A variety of experiments confirmed that prostaglandins, particularly dmPGE2, promote blood stem cell formation, while chemicals that block prostaglandin synthesis (such as aspirin or ibuprofen), suppress blood stem cell formation. Finally, in zebrafish whose marrow was depleted by irradiation, those given dmPGE2 recovered blood cell populations more quickly.

Prostaglandins are known to be released by the body when inflammation is present -- such as after an injury -- and may be among the compounds that aid recovery. "So it makes some sense that prostaglandins would have the ability to enhance regrowth of cells," Zon says.

"The zebrafish is ideal for investigating blood formation," says North. "It reproduces quickly and in large number and has a blood-forming system that shares many similarities with that of mammals." Zebrafish embryos develop outside the mother's body and can take up chemicals through their skin, making it easy to test the developmental effects of large numbers of compounds very rapidly, while their transparent skin makes it possible to visualize the blood stem cells in live fish.

The researchers also confirmed their observations in mammalian models. When dmPGE2 was added to mouse embryonic stem cells in the lab, production of blood stem cells increased. In mice that underwent bone marrow transplant, treatment with dmPGE2 led to enhanced blood-stem-cell formation, and the stem cells remained present in the marrow more than six months after transplantation, indicating long-term engraftment. "The fact that we confirmed the zebrafish discovery in a mammalian system suggests it may also be applicable in humans," says Goessling.

The clinical trial, projected to begin in 2008 at Children's Hospital Boston in conjunction with the Dana-Farber/Harvard Cancer Center, will recruit patients undergoing cord blood transplant for leukaemia. Patients will receive cord blood to replenish their blood systems, some of it treated with dmPGE2 to enhance blood-stem-cell formation. "Having more stem cells should help the blood system to regrow faster and minimize complications, such as infections," says North.


Study identifies novel Parkinson's disease drug target.

Researchers at the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND) have identified a potential new drug target for the treatment of Parkinson's disease and possibly for other degenerative neurological disorders. In a recent issue of the journal Science, the investigators describe finding, in cellular and animal models, that blocking the action of an enzyme called SIRT2 can protect the neurons damaged in Parkinson's disease from the toxic effects of alpha-synuclein, a protein that accumulates in the brains of Parkinson's patients. The study, which also suggests that inhibiting this pathway could help in the treatment of other conditions in which abnormal proteins accumulate in the brain, is receiving early online release on the Science Express website.

"We have discovered a compelling new therapeutic approach for Parkinson's disease, which we expect will allow our scientists - as well as those at pharmaceutical and biotech companies - to pursue innovative new drugs that will treat and perhaps even cure this disorder," says Aleksey Kazantsev, PhD, director of MGH-MIND Drug Discovery Laboratory, who led the Science study. "Since the same sort of aggregation of misfolded proteins has been reported in Huntington's and Alzheimer's diseases - as well as Lewy body dementia, which also involves alpha-synuclein deposits - we plan to test this approach in those conditions as well."

Parkinson's disease - characterized by tremors, rigidity, difficulty walking and other symptoms - is caused by the destruction of brain cells that produce the neurotransmitter dopamine. In recent years researchers at several centres have been studying the role of alpha-synuclein accumulations in dopamine-producing neurons, observed in patients with both inherited and sporadic Parkinson's disease. MGH-MIND investigators have discovered that, in Parkinson's, the alpha-synuclein molecule folds abnormally and form aggregates called inclusion bodies. Such inclusions of other abnormal proteins are seen in several disorders, but whether inclusions are toxic or protective to neurons has been controversial.

In a paper published last year in the Proceedings of the National Academy of Sciences, a research team led by Kazantsev analysed ways to reduce the size of inclusions containing misfolded versions of alpha-synuclein or of the Huntington's disease-associated protein huntingtin. They found that a compound called B2, which promotes the formation of larger inclusions, paradoxically appeared to reduce toxicity in cellular disease models, possibly by reducing the overall number of inclusions.
In the current study, the investigators began by seeking the mechanism underlying the observed effects of B2. Assays of the compound's activity against a panel of key enzymes identified only one significant association - a weak but selective inhibition of SIRT2, which is known to regulate the cell cycle and may have a role in aging. An experiment using RNA interference to suppress SIRT2 and a related enzyme in human cell lines expressing alpha-synuclein confirmed that only the inhibition of SIRT2 reduced alpha-synuclein toxicity.

Kazantsev's team then developed and identified more powerful inhibitors of SIRT2, based on the structure of B2. One of these novel inhibitors called AGK2 had 10 times the potency of B2 and was shown to protect dopamine-producing neurons from alpha-synuclein toxicity in cultured rat neurons and in an insect model of PD. Several additional compounds that act on the SIRT2 pathway have been identified, some which may be even better than AGK2 as candidates for drug development.


Researchers have identified a potential new drug target for the treatment of Parkinson’s disease.

SIRT2 is known to act on a major protein component of microtubules, cellular structures that help move objects within cells, among other functions. The researchers theorize that inhibiting SIRT2 might promote microtubule-dependent transportation of alpha-synuclein into large aggregates; or it could strengthen microtubules that have been destabilized by misfolded alpha-synuclein.

Kazantsev explains, "For Parkinson's disease, we can now pursue a straightforward drug development process by identifying potent and selective candidates from this class of compounds that can be tested in animal studies and eventual human trials. One of the most satisfying aspects is how this discovery validates our approach to drug discovery, which incorporates both the most advanced tools for screening candidate compounds and outstanding collaboration with our clinical and scientific experts in human disease." Kazantsev is an assistant professor of Neurology at Harvard Medical School.


Combined screening approach leads to discovery of gene linked to breast cancer.

Using a novel three-part screening process, scientists at Dana-Farber Cancer Institute have identified a gene that is made inappropriately in about a third of all breast cancers. The discovery, reached in collaboration with researchers at Brigham and Women's Hospital (BWH) and the Broad Institute of Harvard and MIT, was reported in the June 15, 2007, issue of the journal Cell.

Unlike breast cancer-susceptibility genes such as BRCA1 and BRCA2, the newly identified gene, called IKBKE, is not inherited in a mutated form that increases the risk of developing breast cancer at an early age. Rather, the mutation arises during a woman's life, causing an overproduction of the IKBKE protein. That, in turn, spurs cell growth and proliferation. The mutation is found in 30-40 percent of all breast cancers, making it a prime target for future drugs for the disease.

The method used to home in on the gene - a combination of three existing experimental approaches - offers an elegant solution to one of the major hurdles of genome-age research: how to sift through the multitude of genes identified by advanced screening technology as potential cancer-causers to find those with the most profound role in the disease. As such, the new approach can be used to discover genes associated with many types of cancers, the study's authors state.

"The genetic material within many human cancer cells is in such disarray that there can be numerous gene mutations," says the study's co-senior author, William Hahn, MD, PhD, of Dana-Farber, BWH, and the Broad Institute. "Current technologies - particularly ‘microarray' sensors, which read the activity and changes in thousands of genes at a time - enable us to locate dozens or even hundreds of gene abnormalities in cancer cells. The challenge is to winnow this group to find the genes most centrally involved in cancer initiation and maintenance.

"In the current study, we used several complementary approaches to identify an important breast cancer gene," he continues. "Each method helps ‘filter' the information from the previous one, enabling us to zero in on the strongest candidate."

Hahn and his colleagues focused on a class of proteins known as kinases, which serve as molecular "starting guns" for chemical reactions within cells. Overproduction of certain kinases has been linked to a variety of cancers. To determine which, if any, kinases play a role in breast cancer, investigators conducted a sequence of experiments to refine their results.

They began with a cell protein called Ras, a courier of signals from the cell surface to the interior. Abnormalities in Ras or its partner proteins - including kinases - occur in the vast majority of "epithelial" cancers, which, like breast cancer, arise in the lining of bodily tissues. Ras transmits signals to a variety of "downstream" proteins - among them, proteins called MEK or PI3K. When both of these become active at the same time, cells become cancerous, investigators found.

The team then created a set of 354 human kinases and injected each into normal epithelial cells to see if any mimicked PI3K's ability to transform them into cancer cells. They found five that did.

To narrow this field, investigators conducted a second group of screening procedures. Using a variety of genome-scale approaches, they sought to determine if genes for any of the five kinases were unusually abundant in cancer cells. They found extra copies of IKBKE, but not of the other genes - and correspondingly high levels of the IKBKE protein. This pointed to IKBKE's role as a breast cancer oncogene.

In the third part of the study, the investigators explored whether breast cancer cells depend on IKBKE for survival. In an earlier study, they had used a technique called RNA interference - whose discovery was recognized with the Nobel Prize in Medicine and Physiology last year - which uses bits of genetic material to systematically stile certain genes. With a high-throughput version of this technique, they found that when IKBKE was switched off, the cancer cells tended to stop proliferating and died.

"This triple screening approach enabled us to study what happened to cells when IKBKE was turned on and when it was shut off, and to take a global look at the genetic alterations within breast cancer cell lines and tumours," Hahn says. "Integrating these techniques allowed us to identify a new breast cancer oncogene and show that it plays a crucial role in the formation and survival of tumours."

The discovery that mutated IKBKE helps sustain a sizable percentage of breast cancers may spur the development of new treatments for the disease, Hahn remarks. Drugs able to target the oncogene and shut it down could offer an effective therapy for women whose tumour cells harbour the mutation.

The three-stage approach to finding breast cancer genes may be used in other forms of cancer as well, Hahn continues. "Our study provides a framework for integrated genomic methods of oncogene discovery."

Research Matters brings together selected research being conducted at Harvard Medical School's 18 affiliated institutions. For more information, visit the Harvard Medical School website at www.hms.harvard.edu

This article is provided courtesy of Harvard Medical International.© 2007 President and Fellows of Harvard College.

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