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2006-2007

PIN 1 GUARDS AGAINST ALZHEIMER'S
Since the disease was ﬁrst identiﬁed more than a century ago, autopsies of patients with Alzheimer's disease have shown an abundance of knotted tangles and clumps of plaques in the area of the brain responsible for memory. This is literal evidence that healthy neurons are being crushed by the weight of these lesions, leading to this devastating form of dementia. But what causes these lesions to develop in the ﬁrst place? A study by Kun Ping Lu, MD, PhD, Division of Hematology and Oncology, reported in Nature offers an important clue, demonstrating that an enzyme known as Pin1 can prevent the formation of both tangles and plaques, a ﬁnding that offers important new insights as scientists work to develop therapies for the treatment of this widespread disease.

PIN 1 GUARDS AGAINST ALZHEIMER'S

Since the disease was ﬁrst identiﬁed more than a century ago, autopsies of patients with Alzheimer's disease have shown an abundance of knotted tangles and clumps of plaques in the area of the brain responsible for memory. This is literal evidence that healthy neurons are being crushed by the weight of these lesions, leading to this devastating form of dementia.

But what causes these lesions to develop in the ﬁrst place? A study by Kun Ping Lu, MD, PhD, Division of Hematology and Oncology, reported in Nature offers an important clue, demonstrating that an enzyme known as Pin1 can prevent the formation of both tangles and plaques, a ﬁnding that offers important new insights as scientists work to develop therapies for the treatment of this widespread disease.

INSIGHTS ON SURVIVAL EMERGE FROM AIDS VACCINE RESEARCH
A study published in Science offers a possible new means of predicting an AIDS vaccine's effectiveness, a discovery that could help scientists as they test candidate vaccines in clini¬cal trials. Says lead author Norman Letvin, MD, Divi¬sion of Viral Pathogenesis, "These findings provide us with an important new way of looking at subpopulations of CD4 helper T-cells and how they provide immu¬nity and promote survival following infection with an AIDS-like virus."

INSIGHTS ON SURVIVAL EMERGE FROM AIDS VACCINE RESEARCH

A study published in Science offers a possible new means of predicting an AIDS vaccine's effectiveness, a discovery that could help scientists as they test candidate vaccines in clini¬cal trials. Says lead author Norman Letvin, MD, Divi¬sion of Viral Pathogenesis, "These findings provide us with an important new way of looking at subpopulations of CD4 helper T-cells and how they provide immu¬nity and promote survival following infection with an AIDS-like virus."

MASS SPECTROMETRY CORE SEQUENCES T-REX PROTEIN
In a venture once thought to lie outside the reach of science, researchers from BIDMC captured and sequenced tiny pieces of collagen protein from a 68 million-year-old Tyrannosaurus rex. As reported in the journal Science, the protein fragments appear to most closely match amino acid sequences found in collagen of present-day chickens, lending support to a recent and still controversial proposal that birds and dinosaurs are evolutionarily related. Using highly sensitive mass spectrometry methods, John Asara, PhD, Director of BIDMC's Mass Spectrometry Core and Lewis Cantley, PhD, Director of Signal Transduction, demonstrated for the ﬁrst time that these techniques are capable of sequencing minute amounts of ancient proteins - a mere seven collagen fragments weighing a total of only 40 milligrams, representing low-sub nanogram amounts of protein from ﬁ ve grams of femur bone. "Mass spectrometry was initially used to develop new protein-based tests for prostate cancer and other diseases," explains Cantley. "Our aim is that the incredible advances made in the course of the T-rex analysis will feed back into that effort as we attempt to sequence minute amounts of protein from human tumors." The discovery garnered worldwide media attention.

MASS SPECTROMETRY CORE SEQUENCES T-REX PROTEIN

In a venture once thought to lie outside the reach of science, researchers from BIDMC captured and sequenced tiny pieces of collagen protein from a 68 million-year-old Tyrannosaurus rex. As reported in the journal Science, the protein fragments appear to most closely match amino acid sequences found in collagen of present-day chickens, lending support to a recent and still controversial proposal that birds and dinosaurs are evolutionarily related.

Using highly sensitive mass spectrometry methods, John Asara, PhD, Director of BIDMC's Mass Spectrometry Core and Lewis Cantley, PhD, Director of Signal Transduction, demonstrated for the ﬁrst time that these techniques are capable of sequencing minute amounts of ancient proteins - a mere seven collagen fragments weighing a total of only 40 milligrams, representing low-sub nanogram amounts of protein from ﬁ ve grams of femur bone.

"Mass spectrometry was initially used to develop new protein-based tests for prostate cancer and other diseases," explains Cantley. "Our aim is that the incredible advances made in the course of the T-rex analysis will feed back into that effort as we attempt to sequence minute amounts of protein from human tumors." The discovery garnered worldwide media attention.

AIDS RESEARCHERS AWARDED GATES FOUNDATION GRANTS
Last year, BIDMC found itself amoung a prominent group of 16 international research institutions to be awarded grants from the Bill & Melinda Gates Foundation as part of a sweeping global initiative to develop a vaccine to protect against HIV, the virus responsible for AIDS. Chief of Viral Pathogenesis Norman Letvin, MD, serves as principal investigator of a five-year, $18 million grant for his work on adenovirus-vector based and mycobacteria-vector based vaccines. BIDMC scientists Dan Barouch, MD, PhD, Raphael Dolin, MD, and Michael Seaman, PhD, as members of this and other teams, have also received signiﬁcant funding from the foundation. The foundation's coordinated initiative - totaling $287 million - involves more than 19 countries and 165 investigators from throughout the world.

AIDS RESEARCHERS AWARDED GATES FOUNDATION GRANTS

Last year, BIDMC found itself amoung a prominent group of 16 international research institutions to be awarded grants from the Bill & Melinda Gates Foundation as part of a sweeping global initiative to develop a vaccine to protect against HIV, the virus responsible for AIDS.

Chief of Viral Pathogenesis Norman Letvin, MD, serves as principal investigator of a five-year, $18 million grant for his work on adenovirus-vector based and mycobacteria-vector based vaccines. BIDMC scientists Dan Barouch, MD, PhD, Raphael Dolin, MD, and Michael Seaman, PhD, as members of this and other teams, have also received signiﬁcant funding from the foundation. The foundation's coordinated initiative - totaling $287 million - involves more than 19 countries and 165 investigators from throughout the world.

ROSENZWEIG LEADS PROMINENT INTERNATIONAL RESEARCH GRANT
Director of Cardiovascular Research Anthony Rosenzweig, MD, has been named the American Coordinator of a prestigious grant from the Paris-based Leducq Foundation. The ﬁve-year grant, which totals $6 million, supports investigations into the intersection of heart failure and metabolic diseases such as diabetes. With European coordinator Timothy Aitman, MD, PhD, the Transatlantic Network of Excellence grant aims to encourage international cooperation and to accelerate the pace of discovery on both sides of the Atlantic. "Heart failure and metabolic disease are enormous clinical problems that often occur in tandem," says Rosenzweig. "We believe that common molecular mechanisms contribute to both, and we hope to unravel these mechanisms so that, ultimately, we can learn how to target them therapeutically."

ROSENZWEIG LEADS PROMINENT INTERNATIONAL RESEARCH GRANT

Director of Cardiovascular Research Anthony Rosenzweig, MD, has been named the American Coordinator of a prestigious grant from the Paris-based Leducq Foundation. The ﬁve-year grant, which totals $6 million, supports investigations into the intersection of heart failure and metabolic diseases such as diabetes.

With European coordinator Timothy Aitman, MD, PhD, the Transatlantic Network of Excellence grant aims to encourage international cooperation and to accelerate the pace of discovery on both sides of the Atlantic. "Heart failure and metabolic disease are enormous clinical problems that often occur in tandem," says Rosenzweig. "We believe that common molecular mechanisms contribute to both, and we hope to unravel these mechanisms so that, ultimately, we can learn how to target them therapeutically."

MOLECULAR IMAGING LABORATORY RECEIVES MAJOR NCI GRANT
The strength of academic-industrial partnerships was demonstrated when the laboratory of John Frangioni, MD, PhD, together with GE Global Research, was awarded a $6.5 million grant from the National Cancer Institute as part of a ﬁve-year research collaboration to enhance the imaging of cancerous tumors during surgery. "The question most often asked by patients and family members following cancer surgery is, 'Did you get it all?'" says Frangioni. "Through the innovative optical imaging technology of our lab, surgeons can better identify and remove more cancerous cells. By being able to see cancers - during surgery, in real time - we can tell patients that we did indeed 'get it all.'" Immediate cancer surgery applications of this system would include: image-guided sentinel lymph node mapping, image-guided cancer resection with real-time assessment ofsurgical margins, and intraoperative detection of occult metastases in the surgical ﬁ eld. In addition, Robert Lenkinski, PhD, together with GE Global Research, received a grant from the National Institute of Biomedical Imaging and Bioengineering to develop a new class of contrast agents for magnetic resonance imaging.

MOLECULAR IMAGING LABORATORY RECEIVES MAJOR NCI GRANT

The strength of academic-industrial partnerships was demonstrated when the laboratory of John Frangioni, MD, PhD, together with GE Global Research, was awarded a $6.5 million grant from the National Cancer Institute as part of a ﬁve-year research collaboration to enhance the imaging of cancerous tumors during surgery.

"The question most often asked by patients and family members following cancer surgery is, 'Did you get it all?'" says Frangioni. "Through the innovative optical imaging technology of our lab, surgeons can better identify and remove more cancerous cells. By being able to see cancers - during surgery, in real time - we can tell patients that we did indeed 'get it all.'" Immediate cancer surgery applications of this system would include: image-guided sentinel lymph node mapping, image-guided cancer resection with real-time assessment ofsurgical margins, and intraoperative detection of occult metastases in the surgical ﬁ eld. In addition, Robert Lenkinski, PhD, together with GE Global Research, received a grant from the National Institute of Biomedical Imaging and Bioengineering to develop a new class of contrast agents for magnetic resonance imaging.

A THERAPEUTIC ROLE FOR CARBON MONOXIDE
In a medical case of Jekyll and Hyde, carbon monoxide, the highly toxic gas emitted from auto exhausts and faulty heating systems, was shown to be effective in treating pulmonary arterial hypertension (PAH), an extremely debilitating condition that can lead to right heart failure and eventual death. Published in The Journal of Experimental Medicine, the findings, by Leo Otterbein, PhD, of BIDMC's Transplantation Center, Department of Surgery, show for the ﬁrst time that this toxic gas can reverse existing disease. "Carbon monoxide was ﬁrst proposed to prevent the onset of certain inﬂammatory conditions nearly 10 years ago," says Otterbein. His lab has been instrumental in demonstrating that when administered at low, nontoxic concentrations prior to organ transplant surgery or balloon angioplasty, CO provides potent protective effects against organ rejection or blockage of the carotid arteries.This has led to clinical trials to test the use of CO among kidney-transplant patients. In this latest research, Otterbein and colleagues discovered that CO was able to induce the death of smooth blood cells, which in PAH patients have inexplicably thickened to the point that blood ﬂow is impeded and stenosis develops.

A THERAPEUTIC ROLE FOR CARBON MONOXIDE

In a medical case of Jekyll and Hyde, carbon monoxide, the highly toxic gas emitted from auto exhausts and faulty heating systems, was shown to be effective in treating pulmonary arterial hypertension (PAH), an extremely debilitating condition that can lead to right heart failure and eventual death.

Published in The Journal of Experimental Medicine, the findings, by Leo Otterbein, PhD, of BIDMC's Transplantation Center, Department of Surgery, show for the ﬁrst time that this toxic gas can reverse existing disease.

"Carbon monoxide was ﬁrst proposed to prevent the onset of certain inﬂammatory conditions nearly 10 years ago," says Otterbein. His lab has been instrumental in demonstrating that when administered at low, nontoxic concentrations prior to organ transplant surgery or balloon angioplasty, CO provides potent protective effects against organ rejection or blockage of the carotid arteries.This has led to clinical trials to test the use of CO among kidney-transplant patients.

In this latest research, Otterbein and colleagues discovered that CO was able to induce the death of smooth blood cells, which in PAH patients have inexplicably thickened to the point that blood ﬂow is impeded and stenosis develops.

GENETIC KIDNEY DISEASE REPSONDS TO STEM-CELL TREATMENT
The kidney disease Alport syndrome is one of 31 human diseases that occur because of direct genetic defects in the body's extracellular matrix and basement membrane proteins. A discovery by Raghu Kalluri, PhD, Chief of the Division of Matrix Biology, offers an early example of how bone-marrow-derived stem cells may be useful in repairing such defects. Reported in the Proceedings of the National Academy of Sciences, the ﬁndings offer a possible new therapeutic opportunity for both children and adults with Alport syndrome, whose current treatment options are limited to kidney transplantation or lifelong dialysis. Furthermore, says Kalluri, "This evidence suggests that stem-cell therapies can be explored for other diseases that result from extracellular matrix defects."

GENETIC KIDNEY DISEASE REPSONDS TO STEM-CELL TREATMENT

The kidney disease Alport syndrome is one of 31 human diseases that occur because of direct genetic defects in the body's extracellular matrix and basement membrane proteins. A discovery by Raghu Kalluri, PhD, Chief of the Division of Matrix Biology, offers an early example of how bone-marrow-derived stem cells may be useful in repairing such defects.

Reported in the Proceedings of the National Academy of Sciences, the ﬁndings offer a possible new therapeutic opportunity for both children and adults with Alport syndrome, whose current treatment options are limited to kidney transplantation or lifelong dialysis. Furthermore, says Kalluri, "This evidence suggests that stem-cell therapies can be explored for other diseases that result from extracellular matrix defects."

STROM HONORED BY AMERICAN SOCIETY OF NEPHROLOGY
In recognition of his groundbreaking work in the ﬁeld of immune tolerance - the immune system's ability to recognize and "tolerate" the body's own cells and molecules and thereby prevent rejection of transplanted organs even following the cessation of drug therapy - Terry Strom, MD, Chief of the Division of Transplant Immunology and Director of BIDMC's Transplant Research Center, was presented with the 2006 Homer W. Smith Award from the American Society of Nephrology. The honor is presented annually to "an individual who has made outstanding contributions which fundamentally affect the science of nephrology." Strom's laboratory has been instrumental in devising means to prevent organ rejection, chiefly through the development of several agents now used in clinical practice, as well as several other agents which are scheduled to soon be tested in clinical trials.

STROM HONORED BY AMERICAN SOCIETY OF NEPHROLOGY

In recognition of his groundbreaking work in the ﬁeld of immune tolerance - the immune system's ability to recognize and "tolerate" the body's own cells and molecules and thereby prevent rejection of transplanted organs even following the cessation of drug therapy - Terry Strom, MD, Chief of the Division of Transplant Immunology and Director of BIDMC's Transplant Research Center, was presented with the 2006 Homer W. Smith Award from the American Society of Nephrology. The honor is presented annually to "an individual who has made outstanding contributions which fundamentally affect the science of nephrology." Strom's laboratory has been instrumental in devising means to prevent organ rejection, chiefly through the development of several agents now used in clinical practice, as well as several other agents which are scheduled to soon be tested in clinical trials.

NOTED CANCER GENETICIST RECRUITED TO BIDMC
As part of its commitment to trans¬late laboratory breakthroughs in the molecular diagnosis of cancer into in¬dividualized patient treatments, BIDMC recruited Pier Paolo Pandolﬁ, MD, PhD, a leading scientist in the ﬁeld of cancer genetics, to the BIDMC faculty in 2007. Pandolfi comes to BIDMC from New York's Memorial Sloan-Kettering Cancer Center. Pandolfi serves as director of a new Cancer Genetics Program as well as Associate Director of Basic Research for BIDMC's newly developed Cancer Center. Says Cancer Center Director Lewis Cantley, PhD, "Dr. Pandolﬁ, at a relatively early age, has become a world leader in cancer genetics and cancer cell biology. His research has led to major breakthroughs in our understanding of how mutations in oncogenes and tumor suppressor genes result in leukemias, lymphomas and solid tumors." Adds Pandolfi, "As our fundamental understanding of cancers continues to develop, I'm extremely optimistic that we will indeed produce a new class of pharmaceutical agents speciﬁcally tai¬lored to individuals' genetic proﬁles."

NOTED CANCER GENETICIST RECRUITED TO BIDMC

As part of its commitment to trans¬late laboratory breakthroughs in the molecular diagnosis of cancer into in¬dividualized patient treatments, BIDMC recruited Pier Paolo Pandolﬁ, MD, PhD, a leading scientist in the ﬁeld of cancer genetics, to the BIDMC faculty in 2007. Pandolfi comes to BIDMC from New York's Memorial Sloan-Kettering Cancer Center.

Pandolfi serves as director of a new Cancer Genetics Program as well as Associate Director of Basic Research for BIDMC's newly developed Cancer Center. Says Cancer Center Director Lewis Cantley, PhD, "Dr. Pandolﬁ, at a relatively early age, has become a world leader in cancer genetics and cancer cell biology. His research has led to major breakthroughs in our understanding of how mutations in oncogenes and tumor suppressor genes result in leukemias, lymphomas and solid tumors."

Adds Pandolfi, "As our fundamental understanding of cancers continues to develop, I'm extremely optimistic that we will indeed produce a new class of pharmaceutical agents speciﬁcally tai¬lored to individuals' genetic proﬁles."

RBP4 PROTEIN PREDICTS TYPE 2 DIABETES
With the identiﬁcation of a molecule called RBP4 (retinol binding protein 4), scientists have discovered a potential early means of identifying individuals at risk of developing Type 2 diabetes, as well as a possible novel target for treatment of this disease. Described in The New England Journal of Medicine, the study by Barbara Kahn, MD, Chief of Endocrinol¬ogy, Diabetes and Metabolism, and Timothy Graham, MD, demonstrates that elevated RBP4 levels foretell early stages in the development of insulin resistance, a precursor to overt diabe¬tes. Says Kahn, "Being able to diagnose this disease at an earlier stage would enable patients to take preventive measures to lessen the risk of complications and improve their health." A number of companies are currently developing drugs to lower RBP4 in the blood to prevent or treat diabetes.

RBP4 PROTEIN PREDICTS TYPE 2 DIABETES

With the identiﬁcation of a molecule called RBP4 (retinol binding protein 4), scientists have discovered a potential early means of identifying individuals at risk of developing Type 2 diabetes, as well as a possible novel target for treatment of this disease.

Described in The New England Journal of Medicine, the study by Barbara Kahn, MD, Chief of Endocrinol¬ogy, Diabetes and Metabolism, and Timothy Graham, MD, demonstrates that elevated RBP4 levels foretell early stages in the development of insulin resistance, a precursor to overt diabe¬tes. Says Kahn, "Being able to diagnose this disease at an earlier stage would enable patients to take preventive measures to lessen the risk of complications and improve their health." A number of companies are currently developing drugs to lower RBP4 in the blood to prevent or treat diabetes.

PASCUAL-LEONE HONORED FOR PIONEERING TMS RESEARCH
For his "outstanding contri¬bution to the understanding of higher cognitive func¬tions and the treatment of neuropsychiatric disorders using transcranial mag¬netic stimulation [TMS]," Alvaro Pascual-Leone, MD, PhD, was awarded the 2006 Ramon y Cajal Award from the International Neuropsy¬chiatric Association. Transcranial magnetic stimu¬lation - the induction of a current in the brain using a magnetic field - has proven effective in the treatment of depression and stroke. The technology is also proving critical as neuroscientists work to better understand and "map" the brain. A pioneer in the ﬁeld of TMS research whose work has recently been featured in Time and Newsweek maga¬zines as well as on National Public Radio, Pascual-Leone aims to gain a greater understanding of neural plasticity - the brain's ability to "rewire" itself, as occurs, for example, among individuals who have lost their vision.

PASCUAL-LEONE HONORED FOR PIONEERING TMS RESEARCH

For his "outstanding contri¬bution to the understanding of higher cognitive func¬tions and the treatment of neuropsychiatric disorders using transcranial mag¬netic stimulation [TMS]," Alvaro Pascual-Leone, MD, PhD, was awarded the 2006 Ramon y Cajal Award from the International Neuropsy¬chiatric Association.

Transcranial magnetic stimu¬lation - the induction of a current in the brain using a magnetic field - has proven effective in the treatment of depression and stroke. The technology is also proving critical as neuroscientists work to better understand and "map" the brain. A pioneer in the ﬁeld of TMS research whose work has recently been featured in Time and Newsweek maga¬zines as well as on National Public Radio, Pascual-Leone aims to gain a greater understanding of neural plasticity - the brain's ability to "rewire" itself, as occurs, for example, among individuals who have lost their vision.

RESEARCH IDENTIFIES SOURCE OF FEVER
By identifying a site in the brain only slightly larger than the head of a pin, Clifford Saper, MD, PhD, has helped explain how fever aids the body in ﬁghting infection. "Fever is part of an adaptive response coordinated by the hypothalamus," explains Saper, Chairman of the Depart¬ment of Neurology. When body temperature is elevated by a few degrees, white blood cells can ﬁght infections more effectively. And, because fever leads to lethargy, sick people tend to rest, thereby conserving energy. Described in Nature Neuroscience, Saper's ﬁndings demonstrate for the ﬁrst time that the fever response is elicited at the point in the brain where the prostaglandin E2 (PGE2) hormone acts on the EP3 receptor. "We think that other aspects of sickness behavior, such as the achiness caused by increased sensitivity to pain, also come from speciﬁc sites in the brain," he adds. Saper's group plans to investigate these other brain responses to dissect the various symptoms of illness.

RESEARCH IDENTIFIES SOURCE OF FEVER

By identifying a site in the brain only slightly larger than the head of a pin, Clifford Saper, MD, PhD, has helped explain how fever aids the body in ﬁghting infection.

"Fever is part of an adaptive response coordinated by the hypothalamus," explains Saper, Chairman of the Depart¬ment of Neurology. When body temperature is elevated by a few degrees, white blood cells can ﬁght infections more effectively. And, because fever leads to lethargy, sick people tend to rest, thereby conserving energy.

Described in Nature Neuroscience, Saper's ﬁndings demonstrate for the ﬁrst time that the fever response is elicited at the point in the brain where the prostaglandin E2 (PGE2) hormone acts on the EP3 receptor. "We think that other aspects of sickness behavior, such as the achiness caused by increased sensitivity to pain, also come from speciﬁc sites in the brain," he adds. Saper's group plans to investigate these other brain responses to dissect the various symptoms of illness.

DVORAK HONORED FOR "EXTRAORDINARY CONTRIBUTIONS"
Harold Dvorak, MD, Director of the Center for Vascular Biology, was awarded the inaugural Albert Szent-Gyorgyi Prize for Progress in Can¬cer Research from the National Foundation for Cancer Research (NFCR) in a ceremony in the spring of 2006. The honor recognizes Dvorak's groundbreak¬ing discovery, made in 1983, that tumor cells secrete vascular endothelial growth factor (VEGF), a finding that helped take cancer research in a new direction, advancing the fundamental understanding of tumor angio¬genesis. "Dr. Dvorak's work is now being utilized in very real, practical applications, offering hope for angiogenesis-centered treatments to halt, and even reverse, tumor growth," noted NFCR Chief Scientiﬁc Ofﬁcer Sujuan Ba, PhD, in announc¬ing the award. "Dr. Dvorak's seminal discover¬ies in basic science have led to signiﬁcant clini¬cal beneﬁ ts for cancer patients."

DVORAK HONORED FOR "EXTRAORDINARY CONTRIBUTIONS"

Harold Dvorak, MD, Director of the Center for Vascular Biology, was awarded the inaugural Albert Szent-Gyorgyi Prize for Progress in Can¬cer Research from the National Foundation for Cancer Research (NFCR) in a ceremony in the spring of 2006.

The honor recognizes Dvorak's groundbreak¬ing discovery, made in 1983, that tumor cells secrete vascular endothelial growth factor (VEGF), a finding that helped take cancer research in a new direction, advancing the fundamental understanding of tumor angio¬genesis.

"Dr. Dvorak's work is now being utilized in very real, practical applications, offering hope for angiogenesis-centered treatments to halt, and even reverse, tumor growth," noted NFCR Chief Scientiﬁc Ofﬁcer Sujuan Ba, PhD, in announc¬ing the award. "Dr. Dvorak's seminal discover¬ies in basic science have led to signiﬁcant clini¬cal beneﬁ ts for cancer patients."

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