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Goldman Philanthropic Partnerships inspires, validates and secures half of the funding for breakthrough research that can accelerate the cures for catastrophic diseases.  The following projects, secured from and co-funded by the finest research institutions in the world, give real hope to patients and their loved ones that cures will be found in time to aid those who need help now.  To view past projects, click here: Past Projects

Abstracts of 2004-2005 Culpeper Biomedical Pilot Initiative Grants

Deconstructing & Reconstructing Myelin-Regenerative Medicine in the Brain
Amit Basu, PhD, Brown University

Every nerve in the body functions like a tiny electrical cord, carrying impulses to the spinal cord and the brain.  Just like an electrical cord, these nerves have a protective and insulating coating, which is called myelin.  Many diseases of the nervous system, such as multiple sclerosis, are caused by the breakdown of myelin around the nerves.  There is considerable research around the world looking at ways to regrow myelin on nerves, but so far none of it seems to work in people.  One issue is getting the first layer of new myelin cells to stick to the nerves.  Dr. Basu and his team have an idea to overcome this problem.  They will try to create a variety of synthetic molecules that could be injected into a patient and would strongly attach to the frayed part of the nerve.  This molecule would then serve as the “glue” to allow new myelin cells that the body would produce to attach and build up around the nerve, reversing the diseases of the nerves.

Early Detection Test for SARS
Natalia E. Broude, PhD, Boston University

SARS is a deadly human illness that first appeared in 2002 in China and has spread to more than 30 countries.  SARS is caused by a coronavirus, the genome of which has been sequenced.  Knowledge of the SARS genome makes it possible to develop an early detection test for SARS, preventing the global spread of SARS.  This study will develop this innovative test for SARS, which would hook a molecule that glows in the dark to a protein that would attach a specific spot on the SARS gene.  An infected patient’s blood sample would immediately glow, simplifying and speeding up detection at a very low cost.  If this technology works, it would open new doors for all kinds of instant diagnostic medical and forensic tests at a much lower cost.

Vibrational Imaging: Making the Microscope Work Harder
Ji-Xin Cheng, PhD, Purdue University

This project will develop a new highly sensitive microscopy for the imaging of molecules using vibrational imaging.  Traditional microscopy suffers from noticeable background noise that limits its sensitivity when looking at the smallest molecules.  Vibrational imaging records simultaneous pictures of the molecules and superimposes them on each other eliminating the background noise. This imaging technique will “clearly” bring microscopy to a new level.

Not only will this research help us to look at things we know about now, it will undoubtedly lead to discoveries that would otherwise be impossible.  Once we are able to tune our vision to look at things smaller than we’ve every seen before, we can tune our minds to new frequencies of thought that will lead to better treatments and cures.

A New Self Monitor for Anemia
Gregory Crawford, PhD, Brown University

Anemia, the lack of healthy red blood cells, has long been viewed as the innocent bystander of disease; however there is compounding evidence indicating that anemia is a significant free-standing health issue that is severely under diagnosed and rarely managed properly in patients with life altering and chronic diseases.  Just as patients can monitor their own heart rate, blood pressure, and blood sugar, enabling patients to measure their own anemia by monitoring their red blood cells at home will empower patients and improve their quality of life. This proposal will create a device that will take a photo of the lining of the lower eyelid using a small camera.  A computer program will compare the red color of the photo with a standard to determine in real time how many red cells are present to determine the patient’s anemia. The device could provide accuracy similar to the current lab test when the physician draws blood from the patient. Dr. Crawford and his research team envision the final device to be small, inexpensive and integrated onto a PDA (personal digital assistant) device or a cell phone so that it can be integral to home health care situations in helping people better manage the consequences of life altering diseases. 

A Potential Cure for Colon Cancer
Benoit de Crombrugghe, MD, M.D. Anderson Cancer Center

The walls of gut are folded into numerous valleys and peaks that increase surface area for absorbing nutrients.  The surface cells are consistently renewed from stem cells located toward the bottom of the valleys.  In most colorectal cancer, a protein becomes abnormally active in these stem cells and they multiply out of control. 

Dr. de Crombrugghe and his team will discover whether control of this protein could halt colorectal cancers.  This research could be a life-saver for the more than 130,000 American diagnosed with colon cancer each year.  Maybe more importantly, the discovery that stem cells may play a role in cancer is important to a wide variety of cancers, and may lead to discoveries that can help not only cancer patients, but those of us who want to keep from becoming a cancer patient.

Blocking the Molecules that Reduce the Effectiveness of Chemotherapy
Stephen Kron, MD, PhD, University of Chicago

Most cancer therapy works by damaging the DNA of cancer cells.  When these cancer cells divide, the damaged DNA causes the cell to die.  All cells, especially cancer cells, have the ability to repair the damaged DNA before the cell divides.  If the DNA is repaired before the cell divides, the cancer cell will not die. 

Dr. Kron and his colleagues have discovered a key molecule in cancer cells, HA2X, which is required to rapidly repair DNA damage.  This study will test over 20,000 small molecules that can block the effectiveness of HA2X.  A molecule that can block HA2X will theoretically deliver the knock-out punch that would allow chemotherapy or radiation therapy to kill all cancer cells, especially in cancers that have spread around the body.  Dr. Kron’s breakthrough research could have a significant impact on survival and quality of life of all cancer patients. 

A New Environment for Testing Drug Interactions
Brenda Mann, PhD, University of Utah

Drug development must identify compounds that are toxic to healthy human cells.  Early identification of toxicity reduces the danger to patients and costs to the pharmaceutical companies.  Lab studies do not always predict how the drug will affect cells when it is given to animals or humans in clinical studies because cells tested in the lab are not in the actual “body environment”.

This project will create a three dimensional structure in the lab, in which test cells are in contact with each other, mimicking the “body environment”.  This tissue-like environment should more accurately predict toxicity of drugs when they are actually given to humans.

A New Understanding of How Blood Vessels Work
Michael Marletta, PhD, University of California, Berkeley

Dilation of the blood vessels in the heart and other tissues is controlled by a reaction inside cells that gives off the chemical nitric oxide (NO).  NO causes the muscle cells of the blood vessel walls to relax so the vessel can expand.  Dr. Marletta and co-workers recently discovered that the accepted mechanism for how NO causes this relaxation is fundamentally incorrect. Determining the details of these new findings will lead to a better understanding of normal heart and blood vessel function, and to new approaches for treating heart disease and other cardiovascular ailments.  This proposal will explore the action of NO on a specific enzyme target in the cardiovascular system.  Based on current data, the consensus opinion is that nitric oxide directly activates the enzyme, and that another molecule deactivates the enzyme.  Pilot data suggests that a novel feature of the enzyme itself controls both activation and rapid deactivation.  Confirming these results could provide novel treatments of cardiovascular disease through manipulation of the target enzyme.

Preventing Transmission of HIV
Malcolm Potts, PhD, University of California, Berkeley, CA

Sexual transmission of HIV and other sexually transmitted diseases (STDs) continue at epidemic pace globally.  HIV researchers believe that microbicides, chemicals that can kill bacteria and viruses, can reduce the transmission of HIV and other STD pathogens when applied vaginally.   Current academic and pharmaceutical research is focusing on the lengthy and expensive process of developing new microbicide drugs that will make a large profit for these companies.

Women around the world have used diluted lemon or lime juice vaginally as a microbicide for hundreds of years.  Lemons and limes are inexpensive and locally available in nearly every country.  In lab studies, lemon/lime juice kills HIV on contact and has been proven safe when applied to the vaginas of monkeys. 

If lemon juice is effective in reducing HIV transmission in humans, the world will have an inexpensive and life saving technique for the reduction of a catastrophic disease, and a benchmark of safety and effectiveness for testing futures microbicides.  Dr. Potts and his team will test whether lemon juice is safe when self-applied to a woman’s vagina. 

If this test proves that dilute lemon juice is safe, a human clinical trial will begin to test whether lemon juice does reduce HIV infections and other STD’s.  Dr. Potts’ research has the potential to introduce a safe, effective, available, and inexpensive method years before a commercial microbicide becomes available. 

Stopping Spread of Multiple Myeloma Cells
Peter Rowley, MD, University of Rochester

Multiple myeloma is an incurable blood-bone cancer.  The disease is caused by two or more defective genes.  One of the reasons it is so hard to defeat is that these multiple gene defects create a variety of pathways the disease uses to keep growing.  There are many therapies that can kill myeloma cells, but other myeloma cells just keep growing using alternative pathways, and eventually the patient succumbs to the disease.

Dr. Rowley and his team have developed a new technology that can stop more than one defective gene at the same time.  His team has already shown that this therapy, a gene inhibitor called peptide nucleic acid (PNA), can block one defective gene in multiple myeloma cells. 

This new project will create a PNA to the other major gene defects, so that myeloma cells will be killed without having an alternative path around the therapy.  If this project is successful, there is hope that this incurable disease will soon be conquered, and that other resistant, incurable cancers can also benefit from this powerful therapy.

Finding a Cure for Untreatable Non-Small Cell Lung Cancer
Sreenath V. Sharma, PhD, Massachusetts General Hospital Cancer Center

Lung cancer is the leading cause of cancer-related deaths worldwide.  Non-Small Cell Lung Cancer (NSCLC) accounts for a majority (80%) of cases of lung cancers.  Overall, fewer than 10% of lung cancer patients are alive 5 years after initial diagnosis and this number drops to less than 5% in individuals with advanced-stage NSCLC.  Even the most aggressive conventional chemotherapy is excessively toxic and only marginally improves survival rates.  Thus, there is a tremendous need to develop better therapies for lung cancer treatment.

Recent studies have identified Epidermal Growth Factor Receptor (EGFR) as a protein that is found at high levels in NSCLC.  This formed the basis for the development of drugs that inhibit the EGFR for the treatment of NSCLC.  Two such drugs, namely, Gefitinib/Iressa (AstraZeneca) and Erlotinib/Tarceva (OSI Pharmaceuticals, Genentech and Roche), received “fast track” approval from the US Food and Drug Administration (FDA) for use as drugs of last resort in patients with advanced NSCLC.  The focus of this research is on these two drugs.  Early experience from clinical trials of these drugs indicated that they are able to create dramatic clinical responses in about 10% of treated patients - responses that could not be achieved by any other treatments available to date.  However, 90% of cases failed to respond and even the 10% of cases that show response to the drug were prone to developing resistance to the drug after some time. 

Dr. Sharma and his co-researchers observed that sensitive lung cancer cells that become resistance to these two drugs, as well as lung cancer cells that were insensitive to them in the first place are effectively killed by combination of these drugs and a well known anti-malaria drug.  This combined drug approach might expand considerably the range of lung cancers that can be effectively treated by Iressa and Tarceva.   In addition, adding the anti-malaria drug might allow physicians to reduce the dosage of Iressa and Tarceva to substantially decrease toxicity and the cost of treatment.  Finally, it is possible that other tumors besides lung cancer may also be treatable by the anti-malaria drug combination approach. 

Using Nanotechnology to Cure Pediatric Cancer
Jason Shohet, MD, PhD, Baylor College of Medicine

Most of the time, when something goes wrong in a normal cell, the cell is programmed to self-destruct. Cancer is caused when something goes wrong in normal cells and they don’t self-destruct.  Neuroblastoma is a cancer which causes 15% of all childhood cancer deaths.  No new therapies for this cancer have emerged in the last few years.  This cancer is so difficult to treat because the self-destructive capacity of these cancer cells is totally ineffective.  Dr. Shohet and his team recently discovered a molecule, called MDM2, which helps keep cancer cells from self-destructing.  Neuroblastoma cells have an abnormally high level of MDM2.  Dr. Shohet’s lab recently tested a molecule which blocked MDM2 in lab tests so that neuroblastoma cells self-destructed.  This project will use nanotechnology to deliver this molecule to test animals to see if the lab success will translate into success treating “patients”.  If this works on the test mice, the next step would be to get ready to test this on humans with neuroblastoma, and to determine if MDM2 plays a role in other kinds of cancers.

Replacing Light Receptor Cells
Gabriel Silva, PhD, University of California, San Diego

More than 50 million people worldwide are going blind because the light receptor cells in their eyes have broken down.  There are few treatments that can slow these diseases, and none that can cure them.  The most promising research is centering on replacing the damaged light receptors cells.  Researchers have found certain blood cells from the bone marrow can be transformed into light receptor cells.  These blood cells are called adult stem cells because they can turn into a wide variety of cells in the body.   Other researchers have made some of these blood stem cells look like light receptor cells.

However, while they look like light receptor cells, they don’t function like light receptor cells.  Dr. Silva and his team have hypothesized two breakthroughs that may lead them to rapidly develop new light receptor cells that can be transplanted into the eye to restore the vision that these patients have lost.  The first breakthrough that Dr. Silva and his team believe is necessary is to provide these blood stem cells with the same mix of chemical and other signals that normal light receptor cells would receive as they are maturing. 

More importantly, a second breakthrough is needed, to create a special three dimensional nano-environment on which these blood stem cells can grow.  This three dimensional structure mimics the structure of the retina where light receptor cells normally grow.  Dr. Silva and his team are trying to re-create the exact environment in which normal light receptor cells grow, so these stem cells can grow into functional light receptor cells.

If Dr. Silva and his team are correct, these new “Supercells” will be able to save the sight that so many people continue to lose. 

Extra-Cellular Matrix
Randy Sigle, PhD, Fred Hutchison Cancer Center

The cells of the human body are held together by something we call extra-cellular matrix.  Extra-cellular matrix is a complex of proteins and other components that not only provide structure for the body, but also provide a way for nutrients and signals to get from one cell to another.  When the extra-cellular matrix breaks down in a wound, or is pushed out of the way when a tumor takes over, the body no longer functions normally.

The search is on to create a synthetic extra-cellular matrix that we envision can be used for four purposes: 1) research on how changes in the extra-cellular matrix affect the body, 2) replacing damaged extra-cellular matrix in wound situations, 3) as a therapy when drugs are incorporated into the synthetic extra-cellular matrix before it is placed into the body, and 4) as a scaffold for designing artificial body parts. 

 Silk from silkworms is a compelling candidate for this synthetic extra-cellular matrix.  It is abundant, nearly pure, can be made in both water soluble and non-water soluble forms.   Dr. Sigle and his team will begin to determine whether or not the biological activities of the human extra-cellular matrix can be incorporated into silk.  If their hypotheses are correct, this research could lead to the development of new therapies for wound healing and cancer, as well as the initiation of a new paradigm for tissue engineering.

 What Can Stem Cells Teach us about Curing Cancer?
Yanhong Shi, PhD, City of Hope Medical Center

Stem cells have the unique abilities to self-renew and to change into other kinds of cells.  This is good.  Cancer cells have the same characteristics.  This is bad.  Dr. Shi and her colleagues believe that many of the pathways that help stem cells self-renew and change are the same pathways used by cancer cells, especially brain tumor cells.

Dr. Shi has discovered a compound called TLX which is critical to the self-renewal process in adult brain stem cells.  When cells don’t have TLX, they can’t grow.  If you give these cells TLX, they will begin to multiply.    These discoveries have created this research, through which the Dr. Shi team will determine whether brain tumor cells use TLX to help them grow and multiply.

If they team finds TLX is required for brain tumor growth, they will find the genes that TLX affects in both brain stem cells and brain tumor cells.  Comparison of these two cell types will allow researchers to create anti-tumor therapies that can attack the TLX sensitive genes in brain tumor cells, creating treatments for these devastating, incurable cancers, and for other brain related diseases.

A Cure for Mad Cow Disease
Gultekin Tamguney, PhD, University of California, San Francisco

Mad Cow Disease is a rare, fatal disorder in humans with no current treatment or cure. The disease is caused by an abnormally folded piece of cellular protein called a prion that accumulates in the brain.  Research has shown that antibodies, a special molecule produced by the body’s immune system that recognize and help fight infectious agents, can bind to the prion to “cure” a prion infection in a cell culture model.  Until recently antibody therapy for human prion diseases did not seem feasible since prion-binding antibodies could not cross the blood-brain barrier.

The aim of this proposal is to link prion-binding antibodies with a molecule that will cross the blood brain barrier, like hooking a caboose (the prion-binding antibody) to an engine (the molecule that will cross into the brain) so the caboose can get to where it needs to go. The “engine” molecule will release the antibody once it is inside the brain, so the antibody can bind to and destroy the prions.

This type of treatment could either provide a vaccine that would protect a person from prion disease or a treatment that would cure prion disease after infection.  Further, a successful outcome for this project could open the door to novel treatment strategies for similar brain diseases associated with the accumulation of mis-folded proteins such as Alzheimer’s and Huntington’s Disease.

 Translating Knowledge from One Disease to Cure Another
David Teachey, MD, University of Pennsylvania School of Medicine

Normally, the body creates new cells and eliminates worn out cells in a process called apoptosis, or cell death. In ALPS (Autoimmune Lymphoproliferative Syndrome), the body accumulates old white blood cells, which damage organs and red blood cells causing anemia, fatigue, internal bleeding, and infection.  The drug Rapamycin prevents organ transplant rejection and is also effective in treating white blood cell cancers, by causing cell death.  Dr. Teachey and his colleagues believe Rapamycin might be effective in treating ALPS.  This study will first test the drug in a mouse model of ALPS.  If it works, the drug will be tested on ALPS patients, who have no other effective form of therapy and usually do not survive the disease.

Halting Malaria in Transmission
Joseph Vinetz, MD, University of California, San Diego

Malaria is one of the world’s most prevalent diseases, killing 1-3 million people (mostly children) annually.  Mosquitoes spread malaria to humans. This project will use genomics to determine how malaria moves from humans to mosquitoes and back, testing a breakthrough to keep the malaria parasite from reproducing in the mosquito, breaking the transmission cycle.  After understanding this mechanism, novel methods of interrupting the transmission of malaria can be created.   If this proves successful, this technique can be used to design a cure for other insect borne diseases, such as West Nile Fever, Eastern Equine Encephalitis, and Dengue Fever.

Eliminating Resistance to Chemotherapy
Steven J. Weintraub, MD, Washington University School of Medicine, St. Louis

Unfortunately, chemotherapy agents do not cure most types of cancer and their administration causes significant side effects.  These agents have many effects on cancer cells, and little is known about which effects cause cancer cell death.  Many drugs kill cancer cells by modifying cell proteins that make it impossible for the cell to survive.  When the modification of this protein is blocked, the cells become resistant to chemotherapy.  Recently, Dr. Weintraub and his team discovered compounds found in many cancers that block the chemotherapy protein changes.  Cancers with these compounds are quite resistant to chemotherapy.  Understanding the mechanism by which these cancer compounds block chemotherapy could lead to an improvement in the treatment of a wide variety of cancers.

Abstracts of 2004-2005 Culpeper Medical Scholar Grants

 Functional Genomic Dissection of Human Mitochondrial Disorders
Vamsi K. Mootha, M.D. Massachusetts General Hospital, Harvard Medical School, Broad Institute of MIT and Harvard

Mitochondria are tiny structures found in each of our body’s cells.  They are responsible for converting the food we eat into “cellular fuels” that can be used by our muscle, brain, heart, and other organs, to perform work.  Recent studies have shown that dysfunction of mitochondria can give rise to rare inherited disorders, as well as some very common human diseases, such as diabetes, neurodegeneration, and cancer.  With funding from the Charles E. Culpeper Scholarship, I plan to focus a portion of my lab’s efforts on a class of mitochondrial disorders that are characterized by devastating metabolic dysfunction, particularly in children.  At present, the diagnosis of these disorders is extremely difficult, and we have no therapeutic options for them.  Although these disorders are due to mutations in single genes, they give rise to a variety of symptoms – how lesions in individual genes can give rise to such a spectrum of clinical presentations remains a puzzle.  Using new tools that enable scientists to systematic disrupt individual genes my team will create cellular models of mitochondrial disease that we can then study in our laboratory.  In particular, we will use new technologies that enable us to monitor all the genes in the human genome and their response to these single genetic lesions.  Through the combined use of biochemistry, genetics, and mathematics, we then hope to identify the cellular pathways that go awry in these disease models, with the goal of identifying molecular targets against which rational therapies can be designed.

Therapeutic discovery for obesity
Kevin Niswender MD, PhD, Vanderbilt University, Department of Medicine, Division of Diabetes, Endocrinology and Metabolism and Department of Molecular Physiology and Biophysics

Obesity is both common and hazardous.  The incidence of obesity is increasing dramatically worldwide.  Fully one-third of adults in the U.S. are obese, and suffer a 3-4 fold increase in the risk of stroke, coronary artery disease, hypertension and diabetes mellitus.  Despite annual obesity-related costs approaching 240 billion in the US, effective treatments do not yet exist for this disorder, which has emerged as one of the greatest threats to human health worldwide.

Obesity does not result simply from a lack of will-power, but from a strong regulatory system gone awry.  Much like the blood sugar level, body weight is normally maintained within a narrow range by a powerful physiological regulatory system.  When tissues in the body become resistant to the effects of insulin, the hormone that controls blood sugar, abnormally high blood sugar results, a condition known as type II diabetes.  Likewise, most patients with obesity are resistant to the effects of the critical hormone, leptin, which is made in fat cells and is secreted into the blood stream in proportion to the amount of energy stored in the body (in the form of fat).  Through the blood circulation, leptin enters a key brain region known as the hypothalamus where it binds to its receptor on specific hypothalamic brain cells (called neurons) and generates a signal that ultimately decreases appetite and promotes weight loss.  When this signal does not work appropriately, leptin resistance and obesity result.  Interestingly, in addition to regulating the blood sugar level, insulin has effects in the brain that are very similar to the effects of leptin and insulin is considered a second body weight regulating hormone.  

Leptin (and insulin) resistance poses a major obstacle to obesity treatment.  Scientists have learned a great deal about how the hypothalamus controls body weight, yet we still do not understand how leptin and insulin control the function of hypothalamic neurons, and therefore have little understanding of resistance in obese individuals.  The drug discovery approach outlined in this proposal is based on new data generated by the applicant regarding how these hormones normally work within hypothalamic neurons, and how this normal function becomes disrupted in obesity.

We have recently discovered that a “signaling” molecule known as phosphatidylinositol 3-kinase (PI3K) is critical for the ability of leptin and insulin to cause animals to eat less.  The first step in understanding how leptin and insulin work and, therefore, how to repair resistance, is to understand how these two hormones translate an increase of body fat stores into a message within the brain that results in decreased food intake.  We have demonstrated that a specific signaling molecule present within hypothalamic neuron cells is necessary for leptin and insulin to activate the neuronal cascade that leads to reduced food intake.  Surprisingly, this molecule, known as PI3K, is also a critical mediator of the action of insulin in tissues (like muscle) that help to lower blood glucose.   As mentioned above, the ability of insulin to activate PI3K in muscle cells becomes impaired and leads to insulin resistance in obese individuals, and this in turn favors the development of diabetes.  Just like in muscle, we have observed that in obesity insulin and leptin no longer are able to activate PI3K within the key cells in the hypothalamus and are therefore unable to reduce food intake.  We have also learned about the biochemical mechanisms involved in this process.

With this information we have developed an idea for the discovery of potential medications to reverse this process in obesity.  It turns out that as with the analogies between muscle and brain mentioned above, numerous similarities exist between pancreatic islet cells, responsible for secreting insulin, and the important nerve cells in the brain.   Specifically, the processes whereby the cell responds to the important hormones insulin and leptin are very similar, including PI3K activation, and a similar process causing hormone resistance also occurs in islet cells.  Thus, because pancreatic islets and hypothalamic neurons respond to various stimuli, including insulin, leptin, glucose and fats in a very similar way, a process called secretion-coupling, we will utilize pancreatic islets to model neuronal function and to screen for compounds that improve function.  This is necessary because it is not possible to purify sufficient quantities of hypothalamic neuron cells to perform drug discovery work.  Furthermore, because we understand some of the processes involved in the development of resistance, we can re-create resistance in pancreatic islets by culturing them under specific conditions.

High-throughput screening as a mode of drug discovery is now possible at Vanderbilt University because we have established a fully operational facility and we own a 160,000 compound small molecule library.  This approach seeks to simply treat an experimental sample with each of the 160,000 compounds to determine whether any look promising as a new medication.  The 160,000 compound library has been designed to be maximally chemically diverse and also to have compounds with structures that are likely to work as medications.  Thus, we are essentially performing in excess of 160,000 separate experiments which is only feasible because this facility is fully automated and has a number of instruments that are run by robots.  Each “experiment” is performed in a single well in a 384 well dish and with this miniaturization and automation we are capable of screening this complete library over the course of several weeks. 

Thus, the basic premise is to detect an experimental response in islet cells that can be measured by the robotic instruments.  In our case, pancreatic islets secrete insulin by having an increase in calcium levels in the cell.  Our instruments can measure this increase in calcium and we can, therefore, easily and quickly determine when a test compound has caused insulin secretion.  The islets will be treated to generate insulin resistance and then will be plated in 384 well plates. In the screening facility, the instruments will then add insulin and one of the 160,000 compounds from the library to a single well of the plate (all 384 wells simultaneously receive different compounds) and determine whether these individual compounds restore the ability of insulin to stimulate insulin secretion.  Our first goal of this project will be to adapt our concept to the robotic instruments used within the screening facility.  Once the assay has been optimized, with the robots and “high-throughput” instrumentation, we expect that completing the screen of the 160,000 compound library will take several weeks. 

The use of “primary” cells, or cells and tissues derived straight from an animal is unique in high throughput screening, as is the concept of re-creating the disease process in the cells to be screened.  This approach is considered to be cutting edge, and is not the standard approach taken because it is technically more difficult, and therefore risky.  One very important reason we have chosen this approach is that we will be able to discover compounds that restore insulin secretion by acting anywhere in the process, not just at specific points.  Thus, we will not be limited by our current understanding of the disease process; we may actually identify completely new pathways and medicines for the treatment of diabetes and obesity.  We have already developed important evidence in proof that this concept can be utilized and are working to “miniaturize” the experiments to the high-throughput screening format. Once the complete library has been screened and we have identified compounds that potentiate or improve insulin-stimulated insulin secretion in insulin resistant islets, we will further characterize these compounds to determine at what point in the insulin secretion pathway they work.  Ultimately, of course, we will test the effect of these compounds in obese animals, and then begin to work with pharmaceutical companies to develop any promising compounds for the treatment of human obesity.   Importantly, because we are using pancreatic islets for this screen, we will also identify compounds that may be useful in the treatment of diabetes.

The Role and Regulation of Autophagy in Epithelial Cell Homeostasis and Cancer
Jayanta Debnath, MD, Assistant Professor of Pathology at the University of California San Francisco

Cancer is a deadly disease because an individual’s own cells develop genetic and biological changes allowing them to survive and grow in places where they do not belong. Extensive research has shown that one reason that cancer cells survive in unusual places is because they are protected from a process called programmed cell death, or apoptosis. Normally, apoptosis acts as a surveillance mechanism in the body that kills excess cells to prevent them from building up; this is not the case during cancer progression.

Although reduced apoptosis contributes to the ability cancer cells to survive, recent evidence is now indicating that other, less appreciated mechanisms, are also likely to regulate cancer progression. Without clarifying how such critical processes work, we are unlikely to develop effective treatments against cancer.

I recently found that when apoptosis is blocked, a second process, called autophagy, may act as a back-up mechanism to kill wayward tumor cells.  Autophagy is a widespread biological process in which a cell digests its own contents in response to various stresses.  When excessive autophagy occurs within a cell, it dies, because the cell literally “eats itself” to death. However, very little is known about the function or regulation of autophagy in human cells. My proposed studies intend to further explore the role of autophagy during cell death in both normal and cancer cells as well as determine how cancer genes and pathways regulate this poorly understood process.  These studies may provide novel information about the survival of cancer cells during cancer progression, and may enlighten the diagnosis and treatment of many different kinds of human cancer. 

Activating Apoptosis in Cancer Using Hydrocarbon-Stapled Helices
Loren David Walensky, MD, PhD, Harvard Medical School and Attending Physician and Research Fellow in the Department of Pediatric Hematology/Oncology at the Dana-Farber Cancer Institute/Children’s Hospital Boston. 

Whether our cells will live or die, and whether we are therefore healthy or ill, is controlled by how proteins interact with each other inside our cells.  There are a huge number of proteins in our cells, and each one has a specific job to do.  Whether a protein can do its job depends on which other proteins are present inside the cell and what they are doing.  Think of a cell as the most complex assembly line in the world, and each protein as a worker on that assembly line.  How each protein gets its job done inside a cell depends on how it communicates with and interacts with the other proteins inside the cell.  Even a minor breakdown in communication between the proteins can have a dramatic effect on cells, and on our health.

There are certain proteins inside a cell called “BCL-2” proteins.  These proteins interact with one another to regulate whether a cell dies when it is old, diseased or no longer needed.  This cell death is called “apoptosis”.  Many human diseases directly results when apoptosis does not occur the way it should.  Premature cell death that reduces the number of healthy cells needed to continue important body functions can lead to illnesses like Alzheimer’s disease or stroke.  On the other hand, cancer occurs when diseased and damaged cells don’t die on time.  These and other diseases are the direct result of BCL-2 protein interactions that have gone awry.  Cures can come from fixing these BCL-2 protein problems.


BCL-2 proteins control cell death through small protein subunits called “peptides” that are helical, or spring-like, in shape.  Scientists can create other peptides that interact with these helical BCL-2 peptides to slow down or speed up cell death.  However, most current attempts to manufacture these artificial peptides have failed because the helical shape is so complex.  Peptides that have been manufactured in the right shape are so fragile that they break down before they can do their job.  Attempts to strengthen these fragile peptides have made it impossible for the peptides to get inside the cells to do their job. 


Dr. Walensky’s research focuses on developing and applying new approaches to this problem.  He will address two issues-using natural versus artificial peptides, and strengthening them without destroying their effectiveness.  Dr. Walensky will use a new process to chemically brace these natural peptides so that their shape, and therefore their curative activity, can be maintained.  He has used this chemical strategy, called “hydrocarbon-stapling”, to make a number of peptides with dramatically improved properties. 


Dr. Walensky has demonstrated that the stapled peptides are the right helical shape, are sturdy, and can enter and kill leukemia cells by turning on the BCL-2 death pathway.  When he administered these stapled peptides to mice with leukemia, the stapled peptide successfully blocked cancer growth and prolonged the lives of treated animals.  As a Culpeper awardee, Dr. Walensky’s future work will employ this new peptide-stapling strategy to produce a wide array of peptides that can interact with the BCL-2 pathway, in order to control cell death in a variety of human cancers.  The goal of Dr. Walensky’s research is to produce an arsenal of new compounds, a “peptide toolbox,” to block protein interactions that cause cancer, as illustrated by the anti-leukemia effect of his stapled BCL-2 peptide.  

Treatment of Preeclampsia by sFlt1 Knock-Down Using RNA Interference
Sharon Maynard, MD, Assistant Professor in the Renal Division, George Washington University Medical School 

Preeclampsia is a life threatening condition that affects pregnant women and their babies.  It occurs in 3-5% of all pregnancies and has no effective treatment except immediate delivery of the baby, no matter how far the pregnancy has progressed and whether or not the baby is ready to be born.  Preeclampsia causes high blood pressure in the mother and protein in her urine. If untreated, it can cause seizures, stroke, kidney failure, liver failure, and clotting/bleeding disorders in the mother. Often the baby needs to be delivered prematurely to preserve the health of the mother, resulting in serious consequences for the newborn.  A treatment which could allow physicians to safely delay delivery would make a significant impact on the health of the mother and of the newborn. 

Dr. Maynard helped discover that a protein found in the blood of pregnant women, called sFlt1, is overproduced in women who have preeclampsia.  Pregnant rats exposed to high levels of the sFlt1 protein develop hypertension, protein in the urine, and microscopic changes in the kidney, all symptoms characteristic of preeclampsia.  This suggests that the sFlt1 protein may actually be the cause of preeclampsia, and blocking the production or action of sFlt1 may create an innovative treatment or cure.  Dr. Maynard is researching whether RNA interference could block the production of sFlt1.

RNA interference is a technique that stops a specific portion of a bad gene from creating a protein that can damage in the body.  Think of this defective gene as a locksmith shop gone bad.  The locksmith shop employs an evil locksmith, who will make a key that will unlock your door for a criminal.  A defective gene employs an evil RNA messenger molecule, which makes a protein that can unlock a damaging process inside your cell.  At the locksmith shop, if the police interfere with the evil locksmith, he cannot make a key and your door cannot be unlocked.  At the gene, if the RNA interference police tie up the evil RNA messenger molecule, it cannot make the protein and the bad process in your cell cannot be unlocked.

RNA interference appears to be an innovative way to reduce the levels of sFlt1in the blood.  Dr. Maynard will study how RNA interference will significantly reduce production of the sFlt1 protein in the cells of a woman with preeclampsia.  She will first use cells in the lab to design and optimize an RNA interference molecule that will interfere with the bad gene RNA messenger that produces the protein sFlt1.  She will then use an animal model of preeclampsia to determine if RNA interference of sFlt1 can reverse the hypertension and kidney damage that occur in these animals.  If this works in the animal model, it may prove that the protein sFlt1 is the culprit that causes preeclampsia, and a human clinical trial will be considered.  If preeclampsia is truly a result of overproduction of this single protein, reducing its production may be an effective treatment, which could have a great impact on clinical outcomes in this important

Mechanism and Significance of Adult Excitation-Neurogenesis Coupling
Karl Deisseroth, MD, PhD,
Assistant Professor of Medicine, Stanford University, Assistant Professor of Bioengineering and Psychiatry

Scientists have recently made an astounding discovery-adult brains can and do produce new brain cells, called new neurons.  Until now scientists believed that once a newborn’s brain development ended, no new brain cells were ever created.  In humans, these new adult neurons are created from adult stem cells in a region of the brain called the hippocampus.  The hippocampus helps control memory and mood, which makes it an important area of the brain to study when looking for cures for anxiety, depression, suicide, and memory loss.

Dr. Deisseroth and his colleagues have found that the brain’s own electrical activity can cause adult stem cells to turn into new neurons, and have begun to figure out how and why this occurs.  These findings have huge scientific and clinical significance because scientists and doctors know how to control brain electrical activity using a variety of behavioral and clinical techniques that don’t require surgery or other invasive procedures.  Dr. Deisseroth and his colleagues will further describe how and why electrical activity in the brain causes adult stem cells to change into new neurons.  These discoveries will lead to methods of controlling new neuron development in adults who have memory loss or mental illness.  This research will lead to a deeper understanding of the function of the hippocampus and to new treatments for major depression and other disorders of the brain.