Heart Disease

Research in the Del E. Webb Neuroscience, Aging and Stem Cell Research Center is attacking the problem of heart disease on two fronts. Investigators are employing strategies based on cell and molecular biology to stave off the death of heart cells and to develop replacement cells that can rebuild damaged organs. This two-pronged approach can be thought of as: "Protecting what you have and replacing what you've lost."

On the protection front, Professor Rolf Bodmer and Assistant Professor Giovanni Paternostro are using genetics to examine how hearts age. It has been known for many years that the ability of a heart to adapt to stress and recover decreases with age, but the underlying biology is not well understood. Bodmer and Paternostro use a simple organism, the fruit fly, which has been studied by geneticists for a century, to identify the genes that control the aging process.

In flies, just as in humans, aged hearts do not withstand stress as well as younger hearts. Paternostro has found mutant flies whose hearts appear perennially robust. He and his colleagues are currently working to isolate and examine the genes that cause these mutations. Bodmer and his team are studying a number of genes that are believed to cause heart defects in humans born with Downs syndrome, a birth defect caused by the presence of an extra copy of chromosome 21. These genes have “cousins” in flies, and Bodmer’s group has found that several of them do affect heart function. Bodmer’s group has also identified genes in flies that cause their hearts to age prematurely or, conversely, to remain young relative to the age of the fly. Many of these genes are also found in humans, and a number of them are associated with congenital heart malformations. By manipulating some of the genes they have found, Bodmer’s laboratory can cause hearts to age more slowly than normal. Their hope is that drugs or genetic therapies can be devised, based on their work, that will help to delay or treat heart failure in humans.

Other Sanford-Burnham scientists are working on strategies to replace heart tissue damaged by disease. These strategies employ stem cells, relatively immature cells that can be directed to become different types of specialized cells, including, it is hoped, cardiac muscle cells, known as cardiomyocytes. These newly-derived heart cells would then be grafted to fill the lesions created by cardiac disease.

Professor Mark Mercola has identified a number of genes that guide initial formation of the heart in developing embryos. His laboratory has applied this knowledge to induce mouse embryonic tissue and embryonic stem cells to take on heart-like properties. For instance, a dish of cultured cells will beat in unison, much like the rhythmic beating displayed by a functioning heart. Their work indicates that it should be possible to develop protocols to induce stem cells to differentiate into functioning cardiac cells.

Cardiomyocytes derived from embryonic stem cells can be cultured in the same dish with genuine cardiac muscle cells, and in fact, some will "pair up" with the mature cells and take on heart-like appearance and function. Mercola and his team have shown that problems develop, however, with these stem cell-derived “heart” cells. The cells appear normal for a time, but then undergo hypertrophy, similar to the enlarged heart cells seen in people with heart failure. Although the cells appear normal alone, contact with normal functioning cardiomyocytes triggers their abnormal growth.

In collaboration with Assistant Professor Vincent Chen, Mercola’s group is examining how the stem cells in these cultures are communicating with their mature cardiomyocyte neighbors. Cardiac cells are "electrically coupled," and exchange signals that allow them to beat in harmony. Chen’s expertise in measuring electrical activity in cells and the communication between them is allowing the team to characterize the electrical behavior of the differentiated stem cells and compare it to that of normal mature cardiomyocytes. The results of this work should constitute a basis for developing methods to normalize electrical activity in differentiated stem cells.

Mercola’s laboratory is also collaborating with a team of chemists to develop candidate drugs to combat the hypertrophy seen in heart-like stem cells. He and his colleagues have identified one chemical compound that appears to block this trend in the stem cells co-cultured with mature heart cells. Now, the team will use their knowledge of the signaling that triggers the stem cells’ abnormal growth to develop drugs that are particularly suited to block the abnormal growth. They are also pursuing other potential compounds that may lead to new agents to protect against enlarged hearts in patients with chronic heart disease.

When engineering heart tissue from stem cells, however, scientists will need to be careful not to halt their proliferation too soon. Otherwise, they will not obtain sufficient tissue to transplant. If the cells mature too soon, they stop dividing; if they do not mature and keep dividing too long, they risk displaying the hypertrophy described above. Therefore, a balance needs to be achieved between cell division and maturation.

One way to control that balance is to replicate the mechanisms the developing embryo uses to ensure it has enough cells to build heart muscle. Mercola’s group is studying a number of genes that control cell proliferation during embryonic heart development. One of these is called Notch, which prevents heart cells from reaching a point at which they can no longer divide. Their long-term goal is to develop protocols, using a combination of genetic and drug-based approaches, that will balance division and maturation appropriately in differentiating stem cells. Such protocols should result in a population of healthy, mature cardiac cells that can be transplanted into patients suffering from heart disease.

Crohn's Disease (Colitis)

Crohn’s disease and ulcerative colitis, which affect approximately a million people in the United States, are fundamentally diseases of inflammation. Those suffering from the disease display excessive inflammation in the lining of the small intestine, which leads to abdominal pain, diarrhea, and, in some cases, bleeding that can cause anemia. Typical treatments aim to reduce inflammation, and severe cases may require surgery. No treatment at this time, however, constitutes a cure – the condition returns even in those patients who undergo surgery. Furthermore, all currently available treatments have associated side effects such as nausea, heartburn and increased susceptibility to infections. Additional research is needed in order to develop more effective treatments.

Professor Hudson Freeze and his colleagues at The Sanford-Burnham Institute are examining inflammation at the level of individual cells and molecules that mediate the process. They hope their work will lay the foundation for a new generation of treatments for inflammatory diseases.

The team recently produced an antibody that blocks inflammatory intestinal conditions in animal models. Mice given a control antibody, or placebo, lost approximately a quarter of their body weight and suffered from severe diarrhea. But mice treated with Dr. Freeze’s antibody showed minimal weight loss (less than 10%), were healthy, and had no signs of diarrhea. The antibody inactivates a group of novel sugar chains the laboratory had identified as important in fueling various types of inflammation. Sugar chains are found attached to many of the proteins that carry out the body’s functions and they often modify those functions. The sugar chains discovered by the Freeze group are found on proteins and cells of the immune system known to play a key role in inflammation.

Inflammation is a critical bodily process that helps to protect us from infection, but when it goes awry and attacks our own tissues, as in Crohn’s and other conditions such as arthritis, it must be reined in. This is the aim of many current therapies, such as corticosteroid drugs, which damp down the immune system. An unfortunate side effect of such treatment, however, is to compromise the body’s ability to ward off infections. A promising aspect of the Freeze antibody is that it appears to affect cells of the immune system specifically in the intestinal lining, and not in critical tissues such as the lung.

Dr. Freeze and his group continue working to pinpoint the underlying mechanism of the antibody’s action and determine what other types of inflammation may be treatable with it.

Sanford Children's Health Research Center

Fred Levine, M.D., Ph.D.
Director, Sanford Children's Health Research Center

The Sanford Children’s Health Research Center was established at Sanford-Burnham’s San Diego campus by a $20 million gift from South Dakota philanthropist Denny Sanford through Sanford Health. The gift serves as the foundation for collaboration between Sanford Health of Sioux Falls, South Dakota and the Sanford-Burnham Medical Research Institute.

The collaboration combines world-class scientific talent with state-of-the art technology to conquer childhood diseases. In addition to the new center in La Jolla, Sanford Health will develop a Children’s Health Research Center in Sioux Falls. The collaboration between the two locations will establish the basis of an integrated, world class, academic pediatric research network.

“I have the utmost confidence that this collaboration will promote solutions to some of the most troubling health issues that affect children,” said Denny Sanford when the gift was announced. “Nothing gives me greater pleasure than to encourage efforts and activities that I know will help children enjoy the gift of good health.”

As part of the collaboration, Sanford-Burnham will advise Sanford Health in recruiting talented research scientists to work at Sanford Health in Sioux Falls. In addition, Sanford-Burnham will dedicate nine senior faculty to be supported by approximately 40 scientists and related staff in approximately 25,000 square feet of research and support space in La Jolla, California.

Sanford Health serves an 80,000 square mile, four-state region including parts of South Dakota, Iowa, Minnesota and Nebraska. Their comprehensive, integrated system includes more than 360 physicians in 115 clinics, 23 hospitals, 13 nursing homes, 17 assisted living facilities and congregate living locations, 27 home health services and 19 pharmacies. With approximately 12,000 employees, Sanford Health is the largest employer in the region. Its primary 500-bed nonprofit tertiary care hospital serves an average of more than 30,000 inpatients annually. With more than a million outpatient visits each year, Sanford Health is the largest healthcare system between Mayo Clinic in Rochester, Minnesota and Denver, Colorado. Its divisions include Sanford University of South Dakota Medical Center, Sanford Clinic, Sanford Health Network, Sanford Health Plan and Sanford Health Foundation. Originally known as Sioux Valley Health System, the organization changed its name to Sanford Health to recognize a transformational gift of $400 million made by Mr. Sanford in early 2007. The gift is the largest single donation ever made to a hospital or health system.

“The opportunity to collaborate with Sanford Health expands our ability to combine Sanford-Burnham’s worldclass laboratory research with a powerful clinical partner dedicated to advancing medicine,” said John Reed, M.D., Ph.D., Sanford-Burnham’s CEO and Professor and Donald Bren Executive Chair. “Denny Sanford’s gift and his commitment to improving child health will enable us to consolidate and expand our present pediatric medical research activities and to speed our progress towards solving the unmet medical needs of children. We are honored for the opportunity to work with Mr. Sanford and the Sanford Health organization towards this noble goal.”

http://www.sanfordhealth.org/research

Diabetes and Obesity Research Center

We are witnessing an obesity and diabetes pandemic. In the United States alone, over 60% of adults are overweight or obese. Type 2 diabetes, which is driven by obesity, has increased nearly 30% in the last decade alone. Children are increasingly obese, and some are beginning to develop insulin resistant forms of diabetes that were rare in children just 10 years ago. Diabetes is often accompanied by an aggressive form of cardiovascular disease and greatly increases the risk of atherosclerosis and heart failure.

The mechanisms linking obesity-related diabetes and its cardiovascular complications are unclear. Understanding these linkages requires an interdisciplinary approach, which is why Sanford-Burnham has established a thematic Center comprised of scientists with diverse and complementary expertise including molecular biology, cellular and organismal metabolism, vascular and myocardial biology, physiology, chemistry and structured biology.

The overall mission of the Sanford-Burnham at Lake Nona Center in Orlando, Florida, is to use a multi-disciplinary approach to promote fundamental discovery relevant to obesity-related diabetes and its cardiovascular complications. The specific goals of the Center are:

• Fundamental Discovery to elucidate the pathophysiology of common metabolic diseases and corresponding cardiovascular complications. Active and planned research activities include (but are not limited to): cellular signaling mechanisms involved in the response to insulin; brain-body “crosstalk”; islet cell biology; transcriptional and epigenetic control of cellular fuel and energy metabolism; genetics of metabolism; neurophysiology of appetite and energy expenditure; adipocyte biology; and systems and NMR approaches to cellular/organ metabolic flux.
  
  In the cardiovascular arena the following areas are emerging: molecular control of mitochondrial biogenesis and function; cardiovascular GPRC signaling; cardiac myocyte signaling/transcription/epigenetics; non-coding RNA in development and physiological adaptation; angiogenesis; and progenitor cell biology.

• Translational Studies to move discovery toward new paradigms in patient care.

• Technology Platform Development to enable our fundamental and translational research objectives.

The Center is supported by an extensive Shared Resources platform across Sanford-Burnham sites, including the Conrad Prebys Center for Chemical Genomics; Mouse Cardiometabolic Phenotyping Core; Metabolomics Core; Analytical and Functional Genomics; Medicinal Chemistry; and Pharmacology.

The Center will be home to 2 research programs to promote cross-disciplinary research within each area and at their intersection.

• Metabolic Signaling and Disease

• Cardiovascular Pathobiology

Infectious & Inflammatory Disease Center

The human body is home to approximately 100 bacterial cells for every one human cell. Yet, remarkably little is known about the complex interplay that occurs daily between the genomes of bacteria living in the body and our own genome. Systems biologists have identified the field of host-pathogen interactions as one of the bold new frontiers for applying tools of genomics, proteomics, and bioinformatics towards the goals of elucidating communication between the genomes of microorganisms and mammalian genomes, in health and disease. This is the goal of investigators in the Sanford-Burnham Medical Research Institute's Inflammatory and Infectious Disease Center.

The need to understand and develop treatments for inflammatory and infectious diseases is very great. It is currently estimated that within the next ten years, many antibiotics currently employed for treating bacterial infections will no longer be effective due to microbial resistance. Drug-resistant strains of some pathogens, such as the bacteria that cause tuberculosis, have already appeared. Also, very few treatments for viral infections exist to date. Moreover, several deadly viral agents are on the rise, threatening increasingly larger numbers of persons worldwide. Recent world events have made clear the need for an understanding of the molecular mechanisms of disease in order to counter threats created by terrorists seeking to weaponize anthrax, ricin, smallpox, yersinia, SARS, and other biological agents against the United States.

A wide variety of chronic inflammatory diseases have been linked to dysfunctional host responses to pathogens, including rheumatoid arthritis, which affects more than 40 million Americans, inflammatory bowel diseases, affecting more than 55 million persons in this country alone, and multiple sclerosis, a progressive neurodegenerative disease. Researchers at the Sanford-Burnham Medical Research Institute are studying the cells responsible for inflammatory disease and recently discovered a human gene variant that prompts cells of the immune system to attack insulin-producing cells, causing type 1 diabetes. This gene variant also predisposes to rheumatoid arthiritis and other inflammatory diseases. These diseases are extremely debilitating and are becoming increasingly common in our aging population.

Study of infectious and inflammatory diseases is highly synergistic with the Sanford-Burnham Medical Research Institute's research strengths. The Institute has a strong presence in areas including: (a) cell adhesion, relevant to the mechanisms bacteria and viruses use to penetrate human cells; (b) apoptosis and cell death, processes that constitute part of the inflammatory response and are manipulated by pathogens to both kill and resist the immune system; (c) genomic instability, in which genetic changes result in the emergence of drug resistance; and d) carbohydrate structures as key recognition elements for inflammatory cells.

A central focus in the Inflammatory and Infectious Disease Center is the rational, structure-based design of small molecule inhibitors, using: crystallography and NMR to determine structures; and chemistry, high through-put screening, and in silico approaches to identify and test inhibitors. Sanford-Burnham scientists have a track record of success with these approaches. A team effort, published in the fall of 2001, determined the three-dimensional structure of the anthrax lethal factor, and based on this knowledge, two potential drug candidates are now under development to treat patients after anthrax infection.

Research in the Infectious and Inflammatory Disease Center is synergistic with work in the Sanford-Burnham Medical Research Institute's other major research centers, the Cancer Center and the Del E. Webb Neuroscience, Aging and Stem Cell Research Center. Microbial infections are linked to several cancers, and chronic inflammation is commonly associated with an increased risk of cancer; inflammation is also an exacerbating component of neurodegenerative diseases such as Alzheimer's.

Stem Cells and Regenerative Biology

All cells in our body have a repertoire of approximately 40,000 genes upon which to draw, but at any moment in time, only about one-quarter of these genes (10,000) are turned on (expressed). The fundamental basis for differences in the various types of cells (heart, brain, liver, skin) that comprise our body is found in the cell's decision as to which genes it turns-on and which genes it represses. During fetal development, embryonic stem cells with full access to the genome give rise to the multitude of cell types required for formation of a complete individual, spinning out progeny with progressively restricted access to the genome which are committed to certain cellular fates.

It is now recognized that the adult body contains reservoirs of residual stem cells resembling the primitive cells of the embryo, and that these cells may have the capacity to be instructed to produce a panoply of cell types for therapeutic benefit. Technologies for returning full access to the genome of mature, differentiated cells are also rapidly being developed, forecasting a day when almost any cell might make suitable starting material for re-programming to produce cells with stem cell-like qualities.

The need for progress in cell and organ replacement therapies is already acute and growing, as society trends towards a more aged population. Furthermore, it is clear that many diseases simply cannot be cured by small-molecule drugs, including Type I diabetes, Parkinson’s Disease, liver failure, and cartilage deterioration (degenerative joint disease). For these diseases, therapies based on introduction of replacement cells or organs are the keys to progress.

The overall goal of the Stem Cell Biology and Regenerative Biology program is to promote regeneration of tissues in disease and normal aging. Progress in this area of “regenerative medicine” will depend on progress in stem cell biology and will require development of expertise and technology in the isolation, culture, and manipulation of cells with the capacity to differentiate into various cell types. Recent research suggests that a single or a few classes of stem cells reside in many adult tissues, and that environmental signals determine how these cells differentiate. It will be important to determine what those signals are. In this regard, the Institute has a long tradition of working on mouse embryonic stem cells and differentiation developmental biology, which lays the foundation for this initiative.

Scientists collaborating within this Program have recently demonstrated that cells within the bone marrow of adult mice (mammals) are constantly migrating into the brain and producing new nerve cells. Though occurring in very small numbers, this seminal observation suggests the existence of a naturally occurring pathway for regeneration of the nervous system, and forecasts a day when drugs might be developed to boost the endogenous production of new brain cells from the bone marrow. Sanford-Burnham Institute researchers have also identified a gene regulator (transcription factor) that operates as a master-switch in stem cells, driving them to become brain cells (neurons). Studies of muscle stem cells by scientists affiliated with this Program have also provided an animal (mouse) model for testing cell replacement therapies for muscular dystrophies. Engineering cell replacement therapies for restoration of insulin-producing cells in patients with Type I diabetes is another goal of this Program.

Del E. Webb Neuroscience, Aging and Stem Cell Research Center (NASCR)

Stuart Lipton, M.D., Ph.D.
Professor and Director

In 1999, the Sanford-Burnham Medical Research Institute dedicated the Del E. Webb Center for Neuroscience and Aging Research. The mission was soon expanded to include Stem Cells/Regenerative Biology for therapeutic purposes in the areas of neurology, cardiology, and endocrinology (principally diabetes mellitus). The rationale for creating this new Center was to exploit scientific synergy with the Institute’s Cancer Center to meet exceptional clinical needs, for which currently available treatments are inadequate or lacking entirely. For example, studies of why treatment-resistant cancer cells are so difficult to kill resulted in discovery of anti-death genes, which are now being exploited for protecting the brain. Similarly, infidelity in maintenance of the genome (DNA) is associated with increased risk of cancer and early-onset neurodegeneration, suggesting commonality of mechanisms. Indeed, both cancer and neurodegenerative diseases such as Alzheimer's are diseases of aging, which most of us will contract if we live long enough.

As individuals beyond 60 years of age comprise the fastest growing segment of our population, diseases associated with aging represent a compounding set of medical challenges. Heart disease represents the number one cause of death in the USA. Taken together, acute and chronic neurodegenerative disorders, such as stroke, Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis (Lou Gehrig's disease), multiple sclerosis, and Huntington's disease, represent the second most common cause of death and are responsible for the fastest-rising rate of death in the United States. HIV-associated dementia also falls into this category and represents a form of neurodegeneration that is precipitated by AIDS; it has become the most common cause of dementia worldwide in persons age 40 or less. Diabetes provides yet another example of a disease with degenerative consequences and is the most common cause of chronic pain syndromes from peripheral neuropathy in the USA.

For clinical information for diagnosis and treatment of each of the diseases mentioned here, see www.ninds.nih.gov (for neurological disease), www.nhlbi.nih.gov (for heart disease), and http://www2.niddk.nih.gov (for diabetes mellitus and other endocrine disorders).

NASCR exists to advance understanding and treatment of these degenerative diseases, as well as the normal aging process. A key feature of the Center is its basic molecular approach coupled with the intent to spearhead translational research in a systems-wide manner, which will expedite the pathway from bench science to clinical trials in order to develop new therapeutic approaches. Our two main missions are (1) to produce new drugs to protect the brain, heart, and pancreas, and (2) to develop regenerative brain, heart, and diabetes therapies using stem cells.

There are three primary programs in our Center to help us accomplish this mission: (i) Neurodegenerative Disease Research, (ii) Stem Cells and Regenerative Biology, and (iii) Development and Aging.

Already, discoveries made by scientists in the Center have paved the way for development of a new drug (Memantine/Namenda®) for Alzheimer's that, for the first time, gets to the root of the problem, possibly preventing brain cell death, rather than merely masking symptoms caused by loss of these cells. Numerous other strategies are being developed for either protecting cells or replacing cells lost during degenerative diseases of the brain and other organs. A major thrust of recent work at the Center focuses on embryonic and adult stem cells, and efforts to lay the foundation of knowledge necessary for eventual development of cell replacement therapies for neurodegenerative diseases, stroke, heart attack, diabetes, and other ailments where cells are irrevocably lost.

NCI-designated Cancer Center

Cancer research at Sanford-Burnham aims to pre-empt cancer before it develops, detect cancer at its earliest point and eliminate cancer’s deadly spread, confining the disease as a condition treatable with surgery. Other major efforts at the Cancer Center include developing targeting technologies that deliver anti-cancer drugs specifically to the tumor -- thereby avoiding side-effects -- and technologies for tricking cancer cells into committing suicide through restoration of a natural mechanism for cell death.

The Cancer Center is an interdisciplinary effort mobilizing over 400 individuals working in a highly collaborative and interactive program structure, each of which addresses a particular aspect of cancer.

Cancer research is funded by individual grants to Sanford-Burnham scientists, and since 1981, support in the form of a cancer center grant from the National Cancer Institute as an NCI-sponsored Basic Cancer Center. The "basic cancer center" designation indicates that Sanford-Burnham's Cancer Center is focused entirely on cancer-related research rather than a combination of research and clinical management of cancer patients.