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NIDDK Strategic Plan 2000

DRAFT 01/10/00

• Message from the Director
• About the NIDDK
• Magnitude of Challenges
• About the Planning Process
• Strategic Plan

Message from the Director, NIDDK

As the new Director of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), I am pleased to present to you our Institute's first five-year Strategic Plan. The strategies outlined in this plan speak to the opportunities and challenges facing our Institute, and are the product of the NIDDK's senior scientific management team, working in collaboration with the National Advisory Council, the scientific community at large, lay and professional organizations, and the public.

All agree that much is at stake. The many diseases within the NIDDK's research mission affect millions of individuals of all ages, are often chronic in nature, may cause significant morbidity, reduce life expectancy, and exert an enormous economic burden on society--in excess of $300 billion annually.

It is our expectation that the successful implementation of our Strategic Plan will enable the NIDDK to harness the tools, technologies, and talent needed to further understand, treat, and prevent the diseases and disorders within our mission while, at the same time, help us to keep our ultimate goal in sight. That goal is to improve the quality of life for those afflicted with these diseases, their families, and society, in general.

Opportunities We See

These are exciting times. Opportunities have never been greater for scientific discovery made through basic research--and the ability to adapt and apply those discoveries to clinical settings. The overriding objective of our Strategic Plan, therefore, is to take full advantage of the opportunities at hand for the benefit of human health.

The NIDDK's Strategic Plan acknowledges and incorporates into its objectives the revolution in biomedical research that is being spurred by a wave of new and improved technologies:

• Gene discovery and genetics research are opening the way to impressive new approaches in the diagnosis, treatment and prevention of disease.
• Breakthroughs in basic cell biology are helping to unravel the complexity of living systems by identifying the impact that subtle molecular changes have on cells and tissues.
• Advances made through epidemiology and clinical investigation are making it possible to identify risk factors for the occurrence and progression of disease, which in turn is stimulating new research directions and therapeutic approaches.

Challenges We Face

At the same time that our Strategic Plan identifies opportunities, it also addresses the challenges that need to be overcome in order to achieve those objectives. Foremost among these challenges, and a theme that runs throughout the plan, is the need for improved research infrastructure and capacity, including the need to attract and retain talented researchers, recruit more volunteers to participate in the evaluation of new disease treatments, increase the number of model systems for our studies, and make data more accessible to a wider range of investigators through the use of new medical imaging and bioinformatics technologies.

Also, to enhance the mobilization and leveraging of resources to fight disease, the NIDDK is taking a leadership role in trans-NIH initiatives, and we believe that the cross-cutting scientific themes in our Strategic Plan will help to spur this effort as well. In October 1999, 26 speakers representing voluntary and professional health organizations concerned about diseases within the NIDDK's research mission endorsed and commended NIDDK for the cross-cutting scientific approach and conceptual framework of our plan.

The Course We Are Charting

In addition to our Strategic Plan, this document also includes an overview of the magnitude of the challenges posed by the diseases within the NIDDK's mission, a summary of many of the ongoing programs and mechanisms supported by the NIDDK, examples of the relevance of cross-cutting scientific research to disease, and an overview of the process that resulted in our Strategic Plan.

It is our hope that, as you read through this document, you will gain a deeper understanding of the NIDDK's structure and mission, as well as the course our Strategic Plan is helping us to chart so that we can capitalize fully and productively on this era of unprecedented scientific discovery.

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About the NIDDK

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) is the fifth largest among the institutes that the National Institutes of Health (NIH) comprise. The NIDDK conducts and supports a broad range of fundamental and clinical sciences related to programs in numerous diseases affecting the public health, including diabetes, endocrinology, and metabolic diseases; kidney, urologic and blood diseases; and digestive diseases and nutrition. The economic burden to society of these diseases is estimated to exceed $300 billion annually.

The NIDDK also maintains a strong commitment to research training and research career development, with a special emphasis on the physician-scientist, as well as our recruiting and retaining under-represented minorities and women in biomedical research careers.

Because of its broad mission, the NIDDK interacts with more than 100 voluntary health and professional organizations with a special interest in the Institute's programs.

Divisions That NIDDK Comprises

The NIDDK is composed of four scientific operating divisions and one administrative division.

The Division of Diabetes, Endocrinology, and Metabolic Diseases is responsible for extramural research and research training related to diabetes mellitus; endocrinology, including hormone and growth factors important in osteoporosis and breast and prostate disease; and metabolic diseases, including cystic fibrosis.

The Division of Digestive Diseases and Nutrition is responsible for managing research programs and research training related to liver and biliary diseases; pancreatic diseases; gastrointestinal diseases, including motility, immunology, and digestion in the gastrointestinal tract; nutrient metabolism; obesity; eating disorders; and energy regulation.

The Division of Kidney, Urologic, and Hematologic Diseases supports research and research training related to the physiology, pathophysiology, and diseases of the kidney, genitourinary tract, and the blood-forming organs to improve or develop preventive, diagnostic, and treatment methods.

The Division of Intramural Research conducts research and training within the Institute's laboratories and clinical facilities in Bethesda, Maryland, and Phoenix, Arizona. The hallmarks of the NIDDK Intramural program are excellence in scientific productivity and diversity. The research conducted by this division spans the breadth of biomedical investigation, from basic science to clinical studies.

In addition, NIDDK scientific divisions support a variety of trans-NIDDK and trans-NIH career development and training awards.

The Division of Extramural Activities, an administrative division, is responsible for issues related to grant and contract administration and review.

Cross-Cutting Programs

The NIDDK is a strong supporter of research that spans the division lines, such as studies of diabetes and obesity. The NIDDK's scientific operating divisions and programs are linked by a shared interest in the biochemical and genetic processes underlying disease. Close communication among the NIDDK, other NIH institutes, voluntary and professional organizations with an interest in the diseases within the NIDDK's research mission, and related Federal agencies help to mobilize and leverage the resources in these vital areas of scientific investigation.

Budget Allocations

The majority of the NIDDK's budget supports investigator-initiated research grants. During FY 1999, for example, the NIDDK funded 2,653 research grants; 65 research centers; 249 career and other research awards; 926 research training slots; 68 research and development contracts; and 20 intramural laboratories and branches. This type of research investment enables the Institute to maintain a high degree of budget flexibility so as to take full advantage of newly emerging scientific opportunities and apply them to the various needs of its programs and divisions.

To ensure high scientific standards among NIDDK-funded projects, all grant applications, whether initiated by a researcher or solicited by the NIH, are evaluated through a two-step peer review process, mandated by law. That is, all applications are first assessed for their scientific and technical merit by a group of non-Federal expert scientists. Applications are then reviewed for program relevance by the NIDDK National Advisory Council, comprising a group of eminent scientists and lay individuals.

In FY 1999, the NIDDK invested 70% of its $994 million budget in investigator-initiated research. About 8% of the NIDDK's FY 1999 grant budget was allocated for clinical trials that support testing of various methods of therapy and/or prevention in disease areas; approximately 4% went for Merit Awards to support the work of distinctly superior researchers identified by the NIDDK National Advisory Council; and about 8% was in program project grants for the support of broadly based, multidisciplinary research programs that have specific major objectives.

As mandated by law, 2.65% of the NIDDK's grant budget was in the Small Business Innovation Research Program, a mechanism that allows the government to enter into partnerships with small companies.

In addition to supporting research grants proposed by investigators, the NIDDK issues research solicitations in the form of Program Announcements (PAs), Requests for Applications (RFAs) and Requests for Proposals (RFPs) to stimulate scientific investigations in specific areas. These solicitations are typically issued to capitalize on compelling new research findings, and to stimulate research activities in vital areas of programmatic importance. The NIDDK also leads the development of, or participates actively in, trans-NIH research solicitations.

The NIDDK sponsors a wide range of scientific conferences and workshops, ad hoc program planning meetings, and other efforts to secure external scientific advice and public input into the development of its grant research portfolio, as well as to recruit new research talent into specific fields of study. The Institute also encourages both new and experienced investigators in related disciplines to expand their efforts to other disciplines.

The 30% of the NIDDK's FY 1999 budget that is not directed to investigator-initiated research grants was allocated as follows: 5.5% for research centers; 3.3% for research careers and other research; 3.7% for research training; 3% for research and development contracts; 10.6% for intramural research; and 2.6% for research management and support, i.e. administrative costs.

Programs to Enhance the Health of Minorities and Women

The NIDDK participates in a number of programs targeted to under-represented minorities in biomedical research. Included among these programs is the NIH Minority Supplement Program that supports minority group members from secondary schools through to new investigator status. Another program provides additional positions on training programs for minorities, principally at the postdoctoral level.

The Institute also awards "re-entry" supplements to research grants to support women who have completed their research training but have had to leave research for a period of time, generally because of family obligations.

With respect to minority health issues, the NIDDK and the Office of Research on Minority Health have developed an effective and synergistic partnership over the last few years. By working together, we have established several major collaborations that assist minority researchers and benefit research on diseases and disorders within our mission that disproportionately affect minority populations. We also are working on concepts to enhance clinical research in minority populations and at minority research institutions.

In addition, the research programs of the NIDDK are dedicated to studying chronic diseases of direct relevance to women's health and also has a strong and synergistic partnership with the Office of Research on Women's Health. The NIDDK is committed to closing the gaps in understanding disease processes that pose a special problem for women and to developing effective preventive and therapeutic measures in these disease areas.

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Magnitude of the Challenges Facing the NIDDK

The diseases within the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK's) research mission cut across the entire range of internal medicine and related areas of medical practice, and are models of the complex interaction of genetic, autoimmune, neuroendocrine, metabolic, and other mechanisms of disease. Collectively, these diseases affect virtually every part of the body, from the level of the cell, to organ systems, to the interactions of the human body as a whole. They all seriously diminish the quality of life of those afflicted, their families, and loved ones. In addition, the health care costs of the diseases represented in NIDDK-supported research are significantly large segments of the total national burden of disease, estimated at $1 trillion a year by HCFA.

Documented statistics show, for example, that more than half of the entire U.S. population is affected by one or more of the diseases within the NIDDK's research mission, and, according to the Health Care Financing Administration (HCFA), these diseases consume up to 30% of the nation's health care costs paid by Medicare.

These numbers are staggering in terms of human life diminished or lost and dollars spent. However, even these numbers may not reflect the true impact of these diseases. For example, the death of a diabetic patient with cardiovascular disease is traditionally recorded as a cardiovascular death, even though diabetes may have been the root cause of the individual's cardiovascular condition and resultant death.

The magnitude of the challenges facing the NIDDK is demonstrated by the following disease areas for which there are documented statistics. Keep in mind that the information below does not take into account the hundreds of conditions related to these major disease areas for which no reliable data are available.

Endocrine and Metabolic Diseases

Most common among these types of diseases are diabetes and obesity. Both type 2 diabetes and obesity, for example, involve resistance to insulin action, which results in an increase in blood lipids (especially low density lipoprotein and triglycerides) leading to atherosclerosis, as well as certain defects in cellular signaling. Kidney disease of diabetes (KDDM), a chronic and disabling complication of diabetes, is the most common cause of end-stage renal disease and a perfect example of how certain diseases span the mission of the NIDDK. Osteoporosis (a condition that results in loss of bone density) is a severe problem for post-menopausal women while benign prostatic hypertrophy, more commonly referred to as enlargement of the prostate, affects a high percentage of men older than 60.

Diabetes

• Affects 16 million people in the U.S.
• 800,000 new cases each year.
• Leading cause of new blindness, end-stage renal disease, and non-traumatic leg amputations.
• Major risk factor for heart disease, stroke, and birth defects.
• Leading cause of death in people with diabetes is coronary heart disease.
• Leads to higher death rates from pneumonia, influenza, and many other illnesses.
• Affects all segments of the population, but manifests highest incidence in non-Hispanic African Americans, Mexican Americans, other Latin Americans, Native Americans and Alaskan Natives, as well as in Asian Americans and Pacific Islanders.
• Cost to nation: More than $98 billion annually, including direct and indirect costs (i.e. disability, work loss, and premature death).
• Shortens average life expectancy by up to 15 years.

Obesity

• Affects 60 million people in the U.S. (25% of all women; 20% of all men; 37% of all minority women).
• Associated with greatly increased risk of complications similar to those in type 2 diabetes, including cardiovascular problems, higher levels of harmful lipids in the blood, and increased mortality, as well as other complications more specific to obesity such as hypertension; certain cancers; arthritis in the hips, lower back and legs; gout; and gallbladder disease.
• Increasing in prevalence among children.
• Cost to nation: More than $99 billion annually in both direct and indirect costs.

Kidney Disease of Diabetes (KDDM)

• Most common cause of end-stage renal disease (ESRD).
• Each year, more than 50,000 people are diagnosed with ESRD caused by KDDM.
• ESRD, like diabetes and obesity, is most prevalent in African Americans and Native Americans.
• High blood pressure, as well as high blood sugar levels increase the risk that a person with diabetes will progress to ESRD.
• Each year, nearly 200,000 Americans undergo dialysis while more than 12,000 receive kidney transplants.
• Cost to the nation: More than $15.64 billion annually, more than $10 billion of which comes in the form of Medicare expenditures.

Osteoporosis

• Severe problem for post-menopausal women and older men.
• Responsible for more than 15 million fractures annually, including hip, vertebrae, and wrist fractures.
• These fractures are a major cause of disability, hospitalization, and loss of independence, especially for people over the age of 50.
• Cost to the nation: Direct costs of medical care alone are about $13 billion annually.

Benign Prostatic Hypertrophy (BPH)

• More than half of all men in their sixties, and as many as 90% in their seventies and eighties, have symptoms of BPH, commonly known as enlargement of the prostate gland.
• Can lead to incontinence, infections, stones, and kidney damage.
• BPH results in about 375,000 hospital stays each year.
• Although there is no evidence that BPH itself increases the chances of getting prostate cancer, approximately 30,000 of the 120,000 men each year diagnosed with prostate cancer die of the disease.

Autoimmune Diseases

An important class of illness is autoimmune diseases, in which antibodies develop against one's own tissues and harm the affected organ system. There are many autoimmune diseases for which the NIDDK has research responsibility. These include: type 1 diabetes; autoimmune thyroiditis; hyperthyroidism; other autoimmune endocrine syndromes (including primary adrenocortical insufficiency); autoimmune hepatitis; primary biliary cirrhosis; primary sclerosing cholangitis; chronic gastritis; inflammatory bowel disease; glomerulonephritis; lupus nephritis; and aplastic and hemolytic anemias.

What follows are documented statistics on two of the more prevalent autoimmune diseases within the NIDDK research mission:

Type 1 Diabetes

• Involves a genetic predisposition and usually begins in childhood.
• Gradually destroys the pancreatic insulin-secreting cells (beta cells), which leads to life-long dependence on insulin to survive.
• Affects approximately 750,000 to one million Americans, or 5% to 10% of the 10.3 million people with diagnosed diabetes.
• Complications as a result of type 1 diabetes are essentially the same as described earlier.

Inflammatory Bowel Disease

• Affects approximately 500,000 Americans each year.
• Results in more than 100,000 doctor visits annually, most of which (two-thirds) are related to Crohn's Disease, a disorder affecting primarily the small intestines.

Genetic Diseases

Diabetes and obesity, discussed above, are now being studied for causative genes along with a host of other disorders, including several hundred disorders resulting from inborn errors of metabolism. Now that genes are being identified in many conditions not traditionally thought of as genetic, the phrase "genetic diseases" has evolved into a much broader definition than just "inherited diseases" present from birth. We know, for example, genetic mutations can cause diseases often precipitated by environmental triggers. While exacting a heavy toll on those affected, the overwhelming majority of these genetic disorders are not common enough to have extensive statistics on their burden of illness. Cystic fibrosis and polycystic kidney disease (PKD), however, are exceptions.

Cystic Fibrosis (CF)

• One of the most prevalent and tragic genetic diseases of the young. Approximately 1,000 new cases are diagnosed each year, usually before 3 years of age.
• Characterized by changes in the functioning of many exocrine organs as well as excessive production of thick, sticky mucus in the airways.
• Major gene associated with CF was found in 1989, with subsequent discovery of protein it produces.
• An individual must inherit two copies of the defective gene--one from each parent--to acquire the disease. An estimated 8 million people carry a single copy of the defective gene.
• With improved treatment, CF no longer means death in early childhood; as a chronic disease, it allows patients to live into their 30s or 40s.
• Most adult CF patients eventually succumb to lung infections and respiratory failure.

Polycystic Kidney Disease (PKD)

• Genetic-based disease that results in the development of numerous cysts in the kidney, liver, and other organs.
• Cysts slowly replace much of the kidney, thereby reducing kidney function, often leading to kidney failure.
• Causes infections, hematuria, stones, high blood pressure, and other problems.
• Affects 500,000 Americans and is the fourth leading cause of kidney failure.

Chronic Infections and Inflammatory Diseases

Viral and bacterial infections not treated or eliminated in the acute stage go on to produce chronic diseases, such as hepatitis, nephritis, gastritis (and non-ulcer dyspepsia), pancreatitis, and others. The impact of such conditions on health and human suffering is sizeable.

Hepatitis C (HCV)

• The most common blood-borne infection in the U.S. and a major cause of end-stage liver disease.
• An estimated 4 million Americans are infected with HCV, although most do not know they carry the virus.
• 85% of those infected become chronic carriers; about 20% develop cirrhosis, some of whom develop liver cancer.
• Leading cause of liver transplants.
• Causes 8,000 to 10,000 deaths annually. The number is expected to triple in the next 10 to 20 years.
• Cost to the nation: Approximately $6 billion annually.

Liver Disease

• Chronic liver disease and cirrhosis affect about 400,000 people annually.
• Each year, chronic liver failure results in an estimated 1 million doctor visits, 300,000 hospitalizations, more than 100,000 newly disabled people, approximately 3,300 liver transplants and 26,000 deaths.

Food-borne Illnesses and Chronic Infectious Diarrheas

• Nearly 100 million new cases diagnosed each year resulting in several thousand deaths annually.
• Hemolytic uremic syndrome is a particularly serious form of chronic infection in which a bacterial invader (Eschericia coli O157:H7) may cause destruction of red blood cells, resulting in kidney damage.

Peptic Ulcers

• Approximately 5 million new cases diagnosed annually.
• Lead to 3 to 5 million doctor visits and nearly 650,000 hospitalizations each year.
• Bacterial infections (by Helicobacter pylori) appear to cause at least 2.5 million cases annually.

Common Disorders with Multiple Causes

Kidney Stones in Adults

• Most common disorder of the urinary tract. It is estimated that 10% of all people in the U.S. (men more than women) will form a kidney stone at some point in their lives.
• Occurrences have increased over the last two decades.
• Commonly caused by excess calcium excreted in the urine, but also are due to kidney infections, as well as to inherited metabolic abnormalities.
• Result in an estimated 900,000 doctor visits and more than 300,000 hospitalizations annually.
• Cost to the nation: Approximately $1.9 billion annually.

Gallstones

• Affect 1 in 10 Americans (women more than men) and are associated with about 3,000 deaths each year.
• Stones large enough to cause pain require 600,000 hospitalizations and more than 500,000 operations annually.
• Obesity is a strong risk factor for gallstone formation.
• Diets associated with rapid loss of excessive weight also increase the risk of gallstones.

Gastroesophageal Reflux Disease (GERD)

• Affects more than 60 million American adults at least once a month; about 25 million adults suffer daily, as do 25% of pregnant women.
• Major symptoms include heartburn and acid indigestion.

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About the NIDDK Planning Process

The National Institute of Diabetes and Digestive and Kidney Diseases' (NIDDK's) Strategic Plan, as part of the NIH response to recommendations of the Institute of Medicine Study on NIH priority-setting and public input, represents an effort on the part of the NIDDK to identify and address the global challenges and opportunities it faces in the next five years with respect to its research mission. The overall objective of the Plan is to create an environment and strategy within the NIDDK to support and enhance scientific and clinical research leading to scientific advances. The ultimate objective, of course, is to improve the quality of life for those affected by disease, their families, and society, in general.

The strategies outlined in this plan are not the product of the Institute acting on its own. Rather, they reflect input to the NIDDK, working in close collaboration with its National Advisory Council, the scientific community at large, and lay and professional organizations with an interest in the disease areas for which the Institute has research responsibilities.

By design, the NIDDK's Strategic Plan is not a budget or advocacy document. Nor is it disease specific. Instead, the Plan's scientific orientation targets the most promising research the Institute believes is achievable within a five-year time frame, and focuses on long-term, trans-NIDDK and trans-NIH, cross-cutting scientific themes. These themes include: genes and their impact on disease; cell biology; prevention and treatment of disease; and research infrastructure.

The strategies built around the goals and objectives identified through these cross-cutting scientific themes are broadly relevant to a wide range of diseases within the NIDDK research mission.

Scientific Working Groups

The NIDDK's Strategic Plan was developed through a series of scientific working groups, one group for each of the Strategic Plan's four themes (see above). Each working group consisted of 12 or more participants, an NIDDK writing chair, at least one intramural scientist, one lay person, and at least one member from our National Advisory Council. The NIDDK Senior Management served as the writing chairs and helped to cross-fertilize ideas among the working groups.

Working groups were responsible for identifying and emphasizing the common themes, scientific opportunities, and research challenges across the programs and divisions of the NIDDK.

Some key features of the planning process that working groups needed to take into consideration included procuring public involvement and input, and making the Plan understandable to lay audiences so as to foster wide distribution.

A Strategy Built Upon the NIDDK's Annual Program Plan

The cross-cutting themes of the NIDDK's Strategic Plan are designed to help the Institute set a scientific vision to aid in its development of specific initiatives on an annual basis. As such, the Strategic Plan complements and builds upon already existing planning processes within the NIDDK's operating divisions and the Institute as a whole. Insight into the NIDDK's annual program planning process, therefore, will provide a greater understanding of the Institute's five-year Strategic Plan.

The NIDDK Program Plan

Taking into consideration available resources, the NIDDK's annual program planning process helps guide the development and implementation of specific research initiatives for each upcoming fiscal year. It sets a framework for future program activities, as well as for facilitating the efforts of the NIDDK's scientific and lay constituents. Each year, this process culminates in the presentation to, and discussion by, the NIDDK Advisory Council of a planning document called the "NIDDK Program Plan."

The NIDDK Program Plan contains two major components, which are presented to the Advisory Council at different times of the year. The first component is the Research Progress Reviews. These reviews provide examples of recent major areas of scientific accomplishments within the NIDDK research mission and are presented to Council in February.

The second part of the NIDDK Program Plan is the Program Initiative Concepts component, which is basically a "wish list" put forth by the NIDDK's three extramural scientific operating divisions. This component of the Program Plan contains scientific initiative concepts the divisions would like to see implemented if funding is made available. Each concept is based on recommendations of the research community, and the NIDDK advisory groups, or directives from the U.S. Congress and/or the Administration. This component also provides a summary overview of the NIDDK's major ongoing initiatives and is presented to the full NIDDK Advisory Council each September.

Initiatives proposed in the NIDDK Program Plan:

• Build on past accomplishments;
• Reflect emerging scientific needs and opportunities;
• Are responsive to the changing fiscal environment and new Congressional and Administration directives; and
• Are consistent with the NIDDK's commitment to investigator-initiated research.

The Program Plan is actually a compilation of the separate annual planning processes of the NIDDK's three extramural scientific divisions and reflects an effort on the part of each division to identify the best scientific opportunities to pursue.

Annual Planning Process of the NIDDK's Extramural Scientific Operating Divisions

Each of the three extramural divisions employs a range of planning mechanisms, starting at the programmatic staff level.

Program staff assess the state-of-the-science in their respective areas by attending and convening scientific meetings, reviewing their grant portfolios and published literature, and through discussions with grantees and other individuals and organizations within the scientific community.

For example, when areas of scientific opportunities are identified by both the NIDDK and the extramural communities, they are prioritized through discussions held with program staff and their respective division directors. Preliminary program initiatives are then discussed with the division's sub-council of the Institute's National Advisory Council.

Divisions also seek participation from leading professional societies and lay organizations that have an interest in the areas of the division's research portfolio. Input is also solicited from experts in specific areas through specially created ad hoc advisory groups. Workshops are another venue through which the NIDDK extramural divisions seek input into their planning activities. Divisions do not undertake major initiatives without first seeking input and advice from these groups.

Benefits of the NIDDK's Planning Process

In addition to being a requirement of the NIH and an expectation on the part of the U.S. Congress, the NIDDK program planning process:

• Enables the Institute to reply accurately to frequent public and Federal inquiries regarding its programs, i.e. the state of the science in a particular field; examples of recent scientific progress; perceived research needs and opportunities; resource needs and allocations; and the Institute's approaches for meeting its responsibilities.
• Serves as a means to aid Institute staff members in keeping abreast of developments in their areas of responsibility. It is through this expertise that management responsibilities are coordinated.
• Permits the Institute to be in a position to act in a timely manner to implement a given program or to stimulate work in a certain special-emphasis area should the need or opportunity arise and the funds be made available for that purpose.
• Provides material to justify the value of existing scientific activities and to be able to identify compelling scientific needs and opportunities that warrant the allocation of additional resources.

Strengthening the NIDDK's Planning Process

The NIDDK's program planning process is continuously evolving and, as stated previously, is predicated on wide-ranging and continuous collaboration between the NIDDK and non-Federal scientists and other advisors, including the Institute's National Advisory Council and sub-councils, as well as ad hoc advisory groups to the NIDDK operating divisions, NIDDK-sponsored workshops and conferences.

Since 1997, the NIDDK has solicited wider input from the Advisory Council and the broader scientific community in an effort to strengthen its program planning process. Each of the NIDDK extramural operating divisions, for example, is now interacting more fully with its respective communities through a variety of means, ranging from ad hoc meetings to conference calls.

As a result of the interaction and feedback received from the Advisory Council and other external advisors, the approach to the Program Initiative Concepts portion of the Program Plan document has been changed.

Changes already introduced to strengthen the Program Initiative Concepts document include:

• Greater linkage between the Program Initiative Concepts and ongoing initiatives within the NIDDK research portfolio.
• Greater emphasis on the scientific rationale for Concepts and less emphasis on the "instrument" or mechanism through which the scientific need and/or opportunity may be pursued or implemented.
• Linking Concepts to the NIH Director's Areas of Emphasis

In future planning processes linkages will be made between Annual Program Initiative Concepts and the cross-cutting themes of the NIDDK Strategic Plan.

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The National Institute of Diabetes and Digestive and Kidney Diseases' Strategic Plan

The National Institute of Diabetes and Digestive and Kidney Diseases' (NIDDK) Strategic Plan addresses the global challenges and opportunities facing the NIDDK, and outlines research directions within the Institute's mission that be should pursued over the next five years. The Plan represents a collaborative effort, with input coming from NIDDK's senior scientific management working with the National Advisory Council, the scientific community at large, lay and professional organizations, and the public.

During 1999, NIDDK senior management held multiple Working Group meetings, had discussions with Working Group members, analyzed the existing NIDDK research portfolio, solicited comments from lay and professional organizations, and heard public comment. During the development of the Plan, Working Groups interacted closely with one another to cross-fertilize ideas among themselves. They also evaluated current state-of-the-art science in an effort to develop a comprehensive and scientifically achievable plan.

Working Groups were responsible for identifying and emphasizing the common, scientific, cross-cutting themes, scientific opportunities, and research gaps and challenges across the programs and divisions of the NIDDK. In order to adequately reflect the compelling scientific opportunities and public health needs identified through this deliberative process, the Plan has been divided into the following four sections or themes:

• Genes and Disease
• From the Cell to the Organism: Unraveling the Complexity of Living Systems
• Prevention and Treatment of Disease: Epidemiology and Clinical Investigation
• Research Infrastructure

These themes were presented to and broadly endorsed by the NIDDK's National Advisory Council, the NIDDK research community and the many lay and professional organizations with an interest in the research conducted and supported by the NIDDK.

In the sections that follow, each Working Group presents background information related to its respective theme, and sets forth a series of objectives; insights related to those objectives; and a series of implementation strategies for achieving those objectives.

Working groups made every effort to articulate their portion of the Plan in non-technical language that would be understandable to a broad public audience. However, given the intensely science-oriented nature of the research conducted and supported by the Institute, the Plan does contain some scientific terminology. Therefore, a glossary of scientific terms and acronyms has been appended.

A summary of the broad and overarching goals, objectives and strategies of the Institute over the next five years is as follows:

• To promote the health of the American public through scientifically meritorious basic and clinical biomedical and behavioral efforts and related programs.

• To develop a sound base of fundamental science on which future clinical research advances can be built.

• To understand the natural history and processes of diseases and disorders within the NIDDK mission.

• To gain insight into, and develop more effective treatment and prevention strategies for, diseases and disorders that disproportionally affect ethnic groups and other special populations, such as women and children, so that these health disparities can be reduced or eliminated.

• To develop effective treatments for the diseases and disorders within the NIDDK mission and strategies for preventing or delaying their onset.

• To develop effective means of preventing, delaying or ameliorating the complications of the diseases and disorders within the NIDDK mission.

• To develop and apply technologies, innovative research techniques and methods from which will flow future basic and clinical research advances and improvements in the health of all Americans.

• To facilitate the continuation of an adequate cadre of basic and clinical biomedical research investigators through the recruitment and retention of talented individuals to research training and research career development programs, with special attention to minority recruitment and retention programs.

• To promote dissemination and application of research results emanating from the NIDDK basic and clinical research studies, through outreach programs, education programs, and other means, in ways that are culturally appropriate and meaningful to target audiences.

 

GENES AND DISEASE

Overall Goal: To strengthen our understanding of the role of genes in disease in order to improve prevention and treatment, and ultimately to cure the diseases for which NIDDK has research responsibility.

BACKGROUND

Opportunities and Challenges

Why Emphasize Genes?

Over the next 5 years, NIDDK's mission--to improve understanding and ultimately to find better ways to prevent, treat and cure diseases in its areas of responsibility--will be achieved in part through intensified study of genes and disease. A major driving force behind the dramatic scientific opportunities of the next decade, therefore, will be the information emerging from the Human Genome Project. Even now, scientists regularly discuss the imminent arrival of the "post-genomic era," recognizing that within 2 or 3 years, as the sequence of the entire human genome becomes known, we will face great opportunities and new challenges.

These opportunities and challenges include:

Determining How Gene Defects Relate to Inherited Diseases

Many diseases "run in families," and every physician knows that family history tells much about the risk of disease. Understanding how diseases are inherited and identifying the specific gene or genes that confer susceptibility are critical to understanding the diseases and, ultimately, improving prevention and treatment.

Some familial diseases have the relatively simple and predictable patterns of Mendelian inheritance, named after Gregor Mendel, the Austrian monk who first described them. We also call these diseases monogenic, reflecting the fact that, by and large, they are caused by a defect in a single gene.

The last decade has seen breathtaking progress in identifying underlying defects in monogenic diseases. In virtually every case, identification of the genetic defect has intensified research of the disorder and increased understanding of the mechanisms of disease. These cascading events are spawning new diagnostic tests, earlier diagnosis and, in many cases, new therapeutic strategies.

Some familial diseases are quite rare, and sometimes the identified genetic defects are responsible for only a small portion of cases. But the known defects provide important clues for all cases. With the availability of the complete sequence of the human genome, identifying the genes responsible for monogenic disorders will become faster and easier.

A second category of familial diseases are polygenic, also sometimes called "complex traits." Many serious and very common diseases run in families, but the inheritance pattern suggests that they result from interactions of several genes, not from a single defect.

Compared to monogenic diseases, identifying defective genes in polygenic disorders has proven much more difficult. Genes involved in a few polygenic disorders have been identified, but by-and-large, this is an area of research that is just beginning. The complete sequence of the human genome will permit new approaches to understanding polygenic diseases.

Understanding Gene Function

After identifying a faulty gene, the next--and absolutely critical--step is to understand the gene function, that is, how the gene works and how defects in it lead to disease. Modern methods have revolutionized the process of studying gene function, and investigators have clarified how mutations disturb the function of many disease genes. Nevertheless, enormous scientific hurdles remain. Strategies to strengthen studies of gene function are also a major focus of all parts of this Strategic Plan.

Determining How Environments Affect Genes

Inheriting a specific gene, alone, does not necessarily mean an individual will develop a disease. In fact, most chronic diseases result from interactions among genes, life-style, and environment. Thus, diet, exercise, stress, and many other environmental factors influence whether an individual gets a disease and how severe it will be. But, because genes determine how we respond to diet, environmental toxins, drugs, and stresses of daily life, what we learn about genes may also help us deal with these other factors.

Understanding the interplay of these factors--and how people vary in their responses--may teach us how to promote health better and, potentially, predict who will be vulnerable to drug side-effects and who will benefit from diet and other life-style changes.

Understanding How Modifying Genes Affects Disease

Genes do not act alone. Even the "same" genetic disease can manifest itself differently. For example, some very young children with cystic fibrosis have a massively debilitating disease, while others--even those with the same mutation--may be relatively free of symptoms until late adolescence or early adulthood. Similarly, polycystic kidney disease may result in early kidney failure in one family member and no apparent kidney problems in another family member. This variability suggests that the product of other genes may alter the function of the primary disease gene; in some instances, for example, one gene product may be able to substitute for another. Knowing more about these modifying genes and how they effect disease has enormous promise as a way to identify new approaches to therapy.

Understanding How Genes Determine the Development of Cells and Organs

By identifying and understanding genes that control the formation of healthy specialized cells and organs, we may better understand what errors lead to disease. Disease processes, even late in life, often cause reactivation of genetic programs that participated in early development and organ formation. Genes determine which cells have the potential to continue to divide and allow regeneration of organs. We will be better able to harness the body's capacity to regenerate and heal when we better understand normal development.

Focusing on Strategies to Exploit Genomic Information

Understanding genes, their function, their role in disease and tissue injury, exploiting information about genes to find new diagnostic methods and new therapies are themes that recur in all parts of the NIDDK's Strategic Planning Processes. The focus of this crosscutting theme--Genes and Disease--focuses particularly on the approaches to inherited diseases and on strategies to exploit genomic information to yield critical understanding.

OBJECTIVES

Because genes are important for all aspects of the NIDDK's investigative portfolio, the Working Group on Genes and Disease emphasized genetic diseases and genetic investigation, as well as approaches to disease that rely on systematic application of genomic information.

In formulating the following objectives, the Working Group chose priority areas that cut across the Institute's disease interest areas. These objectives are not intended to be all inclusive, and it is recognized that many important and relevant research projects will fall outside these priority areas.

A. INHERITED DISEASES

A1. OBJECTIVE: Identify the genetic loci and the underlying genes that are responsible for the principal diseases in the NIDDK portfolio, which show familial patterns of susceptibility, both monogenic and polygenic.

INSIGHT: The last decade has seen breathtaking progress in the understanding of monogenic disorders. Many of the diseases caused by a mutation at a single genetic locus are now characterized at a molecular level. Progress in understanding the complex (or polygenic) diseases has been much slower, and will be a key challenge for the next decade.

A2. OBJECTIVE: Identify genetic loci that explain the variable clinical presentation of certain key monogenic diseases and begin to clarify how the interaction of several genetic loci can produce polygenic diseases.

INSIGHT: As discussed previously, a number of genetic diseases are highly variable in their presentation. Environmental factors may explain part of this variability. However, work in animal models, particularly mouse models, has established that secondary modifying genes can alter the expression of a disease gene or substitute for its function. In polygenic disorders the interaction of two disease loci may operate in a similar fashion to that between the primary gene which causes a monogenic disorder and a modifying locus. Identification of such modifying genes, both in animal models and in human disease, is a valuable approach to finding new therapeutic approaches to diseases and understanding gene interactions.

A3. OBJECTIVE: Improve the precision with which we can characterize the clinical phenotype of the key diseases in our portfolio, with the goal of identification of genetically homogenous sub-groups.

INSIGHT: Many of the important complex disorders in areas of NIDDK interest are extremely heterogenous. Current classification schemes and diagnostic categories often do not adequately address this heterogeneity. Systematic collection of patient information and a new generation of clinical tools--including new molecular methods--may in some cases lead to recognition of homogeneous sub-groups, sharing genetic predeterminants. This more precise characterization is expected to speed genetic investigation.

The informed physician-scientist will be critical for this process. The Genes and Disease Working Group emphasized the important role of strengthening clinical investigation for the new scientific opportunities.

A4. OBJECTIVE: For certain key diseases of concern to NIDDK, clarify the extent of familial aggregation.

INSIGHT: For a number of important diseases the extent of familial aggregation is still unclear. Careful studies to establish the relative risk to family members of patients with these disorders is an important step in determining whether or not genetic approaches will be helpful.

A5. OBJECTIVE: Identify the genetic differences that contribute to population differences in susceptibility to disease.

INSIGHT: In many cases, the disproportionate burden of disease experienced by ethnic or racial sub-groups in the population can be explained by genetic differences. These differences may ultimately identify therapies of special efficacy in such sub-groups.

A6. OBJECTIVE: Understand the genetic basis of variable responses to important categories of therapeutic drugs, including genes that result in susceptibility to drug toxicity.

INSIGHT: Some therapies are very effective for some individuals and are virtually totally ineffective for others. The ultimate goal of tailoring the right therapy to each patient will be fostered by intensified study of the role of genetic variability in determining the response to therapeutic drugs and the vulnerability to drug toxicity.

B. GENE PROFILES ALTERED BY DISEASE

B1. OBJECTIVE: Establish for selected major diseases in the Institute's portfolio the patterns of altered gene expression in important target tissues.

INSIGHT: Part of the study of genes and disease needs to include defining the effects of key diseases on the pattern of genes expressed in damaged tissues. Gene expression profiles have special promise for a number of reasons. They are likely to: assist in identification of new therapeutic targets; define candidate genes for studies of complex traits; and provide new tools for diagnosis and management. (NOTE: These methods are discussed further in the following section on strategies to meet our objectives.)

B2. OBJECTIVE: Exploit the potential of gene profiling and other molecular methods to improve methods for disease identification, classification, and determination of prognosis.

INSIGHT: Currently, most diagnostic methods use radiographic tests, biochemical methods or microscopic study of pathological tissue. The methods of molecular biology and new understanding of the role of genes in disease are, however, opening up a range of new diagnostic methods. It will be important to ensure that the potential of these new methods is fully exploited for diseases within the NIDDK mission.

C. GENE PATHWAYS IN ORGAN DEVELOPMENT

C1. OBJECTIVE: Identify the genetic pathways critical for the formation of organs in the NIDDK areas of research responsibility, and understand how these genes work to dictate cell lineage specification.

INSIGHT: Developmental pathways are often reactivated by tissue injury, and regeneration and healing may use the same genes that are active when an organ forms. Strengthening Institute programs in organogenesis, with particular focus on understanding gene pathways that dictate cell lineage, is considered an important objective for ultimately harnessing the potential of these pathways.

C2. OBJECTIVE: Use knowledge of these gene pathways to develop strategies to facilitate healing and regenerative processes and the maintenance and differentiation of stem cell populations.

INSIGHT: Practical implications of intensified study of developmental biology include new strategies for cell and tissue engineering, as well as potential identification of new target molecules for therapeutic intervention.

D. GENE FUNCTION AND REGULATION

D1. OBJECTIVE: Foster investigation that will clarify molecular function of key disease genes.

INSIGHT: A number of the objectives developed in this chapter focus on the identification of disease genes. It is important to reiterate that identification of a disease-causing gene is just a beginning that needs to be followed by intensified study of disease mechanism. (NOTE: Subsequent sections in this Strategic Plan include discussion of functional studies of genes at the cell and organ levels, and studies of how genes participate in the injury process.)

D2. OBJECTIVE: Foster investigation that will clarify fundamental mechanisms of gene regulation by hormonal, dietary and environmental variables.

INSIGHT: Study of regulation of gene expression is a key area of strength in our investigative portfolio. Elaborate networks of interacting proteins, the complexity of which is just beginning to be understood, regulate gene expression in the cell nucleus. Many new scientific opportunities exist to untangle these regulatory mechanisms. Intensified study of the regulation of gene expression is anticipated to yield new understanding and ultimately to identify new therapies.

IMPLEMENTATION STRATEGIES

Progress toward each of the objectives defined above will most likely result from the collective achievement of a number of individual investigative teams supported by the NIDDK's scientific research portfolio that consists of investigator-initiated grants. The strategy of funding such grants and making them the core of the Institute's scientific research portfolio has been highly successful in the past and should continue.

However, in the process of developing its portion of the NIDDK's Strategic Plan, the Working Group on Genes and Disease identified a number of barriers that can limit the capacity of the individual investigator to make progress toward these objectives.

The proposed implementation strategies that follow recognize these barriers. Subsequently, a number of the strategies recommend investment in the development of research resources and research tools that will enhance the ability of the individual investigator-led teams to achieve their objectives.

(NOTE: Discussion of implementation strategies did not attempt to determine the best mechanism for the NIDDK to encourage each type of effort. It was recognized that in some instances specific and targeted research solicitations would be appropriate, and in others educational efforts such as workshops might be the most effective response.)

A. STRATEGIES TO STRENGTHEN GENETIC STUDIES

The Working Group on Genes and Disease felt the process of identifying the genetic defects responsible for monogenic disorders has substantial momentum and current strategies were viewed as having a track record of success. Vigorous continued support for such efforts was enthusiastically recommended.

The Working Group also identified a number of barriers to identification of the genes responsible for polygenic or complex traits, the most notable being the major scientific difficulty of the undertaking. Investigators studying polygenic disorders uniformly face resource limitations, particularly because of the need for large cohorts of patients, and the costs and difficulty of good clinical phenotype characterization.

Because of the substantial difficulty and costs of studying polygenic disorders, the Working Group strongly advised that efforts in this area need to be carefully targeted. Priority setting should weigh the public health burden of the disease in question, the extent to which familial aggregation is clear-cut, and the likelihood of identification of functionally important genetic pathways.

Implementation strategies to strengthen genetic studies are as follows:

A1. STRATEGY: Facilitate the development of cooperative consortia in order to permit large-scale genetic studies, particularly for polygenic disorders. Create innovative models for cooperative consortia, in which the advantages of cooperation are secured, but innovative approaches, particularly for phenotype characterization, are not discouraged.

A2. STRATEGY: Exploit fully homogeneous populations and patient sub-groups with monogenic inheritance patterns to reduce genetic complexity.

A3. STRATEGY: Develop methods to strengthen patient recruitment into genetic studies and to improve public awareness of the potential benefits of genetic research.

A4. STRATEGY: Encourage development of innovative analytic strategies for genetic studies.

A5. STRATEGY: Generate clear expectations for patient data and DNA sharing in all NIH-funded genetic studies.

A6. STRATEGY: Encourage research that will improve the precision of phenotypic characterization with the goal of identification of genetically homogenous sub-groups. Strengthen population-based studies of certain key NIDDK diseases to improve definition of natural history and its variability.

B. STRATEGIES FOR SYSTEMATIC ASSESSMENT OF GENETIC INFORMATION

One important strategy to exploit information emerging from the Human Genome Project is to undertake systematic studies of patterns of gene expression. The rapidly evolving technology for gene profiling currently permits assessment of the expression profiles for large numbers of genes in cultured cells and organs, and it may soon be feasible to assess gene expression at the level of a single cell or a few cells. Also under development are methods to assess gene expression systematically at the protein level.

The techniques show substantial promise to open unexplored and unanticipated avenues for research. Applied to diseased tissue, gene expression profiles can identify candidate genes for genetic studies and target molecules for therapeutic intervention. Applied to sequences for which the gene function is still unknown, these methods can identify important new genes and provide important clues to gene function. Used to study gene transcription, the methods can establish groups of genes that show coordinate regulation.

The Working Group on Genes and Disease considered it important to encourage promising applications of these methods and to make the information from these techniques broadly available.

Implementation strategies for systematic assessment of genetic information are as follows:

B1. STRATEGY: Use systematic studies of gene expression in diseased human tissue from patients with polygenic disorders to identify candidate loci.

B2. STRATEGY: Use systematic studies of gene expression to characterize stem cell populations and cell lineage specification.

B3. STRATEGY: Characterize animal models of disease and determine the extent to which gene profiles mimic human disease.

B4. STRATEGY: Ensure--in cooperation with trans-NIH efforts--investment in technology development for systematic gene expression studies.

B5. STRATEGY: Ensure ready availability of methods and reagents to NIDDK investigative communities.

C. STRATEGIES FOR DEVELOPING GENETIC MODELS TO STUDY DISEASE

Deciphering the human genome will require a wide range of biological models and systems, and matching the scientific question to the right model will be of critical importance. Good choice of animal models and other model systems can have substantial impact on the rate of progress in studying disease.

Many fundamental biological processes show extensive evolutionary conservation, and there are a number of striking examples where findings from simpler organisms, such a C. elegans, fruit fly, yeast and zebrafish, have yielded immediately relevant insights into human disease.

The mouse is emerging as a model for human disease of particular importance, in part because it is the mammalian model in which both genetic studies and genome manipulation are most advanced.

Implementation strategies strengthen studies of genes and disease in animal models are as follows:

C1. STRATEGY: Encourage the development of animal models that more faithfully replicate human disease processes.

C2. STRATEGY: Use systematic gene expression profiling to establish relevance of animal models to human disease.

C3. STRATEGY: Encourage the exploitation of a wider range of model organisms.

C4. STRATEGY: Participate in the development of genomic and genetic tools for model organisms of particular promise for the NIDDK areas of science.

C5. STRATEGY: Develop shared molecular tools and reagents for model organisms important for study of the genetics of disease.

D. STRATEGIES FOR THE EFFECTIVE USE OF INFORMATION TOOLS

It is widely recognized that the provision of certain kinds of easily accessible, searchable information is dramatically changing the process of science. The Working Group on Genes and Disease felt that informatics needed for each investigative community varied substantially, and that activities in this area needed to be carefully tailored to scientific need, and well-coordinated with other trans-NIH efforts.

Implementation strategies for the effective use of information tools are as follows:

D1. STRATEGY: Develop programs to improve availability of organ-specific annotated sequence information.

D2. STRATEGY: Develop appropriate informatics tools and databases for study of the genetic basis of disease.

D3. STRATEGY: Ensure that investigative communities have access to training in the use of informatics tools.

FROM THE CELL TO THE ORGANISM: UNRAVELING THE COMPLEXITY OF LIVING SYSTEMS

Overall Goal: To understand the internal workings of each cell type in isolation, how cells function in the communities that make up tissues and organs, and how cell function is integrated in the intact human body so as to better prevent, treat and cure diseases.

BACKGROUND

The Importance of Studying Cells

To repair and maintain a car a mechanic must understand the function of each part of the vehicle, how each part connects to form a system such as the engine, brakes or steering, and how these systems work together to allow the car to operate. Similarly to prevent, treat and cure disease, we must understand the make-up, function and interactions of living cells, tissues and organ systems.

To understand when and how cells are harmed in the course of disease, we must first understand how healthy cells function and communicate with each other at the molecular level. Such knowledge is essential to our ability to identify subtle but crucial molecular changes in cells and tissues. This knowledge also has implications for early detection of disease, prediction of disease course, response to particular therapies, and identification of molecular targets for development of new therapies.

All cells share common features

Human cells are composed of the same substances (proteins, fats, carbohydrates, nucleic acids, salts and water) that are found in all living cells. Many of the more complex molecules within cells, such as genes and the proteins they encode, occur in what is often referred to as families, with each protein or gene having a similar but not identical genetic sequence.

Human cells may contain many members of each family, often with overlapping functions. This complexity can make it difficult to tease out the function of individual molecules. Often clarification of the function of these molecules is easier in simpler organisms, such as yeast, worms or flies, which generally share at least one member of each family of proteins found in humans but contain fewer such family members.

As a consequence of the fundamental similarities in mechanisms by which all cells operate, keys to understanding function, such as digestive or kidney function, and diseases such as diabetes, or liver disease may lie in research in these simpler systems. These connections between humans and lower life forms must be recognized and exploited through study of simpler "model organisms" that are directly relevant to human cells.

Major differences among cell types

Despite the similarities common to all life forms and the principles underlying cell function, cells vary greatly in size, shape and function. In each person a single cell, the fertilized egg, gives rise to hundreds of different cell types. Each cell in the body contains the same set of genes. If it can be determined how, from this common cell, the diversity of mature cell types (muscle, fat, liver, pancreas, intestine, kidney, bladder, blood, bone, thyroid, etc.) is generated, the secrets needed to regenerate and restore damaged or destroyed tissues may be unlocked.

From the cell to the organism

In each individual, the fertilized egg, a single cell, gives rise to all the cell types necessary to form a functioning human being. Each of these cell types contains an identical set of genes. Human life depends on the cooperation and specialization of all of these diverse cell types.

OBJECTIVES

To understand, treat, prevent, and cure diseases, we must understand the internal workings of each cell type in isolation; how each cell functions within a community such as tissues and organs; and how cell communication function is further integrated in the intact human body. To accomplish these goals the Working Group on From the Cell to the Organism: Unraveling the Complexity of Living Systems has delineated the following objectives.

A. CELL STRUCTURE AND ORGANIZATION

The following objectives are critical for understanding cell processes, such as how hormones generate cell response, how substances are transported in the body, and how cells metabolize fuel:

A1. OBJECTIVE: To define the mechanisms by which cells interpret and integrate signals to produce a cellular phenotype, including: the molecular-structural bases for signal transduction: the structural components of receptors, channels, pumps, transcription factors, kinase cascades, and other signal transducers that define cellular function and confer specificity; the mechanisms by which specificity of cellular responses is achieved with a common set of signaling molecules; the interplay and interaction among signal transduction pathways; the mechanisms by which signals are conveyed to the nucleus resulting in the regulation of gene expression; and the role of extracellular, cyto-and nuclear architecture in the regulation of tissue-specific gene expression.

A2. OBJECTIVE: To define novel components of relevant supramolecular assemblies and elucidate their interactions and functions.

A3. OBJECTIVE: To understand the molecular mechanisms underlying assembly, processing, localization, and turnover of macromolecules.

A4. OBJECTIVE: To elucidate the biogenesis and functions of specialized membrane compartments, such as mitochondria, vesicles, and lysosomes.

A5. OBJECTIVE: To determine how cells establish polarized domains and localize supramolecular complexes to modulate their function.

INSIGHT: A membrane surrounds each human cell. This membrane keeps the cell intact and provides an anchor for channels that open and close to allow specific molecules to enter and/or leave the cell, and for receptors, which relay messages between cells and from the environment to the interior of the cell. Many structures found within a cell are enclosed in similar membranes, all of which serve the same functions. These membranes play key roles in allowing cells to interact with each other, with their environment, and in compartmentalizing and organizing functions in a cell.

Membranes contain proteins that give each type of cell unique properties. For example specific cell types have different forms of membrane proteins that transport sugar into the cell, called glucose transporters. Uptake of the sugar glucose plays a key role in the regulation of insulin production in the pancreatic beta cell and further regulates production, storage and release of sugar by liver, muscle, kidney and fat cells. Each of these cells has an important role to play in regulating blood sugar levels and the diverse forms of the glucose transporters are key in allowing these cells to carry out their unique metabolic functions.

Membrane proteins also help transmit messages from the environment to specific cell types, regulating cell function. Cell membranes also are targets for a large number of drugs and of hormones, which bind to membrane receptor proteins. These receptors transfer the hormone signal to the interior of the cell, generating "second messengers" within the cell that regulate key cellular activities. For example, blood-forming cells have receptors for erythropoietin (Epo), a hormone made in the kidney which regulates red blood cell formation. Too little of this hormone leads to anemia and inadequate transport of oxygen within the body, causing fatigue and weakness; too much of this hormone causes excessive blood formation, increasing an individual's risk for stroke. Therapy with Epo represents one of the great successes of biotechnology, dramatically improving the wellbeing of patients with end-stage renal disease.

The 1999 Nobel Prize for Physiology or Medicine was awarded for the discovery that ''proteins have intrinsic signals that govern their transport and localization in the cell." The biotechnology industry has used these signaling mechanisms to manipulate cells to produce large quantities of insulin, growth hormone, Epo and other proteins for therapeutic use. This discovery also helps explain how errors in protein localization--arrangement of proteins within a cell or membrane--occur and cause disease. Each newly formed protein must be appropriately processed to its mature, functional form, and targeted to its correct location within the cell. Cellular proteins must be properly folded into a complex, three-dimensional structure that is essential for performing a specific function. Proteins that are not correctly folded are targeted for destruction. A number of diseases are due to folding defects in specific proteins. For example, in cystic fibrosis, deletion of one of 1284 amino acids in the CFTR protein produces a misfolded protein that is degraded rather than properly transported to the cell membrane where it normally functions as a transporter. Understanding the mechanisms by which proteins are correctly folded and transported could lead to new approaches for therapy of cystic fibrosis and other diseases.

Within each cell are specialized compartments, walled off by internal membranes, to form discrete spaces where cellular processes occur. In mitochondria energy is transferred from sugar to storage as ATP. Other compartments sort proteins, such as secreted hormones, into packages addressed for their final destinations. In the lysosomes and peroxisomes, enzymes break down food and other substances. A large number of genetic metabolic diseases arise as a consequence of defects in specific proteins required for activities that occur in these specialized compartments. For example, in storage diseases such as Hurler disease, cells and tissues are damaged by massive accumulation of material in the lysosomes that cannot be digested.

Compartmentalization occurs not only as a result of separation of activities by cell membranes, but also due to formation of supramolecular complexes. We know that an elaborate network of control mechanisms regulates and coordinates these interactions. Unraveling the mechanisms of molecular recognition leading to formation of these complexes, and the nature of the cooperative interactions which occur as a consequence, is essential to understand the mechanisms by which signaling occurs within cells. For instance, formation of such complexes is important in insulin signaling and defects in specific components of the complex may contribute to diabetes.

B. CELL DIFFERENTIATION, GROWTH AND EXPANSION

The following objectives are critical for understanding cell differentiation, proliferation and death:

B1. OBJECTIVE: To define the characteristics of pluripotent cells which permit them to progress along a specific developmental pathway or to maintain a pluripotent state.

B2. OBJECTIVE: To define the function of cell products relevant to development and differentiation.

B3. OBJECTIVE: To define the mechanisms by which commitment to a specialized cell type is initiated and maintained.

B4. OBJECTIVE: To define functional correlates of the life cycle of the cells: for example, the temporal and spatial patterns of gene expression, which explain cell proliferation, cell death and control of cell number.

INSIGHT: Every cell in the human body contains the same genes. During development, cells are programmed so that some genes are expressed and others are silent. This process is called differentiation and is responsible for the specialized characteristics that make one cell a liver cell and another a thyroid cell. The ability to control differentiation and to identify, isolate and characterize stem cells holds great potential for therapeutics, particularly tissue replacement.

Stem cells are undifferentiated cells that can give rise to many cell types. Totipotential stem cells can give rise to an entire organism. Pluripotent stem cells can generate all the cell types of an organism, but not the entire organism. Other types of stem cell can give rise to a more limited repertoire of differentiated cells. For example hematologic stem cells can generate all types of blood and many bone cells. An array of stem cells can now be isolated from mice and other research animal models and tools are being developed to identify, characterize and purify these cells. These cells hold promise for development of therapeutics and replacement tissues through understanding of control of their differentiation.

Recently, two groups of scientists have succeeded in isolating and culturing the first human pluripotent stem cell lines. These cells can give rise to all of the different types of specialized cells in the body, yet they are not totipotent and thus cannot give rise to an entire human being. The excitement surrounding this discovery lies in the ability of these cells to divide and self renew as well as to commit to become cells with more specialized function, such as liver, blood, bone or pancreatic beta cells. The use of these cells for transplantation to replace or repair damaged tissue is discussed under therapeutic applications, later in this chapter. To make these applications a reality, fundamental research is needed to identify the signals that direct the differentiation of a stem cell and cause it to develop into a specific cell type. Understanding the cellular decision making process will give us the tools to direct pluripotent stem cells to become the cells and tissues needed for transplantation.

It is by the growth and division of cells that organisms are formed. Cell growth and division is organized into a cycle of events. This cell cycle is influenced by external regulatory signals. Although formation of new cells and cell death might appear to be opposing processes, they are closely coupled. Apoptosis, or programmed cell death, is a normal consequence of cell proliferation. This cell suicide mechanism enables control of cell number and eliminates individual cells that threaten the body's survival. Certain cells have unique sensors, termed death receptors, on their surface which recognize signals from outside the cell and trigger cell death. Survival signals from nearby cells may block this death mechanism. This communication regulating apoptosis is critical to immune system function. One type of cell targeted for destruction is that which recognizes self. A malfunction in elimination of these cells can lead to an attack on the body's own cells, resulting in autoimmune disease, such as type 1 diabetes or inflammatory bowel disease.

Cell proliferation and death are closely regulated processes. Mechanisms to replace worn out cells or make more cells are highly regulated. While some cells are very short-lived and are continually replaced, others cannot reproduce and cell death leads to a permanent deficit. Even small imbalances in cell number can have devastating consequences. For example, the cells that form and remodel bone are continuously dying and being replaced by new cells arising from the bone marrow. Changes in the numbers of these active bone cells due to altered rates of cell proliferation or cell death can lead to bone loss. The gastrointestinal tract provides another example of the catastrophic consequences of altered regulation of cell growth. When the gene for a transcription factor (which regulates expression of other genes) was "knocked out" in mice, the animals died shortly after birth because their intestinal lining cells could not regenerate and properly absorb food. In contrast, mutations in a gene involved in the regulation of this same transcription factor causes excessive cell growth and tumor formation in the colon.

C. ORGANIZATION OF CELLS INTO TISSUES AND ORGANS

The following objectives are important for understanding organization of cells into tissues and organs:

C1. OBJECTIVE: To define fundamental mechanisms of organogenesis, including cell migration, differentiation, and cell-matrix and cell-cell interaction.

C2. OBJECTIVE: To define the mechanisms that promote and restrict cell growth and proliferation, so that each organ and tissue maintains only the proper number and size of cells of each type in the proper spatial distributions during ontogeny, repair and regeneration.

C3. OBJECTIVE: To determine how cell-cell interactions influence organ function.

INSIGHT: Much remains to be learned about how cells organize to form tissues and how tissues then form organs. We know that connections between cells must be precisely ordered. During development, tissues are formed from cells originating in various parts of the body. How do migrating cells reach their destination and how do organs form in particular locations? This process requires that cells selectively recognize each other and attach. To accomplish this, cells produce an extracellular matrix, a network of secreted proteins and carbohydrates, which helps to bind cells together and forms a lattice through which cells can move. This matrix also serves as a reservoir for hormones that control cell growth and differentiation and mediates interactions important for wound healing and tissue repair and regeneration.

Of particular importance for NIDDK is understanding how cells unite to form epithelial tissues, the sheets of tightly bound cells that line all the cavities and free surfaces of the body, including the gastrointestinal tract, bile and pancreatic ducts, kidney collecting ducts, ureter, bladder and skin. Epithelial tissues have specialized junctions between cells, forming seals to separate fluids with different compositions on each side of this barrier. Each type of epithelia is specialized to accomplish particular functions. The epithelial cell layer separating the intestinal lumen from the blood is specialized to permit the absorption of nutrients and their transfer from intestine to blood. Renal tubular epithelium, the site of damage in acute renal failure, has important reabsorptive, metabolic and endocrine functions. Knowledge of its role in maintaining homeostasis is essential to development of strategies to replace these lost functions and reduce the high mortality associated with this condition.

The origins of a number of diseases lie in the failure to correctly generate components of the highly ordered cell architecture of tissues and organs. We know that proper formation of specific cell types in the pituitary requires a precise balance among the factors that regulate gene expression in these cells. From this knowledge has emerged an understanding of how some forms of dwarfism, as well as more generalized disorders involving growth and reproductive and thyroid function, arise from genetic changes which impair the formation of specific pituitary cells. To uncover the mechanisms of cyst formation and growth in polycystic kidney disease, the role of the polycystins, the products of the disease causing genes, in development and function of the normal kidney must be understood.

D. INTEGRATED CELL FUNCTION AND ENVIRONMENTAL RESPONSE

The following objectives relate to understanding the interaction of cells and tissues with each other and with their environments:

D1. OBJECTIVE: To understand how signaling processes are integrated among individual cells and interact to create networks with coherent and predictable functions.

D2. OBJECTIVE: To understand the integrated combinatorial nature of local environmental signals.

D3. OBJECTIVE: To understand how specialized cells and tissues modulate other cells in their local environment.

D4. OBJECTIVE: To define the mechanisms by which specialized cells and tissues interact with immunocytes and immune mediator molecules.

D5. OBJECTIVE: To understand the interaction of the cell with its metabolic environment.

D6. OBJECTIVE: To understand mechanisms by which cells adapt to unusual environments, such as extremes of pH, oxygen tension, or osmolarity.

D7. OBJECTIVE: To define the interplay of cells, tissues and organs to regulate homeostasis of the intact organism, such as regulation of glucose, salt and mineral concentrations.

INSIGHT: Intercellular signaling is necessary for cooperation between specialized cell types and for the capacity of specialized tissues to function in an integrated fashion. This is particularly apparent in the hypothalamus, a brain region with a critical role in integrating neural control of the endocrine system and endocrine control of neural function. Here communication occurs almost exclusively through chemical messengers; cells influence adjacent cells with their secretions and signaling pathways connect neighboring regions whose integrated function is essential for regulation of appetite and thirst, response to stress, reproductive function, metabolism, and salt and fluid balance. Understanding the complex interconnections between specialized hypothalamic cells, which make and respond to key hormones and neurotransmitters involved in appetite regulation, will provide targets for pharmacologic approaches to control food intake and weight gain. The hypothalamus also has a key role in sensing and responding to hypoglycemia. Understanding the signaling pathways involved is important for prevention and reversal of hypoglycemia unawareness, a key problem limiting therapy of people with diabetes.

Understanding the cell signaling pathways involved in maintenance of tolerance and pathways that trigger immune activation are prerequisites for the development of new therapies to prevent or reverse autoimmune diseases and to prevent rejection of transplanted organs and cells. The molecular signals that govern immune cell communication are the targets for new approaches to immune modulation. Immune cells called T cells have one receptor responsible for accurately identifying a potential target. More recently, these cells were found to have a second signaling system involving a costimulatory receptor which activates the T cell once target recognition has occurred. Now a number of agents have been developed that interfere with this costimulatory receptor. By blocking the specific immune cells that attack transplanted tissue, these drugs may be safer and more effective than immunosuppressive drugs in preventing transplant rejection. This approach to redirecting the immune system to maintain tolerance may also be useful in restoring self-tolerance in autoimmune diseases.

Wound healing is a process that involves extensive interaction of cells and tissues with their local environments. In the area of a skin ulcer, a network of secreted proteins and carbohydrates, called the extracellular matrix, fosters interaction of the local affected cells with blood cells and growth factors secreted locally. Blood cells infiltrate the wound and attach to the extracellular matrix where they are transformed into specialized cells to cleanse the wound, and initiate and propagate new tissue formation. The extracellular matrix helps with the formation of new blood vessels needed to sustain the new tissue. Local release of growth factors stimulates these processes. In diabetes, high blood sugar, reduced delivery of oxygen and other nutrients due to vascular disease, and other alterations in the local metabolic environment can impede this healing process.

Our cells function best in a carefully controlled environment maintained by a complex system of regulatory networks designed to maintain key parameters within the narrow range optimal for health. Hormones are essential to regulate cell function to maintain this internal environment. For example, calcium concentration is tightly controlled by hormonal mechanisms. Specialized cells in the parathyroid gland have a calcium sensor that triggers rapid release of parathyroid hormone (PTH) in response to any fall in blood calcium levels. PTH stimulates release of calcium from bone, reabsorption of calcium from urine, and activation of vitamin D to enhance absorption of calcium from the intestine. The ensuing rise in calcium then stimulates mechanisms to shut off a further rise in calcium and inhibit further PTH release. Similar regulatory mechanisms, involving synergistic effects of multiple hormones on many organs and tissues, exist to maintain blood sugar and salt concentrations, fluid balance, blood pressure and other critical parameters within narrow limits. These involve coordination of simultaneous responses involving multiple hormones, counterbalancing influences to fine tune responses, and mechanisms to terminate the hormone response.

Many drugs affect multiple tissues, with effects on one tissue conferring benefit, while risks or side effects derive from effects on another tissue. For example, estrogen replacement therapy is clearly beneficial in preserving bone mass, yet its effects on the cardiovascular system, blood clot formation, breast and other tissues are less well understood. The recent discovery of two separate estrogen receptors with different tissue distributions and new understanding of how the estrogen receptor interacts with other signaling molecules within cells to turn genes on and off have important implications for development of more selective drugs. These "designer estrogens" are intended to produce beneficial effects of estrogen in some tissues and to actually antagonize harmful effects in other tissues. Diverse effects on different tissues are also seen with thiazolidenediones, a class of drugs, which activate the nuclear receptors that modulate gene expression in response to fatty acids and lipid metabolites and are currently being used as insulin sensitizers in the treatment of type 2 diabetes. These drugs, originally shown to cause differentiation of fat cells, were more recently implicated in the formation of scavenger cells that take up lipids and in the inhibition of apoptosis in colon cells; recognition of these latter effects stimulated investigation of their possible effects on atherogenesis and intestinal tumors. The drug discovery process could be streamlined if cultured cell lines or other methods were available to determine or predict the integrated effects of a drug on the many cells and tissues of the intact organism.

E. THERAPEUTIC APPLICATIONS

The following objectives are important to developing therapeutic applications based on understanding of cell biology:

E1. OBJECTIVE: To define key molecules and critical pathways which are essential for specialized cell function and which must be provided and/or regulated to enable functional replacements for specialized cells.

E2. OBJECTIVE: To identify key targets for molecular modulation to promote cell regeneration and repair.

E3. OBJECTIVE: To understand factors that maintain stem cells and control their commitment, as a precursor to their use for tissue/organ replacement.

E4. OBJECTIVE: To devise methods to enhance growth and yield of cells produced and modified for therapeutic purposes.

INSIGHT: The life-saving value of donated kidney, liver, intestine, pancreas and other organs is well established, yet the number of people who could benefit from transplantation far outstrips the number of organs available for transplantation. Pluripotent stem cells have the potential to serve as a renewable source of replacement cells and tissues to treat many diseases important to NIDDK. The Institute is committed to applying insights derived from basic investigations of cell biology to realize the promise of stem cell therapy as well as develop better methods of cell and organ transplantation and methods to stimulate tissue regeneration.

Stem cell biology may have important applications, not only for transplantation, but also for differentiation therapy using an individual's own cells. During fetal development, pluripotent stem cells develop into types of stem cells with more limited capacities to form specialized cells. For example, hematopoietic stem cells can form all the blood cells and some bone cells, but not other tissue types. Our bodies contain many types of stem cells that could be used to repair or regenerate some tissues. Research is needed to identify cells with these capacities and to develop methods to stimulate their differentiation into specialized cells. We know that the human body has the ability to permit new growth and renewal of liver, intestinal lining, renal tubule, bone, skin and other cells. We must discover whether this ability also exists for other critical cell types, such as pancreatic beta cells, and discover methods to enhance the body's regenerative capacity.

Cellular engineering is another promising approach to replace vital functions lost to tissue destruction. Development of such therapies requires an understanding of the molecular mechanisms underlying the unique functions of each cell type so that these can be recreated in the therapeutic cells. For example, if we can define every step in the process by which the beta cell senses the level of blood glucose and modulates the secretion of insulin in response to changing blood glucose, we could attempt to recreate this process in a therapeutic cell protected from autoimmune destruction. In these therapeutic cells, genes and regulatory elements would be introduced to provide the functional components needed to mimic the specialized cell function to be replaced. Cell engineering may also be a useful approach to induce tolerance once we know which genes should be introduced to accomplish this. Yet another application of cell engineering involves creation of animal models, which mimic human disease processes, and can be used to test promising therapeutic approaches.

IMPLEMENTATION STRATEGIES

The Working Group From the Cell to the Organism: Unraveling the Complexity of Living Systems developed the following strategies accomplish the objectives identified above:

A. CELL STRUCTURE AND ORGANIZATION

A1. STRATEGY: Apply microarray technology and computational biology to the study of the regulation of gene expression: specifically, to understand the relationship between strength and duration of a stimulus and the response of a gene.

A2. STRATEGY: Develop methods to measure very low concentrations and affinities of molecules in cells.

A3. STRATEGY: Encourage new efforts to use biochemical approaches to study protein-protein interactions.

A4. STRATEGY: Encourage the use of mass spectroscopy to identify protein components in macromolecular complexes.

A5. STRATEGY: Encourage new efforts at determining the three dimensional structure of proteins and macromolecular assemblies, using methods such as NMR, immuno-electron microscopy and 3D imaging.

A6. STRATEGY: Enhance understanding of dynamic interactions of macromolecules in living cells, employing methods such as fluorescence energy transfer.

A7. STRATEGY: Develop new optical methods to study sub-nuclear organization in the context of living cells.

A8. STRATEGY: Develop in vivo imaging methods to monitor the organization of molecules in supramolecular complexes and subcellular organelles and encourage the establishment of functional assays that reconstitute interactions between such assemblies and organelles.

B. CELL DIFFERENTIATION, GROWTH AND EXPANSION

B1. STRATEGY: Apply information from model organisms to understanding cell differentiation, proliferation and death in higher vertebrates.

B2. STRATEGY: Develop systematic approaches to study gene expression patterns during different stages of development and the cell cycle.

B3. STRATEGY: Use the power of computational biology (i.e. pathway prediction analysis) and comparative genomics to understand functional integration in cells and tissues.

B4. STRATEGY: Develop techniques for rapid and efficient analysis of changes in protein expression in whole cells and whole tissues.

B5. STRATEGY: Identify promoters with desirable properties such as lineage and cell specificity.

B6. STRATEGY: Identify cell lines in which differentiation can be directed and develop tissue culture methods to study cell differentiation.

C. ORGANIZATION OF CELLS INTO TISSUES AND ORGANS

C1. STRATEGY: Develop in vivo measurements to quantitate and assess the effect of gene perturbations.

C2. STRATEGY: Utilize model organisms to gain insight into the roles of single genes that operate in complex systems.

C3. STRATEGY: Develop simple and efficient methods to modulate gene expression in intact animals or organ culture.

C4. STRATEGY: Produce antibodies to epitopes within specialized regions of extracellular matrix to define the composition of the matrix and understand its function.

C5. STRATEGY: Develop optimized, chemically-defined media and matrices for propagation of cells, tissues and organs.

D. INTEGRATED CELL FUNCTION AND ENVIRONMENTAL RESPONSE

D1. STRATEGY: Understand the molecular mechanisms by which cells act as sensors.

D2. STRATEGY: Learn how to measure the concentrations of paracrine factors near or on cells and develop methods to detect single or small numbers of extracellular molecules in vivo.

D3. STRATEGY: Develop model hormonal environments that incorporate pulsatility.

D4. STRATEGY: Develop methods to look at the response of an entire organism to agents that may engender disparate responses in different tissues.

D5. STRATEGY: Use non-invasive imaging to understand physiologic functions at an organism level.

D6. STRATEGY: Apply information from model organisms to understanding function in higher organisms.

D7. STRATEGY: Use the power of computational biology and comparative genomics to understand the integration and interplay among cells, tissues, organs and environmental factors, nutrition and toxins on the organism.

E. INJURY AND REPAIR OF CELLS, TISSUES AND ORGANS

E1. STRATEGY: Analyze the role of the immune system in causing disease and injury, both in diseases known to be caused by specific infectious agents, as well as diseases in which the primary cause is unknown.

E2. STRATEGY: Analyze the basis of tolerance using animal model systems with state-of-the-art techniques, including transgenic animals and DNA arrays, that allow for dissection of each component of immune cells, cytokines, and growth factors.

E3. STRATEGY: Examine the role of hemodynamic factors and ischemia in injury to cells, tissues and organs, dissecting the steps of ischemic injury and the process through which hypoxia leads to cell death.

E4. STRATEGY: Evaluate the mechanisms of repair of epithelial cell injury.

E5. STRATEGY: Evaluate the mechanisms of regeneration in response to injury of liver, pancreas, kidney and hormonal organs.

E6. STRATEGY: Evaluate the mechanisms of fibrosis that can result from different forms of injury, but have an impact on a range of diseases and conditions.

E7. STRATEGY: Elucidate the impact of behavior on diseases through the study of preclinical models.

E8. STRATEGY: Study the influence of nutritional factors such as anti-oxidants in ameliorating damage to cells, tissues, organs in animal models of disease.

F. THERAPEUTIC APPLICATIONS

F1. STRATEGY: Encourage basic stem cell research.

F2. STRATEGY: Develop novel methods to safely culture and expand cells without transformation.

F3. STRATEGY: Develop new ways to increase the quantity and viability of tissues harvested from cadavers and living donors for transplantation.

F4. STRATEGY: Develop a deeper understanding of immune tolerance and rejection.

F5. STRATEGY: Explore innovative, less toxic ways of preventing rejection, such as inducing immune tolerance or cell encapsulation.

F6. STRATEGY: Devise methods and innovative delivery systems to promote controlled cell and tissue regeneration in patients.

F7. STRATEGY: Identify novel cell components that can serve as new targets for drug discovery.

F8. STRATEGY: Develop cell systems and animal models of different types of injury that are appropriate for assessing therapies.

F9. STRATEGY: Develop therapeutic strategies that enhance or modify immune response to mediate clearance of persistent pathogens and terminate chronic infections or ameliorate and limit autoimmune disease.

F10. STRATEGY: Develop improved gene therapy methodologies applicable to humans.

F11. STRATEGY: Develop transplantation models and apply these to assess methods of inducing tolerance.

PREVENTION AND TREATMENT OF DISEASE: EPIDEMIOLOGY AND CLINICAL INVESTIGATION

Overall Goals: (1) To move advances in science and technology into patient-oriented applications in a timely and efficient manner; and (2) to develop targeted interventions for diseases and complications that are tailored to the needs of specific individuals and populations.

BACKGROUND

Opportunities and Challenges

As stated earlier in this document, the NIDDK has responsibility for areas of clinical research related to many diseases, including cystic fibrosis, diabetes, digestive diseases, endocrine disease, hematologic diseases, inborn errors of metabolism, kidney diseases, liver diseases, nutrition, and urologic disease.

These diseases affect individuals of all ages, are often chronic with a long natural history, and may cause significant morbidity and reduced life expectancy. In addition, they usually require long-term management, burdensome self-management, and long-term coping by affected individuals and their families.

Many diseases within the NIDDK's research mission also may have several elements that affect the natural history of the disease. For example, there may be genetic, environmental, and behavioral factors that influence the development of the disease, disease progression, and final outcomes. There is also considerable variability in an individual's susceptibility to the effects of the disease, as well as certain populations that may have increased or decreased risk, including children, racial and ethnic minorities, women, men, and the elderly.

Advances in basic and clinical science are leading to a greater understanding of the causes and mechanisms of these diseases and their complications. Many new interventions, for example, are available that have the potential to prevent, cure, or ameliorate the complications of diseases within the research mission of the NIDDK. Furthermore, application of new or improved technologies will make it possible to identify risk factors for disease occurrence and progression, which will stimulate new research directions.

Expanding the knowledge base of disease through clinical research, based on advances in basic science and technology, is critical to develop effective strategies for disease prevention. With greater knowledge and understanding of the disease processes and their effects on different individuals and populations, it will be possible to develop interventions that are specifically targeted to their needs.

OBJECTIVES

The NIDDK conducts clinical research on all aspects of disease prevention: primary prevention for those who are at risk for developing disease; secondary prevention for those who have the disease; and tertiary prevention for those who have developed complications of the disease. This comprehensive approach is needed to ensure the best possible outcomes for people who are at different stages in the disease process.

However, through the Strategic Planning process, NIDDK, working in collaboration with its National Advisory Council, the scientific community, and lay and professional organizations, identified several barriers that impede the development and implementation of new prevention and treatment strategies for the diseases within the research mission of the NIDDK. These barriers include research infrastructure; scientific understanding; and the identification and recruitment of volunteers to participate in the evaluation of new prevention strategies.

The following objectives are meant to address these barriers in such a way as to achieve the overall goals of (1) moving advances in science and technology into patient-oriented applications in a timely and efficient manner, and (2) developing targeted interventions for diseases and complications that are tailored to the needs of specific individuals and populations.

OBJECTIVE: Increase and enhance the research infrastructure by addressing the issues of manpower shortages and insufficient information resources.

INSIGHT: At present, there is limited capacity within the research community to develop and evaluate the many new treatments and prevention strategies that are currently available. This limitation will increase as more new approaches to disease treatment and prevention are developed. For example, there is a manpower shortage because biomedical research scientists are not choosing careers in clinical research. Those who do choose careers in clinical research find that there is insufficient infrastructure to support their research. In addition, there are insufficient resources in the areas of biostatistics, bioinformatics, data management, laboratory support for clinical studies, and for recruitment and retention of research volunteers. As a result of these limited resources, there are often long delays in planning, organizing, and implementing clinical trials, and only a few large trials can be conducted concurrently.

OBJECTIVE: Advance the science knowledge base so as to gain a better understanding of the natural history of disease based on more precise characterization.

INSIGHT: Many of the diseases within the NIDDK research mission are affected by complex interactions between behavior, genetics, and the environment. These factors, coupled with variability in individual susceptibility to the disease processes, make the design and conduct of clinical studies difficult, and impede the development of targeted interventions for specific populations and individuals. Thus, there is a need for much better phenotyping and genotyping of the diseases within the mission of NIDDK, and for better understanding the natural history of the diseases based on more precise characterization.

OBJECTIVE: Identify, recruit, and retain more research volunteers.

INSIGHT: Evaluation of new prevention and treatment strategies developed in animal studies must eventually be evaluated in humans. Because of the unique and complex nature of humans, many prevention strategies can only be tested in humans. In particular, identification of potential research volunteers is a major obstacle for the uncommon or rare diseases within the NIDDK's research mission. A nationwide or even worldwide recruitment effort is often needed, because no one particular center has sufficient numbers of patients to participate in clinical research.

Once potential research volunteers have been identified, there are significant barriers to their participation in clinical studies and clinical trials. For example, currently available research methods are often time-consuming and entail inconvenience and discomfort that many subjects find unacceptable. The study of self-selected patients who are willing to undergo the necessary inconvenience and discomfort limits the generalizability of research findings. In addition, there are often historical, cultural, and language barriers that discourage the participation in clinical research, often of the individuals who would derive the greatest benefit from the research advances.

Finally, advances in science and technology are encountering significant ethical, legal, and social barriers to the participation of individuals in clinical research. These barriers relate to the participation of children in clinical research, the identification of disease susceptibility, informed consent, insurability, job discrimination and job security.

IMPLEMENTATION STRATEGIES

To achieve the objectives stated above, the Working Group on Prevention and Treatment of Disease; Epidemiology and Clinical Investigation, developed the following strategies:

A. STRATEGY FOR DEVELOPING CLINICAL RESEARCH INFRASTRUCTURE

The NIDDK believes that the most efficient strategy to build a stronger clinical research infrastructure is to establish dedicated clinical research and clinical trial networks in selected areas of interest. Specific areas will be targeted for development based on scientific opportunity, disease burden on individuals and society, and on the need for a multicenter approach to the disease.

The charge to a particular network also will depend on the knowledge base and scientific opportunity. Thus, networks might be charged with conducting clinical research in areas of interest, epidemiologic studies, or clinical trials using state-of-the-art techniques. For some diseases, pilot and feasibility studies of new interventions are needed to evaluate and prioritize them for future large-scale trials. These networks might also conduct clinical trials in rare and orphan diseases, or where there are major public health questions that require a large, multicenter study. Collaboration with industry, rather than competition with industry-sponsored clinical trials, will be the most efficient utilization of manpower and other resources.

The components of the individual networks will depend on the specific disease or diseases under study. NIDDK envisions supporting key research personnel, biostatistics and research coordinating functions, central laboratories where necessary, and bioinformatics to facilitate recruitment of individuals into clinical studies and trials. Efficient functioning of the networks will require mechanisms to assess potential studies and interventions and prioritize the research agenda. Funding for pilot and feasibility studies will be provided in specific instances to facilitate timely evaluation of new interventions.

B. STRATEGY FOR DEVELOPING BETTER METHODS FOR STUDYING NORMAL AND DISEASE PROCESSES IN HUMANS

NIDDK will support research to develop new or improved methods for studying normal and disease processes in humans. The development of non-invasive or minimally invasive methods is viewed as essential to increase the science knowledge base, and to encourage participation of research volunteers. Better processes are needed to assess organ size and function, pathologic processes, and physiology. Better methods are also needed for screening, diagnosis, and staging of many diseases within the mission of NIDDK. New or improved methods for studying human behavior and its role in disease processes are also needed. Methods are also needed to predict progression of disease. Surrogate measures of disease outcomes are needed to shorten the duration of clinical trials and to allow evaluation of a greater number of interventions concurrently.

C. STRATEGY FOR DEFINING DISEASES MORE PRECISELY

With the development of clinical research infrastructure and new or improved methods for studying normal human functions and disease, it will be possible to precisely define the diseases within the research mission of the NIDDK.

Precise phenotypic definition of disease is a critical first step in discovering the genetic factors that underlie the disease. Subsequently, the NIDDK will support research to phenotype diseases of interest, including biochemical, physiologic, histologic, anatomic, behavioral, and sociodemographic measures. Close collaboration between clinical researchers and geneticists will be encouraged and supported. Once the genetic factors are discovered, newly emerging array technology will make it possible to precisely genotype individuals within the population. Genotyping, along with precise phenotyping, will lead to the design of better clinical studies and clinical trials of targeted interventions that are tailored for specific disease processes.

D. STRATEGY FOR APPLYING STATE-OF-THE-ART METHODS

With the development of the clinical research infrastructure, new or improved methods for studying normal function and disease, and more precise phenotyping and genotyping, it will be possible to increase understanding of the diseases within the NIDDK's research mission.

The NIDDK will support research to identify the factors accounting for health disparities among different populations and the development of targeted interventions tailored to the needs of specific populations. The NIDDK also will support research that defines the role of environmental factors in disease, including drugs, toxins, viruses and other infectious agents, behavior, stress, and nutrition. With an increase in the knowledge base it will then be possible to develop targeted intervention for minority populations, children, men, women, and the elderly.

E. STRATEGY FOR ADDRESSING THE ETHICAL, LEGAL, AND SOCIAL BARRIERS TO CLINICAL RESEARCH

The ability to precisely phenotype and genotype individuals at risk for, and with disease requires careful consideration of the potential risks to the individual. These include the risks of the research itself, particularly in children, and the threats to insurability and job security that discovery of disease susceptibility may entail. Psychosocial effects resulting from the discovery of disease susceptibility may be significant. Research is needed to understand these effects, and to develop management strategies.

The NIDDK will support research in these areas, and will work with the scientific and lay communities to address these ethical, legal, and social barriers to clinical research on disease prevention and treatment.

F. STRATEGY FOR DEVELOPING AND INVESTIGATING NEW APPROACHES TO DISEASE PREVENTION AND TREATMENT

Advances in basic and clinical research and technology will make it possible to develop new approaches to disease prevention and treatment.

The NIDDK will support r