Strategic Goal: Goal 2: Reduce Human Disease

Bringing Personalized Biochemistry and Biophysics to Bear on Problems of Personalized Heart, Lung and Blood Medicine

Precision medicine will provide unprecedented opportunities to tailor health care based on knowledge of personal patterns of genetic variations. These variations usually impact protein or RNA sequences, resulting in altered properties. These alterations can result in increased susceptibility to a particular disease or intolerance to common therapeutics. To take full advantage of knowing a patient’s set of gene variations, ...more »

Submitted by (@chuck.sanders)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

As detailed in the attached review (Kroncke et al. Biochemistry 2015, 54, 2551−2559) the successful practice of personalized medicine will in many cases require a molecular-level understanding of the nature of the defects that are caused by disease-predisposing genetic variations. As widespread personal genome sequencing becomes routine, numerous genetic variations (many millions) of uncertain significance will be discovered. Using both experimental and computational tools associated with the fields of biochemistry, biophysics, and structural biology it is in many cases possible to ascertain whether a newly-discovered gene variation adversely impacts a critical protein or RNA function and, if so, how. Among various clinical applications this information can be used (i) to project whether a patient not currently showing symptoms for a particular disease is likely to present with that disease in the future (sometimes enabling prophylactic therapy), (ii) to help establish the molecular etiology of a disease currently afflicting the patient, and (iii) to guide the therapeutic strategy pursued for that patient.

Feasibility and challenges of addressing this CQ or CC :

My lab is already participating in a project (RO1 HL122010) with two other labs (those of Drs. Jens Meiler--Vanderbilt and Alfred George--Northwestern) to develop personalized biochemical and biophysical approaches for application to genetic variations impacting the KCNQ1 gene, potentially predisposing patients to long QT syndrome, a cardiac arrhythmia. However, our project deals with one gene and one disorder only. There clearly is a need for improved and expanded communication and collaboration between those practicing personalized/precision medicine and those who are well-equipped to provide medically actionable molecular insight using the approaches of personalized biochemistry, biophysics, and structural biology.

Name of idea submitter and other team members who worked on this idea : Charles R. Sanders, Prof. of Biochemistry, Vanderbilt University (With Drs. Alfred George--Northwestern University and Jens Meiler--Vanderbilt University)

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Strategic Goal: Goal 4: Develop Workforce and Resources

DEVELOPMENT AND SUPPORT FOR APHERESIS MEDICINE INVESTIGATORS

The apheresis medicine encompasses treatment of numerous diseases many of which are directly related to blood, lung and heart. However, there are very limited opportunities for training young investigators in basic and translational research related to Apheresis Medicine. There is a need to promote Apheresis Medicine as a viable field of research for junior and established investigators. The influx of well-trained junior ...more »

Submitted by (@zbigniew.m.szczepiorkowski)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Therapeutic apheresis is the process of transiently removing whole blood from the body, separating it into various components (e.g., cells, plasma, proteins, antibodies, antigen-antibody complexes, lipids, etc.), removing those components that contribute to disease, and then returning the remaining blood with possible addition of a blood component to the body.

 

Hundreds of thousands of apheresis procedures are being performed every year in the US. Many of these procedures are life-savings while others are likely to be of limited benefit to patients and healthcare system at large. There is lack of good understanding pertaining to basic mechanisms of apheresis and optimal ways of applying apheresis to the improvement of underlying conditions as well as to the ability of apheresis to enhance other treatment modalities. This in turn is caused by significant shortage of well-educated and trained physician scientists willing to address basic science and translational-clinical questions related to applications of apheresis in clinical practice.

 

Currently there are no specific mechanisms for training such individuals. Utilization of and integration with existing educational/training programs, such as T32 grants, K23/K24/K25 grants, institutional K12 awards and CTSA educational programs would likely result in the cadre of junior investigators who can tackle questions related to basic mechanisms as well as clinical approaches to treating diseases using apheresis strategies.

Feasibility and challenges of addressing this CQ or CC :

Feasibility: Incorporation of apheresis medicine training into currently available resources is likely to be highly feasible. This training can be provided across many medical specialties including hematology, transfusion medicine, cardiology, pulmonology and others. Inclusion of basic scientists involved in research of blood disorders, lung and heart disorders, as well as immunology will expand the outreach. Identification of individuals interested in pursuing research in apheresis medicine might be accomplished on different levels of training starting with medical school, internship, residency and fellowship as well as early years of medical career in a variety of medical specialties.

 

Challenges: The primary challenge is related to perception. Apheresis has an undeserved reputation as an "old" science; one that in recent years has been overtaken at times by newer medical treatments. Yet it still is the only and often life-saving treatment for certain conditions. Apheresis remains the go-to procedure for treating many common and rare maladies alike, such as TTP, and new treatment indications are being added. Although many specialists like hematologists, neurologists, nephrologists see the evidence and benefits of therapeutic apheresis in their everyday work, the progress of Apheresis Medicine as a medical specialty has been generally slow. The other major challenge is lack of funding of basic research and translational research related to Apheresis Medicine.

Name of idea submitter and other team members who worked on this idea : Zbigniew M. Szczepiorkowski, Yanyun Wu on behalf of ASFA

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Strategic Goal: Goal 2: Reduce Human Disease

The importance of cosidering sex and gender in presicion medicine

Precision medicine will be invested in across NIH, as per the President's "Precision Medicine Initiative". It is critical that the population base be reflective of the US population, including 50% women. Gender, especially as it relates to exposures, must be a dominant consideration, as these factors are critical to the development of human disease and therefore will be important to prevention.

Submitted by (@pajohnson)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Precision medicine that can be applied accurately to different groups within o our population, in particular women and racial and ethnic minorities.

Feasibility and challenges of addressing this CQ or CC :

Achieving this goal is feasible and essential.

Name of idea submitter and other team members who worked on this idea : Paula Johnson

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Strategic Goal: Goal 3: Advance Translational Research

Understanding Chronic Lung Disease Subtypes

What are the subtypes of chronic obstructive lung disease that share a common pathogenesis and can be a basis for precision medicine?

Submitted by (@jdc000)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Chronic Obstructive Pulmonary Disease (COPD) is a complex heterogeneous syndrome. The current approach of regarding this disease as a single entity has limited the ability to develop effective therapies and prevention. Understanding the major subtypes of COPD could lead to more biologically relevant disease classifications, improved prognostic information, and precision medicine treatment.

Feasibility and challenges of addressing this CQ or CC :

The optimal analytical approaches and data types to define complex disease subtypes have not been determined.

Name of idea submitter and other team members who worked on this idea : Ed Silverman, James Crapo and COPDGene Executive Committee

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Strategic Goal: Goal 3: Advance Translational Research

Stem Cell Biology

There is a need to develop “designer platelets” and “designer red cells,” as well as facilitate large-scale production of these products for therapeutic and diagnostic use.

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

The reprogramming of adult stem cells has resulted in the generation of induced pluripotent stem cells (iPSCs) that can develop into any tissue of the body. These iPSCs ultimately may be used as a transplantable source of stem cells for a variety of hematologic diseases. Although this technology has enabled the generation of patient-specific or disease-specific stem cells that are also amenable to genetic manipulation, the major scientific hurdle has been the ability to create clinically meaningful functional blood products, including transplantable HSCs from differentiating iPSCs. The production of clinically functional blood products -- i.e. red blood cells derived from autologous iPSCs --could replace allogeneic products in highly immunized patients and the generation of megakaryocytes for patient-specific platelet production from iPSCs could drive significant progress in this area. Furthermore, disease-specific iPSCs could serve as targets for both drug development and drug screening in patients with rare hematologic disorders. In addition, support for scale-up and GMP processes, which are difficult to fund via the R01 mechanism will require specific grant opportunities tailored to infrastructure and process development.

Name of idea submitter and other team members who worked on this idea : Alice Kuaban on behalf of the American Society of Hematology (ASH)

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Strategic Goal: Goal 3: Advance Translational Research

Durable gene activity map at the individual level

A durable gene activity map of the individual to understand when certain gene sets are on vs off or dysfunctional over an individual’s lifetime as one way of guiding the precision of medicine for that patient. It would need to be person portable and universally exportable and interpretable across all of the EHRs.

Submitted by (@greg.martin)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Name of idea submitter and other team members who worked on this idea : Society of Critical Care Medicine Executive Committee/Council

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Strategic Goal: Goal 2: Reduce Human Disease

The role of Extracorporeal Photopheresis (ECP) in the prophylaxis and treatment of acute & chronic Graft Versus Host Disease

In Acute Graft Versus Host Disease (aGVHD), we would like to examine whether early and intensified delivery of ECP as part of standard prophylaxis will decrease overall corticosteroid exposure while preserving expected relapse rates in patients undergoing unrelated donor hematopoietic stem cell transplantation (HSCT). Chronic GVHD (cGVHD) is common after HSCT (30-50% recipients) and is a major contributor to late transplant-related ...more »

Submitted by (@js2745)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Patients who develop aGVHD undergo toxic therapy with high-dose corticosteroids, often for long durations, resulting in high morbidity and treatment related mortality. Alternatively, T cell depletion of the donor graft to reduce GVHD is associated with high rates of infection and relapse of the disease that led to the HSCT. Targeting other pathways of GVHD pathogenesis may preserve the beneficial immune reconstitution and graft-versus-tumor (GVT) effects, while ameliorating the severity of GVHD. One such pathway involves regulatory T cells (T regs), which inhibit T cell alloreactivity, and are correlated with the incidence and severity of GVHD without loss of GVT. To date, there is no consensus on a standard second-line therapy for aGVHD, and current approaches focus mainly on intensification of immunosuppression. Addressing this compelling question will help to decrease overall corticosteroid exposure while preserving the expected relapse rates in patients undergoing unrelated donor HSCT.

 

Appropriate initial therapy for cGVHD involves high doses & prolonged use (yrs) of corticosteroids, while patients still develop irreversible sclerotic manifestations of disease. Early intervention prior to disease onset may help prevent cGVHD development or lessen its severity, requiring less corticosteroid exposure. Addressing the compelling question for cGVHD will help decrease exposure to drugs with associated morbidity, while preserving expected relapse rates in these patients.

Feasibility and challenges of addressing this CQ or CC :

Feasibility:

 

* GVHD has relatively high incidence after HSCT and at the same time there is a lack of consensus on standard second line therapy for the disease. Thus, there will be increased interest in developing and participation in those studies.

 

** ECP is generally well tolerated and complications are infrequent.

 

*** There is a great potential for multi-discipline collaboration approach in this patients’ population.

 

*** There is an opportunity to engage industry partners in the design and support for these studies.

 

**** There are numerous scientific opportunities for meritorious science as there have been limited systematic studies of ECP mechanisms of as well as standardization of apheresis protocols based on GVHD disease state.

 

 

 

Challenges:

 

* Limited number of institutions providing ECP treatment.

 

** Cost of the procedures (although Centers for Medicare and Medicaid Services now covers ECP for cGVHD).

 

*** There is a very limited number of animal models available for apheresis research in general, and studies of the mechanism(s) of action of photopheresis have been very limited as well as difficult and expensive to perform. However understanding pathological mechanisms and its relationship to response to apheresis is critical for optimization and advancement of patient care.

 

****Lack of infra-structure for apheresis research.

Name of idea submitter and other team members who worked on this idea : Joseph Schwartz on behalf of ASFA

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Strategic Goal: Goal 3: Advance Translational Research

Study on the Immunologic Effects of ECP (Extracorporeal Photopheresis)

The clinical use of extracorporeal photopheresis (ECP) is expanding. It is known that dendritic cells plays critical role key to its efficacy, but exactly how ECP impacts other immune components and their interactions is not fully understood. There are many unanswered questions such as: “ What are the critical factors in ECP that result in a shift of the dendritic cell population from immune activating to immune tolerant? ...more »

Submitted by (@yanyunw)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Further basic science research is necessary to elucidate how these cellular activities are functionally integrated and regulated.

It is critical to understand the role of ECP in immunomodulation and tumor immunotherapy, thus better clinical protocol can be developed with optimal immune balance to achieve therapeutic target and minimize side effects.

Feasibility and challenges of addressing this CQ or CC :

Studying immunomodulation in ECP patients offers a true bench to bedside opportunity. Experimental protocols can utilize in vitro, animal and clinical study designs targeted at immunotolerance and tumor vaccines

There are a very limited number of animal models available for apheresis research in general, and studies of the mechanism(s) of action of photopheresis have been very limited as well as difficult and expensive to perform. Funding support is critically needed in this area.

Name of idea submitter and other team members who worked on this idea : Yanyun Wu on behalf of ASFA

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Strategic Goal: Goal 2: Reduce Human Disease

Balancing Risks and Benefits: How Do Clinical Guidelines in Cardiovascular Medicine Promote the Health of an Individual?

Much of the hopes for precision medicine (as outlined Dr. Dr. Collins) are based on deriving large amounts of genomic, proteomic, epigenomic and metabolomic data on large cohorts of patients. It will take decades to build these cohorts and even more time to analyze them and derive specific conclusions on how these will help individualize treatments. However, there is a pressing need for how to individualize contemporary ...more »

Submitted by (@jalees)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Decisions on whether or not to place a patient with atrial fibrillation on chronic anticoagulation or on statin therapy are often based on guidelines and cardiovascular risk calculators.

 

Patients with a higher risk of stroke are more likely to receive anticoagulation and patients with a higher risk of a myocardial infarction are more likely to receive statin therapy.

 

However, these cardiovascular risk calculators do not really take into account the potential side effects and impact on the lifestyle of the patients.

 

Physicians will stop anticoagulation in a patient with atrial fibrillation if the patient has suffered a life-threatening bleed but there are no specific evidence-based guidelines as to how one should proceed if the bleeding is minor.

 

it is easy to compute the cardiovascular risk and overall mortality benefit of placing a patient on statins but how does one factor in the impact that statins have on the quality of life of an individual?

 

Developing novel evidence-based approaches to individualize therapies that factor in cardiovascular benefits as well as potential side effects and diminished quality of life could have a major impact on appropriately using treatments and reduce the arbitrariness of some medical decisions.

Name of idea submitter and other team members who worked on this idea : Jalees Rehman

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Strategic Goal: Goal 2: Reduce Human Disease

Basic Research & Precision Medicine

How can NHLBI best encourage basic research areas that are critical to the development of precision medicine approaches for lung disease?

Submitted by (@skrenrich)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Name of idea submitter and other team members who worked on this idea : Cystic Fibrosis Foundation

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Strategic Goal: Goal 1: Promote Human Health

Use of Evolutioinary Biology in Medicine

Given that chronic diseases are 'Evolutionary Biology' in reverse, can we use developmental and phylogenetic principles to diagnose and treat them safely and effectively?

Submitted by (@johntorday)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Biomedical research is currently in crisis. Both basic science and translational science are failing to provide new insights to the causes of disease and their eradication. Instead, we are encouraged as biomedical researchers to devise ways of eliminating the symptoms of disease. This is a very bad practice since it facilitates the retention of maladaptive genes in the gene pool.

 

This practice is the result of continuing to practice biology and medicine descriptively, like Chemistry and Physics were as Alchemy and Astrology. The lack of a fundamental understanding of the First Principles of Biology originating in unicellular organisms fosters continued study of associations and correlations instead of causal mechanisms. If the National Science Foundation were still funding Astrology, we would see the same lack of predictive value that we see in biology and medicine today. Society cannot afford to continue sponsoring such pseudoscience. This problem is already recognized indirectly due to the failure of the Human Genome Project to fulfill its promise of curing common chronic diseases such as heart attack, stroke, diabetes and obesity. But the withholding of funding from the NIH to shake out the dead wood will not solve the problem, because it is due to the use of the wrong paradigm. Understanding how and why vertebrates evolved on the cellular-molecular level offers a way of understanding causation in biology and medicine rendering them predictive.

Feasibility and challenges of addressing this CQ or CC :

This initiative is highly feasible since we already have the methods available to us in the biomedical research community. The problem is in recognizing that applying 'omics' to the problems we face using same old same old Pathophysiology will not solve the problems of medicine. That precept is founded on Health as the absence of disease, which proved useful for a century, but we are now attempting to tackle more difficult fundamental problems that require a more powerful approach. The Evolutionary Biology approach offers the opportunity to define Health objectively rather than relativistically, i.e. health and disease are a continuum generated by the mechanisms of evolution.

Name of idea submitter and other team members who worked on this idea : John Torday, Virender Rehan, Neil Blackstone

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Strategic Goal: Goal 3: Advance Translational Research

Regenerative Medicine 2.0 in Heart and Lung Research - Back to the Drawing Board

Stem cell therapies have been quite successful in hematologic disease but the outcomes of clinical studies using stem cells for cardiopulmonary disease have been rather modest. Explanations for this discrepancy such as the fact that our blood has a high rate of physiologic, endogenous turnover and regeneration whereas these processes occur at far lower rates in the heart and lung. Furthermore, hematopoietic stem cells ...more »

Submitted by (@jalees)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Some barriers to successfully implementing cardiopulmonary regeneration include the complex heterogeneous nature of the heart and lung.

 

Hematopoietic stem cells can give rise to all hematopoietic cells but the heart and lung appear to contain numerous pools of distinct regenerative stem and progenitor cells, many of which only regenerate a limited cell type in the respective organ. The approach of injecting one stem cell type that worked so well for hematopoietic stem cells is unlikely to work in the heart and lung.

 

We therefore need new approaches which combine multiple regenerative cell types and pathways in order to successfully repair and regenerate heart and lung tissues. These cell types will likely also require specific matrix cues since there are numerous, heterogeneous microenvironments in the heart and lung.

 

If we rethink our current approaches to regenerating the heart and lung and we use combined approaches in which multiple cell types and microevironments are concomitantly regenerated (ideally by large scale collaborations between laboratories), we are much more likely to achieve success.

 

This will represent a departure from the often practiced "Hey, let us inject our favorite cell" approach that worked so well in hematologic disease but these novel, combined approaches targeting multiple endogenous and/or exogenous regenerative cells could fundamentally change our ability to treat heart and lung disease.

Name of idea submitter and other team members who worked on this idea : Jalees Rehman

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