Attracting private sector support earlier in the development pipeline would help fill an important funding gap between academic discoveries and product commercialization, enabling products to reach patients more quickly, and improving the return on NHLBI’s investments in basic research.

Some existing initiatives such as the SBIR Phase IIB Bridge and Small Market Awards encourage non-federal investors to invest earlier in NHLBI-funded technologies. In addition, the NCAI is designed to support critical feasibility studies and business case development to de-risk earlier investment by the private sector. These efforts are showing early signs of success, but impact only a small proportion of NHLBI-funded basic research discoveries.
Estimates for the cost of developing a new drug or device range from the hundreds of millions to billions of dollars and 10-15 years to get from the lab to the patient. The NHLBI cannot fully support that development, so private sector support is critical for biomedical technologies to be commercialized. Overall private capital investment in the life sciences is increasing, but it is not being targeted at heart, lung, blood, and sleep technologies or at the seed stage of development. Venture capital investment in heart, lung, blood, and sleep technologies has declined or remained stagnant since 2008 (http://graphics.wsj.com/venture-capital-and-the-human-body/) and seed stage investment from the private sector for early stage high-risk projects is in short supply (PWC Moneytree: https://www.pwcmoneytree.com/HistoricTrends/CustomQueryHistoricTrend).

Understanding the molecular and cellular bases of differences in prevalence and outcomes of lung diseases will offer insight into disease mechanisms and help to address disease disparities. Some potential bases for disparities, such as differences in hormone levels between men and women, could potentially be therapeutically modulated to mitigate the effects of disease.

The increased understanding of lung cell biology, along with a renewed focus on sex and gender differences, make this the perfect time to start addressing these questions.
Multiple diseases affecting the lung, such as LAM (lymphangioleiomyomatosis), sarcoidosis, asthma, and COPD, have distinct prevalence or associated mortality in a sex-dependent manner. The reasons for these differences are still unknown.

The current standard-of-care for sepsis patients involves supportive therapy and the early administration of antibiotics, which has been essentially unchanged in 40 years. Therapies that prevent the loss of immune cells are likely to be beneficial to avoid immune suppression and prevent the development of life-threatening systemic infection.

One of the challenges of addressing this question are the large number of biochemical pathways that influence hematopoiesis. Most have not been studied in the context of infection in animal models or in clinical samples. But many animal models and reagents exist that would enable researchers to study this problem. The study of hematopoiesis during infection is feasible and a number of broad questions could be addressed:
a. Do hematopoietic cells and their precursors undergo cell death in response to intracellular pathogens leading to immune suppression?
b. Are hematopoietic cells and their precursors affected by extracellular pathogen-derived products or host-derived molecules resulting from severe injury? Does this lead to cell death and/or prevent the proliferation and differentiation of hematopoietic stem and progenitor cells?
c. How do genetic factors, chronic infection and comorbidities increase the activity of cell death pathways and/or impair the proliferation and differentiation of hematopoietic stem and progenitor cells?

With the challenging NIH funding climate, many junior investigators are struggling to obtain their first R series grant. Without better support of our junior investigators, the next generation of investigators in academic medicine is in peril.

While novel RBC storage methods have been described, the mechanisms underlying their efficacy has not been defined, a step that will be important for further improvements in this area. Some of these methods appear to improve efficacy of the RBC bioenergetic pathways; however, to date there have not been notable advances in reducing cytoskeletal defects common in stored RBCs. The development of new RBC preservation methods that minimize the impact of the storage lesion on specific areas of concern (e.g., diminished oxidation/peroxidation, decreased membrane fragility) is needed.

Use of ex vivo generated RBCs is an alternative to conventional donor-derived RBCs which can potentially improve product consistency, reduce the storage lesion, and improve safety. However, advances are needed before this approach is feasible on a large scale. While the development of blood substitutes including blood pharming will likely require more than 3-10 years before it can be ready for the clinic, Blood Pharming from hematopoietic stem/progenitor cells is now technically feasible and the recent development of genome editing methods suggests the exciting possibility of generating GMP compliant “immortal” stem cell sources to produce transfusable RBCs.

Research should include both pre-clinical and clinical studies to define optimal combinations of known factors preserving red cells (e.g. hypo-osmolarity, energy sources, antioxidants), and the development of methods for RBC pathogen reduction that do not increase the storage lesion.

Procedures for generating blood cells from cultured stem/progenitor cells is not currently cost-effective, limiting near term applications to special patient populations such as specific RBC phenotyping of rare donors for chronically transfused patients. Areas of research needed to advance the development of blood substitutes and blood pharming include: (a) new approaches to blood substitutes including artificial oxygen carriers generated from red cell lysates/components or engineered from combinatorial chemico-biological approaches (e.g., derivatization of hemoglobin, encapsidation of modulated oxygen carriers); (b) a better understanding of the biological properties of cultured RBCs with the goal of reducing blood pharming costs; (c) optimizing methods to expand stem cell populations while allowing differentiation to selected clinically relevant blood cell populations at clinically relevant levels; and (d) optimizing methodologies that faithfully replicate embryonic development to develop the cells of interest.

Understanding pathophysiology of coagulopathy in trauma patients due to these drugs may lead to innovations in management of coagulopathy and help increase our ability to predict/prognostic poor clinical outcomes in patients on these new anticoagulants, detect these drugs in a timely manner and develop antidotes/reversal agents. 

These are eminently feasible with adequate support from the NHLBI. Challenges will be finding collaborations or institutions that have enough clinical volume and adequate basic science/translational research infrastructure to look at these questions seriously.

Developing tools to facilitate and streamline the day-to-day performance of clinical trials would help investigators and NHLBI alike. Trials would recruit more quickly, at less cost. We could, therefore, potentially fund more trials. In addition, if we have common templates, this would facilitate a number of things ranging from peer review to IRB submissions, and would also be beneficial to new investigators by providing a framework for them to use.

Some of it will involve 'just doing it' - for example, we have the capability now to require common protocol and informed consent formats. We have sufficient data to develop performance milestones and implement them. The hardest part will be figuring out how to develop pools of patients, or with which organizations to collaborate in order to achieve this. However, 5-10 years should be ample for this and related activities.
For example, we need to emulate and collaborate with other organizations in figuring out how to identify large numbers of patients willing to participate in our trials. We need performance milestones and metrics, and we need tools like common templates for protocols and informed consent forms that all NHLBI-funded trials would use.

Exploring and understanding the molecular determinants of pulmonary failure will impact not only the predictable complications of acute respiratory illnesses such as influenza, but also inform our understanidng and treatment of myriad other common respiratory illnesses resulting in pulmonary failure, such as pneumonia, chronic obstructive pulmonary disease, asthma, obesity hypoventilation, etc.

Patients receiving critical care services in the United States are among the most close monitored, including continuous monitoring of cardiorespiratory physiology. This highly monitored population is a nature source for studying longitudinal changes in molecular patterns and respiratory physiology.