Stem cells in tissues exhibit unique metabolic states that could distinguish them from other more specialized cells. Using a new type of microscopy we can image the metabolic states of cells in living tissues and, therefore, attempt to identify stem cell populations. Because stem cells can give rise to tumors that are metabolically very different from normal tissues, being able to identify cells that are about to form tumors could be immensely useful for early cancer diagnosis. Such methods can also be used to study embryonic stem cells as a model of early development, thus providing new information about early development and the risks to the embryo from the environment. along a continuum of oxidative phosphorylation and glycolysis that can be used to distinguish them from differentiated daughters and from surrounding niche cells. If successful these methods could be used in clinical settings for better diagnoses of human disease.
A goal of Prop 71 is to take basic stem cell research to clinical application. Disability and loss of earning power and personal freedom resulting from a disease are devastating, creating a financial burden for the State in addition to suffering caused to patients and families. Therapies using human stem cells have the potential to change millions of lives. Using hES cells as disease models will help us understand the underlying causes of disease and aid in the development of drugs to treat them. Our research is aimed at identifying key changes in stem cells in normal development and disease. These studies could aid in understanding normal developemnt, risks to the embryo, as well as early cancer detection. Anticipated benefits of our research include:
1.Development of new cell-based treatments for diseases
2.Improved methods for understanding development and risks to the embryo
3.New methods for detecting effects of toxicants in the environment/workplace
4.Development of new methods for developing drugs for treating disease
5.Transfer of new technologies and IP to the public realm with resulting revenues coming to the state
6.Creation of new biotechnology companies based on new IP
7.Creating research teams with a competitive edge for obtaining out of state funding
8.Creation of new jobs in the biotechnology sector.
It is anticipated that, in the long term, the return to the State in terms of revenue, health benefits for its Citizens and job creation will be significant.
The applicant has developed a non-invasive imaging technique to visualize metabolic states of individual cells within living tissues. The goal of this Exploratory Concepts proposal is to determine whether this methodology can be used to distinguish stem cells from their differentiated derivatives and surrounding cells, and to study the dynamics of stem cells and progenitor populations within their niche. The applicant will test this premise by exploring the effect of key growth factor pathways on the metabolic output of human embryonic stem cells (hESCs) and comparing these to the changes that occur during normal embryonic development (Aims 1 and 2). In a third Aim, the applicant will test whether changes in growth factor signaling pathways alter the metabolic output of adult stem cells and whether these changes can be detected non-invasively.
Novelty and Transformative Potential
- Reviewers found the concept of adapting this recently described, non-invasive imaging technique towards investigating fundamental questions of stem cell biology to be innovative. If successful, this project has the potential to advance high-efficiency stem cell differentiation methodologies, to provide insights into early human development, and to provide a method for detecting abnormal or precancerous cells in adult tissue.
- If successfully implemented, the proposed imaging technology could overcome the need to invasively label cells for study and provide dynamic insights into biological processes that are typically assessed through static methods. If made broadly available, these advantages could represent a breakthrough for the field.
- The proposal is high risk, since it has not yet been firmly established that human cells, which have lower metabolic rates than their murine counterparts, could be imaged with a similar level of resolution. There are preliminary data, however, to suggest that this may be possible in some circumstances, and the applicant plans to test this premise in different contexts.
- It is not clear how useful the imaging approach would be in deep or dense tissues, or whether it could be modified for clinical use.
- In terms of biological insights, reviewers found Aim 3 to be the most novel and interesting part of the proposal. Aims 1 and 2 are focused on more routinely studied mechanisms, but may prove useful for testing the capabilities of the imaging approach for revealing new information.
Feasibility and Experimental Design
- Some reviewers considered the scope of the proposal to be excessively broad, involving a broad range of experimental procedures in three different model systems, with little allowance for failure. While they were not convinced the research plan could be realistically achieved within two years, reviewers acknowledged that completing even one of the goals could represent a significant contribution.
- The research plan lacked various details about experimental design, and how new data would be interpreted in the context of previous findings.
- The Facilities and Environment in which the research will be conducted are conducive to project success.
Principal Investigator (PI) and Research Team
- The PI is a highly experienced investigator with relevant expertise in pluripotent stem cell and developmental biology. He/she has a good track record of publications, including some related to the new imaging technology.
- The research team comprises an interdisciplinary group with expertise in stem cell biology, development, biophysics, and pathology.
- Some key members of the research team are fairly early in their career paths and have limited track records by which to judge their productivity, especially in the areas of mouse embryology and adult tissue biology. It may prove especially challenging to translate the imaging approach from live cells into organoid culture (Aim 3).
-Some reviewers were concerned that a key developer of the imaging approach, who has worked with the PI previously, was not specifically named as a collaborator on this grant application.
Responsiveness to the RFA
- The proposed research, including the determination of cell fate and identity, is directly related to stem cell biology and responsive to the RFA.
- Reviewers considered the non-human studies proposed in this application to be justifiable and translatable to the human system, but noted that the majority of work would be undertaken in mouse tissues and that human/cells and tissues could be more prominently included.