Genetic and environmental rejuvenation of aging stem cells

The Buck Institute for Research on Aging held a symposium on Stem Cell Research and Aging March 1-2, 2012 in Novato, California. A range of levels of talks were given by scientists in the field to an audience of approximately 100 people. Three of the overall themes included a focus on the commonality of systemic cellular processes in development, aging, and rejuvenation, the importance of intervention in middle age when pre-clinical conditions are already in effect (for example, synapse loss, and over/under-expressed transcriptional profiles), and some of the challenges encountered thus-far in human stem cell clinical trials. The stage of the research is still more focused on characterization in a variety of model organisms rather than translational intervention for humans. Two of the most interesting areas of presentation were epigenetics and neurodegenerative disease.

Epigenetics
Since a good definition distinguishing young and old cells is not yet available, it was suggested that a cell’s epigenetic state and transcriptional network could be used to determine cell age and measure the impact of rejuvenation interventions. The stem cell environment is a critical factor to stem cell health and operation, and it has been found that aging can be reversed by altering the stem cell environment. One technique uses heterochronic parabiosis (pairing older and younger cells together), where each cell takes on the expression profiles of other. Genes that are downregulated in aging are reexpressed when exposed to younger cells, and stem cells put in an old environment take cues and act old (e.g.; have different expression profiles and lose lineage fidelity). Other rejuvenation techniques involve manipulating the transcriptional network, the networks of small RNAs that regulate the stability of the stem cell niche, and function appropriately in younger cells but not in older cells. However, in addition to heterochronic parabiosis, muscle stem cells may be rejuvenated through transcriptional interventions such as overexpressing the protein upd, activating the notch gene, inhibiting the Wnt gene or the TGF-beta gene, and stimulating proteins secreted by embryonic stem cells. The good news is that given the right genetic and environmental clues, aging cell states may be reversed.

Neurodegenerative disease
Regarding neurodegenerative disease, there is a new understanding of human cortical neurogenesis; that it occurs in the outer sub-ventricular zone (OSVZ) as opposed to the ventricular region, which also may explain how so many cortical columns are generated. The results of a four-year NINDS-sponsored clinical trial injecting fetal brain stem cells into aged patients with Parkinson’s disease were discussed; that the outcome and side effects were discouraging. This type of trial might fare better in patients who did not already have the movement disorder dyskinesia and with an improved understanding of the biological mechanisms of the disease, and better cellular delivery methods. Also regarding Parkinson’s disease, synapse loss is already beginning in middle age; for example there may be a 60% synapse loss before the disease is detected. Pacemaker neurons degenerate synapses and then synapse loss degenerates soma (the cell body of neurons).

Cost of each new drug: $1.3 billion

The Tufts Center for the Study of Drug Development¹ estimated that it was costing $1.3 billion in 2006 to bring each new drug to market. Why is it so expensive and why does the cost keep growing precipitously? There have been some technology advances, but they are expensive and have helped to raise the number of discoveries but not the number of approved drugs. Little cost-scaling is available at present for the clinical trial and production process bottlenecks of current drug development.

Quadrupling from $318m (1987) to $13 billion (2006).
Tufts Center for the Study of Drug Development¹

Biggest cost component: clinical trials
The biggest cost in bringing a new drug to market is human clinical trials, and these costs continue to grow. Without standardized electronic health records and other obvious initiatives, it is time-consuming and costly to source and enroll appropriate clinical trial participants. The cocktail problem is also in effect as people have had more varying health issues and remedies over time. The amount of detail to be collected and assessed increases and homogeneous and isolated factor patient comparisons are more difficult.

Increased complexity and amortization of failed drugs
The low-hanging fruit drugs have already been discovered. The diseases currently studied have less readily identifiable and more complex target molecules in the body. The target molecules have more intricate biological interactions and less easily matchable compounds for therapies. Each successful drug includes the cost of failed drugs as only one in five marketed drugs is able to pay for its R&D costs.

No cost decreases for biologic drugs
One of the main kinds of drugs produced starting in 1998 is biological drugs. These are drugs that mimic the effects of substances naturally made by the body. The fixed time, process and other costs required to produce these genetically engineered substances means that economies of scale do not ensue for larger volumes. This is compared to traditional drugs which became cheaper over time in production, helping to offset the cost of new discoveries.

Unclear benefits of newtech
How can the paradox of technology advances yet constant numbers of approved drugs be explained? Technology advances have been proliferating in areas such as mass spectrometry, protein crystallography, chromatography, flow cytometry, microfluidics, genetic scanning and synthesis and atomic force microscopy, all of which are helpful but expensive. The ongoing cost to maintain a state of the art lab has skyrocketed. Newtech has meant that the rate of discovered substances and medicines in development is increasing (2,700 compounds are in development in 2007 vs. 2,000 in 2003)², but the complete process of creating viable therapies and moving them through clinical trials to approval is the bottleneck.


¹ J.A. Dimasi and H.G. Grabowski, “The Cost of Biopharmaceutical R&D: Is Biotech Different?,” Managerial and Decision Economics 28 (2007): 469-479
² Adis R&D Insight Database, 27 February 2008