It is once again time to suggest possible areas of focus for new startups intending to develop means to treat aspects of degenerative aging, or accelerate that development. We live in the formative decades of a barnstorming era of endless possibility when it comes to biotechnology and the manipulation of cellular biochemistry. Sadly, this is joined at the hip to a risk-averse regulatory environment determined to bury every new idea beneath an ever-expanding sea of costs and requirements, most of which are unnecessary. Of the realm of the possible in biotechnology and pharmaceuticals, very little emerges from laboratories and successful animal studies to successfully make the leap into human medicine, and the vast costs force much of that progress to focus on unambitious incremental steps forward, rather than more rapid, radical progress.
Still, even within this dire state of affairs it is possible to build ambitious new medicine. The best approaches can still obtain backing. There are many, many dire unmet needs in the patient population. Aging corrodes the bodies and minds of the entire population, imposing a vast cost on individuals, governments, medical systems. Every potential therapy capable of repairing some of the cell and tissue damage of aging in order to produce rejuvenation has a potentially vast market at the end of the day. That motivates investors even given the daunting hurdle of regulatory costs that lies between a promising preclinical therapy and its adoption in the clinic.
Better Approaches to the Chronic Inflammation of Aging
The present dominant approach to chronic inflammation characteristic of aging and many age-related conditions is a broken record: identify a signal molecule or molecular interaction involved in the inflammatory response, and find a way to suppress it. Small molecules, siRNAs, and monoclonal antibodies are all excellent tools to achieve this sort of result. The identification of targets and attempts to interfere in these targets represents much of modern medical development. The problem here is that the immune system makes use of exactly the same signals and pathways for unwanted chronic inflammation as it does for necessary short-term inflammation. Well established TNF inhibitor therapeutics in use for more than 20 years illustrate the problems facing every future therapy based on this identify-and-interfere approach, in that all such treatments degrade the effectiveness of the immune system as a side-effect of reducing inflammation. There must be a better way forward.
Reversal of Cellular Senescence
Considerable skepticism has attended efforts to reverse cellular senescence, to force such cells back into the cell cycle and change their behavior back to that of an ordinary somatic cell. Senescent cells exhibit a lot of DNA damage as a result of entering the senescent state, and further, many senescent cells are senescent for good reasons - such as potentially cancerous DNA damage. All this said, recent data demonstrates that reversal of senescence throughout the body of an aged mouse is in fact beneficial, producing improved health and extended life. Thus it seems a good time to work towards novel means of allowing cells to escape senescence, expanding on the existing small portfolio of approaches, and better assessing the long term results of doing this in larger mammalian species.
Build a Gut Microbiome in a Capsule
The composition of the gut microbiome changes with age in ways that provoke harm: more inflammation, and the generation of fewer beneficial metabolites. How to address this? Fecal microbiota transplantation enables permanent alteration of the gut microbiome. In animal studies, transplanting a young microbiome into old individuals produces lasting rejuvenation of the gut microbiome, and consequent improvements in health and extension of life span. Unfortunately, there is something like a 1% risk per year in young adults of developing one of the number of chronic pain or autoimmune-like idiopathic conditions, such as fibromyalgia, that may be caused by as yet unmapped microbial activities in the gut microbiomes of patients. If a donor who is otherwise screened as clear of pathogens goes on to develop such a condition, the recipient may do so also. This is a risk that cannot presently be quantified, too little is known.
The solution is to produce artificial gut microbiomes with known constituents, building up to the scores of microbial species known to change in prevalence with age in suitable bioreactors. Delivery could involve, say, use of a handful of enteric-coated capsules to delivery a few ounces of material via oral administration rather than an enema as is presently the case. This goal requires a considerable advance over the present state of the art for culturing commensal microbes at scale. It is, however, the most likely endpoint for this end of the industry. Those developers who are first to market with pseudo-natural youthful mixes of gut microbiota capable of producing lasting change with a single administration will likely do well.
More Initiatives Aimed at Repairing the Aged Extracellular Matrix
The extracellular matrix changes in many ways over the course of aging. Some of this is the result of altered behavior in the cells responsible for maintaining the matrix. Perhaps the most well understood of these situations is the path to osteoporosis, where the activity of cells breaking down bone extracellular matrix progressively outweighs the activity of cells building up bone extracellular matrix. But more generally, all too little is understood of the ways in which maintenance of the extracellular matrix changes with age, how these changes cause further harm, and how best to intervene somewhere close to the causes of these problems.
Further, beyond the question of cell maintenance of the extracellular matrix, matrix molecules become altered and damaged in ways that provoke harm, such as through altered cell behavior in reaction to matrix changes, or altering the physical properties of the tissue, such as elasticity. Cross-linking of molecules is one of the better known issues, but while considerable effort has been devoted towards expanding the size of the research community involved in studying cross-linking, there is a long way to go yet. Few efforts have made the leap to for-profit development. More initiatives here would be welcome, particularly in areas beyond cross-linking where comparatively little work has been carried out on harmful matrix alterations, their characterization, causes, and possible remediation.
An Infrastructure for Cheaper, Faster Clinical Trials
Clinical trials are far too expensive. This dramatically slows the pace of development, and leads to a situation in which a whole range of interventions are never rigorously assessed because it would be impossible for investors to recoup the cost of a clinical trial. Small initiatives have nibbled away at the edges of this problem for years, largely with only small gains to show for it. They range from crowdfunding trials for off-patent drugs such as rapamycin to attempts to establish parallel clinical trial infrastructures outside the US and EU. That latter path has on the one hand given rise to the Australian clinical trial industry which enables early stage trials to run at something like half the cost of the US, by greatly reducing the requirements for GMP manufacturing, and devolving most of the regulation of trials to competing institutional review boards rather than a centralized government agency. At the other end of the spectrum, initiatives such as Próspera attempted to build an even cheaper solution with a far more libertarian regulatory framework. In between these two extremes, one finds countries such as the Bahamas or Eastern European nations trying to attract a clinical trial industry by offering lower regulatory burdens, tax incentives, and cheaper costs.
The existing US and EU pharmaceutical industry, deeply embedded in regulatory capture, is hostile to most of the efforts made to escape the regulatory costs of clinical trials, as it wields those costs as a defense against upstart competitors. The biggest challenge facing any novel effort to reduce costs and streamline trials beyond the line in the sand set by Australia is that companies taking advantage of the lower costs and regulatory burden will suffer attacks on their reputation, informal censure and hindrance by regulators, and other consequences should they try to proceed with clinical development in heavily regulated markets such as the US and EU. Most biotech startup entrepreneurs look at what that would do to their ability to obtain future funding and avoid this path. A solution to this problem is very much needed, one that provides the right incentives to build a sizable parallel clinical trial infrastructure that can operate at a fraction of the present cost.
Fix Medical Tourism, Free the Data
Medical tourism is an extremely messy industry. Discovery of and comparison between the clinics scattered between jurisdictions is extremely difficult, next to no clinic publishes any data beyond a few carefully cherry-picked case studies, and there is little development of an industry of guidance and review to assist with these problems. Nonetheless, enormous amounts of data are being generated for forms of stem cell therapy, to pick one example, and then essentially thrown into the void. There is no incentive for any given clinic to submit to rating and review, or to publish data. There is no incentive for clinics with particularly successful protocols to share those protocols or their data. Too little is known of how to optimize protocols around cell therapy and exosome therapy, a very data-driven endeavor. In principle, there is a vast mine of valuable data out there waiting to be tapped, to accelerate progress and improve widely used therapies. In practice the incentives all line up against that outcome. Somewhere out there is a way to do better than this.
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