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Nov 26, 2014

A fanciful approach to curing ageing: biotechnology in clinical practice

Posted by in category: life extension

Technologies based on stem cells, genetic engineering or tissue engineering may eventually have considerable impact in alleviating certain diseases such as arthritis, heart disease, or dementia. But these rejuvenation biotechnologies cannot be used by the general public at large in order to negate the ageing process itself.

1. Problems with Stem Cell Therapies

One methodology for delivering biotechnology rejuvenation therapies (such as stem cell therapy) is bone marrow transplant. This is a complex, clinically risky, and administratively complicated procedure. It is well beyond the technical issue of artificially manipulating and repairing cells in the laboratory. Cells need to be harvested from a patient, manipulated in the laboratory, and then re-transplanted in the patient.

Consider what happens during an autologous cell harvest. The patient has to attend a clinic and this may involve a pre-procedure physical assessment, followed by administration of a Colony-Stimulating Factor which is given as an injection every day for up to 14 days, (the patient must be instructed on how to do this at home). A course of chemotherapy may be needed in order to regulate the production of stem cells. The patient returns for another visit for the harvest. The harvesting process takes three to four hours and it may have to be repeated every day for up to five days in order to collect enough cells for the transplant. It involves an epidural or a general anaesthetic (with all the associated risks), punctures over the pelvic bone and withdrawal of marrow material. Alternatively, intravenous access and blood withdrawal need to be arranged. The amount to be withdrawn must be assessed from person to person. The patient needs to recover from the anaesthetic.

After appropriate laboratory treatment of the cells, the patient needs to return for the transplant itself. The patient will again need to have a pre-treatment visit and (a full day) assessment, pre-treatment conditioning with insertion of an indwelling central venous access line, followed by intravenous (or intra-bone marrow) injection of primed stem cells, (which may need to be repeated the following day or more times soon after).

Following the procedure, it is necessary to observe the patient due to the risk of infection, and the patient must be kept in a germ-free environment, in some cases for up to three months (in hospital). The follow-up period can be one or two years in some cases, and there is a need for specialist nutritional input, home care, occupational therapy, medical follow-ups and regular clinic appointments. Even then, the fate of the injected stem cells remains unclear, both in functional and in duration terms. For instance, the injected stem cells need to develop cross-talking pathways with existing mesenchymal and endothelial cells, which involves a precise, co-ordinated, dynamic and hierarchical expression of genes and proteins, many of which are based upon stochastic elements, which are impossible to predict. This may influence the lifespan of the injected stem cells and require an earlier-than-planned re-treatment.

2. Problems with Tissue Engineering

Another proposed biotechnological therapy against age-relate degeneration such as abnormal tissue function due to cell loss, is tissue engineering. Although the technology necessary for developing large amounts of viable engineered tissue such as bone, skin or even heart can be achieved, a major problem is the transplantation of this engineered tissue to the appropriate organ in humans. Autologous cells must be harvested from the patient, either surgically or through a bone marrow procedure as discussed above, and then, following appropriate engineering interventions, transplanted surgically in the patient. The clinical sequences of the procedure, particularly those involving more advanced techniques such as in situ or in vivo tissue engineering may take a year from beginning to end. Therapies involving allogenic tissues will require lifelong immunosuppression. This would be a therapy for one type of tissue, and therefore the entire procedure would need to be repeated for other types of tissue, until all tissues affected by age-related damage would have been repaired. Questions about the number of qualified surgeons needed in order to carry out these procedures en masse would need to be addressed. Pre and post procedure assessments, physical rehabilitation therapy, follow up meetings, risk of infection or thromboembolism, and other intrinsic consequences of surgery would add to the existing difficulties.

3. Problems with Genetic Therapies

As a concept, gene therapy appears ideal in treating ageing changes. However, this is an oversimplification fraught with clinical obstacles. It is known there are several hundred genes that can modulate the ageing process. In mice alone there are over 100. Issues with pre-existing immunity to the vector, choice of vector, costs, dose, and many others need to be addressed. Non-viral vectors such as liposomes or methods based on nanotechnology need to be given to the patient via an intravenous route with all the problems discussed above. The new gene may not be inserted correctly on the DNA, or it may be overexpressed, causing more problems than it resolves. The risk of introducing infection or inducing a cancerous change remains.

For these and other reasons, the progress with gene therapy has not been as vigorous as expected. New techniques such as CRISPR cannot easily be applied in clinical situations involving humans. The current administration technique involves a hydrodynamic injection method which in mice has been proven effective in some experiments, but remains unusable in humans.

Discussion

These methods of administration are likely to remain the same (with minor, irrelevant to this argument, technical modifications) in the near-term (10−15 years) and perhaps the medium-term (20−50 years) future. Bone marrow transplant, is currently an appropriate method for patients who have one specific disease, but its applicability must be rigorously questioned when it is intended for people who have many co-existing age-related conditions. Our medical systems can tolerate this type of treatment if it is directed at a few patients having one disease each. But a single stem cell therapy will not have an effect on multiple conditions or organs, therefore if we consider that there are many organs needing treatment against ageing, then this becomes a clinical and administrative nightmare. However, it becomes an impossibility when, in addition to the above, we aim to treat large numbers of people. Worldwide, there are approximately 60,000 bone marrow transplants (BMT) performed each year. If we assume that, over a 10 year period, an arbitrary minimum 1% of all humans could possibly be treated with BMT-dependent rejuvenation biotechnologies each year, then there will be a need to provide 70,000,000 BMT a year! Or, viewing this from another angle, assuming a reasonable yearly 20% increase in our clinical capability to deliver rejuvenation biotechnologies, it will take us 10 years to reach a mere 1 000 000 target patients, (and at that point, the procedures would need to be repeated in the same patients, in order to maintain the status quo). Therefore, even in the best case scenario, we could only possibly treat 0.015% of humans, ever.

In addition, patients would need to undertake other rejuvenation procedures such as vaccinations, cytotoxic and other drugs, multiple crosslink breakers (drugs or enzymes), intravenous immunotherapy, apoptotic-modulators, and other treatment modalities. And this has to be repeated until all organs or tissues where there is accumulation of age-related pathology have been treated. But this is not the end, as all of these procedures will need to be repeated in the same patient in perpetuity (in order to achieve a continual absence or age related pathology for an indefinite time). Let me look at the matter in a different way: One cycle of treating one aspect or group of damages via bone marrow transplant, realistically takes a minimum of 2–3 months. It is likely that the same patient will need to undergo the bone marrow stem cell transplant procedure again in order to treat different organs such as brain degeneration, pancreatic or liver damage, or visual age-related damage. If each such cycle takes 3 months, then there will not be enough months in the year for any patient in order to have the full treatment for each and every organ or tissue. The quality of life of the recipient will be reduced to a minimum, and it will be a miserable and endless cycle of hospital and clinic visits, treatments and follow-up appointments repeated into perpetuity, a kind of dystopian, dehumanised society. The above discussion refers to the difficulties encountered during a scenario where we aim to treat just 10% of humanity. If we now consider the difficulties associated with treating the other 90%, then it must be obvious even to the most ardent advocate of rejuvenation biotechnologies that this method of addressing the ageing problem becomes an impossible delusion.

We should also acknowledge the possibility that, although some therapies could be developed, these may not by themselves result to any appreciable benefit for the patient until other therapies have also been developed and deployed. For instance, if a therapy is devised against atherosclerosis but not against cancer, the patient will perish from cancer-related damage, even if their arteries are healthy. So all of the above interventions need to be developed at an appropriately advanced clinical stage.

At this point it may be worth reiterating that I fully recognise the value of biomedical regeneration technologies but only insofar these are applied on specific and isolated diseases, and not on the biological process of ageing itself. Rejuvenation biotechnologies will not be of any value for the great majority of us who are aiming to avoid ageing and live a life without chronic degeneration.

http://www.ncbi.nlm.nih.gov/pubmed/25072550

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Comments — comments are now closed.

  • Jerome on January 22, 2015 3:29 am

    Hi Marios
    Good points indeed.
    I can however add that MOST humans currently alive will not be interested in any anti aging treatments or at least not a cure for aging. To get these people to change their minds will require an enormous amount of education, and then still no guarantee. The ones who are and will be interested in the future, will be a fraction of the total population of the planet. So, chances are that treating the entire planet’s population is not going to be an issue at all. For those only wanting treatment that will make them age healthier, I suppose that type of technology will not be too complex to administer, at least not 30 years from now. Maybe just one quick visit to the doctor. Or maybe self medication on a daily basis.
    The fact of the matter is, if you remove the “code” that’s responsible for causing the aging process, then there shouldnt be any aging taking place, or at least only a fraction of the current amount. Then add to that continuous repair and maintenance of damage caused by other external factors, then you should be able to live to 1000 yrs quite easily.

  • Marios Kyriazis on January 22, 2015 9:22 am

    It is true that most humans will not take part in the cure for aging. My discussion assumes a maximum of 10% of humanity. And I agree that if we somehow remove the reason responsible for aging, then aging won’t happen, but I don’t think that this will be effected via a biotechnological or medical treatment. It will happen based on reasons found in evolution and technological culture in general.