Would You Accept Stem Cell Therapy when other Treatments Fail?

Induced Pluripotent Stem Cell therapy.
Image credit to Nature

I remember asking a resident doctor in the haematology department, during a tutorial in my 3rd year in med school (currently in my 5th year), whether it was possible to revert a fully differentiated cell (like a white blood cell, or a muscle cell) back to a stem cell, a type of cell that makes up the embryo (the earliest form of a baby in the mother's womb). The question was inspired by two things: back in my first year, I came across what is called induced pluripotent stem cells in a biology text because of my interest in genetics and stem cell science, because these stem cell could be generated from any type of cell in the body averting the need to depend on a human embryo ( a lot of ethical opinions against it) for stem cells; and secondly the tutorial was on haematopoiesis (the formation of the different types of blood cells from a type of stem cell in the bone marrow (the equivalent of the sweet stuff you suck when you crack the bone after eating the flesh off a chicken leg).

Induced Pluripotent Stem Cell Potentials. Image credit to Nature

The response of the doctor I reserve the right not to say; but the first reason--inducing an already differentiated cell back to an embryo-like stem cell-- why that question was asked had already been on the minds of scientists years before I came across it in the text because of the immense present and possible future benefits certified success in exploring such possibility holds. And many scientists across the world did begin exploration on this uncharted sea. Progress started emerging in bits from animal studies. But the big bang came from the success recorded using human tissue and cells by Dr. Shinya Yamanaka (he shared the 2012 Nobel Prize for Medicine and won the 2012 Millennium Technology Foundation Prize for this work) at the Kyoto University, Japan. His team was able to induce fibroblast cells (found in connective tissue) and skin cells back to a fully undifferentiated state; they did not stop there: they were also able to stimulate the same induced pluripotent stem cells to differentiate into specialised cells such as muscle cells and nerve cells. This success spread like wild fire across the scientific world; it led to the emergence of, among other things, new ways of working on degenerative disorders, such as Parkinson and Alzheimer diseases, involving the nervous system whose cells do not undergo division, unlike most other cell types in the body, to replace severely damaged or dead parent cells. Scientists were now able to take normal skin or hair cells from patients with these degenerative disorders, revert them back to the stem cell state and then stimulate them to differentiate into healthy nerve cells, enabling them to compare at the molecular level the changes that occurred during the course of the patient's life, up to his or her present age, in the diseased nerve cells with the newly differentiated healthy nerve cells.

The concept of induced pluripotent stem cells removed the need to experiment with human embryos as one can readily induce and form them in the lab from virtually any other cell type in the body. This ease further extended the application of this technique to areas like restoring sight to blindness caused by damage or death of the retinal cells behind the eyes (they are nerve cells in your eyes responsible for sending what you see to the brain for proper interpretation; and blindness can result from their damage or death). While the field of stem cell therapy is still mostly experimental, would anyone advise their grandmother or elderly dad to go for such treatment if they became blind and the eye doctor confirmed the blindness to be due to the degeneration of their retinal cells, and that there were no other treatment options?

RIKEN Centre for Developmental Biology, Japan. Image
to RIKEN

The choice could depend on how much information the eye doctor gives you (and you're legally entitled to every bit of information regarding any treatment modality from your doctor before making your choice of treatment) concerning the benefits and the risks, mostly unknown, of induced pluripotent stem cell therapy. But it seems that a 70-year old woman in Japan is keen to regain her sight after becoming blind from a condition known as macular degeneration (occlusion of the retinal cells by blood vessels, leading to damage to the retinal cells) without minding the possibility of the unknown outcomes that may be more on the negative side. Scientists at the RIKEN Centre for Developmental Biology in Japan, after a consult with Dr. Shinya Yamanaka, used skin cells from the woman to generate embryo-like stem cells after treating them with four genetic factors (details of which I will not bore you with); then, they immersed the induced pluripotent stem cells in the appropriate growth factors to generate retinal cells which they surgically transplanted into the woman's retina at the back of her eyes, following approval from the Japanese ministry of health.

One assurance in this experimental treatment is that the woman's immune system will not reject the transplanted retinal cells as they were made from her skin cells: and this, I believe, will be the mainstay of organ transplant in the future when the field of regenerative medicine will have gone closer to perfection in growing people's tissues and organs from pluripotent stem cells generated from their own body cells (the term 'host versus graft rejection' may find no place in the medical texts of the future). But there are possibilities for unknown negative outcomes in this treatment as well, the most unpalatable for me being the decision of these transplanted retinal cells to turn into a cancerous growth. A less heart-breaking outcome could be the death of the retinal cells and hence their failure to restore the woman's sight: however, science is gaining momentum of control over this possibility, the latest coming from the work of 18-year old Joshua Meier whose award winning research--begun as a class project when he was 14--has identified the DNA deletions in the mitochondria linked to aging and short life span in induced pluripotent stem cells; my guess will be to fully understand the mechanisms of these DNA deletions, and devise ways to avert them, in the process of stimulating induced pluripotent stem cells to differentiate into specialized cells for therapeutic purposes.

Prodigy, John Meier in his lab. Image credit to John Meier

While stem cell therapy with human embryonic stem cells is the approved option in different parts of the world currently, it is facing an ever increasing pressure from ethics experts in various dimensions, some of which are being successful in dissuading potential candidates for stem cell therapy from going for the treatment. But success in this first trial of induced pluripotent stem cell therapy in a human will open a new window of opportunities to the treatment of degenerative disorders, especially when we have learnt virtually all the possible outcomes on the negative side and devised strategies to eliminate them, leaving our patients with degenerative diseases and disorders on the doorstep to regaining a renewed form of their lost life.

Drug Resistance: Man's greatest threat in the survival of the fittest.

Drug Resistance. Image credit to ZME Science

The rate at which microorganisms harmful to our health are adapting to the various treatment modalities (drugs) currently available is very alarming and dreading. It is unfortunate to say that it seems that we're not one step ahead of these tiny, invisible-to-the-naked-eye organisms that are behind the various diseases that have affected humans since the beginning of history.

Prof. Randy Schekman, Nobel Medicine Laureate. Image credit to Nobel.org

Why it seems that we in the medical field are not one step ahead of these tiny organisms there can be many reasons. Topmost among them is the lag in basic fundamental research. Late last year, Professors Randy Schekman, James Rothman and Thomas Suedhof who jointly shared  the 2013 Nobel Prize in Medicine lamented over what they termed a neglect on basic research when the the US National Institute of Health created a Centre for Advancing Translational Sciences. In the words of Prof. Suedhof "......we don't have anything to 'translate' because we just don't understand the fundamental diseases of the brain....". His opinion is buttressed by the fact that there have emerged strains of the tuberculosis-causing organism, Mycobacterium tuberculosis, that are resistant to all known anti-TB drugs; the same could be said of some strains of the Staphylococcus species which cause myriads of diseases in humans. The problem here is that even the most recent drugs used in eradicating these organisms have the chemical structural framework and pharmacodynamics (a drug's way of carrying out its work in the body) that was developed in the 1960s and 70s; and there is no enemy being fought by its adversary with the same tactics over 4 to 5 decades, who will not evolve defence mechanisms that will one day confer on it total immunity from such tactics and also allow it to mount fatal attack on the adversary.

Another reason for this lag in our effort to be ahead of these disease-causing organisms is the lack of a large scale, collective and multidisciplinary undertaking to study in minute details the various ways in which these organisms evolve drug-resisting defence mechanisms. And what I mean here is an undertaking similar to the global Human Genome Project that saw to the successful sequencing of the whole human genome.

Having outlined these two reasons, I would now set out suggestions as regards how we can totally be in control of this fight against these human disease-causing organisms.

Prof. Kary Mullis. Image credit to NNDB

While it may seem that basic research in the area of drug development is not blossoming as we expect it, some tiny silver linnings I can fathom from some corners around the world. The one that comes to my mind is the work being done by the Nobel Chemistry laureate, Prof. Kary Mullis (he won the 1993 Nobel Prize in Chemistry for his invention of the Polymerase Chain Reaction, a technique used to create billions of a single DNA segment in a few hours).His concept of Altermune which he explained on the TED talk show conference is something that will give our tiny, microscopic adversaries a surprisingly lethal blow. Prof. Kary Mullis is taking a new, novel and radical approach towards fighting drug resistance in bacteria and other disease-causing microorganisms. The Altermune concept is a technique that uses an artificially synthesized molecule called Alphamer or Altermune linker to re-direct our own immune system to destroy these invading bacteria and other disease-causing microorganisms. An Alphamer or Altermune linker consists of a short sugar chain (an alpha galactose oligosaccharide)---which normally is not attacked by the body's immune system despite the immune system producing antibodies in response to its exposure---linked to a synthetic DNA segment called an aptamer with a specificity for only a particular strain of a virus or bacterium such that once this particular microorganism (which may be resistant to all available antibiotics, antiviral agents and other drugs in this case) invades the body, the aptamer segment of the Altermune linker binds to it and the antibodies produced in response to the galactose oligosaccharide exposure (but which does not harm it) will in the process be exposed to fresh food (the invading disease-causing organism), destroying it, both personally and by inviting other hungry guys of the immune system---the macrophages, the cytotoxic T cells and the complement system. Prof. Mullis has tested  his new work on mice infected with a strain of Staphylococcus aureus resistant to even the most potent antibiotic---this became his enemy because it killed his professor friend---and recorded almost 100% wipe out of this bacterium from the blood of the mice after a set period unlike in the controls which used various antibiotics such as doxycycline; further studies are going on in other animals such as chicken infected with the flu virus, using Altermune linkers designed for such microorganisms. Human trials will likely start soon, especially if there are emergency cases where the patient could be at the point of death because every other available option has been explored with no results. And this will unleash a whole new field of fighting against microorganisms causing disease in humans (if this works out well in human, Professor Mullis may win another Nobel Prize but this time in Medicine in about ten to fifteen years' time).

Alphamer or Altermune Linker. Image credit to Prof. Kary Banks Mullis

While this is ingenious, there is also great wisdom in exploring other ways so as to have several novel strategies for attacking these current-drug-resistant microorganisms. And I think one possible way to do this is to extend the kind of global interdisciplinary collaboration enjoyed by the Human Genome Project to the study of drug resistance in every known disease-causing microorganisms, not just some small scale collaborative studies that are obtainable currently (however, this is not condemning small scale collaborative researches as they form the foundation for large scale collaborations). Drug resistance by microorganisms comes into play when these organisms undergo mutations. Mutation is a change in the framework of some portions of an organism's genetic architecture responsible for encoding proteins that make up the structure and function vital to its existence and continual survival in the face of factors (drugs and other therapeutic strategies) that threaten them. What if we have what I call the global MutaGenome Project in which researchers from all fields will collaborate at a global scale to map all the genetic mutations in all known disease-causing organisms over generations? These mutations will then be graded on a conventional scale, depending on the extent to which their phenotypic manifestations cause diseases in humans and mount resistance to our therapeutic strategies. By engaging in such large scale endeavour, we create what I call a mutagenomic database from which patterns in which these genetic mutations occur both among similar organisms and across different organism can be outlined, hence enabling us to use mathematical tools---such as the Nash Game Theory, Permutation and Combinations and so on already employed in evolutionary biology---to predict possible future genetic mutational patterns, outcomes, and understand clearly the working dynamics between each particular threat at the molecular level (in the form of therapeutic modalities) and mutational response (resistance development) in these organisms. This could then lead to different predictive therapeutic designs for a particular bacterium over time in response to its possible resistance development options. With this approach we can have centres for MutaGenomics and MutaGenomic Therapy (Mutational Genomics) in universities and research institutes around the world designing novel therapies for various diseases.

This is a very daunting and big ambition. But we did it in the Human Genome Project, and we can also do it in the global MutaGenome Project.