Induced Pluripotent stem cells are human cells that can become any kind of cell. During the past several decades, the technology for harvesting stem cells has increased to the point where several different functional human cell types can now be created using stem cells. Within the next decade, virtually every type of cell in the human body will be harvested using pluripotent stem cells. The Cellular Dynamics corporation is at the forefront of this technology. In an interview with Sander Olson, Cellular Dynamics Vice-President Chris Parker describes how this new technology could be used to treat a wide variety of diseases, and how the frenetic pace of innovation within this field could even increase.
Question: What are induced pluripotent stem cells, and why do they hold so much potential?
Pluripotent stem cells are stem cells that can differentiate into any type of cell in the human body. In contrast, adult stem cells have already chosen their differentiation path - so an adult cardiac stem cell can only turn into a type of cardiac cell. We derive induced pluripotent stem cells by taking blood samples from patients and extracting CD34+ cells from the blood. These cells are induced by a reprogramming process to a pluripotent stem cell state, at which point they can be differentiated into any cell type. Thus far we have made about a dozen different cell types, but plan to eventually have the capability to make any cell type found in the human body in any quantity desired. We are currently selling these cells as research tools, but this technology will eventually be used for a plethora of applications.
Question: How exactly does this process work?
We inject two or three plasmids containing the genes discovered to cause reprogramming into an adult cell, like skin or blood, and the plasmids reprogram the cells to turn into induced pluripotent stem cells. Importantly, the presence of these plasmids is transient; that is, they do their job of reprogramming and then leave the cell without manipulating the cell’s DNA. During early development, human stem cells follow three distinct developmental pathways to form the primary germ cell layers: mesoderm, ectoderm, and endoderm. These three germ cell layers then further differentiate to become all the tissues in the human body, and CDI has made cells from each of these germ layers. Researchers have created dozens of different types of terminally differentiated cells as proof of principle from iPSCs, including heart cells, neurons, liver cells, retinal epithelial cells, muscle cells, blood cells, skin cells, and more.
Question: How many different types of cells does Cellular Dynamics currently offer?
We currently offer four cell types - cardiac cells and endothelial cells are available to customers today, neurons will be commercially launched this month, and hepatic cells will be available next year. These cells are fully functional. Within the next five years, we will be producing the majority of human cells that are of research interest. Within the next decade, we expect to be able to make all types of cells in the human body.
Question: And these could be cells from any individual?
Yes, we would simply take a blood sample from any individual, and from that single sample we could derive any cell type, in any quantity desired. Moreover, the cells are neither aged nor diseased. We have actually made fully functional stem cells from a 92 year old woman.
Question: At what point will doctors be able to inject these differentiated cells directly into a human body?
Clinical trials are already in place whereby these cells are injected directly into the human body. For example, Geron has put embryonic stem cell-derived neurons into individuals with spinal cord injuries. The difficulty is in understanding the effect of these cells. Continuing research will ensure that we have a better understanding of the effects, which will allow us to treat a wide variety of diseases.
Question: So it is only a matter of time before an individual suffering from liver failure will be able to have stem cell derived hepatic cells injected into their liver?
There are three main challenges to that scenario. First, one must find a way to get the cells to the affected organ - simply injecting the cells via syringe may not be the best way to do that. Second, the cells need to be grafted onto the organ. Third, the underlying problem with the organ needs to also be addressed. So implanting new beta cells into a patient suffering from type 1 diabetes, which is an auto-immune disease, won't help because the body will simply attack those new cells as well.
Question: Is there a risk that these stem cells could start dividing and turn cancerous?
That is a risk, since this process involves extensive cell manipulation. We are doing numerous animal studies to ensure that this doesn't happen. We are doing myriad tests to ensure that these cells do what we program them to do and no more.
Question: Cellular Dynamics injects plasmids (snippets of DNA) into cells in order to turn genes on and off. How exactly does this work?
A plasmid is bacterial machinery that is replicating DNA. Plasmids are specifically designed to produce gene products that in turn trick the cell into reprogramming itself back to a pluripotent state. Previously retroviruses, which would integrate into the human cell DNA, were used to inject DNA into cells, and this has been one of the major concerns related to using iPSC-derived cells as cell therapy. Plasmids do not integrate into the DNA and eventually disappear from the cells, eliminating the risk that foreign DNA will induce additional transformation of the cells. To date, eight gene products or transcription factors have been identified, as well as other small molecules and proteins, that can reprogram cells. We use six of these gene products and have also boosted the efficiency of the process, so that we only need to use tiny amounts of material to begin with.
Question: What is "forward programming"?
Forward programming involves directly turning a cell from an induced pluripotent stem (IPS) cell into a non-proliferating, terminally functioning cell without taking the cell through a series of intermediary steps. A similar method is transdifferentiation, which involves directly turning an already terminally differentiated cell into another terminal cell type. However, these concepts are further out and may take a decade to perfect.
Question: What role do stem cells play in degenerative diseases?
Our bodies have normal turnover to replace lost cells, by using adult stem cells to change into the appropriate cell type. As we age, the process slows down, making us susceptible to degenerative diseases. Many companies are focused on regenerative therapeutics - looking for molecules that could accelerate this adult stem cell to terminal cell transition more efficiently.
Question: What role could IPSCs play in treating cancer?
One of the reasons that bone-marrow transplants fail is that we don't get sufficient cells after ablation into the individual to regenerate the entire blood system. With IPS cells, we have the potential to eliminate the rejection and create an unlimited quantity of autologous needed cells. We could literally dose a patient with their own bone-marrow cells, giving a much higher chance of curing the disease.
Question: The field of molecular biology is advancing quite rapidly. How long can this pace of innovation continue?
I think it will continue at the current pace, if not increase. It took fifteen years to sequence the first human genome. Now we can sequence a human genome within a day, and we will be able to know all genetic aspects of that individual within a very short time. DNA was the operating system of genetics. Stem cells will be the new operating system for understanding biology. There is still quite a bit of guessing in drug development, and the process is inefficient and cumbersome. Stem cells provide another tool to derive insights into the remaining mysteries of biology.
Question: Gene therapy was once touted as having the potential to transform medicine, but is now little more than a niche field. Are you concerned that stem cell treatments might not live up to their potential?
Gene therapy was huge in the mid 1980s and 1990s, but all it took was one person to die to devastate the field. As a result, the funding evaporated and the researchers left to pursue other options. The field of gene therapy isn't dead but it is moribund. We need to be careful to ensure that we rigorously test to make sure that all research is safe, ethical, and conforms to scientific standards.
Question: Where will the field of bioengineering be in 2021?
By 2021 there should be thousands if not millions of IPS lines created from individuals. We won't simply be making cardiac cells in a petri dish, but will be actually growing organs such as hearts and livers. We aim to replace organ donors by having patients grow their own organs. Eventually, elderly patients will have their failing organs replaced by younger organs. It is not an exaggeration to say that stem cell technology will utterly transform the field of healthcare within the next several decades.
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