The Pluripotency Trilogy

How to unite the themes of varying conversations related to a broad field of study into a summary review is often a challenge, yet when stem cell science is the topic invariably the subject of pluripotency and developmental biology arises as a convenient unifying thread. 

via Nature
From afar the concepts within the “black box” of cellular processes that define our make-up and function seems highly complex but with the required knowledge of rudimentary electrical circuitry we can all illuminate some shapes of the machine within. 

Enter the scientists - no stage door - just straight up the aisle and onto the platform. The scene of all these discoveries is their domain. An often infuriatingly slow and arduous responsibility, willingly accepted, yet obscure mostly to all but those that have the calling to search for the answers amongst the molecules. 

Research, I have come to understand and respect, is the very life-blood of the process. For every day spent hunched over the bench, there will be a thousand more, replicated the world over in countless laboratories. The pursuit of knowledge, basic and fundamental, can only be completely appreciated if you are truly a part of that process. 

Businesses are built on outcomes. Patients are helped if and only when products have passed the grade. Health systems and government budgets are factors of the efficiencies built into the very fabric of the quality of that basic discovery process.

We rely on research, more than we'd like to admit. The spirit in which the discovery process operates must be preserved, nurtured, funded and importantly bridged so that the world beyond the bench can truly appreciate it’s importance and voice its support. 

More so today and tomorrow than perhaps in the past...

The development of therapeutics for clinical application may not be the intent nor goal of basic research and in many ways the practical implications of knowledge inhibits the free expression of intellectual pursuit. This is true of Art also and a number of other fields where creative thought is required or problem solving a key focus.

There are always different perspectives, opinions and methods in every field - no more so than in stem cell science where the factual basis for definitive proof is set high. This perhaps goes to the very heart of the issue - human biological system architecture is still largely an unknown and has evolved over the course of countless millennia. Unravelling the machinations of our inner workings will take time and will require a different set of parameters to assimilate - from all stakeholders.

Onto the protagonists of this story - the scientists - and their take on pluripotency.

I had the opportunity to delve somewhat into the background and focus of three leading scientists attending ISSCR 2015 - Prof. Austin Smith of Cambridge, Jeanne Loring of Scripps and Rudolf Jaenisch of the Whitehead Institute. All three kindly entertained questions on the nature of pluripotency and its importance to the stem cell field. 

To set the scene - scientific debate is healthy and an essential component to discovery, as its that essential motivation within the community peer structure that drives insight and translation. 

Pluripotency I have come to appreciate is not a clear biological phenomena, as in many ways it’s a transient in-vivo state that when studied outside of the body is an “artificial artefact” as Rudolf Jaenisch termed it. 

To provide a little background, all three scientists have a history in studying mouse ES cells, going back 25/30 years or so. This is important to note as the nature and definitions applied to pluripotency, from what I can gather, have arisen out of the original study of mouse embryonic developmental biology.

Prof. Austin Smith stated focus is in trying to “understand the relationship between stem cells in culture and cells in the embryo, which are not stem cells because they don’t self-renew. So we’re trying to understand how cells that we can grow in the culture dish relate to real developmental entities in the embryo of mice or, of course, ultimately of humans.” 

All agree that “pluripotency” is the capacity or potential to make any cell of the body and germ line. Yet where there is ongoing debate is in the ambiguity of the developmental biology of the various states, the profiles inherent therein, the direct methodologies and the difference between mammalian studies of the mouse versus human cells and the very concept of “embryonic”...

The classic view, if one can call it such at this young stage of the science, which Austin and Rudolf are leading proponents of, is that there is fundamentally a parallel biological mechanism in the relationship between the mouse development process and that of the human. 

Rudolf attested to the debate within the community on the “controversy” surrounding the various “pluripotent” states, their expression profiles and the pursuit of “naive” mouse like properties. 

These are “interesting scientific questions”, which a number of labs, including Austin & Rudolf’s, are continuing to pursue in the basic research field. Some would say there is a good spirited competition to prove that human cells are or can be made to be equivalent to mouse. 

Jeanne Loring’s view of this is somewhat more pragmatic, having also based her early career in the science on the study of mouse ES cells: “I decided to learn one thing and then move on and learn another and then try to put them together…. I have the mouse ES history, which I share with Austin and Rudolf… human cells don’t act like mouse cells, they’re much harder to grow... whether you can make a human cell with the quality of a mouse” is still being investigated “I just went straight to human pluripotent stem cells and realized they were not going to be like mouse and lived with it… so I just bypassed that… my cells become what I want them to become and that’s it - I’m done.. they don’t need to be mouse cells, they’re human cells”

This internal debate somewhat sheds light on the differences inherent in the basic versus translational aspects of the scientific community. The need for answers and the desire to move forward.

I tried to explore this balance further in the discussions and appreciated that not all science has to be translational, far from it actually, but on the other hand more interconnect perhaps is needed to facilitate translation.

To illustrate Austin and I discussed the issue of pace and method of action - that is we exchanged views on the speed in which scientific discovery is translated and the focus on uncovering the biological roadmap to cellular, molecular and genetics prior to therapeutic treatment of patients in need.

Austin correctly pointed out that “you can’t run before you can walk… and of course from the perspective of a patient or a politician that it seems to be taking an awfully long time… however it is very complex and we have to do it right.” This theme is necessary to broadcast and communicate effectively to the public in a manner which is empathetic to the broader societal issues beyond the lab. There is a need to bridge all perspectives to achieve results.

Further on the topic Austin relayed that “what basic science can contribute is our knowledge & understanding of the mechanisms and of the biology to create a rational approach to therapy…. however, of course you can approach it from the other end, from the clinician’s end which is…. you can try things and you know historically that has been by and large the way medicine has developed and I dare say there will always be a place for that..” 

The pure nature of discovery was clearly Austin and Rudolf’s focus, and rightly so - as I said earlier in the article, it is the very life blood of the foundation on which all is built. For more on Austin’s work & views you can read a post ISSCR article here via Development.

I will be featuring more of Jeanne Loring’s interview separately as we discussed her career and projects, including the Parkinson’s iPS work she is progressing at Scripps and also her interesting effort to help the San Diego Zoo with an endangered species via novel fertilization techniques using reprogrammed germ line cells. Stay tuned for that.

It was a pleasure speaking with Austin, Rudolf and Jeanne and I thank them for their time. Their work in the field of discovery and translation are representative of the commitment and intellect devoted to moving the science forward.

I feel like it’s time for cup of tea - I like mint tea, cools you down in the summer… been hovering around 100 degrees here for weeks… off to the beach I think! Enjoy.

Until next week.