Ghost Organs, Stem Cells, and Frankensteinís Transplant Technology
If youíre a biotech investor, youíre undoubtedly aware of the buzz regarding 3D bioprinting. There have been scores of articles and video presentations in popular outlets heralding the end to transplant organ shortages.
Using living cells rather than inanimate construction materials, 3D printing technologies have been used to build models of organs and other tissues. Excitement about the possibility of mass-produced bioprinted transplant organs has fueled a massive inpouring of capital into companies working on this seemingly science fiction technology.
Iím not writing today to tell you that bioprinting will never succeed in producing viable transplant organs, though the technology has a long way to go with many problems to solve in its path. Iíve lived long enough to know that underestimating future scientific progress is a pastime popular among fools and stock shorters. On the contrary, Iím writing to tell you an even older biotechnology is much, much nearer the target of lab-grown transplant organs.
A few weeks ago, John Mauldin and I visited the Minnesota labs of a company that is pursuing the same goal of transplant organs. During that visit, we held ghost organs, as they are sometimes called, in our hands. In these pictures, John is holding a completely decellularized pig heart. Whatís left is the white extracellular matrix, the scaffolding upon which living cells attached.
We also talked at length to the scientists who believe this new biotechnology will solve the primary problem facing 3D bioprinting. Essentially, that problem is that the myriad processes involved in new organ growth are impossible to duplicate in todayís bioprinters.
Our bodies, including our organs, all began as undifferentiated embryonic stem cells. Each embryonic stem cell contains the totality of the genome that will eventually grow into a fully functional human or other animal. Moreover, these cells are immortal, meaning they donít age until they have differentiated into one of the many adult forms of cells that make up our impossibly complex bodies.
Nothing is more awe-inspiring than that process of transformation from a single zygote to a complete organism with about 37.2 trillion cells. At this point, itís impossible to say exactly how many different cell types exist in our body, but the number is enormous.
Somehow, however, a few undifferentiated stem cells, starting with a single zygote, transform into a complete human being with a full range of organs that function precisely down to the level of individual molecules. The powers inherent in embryonic stem cells also exist, by the way, in certain induced pluripotent stem (iPS) cells.
These iPS cells are essentially embryonic cells, but their development is reversed. They begin as adult cells and are taken back in time via a variety of techniques to become virtually identical to embryonic stem cells. Done correctly, iPS cells can be maintained in cell cultures without ever aging. In fact, my immortalized iPS cells exist in a Northern California lab right now. Itís not critical that you fully comprehend iPS cells at this point in the story, but Iíll return to the subject in the second part of this series.
What I want you to understand now is simply that the process of organ development from identical pluripotent embryonic stem cells is extremely complicated and not fully understood. We know, however, that cells draw on the vast information contained in their DNA as well as sophisticated signals from surrounding cells. Using that constantly transforming information, stem cells transform into functioning organs.
Good News and Bad News
The bad news is that there is no way we can duplicate this impossibly complex process of organ cell differentiation. The precision and sophistication of the genomic machinery is so far beyond the capabilities of nanotechnologists, it is impossible to say when comparable nanomachines will be created, if they can be created at all.
The good news is that we donít have to create such mechanisms. The real promise of regenerative medicine is that we can tap our genomesí astonishing powers to get them to do what they naturally do.
We donít even need to fully understand the molecular biology involved in these genomic processes. We just need to be able to activate them. Remarkably, activation has been found to be surprisingly easy in many cases. In fact, activation can happen accidentally and quite dramatically.
This story began, I believe, in 2007. Drs. Doris Taylor and Harald Ott were working in a University of Minnesota lab, looking for a way to preserve the structure of the heart so that stem cells would attach naturally and grow into a working organ. To do this, they needed a new and improved means of decellularizing cadaver or animal hearts.
Methods existed, but they removed more than the cells of the heart. They degraded the extracellular matrix (ECM), the dense filigree scaffolding of protein fibers that provide organs with their shape and structure. This is a problem because the ECM contains signaling molecules, proteins, and growth factors that communicate with living cells. Without them, developing stem cells canít find their proper places in the heart or develop in coordination with other cells.
Through trial and error, working with rat hearts, Taylor and Ott found that sodium dodecyl sulfate (SDS) dissolved the cells but left the ECMís signaling molecules intact. SDS, by the way, is the basic detergent component of baby shampoo. Moreover, the duo realized that they could vastly improve the process of decellularization by putting SDSóat precise concentrations for specific durationsóthrough the arteries, veins, and capillaries of the hearts. In this manner, decellurization took place quickly from the inside out.
Once the cells had been removed, what was left was the intact ECM. Like cartilage and other connective tissues, itís white; hence the term ghost organs.
In those days, bioreactors were tiny and crude devices compared to current version. Nevertheless, they could be used to circulate nutrients and oxygen for organs in a liquid medium. Taylor and Ott put one of their ghost rat hearts into a bioreactor along with a mix of stem cells from other lab rats. Because lab rats are basically clones of a single animal, their DNA and leucocyte antigens that determine cellular compatibility are basically the same.
In only a few days, rat stem cells had begun to grow on the ghost heart in what was apparently the proper manner. Ten days out, what appeared to be floating in the bioreactor was a brand new rat heart.
One night, however, everything changed. Dr. Ott was working late, sitting in the lab and working on a computer, which is what most science looks like. For no particular reason, he glanced up at the bioreactor and saw the heart beating. I donít know if there was thunder and lightning, but numerous phone calls to colleagues rapidly ensued.
Not surprisingly, the event garnered enormous attention. The teamís findings were published in the journal Nature Medicine and they won the award for best health innovation of 2008 from Popular Science.
I began writing about this innovation in 2010, when Minnesota startup Miromatrix Medical acquired full licensing for the technology from the University of Minnesota. At the time, I spoke extensively with Dr. Robert Cohen, the current president and CEO.
As is the case with media interest in new technologies, the Minnesota breakthrough was slipping away from public attention. In the meantime, however, huge progress has been made by the company, much of it in conjunction with important and world-famous collaborators. This is why John Mauldin and I went to Minnesota, in the flesh.
The private companyís first product, an ECM device approved by the FDA, will begin selling in September. It will improve surgical outcomes and wound healing, but the longer-term implications for this technology are really quite profound. There is a very good chance that recellularized ghost organs are going to have major impacts on medicine and several other important companies and biotechnologies. There will be major winners and huge losers. Iíll talk a little about that in part two.
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