Adipokines are proteins secreted by fat cells-adipose tissue- that control gene expression in other cells.
In NATURE 23 Feb 2017 some excellent work shows just how the fat cells accomplish this. Hard to believe, but the fat cells actually split off tiny bubbles (called exosomes) that contain RNA in very short sequences. They are therefore called “micro RNAs”; our bloodstream is full of them. Discovering their use in gene expression shows just how little we really know (as yet) about metabolism.
Fast forward to the Lipogems story, the concept of using fat derived pericytes (MSCs) to heal tissue; it makes more sense the more we know about adipose tissue. It is NOT just a storage tissue (see: www.lipogems.com). Regenerative medicine has a long way to before we understand all pieces of the puzzle, but this is progress.
Well, yes. It turns out that the blood supply of fat, squeezed in between the fat cells, has a thin layer of vascular cells called “pericytes” that, under the right conditions, have the characteristics of stem cells. Dr. Caplan of Case Western Reserve has recently termed these cells “medicinal stromal cells”, I think to avoid any confusion (and regulatory oversight) with stem cells from other sources. Regardless of what they are called, we have them- some of us in abundance, in the layer of abdominal fat and elsewhere. An Italian company, Lipogems, has developed a simple office procedure for gathering these cells from fat in a form to make them injectable- for example, in a knee joint. There are early anecdotal reports of tremendous pain relief (for osteoarthritis) using this technique, but I know of no formal controlled study as yet.
Please see my previous post about the FDA. What type of oversight, if any, would the agency have over stromal cells from your own body that could be safely used (one assumes) to treat your arthritis?
The best way to learn about stem cell controversies is to listen to what the Food & Drug Administration folks have to say; it is very well balanced, and shows the difficulty in assimilating new lines of research into products that should improve health.
All medical therapies have optimal patient “targets”; the old assumption that one size fits all is incorrect, and has led to the new hype about “personalized medicine”. Nevertheless, there are many treatments which work pretty well for most folks- say, within 2 standard deviations from the average- which would comprise about 66% of patients. Forget the exceptions, for now.
The best “average” patient for PRP treatment of osteoarthritis might look like this: Either under 65 and/OR very fit and active, on few if any medications, non obese, motivated, AND with X-rays that show SOME joint space remaining. Also, the joint in question should not be very stiff and/or crooked. (Note: Many patients have been informed that their X-rays are “bone on bone” when, in fact, this is not the case)
If we reverse these criteria, the failure rate of therapy will markedly increase; that is to say; folks with zero joint space, stiff and crooked, overweight and with multiple medical issues might be better served by surgical intervention rather than commit time and resources to injection therapy. There are exceptions. These occur when a person is either unable or unwilling to undergo surgery, sometimes at a point when independence or employment is threatened. In fact, some of m y most notable successes have been in these outlier circumstances.
Therefore, each recommendation has to be individualized. I am happy to review X-rays for those who have questions. Simply call 703 569 6700 to arrange this electronically.
For diseases and conditions for which there is no acceptable treatment- like paraplegia and stroke, for example, the FDA is lenient in allowing companies to try new approaches.
Two such studies that I am aware of have, unfortunately, failed. Stem Cells, Inc is now winding down its business after many years of effort in trying to provided neurological return to patients with paralysis. Such studies attempt to deliver stem cells to the site of spinal cord disruption in the hope that they will “reconnect” nerve endings. One must realize that some return can seem to occur even without stem cells,,so the noise is such a trial is significant, especially when the number of patients is very, very small (less than 10). So, after a bit of early optimism there is no evidence that the therapy really helps…
Another failed trial was run for hemiplegic stroke by the Cytomedix, Inc, using a particular market for stem cells called ALDH and injecting these cells into the carotid artery. 50 patient treated in “blind” fashion failed to show a difference.
BUT, recently, a team from Stanford shows that the efforts keep on coming; this approach, for stroke patients, injected the stem cells directly into to the brain (through a small hole in the skull). Early results look amazing, but we have all been here before. If and when another group repeats the study, it may be that the route of administration is critical; also it may be that the stem cells simply work by secreting growth factors that allow brain cells to repair themselves. (I would bet on this one).
If that proves to be the case, we will gradually learn that neural tissue, like cartilage, far from being unable to regenerate, can sometimes regenerate if the triggers for cell growth are present.
Wouldn’t that be nice?
The legitimate interest in stem cells and the promise of new therapies sometimes takes a back seat to overhype, false claims, and outright quackery- or at least a very conscientious effort to separate folks from their money. Enter the Food and Drug Administration (FDA.gov), whose main job it is to protect the public. A scheduled meeting at the FDA has now been delayed, but sometime this year a “conversation” will be held between many participants and stakeholders in the field. I suspect that “guidelines” will eventually be determined, and the public should take note; this is a conversation that should be held. A good resource for information is : http://www.ipscell.com/, no need to repeat it all here. We should all advocate safety, proper product labelling, and a post treatment effort to determine efficacy. This gets a bit sticky when the putative stem cell product is autologous (comes from YOU) and there is no drug company involved; but certainly we should at least know IF there are stem cells in the product. Not so easy. In cases where bone marrow aspirate is used, the injections may, in fact, have few if any stem cells …the abundance of such cells is low, and declines with age. Other sources of stem cells should have lot by lot quality control, using appropriate biomarkers, and cell counts. Without better science, the task of separating a real therapeutic advance from a placebo effect becomes daunting.
Please read my previous post on Gene Editing first.
Then have a look at a recent article by Eric Lander http://www.technologyreview.com/view/545741/a-scientists-contested-history-of-crispr/ about the history of the CRISPER/CAS “invention” or “discovery”, take your pick, which attempts to track the numerous findings that has been required to develop this new tool. Editas is apparently the first of several companies to make it to Wall St. with an IPO soon, looking to raise 120M. There will be more.
It will be very interesting to see what the patent office does with the competing claims for “ownership”. Already there are negative comments about the Lander piece, mainly because he does not disclose his own commercial interest in one of these companies. Also, he was a bit sparse on giving credit to the two women best known for spearheading this effort, but he certainly did include them- so that is a bit of a softer call.
But as for conflict of interest, it is here in science & medicine just as it pervades so many other aspects of civilization. So when we read about gene editing in years to come- certain to make headlines- be aware- be aware of what we really know for sure and what other people just want you to believe is true.
The hottest topic in biology this past year has been new methods of slicing and dicing DNA. The new tools, called CRISPER/CAS,https://en.wikipedia.org/wiki/CRISPR are simply enzymes (proteins) borrowed and then modified from bacteria- the bacteria use them as a rudimentary immune system. While DNA clipping tools have been around since the 1970s, the new tools are guided by a strand of RNA to be directed specifically- and programmably- to the site of interest. Since DNA contains billions of sites, this is rather important. If you want to debug a computer program, you had better get to the right line of code. Same thing.
In spite of recent success with a muscle disease in mice, actually doing this in a human is a ways off. First of all, there is the question of slicing and dicing the DNA ONLY in the right place. Secondly, it is a lot easier to cut something out (like in the mouse model) than it is to insert a a corrective sequence. And thirdly, getting the tools to the DNA requires use of a virus as a vector, and these tools can be quite bulky. Improvements will need to be made in all of these areas before a human trial is possible, and the disease will have to be chosen carefully- I assume, pick something relatively easy first. One step at a time.
None of these caveats detract from the excitement that we can now guide an enzyme to the correct site of its work. Look for Nobels in this area real soon, Dr. Doudna and Charpentier, now both competitors in different biotech companies, and then Dr. Zhang’s group from MIT, all squabbling over the intellectual property rights.
As regards arthritis and cartilage loss, one possible approach with such technology would be to disable the enzymes which degrade cartilage…
It is time to weigh in on the repair capabilities of PRP (platelet rich plasma) for isolated cartilage (chondral) lesions. In patients under 20 years old, I now have sufficient experience in 5 patients with lesions of either the knee or the ankle, to say that a sufficient course of PRP can definitely result in clinical and radiographic healing. These patients now have over one year followup and have no symptoms. The dose of PRP may be important, for in my clinic we are counting the number of platelets; 5 B seems to be a threshold for excellent response in Osteoarthritis, and this same protocol was used for the osteochondritic cases noted above. Other than PRP, no other treatment (such as non weight bearing) was performed. Perhaps important, it was thought in all cases that the lesions were of less than one year since presentation.
Our first 6 injections of ASCs have been for osteoarthritis of the knee, and each has been combined with a course of Platelet Rich Plasma. So far, no complications and no adverse reactions at all. The cells have come from 2 different tissue banks, and both have arrived on time in boxes packed with dry ice; upon defrosting, the cells must be used that day.
The tissue banks are clear that they do not advertise “stem cells”, only amniotic cells with stem cell like markers. This is to avoid any conflict with regulatory agencies as the companies involved do not characterize the cells at all; they simply harvest amniotic fluid from scheduled C sections, they test the fluid for a variety of diseases in order to insure safety. For this reason, the ASCs are a tissue bank product and not treated like a drug.
At issue as we move forward will be the number of cells per package and establishing an optimal dose. In terms of efficacy, stay tuned to this web site for clinical information as it occurs. The first group of patients was selected specifically to give us feedback of whether the ASCs plus PRP are better than PRP alone. In about 6 months we should have some early information.