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.
Amniotic Stem Cells
For over a decade the concept of using stem cells for the therapy of various diseases has been in the public discourse and has been the subject of many investigations. There are now journals and professional societies worldwide devoted to this topic, along with a proliferation of international meetings, newspaper articles, named buildings and even taxpayer-funded initiatives, as in California. No wonder that local “stem cell” clinics are springing up nationwide to take advantage of the public’s enthusiasm for new medical approaches.
The question remains: does it work? Let’s examine why the jury is still out on this question, and what the present opportunities may include, and let’s do so without the hype and the overblown promises so common in our culture.
Firstly, there are several ways of getting at the pristine DNA inside a cell. What we want to accomplish is to use good DNA to replicate cells that are making abnormal DNA. This could be a function of disease, like cancer or inflammation, or it could be a function of aging. All of these processes are related.
Young DNA has fewer “mistakes” in its sequence; it is a bit like getting a computer code without the bugs. Stem cells have the ability both to reproduce themselves AND to differentiate into other cells- like heart cells, skin cells, cartilage cells. Cells with a variable degree of “stemness” can be obtained from embryos, from bone marrow, from fat and from ordinary cells like skin cells if they are treated with a “cocktail” of growth factors that convert them into stem cells. These are called “induced” stem cells. It is arguable which cells have the “best” DNA for the purpose we are looking for; one concern of the regulatory agencies is that all of these cells could have the potential of growing abnormally- although so far we have no evidence of this.
Working with stem cells is a bit like working with radioactivity- one has to know what one is doing.
FDA approved trials are now progressing with a variety of stem cell products for ailments that have no effective treatments with conventional methods. For example, bone marrow stem cells have been used for stroke (safe, but no improvement), Parkinsons (ongoing), meniscus tears (no response), paraplegia (perhaps some improvement in a few patients). Each study must be read carefully to convince yourself that the investigators really have stem cells, and that they are alive, and that they are put in the right place. In some cases, the stem cells may work by becoming part of the patient (engrafting) and in other cases they may work by secreting various growth factors that many other cells grow. Nature continues to be complex at all levels.
Using stem cells from another person- allografts- is attractive because- as long as immune or rejection problems do not occur- it does not require taking tissue samples from the patient, such as bone marrow or fat. Furthermore, a high density of stem cells can be assured and this can be monitored at the tissue bank for quality purposes. Amniotic fluid is one such source of cells that can be prepared under strict guidelines for safety. These cells are “immunoprivileged”; similar to other allo products, like cartilage. They do not elicit an immune response and do not need to be tissue typed to the recipient (unlike blood). Also, as these cells are derived from elective C-sections, they are young and their DNA is young. We have learned that the use of juvenile tissues, such as Denovo NT cartilage repair, is favorable.
Since PRP (platelet rich plasma) contains the growth factors that activate stem cells, it makes sense to consider the combination of amniotic stem cells and PRP.
Keep in mind that there is no present evidence- pro or con- that could help us determine the usefulness of this therapy. Therefore, at this point each patient must act as their own “control”.
Many patients have joint problems for which there is just no good solution with older methods. I am therefore offering the amniotic stem cell product to carefully selected patients who are fully informed, and for whom PRP alone has not resulted in an adequate response. In this way we will learn together if the stem cell component and the growth factor component synergize to product a good result.
Over the last year I have used PRP in patients with mild to moderate arthritis of the hip. The injection is guided by ultrasound imaging, and with appropriate use of local anesthetic is not painful. I have been using a 3 injection regimen similar to that used in the knee with a similar target dosage. So far the results have been gratifying in all patients with a good range of motion- some stiffness but not extreme stiffness. I do not think PRP in this application will restore lost motion. Therefore, it seems likely that PRP should be an option for those with mild to moderate OA and minimal hip stiffness; in some cases the diagnosis of FAI (hip impingement) or labral tear- really is confounding the real problem, which is loss of articular cartilage. In some of these cases, hip arthroscopy may not be necessary.
Currently the first trial of engineered stem cells for macular degeneration, a retinal disease that can lead to blindness, are beginning in Japan. The endpoint in the first patient will be for safety, NOT for efficacy. IMO this is the way the FDA is likely to proceed in the U.S.: very carefully, safety first.
This is different from the previously reported Aldagen trial for stroke, which used only separated stem cells from the bone marrow, in that in the Japanese study they are using induced stem cells (from the patient) that have been grown in the lab to reproduce the exact tissue in need of repair. In other words, they have been altered to perform the job required. Clinical standards for an induced stem cell will necessarily be higher, in order to make sure no unanticipated changes- think cancer – are caused by the reprogramming. one concern is how long you should wait before deciding such an issue. The retina may be a good place to begin because it is so easily observed.
Some of my patients have been convinced by others to have simple bone marrow aspirate injected as a kind of “stem cell therapy”. This has been done without adequate scientific proof and at extremely high cost, no insurance accepted. As they say, it can be easy to separate a fool from his money. Bone marrow may be a source of stem cells, but they are certainly rare. Without validation- counting cells- I oppose “selling” BMA as a stem cell therapy. The public should be educated as to the true state of the art, and how we must proceed cautiously, and then measure the outcomes such that we make the technology reproducible, affordable, and effective.
A recent article in the journal NATURE from a team at the University of Washington in Seattle has shown an exciting way of using embryonic stem cells to revitalize heart tissue. The researchers took embryonic stems cells from humans and treated them with a simple growth media to induce differentiation into heart like ‘cardiomyocytes’. They then induced, in monkeys, a large ‘heart attack’ with death of a portion of the wall of the heart- mimicking the situation of a very bad heart ‘attack’ or MI. Injection of the stem cells into the dead tissue resulted in regrowth of the heart muscle- beating heart muscle.
Although this would seem to be far from our cartilage related issues, it is not. This is yet another example of how the DNA in certain cells can be re-programmed (in this case between species!) to make the type of tissue that is desired. If damaged tissue can be restored in situ, think of the consequences. The details of this kind of therapy will have to include a convenient way of introducing the cells to a target, and ‘engrafting’ or holding them in the right spot. Several previous trials at stem cell therapy, simply involving injection of cells into the bloodstream, have failed (including the recent Aldagen trial for stroke). One common factor of these failed trials is the lack of an appropriate delivery system. In this area the need for novel medical devices is obvious.
Over the last four to five years my interest in cartilage regeneration has continued to focus upon new techniques in stimulating cells to self-repair. Concurrently, biotechnology has rapidly advanced to provide us with new tools in evaluating the genome (our DNA sequences) and to explain much of cell behavior in terms of growth factors- proteins that control how our cells work, produce materials, and eventually become senescent. Technologies in the offing will be able to make DNA editing a new therapy for many diseases. Furthermore, the link between aging, cancer, and our immune systems has become increasingly obvious- this is what is driving the marketing of “personalized medicine”.
Although we are not there yet, I feel strongly that this is the (very near)future. The concept of treating all patients with the ‘same’ ostensible problem the exact same way, or with the same drug, will be seen to be quite antiquated. Most of today’s ‘guidelines’ will soon obsolesce. Both physicians and patients will need to get smarter. Part of this will come from patient empowerment, but this will only be possible if the ‘big data’ are organized into a form that makes decisions actionable and reasonable; for example, not everyone should take up marathon running (stress fractures, heart stress), and some folks would really benefit from weight lifting(to build bone mass) at an early age. The doctor will continue to be in the business of giving advice, but it will be more informed advice.
In orthopaedics, new therapies will result in much less surgery. What if: many ACL tears were made to heal in situ? many cartilage lesions and tendinopathies healed with injections? Rotator cuffs and torn meniscii could be treated in the office? Much of this is already true today.
In my practice, patients should look forward to receiving the best synthesis of advice derived from some old methods and some new possibilities. This is how progress is made and this is what keeps life interesting.