Injecting Adult Stem Cells IV Doesn't Work (Unless You Have a Lung Problem)

A recent study has shown what seemed obvious, out of country stem cell outfits injecting adult stem cells IV fail to get those cells to the target organs being treated.  These cells don't end up in the brain, liver, heart, joints, etc... they end up in the lungs.  This is similar to the first pass effect seen in drug delivery (in that case it's the liver).  Credible stem cell delivery is direct to the target organ or tissue.  So if you want cells in the pancreas, you have to place them there.  If you want cells in the joint, again you have to place them in the joint.  Organizations doing this type of credible adult stem cell delivery include Regenerative Sciences  and Regenocyte.  

Stem Cell Mania

There is an underground explosion in cell based medicine brewing.  There already lots of players.  I would break them into the following categories:

1.  Magic:  Lots of these in Europe and Central America as well as third world countries.  The source and type of the cells being used is unclear.  Rather than placing cells in the areas that need treatment, they prefer the more profitable route of injecting them IV.  These companies will treat anything from diabetes to spinal cord injury to ALS.  This is truly the "wild west" of stem cells.

2.  Storage:  Lots of these abound.  Cord blood, peripheral blood CD34+ cells, other blood based progenitors.  While some of these have some science, they all suffer from a lack of the ability to deploy cells to treat disease, so convincing patients to donate cells can be tough.  The most successful of these appears to be cord blood storage.  The best of these companies are those like Neostem, who have scientific focus and high level medical direction.

3.  Big pharma: This is for the most part an off the shelf stem cell solution.  The idea is creating the world's next Penicillin.  The practical problem is even if this works, it will be many years before the details of treatment protocols are worked out.

4.  Stem Cell Application Providers:  This would include the Regenexx procedure.  It would also include companies like Regenocyte.  These groups take more of a scientific approach, use a verifiable cell line, and place the cells at the site in need of repair.  They have expereince with actual working treatment protocols for specific diseases.

5.  Stem Cells in a Box:  These are bedside centrifuge or processing plays.  These boxes produce a very dilute stem cell population (like the Harvest system).  While they quote big numbers of cells, their literature is grossly misleading.  The cell numbers quoted are for CD34+ blood stem cells which aren't usually considered true multi-potent adult stem cells.  So while this cell population might help tissue repair in a young person, in a middle aged person and beyond, the stem cell numbers that count are too dilute to matter.  

Big Pharma Should be Very Concerned...WBC's from the Patient Could Cure Serious Disease

Recent research on autologous WBC's has been nothing less than miraculous Two new articles are important.

The first potential break through is in cancer research. A researcher at Wake Forest is convinced that cancer is caused by white blood cell suppression. In other words, our WBC's fail to do their job of picking off the cancer cells that brew in our bodies every day. However, this researcher believes that by taking healthy WBC's from donors he can cure cancer (at least in mice). This has so upset the traditional oncologic research community that he has been unable to get grants for his work. As a result, he is asking patients to self-fund the first human trial.

The major development other involves rheumatoid arthritis. In this treatment, researchers from the U.K. take white blood cells, reprogram them using a chemical cocktail, then inject them into joints with rheumatoid arthritis. This has been effective in animals in curing the disease and early human trials are beginning now.

What's the upshot? If you can take someones cells and miniammly modify them or provide healthy cells from a donor and cure these horrible diseases, the big pharma business plan will be in disarray. Basically, these are blood banking or minimal culture treatments that combined, would eliminate hundreds of billions in cancer and RA treatment.

All this brings us back to an age of autologous biologics where the idea of using drugs and pharmaceutical cocktails to achieve results may be changed forever, or at least the playing field altered. Already we are seeing biologic approaches such as platelet rich plasma that are gaining popularity among interventional pain physicians and those who treat acute and sub acute sports injuries. In addition, autologous stem cell approaches are allowing the treatment of chronic joint diseases. All of this points in a direction where the future will have a myriad of hybrid treatment approaches. In the end, we may all be using bits and pieces of ourselves as therapy.

A recent investigation into how mechanical loading can turn MSC's toward bone even if they are given chemical signals to become fat, has broad implications for exercise programs. While we fret about calories or eating too much fat, their study suggests that MSC's can become fat cells simply by lack of physical activity. Clinically, we likely see this in many AVN patients who may have part of their disease pathogenesis in their low activity lifestyle. I've always thought that in many of these patients their MSC's would prefer to become fat over bone (hence the lesion-where weak fatty marrow tissue replaces strong bone). This would also have big implications for a host of disease states that are likely activity related and involve poor bone formation such as osteoporosis. We've all known for sometime that being more active is good for our health and our bones, but this new research helps us understand that at the earliest stages of adult stem cell development, activity gives our cells clues to either strengthen our bodies or make them weaker. For example, most animal studies of orthopedic healing would suggest that even in bone or cartilage injuries, more activity promotes better repair. While this can be a two edged sword (too much activity on an injured part can cause it to fail while not enough will reduce the strength of the repair), many cell based treatments now recognize that promoting activity as quickly after the procedure is key to a good recovery. In other words, keeping an animal off a cartilage lesion "to let it heal", in general promotes new cartilage that is not as strong or chemically complete as when an animal is allowed to do what it wants (meaning some limping while it hurts and then full activity when it feels able).

The take home message? We Americans have gotten used to low activity levels that not only promote obesity by reducing our caloric burn, but also increase the tendency of our stem cells to turn into fat when they should be bone (and likely muscle, cartilage, tendon, ligament, etc... )

Et tu Cipro

Looks like another one bites the dust. The antibiotic drug class known by doctors as "The Quinalones" has just been awarded a "black box" warning from the FDA. Seems like these drugs can cause tendon ruptures and in one study tripled the risk of Achilles tendon rupture. Since these are first line antibiotics for various types of infections (including bladder and bone infections), this will have wide reaching impacts.

This general theme is also consistent with our research showing this drug class inhibits the growth of mesenchymal stem cells. In fact, our own research is suggesting a rather dismal picture for prescription drugs in general, many of which seem to inhibit adult stem cell growth. While it's been known for years that all of these drugs can have direct toxicity effects on the liver or kidney, or both organs, what has not been generally known is how they might impact the other side of the equation, namely how they might hamper the local repair effort. Until recently, modern medicine didn't understand that almost any tissue in the body is a balance between killing off cells in daily wear and tear and replacing those cells with local stem cells. While many drugs negatively impact cells of various types (organ cells or in this case cells that maintain tendons), what's also likely happening is a negative impact on the cells who replace these dead or stressed organ cells (adult stem cells). If this data holds up (we have been collecting this for the past few years), it will have wide reaching effects on modern allopathic medicine, namely many prescription drugs are not only directly hurting certain cells, but also killing off the repairmen who are supposed to fix that damage.

A Fatty and Muscular Problem for Cartilage Repair

As you may know from prior posts, I've been concerned that products that claim to mobilize adult stem cells from bone marrow to blood may be barking up the wrong tree when it comes to musculoskeletal repair.  In particular, the cells being mobilized are not true MSC's, but cells which are good at muscle repair and not cartilage, bone, ligament, or tendon repair.  A recent study just confirmed this again, this time in-vivo (meaning placing muscle stem cells in a rat knee joint to see if they were capable of cartilage repair).  This study showed that in fact, muscle derived MSC's performed very poorly, as did cells derived from fat.  However, synovial derived cells and bone marrow cells (the kind currently used by RSI), performed very well at cartilage repair.  While entire industries are now springing up to save adipose derived MSC's from liposuction surgeries, the ability of these cells to produce cartilage remains in doubt.  For now, it looks the bone marrow derived and synovial tissue derived cells are the only game in town.

Adipose Nightmare?

A recent study published in the journal stem cells raises a few questions on the appropriateness of using fat derived stem cells in clinical patients at this time.  While the study injected fat derived mesenchymal stem cells with tumor cells (nothing any clinician would ever consider doing) and found that they created bigger tumors, it does raise a point that long-term MRI follow-up for tumor creation is needed.  RSI has obtained that data over the past two years on the Regenexx procedure and is readying that for publication.  What it shows is that MSC's grown with our proprietary technique do not promote tumor formation as measured by state of the art 3.0 T MRI imaging (images before and after the procedure).  This is very important, as what we don't know is if cells grown with other procedures (for example one that requires exogenous growth hormones or other cells sources-fat instead of the Regenexx source of bone marrow) might promote tumor growth.  We will be readying this data for publication over the next few weeks and hope to have this in the research lexicon by fall of this year.  

Snake Oil?

In the last post, I discussed the sizable buzz out there about the phrase "stem cells" and how multiple groups were cashing in on that buzz with claims that don't make allot of scientific sense.  As an update, I had an exchange this past week with one of the companies using various chemicals to mobilize adult stem cells from the bone marrow to the circulation.  After a bit of scientific back and forth, it became clear that their web site was a bit misleading.  It makes it seem like they are mobilizing adult mesenchymal stem cells into the circulation, when in fact they admit that they are mobilizing a hybrid blood/muscle stem cell progenitor.  While this cell could be helpful from a theoretical standpoint in body building applications (to build muscle), of the 5,000 or so studies currently in the national library of medicine, only a handful reference this cell.  We don't know much about it at this point in time.

Perhaps Brian Alexander of MSNBC put it best:

“ADULT STEM CELLS are the BEST-KEPT SECRET in today’s wellness…” boasted a flyer for a dietary supplement called VitalStem. Take it and increase “the number of circulating stem cells in your body.” Not only can it “replace diseased cells with healthy cells” and provide “anti-inflammatory and immune system support” but also give users “mental clarity and mood elevation.”

But the products are really just a repackaging of a supplement that has been marketed aggressively since the 1980s, a form of blue-green algae called aphanizomenon flos-aquae. The science behind the claimed benefits for aphanizomenon is slight — whether the claim is for immune boosting as it was 20 years ago, or stem-cell enhancement as it is today. In fact, there has long been concern about the presence of toxins in blue-green algae products, though you wouldn’t know it from the marketers at the trade show. 

Brian is describing some of the claims being made at the A4M conference in Las Vegas this week.  Click here for full story.  

As I have blogged before, stem cells and other autologous biologics are no different than Penicillin.  First, a procedure must be put in place to ensure that the autologous biologic is in fact what it claims to be.  This procedure would at least need to involve isolation of that cell and culture expansion to a much higher number.  Then, dosing needs to be figured out. Finally, how the cell is applied to the area becomes a whole area of study in itself.  For example, applying the cell to fix bones is likely different than trying to fix cartilage or tendons.  

So again, there is no easy lunch here.  These cells have great promise, but simply slapping the phrase "stem cells" on a bottle of ancient supplements from the 1960's or a process using otherwise dangerous chemicals to bump up circulating blood cells isn't enough...

Stem Cell Hype vs. Medicine

As the medical director of a stem cell company building procedures that are less invasive and target specific tissues for regeneration, I see allot of hype out there. Here are some examples of stuff that sounds good to the lay reader, but when one looks at the basic science, don't add up:

1. Pills or drugs to mobilize stem cells: There are new supplements claiming to regenerate every tissue in the body from muscle to brain to liver to kidney. The best of these have actually had blood samples tested using Fluoresence Activated Cell Sorting to show some increase in circulating blood stem cells. The problem? The types of stem cells mobilized into the blood stream are cells destined to produce more blood, not repair tissues. In particular, one of the MVP's of the adult stem cell world (MSC's) don't circulate in the blood, so they stay put where they're located. These supplements might help if you had anemia, but not much else.

2. Embryonic stem cell injections or cord blood injections: These are stem cells from someone else injected IV. Most of this is happening in third world countries. A few issues. One question is how these stem cells were isolated, as there has been at least one significant allergic reaction (which should never happen with a true stem cell) reported on a California company offering embryonic stem cells in Mexico. Assuming they are stem cells, the second issue is disease transmission. First, there are the common diseases such as HIV, Hepatitis, and other viral infections we can detect. Second, there is the issue of stem cells being able to transmit genetic disease such as an increased risk for osteoporosis (see earlier post). Finally, there isn't much data that shows that if you have a bum knee, a bad kidney, and liver spots on your skin, that these cells will be able to home to one of these areas to allow repair. In fact, most studies show that even in severe injury models (where a severe life threatening injury is created like a heart attack or a lung injury) direct infusion of cells to the damaged area results in more repair than placing the cells in the blood stream.

3. Adult stem cell injections IV: I have seen clinics beginning to use various marrow concentrate systems to inject marrow nucleated cells into the veins (IV). Again, the issues with IV infusion as discussed above apply here as well. The other big issue that that MSC's make up about 1 in 50,000 to 1 in 500,000 of these marrow nucleated cells. This means a very very dilute stem cell population is actucally being injected. As an example, 50 cc of bone marrow might contain trillions of cells, but only less than 0.0002% (in some older patients) are actually stem cells capable of tissue repair.

4. Bone Marrow concentration via bedside centrifuge: There are companies advertising systems (as above) that take whole bone marrow and magically produce millions upon millions of stem cells. Actually, the stem cells they refer to are CD34+ heme progenitors (stem cells that make more blood products) and not MSC's which can repair tissue. So the same issues as above apply.

So as you can see, there's allot of hype. We at RSI continue to work hard to do the following:

1. Isolate and culture expand true mesenchymal stem cells (MSC's) from the same patient where they are harvested (meaning we can harvest a few hundred thousand stem cells and culture expand them to between 5-200 million in just a few weeks). This is done without exposing the cells to potentially harmful drugs or recombinant growth factors.
2. Test various procedures to place MSC's into the area being regenerated. As an example, the procedure for regenerating disc tissue is wholly different than the procedure that targets cartilage in the knee. As more examples, regenerating a partially torn rotator cuff is different than regenerating bone. We then use patient reported outcomes ("I feel great!") as well as before and after 3.o T MRI (the best quality MRI technology currently available) to convince ourselves that we have repaired the target tissue. We are also constantly pioneering new techniques to get the cells to the target area via injection (such as MRI planned fluoroscopy-this is where we use the MRI image to guide the placement of cells).

Stem cells have great potential, but with that opportunity comes the hype...

Cutting Out Tissue to Cure?

Much of modern surgery on joints involves the idea that cutting out torn or macerated tissue is a good idea. Take for example that a meniscus repair is actually removing the torn part or parts of that tissue that won't heal. While this can provide short-term relief, the research has shown that over the long run, it leads to more arthritis in the joint. This happens because the remaining tissue gets over-loaded and less meniscus tissue means less lubrication for the joint. The advent of regenerative medicine where we can now heal tissue means that we shouldn't be removing torn pieces. This also means that surgical debridement of a degenerative area will likely be replaced by more pro-active care.

Let me use myself as an example of this new paradigm. I injured the cartilage under my knee cap while jumping on a trampoline with the kids. Rather than improving over time, the area worsened over the next year until I had difficulty climbing stairs. Since I had failed conservative care, the next step in the traditional surgical paradigm would be to "debride" the area. This means that a surgeon would go in and cut out some of the cartilage around the area already missing some cartilage. Removing those pieces may have felt better for awhile, but ultimately would have lead to more arthritis in the area. Another option would be micro fracture, but that would mean 12 weeks on crutches, which for me, given the amount of disability wouldn't have been worth it. Since this was a small lesion, I had my one of my partners inject a patent pending Regenexx mixture which consisted of the growth factors isolated from my blood platelets and a component to cause a small micro-injury to kick off a healing cycle. Several days after this injection I was able to climb stairs without pain and to go back to trail running. What happened? A small micro injury was created by the injection at the specific site of the cartilage lesion. The growth factors then went to work to help increase my natural cartilage repair capabilities and lubrication.

As you can see, these new technologies now allow us to get ahead of the problem through promotion of repair rather than cutting out the broken parts. The new paradigm, heal before you consider cutting!

No Easy Stem Cell Lunch

Amgen today announced that Epogen, a blockbuster drug that is often used to produce new blood cells in anemic cancer patients undergoing chemotherapy, has significant risks. The problem is that the drug increases the risk of accelerated tumor growth and death. What does this have to do with stem cells? At least one US company has used this drug to mobilize adult stem cells from the bone marrow into the blood circulation so they could collect them for storage and future use. Several foreign companies are also using similar methods. This approach has been a bit of a scientific mystery, as the stem cells being mobilized were actually what's called CD34+ stem cells and not mesenchymal stem cells. Why is this a problem? CD34+ cells make new blood cells and blood components, but in primates like humans, it's doubtful they can turn into mesenchymal stem cells capable of repairing bone, muscle, cartilage, tendons, organs, or nerve tissue. So why collect them in the first place? Good question.

This problem with Epogen again brings up a big problem with our big pharma approach. Any drug designed to systemically ramp up one system is likely to have unintended side effects. In the end, the only way to treat many problem is a local approach, such as placing stem cells in an area in need of repair via needle guidance.

So in the end, there is no free stem cell lunch...

How Long are Your Telomeres?

In a recent study, 3 hours and 20 minutes of moderate exercise a week increases telomere length by about 200 base pairs. What does that mean? People that exercise like this were about 10 years genetically younger than couch potatoes.

Telomeres are the ends of your DNA that shorten as you age. This is the reason a dog lives 10-15 years while a person lives 70-100 years. The dog's telomeres shorten quicker, so they age faster. In effect, by not getting this amount of exercise, your telomeres are about 10 years shorter than the guy down the street who does.

I see middle aged and elderly patients all the time who are in too much pain to exercise. They have chronic knee, hip, shoulder, problems that prevent them from being active. The problem is that this impacts not just their overall health, but likely how many years they have left. These patients need to find non-invasive ways to get out of pain. The Regenexx procedure in one way to fix that joint pain without being out of commission for 3 months. Whatever you decide to do to help your injured or arthritic joints, one thing is clear, getting active will help more than just your heart, it will also extend your warranty!

Trouble in Big Pharmadise

This past week saw the demise of block buster drugs from our friends at big pharma. These cholesterol lowering drugs (Vytorin and Zetia), either didn't work any better than older drugs or in the case of Zetia, actually increased the amounts of fatty plaque in the carotid artery. This is on the heels of many major big pharma failures over the past few years including Bextra, Celebrex, Avandia, and others. What's going on and what does it have to do with stem cells?

Big Pharma now spends two dollars on ads for every dollar it spends on research. Big pharma has also retreated from the development of one time use drugs like antibiotics. Why? Big pharma has become intoxicated with big business plans. The best long-term biz plan is a "lifetime" drug, or one where the patient needs to take the medication every day forever. The big block buster categories of these drugs have become pain medications, anti-inflammatory medications, and cholesterol medications. The focus on marketing over science has created a problem that is evident from these drugs periodically being pulled from market. In these cases, the business plan trumps the science.

How does all of this fit into stem cells? Over the past few years we've seen an explosion of ways to modify cells to become stem cells, modify stem cells with gene therapy, expose stem cells to experimental drugs and cytokines, etc... While these efforts are to be applauded on a basic science front, there is also a plurality of data documenting multiple types of tissue repair using adult mesenchymal stem cells without such modifications. The Regenexx procedure is an example of this type of minimal manipulation, meaning deploying the repairmen of the body in various ways to repair diseased or damaged tissue. While we may be able to eventually build a better stem cell, these approaches where cells are modified are a bit concerning. Watching the Will Smith movie "I am Legend" this weekend was a great example of what can happen with these approaches. In this movie, a cure for cancer is developed by modifying a virus. The innocuous virus cures cancer, but then mutates into a deadly disease which kills 90% of the world population. While this is a bit severe, the more we manipulate cells to get them to do what we want them to do, the more likely we'll produce unintended consequences. Big pharma is learning these lessons now, with drugs being yanked off the market every few months.

With adult stem cells, we have an opportunity to teach big pharma and modern medicine that the next block buster drug is already within us.

Adult Stem Cell Explosion

I spent the holidays re-reviewing some 1,300 research papers published on mesenchymal stem cells in 2007.  At the turn of the millennium in 2000, just 90 mesenchymal stem cell research papers were indexed in the national library of medicine that year.  Think about that exponential growth.  If this publishing activity represented a business, growth like that would be enviable.  

The amazing thing about this review was the varied applications for these cells.  They are being used for orthopedic applications (like the Regenenexx procedure), plastic surgery, dentistry, heart muscle repair in many heart diseases including heart attack, cancer, healing skin wounds, diabetes, spinal cord injury, nerve injury, hearing loss, liver repair, lung repair, kidney repair, just to name a few.  We are truly seeing an explosion that will revolutionize the medicine of the next 10-20 years.  If you have a few minutes, this link will take you to the more than 4,000 articles that have been published on these powerful cells.