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.

The Autologous Biologics Revolution

All around us we're seeing a revolution in information transfer that has the big established businesses quaking in their shoes. Digital music has meant that the recording industry has to figure out a new distribution model. Digital access to information has also changed the medical world. Researchers frustrated with publishing companies have started to publish their own "open" journals, meaning that they commit to free access to all of the research, rather than allowing publishers to pillage by charging high access fees for research articles. In fact, the existence of this blogging technology shows the decentralization of the traditional news and information sharing power base. Now anyone with a video camera or great ideas can get them to a worldwide access. The same thing will happen in medicine, and Regenexx and Regenerative Sciences are a case study.

In medicine, new technologies and therapies have been largely controlled by Big Pharma or the big device manufacturers, a collection of big corporations with the tens to hundreds of millions that it costs to push these new treatments through our American medical system. First, there is the FDA, then insurance companies, then getting doctors to change their prescribing habits. Each step takes big money. As a result, many promising treatments never make it to patients and small diseases get no effective treatments. Case studies in how this modern medical gantlet has failed society can be found in treatments like "The Ketogenic Diet". This effective treatment for pediatric seizures has been known about since the 1920's, yet it took a motivated a rich Hollywood producer with a severely epileptic child to expose this hypocrisy. He tried the best neurologists in the world who just placed his child on the next blockbuster drug that didn't work. He finally ended up hearing about this well researched diet in a waiting room. He tried the diet, the kid's seizures resolved, and then he went back to his neurologists with a film crew. On national TV, one said that he didn't know about the diet because the drug reps who frequently educate doctors failed to mention it as a therapeutic option. The problem was there simply was no way to monetize the diet in today's medical system.

The next ten years in medicine will see the rise of physician driven, highly technical medical break throughs that will have big pharma reeling, much the way that the RIAA is reeling from open source digital music. Why? Think about what it took to get to a medical break through just 15 years ago. Just to be able to sift through the published world medical literature on a topic took an army of library staff. I remember in medical school what was called, "Index Medicus". This massive book held special search terms that took an experienced medical librarian to interpret. If you knew the magic code, and if you could spend many hours, you could find a few paltry research articles. Compare that to today, when anyone can get daily downloads of hundreds of medical research articles at the touch of a button. Why does this increase in information transfer matter? As discussed by authors such as Ray Kurzweil, the instant access of all of this research data to more brains will result in a much accelerated rate of medical progress.

Where will this type of innovation occur? Autologous biologics are the most likely starting point. This science simply involves taking one part of the body like blood, minimally manipulating it, and transplanting it to another area to produce an effect. This is already happening in simple treatments such as platelet rich plasma, where surgeons are now using the growth factors isolated in this biologic to enhance their surgical results. The next big area will be autologous mesenchymal stem cells, as in the Regenexx procedure being used by RSI.

Part of the reason why this shift will occur is that physicians will also demand more control over care. This has already begun happening with physicians in droves leaving the hospital for out patient care settings like surgery centers. Again, the other reason as above will be that the "knowledge gap" once held securely by big pharma will erode.

My personal observations on this topic from development of the Regenexx Procedure fit this pattern. We were able to integrate this procedure into our practice with a small research team that was much closer to the ground than big pharma could ever muster. By this I mean, our doctors had certain clinical problems they faced that they had to solve. These problems drove development of this procedure. All of this occurred in a fraction of the time otherwise possible. Unlike big pharma, we weren't concerned about government grants or huge clinical trials. We knew we had an outcome endpoint we could observe on MRI (repair of tissue) and as doctors, we had clinical observations that could guide development (what worked in the past and what didn't work). In addition, the Internet and mass access to the latest worldwide research on mesenchymal stem cells allowed us to take the next steps in our studies. I have also seen this in my colleagues. I know many docs who are taking advantage of this new information technology to develop devices that meet their needs. Rapid computerized prototyping and Internet access to online patents has allowed these docs to take a good idea and move it to market quickly and inexpensively. I call these "development docs".

Who will be big winners and looses in this coming wave of autologous biologics? Big pharma will initially be confused by all of this, but will eventually come to understand that their research and development dollars will stretch much further by partnering with "development docs". Big pharma and the universities they partner with will be the air craft carriers of development world. They have the big firepower, but the big boat can't turn on a time. Eventually, this shift from big established research groups to smaller "development docs" will allow more innovation and much quicker medical break throughs to occur.

Stem Cells: There's No Place Like Home

MSC's can clearly Home. What does this mean? They can travel through the blood stream to a site of injury. A new study out this week continues to provide more information that this can happen in the heart. The research seems to be mounting that you can get more stem cells to an injured site if you place them close to where you want them, but all things being equal, many will still find their way to the injured area.



The Regenexx procedure is also showing this homing ability. Our research group at RSI is submitting a new paper which which shows evidence of mesenchymal stem cell homing in a human model. This is evidence of a reduction in the size of bone osteonecrosis lesions in a patient treated with Regenexx. The interesting thing is that the side where the cells were implanted via needle showed the most effect (the lesions got smaller), yet the other side also showed a smaller effect, but still a reduction in lesion size. Again, this is evidence of the same homing capabilities.



What are the implications for the future? It lets us know that in a pinch, a simple IV injection of MSC's will work, as long as there is a site of injury or disease for the cells to home. However, it also tells us that in patients with multiple diseases or sites of injury where cells need to be kept in one spot, placing the cells in the area in need of treatment and making sure they are unlikely to leave is essential.

Progenitor Helper Cells-Stem Cells Don't Act Alone

Several years ago, we introduced the concept of a "Progenitor Helper Cell". At the time, all that was known was that MSC's needed to be present to help other cells like blood stem cells (CD34+). Experiments had shown that these blood stem cells (often used in bone marrow transplants) couldn't be grown outside the body unless MSC's were present.

You see, MSC's live in a "stem cell niche". In the bone marrow, this niche contains many other cells. There is evidence of chemical communication between MSC's and these other cells. Why? When we examined that question in 2005, it seemed logical that if MSC's had to be present to help other cells live outside the body, this would be a two way street. These other cells must have the ability to help MSC's. As a result, we coined the term, "Progenitor Helper Cells" (PHC's), for all of the other cells that assist MSC's.

In 2005, it only seemed a matter of time before we would understand how all the other cells in this stem cell niche helped MSC's get their work done. As it happens, research is now proving this concept. In one study published this week, MSC's and bone marrow cells were both needed to repair a rat pancreas in a diabetic mouse. This is a big deal, in that it means that the traditional concept of culturing MSC's in isolation and deploying them in isolation may be concept that isn't as effective as using the cells in a more natural way (meaning MSC's and PHC's together).

In summary, we believe that MSC's work with these other cells to act as "construction managers", overseeing or managing various parts of the repair processes. So it seems that "it takes a village" to both raise children and repair tissues.