Stem Cells: Real Possibilities in Autism? by James Jeffrey Bradstreet, MD
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Real possiBiliTies in auTism?
By jAMES jEFFrEy BrADSTrEET, MD, MD(H), FAAFP
DR. JEFF BRADStREEt graduated from the University of South Florida College of Medicine and received his residency training from Wilford Hall USAF Medical Center. As a flight surgeon, he was involved in aerospace medicine research, and he has extensive experience and training in environmental medicine, hyperbarics, and toxicology. He is extensively published in autism research and outcome studies and serves as an adjunct professor of pediatrics at Southwest College of Naturopathic Medicine in Tempe, Arizona. Dr. Bradstreet is the founder and director of the International Child Development Resource Center (www.icdrc.org), which is located in Melbourne, Florida, with a satellite office in Irvine, California. His son, Matthew, is recovering from autism with the combined help of biomedical and behavioral interventions.
sTem cells:
(Note: This article was adapted from information on my blog site www.drbradstreet.org, which is accessible to all and gives an option for regular updates on the latest findings on stem cells and the best of integrative medicine.)
or years, i have been studying the immune system in relation to autism, and i always come back to the idea that it needs reprogramming. i wish it were like my computer so that i could just press the power button until it restarted afresh. But the immune system in autism is plagued with quirky reactions to the child’s own body (that is, autoimmunity), with the brain as its special target. i’ve tried a variety of immune agents to help for over a decade. These sometimes help; occasionally, as with intravenous immunoglobulin (iVig), they are truly restorative. 1 But where do we go when these treatments don’t generate the results and recovery our children need? sUppORT fOR ImmUNe CAUses Of AUTIsm Typically in medicine as we encounter something, we move slowly and find it challenging to accept change. Doctors like paradigms and traditions – we invest our lives in memorizing systems. Throwing something new at medicine, like autoimmune brain disease presenting as autism, just doesn’t sit well with the status quo. Despite the odds against them, a few brave thinkers venture outside the comfort of the existing paradigm. in autism, the immune dysregulation
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theory started to emerge with Professor gene Stubbs in the mid-1970s. 2 Through the dedicated efforts of researchers and clinicians, we have slowly progressed, and now, a quarter of a century later, we have our first textbook defining the immune-oxidative stress linkage to autism, Autism: Oxidative Stress, Inflammation, and Immune Abnormalities.3 From the book summary: Autism: Oxidative Stress, Inflammation, and Immune Abnormalities brings together a wealth of cutting-edge evidence that is already influencing how we treat this serious condition. it looks at the role of neuropathological abnormalities, genetics, and those factors common to oxidative stress such as inflammation, immune dysfunction, aberrant cellular signaling, and gene-environment interactions. Among dozens of research topics, this volume — • Looks at interactions between genetic and environmental factors such as the maternal immune environment and prenatal/postnatal environmental stressors • Summarizes evidence for oxidative damage and inflammation in autism • introduces a PDD behavior inventory as a tool for assessing autism
• Considers autism as an aberrant adaptive response to neuroinflammation and oxidative stress • Examines the role of abnormal calcium signaling and the hypothesis that it may represent a target for novel therapeutics • Presents a hypothesis that autism arises from the dysregulation of a unified gut/brain system rather than originating in the brain alone • Proposes the utility of using a biopsychosocial method to treat autism This book, edited by Chauhan, Chauhan and Brown, shows us that autism is not only developmental but also a chronic condition based on active pathophysiology, and that it is not only behavioral but also presents somatic and systemic features. The findings in these chapters support the theory that oxidative stress plays an important role in autism. They also point to the value of conducting in-depth mechanistic studies as a way to uncover new targets for therapeutic intervention in autism. About 4 years ago i presented and participated in the science forum that ultimately led to the book’s publication – it was an honor to be a part of its beginnings. But the real honor goes to the late “Papa” Bernie rimland, who used the resources of
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the Autism research institute to fund the meeting, and to Dr. Woody Mcginnis who coordinated the project on Bernie’s behalf. i‘ve also had the pleasure to participate with Professor Antonio Persico in numerous think tanks and autism brainstorming retreats. During these sessions i’ve come to respect his research and his desire to find the truth. He honestly tries to remove bias from his investigations and ask questions that can be answered. For years, i’ve been lecturing on my clinical observations that autism is related to immune activation with associated oxidative stress. Despite all the evidence we can present during these lectures, i still hear and read in the media that there is no evidence of an immunological link to autism. i simply don’t get it. The majority of clinicians and scientists have largely ignored and not supported the concepts illustrated in the textbook. Now these recent observations of Prof. Persico and his colleagues in italy make it impossible to deny. Genome-wide expression studies in Autism spectrum disorder, Rett syndrome, and Down syndrome. Lintas C, Sacco R, Persico AM. Laboratory of Molecular Psychiatry and Neurogenetics, University “Campus Bio-Medico”, rome, italy. Department of Experimental Neurosciences, i.r.C.C.S. “Fondazione Santa Lucia”, rome, italy. Neurobiol Dis. 2010 Dec 2. [Epub ahead of print] Abstract Though different in their aetiology, autism spectrum disorder (ASD), rett syndrome (rTT) and Down syndrome (DS) are three neurodevelopmental disorders sharing significant clinical and neuropathological overlaps. genome-wide expression studies are reviewed and available datasets from post-mortem brains reanalyzed to identify genes and gene pathways dysregulated in all three disorders. Our results surprisingly converge upon immune, and not neurodevelopmental genes, as the most consistently shared abnormality in genome-wide expression patterns. A dysregulated immune response, accompanied by enhanced oxidative stress and abnormal mitochondrial metabolism seemingly represents the common molecular underpinning of these neurodevelopmental disorders. This conclusion may be important for the definition of pharmacological therapies able to ameliorate clinical symptoms across these disorders. (Emphasis added.) So what does this mean? For me this speaks to a common pathway to neurological dysfunction during development. We know the development of the brain is primarily regulated by microglial cells (see Figure 1).
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figure 1: normal relationship of microglia to neurons and the blood-brain barrier. credit: stanmed.stanford.edu
figure 2: Improper function of microglia causes increase in the toxin quinolinic acid and increased oxidative stress in the neuron. not shown here, but clearly part of the neuronal threat, is increased glutamate and reduction of glutathione (a critical antioxidant for neurons). credit: gladstone.ucsf.edu
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Stem cells possess the potential to regulate the immune system (an intrinsic role of stem cells), which makes stem cell therapy one of the few options we have to redirect brain immune dysfunction apart from long-term immunosuppressive agents. And there are scientific reasons to believe multipotential adult stem cells may be able to correct the ongoing immunological chaos children with autism experience.
The microglial cells are the brain’s custom-made immune cells. They continually work to shape, guide and prune the developing brain in a way reminiscent of a skilled vinedresser tending the grapevines to produce the finest wine. When it works right it is remarkable. However, we are learning this process is too easily disrupted by inflammation. That is the message i see in most of my patients and that is the message from Persico’s team as well. But when the microglial cells become dysfunctional (whether wounded by toxins or turned on by immune activation) the neurons are in danger (see Figure 2). INTRODUCTION TO sTem Cells given the overwhelming evidence of brain immune dysfunction, the use of stem cells as therapeutic agents starts to become appealing. They possess the potential to regulate the immune system (an intrinsic role of stem cells), which makes stem cell therapy one of the few options we have to redirect brain immune dysfunction apart from long-term immunosuppressive agents. And there are scientific reasons to believe multipotential adult stem cells may be able to correct the ongoing immunological chaos children with autism experience. But before i get more into what stem cells are and how they work, i want to dispel a common misconception: stem cells are not “iQ points in a syringe,” nor are they a “new brain looking to happen.” There is no way for stem cells to become functional, mature brain cells that are integrated into the overall circuitry with other brain cells. i know that is what we all want for our children with autism or our grandparents with Alzheimer’s, but it just isn’t going to happen that way. Even if you stuck the stem cells directly into the brain, it is extremely unlikely to have any functional neuronal potential. Protocols using injections into the cerebral spinal fluid (CSF) via spinal taps to inject the stem cells are unjustified. CSF is created in the choroid plexus in the fluid-filled spaces inside the brain (see Figure 3). The pressure flows from blood pressure driving the choroid fluid production, to the ventricles, out of the skull through the foramen magnum (big hole at the bottom of the skull) and then down the spinal cord. it does circulate in part back to the brain and it seems it is exchanged every few hours. But even with this circulation, we aren’t going to deliver stem cells where we want them. We know from many animal studies that stem cells leave the bloodstream and enter the brain.4 So the blood is the best and most logical way to get stem cells into the brain. But even once inside, we can only expect a fresh immune regulation of the brain – not a rebuilt cortex.
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figure 3: The brain and spinal fluid circulation
right now you may be wondering why we should bother discussing stem cells in relation to autism at all. And if it weren’t for the ongoing inflammatory mess that most kids whom i see with autism suffer from, then i would agree with you. So, why consider stem cells? why CONsIDeR sTem Cells fOR AUTIsm? For a few years, overseas stem cell centers have advertised the potential benefits of stem cells for children with autism. They’ve set up operations in Costa rica (now closed), Panama, Mexico, China, the Dominican republic, germany and greece. These centers use a variety of cell types: fetal, embryonal, and mesenchymal. in most cases, the stem cells come from unknown donors. Using a few anecdotes, they have tantalized our hopes that stem cells may be the ultimate cure. i’ve interviewed patients before and after treatments with stem cell therapies for a wide variety of illnesses for the last 3 years. Outside the arena of autism, i’ve seen some truly dramatic positive changes with cerebral palsy, rheumatoid arthritis, diabetes, degenerative joint disease and cosmetic surgery. Studies in these areas are
making their way into the scientific literature and getting presented at medical conferences. yet in autism, there are no published cases to work from, so we are still at the early stages of our use of this intervention. Despite that, there are credible rationales for the application of certain types of stem cell therapies to autism. We have mentioned the great potential of stem cells to regulate the immune system, helping to correct the ongoing immunological chaos in children with autism. But what are stem cells? whAT ARe sTem Cells? Stem cells are an emerging treatment option that – unlike medications – are capable of both repairing and regenerating the body. So what are stem cells? Simply put, these are progenitor cells . . . something like cell seeds. An acorn doesn’t look like an oak tree, but it contains that potential. Stem cells are potential mature cells. They can grow into mature cells in a process known as differentiation. This just means they change from being multipotential to being just one type of cell. (See Figure 4.)
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figure 4: multipotential stem cells can become many different types of mature cells. That is exactly what they do in fetal development. but is that what we need them to do in autism? I actually think the role of stem cells in autism is much different than their role in making new tissue.
mesenchymal Stem cell (mSc)
figure 5: Adipose cells converted from adipose stem cells. Red droplets represent stained fat inside the cells.
Ectodermal cells
mesodermal cells
Endodermal cells
neurons (nerve)
Adipose cartilage bone cardiac Skeletal (fat) muscle muscle
Liver cells
Pancreatic cells
Stem cells can be generated from your own bone marrow or adipose tissue (body fat) (see Figure 5). These are called mesenchymal stem cells (autologous = self-donated). They can also be generated in a similar process, but from a donor of fat or bone marrow (allogeneic). in the United States this is our only option apart from participation in special research studies. in the rest of the world, local rules apply, and this varies from country to country. The general categories of stem cells are as follows: Embryonal: Derived from a human embryo – generally from leftover expanded blastocysts (6 to 8 days) after in vitro culturing. Sources are fertility clinic embryo storage centers (i.e., if the parents donated unwanted fertilized eggs to researchers). These are capable of becoming human life if implanted into a receptive womb. For this reason their use worldwide remains controversial. (These are not presently legal to use in treatment in the US). Fetal: As the name implies, these are from abortions. Even more than the embryonal, use of these types of stem cells is highly controversial and prohibited in many countries. i do NOT use these, NOr do i recommend them, and they are not allowed in the US. Umbilical cord blood or placental: These can be obtained from amniocentesis, the baby’s umbilical cord (UBSC), or the leftover placenta (“after-birth”). Currently there are lots of stored umbilical cords. Any one umbilical cord by itself without culturing is not sufficient to treat anyone medically. Some work has been done with combining multiple umbilical cords (allogeneic) to create enough stem cells. Currently, we are not allowed to use stored umbilical- derived stem cells or placentas. From the individual’s perspective, stored UBSC is unlikely to be beneficial. Collectively they may be valuable to research or treatment, but that is still quite a way off. We are not able to use UBSC at this time.
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Mulitipotential or mesenchymal stem cells (MSC): These have the potential to convert to various cell types: muscle, fat, cartilage, etc. However, the main functional role and reason for the therapeutic use of MSC is their ability to reduce inflammation and to signal repair. While making more fat is sometimes an important function and naturally occurring functional role of stem cells (as in filling in defects after injury), the exciting aspect of stem cell medicine is for the treatment of chronic inflammatory and degenerative diseases (e.g., inflammatory bowel disease, autoimmune disorders, arthritis, and neurological issues). Medicine is just at the frontier of how to best
use MSC to help these disorders, but given the devastating complications of these disorders combined with the safety of MSC, they represent a new and powerful tool in the fight against disease. fOCUs ON meseNChymAl sTem Cells: msC As you have seen, stem cells come in many types, but for my purposes, we are talking about adult stem cells. We use the adult term to distinguish from embryonic, fetal, placental, cord blood, and similar types of cells. My specific interest is in fat, i.e., adiposederived cells. These have important distinctions with their own advantages and disadvantages. Adult MSC derived from either adipose (fat) or bone marrow are capable of another important
figure 6: Stem cell in the brain preventing inflammation.
international Journal of inflammation. volume 2010, Article Id 151097, 18 pages
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MSC uniquely downregulate inflammation in most areas of the body, including the brain. They may be our best hope for repairing inflammatory changes in the gut due to Crohn’s disease, ulcerative colitis, and autistic enterocolitis. But more importantly than that, as described earlier, they hold the potential for regulating inflammation in the brain.
function and one that i think is more likely where they will find their usefulness in autism. MSC are capable of downregulating chronic inflammation (Figure 6). That gets my attention because it is the closest we may be able to come to that “reset button” i’ve been looking for. i believe this is where stem cells will find their place in autism immunotherapy. ImmUNe ReGUlATION by mCs (fAT-DeRIveD sTem Cells) Once activated, MSC seek out areas on the body expressing inflammation. it is their natural programming. Think about any cut you have had. initially it is swollen and red and painful. That is the initial inflammatory defense reaction that will defend the body from infection and start to clean
up the damaged tissue. However, soon after that reaction starts it signals local stem cells to proliferate, and they migrate to the wound. Once on site, they communicate a calming message to inflammatory cells and start to direct the repair process. This is exactly what we want them to do in the brain and the chronically inflamed gut of children with autism. We have already seen an illustration of stem activity in the brain (Figure 6), and it is similar in the gut (see Figure 7 below, and abstract, next page). Figure 7 is complex, but it does a good job of depicting the multiple levels of control the MSC can exert over inflammation. Sitting in the middle of Figure 7 is a MSC. it takes quickly over the immune environment, much like a new general takes command of a combat zone. The MSC increases regulatory counter-inflammatory Treg cells. it
reduces immune chemicals of inflammation (TNFalpha, interferon-gamma, etc). And it communicates a shift in the production of immune proteins, all of which combine to reduce inflammation and to then create an environment of repair. This is important to autoimmune disorders like inflammatory bowel disease (as shown), but should equally apply to neurodegenerative disease, chronic arthritis, allergies, asthma, and – certainly – autism spectrum disorders. As we have mentioned, MSC uniquely downregulate inflammation in most areas of the body, including the brain. They may be our best hope for repairing inflammatory changes in the gut due to Crohn’s disease, ulcerative colitis, and autistic enterocolitis. But more importantly than that, as described earlier, they hold the potential for regulating inflammation in the brain. research from multiple sclerosis indicates that MSC may facilitate repair in the brain – which is truly extraordinary. self OR DONOR sTem Cells? if you want to follow stem cell research and treatment models, you’ll need to learn the difference between autologous (self-donated) versus allogeneic (donated from another person or persons) cells. Strangely enough, adipose-derived stem cells are immunologically privileged, and, even when they come from someone else, they generally live and do not fight the new – genetically different – host they find themselves cohabitating with. The medical literature supports either allogeneic or self-donated MSCs (fat or bone marrow- derived stem cells) in the treatment of inflammatory bowel disease (iBD). Common treatments for iBD seek to suppress the immune system, and with that comes a long list of serious potential complications – even death from infections. But MSC work differently. They “talk” to the deranged immune system to give it new instructions. The result is a more tuned and balanced immune defense in the gi tract – without the dangers intrinsic in many of the suppressive medications. My preference is for the use of autologous (self-donated) stem cells. Allogeneic stem cells create a chimeric (2-in-1) relationship with the body. This means the donor’s genetically different cells cohabitate with the host despite being mismatched. They do not get rejected nor do they initiate attacks on the host. The long-term effects of chimerisms are hard to anticipate at this time (although early observations thus far look safe). From my perspective, self-donated stem cells are the logical choice.
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figure 7: In the graphic, the red box represents the mSc that is downregulating inflammation. from: Singh et al. Stem cells as potential therapeutic targets for inflammatory bowel disease. Front Biosci (schol ed). 2010;2:993-1008.
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Obviously, not all children with autism suffer from chronic inflammation, but for those who do, MSC transplantation may represent a reasonable treatment option when compared to iVig or the long-term use of anti-inflammatory medications.
As we can see in the abstract above, doctors already have stem cell therapy targeted for iBD. Obviously, not all children with autism suffer from chronic inflammation, but for those who do, MSC transplantation may represent a reasonable treatment option when compared to iVig or the long-term use of anti-inflammatory medications. This also means patient selection is important. And adult-derived MSC can be self-donated, meaning we don’t need embryos, fetuses, or even strangers to provide them for us. just to be clear – the term “adult” doesn’t mean 18 or 21 year olds. it just means cells that are derived from a person any time after birth. This distinguishes them from embryos and fetuses, neither of which could be used in autism apart from an FDA approved new drug trial (which i do not expect to see in the next decade). pRODUCING mUlTIpOTeNTIAl ADIpOse-DeRIveD sTem Cells The picture of the two glass tubes (Figure 8) shows the mid-phase of stem cell isolation from adipose (human fat). This was the result after i put the cells through several washes, high speed separation techniques, fat digestion, purification, and isolation.
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By this point i was getting closer to my goal: biological gold (viable multipotential stem cells). it took me about 2 hours in the lab to get to that stage of stem cell extraction, and the process was far from over. At the bottom of the centrifuge tubes are red blood cells, immune cells and several million adiposederived mesenchymal or multipotential stem cells. These prized stem cells (shown below) will be washed several more times and go through several cycles of centrifugation to further isolate them from other cells.
figure 8: Stem cells in the test tube
NOw ThAT yOU mAy wANT Them – CAN yOU GeT Them IN The UNITeD sTATes? yes. i have been trained with adipose-derived stem cells, and this technique provides a straightforward process we can currently use in the US. There are, of course, restrictions placed by the FDA on this process. Some general and understandable regulatory concepts for this process are what we call “the 3 sames”: same person, same building, and same day. Add to this another set of rules that come from the Public Health and Safety Act, section 361: stem cells cannot be highly manipulated or used for purposes other than their normal function. No one really understands what that means in the real world. But it seems clear that you cannot alter the cells with laser stimulation (currently being done in other places), you cannot add chemical tags to them to get them to behave in a special way (currently happening in investigational drug trials), you cannot culture them to increase their number (this is viewed as a manipulation), when you start the process you have to finish in a relatively short time frame (a few hours). Otherwise, the FDA may assume the intent is culturing or amplification of the cell numbers. This also means banked stem cells (including a child’s own cord blood) cannot be used. While we are clear that self-donated and not substantially manipulated stems cells meet the regulatory criteria, it is not clear to me whether these guidelines exclude donor adult stem cells. in other words – with precautions against transmissible diseases – could a parent donate stem cells to their child? At this point, the best answer that i can give you is “probably.” Think about it this way: have you ever donated blood? if so, you donated cells for someone else to use in their body. That is allogeneic. it is also totally permissible. Besides, whole blood always contains a few stem cells. Obviously, blood banks go to great lengths to ensure that the blood products they provide are both safe and clean. in our iCDrC centers (both in California and Florida) we routinely use iVig (a concentrated form of antibodies derived from human blood donors). it comes from hundreds of people per dose, and in the last 15 years of my using iVig there have been no contaminations. The blood donation analogy makes me think a properly screened donor could provide stem cells if the other guidelines were also met. Self-donated adipose tissue (fat) contains large numbers of MSC. All we need to do is harvest 20-50 ml of fat (less than 5 tablespoons) and liberate the stem cells that are trapped within it. That process has been perfected over the last few years and is in use on a daily basis in plastic surgery centers all over the country. Plastic surgeons use stem cells to enhance the successful grafting of fat transfers for cosmetic enhancements. Without stem cells, between 70-90% of the fat transferred will die and be reabsorbed. With fat-derived stem cells, those numbers are reversed. So obviously, for the group of cosmetic surgeons already doing stem cell transplantations, the rules
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figure 9: dr. bradstreet in the
stem cell laboratory isolating mSc from lipoaspirate.
permit an individual having their own bone marrow or fat harvested, and the stem cells isolated and then re-implanted. Preparing the stem cells from the lipoaspirate is a time-consuming and precise process. in Figure 9, we are about halfway through the 2-3 hour long procedure to safely extract the cells without harming them. i used a very busy plastic surgery center to learn about both stem cell harvesting (lipoaspiration) and stem cell isolation and preparation (Figure 9). Harvesting involves gently aspirating a small volume of fat. This is absolutely NOT liposuction. Liposuction damages stem cells and is not suitable for the kind of results we desire. Lipoaspiration uses a very small (3mm) blunt cannula and a syringe – not a vacuum tube. For anyone familiar with gynecology, lipoaspiration is similar to an endometrial biopsy, and liposuction is like a D&C. Lipoaspiration is a safe and simple procedure that can be accomplished in any clean room in a doctor’s office. it does not require an operating room, general anesthesia, or even sedation (although i assume our autistic kids will need some calming agent to get them through the process). The total process requires properly preparing the patient for stem cell harvest to increase the yield of active stem cells. it also requires taking care of our stem cell transplants in much the same way a farmer tends his crop after planting. A sImple wAy TO lOOK AT IT: GeTTING sTARTeD wITh sTem Cells i have been thinking a lot about stem cells for several years, waiting for the science to mature to the point where cost-effective treatment plans start to make sense. Try to think of stem cells the way a farmer or gardener thinks about his seeds. you may not know a lot about farming, but i’m confident we all understand the concept of planting seeds to grow flowers or vegetables. Every experienced gardener or farmer knows what they need to do after buying the seeds. So do
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One thing that seems clear is that hyperbaric oxygen increases both stem cell yields if it is used prior to harvesting, and it also increases the clinical impact favorably when applied after stem cell implantation.
[HBOT] delivered at the right time after the implanted MSC seeds are starting to grow. One thing that seems clear is that hyperbaric oxygen increases both stem cell yields if it is used prior to harvesting, and it also increases the clinical impact favorably when applied after stem cell implantation. Sunlight applies to the vitamin D [D-3] the immune system will need to help guide the seeds in the right direction. Keeping the weeds out naturally means preventing oxidative damage and toxic exposure to our valuable MSC crop. if we do all of that right, we should have clean MSC seeds to plant and an abundant crop of immunemanaging stem cells working to regulate and restore immune health and balance, while restoring function to the individual. ThIs Is GOOD exAmple Of AN INTeGRATIve AppROACh TO sTem Cell TheRApIes fROm OhIO sTATe UNIveRsITy: AND IT Is As seRIOUs As A heART ATTACK These researchers clearly know how best to tend their stem cell garden. hyperbaric oxygenation enhances transplanted cell graft and functional recovery in the infarct heart Mahmood Khan*, Sarah Meduru, Iyyapu K. Mohan, M. Lakshmi Kuppusamy, Sheik Wisel, Aditi Kulkarni, Brian K. Rivera, Robert L. Hamlin1, and Periannan Kuppusamy Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA J Mol Cell Cardiol. 2009 August ; 47(2): 275-287. The more i study this paper, the more i respect the thought that went into it. On my blog i’ve been posting a lot about adipose (fat) derived stem cells – one type of mesenchymal stem cell line (MSC). This paper focuses on bone marrow-derived stem cells. Without going into a lengthy discussion about this, the medical literature documents that adipose and bone marrow stem cells both have similar potentials as stem cells. This paper investigates mice, but in the human application of this technology, adiposederived MSC are far more abundant and practical to manage. given the devastating effects of heart attacks, as well as how common they are, finding better ways to treat these patients is critically important. in a nutshell, what these researchers did was to create heart attacks in mice. Then they studied the natural untreated course, but they also contrasted that with hyperbaric oxygen (HBO) therapy versus stem cells (MSC), and then combined MSC + HBO. The pictures in Figure 10 speak for
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you: prepare the soil where you want to plant seeds. As you might expect, it is even more complex with autologous (self-donated) MSC stem cells. First of all, we get the “seeds” (stem cells) from the very soil (the person’s ecosystem) where we want to replant them. That ecosystem already created problems. Our goal is to correct those problems – not add to them. With the right plan, we can improve our chances of a good harvest from our stem cell seeds. in that troubled ecosystem (the exposures which created the medical problems) lies the potential for a bad crop and a harvest gone wrong. No one would want to try to grow a crop from diseased seeds. So, how can we make this work? Equally no decent farmer or gardener would plant his seeds in poisoned soil. Our stem cell seeds need ideal conditions both before and after transplanting if we are to expect the best results. Based on my years of experience and work with nutrition and toxicology, i have some suggestions to help this entire process. it makes sense to first go through some important detoxification measures prior to collecting the MSC seeds. This will mean something a little different for every patient based on their toxic exposure patterns and individual problems. Then, following our gardening analogy, we will need to: fertilize, water, provide fresh air and sunlight, and keep the weeds out of our new crop. What does all this “gardening talk” mean in real-world terms for repair and regeneration of someone’s health? Fertilizing means giving all of the proper nutrients the MSC seeds require. Watering means providing good circulation (blood) to the area(s) we need to restore. Fresh air means the right amount of oxygen. This is likely from hyperbaric oxygen therapy
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figure 10: The effect of mSc + hbO on mouse heart after infarction.
Post mI dead heart Area
t ear ing w h row ne le g sc mu
themselves. The purple areas represent living heart tissue and the pale blue areas are scar tissue. i will explain the significance of the pictures in Figure 10 above. just by looking at the colors it is clear that MSC + HBO is far better than even stem cells provided alone. This type of study is exactly what we need in the field of integrative medicine. i have been complaining about clinical studies that control for only one variable. i understand the scientific reasons,
but in reality that just isn’t the way complex biological systems work. This study is just awesome. Let’s look at Figure 11 below and get into some more details. i added the dotted lines to help in my discussion. As a primer in cardiology, the active phase of heart muscle work is done during rELAXATiON of the heart muscle. That is where nearly all of the energy is consumed, because heart muscle has to actively recharge for the next beat. Think about a rubber band you want to shoot. you pull it back and that requires energy. Then you let it fly and that took very little effort. The red dotted line in Figure 11 is set at the ejection fraction (EF) (measured in percentage points). in simple terms, that means what percent of blood leaves the heart on any given heart beat (or letting the rubber band fly). Mice are better at this than we are. They are approximately 90% efficient with each heart beat: we humans average 55-70%. The blue line represents fractional shortening, which measures and ratios the change in the diameter
of the left ventricle (main pumping chamber) between the contracted and relaxed states. in this mouse study, the heart attack reduced the EF to 60% (a 1/3 reduction). Hyperbaric oxygen plus stem cells returned the rejection fraction to about 75%. HBO by itself made a marginal, but not significant, increase in the EF. Stem cells by themselves (the MSC alone portion of the study) did help, but significantly less than the combination of MSC and HBO. This study is simply amazing science. it teaches us the specifics about stem cell implanting and why HBO is a valuable adjunct to the process. But more importantly, it teaches us to use integrated therapies to optimize outcomes. For me it seems very clear: stem cells are good, but stem cells plus HBO is significantly better. In other words, integrative medicine means being a better gardener. i hope my analogy helps these concepts to be easily remembered. From my observations of the stem cell industry thus far, it seems that a lot of people want to perform stem cell implanting, but few seem to want to tend to their garden. Please keep this vital analogy and concept in mind as you consider stem cell options for your health or that of your loved ones. fINAlly . . . Even before we start on this journey it is critical to select patients who would seem to be the best candidates for stem cell therapy. We are still learning about patient selection, however, i believe my previous work on biomarkers can be used to help us with the selection process. The full article is presented here: http://www.thorne. com/altmedrev/.fulltext/15/1/15.pdf. Again, i talk about new research with stem cells extensively on my site www.drbradstreet. org. Please check out those discussions for more information.
REfEREncES
1. Gupta S, Aggarwal S, Heads C. Dysregulated immune system in children with autism: beneficial effects of intravenous immune globulin on autistic characteristics. J Autism Dev Disord. 1996 Aug;26(4):439-52. 2. Stubbs EG., Autistic children exhibit undetectable hemagglutination-inhibition antibody titers despite previous rubella vaccination. J Autism Child Schizophr. 1976 Sep;6(3):269-74. 3. Chauhan A, Chauhan V, Brown T (Eds.). (2010). Autism: Oxidative Stress, Inflammation, and Immune Abnormalities. Boca Raton, FL: CRC Press. 4. Crocker SJ, Bajpai R, Moore CS, Frausto RF, Brown GD, Pagarigan RR, Whitton JL, Terskikh AV. Intravenous administration of Human ES-derived Neural Precursor Cells Attenuates Cuprizoneinduced CNS Demyelination. Neuropathol Appl Neurobiol. 2011 Jan 28. [Epub ahead of print]
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Real possiBiliTies in auTism?
By jAMES jEFFrEy BrADSTrEET, MD, MD(H), FAAFP
DR. JEFF BRADStREEt graduated from the University of South Florida College of Medicine and received his residency training from Wilford Hall USAF Medical Center. As a flight surgeon, he was involved in aerospace medicine research, and he has extensive experience and training in environmental medicine, hyperbarics, and toxicology. He is extensively published in autism research and outcome studies and serves as an adjunct professor of pediatrics at Southwest College of Naturopathic Medicine in Tempe, Arizona. Dr. Bradstreet is the founder and director of the International Child Development Resource Center (www.icdrc.org), which is located in Melbourne, Florida, with a satellite office in Irvine, California. His son, Matthew, is recovering from autism with the combined help of biomedical and behavioral interventions.
sTem cells:
(Note: This article was adapted from information on my blog site www.drbradstreet.org, which is accessible to all and gives an option for regular updates on the latest findings on stem cells and the best of integrative medicine.)
or years, i have been studying the immune system in relation to autism, and i always come back to the idea that it needs reprogramming. i wish it were like my computer so that i could just press the power button until it restarted afresh. But the immune system in autism is plagued with quirky reactions to the child’s own body (that is, autoimmunity), with the brain as its special target. i’ve tried a variety of immune agents to help for over a decade. These sometimes help; occasionally, as with intravenous immunoglobulin (iVig), they are truly restorative. 1 But where do we go when these treatments don’t generate the results and recovery our children need? sUppORT fOR ImmUNe CAUses Of AUTIsm Typically in medicine as we encounter something, we move slowly and find it challenging to accept change. Doctors like paradigms and traditions – we invest our lives in memorizing systems. Throwing something new at medicine, like autoimmune brain disease presenting as autism, just doesn’t sit well with the status quo. Despite the odds against them, a few brave thinkers venture outside the comfort of the existing paradigm. in autism, the immune dysregulation
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theory started to emerge with Professor gene Stubbs in the mid-1970s. 2 Through the dedicated efforts of researchers and clinicians, we have slowly progressed, and now, a quarter of a century later, we have our first textbook defining the immune-oxidative stress linkage to autism, Autism: Oxidative Stress, Inflammation, and Immune Abnormalities.3 From the book summary: Autism: Oxidative Stress, Inflammation, and Immune Abnormalities brings together a wealth of cutting-edge evidence that is already influencing how we treat this serious condition. it looks at the role of neuropathological abnormalities, genetics, and those factors common to oxidative stress such as inflammation, immune dysfunction, aberrant cellular signaling, and gene-environment interactions. Among dozens of research topics, this volume — • Looks at interactions between genetic and environmental factors such as the maternal immune environment and prenatal/postnatal environmental stressors • Summarizes evidence for oxidative damage and inflammation in autism • introduces a PDD behavior inventory as a tool for assessing autism
• Considers autism as an aberrant adaptive response to neuroinflammation and oxidative stress • Examines the role of abnormal calcium signaling and the hypothesis that it may represent a target for novel therapeutics • Presents a hypothesis that autism arises from the dysregulation of a unified gut/brain system rather than originating in the brain alone • Proposes the utility of using a biopsychosocial method to treat autism This book, edited by Chauhan, Chauhan and Brown, shows us that autism is not only developmental but also a chronic condition based on active pathophysiology, and that it is not only behavioral but also presents somatic and systemic features. The findings in these chapters support the theory that oxidative stress plays an important role in autism. They also point to the value of conducting in-depth mechanistic studies as a way to uncover new targets for therapeutic intervention in autism. About 4 years ago i presented and participated in the science forum that ultimately led to the book’s publication – it was an honor to be a part of its beginnings. But the real honor goes to the late “Papa” Bernie rimland, who used the resources of
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the Autism research institute to fund the meeting, and to Dr. Woody Mcginnis who coordinated the project on Bernie’s behalf. i‘ve also had the pleasure to participate with Professor Antonio Persico in numerous think tanks and autism brainstorming retreats. During these sessions i’ve come to respect his research and his desire to find the truth. He honestly tries to remove bias from his investigations and ask questions that can be answered. For years, i’ve been lecturing on my clinical observations that autism is related to immune activation with associated oxidative stress. Despite all the evidence we can present during these lectures, i still hear and read in the media that there is no evidence of an immunological link to autism. i simply don’t get it. The majority of clinicians and scientists have largely ignored and not supported the concepts illustrated in the textbook. Now these recent observations of Prof. Persico and his colleagues in italy make it impossible to deny. Genome-wide expression studies in Autism spectrum disorder, Rett syndrome, and Down syndrome. Lintas C, Sacco R, Persico AM. Laboratory of Molecular Psychiatry and Neurogenetics, University “Campus Bio-Medico”, rome, italy. Department of Experimental Neurosciences, i.r.C.C.S. “Fondazione Santa Lucia”, rome, italy. Neurobiol Dis. 2010 Dec 2. [Epub ahead of print] Abstract Though different in their aetiology, autism spectrum disorder (ASD), rett syndrome (rTT) and Down syndrome (DS) are three neurodevelopmental disorders sharing significant clinical and neuropathological overlaps. genome-wide expression studies are reviewed and available datasets from post-mortem brains reanalyzed to identify genes and gene pathways dysregulated in all three disorders. Our results surprisingly converge upon immune, and not neurodevelopmental genes, as the most consistently shared abnormality in genome-wide expression patterns. A dysregulated immune response, accompanied by enhanced oxidative stress and abnormal mitochondrial metabolism seemingly represents the common molecular underpinning of these neurodevelopmental disorders. This conclusion may be important for the definition of pharmacological therapies able to ameliorate clinical symptoms across these disorders. (Emphasis added.) So what does this mean? For me this speaks to a common pathway to neurological dysfunction during development. We know the development of the brain is primarily regulated by microglial cells (see Figure 1).
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figure 1: normal relationship of microglia to neurons and the blood-brain barrier. credit: stanmed.stanford.edu
figure 2: Improper function of microglia causes increase in the toxin quinolinic acid and increased oxidative stress in the neuron. not shown here, but clearly part of the neuronal threat, is increased glutamate and reduction of glutathione (a critical antioxidant for neurons). credit: gladstone.ucsf.edu
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Stem cells possess the potential to regulate the immune system (an intrinsic role of stem cells), which makes stem cell therapy one of the few options we have to redirect brain immune dysfunction apart from long-term immunosuppressive agents. And there are scientific reasons to believe multipotential adult stem cells may be able to correct the ongoing immunological chaos children with autism experience.
The microglial cells are the brain’s custom-made immune cells. They continually work to shape, guide and prune the developing brain in a way reminiscent of a skilled vinedresser tending the grapevines to produce the finest wine. When it works right it is remarkable. However, we are learning this process is too easily disrupted by inflammation. That is the message i see in most of my patients and that is the message from Persico’s team as well. But when the microglial cells become dysfunctional (whether wounded by toxins or turned on by immune activation) the neurons are in danger (see Figure 2). INTRODUCTION TO sTem Cells given the overwhelming evidence of brain immune dysfunction, the use of stem cells as therapeutic agents starts to become appealing. They possess the potential to regulate the immune system (an intrinsic role of stem cells), which makes stem cell therapy one of the few options we have to redirect brain immune dysfunction apart from long-term immunosuppressive agents. And there are scientific reasons to believe multipotential adult stem cells may be able to correct the ongoing immunological chaos children with autism experience. But before i get more into what stem cells are and how they work, i want to dispel a common misconception: stem cells are not “iQ points in a syringe,” nor are they a “new brain looking to happen.” There is no way for stem cells to become functional, mature brain cells that are integrated into the overall circuitry with other brain cells. i know that is what we all want for our children with autism or our grandparents with Alzheimer’s, but it just isn’t going to happen that way. Even if you stuck the stem cells directly into the brain, it is extremely unlikely to have any functional neuronal potential. Protocols using injections into the cerebral spinal fluid (CSF) via spinal taps to inject the stem cells are unjustified. CSF is created in the choroid plexus in the fluid-filled spaces inside the brain (see Figure 3). The pressure flows from blood pressure driving the choroid fluid production, to the ventricles, out of the skull through the foramen magnum (big hole at the bottom of the skull) and then down the spinal cord. it does circulate in part back to the brain and it seems it is exchanged every few hours. But even with this circulation, we aren’t going to deliver stem cells where we want them. We know from many animal studies that stem cells leave the bloodstream and enter the brain.4 So the blood is the best and most logical way to get stem cells into the brain. But even once inside, we can only expect a fresh immune regulation of the brain – not a rebuilt cortex.
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figure 3: The brain and spinal fluid circulation
right now you may be wondering why we should bother discussing stem cells in relation to autism at all. And if it weren’t for the ongoing inflammatory mess that most kids whom i see with autism suffer from, then i would agree with you. So, why consider stem cells? why CONsIDeR sTem Cells fOR AUTIsm? For a few years, overseas stem cell centers have advertised the potential benefits of stem cells for children with autism. They’ve set up operations in Costa rica (now closed), Panama, Mexico, China, the Dominican republic, germany and greece. These centers use a variety of cell types: fetal, embryonal, and mesenchymal. in most cases, the stem cells come from unknown donors. Using a few anecdotes, they have tantalized our hopes that stem cells may be the ultimate cure. i’ve interviewed patients before and after treatments with stem cell therapies for a wide variety of illnesses for the last 3 years. Outside the arena of autism, i’ve seen some truly dramatic positive changes with cerebral palsy, rheumatoid arthritis, diabetes, degenerative joint disease and cosmetic surgery. Studies in these areas are
making their way into the scientific literature and getting presented at medical conferences. yet in autism, there are no published cases to work from, so we are still at the early stages of our use of this intervention. Despite that, there are credible rationales for the application of certain types of stem cell therapies to autism. We have mentioned the great potential of stem cells to regulate the immune system, helping to correct the ongoing immunological chaos in children with autism. But what are stem cells? whAT ARe sTem Cells? Stem cells are an emerging treatment option that – unlike medications – are capable of both repairing and regenerating the body. So what are stem cells? Simply put, these are progenitor cells . . . something like cell seeds. An acorn doesn’t look like an oak tree, but it contains that potential. Stem cells are potential mature cells. They can grow into mature cells in a process known as differentiation. This just means they change from being multipotential to being just one type of cell. (See Figure 4.)
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figure 4: multipotential stem cells can become many different types of mature cells. That is exactly what they do in fetal development. but is that what we need them to do in autism? I actually think the role of stem cells in autism is much different than their role in making new tissue.
mesenchymal Stem cell (mSc)
figure 5: Adipose cells converted from adipose stem cells. Red droplets represent stained fat inside the cells.
Ectodermal cells
mesodermal cells
Endodermal cells
neurons (nerve)
Adipose cartilage bone cardiac Skeletal (fat) muscle muscle
Liver cells
Pancreatic cells
Stem cells can be generated from your own bone marrow or adipose tissue (body fat) (see Figure 5). These are called mesenchymal stem cells (autologous = self-donated). They can also be generated in a similar process, but from a donor of fat or bone marrow (allogeneic). in the United States this is our only option apart from participation in special research studies. in the rest of the world, local rules apply, and this varies from country to country. The general categories of stem cells are as follows: Embryonal: Derived from a human embryo – generally from leftover expanded blastocysts (6 to 8 days) after in vitro culturing. Sources are fertility clinic embryo storage centers (i.e., if the parents donated unwanted fertilized eggs to researchers). These are capable of becoming human life if implanted into a receptive womb. For this reason their use worldwide remains controversial. (These are not presently legal to use in treatment in the US). Fetal: As the name implies, these are from abortions. Even more than the embryonal, use of these types of stem cells is highly controversial and prohibited in many countries. i do NOT use these, NOr do i recommend them, and they are not allowed in the US. Umbilical cord blood or placental: These can be obtained from amniocentesis, the baby’s umbilical cord (UBSC), or the leftover placenta (“after-birth”). Currently there are lots of stored umbilical cords. Any one umbilical cord by itself without culturing is not sufficient to treat anyone medically. Some work has been done with combining multiple umbilical cords (allogeneic) to create enough stem cells. Currently, we are not allowed to use stored umbilical- derived stem cells or placentas. From the individual’s perspective, stored UBSC is unlikely to be beneficial. Collectively they may be valuable to research or treatment, but that is still quite a way off. We are not able to use UBSC at this time.
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Mulitipotential or mesenchymal stem cells (MSC): These have the potential to convert to various cell types: muscle, fat, cartilage, etc. However, the main functional role and reason for the therapeutic use of MSC is their ability to reduce inflammation and to signal repair. While making more fat is sometimes an important function and naturally occurring functional role of stem cells (as in filling in defects after injury), the exciting aspect of stem cell medicine is for the treatment of chronic inflammatory and degenerative diseases (e.g., inflammatory bowel disease, autoimmune disorders, arthritis, and neurological issues). Medicine is just at the frontier of how to best
use MSC to help these disorders, but given the devastating complications of these disorders combined with the safety of MSC, they represent a new and powerful tool in the fight against disease. fOCUs ON meseNChymAl sTem Cells: msC As you have seen, stem cells come in many types, but for my purposes, we are talking about adult stem cells. We use the adult term to distinguish from embryonic, fetal, placental, cord blood, and similar types of cells. My specific interest is in fat, i.e., adiposederived cells. These have important distinctions with their own advantages and disadvantages. Adult MSC derived from either adipose (fat) or bone marrow are capable of another important
figure 6: Stem cell in the brain preventing inflammation.
international Journal of inflammation. volume 2010, Article Id 151097, 18 pages
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MSC uniquely downregulate inflammation in most areas of the body, including the brain. They may be our best hope for repairing inflammatory changes in the gut due to Crohn’s disease, ulcerative colitis, and autistic enterocolitis. But more importantly than that, as described earlier, they hold the potential for regulating inflammation in the brain.
function and one that i think is more likely where they will find their usefulness in autism. MSC are capable of downregulating chronic inflammation (Figure 6). That gets my attention because it is the closest we may be able to come to that “reset button” i’ve been looking for. i believe this is where stem cells will find their place in autism immunotherapy. ImmUNe ReGUlATION by mCs (fAT-DeRIveD sTem Cells) Once activated, MSC seek out areas on the body expressing inflammation. it is their natural programming. Think about any cut you have had. initially it is swollen and red and painful. That is the initial inflammatory defense reaction that will defend the body from infection and start to clean
up the damaged tissue. However, soon after that reaction starts it signals local stem cells to proliferate, and they migrate to the wound. Once on site, they communicate a calming message to inflammatory cells and start to direct the repair process. This is exactly what we want them to do in the brain and the chronically inflamed gut of children with autism. We have already seen an illustration of stem activity in the brain (Figure 6), and it is similar in the gut (see Figure 7 below, and abstract, next page). Figure 7 is complex, but it does a good job of depicting the multiple levels of control the MSC can exert over inflammation. Sitting in the middle of Figure 7 is a MSC. it takes quickly over the immune environment, much like a new general takes command of a combat zone. The MSC increases regulatory counter-inflammatory Treg cells. it
reduces immune chemicals of inflammation (TNFalpha, interferon-gamma, etc). And it communicates a shift in the production of immune proteins, all of which combine to reduce inflammation and to then create an environment of repair. This is important to autoimmune disorders like inflammatory bowel disease (as shown), but should equally apply to neurodegenerative disease, chronic arthritis, allergies, asthma, and – certainly – autism spectrum disorders. As we have mentioned, MSC uniquely downregulate inflammation in most areas of the body, including the brain. They may be our best hope for repairing inflammatory changes in the gut due to Crohn’s disease, ulcerative colitis, and autistic enterocolitis. But more importantly than that, as described earlier, they hold the potential for regulating inflammation in the brain. research from multiple sclerosis indicates that MSC may facilitate repair in the brain – which is truly extraordinary. self OR DONOR sTem Cells? if you want to follow stem cell research and treatment models, you’ll need to learn the difference between autologous (self-donated) versus allogeneic (donated from another person or persons) cells. Strangely enough, adipose-derived stem cells are immunologically privileged, and, even when they come from someone else, they generally live and do not fight the new – genetically different – host they find themselves cohabitating with. The medical literature supports either allogeneic or self-donated MSCs (fat or bone marrow- derived stem cells) in the treatment of inflammatory bowel disease (iBD). Common treatments for iBD seek to suppress the immune system, and with that comes a long list of serious potential complications – even death from infections. But MSC work differently. They “talk” to the deranged immune system to give it new instructions. The result is a more tuned and balanced immune defense in the gi tract – without the dangers intrinsic in many of the suppressive medications. My preference is for the use of autologous (self-donated) stem cells. Allogeneic stem cells create a chimeric (2-in-1) relationship with the body. This means the donor’s genetically different cells cohabitate with the host despite being mismatched. They do not get rejected nor do they initiate attacks on the host. The long-term effects of chimerisms are hard to anticipate at this time (although early observations thus far look safe). From my perspective, self-donated stem cells are the logical choice.
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figure 7: In the graphic, the red box represents the mSc that is downregulating inflammation. from: Singh et al. Stem cells as potential therapeutic targets for inflammatory bowel disease. Front Biosci (schol ed). 2010;2:993-1008.
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Obviously, not all children with autism suffer from chronic inflammation, but for those who do, MSC transplantation may represent a reasonable treatment option when compared to iVig or the long-term use of anti-inflammatory medications.
As we can see in the abstract above, doctors already have stem cell therapy targeted for iBD. Obviously, not all children with autism suffer from chronic inflammation, but for those who do, MSC transplantation may represent a reasonable treatment option when compared to iVig or the long-term use of anti-inflammatory medications. This also means patient selection is important. And adult-derived MSC can be self-donated, meaning we don’t need embryos, fetuses, or even strangers to provide them for us. just to be clear – the term “adult” doesn’t mean 18 or 21 year olds. it just means cells that are derived from a person any time after birth. This distinguishes them from embryos and fetuses, neither of which could be used in autism apart from an FDA approved new drug trial (which i do not expect to see in the next decade). pRODUCING mUlTIpOTeNTIAl ADIpOse-DeRIveD sTem Cells The picture of the two glass tubes (Figure 8) shows the mid-phase of stem cell isolation from adipose (human fat). This was the result after i put the cells through several washes, high speed separation techniques, fat digestion, purification, and isolation.
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By this point i was getting closer to my goal: biological gold (viable multipotential stem cells). it took me about 2 hours in the lab to get to that stage of stem cell extraction, and the process was far from over. At the bottom of the centrifuge tubes are red blood cells, immune cells and several million adiposederived mesenchymal or multipotential stem cells. These prized stem cells (shown below) will be washed several more times and go through several cycles of centrifugation to further isolate them from other cells.
figure 8: Stem cells in the test tube
NOw ThAT yOU mAy wANT Them – CAN yOU GeT Them IN The UNITeD sTATes? yes. i have been trained with adipose-derived stem cells, and this technique provides a straightforward process we can currently use in the US. There are, of course, restrictions placed by the FDA on this process. Some general and understandable regulatory concepts for this process are what we call “the 3 sames”: same person, same building, and same day. Add to this another set of rules that come from the Public Health and Safety Act, section 361: stem cells cannot be highly manipulated or used for purposes other than their normal function. No one really understands what that means in the real world. But it seems clear that you cannot alter the cells with laser stimulation (currently being done in other places), you cannot add chemical tags to them to get them to behave in a special way (currently happening in investigational drug trials), you cannot culture them to increase their number (this is viewed as a manipulation), when you start the process you have to finish in a relatively short time frame (a few hours). Otherwise, the FDA may assume the intent is culturing or amplification of the cell numbers. This also means banked stem cells (including a child’s own cord blood) cannot be used. While we are clear that self-donated and not substantially manipulated stems cells meet the regulatory criteria, it is not clear to me whether these guidelines exclude donor adult stem cells. in other words – with precautions against transmissible diseases – could a parent donate stem cells to their child? At this point, the best answer that i can give you is “probably.” Think about it this way: have you ever donated blood? if so, you donated cells for someone else to use in their body. That is allogeneic. it is also totally permissible. Besides, whole blood always contains a few stem cells. Obviously, blood banks go to great lengths to ensure that the blood products they provide are both safe and clean. in our iCDrC centers (both in California and Florida) we routinely use iVig (a concentrated form of antibodies derived from human blood donors). it comes from hundreds of people per dose, and in the last 15 years of my using iVig there have been no contaminations. The blood donation analogy makes me think a properly screened donor could provide stem cells if the other guidelines were also met. Self-donated adipose tissue (fat) contains large numbers of MSC. All we need to do is harvest 20-50 ml of fat (less than 5 tablespoons) and liberate the stem cells that are trapped within it. That process has been perfected over the last few years and is in use on a daily basis in plastic surgery centers all over the country. Plastic surgeons use stem cells to enhance the successful grafting of fat transfers for cosmetic enhancements. Without stem cells, between 70-90% of the fat transferred will die and be reabsorbed. With fat-derived stem cells, those numbers are reversed. So obviously, for the group of cosmetic surgeons already doing stem cell transplantations, the rules
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figure 9: dr. bradstreet in the
stem cell laboratory isolating mSc from lipoaspirate.
permit an individual having their own bone marrow or fat harvested, and the stem cells isolated and then re-implanted. Preparing the stem cells from the lipoaspirate is a time-consuming and precise process. in Figure 9, we are about halfway through the 2-3 hour long procedure to safely extract the cells without harming them. i used a very busy plastic surgery center to learn about both stem cell harvesting (lipoaspiration) and stem cell isolation and preparation (Figure 9). Harvesting involves gently aspirating a small volume of fat. This is absolutely NOT liposuction. Liposuction damages stem cells and is not suitable for the kind of results we desire. Lipoaspiration uses a very small (3mm) blunt cannula and a syringe – not a vacuum tube. For anyone familiar with gynecology, lipoaspiration is similar to an endometrial biopsy, and liposuction is like a D&C. Lipoaspiration is a safe and simple procedure that can be accomplished in any clean room in a doctor’s office. it does not require an operating room, general anesthesia, or even sedation (although i assume our autistic kids will need some calming agent to get them through the process). The total process requires properly preparing the patient for stem cell harvest to increase the yield of active stem cells. it also requires taking care of our stem cell transplants in much the same way a farmer tends his crop after planting. A sImple wAy TO lOOK AT IT: GeTTING sTARTeD wITh sTem Cells i have been thinking a lot about stem cells for several years, waiting for the science to mature to the point where cost-effective treatment plans start to make sense. Try to think of stem cells the way a farmer or gardener thinks about his seeds. you may not know a lot about farming, but i’m confident we all understand the concept of planting seeds to grow flowers or vegetables. Every experienced gardener or farmer knows what they need to do after buying the seeds. So do
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One thing that seems clear is that hyperbaric oxygen increases both stem cell yields if it is used prior to harvesting, and it also increases the clinical impact favorably when applied after stem cell implantation.
[HBOT] delivered at the right time after the implanted MSC seeds are starting to grow. One thing that seems clear is that hyperbaric oxygen increases both stem cell yields if it is used prior to harvesting, and it also increases the clinical impact favorably when applied after stem cell implantation. Sunlight applies to the vitamin D [D-3] the immune system will need to help guide the seeds in the right direction. Keeping the weeds out naturally means preventing oxidative damage and toxic exposure to our valuable MSC crop. if we do all of that right, we should have clean MSC seeds to plant and an abundant crop of immunemanaging stem cells working to regulate and restore immune health and balance, while restoring function to the individual. ThIs Is GOOD exAmple Of AN INTeGRATIve AppROACh TO sTem Cell TheRApIes fROm OhIO sTATe UNIveRsITy: AND IT Is As seRIOUs As A heART ATTACK These researchers clearly know how best to tend their stem cell garden. hyperbaric oxygenation enhances transplanted cell graft and functional recovery in the infarct heart Mahmood Khan*, Sarah Meduru, Iyyapu K. Mohan, M. Lakshmi Kuppusamy, Sheik Wisel, Aditi Kulkarni, Brian K. Rivera, Robert L. Hamlin1, and Periannan Kuppusamy Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA J Mol Cell Cardiol. 2009 August ; 47(2): 275-287. The more i study this paper, the more i respect the thought that went into it. On my blog i’ve been posting a lot about adipose (fat) derived stem cells – one type of mesenchymal stem cell line (MSC). This paper focuses on bone marrow-derived stem cells. Without going into a lengthy discussion about this, the medical literature documents that adipose and bone marrow stem cells both have similar potentials as stem cells. This paper investigates mice, but in the human application of this technology, adiposederived MSC are far more abundant and practical to manage. given the devastating effects of heart attacks, as well as how common they are, finding better ways to treat these patients is critically important. in a nutshell, what these researchers did was to create heart attacks in mice. Then they studied the natural untreated course, but they also contrasted that with hyperbaric oxygen (HBO) therapy versus stem cells (MSC), and then combined MSC + HBO. The pictures in Figure 10 speak for
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you: prepare the soil where you want to plant seeds. As you might expect, it is even more complex with autologous (self-donated) MSC stem cells. First of all, we get the “seeds” (stem cells) from the very soil (the person’s ecosystem) where we want to replant them. That ecosystem already created problems. Our goal is to correct those problems – not add to them. With the right plan, we can improve our chances of a good harvest from our stem cell seeds. in that troubled ecosystem (the exposures which created the medical problems) lies the potential for a bad crop and a harvest gone wrong. No one would want to try to grow a crop from diseased seeds. So, how can we make this work? Equally no decent farmer or gardener would plant his seeds in poisoned soil. Our stem cell seeds need ideal conditions both before and after transplanting if we are to expect the best results. Based on my years of experience and work with nutrition and toxicology, i have some suggestions to help this entire process. it makes sense to first go through some important detoxification measures prior to collecting the MSC seeds. This will mean something a little different for every patient based on their toxic exposure patterns and individual problems. Then, following our gardening analogy, we will need to: fertilize, water, provide fresh air and sunlight, and keep the weeds out of our new crop. What does all this “gardening talk” mean in real-world terms for repair and regeneration of someone’s health? Fertilizing means giving all of the proper nutrients the MSC seeds require. Watering means providing good circulation (blood) to the area(s) we need to restore. Fresh air means the right amount of oxygen. This is likely from hyperbaric oxygen therapy
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figure 10: The effect of mSc + hbO on mouse heart after infarction.
Post mI dead heart Area
t ear ing w h row ne le g sc mu
themselves. The purple areas represent living heart tissue and the pale blue areas are scar tissue. i will explain the significance of the pictures in Figure 10 above. just by looking at the colors it is clear that MSC + HBO is far better than even stem cells provided alone. This type of study is exactly what we need in the field of integrative medicine. i have been complaining about clinical studies that control for only one variable. i understand the scientific reasons,
but in reality that just isn’t the way complex biological systems work. This study is just awesome. Let’s look at Figure 11 below and get into some more details. i added the dotted lines to help in my discussion. As a primer in cardiology, the active phase of heart muscle work is done during rELAXATiON of the heart muscle. That is where nearly all of the energy is consumed, because heart muscle has to actively recharge for the next beat. Think about a rubber band you want to shoot. you pull it back and that requires energy. Then you let it fly and that took very little effort. The red dotted line in Figure 11 is set at the ejection fraction (EF) (measured in percentage points). in simple terms, that means what percent of blood leaves the heart on any given heart beat (or letting the rubber band fly). Mice are better at this than we are. They are approximately 90% efficient with each heart beat: we humans average 55-70%. The blue line represents fractional shortening, which measures and ratios the change in the diameter
of the left ventricle (main pumping chamber) between the contracted and relaxed states. in this mouse study, the heart attack reduced the EF to 60% (a 1/3 reduction). Hyperbaric oxygen plus stem cells returned the rejection fraction to about 75%. HBO by itself made a marginal, but not significant, increase in the EF. Stem cells by themselves (the MSC alone portion of the study) did help, but significantly less than the combination of MSC and HBO. This study is simply amazing science. it teaches us the specifics about stem cell implanting and why HBO is a valuable adjunct to the process. But more importantly, it teaches us to use integrated therapies to optimize outcomes. For me it seems very clear: stem cells are good, but stem cells plus HBO is significantly better. In other words, integrative medicine means being a better gardener. i hope my analogy helps these concepts to be easily remembered. From my observations of the stem cell industry thus far, it seems that a lot of people want to perform stem cell implanting, but few seem to want to tend to their garden. Please keep this vital analogy and concept in mind as you consider stem cell options for your health or that of your loved ones. fINAlly . . . Even before we start on this journey it is critical to select patients who would seem to be the best candidates for stem cell therapy. We are still learning about patient selection, however, i believe my previous work on biomarkers can be used to help us with the selection process. The full article is presented here: http://www.thorne. com/altmedrev/.fulltext/15/1/15.pdf. Again, i talk about new research with stem cells extensively on my site www.drbradstreet. org. Please check out those discussions for more information.
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1. Gupta S, Aggarwal S, Heads C. Dysregulated immune system in children with autism: beneficial effects of intravenous immune globulin on autistic characteristics. J Autism Dev Disord. 1996 Aug;26(4):439-52. 2. Stubbs EG., Autistic children exhibit undetectable hemagglutination-inhibition antibody titers despite previous rubella vaccination. J Autism Child Schizophr. 1976 Sep;6(3):269-74. 3. Chauhan A, Chauhan V, Brown T (Eds.). (2010). Autism: Oxidative Stress, Inflammation, and Immune Abnormalities. Boca Raton, FL: CRC Press. 4. Crocker SJ, Bajpai R, Moore CS, Frausto RF, Brown GD, Pagarigan RR, Whitton JL, Terskikh AV. Intravenous administration of Human ES-derived Neural Precursor Cells Attenuates Cuprizoneinduced CNS Demyelination. Neuropathol Appl Neurobiol. 2011 Jan 28. [Epub ahead of print]
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Good post
Thanks for this information