THE STEM CELL FIELD IS PROGRESSING RAPIDLY WORLDWIDE. WE FOUND THAT ADULT STEM CELLS IN TISSUE CULTURE WILL SPONTANEOUSLY CELL SORT INTO ORGANIZED JUXTAPOSED TISSUE LAYERS, I.E., CELLS RETAIN THEIR ABILITY TO ORGANIZE INTO ORGANS YIELDING UNEXPECTED COMPLEXITY THOUGHT TO BE ONLY CHARACTERISTIC OF INTACT LIVING CREATURES (HOEFFLER LAB - WANG ET AL., 2000). FURTHER SIGNIFICANT ADVANCES WERE MADE ONCE IT WAS FOUND THAT A SINGLE STEM CELL CULTURED OVER SEVERAL MONTHS CAN GIVE RISE TO AN ORGAN FRAGMENT CONTAINING MULTIPLE CELL TYPES, OFTEN CALLED AN ORGANOID. THIS MODEL ALSO MADE USE OF THE SELF-ORGANIZATION OF MULTIPLE CELL TYPES, WHILE THE CELL TYPES INVOLVED COULD ALL BE DERIVED FOR A PLURIPOTENT STEM CELL. THE WORK OF HANS CLEVERS AND OTHERS HAVE SHOWN THAT THERE ARE MEASUREABLE BIOMARKERS AND GENE DIFFERENCES DURING EARLY ORGAN DEVELOPMENT THAT OFFER IMPORTANT INSIGHTS INTO HOW CELLS ORGANIZE INTO ORGANS. THESE SYSTEMS CAN BE EXPLOIDED TO BETTER UNDERSTAND GESTATION, CANCER, AND TO SCREEN FOR DRUGS MOST EFFECTIVE FOR A BROAD VARIETY OF DISEASES. WE ARE IMPRESSED WITH THE QUALITY OF THE SCIENTIFIC WORK AND EXPECT MANY NEW FINDINGS. YET, HOF THERAPEUTICS STILL OFFERS THE BEST PATH TO ESTABLISHING CELL THERAPY AS A NEW MEDICAL MODALITY BECAUSE OF THE ADVANTAGES OF OUR CELL ASSEMBLY PROGRAMMING (CAP), AS FOLLOWS:

 

1) OTHER ORGANOID MODELS ARE DEPENDENT ON A CANCER CELL MATRIX, MATRIGEL, DERIVED FROM A MOUSE TUMOR CELL. IT IS A COMPLEX MIXTURE CONTAINING MATRICES, GROWTH FACTORS, AND OTHER ANIMAL COMPONENTS THAT VARY IN DIFFERENT PREPARATIONS. HOF DOES NOT USE IT, RATHER DEPENDS ON ADDED MESENCHYMAL CELLS TO PROVIDE THE APPROPRIATE MATRIX, AS DONE IN NATURE. THE FDA IS UNLIKELY TO APPROVE THE USE OF XENOGENIC MATRIGEL TO MAKE ORGANOIDS FOR HUMAN USE.

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2) OTHER ORGANOID MODELS TYPICALLY USE A FEW THOUSAND CELLS, BUT HOF THERAPEUTICS UNIQUE METHOD, CAP, USES 100X MORE CELLS, HUNDREDS OF THOUSANDS OF CELLS IN EACH WELL. WE SEE CORRECT CELLULAR ORGANIZATION ON THE SMALL SCALE, BUT WE ALSO HAVE ACHIEVED THE NEXT HIGHER LEVEL OF CELL ORGANIZATION INTO NEARLY VISIBLE STRUCTURES THAT CAN BE SEEN BY EYE. THUS, ALVEOLI OF THE LUNG APPEAR AS A BAG STRUCTURE, AND OSTEONS OF BONE APPEAR IN THE WELLS. MULTIPLE HAIR FOLLICLES APPEARS IN THE ORGANIZED ARRANGEMENT OF A PLACODE. 

 

3) ALL OF OUR CELL PROGRAMMING OCCURS BY PRETREATING PATIENT CELLS BEFOREHAND AND AS FIRST MIXED, WHEREAS OTHERS INCUBATE EMBRYONIC STEM CELLS AND CYTOKINES FOR MONTHS, SIMILAR TO GESTATION. THE GOAL OF OUR METHOD IS TO INTRODUCE THE PROGRAMMED CELLS INTO THE HUMAN BODY AS A MEANS OF REPAIRING ORGANS. THIS IS POSSIBLE SINCE ALL OUR CAP LAB MANIPULATIONS ARE COMPLETED BEFORE IMPLANTATION (INJECTION, ETC.). CAP ORGANS ARE REPAIR ASSEMBLOIDS AS A METHOD OF RESTORING ORGAN FUNCTION (HOF - HUMAN ORGAN FUNCTION). OTHERS ARE FORCED TO INTRODUCE PRECONSTRUCTED ORGANOIDS BECAUSE ONCE CELLS ARE INTRODUCED INTO PATIENTS IT WILL BE IMPOSSIBLE TO PROVIDE CONTROLLED EXPOSURES TO GROWTH FACTORS, INHIBITORS AND OTHER REAGENTS. THUS, OTHERS ARE IRONICALLY STARTING WITH ORGANOIDS 100X SMALLER THAN OURS BUT WANT TO CREATE LARGER ORGANS IN THE LAB FOR TRANSPLANTATION, MAYBE BECAUSE THEY HAVE NO OPTION. HOF SEES THIS AS REQUIRING MANY DECADES OF MORE ADVANCEMENTS IN ORGAN CULTURE. IN CONTRAST, OUR CAP TECHNOLOGY WOULD BE POSSIBLE NOW TO HELP PATIENTS WHO ARE FACING END-OF-LIFE ORGAN FAILURES. YET, HOF NEEDS SUPPORT FROM GOVERNMENT AGENCIES. GENE EXPRESSION DATA AND HIGHER QUALITY IMAGINING USING BIOMARKERS (NOW PROVIDED BY ILUMINA, 10x GENOMICS, DANAHER-LEICA, NIKON IMAGING, ETC.) ARE PAID FOR USING TAX DOLLARS FOR ONLY A FEW PROJECTS CONDUCTED BY ELITE INSTITUTIONS. HOF REQUESTS SUPPORT TOO. NEVER BEFORE HAS THE DIFFERENCE BETWEEN CONVINCING RESEARCH DATA AND LOWER QUALITY DATA BEEN SO CLEARLY DETERMINED BY SUPPORT DOLLARS PROVIDED AND SPENT. 

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4) THE BATTLE OVER WHO OWNES THE CELLS USED IN CELL THERAPY, THE PEOPLE DO! LARGE INSTITUTIONS TEND TO WANT TO ESTABLISH A PATH TO PROFITABILITY BASED ON OWNERSHIP OF MATERIALS, AND OFTEN LASH OUT AT SMALLER ENTERPRISES FOR ANY USE OF CELLS. MANY PATENTS HAVE BEEN FILED CLAIMING OWNERSHIP OF STEM CELL LINES, WITHOUT PAYING PEOPLE WHO THEY WERE DERIVED FROM. THERE WAS AN EARLY BELIEF THAT ONLY SPECIAL STEM CELL LINES WOULD PRODUCE ORGANOIDS, WHICH IS NOT TRUE. SOME IN THE U.S. MEDICAL COMMUNITY WANT TO OUTLAW THE CULTURING OF CELLS BY ANYONE OUTSIDE OF THE FEW ELITE INSTITUTIONS. THE PREVIOUS FDA LIMITED STEM CELL IMPLANTATION TO CLINICAL TRIALS ONLY RESULTING IN TWO DECADES OF FAILED CLINICAL TRIALS. TREATING CELLS LIKE DRUGS IS A MISTAKE. RESEARCH PROGRESS HAS BEEN INSUFFICIENT FOR DECADES TO CLOSE OFF RESEARCH TO ONLY A FEW AND PROGRESS HAS BEEN GREATEST IN COUNTRIES WITH MULTIPLE LABS SOLVING PROBLEMS. WORLDWIDE PARTICIPATION MEANS THAT CELL TREATMENTS ARE TAKING PLACE WORLDWIDE REGARDLESS OF LOCAL POLICIES THAT WILL STIFLE PROGRESS IN THOSE LOCALS. PROGRESS IN STEM CELL RESEARCH IS GREATER IN ASIA AND HOLLAND, BUT LAGS IN THE U.S. DESPITE TAX DOLLARS SPENT ON ELITE INSTITUTIONS.

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