THE AGE OF REGENERATION
Can you identify which of these embryos will generate a fish, salamander, tortoise, chick, hog, calf, rodent, or human?
By way of introduction to Man’s consciousness about biological generation, the science of regeneration, and leading up to regenerative medicine and the discipline of stem cell research, there are a series of fascinating findings, mythologies, events, and finally a science that should be introduced here first.
Man’s consciousness regarding generation and regeneration in Nature may have begun as early as the days of Paleolithic cave painting 30 to 32 thousand years ago, although this hypothesis is still controversial. Cave paintings from the Paleolithic era in France , Spain, and Australia, show human hands with missing digits beautifully painted on the cave walls. Various hypotheses suggest that the missing digits may be the result of frostbite, or ritual amputations, while critics maintain that the hands with missing digits are fraudulent representations placed in the caves by pranksters.
In early Greek mythology, it was claimed that Hercules employed his knowledge of regeneration with regard to the 9-headed hydra, when he employed Iolaus to hold a torch to tendons of the severed neck to prevent the hydra’s heads from regenerating, until Hercules had cut all of them off to finally conquer the beast.
In 550 B.C., the Promethean myth advanced the idea that for his crime of giving fire to Mankind, Prometheus’s liver would be eaten out each day, then regenerate each night.
During the Christian era, a series of statues at Notre Dame shows St. Denis holding his own severed head after the Romans chopped it off.
In 717, St. John of Damascus prayed to The Mother of God to restore his hand that was severed for his tireless writings that were deemed as acts of treason. After falling asleep and having a dream, The Mother of God restored his hand.
In the 12th Century, Peter of Grenoble lost his leg when he was struck by lightning for not observing the birthday of Mary Magdalene. Following his injury, the crippled Peter devoted himself to The Church, and, he had a vision that The Virgin Mary ordered his leg restored, and parts or pieces of the leg were reassembled on the stump and the entire leg regenerated.
In 1712, the inventor of the alcohol thermometer, Rene Antoine Reaumur, placed crayfish into cages after severing their limbs, and discovered how they regenerate. The work was undertaken because of the phenomenon of autotomy, or the protective self-shedding of limbs by these crustaceans. The economically important crayfish cast off their limbs, much as do certain amphibians cast off their tails as a protective mechanism, but with the crayfish, it was when thunder sounded, or when the fishing boats would sometimes enter the harbor, and cannons were fired announcing the entrance of the fisher boats whose catches would be ruined.
In 1740, Abraham Trembley severed hydra in half to test a “scientific consensus” of his day, that despite the fact that it was known that starfish could regenerate from parts. Most “educated” people believed that only plants could regenerate from parts of plants, whereas animals could not. Although hydra had been described independently by Leeuwenhouk and others approximately at the same time, Trembley was the first to microsurgically amputate the hydra, to demonstrate the animal’s phenomenal regenerative capacity from even small parts.
In 1768, naturalists severed the heads of snails to determine if they could regenerate as it was discovered by the great biologist Spallanzani of that era, who also was the first to document that bacteria divide. It is claimed that following the announcement of these experiments, Voltaire stated: “There are many people for whom the change could hardly be for the worse.”
EFFICIENT CAUSES AS DISTINGUISHED FROM “FINAL CAUSAL” THINKING
What is efficient causal thinking or ideology? This distinction is important to define in the context of understanding natural design principles, generation of living forms, and regeneration. Much of what Man has accomplished has been based on Aristotelian “final causal” thinking, and teleological conceptualization. The purpose of a wine glass is to hold a liquid: a good wine glass doesn’t drip or spill the fluid, and it fits into the hand well. Similarly, the purpose of a house is to accommodate its inhabitants, and provide for basic needs of shelter. Bridges must be able to span a distance and support the weight that travels over them without collapsing. These are man-made artifacts designed with a purpose, and we create them with their final utility in mind as their “creators.”
Simple examples of efficient causal thinking are epitomized in the physical, chemical, biological, and engineering sciences. One example is seen in the fact that an airplane’s wing and a bird’s wing, by necessity, both efficiently employ the same design principle in that the upper surface of each is curved to create a negative air pressure zone causing lift to occur when a specific speed is attained in a less dense medium, like air. Both the plane and bird must fly, if a sufficient speed through the medium is obtained, but yet there is no purpose in the case of the bird’s wing. Similarly, the lens of the human eye, and a camera lens must employ the same design principles because, otherwise, light would not refract correctly. These comparisons constitute “efficient causes,” yet “the creator” of the bird’s wing or eye are the converging physical-chemical forces that Natural Selection has used to sculpt biological designs for eons, instead of a being the handiwork of a “wine glass maker,” who has a specific teleological purpose in mind. This “blind” sculpting of The Universe’s most efficient [living] machines and processes, based on these rigid laws, has been described by the great French molecular geneticist, Jacques Monod, as being fashioned by “teleonomic” processes and projects of Nature, rather than from any purposeful projects or “teleological” designs of “a creator.” How we regard causality itself as the consequence of efficient rather than ultimate causes has come to replace the predominantly anthropomorphic speculations of early man and belief, for the simple reason that in biological systems that create concepts of mortality, and which are constrained by our growth and physiology, it is now increasingly appreciated that efficient causal rather than final causal conceptualization is more descriptive and useful a world view. As mentioned for example by Monod in his famous book, “Chance and Necessity:”
“Without genes (nucleic acids), proteins have no past, but without proteins, nucleic acids (genes) have no future.”
TENSEGRITY GEOMETRY AND THE FORCES GOVERNING INTERACTION
If we assume and agree that living things such as bacteria have been here at least for 3 billion years, and, that no inorganic material or structure in the universe is more stable in design than a living cell, then we must conclude that we need to understand and then transpose the principles by which living cells and tissues have come to be the most stable and efficient designs in all of Nature, and apply these principles to identifying and then recreating the material and force constraints that govern the living cell’s or organism’s inherent capacities to generate new cells or tissues, or to form characteristic patterns of growth and form. For instance, among large groups of cells and at the visible organismic level, gravity is a key constraint that determines why the bones of many birds are hollow, why whales must be confined to the oceans, how large a terrestrial organism like man can become before the weight of his mass becomes too large to exhibit even simple movements like walking, whereas, at the cellular and subcellular level, electrochemical forces, diffusion, and forces such as surface tension predominate. However, geometries unite the forces that come to sculpt both macroscopic and microscopic levels of structure and organization, as shown below in this most efficient design principle observed when cells attach to a substratum, and employ tensegrity architecture, much like a suspension bridge, or a tent or radio tower, with their continuous tension cables, and discontinuous compression-bearing struts:
Above: Actin geodome structures (tensegrity) form in cells as they attach to a surface as shown in this fluorescence micrograph of actin in an adherent epithelial cell.These actin structures constitute the continuous tension cables within a living cell, whereas microtubules comprise the compression-resistant structures, as shown in the cores of neurons with their long processes, or the mitotic spindle of a dividing cell.
Darcy Thomson, perhaps more than anybody before him, in his famous book “Growth and Form” demonstrated how life itself, as Nature’s most efficient and stable design and engineering accomplishment that has persisted for eons or billions of years virtually unchanged in some instances (unlike mountain ranges that come and go due to erosion, or seas that evaporate), could be explained in the context of simple physical-chemical laws, and with a mathematics that describe these laws. He emphasized how there have to be geometrical and interactive rules that account for such things as the forms of animals that need to reduce drag as they swim through the oceans, or how steam ship engine designs, intestinal villi, and lungs containing micro-sacs, are fashioned geometrically and architecturally to obtain maximum surface area in the smallest possible spaces. But added to the modern picture Thomson first described with such precision, such geometrical constraints and forces of interaction as Buckminster Fuller’s tensional integrity (tensegrity) designs now must be recognized, appreciated, and implemented regarding the duplication of any efficient forms and structures employed as the most efficient designs in bioengineering and civil engineering that are possible to attain.
Toward this goal, it may already be appreciated by some readers how Carbon-60 (Buckyballs), the structure of viruses, bacteria, the structure of cellular architecture, the anatomy of giraffe necks, the organization of the intestine or arm, and the efficiencies and structures of all things can be arrived at through consideration of the geometries that are most efficient, and through appreciating the forces that govern interaction that are most powerful or influential.
The materials of living processes may be numerous, but the simple design principles that describe the efficient causes and geometries of life are mechanical and geometrical in nature.
Above: Experiment demonstrating tensgrity design principles in living cells (left) compared to tensegrity sting and stick models of a cell attaching and being distorted. Tensegrity accounts for the coordinated movements of the cell and cell cytoskeleton and nucleus, as shown by adhesion receptor pulling experiments as shown in the two left hand vertical rows of pictures.
Finally, the rigid cellular design principles, together with the non-living matrix scaffolds they make, constitute the constraints imposed upon the developing organism to produce the familiar organ and organism tissue-building phenomena we see, which explains why at early stages of embryonic development, a fish and human and the other 6 vertebrate creatures shown here, are virtually indistinguishable. As the containment vessel of “the soul” and as “The Crown of Creation,” the human brain begins like that of all vertebrates, as a mechanical contraction on the surface of an egg, which then due to a few asymmetrical cell movements, involutes to form the precursors of the brain and nervous system, by efficiently forming a simple tube in each of the organisms shown below. The basic “efficient” design, therefore is recapitulated by necessity, in all creatures containing a vertebrate-level organization, which is why at the earliest stages, they are difficult to distinguish from one another:
MY BACKGROUND, AND THE DEVELOPMENT OF MY INTEREST IN THE STUDY OF GENERATION AND REGENERATION:
I began my scientific and medical education learning about the genetics of mushrooms, human medical genetics, and physical anthropology. I obtained my undergraduate degree in primate biology/ physical anthropology and primate osteology from Washington University in St. Louis, MO. For over two decades, I held funded Research Associate positions at Washington University, St. Louis, The Washington University School of Medicine, The University of California, Berkeley, Harvard University, Boston’s Children’s Hospital, and I’ve held Assistant and Associate Professor and Program Director positions at The University of Iowa, and at The University of Illinois, Chicago, School of Medicine and School of Engineering, and The Department of Surgery.
SPECIALIZING IN: Cell and tissue biological and regeneration research, pathology in the contexts of cancer and AIDS testing development, and non-toxic therapeutics research, bioengineering of cells and tissues, chromosome reconstitution and chromatin research, viral assay development for detection and oncolytic therapies; biomedical (animal) model development, scientific, medical, and legal paradigmatic analysis and revision; biomechanical and nutritionally-based muscle, neuronal, and immune system reconstitution, new approaches in substance dependency science and addiction medicine, and its neuropathology/behavior, and reversal.
AUTHOR: Numerous peer-reviewed scientific publications, reviews, and position statements (please see some of them posted on this website). Five books on the scientific and medical history of cancer, vaccines, and “HIV/AIDS,” also posted in abbreviated form on this website as a resource archive of historical developments in cancer testing and treatment, AIDS diagnosis and treatment, and the history of epidemics, vaccination, and the generation of immunity in human and animal populations.
INTERVIEWS & PUBLIC SPEAKING & EXPERT WITNESS ENGAGEMENTS: Eight hour-long TV interviews and numerous radio interviews are available for free under the Internet rubric of “Conversations in Medical Sciences.” I’ve also been honored to present numerous invited public and government-sponsored speaking engagements; both paid and non-paid service/ invitations as an expert witness in trials regarding science and medicine.
Here are two examples of two of the hour-long interviews downloaded from “ON THE EDGE, CONVERSATIONS IN MEDICAL SCIENCE.”
CANCER, CAUSALITY, AND VIRUSES:
False “HIV” DIAGNOSES:
FOUNDATION ASSOCIATIONS-Present: Partnership For Cures, Chicago, Illinois; Past: Tommy Morrison Children’s Foundation For Sick and Terminally Ill Children; The CHAD (cancer) Foundation; the World Association For Vaccine Education (WAVE); Member and Reviewer of The Foundation and Journal, “Medical Veritas;” member and consultant for the Illinois Vaccine Awareness Coalition and long-time contributor to The Illinois Department of Public Health’s tri-yearly public fora; Scientific Advisory Board: the International Organization of IPTLD (Insulin Potentiation Therapy) Physicians established to coordinate the efforts and communication of the over 300 trained IPTLD providers world-wide, supported by Best Answer for Cancer Foundation (http://www.bestanswerforcancer.org); consultant to The Office of Medical and Scientific Justice, and numerous AIDS foundations including HEAL New York, HEAL San Diego, HEAL London, The Russian Parents Federation, and numerous ongoing trials in China involving the diagnostics and treatment of intractable melanomas, breast cancers, and other cancers.
2010. BARDA award recipient to develop stem cell therapeutics and hormone-mediated (PTH=parathyroid hormone) radio-protection after both during and after occurrence of radiation damage.
2009.Invited lecture: 7th World Congress on Melanoma and 5th Congress of the European Association of Dermato-Oncology, Vienna, Austria.
2009. First Place Winner, Health and Medicine Engineering, UIC., Chicago, IL.
2008. Humbolt Award Recipient, Humbolt University, Berlin, Germany.
2006.TREC Accelerator Award Recipient on Viral Assays, National Center For Supercomputing Applications, Champaign-Urbana, IL. http://www.trecc.org/accelerator/awardees.htm
2005.First and Second Place Winner, Health and Medicine Engineering, UIC., Chicago, IL. http://www.uic.edu/depts/enga/current_students/expo2005.htm
2003.Honorarium: Chromatin Structure and Cancer, Saxon Rivers, VT.
2003.Honorarium: Symposium on Polyamines, New London, CT.
2001.Invited member: Study panel on physico-chemical processes in biological systems in space.
2000. Earnest Orlando Lawrence Berkeley National Laboratory Lectureship, Berkeley, CA.
1999. Invited Lectureship:Biological Physics Colloquium, Banff, Canada.
1998. Work on cellular tensegrity distinguished by The Royal Society, London.
1997. Work presented at The Faraday Society.
1997.Work presented at “The Second Annual Video conference On Space Station Research”, NASA.
1995-1997.Invited Member and scientific adviser of The Boston Vascular Task Force, Children’s hospital, Boston MA. Judah Folkman, director.
1994.Nomination for Zum Thema Wissensbank Honorarium.
1993.Co-organizer of the First Retinal Biology Conference and Computer Modeling, Jackson Hole, Wyoming.
1992. USDA Fellowship in the Molecular Biology of Insect Viruses, Department of Entomological Sciences, University of California, Berkeley, CA.
NIH/NCI STUDY SECTION WORK; 1999. Ad Hoc Grant Reviewer: “Therapeutic Modulation of Angiogenesis in Disease.” Fall 2000. National Cancer Institute Invited Reviewer: “APA, Screening Technologies Branch DTP, DCTD, NCI.” Fall, 2008. Invited Reviewer: NCI Melanoma Program Project Review.
JOURNAL REVIEWER:American Journal of Physiology; PNAS; Journal of Cellular Biochemistry; Arteriosclerosis, Thrombosis, and Vascular Biology; Investigative Ophthalmology and Visual Science; FACEB Journal; American Journal of Pathology; Biochemical Journal; British Medical Journal; Medical Veritas; Molecular Cancer, and others.
Technology development and patents filed at The University of Illinois, Chicago: see http://patent.ipexl.com/inventor/Maniotis_Andrew_1.html
Maniotis Andrew – Inventor
1. Maniotis Andrew J, Folberg Robert, Valyi-Nagy Klara, Valyi-Nagy Tibor, Sandal Tone: Methods and compositions to induce cell death of invasive tumors. The Board Of Trustees Of The University Of Illinois October 2007: WO 2007/114851 Control of tumor reversion and destruction by interfering with fibronectin. Application No. PCT/US2006/013672 provisional.
2. Maniotis Andrew, Folberg Robert, Valyi-Nagy Klara: Methods for assessing the invasive potential of a cell employing chromatin analysis. The Board Of Trustees Of The University Of Illinois December 2004: WO 2004/108951 Embodiments of the invention relate to compositions and methods for evaluating or estimating the invasive potential of cells and thereby differentiating between normal and cancerous cells in accordance with the susceptibility of the cellular chromatin to degradation or other modification by …
4. Maniotis Andrew J, Folberg Robert, Valyi-Nagy Klara, Valyi-Nagy Tibor: Methods for determining the pathogenicity of viral strains. The Board Of Trustees Of The University Of Illinois March 2007: WO 2007/030815
Methods and compositions are provided for rapidly detecting the presence and lytic potential of a pathogenic virus in a sample and for determining the pathogenicity of a viral strain to cells, as compared to merely detecting the presence of viruses in a sample. Assays determine the pathogenicity of …
5. Maniotis Andrew J, Folberg Robert: Constricting gel assay and therapeutic patch. The Board Of Trustees Of The University Of Illinois October 2006: WO 2006/110827
Method and compositions relate diagnostic tools to determine invasive potential of tumor cells. Therapeutic patches include a component from the extracellular matrix seeded with tumor cells from an individual and a fibrin backing. Extracellular matrix-based constriction assays are useful to screen …
6: Cervicure: Device to deliver non-toxic therapeutic medicines to cervical cancers.
7.Biofilm-resistant natural matrix catheters (just completed).
8. PTH and Platelet storage (just filed).
9. A new source and method of stem cell augmentation. (Patent Filed, Sept. 2010).
10. Portable elemental analysis device: a new device built in my lab that is portable which is capable of providing elemental analysis of blood, saliva, urine, tissues, water, or soil that tests for 60 elements that are critical or injurious to human health. Can be used to check soils in the 3rd World context for metals deposited there by industries, and also, to assess in patients the amount of metals and other elements in their saliva, blood, stools, urine, sweat, or other fluids.
SOME OF THE CHALLENGING PROBLEMS THAT HAVE BEEN UNDER INVESTIGATION:
-Problem 1: AUGMENTING THE UTILITY OF ELECTRON MICROSCOPY- in the context of exploring neural anatomy, brain physiology, and submicroscopic surveys of neuronal axons, dendrites, and synapses in experimental excitotoxin-induced seizure research in the setting of the neural pathology laboratory of Dr. John Olney, Washington University School of Medicine, St. Louis.
Knowledge of regeneration cannot occur without a science of degeneration in place, better known as the discipline of pathology. Dr. Olney’s work on neuroexitotoxin-induced seizure research first advanced the research and eventual ban on glutamate as a seizure-inductive compound in baby food, and, during the early 1980’s, our team demonstrated how aspartame and other exitotoxins were and are seizure-inductive and cancer-causing but which are still now widely used in the food supply. My contribution to the projects specifically included the demonstration that these compounds do induce seizures in the range of only 5 ng/kg, and importantly that axons are spared destruction by excitotoxins whereas the damage to the brain (the moth-eaten appearance of excitotoxic seizure damage) is localized to dendrites, and synapses. (Abstract can be obtained at The National Library of Medicine here):
—Clifford, DB.,Olney, J.W., Maniotis, A.,Collins, RC., Zorumski, CF. The functional anatomy and pathology of Lithium-Pilocarpine and high dose pilocarpine seizures. Neuroscience Vol 23 (3): pp.953-968, 1987. Department of Neurology and Neurological Surgery, Washington University School of Medicine, St Louis, Missouri 63110. (http://www.ncbi.nlm.nih.gov/pubmed?term=maniotis%2C%20olney);
-Problem 2: CELL BIOLOGY AND THE REGENERATION OF CENTROSOMES AFTER MICROSURGICAL CENTROSOME REMOVAL:
Elucidation of the formation and inheritance of cellular division centers that control and direct the formation of cellular “twoness,” in the context of The Molecular, Cell, and Developmental Biology program at U.C. Berkeley. This work was published in Cell and reviewed in Nature (see C.V.), and, earned me my PhD and training as a “cellular microsurgeon” and cellular engineer/cytoskeleton expert. Other work exploring the biology of cellular division centers demonstrated tensegrity principles at work at the cellular level with respect to how the extracellular matrix determined the behavior of the division centers (Both abstracts of this work can be obtained at The National Library of Medicine here:
—Maniotis, A., Schliwa, M. Microsurgical removal of centrosomes blocks cellular reproduction and centrosome regeneration in BSC-1 cells, Cell,Vol. 67 pp.201-208, 1991 (http://www.ncbi.nlm.nih.gov/pubmed? term=maniotis%2C%20centrosomes). See also:—Schutze, K., Maniotis, A., Schliwa, M. The position of the microtubule- organizing center in directionally migrating fibroblasts depends on the nature of the substratum. Proc. Nat. Acad. Sci. Vol. 88 pp. 8367-8371, 1991 (http://www.ncbi.nlm.nih.gov/pubmed? term=maniotis%2C%20schliwa);
Some of the critical appraisals of this cell division center and cell regeneration work can be found in these publications:
—Michele Bornens. “Centrosome and Cell Division.” Nature, Vol 355, pp300-301, 1992.
—Greenfield Sluder—“Double or Nothing.” Current Opinions in Cell Biology, Vol 2, Number 5, , pp.243-245, 1992.
—Robert E. Palazzo, Gerald Schatten. The Centrosome in Cell Replication and Early Development. Published by Academic Press, 2000 ISBN 012153149X, 9780121531492 2000.
—Jeffrey L. Salisbury. The Contribution of Epigenetic Changes to Abnormal Centrosomes and Genomic Instability in Breast Cancer. Journal of Mammary Gland Biology and Neoplasia Volume 6, Number 2 / April, 2001.
—Alexey Khodjakovab and Conly L. Rieder. Centrosomes Enhance the Fidelity of Cytokinesis in Vertebrates and Are Required for Cell Cycle Progression. J Cell Biol. April 2; 153(1): 237–242, 2001.
—Edward H. Hinchcliffe, and Greenfield Sluder. “It Takes Two to Tango”: understanding how centrosome duplication is regulated throughout the cell cycle. Genes and Development Vol.15 No. 10, pp. 1167-1181, May 15, 2001.
—Eric Nigg, Editor: Centrosomes in Development and Disease. Wiley-VCH Verlag GmbH & Co. KG2A Weinheim ISBN 3-527-30980-2, pps Chapter 10, page 204, 2004.
—Sluder G., Rieder C. Controls for centrosome reproduction in animal cells: issues and recent observations. Cell Motil Cytoskeleton; 33(1):1-5, 1996.
—Hinchcliffe EH, Miller FJ, Cham M, Khodjakov A, Sluder G. Requirement of a centrosomal activity for cell cycle progression through G1 into S phase. Science Feb 23;291(5508):1547-50, 2001.
—La Terra S, English CN, Hergert P, McEwen BF, Sluder G, Khodjakov A. The de novo centriole assembly pathway in HeLa cells: cell cycle progression and centriole assembly/maturation. J Cell Biol. Feb 28;168(5):713-22, 2005.
—Uetake Y, Loncarek J, Nordberg JJ, English CN, La Terra S, Khodjakov A, Sluder G. Cell cycle progression and de novo centriole assembly after centrosomal removal in untransformed human cells. J Cell Biol. Jan 15;176(2):173-82, 2007.
Electron micrograph image of a mother and daughter centrioles. The problem was to determine if these division centers could be regenerated by the nucleus and cell after they were microsurgically removed. They could not, although other organelles could be regenerated such as the Golgi apparatus.
Below: Karyoplast transfer experiment of two recent daughter cells a and b.Cell b wasmicrosurgically separated into cytoplast. b, and karyoplast. bl (A). One hour after surgery, the karyoplast (br) was transferred to a separate dish ([B]. shown 15 min after transfer) and kept for 38 hr (C). Several hours after transfer of the karyoplast. the cytoplast (b,) and the unoperated cell (a) were processed for immunofluorescence with anti-tubulin (D) and 5051 antiserum (E) to assay for microtubule organization and the presence of centrioles, respectively.Indeed, both possessed a pair of centrioles ([El, arrows and insets). The transferred karyoplast (bJ was fixed after 38 hr and likewise processed for immunofluorescence (F and G). While it, too, exhibited a nice radial microtubule array(F), it lacked a pair of centrioles (G). Magnifications: (A-C) = 118.8x ; (D-G) = 226.8 x : insets = 3240 x.
(From Figure 4: Maniotis, A., Schliwa, M. Microsurgical removal of centrosomes blocks cellular reproduction and centrosome regeneration in BSC-1 cells, Cell,Vol. 67 pp.201-208, 1991).
-Problem 3. ESTABLISHMENT OF CELLULAR TENSEGRITY RULES IN THE CONSTRUCTION OF CELLS AND TISSUES, AND DURING THE REGENERATION OF DISASSEMBLED GENOMES AND CHROMOSOMES AFTER REMOVAL OF ENTIRE GENOMES FROM LIVING MITOTIC CELLS: The development and testing of a new hypotheses regarding non-toxic therapy for cancer, diabetic retinopathy, macular degeneration, wound healing, and psoriasis control known as anti-angiogenesis. This work was supported by an NIH Surgical Research Fellowship invitation and 6 year award in the Departments of Surgery and Pathology at Harvard’s Children’s Hospital, Boston Massachusetts. Under the direction of Dr. Judah Folkman. During this tenure, I became an invited member at Harvard Children’s Hospital’s “Boston Vascular Task Force–a group managing severely ill children harboring terminal illnesses.
With Donald Ingber, the basic research we initiated helped establish, develop, and then advance the cell signaling and cell biology field now known as cellular tensegrity, and it served as a foundation and scientific basis for human diagnostic molecular cancer and viral testing and known as “mechanogenomics.” Abstracts of this work can be obtained at The National Library of Medicine here:
—Maniotis, A., Chen, C., Ingber, D. Demonstration of mechanical interconnections between integrins, cytoskeletal filaments, and nuclear scaffolds that stabilize nuclear structure. Proc. Nat. Acad. Sci . Vol. 94 pp.849-854, 1997;
—Maniotis, A., Bojanowski, K., Ingber, D. Mechanical continuity and reversible chromosome disassembly within intact genomes removed from living cells. J. Cellular Biochem. Vol 65: 114-130, 1997;
—Bojanowski, K., Maniotis, A., Ingber, D. DNA toposiomerase ll can control chromatin topology and drive chromosome condensation without enzymatically modifying DNA. J. Cellular Biochem. Vol. 69:127-142,1998; —Eckes, B., Dogic, D., Colucci-Guyon, E., Wang, N, Maniotis, A., Ingber, D., Merckling, A., Aumailley, M., Delouvee, M., Koteliansky, V., Babinet, C., Krieg, T. Impaired mechanical stability, migration, and contractile capacity in vimentin-deficient fibroblasts. J. Cell Science Vol. 111: 1897-1907, 1998;
—Eckes, B.; Martin, P.; Smola, H.; Dogic, D.; Colucci-Guyon, E.; Maniotis, A.; Wang, N.; Aumailley, M.; Ingber, D.; Babinet, C.; Krieg, T Disruption of tensegrity in vimentin-deficient fibroblasts causes delayed wound healing in fetal and adult mice. J. of Dermatol. Sci. Vol: 16, Issue: 1001, pp. 120, 1998;
—Pourati J, Maniotis A, Spiegel D, Schaffer JL, Butler JP, Fredberg JJ, Ingber DE, Stamenovic D, Wang N. Is cytoskeletal tension a major determinant of cell deformability in adherent endothelial cells? Am. J. Physiol. May; 274 (5 Pt 1):C1283-C1289, 1998.
Critical reviews and appraisals of the work can be found in these publications:
—Ingber, D. Dike, L., Hansen, L., Karp, S., Liley, H., Maniotis, A., McNamee, H., Mooney, D., Sims, J., Wang, N. Cellular tensegrity: exploring how mechanical changes in the cytoskeleton regulate cell growth, migration, and tissue pattern during morphogenesis. International Review of Cytology. 150:173-224,1994.
—Chen, C. Ingber, D, and Maniotis A. A Strategy for Research in Space Biology and Medicine In the New Century. Physiology, Gravity, Space, Chapter 6, 1998.
—Goldman, WF.,Alonso JL, Bojanowski, K.,Bragwynne, C., Chen C.S., Chirchurel, M.E., Dike, L.,Huang, S., Lee, K-M., Maniotis, A., Mannix, R.,McNamee, H.,Meyer, C., Naruse, K, Parker, K.K., Plopper, G., Polte, T., Wang, N., Yan, L., Ingber, D.E. Cell shape Control and Mechanical Signaling Through the Cytoskeleton. The Cytoskeleton and Signaling: A Practical Approach. Chapter 11, 1999.
—James Glanz. “Force-Carrying Web Pervades Living Cell.” Science, Vol 276, pp 678-679, 1997.
—Donald Ingber. “Tensegrity: The Architectural Basis of Cellular Signal Transduction.”Annu. Rev. of Physiol., Vol. 59: 575-99, 1997.
—D. Batten.Mechanical Biology? CEN Tech. J., vol. 11, no. 3, p.262-3, 1997.
—Donald Ingber. “The Architecture of Life.” Scientific American, January, pp48-57, 1998.
-Michael Hendzell—“The integration of tissue structure and nuclear function.” Biochem. Cell Biol. 79: 267–274, 2001.
—Lieber, Michael M. “Force and genomic change.” Frontier Perspectives, March 22, 2001.(http://www.thefreelibrary.com/Force+and+genomic+change.-a0163336403).
—Michael G. Poirier, Tamar Monhait, John F. Marko. “Reversible hypercondensation and decondensation of mitotic chromosomes studied using combined chemical-micromechanical techniques.” Journal of Cellular Biochemistry Volume 85 Issue 2, Pages 422 – 434, 2002.
—Bernhard Palsson, Sangeeta N. Bhatia. Tissue Engineering. Pearson Prentis Hall Biongineering CRC Press, 2003 ISBN 0849318122, 9780849318122.
—Natella Enukashvily, Rossen Donev, Denise Sheer, Olga Padgornaya. Satellite DNA binding and cellular localization of RNA helicase P68. Journal of Cell Science 118, 611-622, 2005.
—Joseph Bronzino. The Biomedical Engineering Handbook. CRC/Taylor & Francis (2006) – ISBN 0849321220, pps 115-4.
—Richard Gordon. Mechanics in Embryogenesis and Embryonics: Prime mover or Epiphenomenon? Int. J. Dev. Biol. 50: 245-253, 2006.
—John F. Marko. “Micromechanical studies of mitotic chromosomes.” Chromosome Research Volume 16, Number 3 / May, pps. 469-497 2008.
This work on cellular tensegrity and cellular mechanics are cited by an additional 99 articles and groups listed by PubMed Central and which are available at:
Regeneration of genomic and chromosomal structure following digestion with enzymes shows the underlying structure of the genome is DNA and not protein. The nearly precise reconstitution of the after picture (on the right) demonstrates an exact likeness to the before picture (far left), following nearly complete dissolution with protein-degrading enzymes (proteinase K, trypsin), and disulfide bond disruption (dtt, B-mercaptoethanol).
-Problem 4: VASCULOGENIC MIMICRY: The discovery of a new cancer phenomenon and mechanism independent of tumor anti-angiogenesis known as vasculogenic mimicry (VM) (the formation of vascular systems and architectural resistance in malignant tumors formed by the malignant tumor cells themselves).
At first this was accomplished through study of the vast tissue-generation ability of melanomas and their tumor-cell derived vasculature. This was accomplished because of an invitation to join the faculty as a Research Assistant Professor at The University of Iowa, in the Anatomy and Neurobiology Department. Now a decade later there are over 212 publications and groups world-wide employing VM to stage and treat resistant tumors of all kinds with several new articles appearing every month (for critical reviews, assessments, and approximately 220 confirmations of the discovery and work on vasculogenic mimicry that are too numerous to list here: please see C. V. or Pubmed http://www.ncbi.nlm.nih.gov/pubmed?term=vasculogenic%20mimicry).
There are pictures of vasculogenic mimicry in melanoma and other cancers under the section of vasculogenic mimicry that is presented in the cancer section on this website, and below I show the first description of vasculogenic mimicry in melanoma, and below it is a photograph of vasculogenic mimicry and molecular endothelial mimicry in a kidney cancer:
-Problem 5. EXPERIMENTAL REVERSION OF BREAST CANCER. As the melanoma and breast cancer research program director in the Department of Pathology, University of Illinois, Chicago (UIC) Medical School, and with an invitation to develop “The Efficient Causes and Designs Consortium” as an Associate Professor in the colleges of Medicine and College of Engineering also at UIC, and with many talented students and colleagues, these programs further helped develop the science of vasculogenic mimicry, both in the context of testing and in therapeutics. In the two inter-departmental programs I launched and nurtured over a 10 year period (The Cell and Developmental Biology of Cancer, and The Efficient Causes And Designs Consortium), the work eventually led to the experimental reversals of breast cancer cells and melanoma cells to form normal-tissues, or indolent tissues. In these programs, I trained post-doctoral students, graduate students, medical students, scientists, and undergraduates in both schools (medical and biomedical engineering / basic sciences) by forming the cancer research, genomics analysis, and therapeutics programs. Our students won First and Second Place Prizes for their inventions at Chicago’s Engineering Expositions on 3 occasions, awarded by judges recruited from academia, medicine, and industry;
COVER IMAGE, AMERICAN JOURNAL OF PATHOLOGY. Tone Sandal, Klara Valyi-Nagy, Robert Folberg, Mina Bissell, Virginia Spensor, Andrew Maniotis. Epigenetic reversion of breast carcinoma phenotype and DNA sequestration. American Journal Of Pathology, Vol. 170(5):1739-49. May, 2007. On the Cover: Malignant tumor-organoid morphology is reverted to normal by PI3 kinase inhibitors, dibutyryl-cAMP, or anti-fibronectin antibody. Normal MCF10A breast epithelial cells (left), transformed T4-2 tumorigenic breast cells (middle), and T4-2 cells treated with anti-fibronectin when grown on laminin (right) in 3-D culture for 10 to 14 days. Cells were stained for β4-integrin (red; top row) or β-catenin (red; bottom row); nuclei were stained with DAPI (blue). Above: Left: Three normal milk glands. Middle: Two large malignant tumor-filled milk glands. Right: Three milk glands regenerated from malignant tumor cells that have been in the presence of anti-fibronectin antibody.
-Problem 6: MOLECULAR TESTING OF MALIGNANT AND NON-MALIGNANT TUMORS USING RESTRICTION ENZYMES.
-Problem 7: EARLIEST DETECTION OF CELLULAR DAMAGE DUE TO VIRAL INFECTIONS USING THE RILA ASSAY (Rapid Lysis and Infectivity Assay):
Problem 8:REGENERATION OF FUNCTIONAL MUSCLES USING TENSEGRITY RULES OF CONTINUOUS TENSION AND ISOLATED COMPRESSION ENGINEERING: Producing the first functional and life-like muscle regeneration process In Vitro in the context of basic developmental biology and muscular dystrophy research at the University of California at Berkeley. The bioengineering designed we developed worked because it employed tensegrity building principles, although we were not aware of this fact at that time-and only later came to realize that the production of functional muscle was an inevitability because the design utilized both continuous tension (fibroblastic sheets) and compression-resistance (fused muscle, a seran-wrap-like substrate and rigid needles to resist tension created by the contractile muscle fibers) to permit total regeneration of muscle, connective tissue, and extracellular matrices deposited in the correct muscle compartments (Abstract can be obtained at The National Library of Medicine here):
—Strohman, R.C., Bayne, E., Spector,D., Obinata,T., Micou-Eastwood, J., Maniotis A. Myogenesis and histogenesis of skeletal muscle on flexible membranes.
In Vitro Cell Dev. Biology, Vol 26: pp. 201-208, 1990 (http://www.ncbi.nlm.nih.gov/pubmed? term=maniotis%2Cstrohman).
-Frozen sections of the first In Vitro engineered functional muscle that contained adult forms of myosin, extracellular matrix in the appropriate compartments, and was possible because the tensegrity rules of efficient design were achieved: continuous tension in a system with isolated compression struts. This is the way the human arm is constructed as the bones (compression struts) are discontinuous, whereas the muscle, ligaments, and tendons are the continuous tension lattice.
-Problem 9: REGENERATION OF VOCAL FOLDS (Vocal cords) DAMAGED BY TRAUMA OR RADIATION: Not shown here.
-Problem 10: REGENERATION OF DOPAMINE AND GABA LEVELS IN THE CONTEXT OF ADDICTION MEDICINE: Not shown here.
-Problem 11: REGENERATION OF IMMUNE SYSTEMS FROM STEM CELLS FOUND IN CRYPTOPATCHES IN THE INTESTINAL ILIUM OF MICE FOR APPLICATIONS IN CANCE, AIDS, RADIATION OR DRUG DAMAGE: Accomplished during my employment as a consultant in The Department of Surgery at UIC where our team established how immune stem cells in the gut may be a far better source of stem cells for tissue regeneration than immune stem cells that are currently derived from bone marrow.
This chart shows the results of flow cytometry measurements of non-committed stem cells expanded In Vitro, which were derived from cryptopatches of the ilium of a mouse. The best achieved from bone marrow for cancer regeneration therapies following chemotherapy is approximately at most about 3%. Here the flow cytometry shows an 87% expansion of stem cells (that are called lineage negative, Sca-1, and c-kit positives) that can be used in the context of cancer treatment or AIDS to restore a wiped out immune system.
-Problem 12. REGENERATION OF NERVE FUNCTION AND PAIN MANAGEMENT THROUGH BIOMECHANICAL TECHNIQUES SUCH AS POWER PLATE AND TAI CHI.New England Journal of Medicine: Tai Chi has a 26% reversal rate in fibromyalgia victims
-Problem 13: GENERATION AND DISSOLUTION OF BIOFILMS FOR APPLICATIONS IN DRUG-RESISTANT OR REFRACTORY DISEASES:
The three plates above harbored thick colonies of intestine-derived biofilm bacteria. The one on the left is untreated. The middle plate is treated with penicillin and streptomycin. The right plate is treated with laminin derived from the intestine, showing that this natural and non-toxic matrix molecule can antagonize biofilm-producing bacteria almost as effectively as the two commonly used antibiotics. Sterile pieces of gauze in each plate were arranged in a triangular pattern after being pre-soaked with nothing (left) penicillin plus streptomysin (middle) or laminin (right). Note the zones of exclusion surrounding the drug or laminin-soaked gauze plugs. Generation of biofilms and their dissolution with non-toxic extracellular matrix molecules such as laminin derived from the intestines of animals may be useful to antagonize cystic fibrosis, dental plaque, contact lens biofilms, catheter biofilms that kill 80% of hospital patients.
-Problem 14: REGENERATION OF ECOSYSTEMS, AND DETECTION OF ELEMENTS IN BLOOD, SALIVA, STOOLS, SOIL AND ENVIRONMENTAL SAMPLES USING A NEW LASER DEVICE THAT QUANTIFIES THESE ELEMENTS AND THAT IS PORTABLE:
Hairless lady chimp friend of mine named Alice. I think she is beautiful and worth saving from the destruction of the rainforest. She suffers from alopecia (baldness), and appears as naked as any human would. Here is what this device looks like and its projected costs:
Problem 15: REGENERATION OF PERSONS THAT HAVE FALLEN OUTSIDE THE CURRENT “STANDARDS OF MEDICAL CARE, AND ASSIGNED TO HOSPICE CARE OR END OF LIFE CARE: Not only is the focus of REGENERATION SOLUTIONS on the science and translational aspects of medicine, but has been instrumental in resolving false or problematic diagnoses cases in both cancer and AIDS. The stories of these case histories are presented in the book “Fighters of AIDS,” and available upon request. Almost without exception most of these case histories involve the regeneration of people’s lives following tragic mismanagement and in many cases stigma. There are dozens of human examples, but I only provide one of them-a case involving false testing as presented in the press release shown below:
Press Release – December 12, 2007 1
Verdict Of $2.5 Million Over False-Positive HIV Diagnosis
Brings up Basic Problems With AIDS Testing and Treatment, Say Scientists
CHICAGO, Dec. 12, 2007—
A lawsuit decided today against the University of Massachusetts Medical Center over consequences of an allegedly false-positive HIV antibody test exposes basic problems with the test and treatments for all persons taking them, according to a high-ranking medical researcher who has advised the plaintiff’s lawyer on the case. The verdict, issued today, awarded $2.5 million to the plaintiff.
The complaint by Audrey Serrano, 45, in court hearings this week in Worcester, Mass., focused on the absence of a “confirmatory” Western Blot test in her records. However, Andrew Maniotis, Ph.D., research assistant professor in the Department of Pathology, University of Illinois-Chicago School of Medicine, contends that, though the reliability of all HIV testing was not on trial in court here, the case history opens questions about it. And, because Serrano developed illnesses commonly defined as “AIDS-related conditions” only after taking HIV medications known as “highly active antiretroviral therapy” (HAART), the drugs themselves appear to have caused “AIDS.”
Rethinking AIDS (RA) has been asking such questions since its founding in 1991. Etienne de Harven, M.D., president of RA, says, “It is urgent that we open a public debate on the highly suspect reliability of all HIV testing. Moreover, I fully share Dr. Maniotis’ concern about the safety of HIV drugs.” Further resources are online at the group’s Web site, http://www.rethinkingaids.com.
Rodney Richards, Ph.D., worked on the development of antibody (ELISA) and genetic “viral load” tests for Amgen and holds some related patents. “The diagnosis of being HIV positive is based on arbitrary combinations of tests, none of which are approved for diagnosing HIV,” he says. “In fact there is no test for HIV. It’s just an illusion.”
Raising issues of informed consent for all persons submitting to HIV antibody testing, the test kits themselves contain disclaimers that doctors rarely, if ever, share with patients. For example, Abbott Laboratories’ ELISA test kit, typically used as a preliminary test, warns:
“ELISA testing alone cannot be used to diagnose AIDS.”
Confirmation of an ELISA result with a Western Blot test is currently required as a “standard of care.” Epitope’s Western Blot package insert reads:
“Do not use this kit as the sole basis for HIV infection.”
“This is somewhat more concerning, since the Western Blot is supposed to be a highly accurate test, used to confirm that an ELISA is not a false positive,” says Dr. Maniotis. “Moreover, the peer-reviewed literature gives substantial evidence that the virus ‘HIV’ has never been isolated in purified form free of contaminating cellular debris in order to generate the so-called ‘specific viral antigens’ used in the test kits.”
Serrano, now acknowledged to have always tested HIV negative and therefore not to have been at risk for developing AIDS, nevertheless suffered from several AIDS-defining illnesses, including wasting, herpes, and oral thrush, while taking HAART. She also suffered from other health problems, including constant diarrhea (AIDS-defining under the African definition), muscle wasting, profound fatigue, non-specific skin lesions, oral thrush, herpes outbreaks, severe nosebleeds, constant gynecological bleeding and pain from ovarian cysts, fibrocystic breast lesions, hyperplastic pituitary lesions, and severe heart and respiratory difficulties.
Labels for HAART drugs actually list these conditions as possible side effects, suggesting that the drugs themselves cause AIDS-related conditions, Maniotis says.
Serrano’s experience is, sadly, not unique. Dr. Maniotis chose to investigate her case because, he says, “it is typical of many cases reviewed and, as it illustrates so clearly the development of AIDS-related conditions in a woman testing HIV negative who was healthy before she took HAART, strongly suggests that profound paradigm shifts are urgently needed to avoid more human rights violations.”
One of the vanguards of science and biomedical research and medicine is increasingly being developed using reductionism to bring forth an ever proliferating cottage industry of molecular testing. Molecular testing, by itself, however, falls short of generating satisfying solutions that evolve into scientific theories that stand the test of time in the context basic research. Much like the invention of the thermometer to measure temperature changes or differences, the context in which the measurement is made is of defining importance. In the context of medicine, the development of actual cures or life-restoring reversals of disease rather than the basic temporary relief of symptoms are all too rare. It is here where reductionism and molecular testing intersect that the most exciting successes and often the most tragic setbacks can be seen to unfold.
For example, during the painstakingly arduous process of disease test kit development, at some point it becomes clear to those involved in making and validating new tests (like pathologists who stage melanomas or breast cancers), especially those scientists or doctors that claim to identify terminal illnesses with some degree of certainty, that perhaps it would be better to develop therapeutic strategies that would regenerate the defect, or reverse or cure the illness, rather than spend time and precious resources finding more accurate ways of predicting outcome in the setting of current ineffective treatment strategies. In infectious disease models and tests, finding so-called disease markers among “healthy carriers” that exhibit no disease or mild self-resolving clinical symptoms, despite the presence of disease markers, has constituted unprecedented public health disasters that arguably are worse than screening programs for cancers that enter the market as non-validated and simply serve to terrorize “positive” populations, and accrue huge expenses (see the quote of Dr. Richard Ablin below, the discoverer of PSA prostate specific antigen or PSA).
A physician may argue that accurate testing lays the foundation for effective treatment, and if the syndrome is not presumed fatal, accurate testing is the first step toward a cure (already an assumption is made-that surrogate markers of disease are or aren’t indicative of a fatal outcome). Without knowing the exact imbalance(s) involved in a disease syndrome through a series of testing, than how is it possible to treat the imbalance or problem let alone cure it?
At the same time, other physicians may argue that “in medical school we are taught not to treat lab tests, but to treat patients.” In all honesty, both of these arguments do not even begin to approach what is needed to reverse what are assumed to be chronic or fatal illnesses.The development of scientific and medical testing aims at placing the daunting complexity of normal physiology and disease within a framework of scientific prediction, so that eventually one can absolutely depend on lab tests to reflect reality or the maintenance of “normal” physiology or prediction of demise within acceptable degrees of certainty. The aim here is to eventually “treat” the lab test, or restore a value back within normal limits. When the philosophy of “we treat patients not lab tests” is pursued, more often than not the conundrum presents the complex balances known to exist in normal homeostasis, and when a particular treatment is applied, often side effects, or unanticipated imbalances result. Application of a weakened microbe, according to the Jennerian paradigm, “primes” the system to vanquish that microbe in the future when it invades, instead of targeting that microbe and killing it directly. Antibodies generated against that microbe are said to be “protective,” accept of course in the case of “HIV,” and several other conundrums we will later explore.
Several other issues may help make this important point. Laboratory investigator X or company Y may have discovered a reliable associated marker(s) for cancer Z, by inventing a test perhaps that is 89% predictive of eventual outcome. Now that test is used to tell a patient (or a patient population) the good news that: “populations of persons presenting with your markers typically show a benign course of disease,” or conversely, “sorry Mr. Maniotis, but this fool-proof test of ours indicates you are gonna die in 3 months tops with 100% certainty (unless you submit yourself to our modestly life-extending experimental protocol”). At some point, regardless of sensitivity and specificity of the test, the looming projected outcome of the syndrome or disease detected by the test motivates the test kit maker to rethink the value of the test, and the value of telling persons they will live or die, and then begin to spend what often amounts to limited time and resources identifying a cure or rational management of the syndrome instead of merely predicting its outcome. Rather than simply being content to tell the victim (patient), “yeah, you are gonna die for sure, and there is nothing for us to do other than to find you a clean well-lit hospice,” the possibility arises that perhaps some simple fact in the case or the science behind the test has been overlooked or ignored. In a New York Times article published not too long ago, Richard Ablin, the discoverer of “prostate specific antigen, which is used to screen for prostate cancers, is quoted as saying:
“ Prostate cancer may get a lot of press, but consider the numbers: American men have a 16 percent lifetime chance of receiving a diagnosis of prostate cancer, but only a 3 percent chance of dying from it. That’s because the majority of prostate cancers grow slowly. In other words, men lucky enough to reach old age are much more likely to die with prostate cancer than to die of it.”
“Even then, the test is hardly more effective than a coin toss. As I’ve been trying to make clear for many years now, P.S.A. testing can’t detect prostate cancer and, more important, it can’t distinguish between the two types of prostate cancer — the one that will kill you and the one that won’t…”
...”The European study showed a small decline in death rates, but also found that 48 men would need to be treated to save one life. That’s 47 men who, in all likelihood, can no longer function sexually or stay out of the bathroom for long.”…
“Testing should absolutely not be deployed to screen the entire population of men over the age of 50, the outcome pushed by those who stand to profit.”
“I never dreamed that my discovery four decades ago would lead to such a profit-driven public health disaster (New York Times, Op-Ed Contributor “The Great Prostate Mistake,” By RICHARD J. ABLIN Published: March 9, 2010).
Cardiac, vascular, mental health, and especially infectious disease testing examples all have given rise to similar “public health disasters,” to use Dr. Ablin’s own words, and they are even more telling but perhaps are in the final analysis good news for those handed a chronic or terminal death sentence, and I will give only one example here of these false and often life-ending tests, namely the case with “HIV” testing:
• “At present there is no recognized standard for establishing the presence or absence of HIV-1antibody in human blood.” (Abbott Laboratories, ELISA HIV Antibody Test Insert).
• “The risk of an asymptomatic person with a repeatedly reactive serum developing AIDS or an AIDS-related condition is not known. ” (Abbott Laboratories, ELISA HIV Antibody Test Insert).
• “The AMPLICOR HIV-1 MONITOR test, is not intended to be used as a screening test for HIV or as a diagnostic test to confirm the presence of HIV infection.” (Roche, Amplicor HIV-1 Monitor Test Kit).
• “Do not use this kit as the sole basis of diagnosis of HIV-1 infection.” (Epitope, Inc., Western Blot HIV Antibody Test Insert).
• “Clinical studies continue to clarify and refine the interpretation and medical significance of the presence of antibodies to HIV-1.” (Abbott Laboratories, ELISA HIV Antibody Test Insert).
And these represent “HIV” tests that haven’t been recalled for violating FDA standards. Let us look at a few of those:
In 2001- FDA recalled 24 antigen test kit;
in 2002, the FDA recalled BioRad Genetic systems HIV Types 1 &2 Synthetic Peptide containing test kits;
in 2004, the FDA recalled bioMerieux NucliSens automated isolation reagent(s), DiaSoran’s HIV-1 – HIV-2 Plus O EIA Testing Software, and Roche’s Amplicor HIV Monitor test;
in 2005, the FDA also recalled Globus Media Rapid HIV test kits;
in 2006, the FDA recalled BioMerieux “HIV-1” test,
in 2006 FDA recalled Vironostika HIV-1 test kit, and Abbott’s Home access HIVAG-1 Monoclonal EIA Test Kit.
I would bet you a nickel that the patients who tested positive for these tests were never notified.
ELISA tests (Enzyme Linked Immunosorbent Assays) measure antibodies, as do WESTERN blots. PCR measures nucleic acid fragments from a person’s peripheral blood. Some of the so-called rapid “HIV” tests ALSO have been withdrawn or banned by the FDA. In 2004, the American Red Cross reported that even after repeated “HIV” testing using different test kit types, that “low-risk” populations, such as blood donors (or military recruits or nuns) will typically yield 12 (PCR) positive or 2 (ELISA) positive results out of 37,000,000 million units of blood, which means that 10 out of 12 were false positives. Another test, supposedly measures p24, the capsid protein of “the virus” shed in tissue cultures infected with “HIV.” Yet many human beings, 50% of dogs, certain goat-milk-fed and thymus-gland atrophied “HIV-negative” children in the world express such molecules as p24 in their blood system naturally (“HIV’s” so-called capsid protein). Here are the titles and authors of these studies:
Strandstrom et al. Studies with canine sera that contain antibodies which recognize human immunodeficiency virus structural proteins. Cancer Res 1990 Sep 1;50 17 Suppl :5628S-5630S;
Willman et al., Heterophile Antibodies to Bovine and Caprine Proteins Causing False-Positive Human Immunodeficiency Virus Type 1 and Other Enzyme-Linked Immunosorbent Assay Results. Clinical and Diagnostic Laboratory Immunology, p. 615-616, Vol. 6, No. 4, July 1999;
Dura WT, Wozniewicz BM. Expression of antigens homologous to human retrovirus molecules in normal and severely atrophic thymus. Thymus.;22(4):245-54, 1994).
What about other tests for “HIV” such as the often fatally fraudulent “viral load” or T-cell tests? Lets review here what the best and most respected doctors have said, and what the most revered reviewers for Science have advertised:
“A large and more recent study in 2006 claimed that viral load does not correlate with T-cell numbers, and the rate of progression (when an individual will exhibit symptoms of AIDS) can only be predicted in 4%-6% of HIV-positives studied (out of 2,800): A nationwide team of orthodox AIDS researchers led by doctors Benigno Rodriguez and Michael Lederman of Case Western Reserve University in Cleveland are disputing the value of viral load tests-a standard used since 1996 to assess health, predict progression to disease, and grant approval to new AIDS drugs after their study of 2,800 HIV positives concluded viral load measures failed in more than 90% of cases to predict or explain immune status…”
“Viral load is only able to predict progression to disease in 4% to 6% of HIV-positives studied, challenging much of the basis for current AIDS science and treatment policy” [Rodriquez B, Sethi AK, Cheruvu VK, et al. Predictive value of plasma HIV RNA level on rate of CD4 T-cell decline in untreated HIV infection. JAMA 296(12):1498-506, 2006. Cohen J. Study says HIV blood levels don’t predict immune decline. Science 313(5795):1868, 2006].
Perhaps these are a few of the reasons why even “the Gold Standard Test,” the WESTERN blot, presents many technical challenges that most clinical chemists would like to forgo, according to Mark Pandori, PhD. Chief microbiologists San Francisco Department of Public Health Laboratory:
“Many samples on WESTERN blots have spurious bands that are difficult to interpret. Or because WB’s are complex to administer and may react as positive if a person is infected with another virus (http/www.avert.org/testing.htm). Therefore, many reference labs and physicians are questioning the WB as a gold standard. The latest APHL/CDC (an “HIV” testing regulatory body of the government) proposed algorithm omits WB’s altogether.”
However, such admissions do not surprise those who study or follow developments in disease testing or disease definitions. We even are told on a frequent basis that flu or hepatitis B vaccines cause “HIV” tests to fire positive, and the titles and data of their peer-reviewed papers published in such journals as The American Journal of Epidemiology, New England Journal of Medicine, or The Lancet suggest:
Simonsen L, Buffington J, Shapiro CN, et al. Multiple fasle reactions in viral antibody screening assays after influenza vaccination. Am J Epidemiol 141: 1089-1096, 1995.
Christian, P. Erickson, Todd McNiff, Jeffrey D. Klausner. Influenza Vaccination and False Positive HIV Results. New England Journal of Medicine, Number 13 , Volume 354:1422-1423, March 30, 2006;
Lee, D, Eby W, Molinaro, G. HIV false positivity after Hepatitis B vaccination. Lancet 339: 1060, 1992.
Another common problem with respect to treating lab tests rather than patients also is encountered in numerous contexts wherein the lab test is not validated against a real disease-inducing entity, and surrogate markers have been instituted as being equal to the suspected disease-causing entity. For instance, in the context of “HIV,” intact “viral-like” particles have been visualized only with the utmost difficulty, and no true animal or culture model exists whereby the Human In Vivo picture is produced with any degree of accuracy to assess infectiousness. To prove this statement wrong, for instance, or to validate the lab tests that first used reverse transcriptase-a ubiquitous cellular enzyme once thought to be specific to retroviruses but turned out that it is found in a plethora of “healthy” non-infected contexts as well, all that would be required would be to visualize a microliter of an “HIV-infected” person’s blood who has a “viral load” reading of perhaps 210,000/microliter as determined by PCR under an electron microscope as the experimental sample, take a non-PCR+ blood sample after placing a similar quantity of 207 or so thousand nanoparticles in it/microliter as a size and number control, and compare them to show that the microscope can visualize objects in that range. As a second control, perhaps, the sample containing the 207,000 “HIV” viral-like particles could be mixed with a preparation containing 207,000 nanoparticles, and the single sample could be photographed and shown to contain approximately 400,000 particles/microliter. Yet such simple “proofs” never have been performed for most viruses, and therefore, the term “viral-like particles” continues to dominate the literature as evidence of caution that such particles may be cellular breakdown products that are caused by, rather than causal of, a particular disease syndrome. And with new acceptance of the idea that 8% or so of the Human genome is “retroviral,” the need becomes now ever more acute to show that particles are not what scientists call “HERVs,” “ERVs,” “retroids” or retroelements,” and not simply so-called “retroviral” sequences.
History and pathology teach that diseases, their definitions, and their suspected pathogenesis inducers are constantly evolving. Recently, in fact, the entire diagnostic field of AIDS according to front line physicians publishing in AIDS Clinical Care now dispute T-cell numbers AND viral load readings, and have promoted a new more definitive diagnostic criteria of AIDS: fibrosis of the lymph nodes (more about this important advance is found in the Cancer section of this website). In other words, since 2009, front line AIDS researchers are advancing the idea that similar to fibrosis of the liver in alcoholism or drug reactions, or as in the formerly suspected viral pathogenesis of hepatitis B before autoimmune mechanisms assumed a leading role, and similar perhaps to vasculogenic mimicry patterns in malignant tumors, neither viral loads or T-cell killing cause AIDS because fibrosis of the lymph nodes causes AIDS. This is how it is described in the language of the doctors on the front lines of AIDS treatment:
“The Puzzle of CD4-Cell Depletion Despite Good Viral Suppression. In some patients, CD4-cell counts fail to rise as expected. Could extensive lymph node fibrosis be responsible?”
“AIDS” is unexpectedly progressing despite treatments with “life saving anti-retrovirals” and in many cases without “HIV” being detected. Even more concerning statements followed:
“In a recent study, NIH researchers sought evidence to support any of several hypothetical explanations for the aberrant CD4-cell responses seen in four patients on combination ART whose CD4 counts had fallen from a median of 719 cells/mm3to a median of 227 cells/mm3despite persistently undetectable plasma viral loads.”
These patients were taking a double or triple AIDS-drug cocktail regimen, no “viral load” could be detected, yet their T-cells were plunging from relatively normal levels to the worrisome and CDC-defined level reached when doctors suggest that drug therapy should begin, at around 200-300 CD4+ cells/mm.
Drug “resistance” was “checked” and found not to be an issue. However, what is most troubling is that Dr. Zugar then writes that:
“Residual replicatingHIV did not seem to be the problem: Results ofultrasensitive PCR and assays for peripheral blood mononuclear cell–associated HIV RNA and proviral HIV DNA — and of assays for cell-associated HIV RNA and proviral DNA in mononuclear cells from inguinal lymph nodes — were similar to those obtained in other, successfully treatedpatients.”
It is not the first time that fibrosis in the lymph nodes has been discussed as being a chief issue in “AIDS patients,” as Dr. Zugar correctly stated:
“The single unusual finding was a striking abnormality in inguinal lymph node architecture…”
Or: “…the unusual lymph node architecture documented in all four patients in this study may be related to (or even responsible for) the inadequate CD4-cell response — i.e., that CD4-cell depletion is independent of specific components of an antiretroviral regimen and is instead caused by lymph node fibrosis. They note that such architectural damage may well be “clinically irreversible with currently available interventions.”
See also: “Evaluation of the pathogenesis of decreasing CD4+ T cell counts in human immunodeficiency virus type 1–infected patients receiving successfully suppressive antiretroviral therapy.” Nies-Kraske E. et al. J Infect Dis. Jun 1; 199:1648, 2009.
Therefore, until such proofs are forthcoming that validate real entities with disease, there are certainly no good reasons for diagnosing, or treating patients using tests no more validated than a coin toss, or with risky or dangerous procedures based on such tests, as if these so-called syndromes’ biology or markers have been proven with the certainty of Papal infallibility…there is no rational or humane excuse for ruining peoples lives with complex medical information or scientific slight of hand, just because it is “better to do something than nothing.” Why not research each specific case first in as much depth as time permits? This website addresses this very problem in all of its scientific, medical, social, legal, and policy mandate dimensions.
I have learned through numerous personal contacts with people to who are often tragically caught in the vortex and quagmire of chronic or terminal illnesses that cannot be alleviated, reversed, cured, or in many cases even addressed by mainstream medicine or modern “standards of care,” that there is an acute need now more than ever, to scientifically reappraise this seemingly irresolvable issue. When analyzed with painstaking chronologic detail that is cross-checked from multiple sources, and compared to the best surveys available on The National Library of Medicine, then scientifically sound solutions to many seemingly irresolvable problems are often (not always) obtainable. In this context, timing really IS everything, and certain principles emerge again and again:
1) One must assume from the start that testing and the results of any testing is always incomplete and should never be assumed to be complete, nor is any critical problem immune from the benefits gained by further testing, analysis, or a second or 50th opinion.
Another principle that has emerged is that:
2) The pertinent information of a scientific or medical problem always is unique in each context or case history, be it a series of scientific results, or a past series of medical problems and interventions, either proposed or implemented, to improve or save a human life.
3) “Established” or accepted science, established biomedical information, established medical hypotheses, established standard protocols of medical care, and the need to protect human rights frequently intersect and clash with, question, or challenge current local, regional, and international laws, policies, and established “best practices,” and standards of care.
These conflicts, however, are not necessary. If it is assumed from the start that all factual testing information has inherent value, as does all life and especially human life, then no data or information can be ignored or assumed to be initially accurate, be it either a scientific problem or a human being’s desperate medical case.
The information presented here is intended to provide a comprehensive background, new perspectives, and methodologies that can help create and assure the development of more satisfactory solutions to difficult problems that occur both scientifically, or medically.
Toward this end, through application of this scientific method of thinking not only to those issues considered best addressed in the realm of basic science, but also to those in the realm of human or medical issues, hypotheses are successively eliminated and further testing always is identified, recommended, and then accomplished. Thus, the emergence of real solutions becomes possible only by using a method of analysis that the unique problem itself suggests, and through the exclusion of hypotheses, rather than trying to pigeon-hole the problem into an existing scientific protocol, into a preexisting paradigm, into an established disease diagnosis, or into attempts or strategies designed to identify THE cause.
This small advance in thinking is a result of an awareness of the fact that modern biological sciences aren’t a series of disciplines that occur in isolation: all of them take place within rigid scientist-created and scientist-specialized cultures. The old dictum of “publish or perish” no longer applies, for the simple reason that the jargon and history inherent to one scientific discipline often is completely inaccessible to another. Financial support and incentives also skew the direction of scientific creativity, but this phenomenon is widely known even among the lay public, and does not require explanation here. What may not seem so transparent to the untrained reader of science, or obvious even to many who are highly trained or experienced in science, is that not only are practitioners of one science expected to reduce a specific research problem to a consensus “mechanistic” approach and explanation, but if certain machines or measuring devices aren’t employed during the study, the research becomes unacceptable to the journals, and the science created is rejected. Such a consensus-seeking culture ignores, if not actively suppresses, new approaches or ideas that do not try to “translate” a new scientific discovery into the language erected by old accepted paradigms or prejudices. At the practical level of biological experimentation, the influence of such “cultures” creates a virtual blindness to most, if not all, potentially useful or revolutionary observations, if for no other reason that that observation must be “groomed” or modified into an “acceptable” form. New advances and observations must employ techniques that are agreed on as “proper,” even if better ones are erected during the course of that discovery process.
This point of view is also a result of the fact that modern medical education as well as the practice of medicine is also in a prison of tacit assumptions and prejudices. Having taught at 3 medical schools and having been involved in new medical education programs, and as a keen observer and critic of new clinical trials, it becomes clear that humans aren’t like cars…if a car has a bad tire or starter, that part can merely be changed and everything will be fixed. Humans and other organisms cannot be fixed like changing a flat on a car. The daunting complexity of a cell, not to mention the complexity of an organism, defies such simple diagnostic and therapeutic “fixes,” or the belief that “what is good for one is good for all” ideology or therapeutic approach, whether the testing or therapeutic strategies follow allopathic, homeopathic, or other philosophies and epistemologies.