STEM CELL RESEARCH AND THE PRACTICING PHYSICIAN
| WHAT TO EXPECT FROM STEM CELL RESEARCH —Lawrence S. Goldstein, PhD, Professor of
Pharmacology, University of California, San Diego, School of Medicine, and Investigator, Howard
Hughes Medical Institute, Chevy Chase, MD
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| Answering patients’ questions: about reports in media that new therapies stem based on cell research
now available for their disease, eg, Alzheimer’s disease (AD), Parkinson’s disease (PD), spinal cord injuries
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| Basic principles: cell basic unit of human body; cells specialized, eg, pancreatic cells make insulin, neurons
transmit signals; many diseases caused by cell breakdown (alive but damaged, eg, heart failure, cancer)
or cell death (eg, type 1 diabetes, PD)
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| Bottlenecks in developing new therapies: limited supply of organs for transplantation—supply growing
more slowly than need; genetic mismatch; delay in drug development—often begins with animal studies;
many therapies safe and effective in animals but not in people, leading to wasted expenditures on clinical
trials; poor understanding of disease mechanisms—even though disease pathology described; impact of genetic
variation—variable response to drugs; differences in susceptibility to disease and in clinical course
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| Stem cells: division gives rise to new stem cells as well as cells that adopt specialized jobs (eg, neurons
produce both neurons and neuronal stem cells); potential source of raw material to replace damaged cells
or organs; tools for understanding and combating disease, as well as testing and developing new drugs
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| Examples of stem cells: totipotent—eg, zygote, able to make all cells in embryo and adult; zygote gives
rise to pluripotent blastocyst; pluripotent—give rise to embryonic stem cells; embryonic—can make all
adult stem cells; “adult” tissue—eg, blood stem cells in bone marrow, neuronal stem cells in brain; limited
in ability to make more than one specialized cell; under tight growth control (impedes cancer); attempts
to grow quantities suitable for treatment unsuccessful thus far; hematopoietic stem cells have
provided understanding of blood-forming and immune systems and treatments of related diseases, but
unlikely to be useful in understanding unrelated disorders, eg, neurologic; claims for wider application to
other conditions unproven currently
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| Source of pluripotent embryonic stem cells: blastocyst—arises after fertilization; ball of ≈200 cells;
outer layer fuses with uterine wall; inner cell mass consists of pluripotent cells; during in vitro fertilization
(IVF), pluripotent cells cultured, and blastocyst implanted in uterus; unimplanted blastocysts from
IVF accumulated in freezers; most subsequently used for reproductive purposes; what happens to unused
blastocysts—some eventually lose viability (can retain ability to start pregnancy ≤10 yr); some discarded
according to directives; others donated for medical research (inner-mass cells extracted and grown in
laboratory; experience with mouse shows cells viable for decades)
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| What’s known about pluripotent/embryonic stem cells: can make any adult tissue in mouse; less evidence
for humans; theoretic and experimental foundation for developing specialized stem cells and solving
rejection problem; researchers seeking to restrict cell growth to single cell types; already produced in
laboratory—embryonic and fetal forms of blood; human cardiomyocytes (organize into electrically coupled
networks and beat synchronously); human neuron-like cells; clinical applications under
investigation—partial repair of spinal cord injury with cells that make myelin; treating PD in animal
models
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| Alzheimer’s disease: neurons in brain lose ability to communicate and eventually die; cause remains mystery;
competing hypotheses based on limited information (cognitive behavior; postmortem phenotypes;
experiments on genetically modified animal models); limited ability to test hypotheses required for drug
development; uses of human embryonic stem cells—to make neurons of different types; to introduce genetic
changes that cause AD; (in cancer, to investigate genetic changes that convert normal cells into
“cancer stem cells”); to test drugs
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| Potential role of nuclear transfer technology: most disorders (eg, AD, cancer, PD) sporadic; nucleus removed
from oocyte; investigators transplant nucleus of tissue cell from donor with sporadic or hereditary
disease into oocyte and treat with chemicals and electricity; hybrid cells grow and divide, producing
blastocysts which give rise to cultured pluripotent stem cells; resulting cells enable investigation of
sporadic disorders; objections to procedure—equals human cloning to those who consider blastocyst
equivalent to adult human; generally agreed, however, that procedure unsafe and should now be prohibited
(most pregnancies in animals spontaneously abort, often killing mother; virtually all animals born
abnormal)
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| Summary of scientific issues: “embryonic vs adult stem cell debate” not really debate; each useful; more
research needed on both
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| Questions and answers: umbilical cord blood—source of hematopoietic (not embryonic) stem cells; can be
stored at birth for future therapeutic use in individual child; currently unable to grow cells; oocyte
donation—unable to properly store and use mature ova; ovaries contain mostly immature oocytes (currently
unable to mature in laboratory); why more cell lines needed—genetic diversity required for matches
in organ transplantation; each cell line reflects genetic diversity of source embryo pool; currently approved
cell lines obtained from IVF clinics (donated by “mostly wealthy white middle-aged guys and
their wives”); wider diversity needed to investigate sporadic disease; source of neuronal cells—fibroblasts
obtained with punch biopsy; central nervous system (CNS) biopsy more difficult; embryonic stem cells
lines obtained from each source could be used to assess genetic changes in person who died with AD;
how to avoid patient perception of arrogance by physician—try to present scientific issues as objectively as
possible, distinguishing ethical beliefs from scientific validity and allowing patient to arrive at own decision;
blastocyst issue—while some believe blastocyst equivalent to person, blastocysts continue to be
created and destroyed in IVF clinics; location of research—allowing shift outside United States would
harm economy; by taking lead in research, United States could expedite development of appropriate regulatory
standards
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| INTERNAL MEDICINE PEARLS —Daniel M. Lichtstein, MD, Associate Professor of Medicine, Director
of Education and Director of Postgraduate Education, Department of Medicine, University of Miami
Miller School of Medicine, Miami, FL
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| Pseudohyperkalemia: potassium (K) normal in vivo but remains elevated in laboratory results; caused by
marked thrombocytosis or leukocytosis; abnormal results due to leakage of K during centrifuge process before
testing; solution—order plasma K rather than serum K
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| Unexplained hypokalemia: consider hyperaldosteronism and factitious use of laxatives or diuretics (most
common cause); may require analysis of urine; rare causes (Barter’s syndrome; Liddle’s syndrome)
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| Welt’s syndrome: suspect when unable to correct hypokalemia; measure magnesium; correct hypomagnesemia
to eliminate hypokalemia due to renal wasting
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| Hypercalcemia: seen in immobilized patient with Paget’s disease of bone or metastatic prostate cancer;
diseases osteoblastic but osteoclastic activity increases with immobilization
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| Syndrome of inappropriate secretion of antidiuretic hormone (SIADH): may occur with selective serotonin
reuptake inhibitors, especially in older patients
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| Lithium: causes endocrine abnormalities; may mimic primary hyperparathyroidism; can cause nephrogenic
diabetes insipidus; associated with decreased release of thyroxine and with hypothyroidism
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| Subacute bacterial endocarditis (SBE): ≈25% of patients present with neurologic findings (eg, stroke,
transient ischemic attack [TIA]); suspect in patient with unexplained symptoms; SBE due to Bartonella
quintana (difficult to culture) seen in homeless patients (transmitted by body lice)
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| Listeria: second most common cause of bacterial meningitis in adults; consider in patient >50 yr of age presenting
with suspected meningitis; add ampicillin to initial antibiotic therapy (ceftriaxone and vancomycin
inadequate)
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| Mononucleosis: may present with symptoms of viral hepatitis in patients >40 yr of age
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| Strongyloidiasis: corticosteroid therapy may cause dissemination of Strongyloides from gut, leading to hyperinfestation
syndrome and gram-negative sepsis; suspect in patient with unexplained eosinophilia
(seen in patients with HIV infection presenting with pneumonia)
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| Ticks and empiric antibiotic therapy: indicated if bite occurs in area with endemic Rocky Mountain
spotted fever (potentially fatal acute disease); not indicated if rash not present and bite occurred in area
with endemic Lyme disease
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| Prolonged use of proton pump inhibitors (PPIs): may interfere with iron absorption
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| Antibodies to tissue transglutaminase: now considered most sensitive test for celiac sprue; much more
sensitive than endomysial antibodies
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| Ischemic colitis: mucosal and submucosal disease; patients present with pain and hematochezia; causes
include vasculitis, coagulopathy, and cocaine; manage with supportive care (fluids; possible transfusion);
arteriography unnecessary; colonoscopy reveals characteristic abnormalities
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Educational Objectives
| The goal of this program is to educate the listener about stem cell research and several pearls in internal
medicine. After hearing and assimilating this program, the clinician will be better able to:
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 | 1. Explain to patients why clinical benefits of stem cell research are currently unavailable.
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| 2. Describe bottlenecks to developing new therapies, including limited supply of organs for transplantation
and delays in drug development.
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| 3. Explain different types of stem cells now being discussed, including embryonic and adult stem cells.
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| 4. Discuss how researchers are using stem cells in an attempt to understand the pathogenesis of diseases
such as cancer, Alzheimer’s and Parkinson’s disease, as well as to develop effective therapies
for these diseases.
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| 5. Employ clinical pearls in the diagnosis and treatment of several disorders, including pseudohyperkalemia,
Welt’s syndrome, and syndrome of inappropriate secretion of antidiuretic hormone
(SIADH).
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Discussed on This Program
Ampicillin [Principen]
Ceftriaxone sodium [Rocephin]
Vancomycin [Vancocin, Vancoled]
Suggested Reading
Dumler JS et al: Rocky Mountain spotted fever--changing ecology and persisting virulence. N Engl J Med
353:551, 2005; Dunner DL: Optimizing lithium treatment. J Clin Psychiatry 61 Suppl 9:76, 2000; Hammarberg
K et al: Deciding the fate of supernumerary frozen embryos: a survey of couples' decisions and
the factors influencing their choice. Fertil Steril [Epub ahead of print] Hampton T: US stem cell research
lagging. JAMA 295:2233, 2006; Huang D et al: Tendon tissue engineering and gene transfer: the future of
surgical treatment. J Hand Surg [Am] 31:693, 2006; Jensen RT: Consequences of long-term proton pump
blockade: insights from studies of patients with gastrinomas. Basic Clin Pharmacol Toxicol 98:4, 2006; Kelly
J et al: Listeria meningitis presenting in an immunocompetent adult patient. Hosp Med 60:140, 1999; Kim
SU et al: Brain transplantation of human neural stem cells transduced with tyrosine hydroxylase and GTP
cyclohydrolase 1 provides functional improvement in animal models of Parkinson disease. Neuropathology
26:129, 2006; Kurpinski K et al: Regulation of vascular smooth muscle cells and mesenchymal stem cells
by mechanical strain. Mol Cell Biomech 3:21, 2006; Limb GA et al: Current prospects for adult stem cell-
based therapies in ocular repair and regeneration. Curr Eye Res 31:381, 2006; Salata R et al: Effects of lithium
on the endocrine system: a review. J Lab Clin Med 110:130, 1987; Salata R et al: Effects of lithium on
the endocrine system: a review. J Lab Clin Med 110:130, 1987; Scheffler B et al: Merging fields: stem cells
in neurogenesis, transplantation, and disease modeling. Brain Pathol 16:155, 2006; Serour Chair GI: Human
reproductive cloning and embryonic stem cell research and use. Int J Gynaecol Obstet 93:282, 2006;
Siddall NA et al: The RNA-binding protein Musashi is required intrinsically to maintain stem cell identity.
Proc Natl Acad Sci U S A 103:8402, 2006.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any
significant financial relationship with the manufacturer or provider of any commercial product or service
discussed. For this issue, the faculty reported nothing to disclose.
Dr. Goldstein was recorded at Topics and Advances in Internal Medicine, sponsored by the University of California,
San Diego, School of Medicine and held March 2-8, 2006, in San Diego, CA; Dr. Lichtstein, at Internal Medicine
Update 2006, sponsored by the University of Miami Miller School of Medicine and held January 22-27, 2006, in Key
Biscayne, FL. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production
of this program.
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