of Kentucky College of MedicineMark O’Neal SpeightIndependent ScholarKavitha SrinivasanUniversity of LouisvilleBrad St. MartinUniversity of Kentucky College of MedicineAvraham SteinbergShaare Zedek Medical CenterKyle StigallUniversity of Kentucky College of MedicineLeslie SuenCedars-Sinai Medical CenterJaved SulemanMount Sinai HospitalJianmin SunLund UniversityArvind SureshIndependent ScholarSajid S. SuriyaDow University of Health SciencesRichard TaingUniversity of Kentucky College of MedicineTetsuya S. TanakaUniversity of Notre DameAli TariqIndependent ScholarAreej TariqIndependent ScholarMuhammad Ali TariqSheikh Khalifa Bin Zayed Al Nahyan Medical and Dental CollegeAkhilesh TiwariUniversity of TorontoMorenike TrenouIndependent ScholarZarish UmarIndependent ScholarGeorge C. Upper IIIIndependent ScholarAtiq Ur-RehmanIndependent ScholarRhea U. VallenteIndependent ScholarNicole Van HoeyIndependent ScholarJohn L. VandeBergTexas Biomedical Research InstituteHenry VasconezUniversity of Kentucky College of MedicineKrishna S. VyasUniversity of Kentucky College of MedicineTracey WeilerHerbert Wertheim College of Medicine, Florida International UniversityLuke WilliamsUniversity of KentuckyAmanda WrightUniversity of Kentucky College of MedicineWudan YanIndependent ScholarAtif ZafarUniversity of Iowa Hospitals and ClinicsMuhammad Junaid Uddin ZaheerAga Khan University HospitalQuratulain ZamirCombined Military Hospital RawalpindiFerkhanda ZareenArmy Medical College, National University of Sciences and Technology
Introduction
The workings of the human body have mystified people for centuries. The search for answers took a whole new turn when cells were discovered. Cells were first observed in 1665 by Robert Hooke, an English natural philosopher, using a rudimentary microscope. More detailed observations were made a few years later by Anton Van Leeuwenhoek, a Dutch scientist who had handcrafted a more powerful microscope. These seminal observations, which had become possible because of technological progress, ignited a debate all over Europe. This debate culminated in the formulation by Schleiden and Schwann in 1838 of the cell theory that holds that all living organisms are composed of cells, the basic unit of life and, importantly, that all cells arise from other cells.
Thus from the very beginning, progress in cell biology occurred through a combination of advances in technology which enabled novel experiments, and extensive theoretical debates to interpret the experiments. This pattern has repeated itself many times in the last three centuries and countless advances have led to our current wealth of knowledge about biology in general and stem cell biology in particular.
Three hundred and fifty years after the first microscopic observation of cells and 170 years after the formulation of the cell theory, we now understand that while all cells arise from other cells, not all cells are equal. Some cells are terminally differentiated, cannot be divided any further, and are destined for a programmed death; other cells can divide but only give rise to cells that are identical to themselves; and finally, a few cells that we call stem cells have the capacity to give rise either to cells that are identical to themselves or to cells that have acquired new properties. This choice between self-renewal and differentiation is the unique fundamental property of stem cells and is governed by environmental clues.
There are two major types of stem cells, embryonic stem cells which are pluripotent stem cells and adult stem cells. Embryonic stem cells exist only transiently during development. Their function is to produce all of the cells that compose an adult organism. Adult stem cells reside in permanence in many organs. Their functions are to maintain homeostasis by replacing dying cells lost by normal wear and tear and to repair damages caused by injuries.
The derivation of mouse embryonic stem cells in England in 1981 ushered in a new era in experimental biology. In combination with advances in molecular biology methods, the availability of these cells has allowed researchers to engineer mice carrying mutations with a very high degree of precision. In the last 30 years, the novel ability to modify the genetic material of mammals has led to considerable progress in our understanding of the biology of higher organisms. In the United States in 1998, methods were developed to culture human embryonic stem cells that were harvested from very young, 4 to 5 day old, embryos that were left-over from in vitro fertilization. This important milestone has raised considerable hopes in the general public and in the press that a cure for many debilitating diseases might finally be at hand, but has also generated a firestorm of ethical and religious concerns because embryos had to be destroyed to derive these cells, and because these novel technologies give biologists unprecedented power over living organisms, including their own species.
In the last 10 years, further technological progress has yielded another great leap forward for stem cell biology. Researchers in Scotland demonstrated that cellular differentiation in mammals could be reversed experimentally by injecting the nucleus of fully mature adult cells into an ovocyte. These experiments resulted in the birth of Dolly the sheep, the first cloned mammal. This important work demonstrated that the genetic material of an adult mature cell could be induced to return to a pluripotent stem cell form if the DNA was placed in the appropriate environment. Since this report, many clones have been produced including some for commercial purpose in the bovine industry.
Even more recently, two Japanese researchers were able to genetically reprogram mature adult cells into cells which are virtually identical to embryonic stem cells by introducing into their genomes a few well-chosen genes. The remarkable production of induced pluripotent stem cells has raised the hopes of therapeutic fallout from stem cell research to new heights because this method can potentially be used to create custom stem cells for each patient. If researchers can learn how to transform custom induced-pluripotent stem cells into therapeutically useful cells, cellular therapy based on transplantation would be greatly facilitated because the therapeutic cells would be perfectly matched to the recipient, eliminating the need to search for compatible donors and greatly decreasing the potential for transplant complication. In addition, therapies based on such cells might be less controversial because the production of induced-pluripotent stem cells does not require the use of any embryos.
How Far Are We From the First Therapeutic Applications of Stem Cell Research?
Both pluripotent and adult stem cells hold considerable promise for the treatment and prevention of human diseases. The realization of these promises will require a constant dialog between clinicians, translational and basic scientists. Adult stem cells have been in clinical use for over 40 years. One of the most successful therapeutic uses of adult stem cells is hematopoietic stem cell transplantation which is an effective way to treat a variety of leukemias and other disorders and is starting to be used in conjunction with gene therapy to cure a number of inherited diseases. However, the use of hematopoietic stem cell transplant is limited to only the most severe diseases by a shortage of donors and by the risks associated with the transplant procedures. A better understanding of the basic biology of stem cells is necessary to develop new culture and amplification methods that will eliminate the shortage. Generally, the intimate details of the biology of all stem cells found during development and in adults are progressively being deciphered by scientists all over the world. This massive effort will eventually yield a wealth of therapies for many ailments from the most benign to the most severe.
Pluripotent stem cells hold a special place in stem cell biology because they are the source of all other cells; there are great hopes that it will eventually be possible to produce many cell types, including adult stem cells, that will be used in a wide range of therapies derived from pluripotent stem cells. Biology and pharmacology are experimental sciences which require access to experimental samples. Studies of human biology during development and in adulthood have long been hampered by the difficulties in obtaining experimental cells. In addition to potential transplantation applications, pluripotent stem cells are extremely useful as an unlimited, reproducible source of human cells that can be used experimentally to better understand the biology of many inherited and acquired diseases and to test and screen for new drugs using highly purified human target cells. These novel experimental models that can complement studies in animals are likely to speed up the development of novel diagnostic and prognostic tools, and of novel drugs and other therapeutic agents.
Differentiation
