Nanomedicine, Volume I: Basic Capabilities
© 1999 Robert A. Freitas Jr. All Rights Reserved.
Robert A. Freitas Jr., Nanomedicine, Volume I: Basic Capabilities, Landes Bioscience, Georgetown, TX, 1999
126.96.36.199 20th Century Medicine
The 20th century saw more discoveries and advances in medical science than all previous centuries combined. In this period, medicine became more powerful than ever before as scientists gained knowledge of matters and processes of illness that, at the beginning of the century, were still unknown or mysterious. Unlike the mere palliatives of earlier eras, 20th century physicians could actually cure some diseases, reverse some physical traumas, and save many lives that could not be saved before.
In the first half of the 20th century, the rational scientific paradigm that arose in the 19th century was pursued and extended. Acceptance of the germ theory of infection and the discovery of leukocytes led to the rapid emergence of immunology. This allowed medical scientists to produce protective vaccines and antisera which largely eliminated many diseases that were previously prevalent and dangerous, including whooping cough, measles, and diphtheria -- the first truly effective medical treatments (Figure 1.2). Acceptance of the germ theory also led to the discovery of filterable viruses (organisms that could pass through the pores of all known filters) in the 1890s, and subsequently to the identification of viruses as specific causes of yellow fever, smallpox, typhus (a Rickettsia organism), measles, poliomyelitis, rabies, and viral meningitis. Biochemists synthesized vitamins which were recognized as essential constituents of a healthy diet, thus allowing the elimination of vitamin deficiency diseases such as scurvy, rickets, osteomalacia, beriberi, pellagra, xerophthalmia, nyctalopia, and pernicious anemia, via dietary supplements. Many metabolic diseases became treatable due to biochemical investigations; for example, the discovery of insulin in 1921 by the Canadian physiologists Sir Frederick Banting (1891-1941) and Charles Best (1899-1978) rapidly transformed diabetes from an invariably and often rapidly fatal disease into one that could be at least partially controlled, allowing sufferers many years of good life.
Blood group specification made transfusions convenient, facilitating dramatic advances in many branches of medicine,especially surgery. The first report of a successful autotransplant of a kidney into the neck of a dog was performed by Emerich Ullmann (1861-1937) in 1902. The first successful kidney graft between identical twins was performed in 1954 by Joseph E. Murray (b. 1919), who received a Nobel Prize for his work. The first heart transplantation in man was achieved by Christiaan Barnard (b. 1922) in 1967. Results were poor at first, but the use of new anti-rejection techniques such as the drug cyclosporin in the late 1970s, aided by advances in immunology, greatly improved the success of this and other organ transplants. By 1987, a total of ~7000 human hearts had been transplanted. At the close of the 20th century, heart, lung, heart-lung, and liver transplants were standard procedures, while grafts of small intestine and pancreas (the latter for refractory diabetes) were under active clinical investigation.
Two pivotal events transformed scientific medicine from a merely rational basis to a molecular basis, thus laying the groundwork for 21st century nanomedicine. The first pivotal event was the drug revolution, among which the most useful and spectacular were the antibiotics introduced between 1935-1945 and widely used ever since. Antibiotics are significant because they actively interfere with microbial metabolism and growth at the molecular level. The first antibiotic drugs were the sulphonamides, in 1935. Then penicillin became available in the 1940s, initially in very small quantities, then mass-produced by Pfizer during and after World War II, as a result of the research work of Alexander Fleming (1888-1955), Howard Florey (1898-1968) and Ernst Chain (1906-1979). In 1943, Selman A. Waksman (1888-1973) discovered streptomycin, the first effective anti-tuberculosis drug, for which he received the 1952 Nobel Prize. For the first time, physicians had true cures for many diseases,especially the most common bacterial diseases. Antifungal, anti-parasitic, and antiviral drugs of more limited effectiveness soon followed.
The 20th century also produced drugs that altered mood and levels of consciousness. Barbiturates were first introduced in 1903 (e.g. barbitone or Veronal), followed by phenobarbitone (Luminal) in 1912 and Evipan, the barbiturate anesthetic, in 1932. By mid-century these highly addictive drugs began to be replaced by the somewhat less-addictive benzodiazepines, including Valium and Librium. Tranquilizers, largely the phenothiazines such as chlorpromazine (Thorazine) and antimanics such as lithium carbonate, came to be widely used in psychiatry as effective medications for major mental illnesses including schizophrenia and manic depression.
The second pivotal event was the genetics revolution, starting with the discovery in 1953 of the information-carrying double-helix structure of DNA by Francis Crick (b. 1916) and James D. Watson (b. 1928),2974-2975 followed in the 1980s by the ability to chemically read the genetic code, isolate specific genes and clone them for further study. In the mid-1980s, the Human Genome Project (Chapter 20) was launched, with the objective of fully sequencing every gene in the human genome. The first phase of this project neared completion as the 20th century drew to a close.2322
Molecular biology became the premier scientific discipline of the latter 20th century.2217 By 1998, the compositions of organs, tissues, cells, organelles, and membranes had been defined, and the biosynthesis and catabolism of hundreds of compounds had been elucidated. The regulation of body processes was described at progressively finer levels in biochemical language. Many pharmacologic agents were finally understood in terms of specific molecular loci and mechanisms of action. Advances were particularly rapid inimmunology, virology, cellular biology, peptide research, and structural biology. A beginning was made in explaining human behavior in mechanistic terms, as more and more chemical mediators and pharmacologic modifiers were discovered. In biology, these disciplines developed porous boundaries with related disciplines such as physiology, pharmacology, neurosciences, biochemistry and biophysics. All entered a phase of confluence, employing the common language of chemistry.
Thus the late 20th century is best regarded as the molecular age of basic biological science.2207 The molecular influence pervades all the traditional disciplines underlying clinical medicine. As of February 1999, one source2998 listed exactly 1446 genetic disorders, most of which could be linked to a specific human chromosome; another source2999 stated that ~4000 genetic disorders were known in 1998. There were more than 575 known abnormal human hemoglobins, and for each of these the precise structural defect in the DNA of the mutant gene could be defined. Knowledge of membrane, cytoplasmic, and nuclear receptors for hormones and drugs was exploding, with old as well as new diseases being defined in terms of receptor abnormalities -- for example, type II hyper-cholesterolemia and nephrogenic diabetes insipidus. Recognition of opiate receptors led to the discovery of endogenous peptides (endorphins) with analgesic activity. Their localization promised further understanding of the limbic system, affective states, and addictions. Defects in a subcellular organelle, the peroxisome, were known to be responsible for a growing list of important genetic afflictions such as Refsum disease, Zellweger syndrome, and X-linked adrenoleukodystrophy. The genetic defect responsible for Huntington's disease was discovered, and in the 1990s the genetic defects responsible for many other important neurological disorders were becoming known, including forms of Alzheimer's disease, Charcot-Marie-Tooth disease, and common blinding retinal degenerative disorders such as retinitis pigmentosa, Leber's hereditary optic neuropathy, Norrie's disease, and choroideremia.2218
DNA sequencing techniques and restriction endonucleases permitted precise identification of the exact structural alteration of the gene in an increasing number of hereditary diseases. For example, Burkitt's lymphoma is characterized by a translocation of the distal end of the long arm of chromosome 8 to loci on chromosomes 14, 22, or 2.2219 Gene therapy -- both pharmacologic modification of specific gene action and physical replacement of damaged genetic segments -- became possible in experimental systems. Complete maps of the entire genomes of 18 microbial species had been compiled and published by the end of 1998, with more than 60 others in progress.2345 In 1992, wrote the conservative Cecil Textbook of Medicine:2207 "The expansion of the knowledge bank of the past quarter century justifies great optimism for the eventual control and cure of major diseases and the possible elimination of premature death from illness."
Global changes in progressive aging dysfunction were shown to be strongly related to declining secretion of growth hormone by Rudman2976 in 1990. Shortly thereafter, anti-aging medicine was recognized as a distinct discipline and was promoted by the American Academy of Anti-Aging Medicine (A4M), a group2981 that claimed >6000 physician and scientist members worldwide by 1998 and had held numerous conferences.2977 In a book on the subject,2979 Ronald Klatz,2978-2980 A4M's president, first comprehensively documented the implications of Rudman's work.
While biological science was vaulting forward into the molecular realm at a blistering pace, biomedical engineering lagged considerably behind, though many remarkable successes had been achieved since mid-century. Radiology expanded with sophisticated radiotherapy, ultrasound, scanning and imaging techniques (e.g., CAT, PET, NMR), with submillimeter resolution in living tissues. Surgical instruments became less damaging and less invasive; minimally invasive techniques used OK (orifice and keyhole) surgery and surgery performed under the "eye" of a scan. Fetuses could be screened for abnormality and surgery then performed upon them inside the womb, or they could be removed temporarily from the womb and then returned to continue gestating, after surgery. Prospective parents with fertility difficulties could make use of a wide range of therapies including in vitro fertilization. Implantable pacemakers, defibrillators, and ventricular assist devices were commonplace, and in 1998 artificial wearable/implantable and full/partial replacements for lungs, heart, kidney, liver, and pancreas were either available, in clinical trials, or under development (Volume III). Electron microscopes with 200,000X magnifications allowed many details of internal cellular and viral structures to be resolved as early as 1946; by 1998, atomic-force (AFM) and scanning-tunneling microscopy (STM) permitted direct tactile examination of individual biomolecules in fixed cells.
As the 20th century drew to a close, a few preliminary efforts had been made to apply the molecular approach to medical diagnostic and clinical tools. Biotechnology was one avenue being pursued, with the rational design of artificial enzymes and specified-ligand binding sites having already been achieved in certain limited cases, and the beginnings of gene therapy as noted earlier. Carbon fullerenes (Section 2.3.2) had been used to create a water-soluble inhibitor of HIV protease,2633,2634 and had other biological applications.2642 AFM-based force-amplified biological sensors2313 could detect defined biological species such as cells, proteins, toxins, and DNA at concentrations as low as 10-18 M (~1/mm3), and automated laboratory systems for sorting and handling individual cells2314 and viruses3219 were commonplace. Biotech companies such as Physiome Sciences of Princeton NJ had developed three-dimensional computer models of the heart and other organs. Physiome's heart model was based on detailed molecular, biochemical, cellular and anatomical information, including submodels of all the different cell types found in the heart embodying knowledge of the function of each cell type in healthy and diseased hearts, and information on gene function and the causes and effects of congestive heart failure, arrhythmias and heart attacks. Other cell biochemistry simulators included E-CELL (http://www.e-cell.org) and the Virtual Cell (http://www.nrcam.uchc.edu).3199 There was also much progress and interest in nanostructure analysis and nanomaterials fabrication for medical and biological purposes, with research groups emerging at major universities such as the Cornell Nanofabrication Facility, theUniversity of Michigan Center for Biologic Nanotechnology, the Rice University Center for Nanoscale Science and Technology, the CalTech Materials and Process Simulation Center, the Washington University Nanotechnology Center (St. Louis, MO), the USC Laboratory for Molecular Robotics, the UCLA Exotic Materials Center, the Institute for Molecular Medicine of the University of Oxford, and at many biotechnology-oriented corporations such as Nanogen and Affymetrix.
However, the greatest medical revolution of all awaits the ability to engineer and fabricate whole devices and systems at the molecular scale. Along this course lies nanotechnology and molecular manufacturing, a deep well from which nanomedicine will inevitably spring.
Last updated on 31 July 2011