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 Examination

The first step in any treatment process is the examination of the patient, including the individual's medical history, personal functional and structural baseline, and current complaints. In classical medicine, interview and observation have long been the cornerstone of examination. In ancient times this was limited to obvious manifestations and simple constellations of observables, such as the Hippocratic facies, the four signs of inflammation noted by Celsus, or pulse rate and fever. Clinicians recognize that the traditional taking and interpreting of oral medical histories from new patients is a subtle and complex art,2235 although some aspects of this process might be automated using voice recognition and text preinterpretation software, somewhat easing the physician's burden.

Advancing technology has also brought a plethora of tests that contribute to accurate diagnosis, including auscultation, microscopy and clinical bacteriology in the 19th century, and radiological scanning, clinical biochemistry, genetic testing, and minimally invasive exploratory surgery in the 20th century.2694

In the 21st century, new tools for nanomedical testing and observation (Chapter 18) will include clinical in vivo cytography; real-time whole-body microbiotic surveys; immediate access to laboratory-quality data on the patient (e.g. blood tests such as blood counts, dissolved gases and solutes, vitamin and ion assays); physiological function and challenge tests; tissue composition including direct organelle counts in specified tissue populations; quantitative flowcharts of in cyto secondary messenger molecules, extracellular hormones and neuropeptides; per-compartment cytoglucose inventories; and so forth. Before a proper diagnosis can be made, the physician must also establish the patient's personal functional and structural baseline against which any deviations can be noted and corrected, in keeping with the volitional normative model of disease (Section 1.2.2).

The capabilities of nanomedical testing are explored at length in Chapter 18. By way of introduction, it is instructive to think about a trivial class of test procedures that might be used to diagnose a simple infectious disease at several different levels of technological competence. Let us consider a patient who presents with signs and symptoms that are nonspecific in nature but which suggest an infectious process -- e.g. nasal congestion, mild fever, discomfort and cough. The initial signs are due in part to the body's inflammatory response and in part to the infectious agent itself. The diagnostic goal is to identify the infectious agent.

In the late 20th century, the usual procedure would be to culture a sample taken from the patient, in the microbiology laboratory, using various broths, petri plates, and biochemical tests. Some infectious agents are easy to demonstrate. Beta hemolytic streptococci from a throat swab will grow overnight on a blood agar plate, and colony counts for E. coli in a urine sample are available in 24 hours. A throat culture that the lab reports as a mixed culture causes no excitement, and a single isolate of Staphylococcus epidermidis in a blood culture is usually regarded as a skin contaminant.

Moving up to a higher level of technological competence, biotechnologists describe an ideal diagnostic scenario which takes a molecular approach to the diagnosis of infectious disease using recombinant DNA technology. This approach was not yet possible in 1996 when first suggested,2233 but was regarded as a reasonable and likely future application* of biotechnology in the early 21st century given rapid progress in single-molecule DNA assay techniques:2682

"A patient presents in the clinic with mild fever, nasal congestion, discomfort, and cough. A swab of his throat is taken. Instead of culture to identify abnormal microorganisms by their pattern of growth, the sample is analyzed by recombinant DNA techniques. The cotton throat swab is mixed with a cocktail of DNA probes. Enzymes that digest and release the DNA from both host cells and invading bacteria make the DNA in the sample immediately available for hybridization to the probes. The swab is swirled in the liquid mix of the prepackaged test kit for 1 minute. The liquid is then poured through a column that separates hybridized DNA molecules (bacterial target DNA sequences bound to probe DNA) from all other debris [taking several minutes]. A chemiluminescence detection system for the probes shows two of several possible colors indicating mixed infection. The diagnostic result, available in 10 minutes, indicates a Rhinovirus of a strain known to be epidemic in the geographic area. A significant superinfection with a penicillin-resistant streptococcus is also identified. With a definitive diagnosis, the patient is started on the appropriate antibiotic."

* In 1997, kits were being manufactured in Moscow, Russia, that allowed routine PCR diagnosis of multiple microorganisms in both clinical and agricultural settings [R. Bradbury, personal communication, 1999], and by 1998 PCR detection of bacteria in <10 minutes was well-known.3226

How might nanomedicine handle this test? In the nanomedical era, taking and analyzing microbial samples will be much simpler for the practitioner. Such analysis will be as quick and convenient as the electronic measurement of body temperature using a tympanic thermometer in a late 20th-century clinical office or hospital. As described in Chapter 18, the physician faces the patient and pulls from his pocket a lightweight handheld device resembling a pocket calculator. He unsnaps a self-sterilizing cordless pencil-sized probe from the side of the device and inserts the business end of the probe into the patient's opened mouth in the manner of a tongue depressor. The ramifying probe tip contains billions of nanoscale molecular assay receptors mounted on hundreds of self-guiding retractile stalks. Each receptor is sensitive to one of thousands of specific bacterial membrane or viral capsid ligands (Section 4.2).* An acoustic echolocation transceiver provides gross spatial mapping. The patient says "Ahh," and a few seconds later a three-dimensional color-coded map of the throat area appears on the display panel that is held in the doctor's hand. A bright spot marks the exact location where the first samples are being taken. Underneath the color map scrolls a continuously updated microflora count, listing in the leftmost column the names of the ten most numerous microbial and viral species that have been detected, key biochemical marker codes in the middle column, and measured population counts in the right column. The number counts flip up and down a bit as the physician directs probe stalks to various locations in the pharynx to obtain a representative sampling, with special attention to sores or any signs of exudate. After a few more seconds, the data for two of the bacterial species suddenly highlight in red, indicating the distinctive molecular signatures of specific toxins or pathological variants. One of these two species is a known, and unwelcome, hostile pathogen. The diagnosis is completed, the infectious agent is promptly exterminated (Chapter 19),3233 and a resurvey with the probe several minutes afterwards reveals no evidence of the pathogen.

* Inexpensive biosensor devices capable of detecting salmonella contamination in meat and poultry were already commercially available in 1998.

Last updated on 5 February 2003