Chemistry: molecular biology and microbiology – Apparatus – Including measuring or testing
Patent
1996-10-03
1998-11-24
Sisson, Bradley L.
Chemistry: molecular biology and microbiology
Apparatus
Including measuring or testing
435 912, 4352866, 4352867, 422102, 422105, 422109, C12M 100, C12M 302, B01L 300, G05D 2300
Patent
active
058405739
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to a molecular analyzer and method of use that enables specific molecules in a liquid sample, or specific parts of molecules in a liquid sample, to be rapidly and accurately detected. The molecules may be present as independent entities in solution or as part of molecular complexes associated by weak or by covalent bonds. In the case of biopolymers, the element detected may be restricted to a unique physical configuration such as an epitope on a protein or a particular sequence of nucleotide bases in a larger RNA or DNA molecule.
There is a widespread need by scientists and technical workers to have means for safely carrying out experiments that employ substances which may be radioactive, carcinogenic, corrosive, toxic or infectious. Diagnostic tests using blood or laboratory experiments employing biologically active compounds or radioisotopes carry a risk of contamination of the environment and harm to personnel, particularly if these tests or experiments involve manual manipulations of samples. Other risks of contamination arise when the products of a chemical or enzymatic reaction are themselves deleterious. An example of such is the polymerase chain reaction ("PCR"), which permits the amplification a specific nucleic acid sequence many million-fold. If traces of the amplified product from one experiment escape into the environment, they may contaminate a second PCR experiment, and serving as a template for amplification, falsely indicate the presence of the original nucleic acid sequence in the second sample. Contamination by even a single molecule of amplified product from one experiment is sufficient to generate a false-positive signal in another experiment. The present invention is described primarily in terms of embodiments adapted to carry out PCR, but those of skill in the art will recognize that the present invention is equally applicable to other chemical reactions or means of analyses.
Use of PCR for the detection of Human Immunodeficiency Virus-1 ("HIV"), the causative agent of Acquired Immune Deficiency Syndrome ("AIDS"), has provided a means for detecting small numbers of HIV nucleic acid molecules in blood. Similarly, accurate detection of minute amounts of other pathogens is possible using PCR. However, even though it is well-known that PCR tests provide for a direct detection of pathogens and are potentially more sensitive than other methods that are based on screening for surrogate markers, PCR is not in widespread clinical use at present. This is due to the higher cost of testing using PCR and the practical difficulties of preventing contamination of the testing facility. Thus, PCR has not been used by Blood Banks to protect the blood supply from HIV or other pathogens and has not been routinely used in the clinical diagnostic, biotechnological, pharmaceutical or food industries where its sensitivity would confer greater benefits than tests currently being used.
PCR is a process for amplifying and detecting any target nucleic acid sequence if it is present in a test sample. In general, it is carried out as follows. A test sample that may contain target double-stranded DNA is first heated to separate the two complementary strands that make up the DNA double helix. Each separated DNA strand becomes a template for making a mirror-image of copy itself. The DNA solution is then cooled in the presence of short complimentary DNA strands and DNA polymerase, an enzyme that extends the DNA strands until a new mirror-image copy is made of the original template, and two new double helix DNA molecules are generated.
If the solution is heated again to melting temperature, the strands of the two newly-formed DNA molecules separate to become four template strands. Further cycling of the reaction mixture exponentially increases the number of DNA molecules. After thermal cycling, the molecules of amplified DNA are detected by any of a number of laboratory methods known to those of skill in the art.
PCR as described by Mullis in U.S. Pat. No. 4,6
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Haley, Jr. James F.
Sisson Bradley L.
Weissman Jennifer T.
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