Chemistry: analytical and immunological testing – Automated chemical analysis – With conveyance of sample along a test line in a container...
Reissue Patent
1998-03-11
2001-12-25
Soderquist, Arlen (Department: 1743)
Chemistry: analytical and immunological testing
Automated chemical analysis
With conveyance of sample along a test line in a container...
C250S281000, C250S282000, C250S286000, C250S288000, C250S289000, C250S442110, C436S173000, C436S181000
Reissue Patent
active
RE037485
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to mass spectrometer systems useful for obtaining matrix-assisted laser desorption measurements. More particularly, this invention is directed to an automated mass spectrometer system for combining high sample throughput with high reliability.
BACKGROUND OF THE INVENTION
Matrix-assisted laser desorption and ionization (MALDI) is a relatively new technique that allows very large molecules, such as DNA fragments and proteins, to be desorbed from a solid sample and ionized without significant decomposition. Coupled with mass spectrometry, this technique allows the molecular weights of biological polymers and other large molecules, including industrial polymers, to be precisely determined. One version of MALDI is described in a 1991 article in Rapid Communications in Mass Spectrometry, Vol 5, Pages 198-202. A mass spectrometer suitable for obtaining highly reliable matrix-assisted laser desorption measurements is described in U.S. Pat. 5,045,694.
Most MALDI applications to date have employed time-of-flight mass spectrometers, although magnetic deflection, Fourier Transform ion cyclotron resonance, and quadrupole ion trap mass analyzers have also been used. A liquid solution of the sample to be analyzed is mixed with a solution containing an appropriate matrix, and a small aliquot of this mixtures is deposited on the source of the mass spectrometer (inside a vacuum system). A vacuum lock is generally utilized to avoid venting the vacuum system. Loading a sample typically requires from one to several minutes, and the attention of a skilled operator. A diligent operator should theoretically be able to load and run a sample every five or ten minutes using such a system, but it is difficult to maintain such a rate over an extended period. U.S. Pat. 5,288,644 discloses one technique for reducing the required time. A plurality of samples are loaded onto the solid surface of a disk, which is rotated by a stepper motor for positioning each sample respectively for striking by a laser beam.
Further improvements in the loading of samples for the laser desorption mass analysis are required for this analytical procedure to gain greater acceptance and significantly increase the use of this analytical tool. The disadvantages of the prior art overcome by the present invention, and an improved system is hereinafter disclosed for obtaining matrix-assisted mass spectrometer measurements. The loading of the samples is highly automated for achieving both high sample throughput and high reliability. The present invention has a wide range of application, and may be used with various analytical methods.
SUMMARY OF THE INVENTION
The present invention provides a highly automated system for preparing, loading, and running samples by MALDI mass spectrometry. Each step in the process may be controlled and monitored by a computer. All sample processing and identification information is recorded along with the mass spectra measurements, so that automated processing of the data may be performed. The typical input to this system is a collection of samples in relatively crude or unprocessed form, and the output provides direct answers to specific questions posed by the scientists relative to the samples. This system is particularly useful in applications that require processing a large number of samples to provide the required data. Examples include DNA sequencing on the scale required by the Human Genome Project, protein sequencing, and determination of the locations and nature of post-translational modifications of proteins. While there are many potential applications of this invention, the Human Genome Project provides a particularly timely example of the need for this advancement. The DNA that composes the human genome has about 3.5 billion base pairs. Although highly developed techniques for sequencing DNA has been developed, at least a decade would be required using available techniques to accurately sequence even one such DNA. Completion of the genome project will require sequencing thousands or possibly millions of such genomes from both humans and other oganisms. The present invention will accordingly be described in detail below with particular emphasis on its application to DNA sequencing, but it should be recognized that it has other applications.
It is an object of this invention to provide improved equipment and techniques for performing MALDI mass spectrometry analysis. The equipment and techniques of this invention substantially reduce both the time and expertise required to load, run, and analyze multiple samples, thereby significantly reducing the cost of the analysis.
A significant feature of this invention relates to the effective combination of mass spectrometry equipment and techniques with matrix-assisted laser desorption ionization equipment and techniques. The equipment and techniques may be utilized to substantially reduce the cost of DNA sequencing. The invention may also be used for determining the molecular weight of various large molecules, such as biological and industrial polymers.
A significant advantage of this invention relates to the reduced time required for mass spectrometry analysis of multiple samples. The invention is particularly well suited for use with a time-of-flight mass spectrometer.
These and further objects, features, and advantages of the present invention will become apparent from the following detailed description, wherein reference is made to the figures in the accompanying drawings.
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PerSeptive Biosystems Inc.
Soderquist Arlen
Testa Hurwitz & Thibeault LLP
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