Molecular Dynamics Inc.

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Molecular Dynamics Inc. (MDI) was founded in July 1987 by Bala Manian, Jim Schlater, Jay Flatley, and Rick Johnston to develop life science products.  The first project developed an instrument to detect proteins in gels by the change in the refractive index.  Only a few systems were sold.

The first successful commercial product was the PhosphorImager SI, launched in 1989, which used storage phosphor as a solid‐state liquid scintillation device to localize and quantify the radioactive decay from a separation gel, e.g., DNA sequencing or protein analysis.  The stored energy in the storage phosphor was ‘read out’ using a laser to produce a digital image which could be quantified with ImageQuant software.  This began the transition from qualitative pictures of gels to quantitative digital imaging with data analysis by software packages.  

In 1990, a confocal imaging microscope product line, was acquired with the purchase of a Swedish company, Sarastro, bringing confocal imaging to Molecular Dynamics.[1]. Later imaging products (FluorImager, Personal Densitometer, Storm, Avalanche, and Typhoon) added the detection of fluorescent labels and confocal scanning.

Capillary Array Electrophoresis[edit]

Molecular Dynamics Inc, working with Dr. Richard Mathies[2] of the University of California Berkeley, began development of a four-color fluorescence 96-capillary array electrophoresis DNA sequencer in 1991 for the Human Genome Project.  The early breadboard work leveraged the Molecular Dynamics expertise in imaging and required the development of a separation gel, the coating of the inside of the 75 um ID capillaries to prevent electroosmotic flow, the injection of a focused ‘plug’ of the sample, four color sequencing separation software, and the reuse of the array of capillaries for hundreds of runs to be economically feasible.

To build a complete product that scientists could use required developing four-color sequencing chemistry to prepare Sanger sequencing products from plasmids or PCR products.  Amersham plc had a license to four-color fluorescent sequencing from Cal Tech[3], dye chemistry, and biochemical kits capabilities including both natural and engineered DNA polymerases for Sanger sequencing.  In 1994, Amersham and Molecular Dynamics partnered to combine their capabilities in the Vistra program to advance DNA sequencing and develop the MegaBACE1000[4].  The MegaBACE1000 project development was managed by Dr. Dennis Harris (on secondment from Amersham) with Dr. John Bashkin leading the scientific development.  By 1995, five ‘shippable breadboard’ 48 capillary systems were built and shipped to early customers for beta testing for DNA sequencing and genotyping.

The MegaBACE was launched in 1997 as a commercial product as the MegaBACE® 1000, using dye primer chemistry with read lengths of about 550 bases with a two hour run time to sequence 96 samples[5].  In 1998, energy transfer dye terminations, invented in the Mathies laboratory[6], were commercialized and subsequently became the dominant chemistry on the MegaBACE and all competing systems.  With funding from the Advanced Development Programs of NHGRI[7], a 384-capillary version was developed and later commercialized as the MegaBACE 4000.  Upgrades to the separation polymer and higher operating temperatures allowed the follow-on MegaBACE 4500 to achieve readlengths over 1,100 bases. The MegaBACE system was also used for fragment analysis including STRs[8].

DNA microarrays[edit]

In 1996, Molecular Dynamics developed a prototype DNA microarray spotter and microarray reader to miniaturize gene expression analysis.  The spotter used a three-axis robot and miniaturized ‘spotter pens’ that deposited 200 um spots of PCR-amplified DNA fragments onto microscope slides with silanized coatings.  The first systems could deposit 9,600 spots on a slide from ten 96 well plates allowing the analysis of the gene expression of 9,600 different loci.  The microarray scanner was a galvanometer-based scanner with two PMTs that could scan a slide in two colors about five min.

To determine the gene expression in a sample, the sample was lysed and the RNA extracted.  The RNA was then reverse transcribed into cDNA with incorporation of a Cy3 or Cy5 label.  The gene expression difference between two conditions, such as diseased and normal tissue, could be compared by labeling one sample with Cy3 and the other with Cy5.  The pooled cDNA was then hybridized to the spotted array.  The data was analyzed by ImageQuant software which identified the edge of each spot and determined the ratio between the two colors, Cy3 and Cy5.

The microarray scanner, spotter, software and reagents were distributed through the Microarray Technology Access Program until commercial release of the scanner as the Avalanche scanner, followed by the Lucidea line of spotters and scanners.

Microfluidic sample preparation and sequencing and genotyping on microchips[edit]

In 1994, Molecular Dynamics Inc. and Affymetrix were awarded a $31 m NIST Advanced Technology Program (ATP) grant to create miniaturized integrated DNA diagnostic systems using their respective sequencing and microarray technologies on glass microchips[9].  The grant lead to the development the development of the MegaBACE sequencer and the Affymetrix GeneChip microarray system.  The development of high throughput DNA sequencing and gene expression microarrays was the birth of genomics.  However, the vision of the handheld system was not achieved.

As the MegaBACE was developed, the sample preparation was a critical element for customers.  To achieve a lower reagent cost system, miniaturized sample preparation was explored.  A flowthrough sample preparation system was developed using small boluses of samples separated by immiscible fluids inside capillaries with NIH funding[10].  The sample preparation system later was developed as arrays of 96 or 384 capillaries that performed cycle sequencing in 500 nL volumes[11]

Molecular Dynamics, Inc. was a leader in the research of electrophoretic separations on microchips.   The first multi-channel sequencing separation on microchips was achieved wtih readlengths of 450 bp on a 16-channel microchip[12].  An automated microchip DNA analysis system robot that loaded and analyzed 96 samples using a miniaturized DNA sequencer on a microchip[13] was developed with NIH[14] and company funding.

In 1998, Nycomed Amersham plc bought Molecular Dynamics[15] and integrated its product lines under the Amersham Pharmacia Biotech name.

References[edit]

  1. "Image Is Everything". The Scientist Magazine®. Retrieved 2020-08-17.
  2. "Richard A. Mathies | College of Chemistry". chemistry.berkeley.edu. Retrieved 2020-08-17.
  3. Smith, Lloyd M.; Sanders, Jane Z.; Kaiser, Robert J.; Hughes, Peter; Dodd, Chris; Connell, Charles R.; Heiner, Cheryl; Kent, Stephen B. H.; Hood, Leroy E. (June 1986). "Fluorescence detection in automated DNA sequence analysis". Nature. 321 (6071): 674–679. doi:10.1038/321674a0. ISSN 0028-0836.
  4. Bashkin, John; Bartosiewicz, Matt; Roach, David; Leong, J; Barker, David; Johnston, Richard (March–April 1996). "Implementation of a Capillary Array Electrophoresis Instrument". J. Capillary Electrophoresis. 3 (2): 61–68. PMID 9384752.
  5. "The MegaBACE 1000 DNA Sequencing System" (PDF). Unknown parameter |url-status= ignored (help)
  6. Ju, Jingyue; Glazer, Alexander N.; Mathies, Richard A. (February 1996). "Energy transfer primers: A new fluorescence labeling paradigm for DNA sequencing and analysis". Nature Medicine. 2 (2): 246–249. doi:10.1038/nm0296-246. ISSN 1078-8956.
  7. "Project Information - NIH RePORTER - NIH Research Portfolio Online Reporting Tools Expenditures and Results". projectreporter.nih.gov. Retrieved 2020-08-17.
  8. Mansfield, Elaine S.; Robertson, James M.; Vainer, Marina; Isenberg, Alice R.; Frazier, Rachael R.; Ferguson, Karin; Chow, ShiTse; Harris, Dennis W.; Barker, David L.; Gill, Peter D.; Budowle, Bruce (January 1998). "Analysis of multiplexed short tandem repeat (STR) systems using capillary array electrophoresis". Electrophoresis. 19 (1): 101–107. doi:10.1002/elps.1150190118. ISSN 0173-0835.
  9. "Molecular Dynamics Inc. 10-k-annual-report". Unknown parameter |url-status= ignored (help)
  10. "Project Information - NIH RePORTER - NIH Research Portfolio Online Reporting Tools Expenditures and Results". projectreporter.nih.gov. Retrieved 2020-08-17.
  11. Jovanovich, S.B., D. J. Roach, A. G. Hadd, and B. E. R. Hellman.  Low volume chemical and biochemical reaction system. July 23, 2002.  U.S. Patent 6,423,536
  12. Liu, S.; Ren, H.; Gao, Q.; Roach, D. J.; Loder, R. T.; Armstrong, T. M.; Mao, Q.; Blaga, I.; Barker, D. L.; Jovanovich, S. B. (2000-05-02). "Automated parallel DNA sequencing on multiple channel microchips". Proceedings of the National Academy of Sciences. 97 (10): 5369–5374. doi:10.1073/pnas.100113197. ISSN 0027-8424.
  13. Roach, D., R. Loder, T. Armstrong, D. Harris, S. Jovanovich and R. Johnston.  Robotic microchannel bioanalytical instrument.  Sep. 30 2003.  US Patent 6,627,446.
  14. "Automated Microchip DNA Analysis System". www.sbir.gov. Retrieved 2020-08-17.
  15. http://www.prnewswire.com/news-releases/nycomed-amersham---agreement-to-acquire-molecular-dynamics-76126457.html


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