worth the added code complexity. Gish also envisioned at this time a centralized search service, wherein all nucleotide sequences from GenBank would be maintained in memory to eliminate I/O bottlenecks—and stored in compressed form to conserve memory—with clients invoking FASTN searches remotely via the Internet. Gish's earliest contributions to BLAST were made while working at the NCBI, starting in July 1989. Even in early prototypes BLAST was typically much faster than FASTA. Gish recognized the potential added benefit in this application of using a DFA for word-hit recognition. He morphed his earlier DFA code into a flexible form that he incorporated into all BLAST search modes. Others of his contributions to BLAST include: the use of compressed nucleotide sequences, both as an efficient storage format and as a rapid, native search format; parallel processing; memory-mapped I/O; the use of sentinel bytes and sentinel words at the start and end of sequences to improve the speed of word-hit extension; the original implementations of BLASTX, TBLASTN and TBLASTX (unpublished); the transparent use of external (plug-in) programs such as seg, xnu, and dust to mask low-complexity regions in query sequences at run time; the NCBI BLAST E-mail Service with optional public key-encrypted communications; the NCBI Experimental BLAST Network Service; the NCBI non-redundant (nr) protein and nucleotide sequence databases, typically updated on a daily basis with all data from GenBank, Swiss-Prot, and the PIR. Gish developed the first BLAST API, which was used in EST annotation and Entrez data production, as well as in the NCBI BLAST version 1.4 application suite (Gish, unpublished). Gish was also the creator of and project manager for the earliest NCBI Dispatcher for distributed services (inspired by CORBA's Object Request Broker). First opened to outside users in December 1989, the NCBI Experimental BLAST Network Service, running the latest BLAST software on SMP hardware against the latest releases of the major sequence databases, quickly established the NCBI as a convenient, one-stop shop for sequence similarity searching. At Washington University in St. Louis, Gish revolutionized similarity searching by developing the first BLAST suite of programs to combine rapid gapped sequence alignment with statistical evaluation methods appropriate for gapped alignment scores. The resulting search programs were significantly more sensitive but only marginally slower than ungapped BLAST, due to novel application of the BLAST dropoff score X during gapped alignment extension. Sensitivity of gapped BLAST was further improved by the novel application of