At least one U.S. government program is coming in ahead ofschedule.

In announcing the second five-year plan for the U.S. HumanGenome Project last week, director Francis S. Collins declaredthat the initiative is progressing so well that "we had to startthinking about our next steps much sooner than we hadoriginally expected."

Collins spelled out those steps in "A New Five-Year Plan for theU.S. Human Genome Project" in last week's issue of Science. Thisprojection redefines and extends the program's goals throughSeptember 1998 (see sidebar).

The U.S. effort, undertaken jointly by the National Institutes ofHealth (NIH) and the Department of Energy (DOE), joins aninternational 15-year push to sequence all 3 billion base pairsof the human DNA complement by the year 2005.

"Thanks to advances in technology and a tightly focused effort,the project is on track with respect to its initial five-yeargoals," the paper stated. These technological improvements"that could not have been anticipated in 1990 have in someareas changed the scope of the project and allowed moreambitious approaches." High on the list of innovations isincreased emphasis on gene identification in the mapsproduced.

Since its inception, the project's first priority has been todevelop genetic linkage maps of the human genome and ofseveral animal models: mouse, yeast, roundworm, E coli. Thispart of the program is ahead of schedule and under budget.

Among its technological advances, the genome mappers havenow produced their first 1 million base pairs of contiguous DNAsequence ("contigs") at a cost much lower than that of threeyears ago.

But not all aspects of the undertaking are ahead of the curve.

Its physical map, "if not ahead of schedule is at least on target,"but "the resolution of these maps is less than ideal," the Sciencereport conceded. Its markers are spaced every 300 kilobaseson average instead of the original 100-kb target set for 1995.

While mapping is ahead of schedule, sequencing lags, althoughits speed has gone up lately and cost per base pair has gonedown. To meet its year 2005 deadline, sequencing speed mustrise 100-fold, Collins asserted. "The roadblock in sequencing isnow money," he said.

At least one cynical observer has been heard to mutter, "Moneyis not everything in the Human Genome Project; the other 1percent is new technology." As originally launched four yearsago, the U.S. share of the 15-year international undertakingwas penciled in at $200 million a year, adjusted for inflation, tobe shared by NIH and DOE.

Reality has cut this wishful budgeting back to an average$167.7 million appropriated in each year from 1991 through1993. Projected needs to complete the first five-year planamount to $246.8 million for 1994 and $259.9 million for 1995."This funding level has not yet been achieved," the papernoted.

Inflation-buffering increases did not materialize, and Collinssaid ruefully, "We are now being asked to do the project at 60percent of the funding that the National Research Council said itshould cost. In consequence, "the revolutionary sequencingtechniques envisioned earlier simply have not materialized."Unless moneys come through to bring the funding level backup to $200 million a year in the future, Collins predicted, "theconsequences would be grim, both in terms of delayed medicalbenefits and the loss of U.S biotechnology competitiveness."

As initially designed in the time of is first director, JamesWatson of double-helix fame, the Human Genome Project aimedat nothing less than sequencing the entire suite of DNA in all 46human chromosomes. But isolating individual genes of medicalinterest was outside its purview.

Collins' new blueprint for the second five years said that"Identification of all the genes in the human genome I is animplicit part of the human genome project. ... Progress inmapping and in technology now makes it desirable to do so." Henoted, moreover, that "the genome project has already had aprofound impact on biomedical research, as evidenced by theisolation of a number of genes associated with importantdiseases," such as Huntington's, amyotrophic lateral sclerosis(Lou Gehrig's disease), neurofibromatosis and fragile Xsyndrome.

A Science editorial pointed out that while Collins was at theUniversity of Michigan, he had a scientific hand in identifyingthe Huntington's and neurofibromatosis genes, as well as thegene for cystic fibrosis. One condition on which Collins agreedto head the Genome Project was continuing his medical generesearch, now centered on predisposition to breast and ovariancancer.

But gene mapper Leroy Hood, who heads molecularbiotechnology at the University of Washington, Seattle,demurred on adding medical gene hunting. "There is simply notenough money to go around," he told Science.

In announcing the new plan, Collins asserted that the privateR&D sector "probably more than we know about" is busypartially sequencing all the expressed genes or cDNAs. "Pendinga decision of the patentability of these gene fragments," he toldScience, "most of the sequences are being kept secret, and thegenes are not being put on the (Human Genome) map."

Collins and his co-author, David Galas, former head of the DOEhuman genome program, concluded by saying that "excitingyears lie ahead as the Human Genome Project moves toward itssecond set of five-year goals."


The Human Genome Project's 11-point target for fiscal 1993-98adds new objectives to the original goals set in 1990. Here aresalient excerpts of these add-ons:

1. Genetic Map: Complete the 2.5 centimorgan map by 1995, itsoriginal time target, thanks to new types of DNA markers suchas PCR-amplified micro-satellites.

2. Physical Map: Complete a sequence-tagged site (STS) map ofthe human genome at 100kb resolution, within the next two orthree years, thanks to new large-capacity cloning vectors.

3. DNA Sequencing: Develop technologically novel approaches tosequencing 1-2 megabase regions of DNA of high biologicalinterest, at original cost estimate of 50 cents per base pair orbetter. Build up capacity to reach an aggregate of 80Mb of DNAby the end of fiscal 1998.

4. Gene Identification: Develop efficient methods for placinggenes on physical maps or sequenced DNA.

5. Technology Development: Develop innovative technologies tosequence from 1 million to several million bp of DNA regions ofhigh biological interest.

6. Model Organisms: Finish STS map of mouse genome at 300kbresolution. Finish E. coli and S. cerevisiae sequences by 1998 orearlier.

7. Informatics: Continue to create data bases and data basetools for easy access to data.

8. ELSI (Ethical, Legal and Social Implications): Develop anddisseminate policy options regarding genetic testing services,notably "privacy of genetic information," its safe and effectiveclinical introduction and fairness in use.

9. Training: Continue to encourage the training of scientists ininterdisciplinary sciences related to genome research.

10. Technology Transfer: Encourage and enhance PP into and outof -- genome research centers.

11. Outreach: Cooperate with those who would establishdistribution centers for genome materials, sharing allinformation and materials within six months of theirdevelopment.

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.