29—
The Telescope and the Genome

Mrs. Marion Hoffman died on Friday, 16 December 1983, a sad event that was to have remarkable consequences.

Not long after I became chancellor at UC Santa Cruz, I was made aware that I also thereby became responsible for the fortunes of Lick Observatory. Lick Observatory was established in the 1880s as the observatory of the University of California as a memorial to James Lick, an eccentric Bay Area millionaire who donated the then considerable sum of one million dollars for this purpose. (A prior notion of Lick had been to build a great pyramid rivaling that of Cheops in what is now downtown San Francisco.) When dedicated in 1888, Lick Observatory was the first major telescope on the West Coast and possessed the largest refracting telescope anywhere. Not long after, it acquired the first Crosley reflecting telescope, which established that reflectors could provide images of quality comparable to that of refractors. Throughout the years, Lick had been a premier observatory although overshadowed by larger instruments in southern California at Mt. Wilson and later Mt. Palomar. After World War II, Lick had obtained funds from the state and built a 120-inch telescope, then one of the largest telescopes in the world.

Originally, Lick had been an autonomous unit of UC. The astronomers had lived in considerable isolation on the top of Mt. Hamilton. With the establishment of the Santa Cruz campus in 1965 and the greatly increased case of transportation, it had been decided that the observatory, while still a UC systemwide facility, should be assigned to

Santa Cruz, and that the astronomers would move off the mountain and teach and have their facilities at Santa Cruz.

But now Lick had a new problem. San Jose, once a small, semirural area, had become the focus of Silicon Valley. With the rapid increase of population came light pollution, harming the visibility, at Mt. Hamilton forty miles away. To escape the glow of light in San Jose, the university was considering the establishment of a new facility about a hundred miles to the south on Junipero Serra Peak, in the Santa Lucia Mountains west of King City. Light pollution was nonexistent in this area and seemed likely to remain so for many decades. Whether the telescopes on Mt. Hamilton could be moved or whether new ones should be built was as yet an unanswered question.

Junipero Serra was on land belonging to the Bureau of Land Management. Surveys had already been made and consideration given as to how a road might be routed into the area and up the mountain. However, a major obstacle had arisen. As the highest peak in the Santa Lucias, Junipero Serra was a sacred mountain to the indigenous Native American tribes. The tribe leaders were vigorously opposed to granting of a permit to build a road and observatory. Attempts to persuade the tribal leaders of the value of the observatory, of the abstract and aesthetic quality of its astronomical uses were futile. Attempts to compromise the intrusion and proposals to minimize construction on the peak and to avoid some road construction by the use of aerial tramways and so forth likewise were bluntly rejected.

Stymied at least for the moment but stimulated by the thought of other telescopes and other sites, another idea began to take form in the minds of the Lick astronomers. If a new telescope were to be built, should they not seek to surpass any existing instrument? The largest effective telescope was the Hale telescope at Mt. Palomar, a two-hundred-inch reflecting mirror. It and its supports and machinery had been designed in the 1920s, when it represented the forefront of the technology of that day. Indeed, all subsequent telescopes, albeit of somewhat lesser size, had been modeled on the Hale telescope design.

Now, a half-century later, could not a more advanced design be conceived? A larger mirror would provide more light-gathering power. This would permit studies of more distant galaxies, out so far that their light began its journey not long after the Big Bang that originated the universe. A ten-meter (four-hundred-inch) telescope, twice the size of Mt. Palomar, would collect four times as much light. But given the laws of geometry, and the need for the mirror to bear its own weight, a ten-

meter telescope based on the Palomar design would weigh eight times as much. The machinery to move the mirror with precision would be correspondingly more massive. It was estimated that a scale-up of the Palomar design to ten meters would cost about five hundred million dollars, if indeed it could be built. A technological breakthrough was needed that would permit the use of a much lighter mirror and correspondingly simpler machinery.

Two approaches were developed. The one at Lick was a single "meniscus" mirror, ten meters in diameter and very thin, whose shape would have to be precisely maintained by its supporting structures. Another approach, by Jerry Nelson at Lawrence-Berkeley Laboratory, was a mirror composed of thirty-six hexagonal sectors, each nearly six feet across, to be maintained in precise register by a series of sensors that monitored the relative positions of the edges of each sector and in turn controlled the position and inclination of each mirror through an integrating computer program. The mirrors themselves were to be formed by a new technique of stressed mirror polishing in which a circular glass blank was first appropriately deformed by peripheral weights and then polished to a spherical figure (a simple task), after which the constraints were removed to allow the blank to relax back to the proper parabolic shape.

By 1980, a decision had to be made if the project were to proceed. A committee of senior astronomers from outside UC was convened to make a recommendation. By a vote of four to three, they opted for the sectional concept. Personally, I was very pleased with this result. The meniscus concept might work, but ten meters, if attainable, was clearly an upper limit for this approach. If a ten-meter sectored telescope could be built and worked well, extension of this concept to even greater size was straightforward.

We now needed a substantial influx of funds to develop the technology to the point at which a full-scale telescope could be built. We also needed to launch a search for the necessary funding, estimated at that time at fifty million dollars, for construction. We took the matter to President David Saxon. A physicist, he immediately grasped the virtue of the proposal and the ingenuity of the concept and supported it in principle. He convened a meeting of the chancellors of the four campuses—Berkeley, Los Angeles, San Diego, and Santa Cruz—with interests in astronomy to discuss the proposition. Opinion among the chancellors was certainly not unanimous. I was the most vigorous advocate; Mike Heyman, then new at Berkeley, was supportive; Chuck

Young at UCLA was neutral or perhaps moderately disinclined; Atkinson of San Diego was clearly opposed, given the other needs for funds as he saw them.

After strong argument and with unconcealed but not leading support from Saxon, this group agreed to proceed with the project. Saxon would find funds, about one million dollars a year, to carry the design process forward. A seven-member executive committee comprising chancellors or their representatives from the four campuses, the Lick director, the LBL director, a representative of the user-astronomers, and the vice-president for academic affairs would oversee the operation and a search would begin for the needed funding. At the end of the initial meeting, Saxon recalled how in the midst of the Depression President Sproul had managed to devote one million dollars of university funds to E. O. Lawrence to build his early cyclotron, to the university's and the nation's everlasting benefit. Saxon indicated that he thought this to be an analogous prospect.

The search for funds took the form of seeking a single large donor who would be intrigued by the project and wanted a personal memorial. Eugene Trefethen, a loyal Berkeley alumnus and former vice-president of Kaiser Industries, a man well acquainted among the ultra-wealthy, agreed to seek to find such a donor either in the United States or abroad, specifically in Japan or Hong Kong. He thought there were a reasonable number of prospects and felt confident.

The technical development, largely under the supervision of Jerry Nelson at LBL, proceeded more slowly than anticipated but systematically and without encountering major difficulties. Costs seemed to escalate, but President Saxon loyally managed to find the funds needed.

The search for the single donor, however, had proven fruitless. Tax laws in Japan diminished the incentive for multimillionaires in that country. Meanwhile, more refined cost estimates had risen to about seventy million dollars.

Discussion of a possible site had fairly quickly settled on Mauna Kea, an extinct volcano on the big island of Hawaii. Three telescopes had already been located on this peak. Light pollution was negligible. At fourteen thousand feet, on an island surrounded by water at uniform temperature, studies of the lower atmospheric turbulence had indicated that the "seeing"—the stability of the optical image of a distant object—was consistently superior. Further, some of the more interesting research in astronomy now revolves the study of light received in the infrared region of the spectrum. Certain portions of the infrared are,

however, absorbed by water vapor in the atmosphere diminishing the light of such wave lengths that can reach the telescope. At fourteen thousand feet, the telescope would be well above most atmospheric water vapor.

Funding of the magnitude needed from California seemed out of the question. Requests for federal funding would lay the project open to the politics of the astronomical community. In general, the National Science Foundation supports centralized facilities for the use of astronomers such as Kitt Peak and Cerro Telolo in Chile. However, the access to such facilities must of necessity be widely shared and thus infrequent. The Lick astronomers emphasized the need for some important studies to be assured of sustained time on the telescope—at least a few nights per month over a period of several months—which could not be had at the national observatories.

Early on in this project, given my long acquaintance with the Caltech astronomers, I had proposed that Caltech be brought into the project to share in the design and the cost. This idea was opposed by the Lick astronomers. They wished to retain full control of the project and they saw the telescope as the means to restore the preeminence of Lick over the Hale observatories. It should be added that the rather proprietary attitude of Caltech and the Carnegie Institute astronomers toward the Palomar facility and their long-standing reluctance to share its use had not endeared them to the astronomical community. At this time, in view of our growing funding problem, I again raised the possibility of a Caltech connection; however, the time was not yet ripe.

On 23 August 1983, Joe Calmes, the assistant to the director of Lick Observatory, received a telephone call from a Mr. Edward Kain in San Jose. Mr. Kain's accountant was Bill Unruh, an astronomy buff who had developed a great interest in the history of astronomy in general and Lick Observatory in particular, and who gave popular lectures on this subject at Lick to summer visitors. While doing Mr. Kain's taxes, Unruh had mentioned the plan for the new telescope and our inability thus far to find an "angel." Mr. Kain had been intrigued by this discussion and had a suggestion of a possible donor, Mrs. Marion Hoffman, Mr. Kain's sister who lived in Los Angeles. Her husband, Max Hoffman, had died two years earlier and Mrs. Hoffman was seeking a unique memorial for him.

We had earlier agreed that if a donor provided half or more of the construction cost (then estimated to be seventy-two million dollars) he or she could name the observatory. It was indicated, therefore, to Mr.

Kain that such a memorial would require a gift of at least thirty-six million dollars. He did not think that such an amount was infeasible. We investigated and found that Max Hoffman had likely left a substantial fortune acquired by his ownership of the import licenses for VW and BMW cars into the United States since 1946.

Through Mr. Kain, Mrs. Hoffman was contacted and the telescope project was explained to her. It developed that her late husband had had a lifelong interest in machinery and technological advancement. The idea of this unique, highly advanced, and novel telescope appealed to her as a potential memorial. The sum required seemed impressive but not daunting. She would have to consult with her accountants and lawyers.

Negotiations with Mrs. Hoffman proceeded rather slowly. We learned that she herself was not well and made repeated visits to a clinic in Cleveland. President Saxon had retired in 1983, and he was replaced by David Gardner, then president of the University of Utah. I had visited Gardner in Salt Lake City, after his selection and had briefed him on the telescope project, in addition to the state of affairs at UC Santa Cruz. Although not a scientist, Gardner recognized the significance of the project and undertook to carry it forward.

Clearly at this stage the president's office had to be brought into the negotiations with Mrs. Hoffman. On 15 December 1983, President Gardner met with Mrs. Hoffman in Los Angeles. Agreement was reached on the size and nature of the gift (to be worth thirty-six million dollars) and the university's commitment with regards to the naming and securing the additional funding. Legal documents were to be drawn up. The next day, Mrs. Hoffman passed away from throat cancer.

The funds had earlier been transferred to a Hoffman Foundation. The three trustees of this foundation were Mrs. Hoffman, Ms. Ursula Niarakis, her longtime secretary, and Mrs. Doris Chaho, her sister. In the event of the death of any one trustee, the remaining two were to select a third. It soon developed that the two remaining trustees had no great affection for each other. They were completely unable to agree on the choice of a third trustee. It also developed that one of the trustees, while grudgingly conceding the intent of Mrs. Hoffman to fund the telescope, was less than enthused about this use of the funds. Matters ended up in probate court in New York and the university did in fact receive cash and title to tangibles worth thirty-six million dollars—the largest single gift in the history of the University of California.

We still needed to raise the additional thirty-six million dollars. In

early 1984, I revived the notion of a partnership with Caltech as the other eminent astronomical center in California. The Lick astronomers were still not enthused, but with the prospect of a wondrous telescope looming, they acquiesced. President Gardner convened a meeting of the four chancellors, which brought general agreement. Chuck Young and I had a lunch meeting with Murph Goldberger, president of Caltech, to explore the idea. He was favorably inclined and agreed to discuss the idea with astronomers and others at Caltech. Further discussion proceeded through President Gardner's office. It was agreed that Caltech would undertake to raise twenty-five million dollars toward the telescope in return for which they would receive a proportionate share of the observing time.

It was in late August that I learned, via Harold Ticho, the UCLA representative on the executive committee, of a startling development. President Goldberger, in seeking to raise the twenty-five million dollars, had solicited several sources for gifts of five million dollars. He had received one such pledge when he received a telephone call from Mr. Howard B. Keck, a Caltech trustee. Mr. Keck's father, William M., had established the Superior Oil Company, which had been sold some years later for several hundreds of millions. A large share of the proceeds had gone to create the Keck Trust, which in turn supported the Keck Foundation of which Howard Kcck was the chairman. Howard Keck proposed that the foundation provide, instead of five million dollars, the entire seventy-two million dollars to make this a Caltech telescope and to be named the William M. Keck Telescope. To Caltech's credit, it was not willing to take UC's design and build its own telescope, but the seventy-two million dollars was irresistible.

But what of the Hoffman estate? A rather ingenious proposal was formulated. Two ten-meter telescopes would be built, one to be named after Keck, the other after Hoffman. The cost for two would be considerably less than twice that of one. Both would be located on Mauna Kea about a hundred yards apart. They could be operated separately, providing twice the observing time, or jointly. In the infrared, they could be operated in an interferometric mode to provide extraordinary resolving power; in the visible region, their output could be pooled, providing no better resolution but twice the light-gathering power.

Ingenious, but unacceptable. The fractious and divided trustees of the Hoffman estate found this idea unacceptable. The telescope would no longer be a unique memorial and they seized on this opportunity to withdraw from the project. UC, with great regret, returned the largest

gift it had ever received. The trustees divided the thirty-six million dollars to create two separate foundations, one for each with eighteen million dollars apiece.

Caltech and UC established a third corporation, CARA (California Astronomical Research Association), with a joint board of directors to oversee the construction of the telescope and its future operations. Caltech was to provide the construction funding, UC to provide operating funds for a period of years until its contribution equaled the construction cost. Thereafter, operating costs would be shared. Observing time would be shared equally and allocated by a joint committee. "First light" was seen in December 1990 and the telescope is now in full operation. Also, plans are underway, with a sizable second grant from the Keck Foundation, for the adjacent second telescope to form the "binocular."

What now would the two Hoffman Foundations do with their eighteen million dollars each? Could either be induced to devote the bulk of this money to a worthy technical or scientific project? The prospect coalesced several ideas in my head, answers to several questions that fit neatly into what has become the Human Genome Project.

As chancellor, I had become at least peripherally involved with several projects of Big Science. Indeed, harking back to Radiation Laboratory days, I had seen the power and progress made possible by the coordinated actions of diverse talents on a large scale, with ample funding. The ten-meter telescope was such a project, although on a relatively modest scale. Several of our astronomers were also involved in the Hubble Telescope project, an enterprise of five hundred million to one billion dollars. At chancellors' meetings we had had frequent discussions of the leading role of the university in the formulation of a proposal by the state to locate the proposed giant accelerator, the superconducting supercollider, a six billion dollar project, within California. Some of the UCSC faculty working in high-energy physics were directly involved.

Biology had no comparable Big Science projects. It was clear that other areas of science—physics, astronomy, space science—were not bashful about seeking relatively large sums of money to support their programs. Big Science, per se, was not a virtue. But were there important areas of biological research that were not being adequately explored because biologists were not thinking on an adequate scale?

The characteristic of Big Science projects in other fields was that they provided a facility that would be essential to further advance in the field. Biology did not seem to need a comparable facility. What biology

needed, however, was a massive information base—a detailed knowledge of the genetic structure of several key organisms, including—for obvious reasons—man.

Mapping of genetic factors had been initiated with drosophila in the early years of the century. Extensive maps had also been developed since World War II for bacteria, yeast, maize, and mice. The first assignment of human genes to chromosomes other than the X became possible in the 1960s; by the mid-1980s, some four to five hundred genes had been so located. With the understanding that genes were composed of DNA and the development through recombinant DNA of the ability to isolate genes and sequence them, an extension of genetic mapping to the molecular level became possible. Some entire viral DNAs, ranging from a few thousand nucleotides to more than 100,000 had been sequenced. Efforts were underway to sequence entire bacterial DNAs (4.5 million base pairs) and the DNA of nematodes (about 80 million base pairs). Sequences of mouse or human DNA (genome 3 × 10⁹ nucleotide pairs) were known only in certain small regions where they had been painstakingly worked out by groups interested in the genes of that region. Each group interested in a particular gene or gene cluster had to develop the appropriate technical expertise to sequence those genes.

What if a project could be undertaken to sequence, once and for all, the entire human genome. This would be Big Science, but the product would be an invaluable resource for all of biology and medicine. Was it feasible? What would it cost? How long would it take? How might it be organized?

Another question concerned the future of UC Santa Cruz. In its early stages, the campus had understandably attempted to develop a competence in the basic fields and disciplines expected of a university. But now with prospects of future growth brightened, the campus had to develop several centers of excellence, to focus a portion of the additional resources that would come with growth in the establishment of selected programs that would merit national and international attention. Naturally, I wanted to see such a center of excellence in biology. Given its significance, an institute for research on the human genome would accomplish this objective Such an institute would be a natural component or a center for the human genome initiative and would insure that UCSC biology would be in the forefront position for many decades.

The establishment of such an institute, however, would require substantial funding. To be on a useful scale, it would require, I estimated,

a building, equipment, and endowments adding up to perhaps twenty-five million dollars. The federal government was a possible source, but I knew that however attractive the concept, NIH or NSF would have to award any sum of this magnitude on a competitive basis, and in such a competition UCSC would never win out against Stanford, MIT, Caltech, Berkeley, and other "heavy hitters." If we had an institute already established, however, the research proposals would surely command support for specific projects from NIH or NSF. But we would need to raise the initial funding from private sources.

The eighteen million dollars now located in each of the Hoffman Foundations beckoned. The boldness and significance of the concept might appeal to one of the trustees. To avoid an unseemly scramble, President Gardner had decreed that any approaches to the Hoffman Foundation must pass through his office. Therefore, on 19 November 1984, I wrote him as follows:

Dear David:

Let me expand a bit on our brief discussion at the regents' meeting on Friday.

If the "Hoffmans" firmly intend to withdraw from the TMT project, then I have another project that we might propose to them. It is an opportunity to play a major role in a historically unique event—the sequencing of the human genome.

A genome is the complete set of DNA instructions for the making of a species The human genome is the complete set of instructions for a human being We know that the haploid human genome is composed of some three billion nucleotide pairs (3 × 10⁹ ). A few months ago, I posed to our biologists the question, Could the human genome now be sequenced, with extant technique, and In a reasonable time (In years)? If so, what scale of effort would be required? (Obviously, I had made a guess as to the answer.)

Their reply is enclosed. It can be done We would need a building in which to house the Institute formed to carry out the project (cost approximately twenty-five million dollars), and we would need an operating budget of some five million dollars per year (in current dollars). Not at all extraordinary.

Clearly, the human genome will be sequenced. It will be done, once and for all time, providing a permanent and priceless addition to our knowledge.

In addition to satisfying our scientific curiosity, this know ledge will provide deep insight into other questions of interest It will have major medical implications: we know that literally thousands of human ailments have genetic bases, in whole or part.

This knowledge will also have highly significant evolutionary implications. The biological differences between Homo sapiens and the chimpanzee are certainly due to the changes and rearrangements in the genomes of each as they have diverged from that of our common ancestor To understand these changes will surely illuminate the ancient human quest to know what we are and where we came from.

The enterprise could be known as the Hoffman Project and, of course, the building could be named the Hoffman Laboratory or Institute. If we had the building and equipment, I feel quite confident we could obtain the operating funds from government and/or private sources.

Needless to say, should the "Hoffmans" not be interested in this project, I will intend to look elsewhere for funding.

I expected David Gardner, too, would be seized by the deep significance of the proposal, but then I'm a biologist and he is not. He wasn't seized. It must have seemed like another in a set of meritorious, costly proposals he was receiving from various parties on various campuses. After a few months it became apparent to me that funds from a Hoffman Foundation were not likely to be forthcoming, if indeed they were ever to be solicited. I would have to look elsewhere. Other sources came to mind—Arnold Beckman, David Packard, Gordon Getty, the Howard Hughes Foundation. Any of these could fund the project, but before I could make such approaches, I needed more certain ground as to the feasibility of the concept.

Until now, I had germinated the ideas in private and in discussion with some of the UCSC biologists—Harry Noller, Bob Edgar, Bob Ludwig. At first dubious, they too had soon been seized with the notion. We decided to convene a small workshop to explore the idea with the people who were most prominent in the sequencing field. As chancellor, I allocated the needed funds and we set the dates for 24–26 May 1985. The membership of the workshop included representatives of the most active sequencing groups, researchers interested in the development of associated automated instrumentation and computer techniques.

The initial mood at the workshop was clearly one of great skepticism about the project. As the various aspects were discussed, it became clear that many elements of the task were indeed feasible and that plausible advances in automation could well make practical the entire sequencing project. When thus pushed to confront the possible reality of such an enterprise, differences of opinion emerged as to its desirability. These were not resolved, but the workshop had changed the question in the minds of the participants from one of feasibility to one of desirability. From can to should.

I prepared the notes and conclusion report, which were sent to the participants and other interested parties. As I said in my letter of 5 June 1985 to Dr. Donald Fredrickson, the president of the Howard Hughes Institute:

Briefly the conclusions were:

(1) A genetic map of the human chromosomes providing well-defined markers (polymorphisms) at reasonable spacings along all of the chromosomes, to use as reference points, could be developed (in collaboration with outside groups) by a group of twenty people in a two- to four-year period.

(2) A physical map of the human chromosomes providing a linearly ordered set of cosmid-size (thirty to forty thousand bases) DNA fragments could similarly be developed by a group of twenty people in two to four years.

(3) A complete nucleotide sequence map of the human chromosomes is not presently feasible with reasonable effort. Sequencing a few percent of the genome around selected markers and in carefully chosen regions is feasible, with a group of some thirty people working over a ten-year period. The availability of such sequences would undoubtedly be of great value At the same time, it is quite reasonable to anticipate advances in and automation of sequencing technology such that the sequencing of the next few percent could be done with one fifth or one tenth of the man-years effort.

(4) There was general agreement that a centralized effort correlating genetic, physical, and sequence mapping, promoting the development of improved technologies, and actively fostering the application of this knowledge and approach to specific problems in human genetics, development, and physiology would be of great value.

Over the next year, I sought unsuccessfully to interest potential donors in support of this project. Somewhat näively, I believed that the project, to determine once and for all the genetic basis of man with all its rich and incalculable consequence, would surely seize the imagination of anyone with even a rudimentary scientific bent. Curiously, it did not. I also believe that the proposal would have been given greater credence and a better hearing had it been put forth by a more prominent, established institution—a Caltech, a Stanford, a Harvard. UCSC was an undistinguished spot on the map of biological research. Ideas should be evaluated purely on their merit, but in the real world, in the battle for attention and credence, that seldom happens.

Elsewhere, however, the concept was demonstrating that it was an idea whose time had come. My summary of the workshop was circulated in the biological community. The idea had come to the attention of the officials of a seemingly unlikely sponsor, the Department of Energy, and in particular to Charles DeLisi.

In fact, this was not so unlikely. The Department of Energy is accustomed to the management of Big Science and the DOE had in existence a biology program dating back to the Manhattan Project. From its inception, this program had been concerned with understanding the

biological effects of radiation, but in recent years scientists in the program had moved opportunistically into related fields.

Using the availability of exceptionally powerful computing facilities, biologists at Los Alamos had established Genbank, the national repository for the DNA sequences that were emerging in a growing stream from biology laboratories. Approximately ten million nucleotides of sequence, from various DNA sources, were already on file at Genbank. At Livermore National Laboratory, biologists taking advantage of the local expertise in laser technology had applied this tool to the fractionation of chromosomes, modifying a biotechnique originally developed for cell sorting.

Thus, in the spring of 1986 DOE convened a conference to discuss the merits of a national program to sequence the human genome. Regrettably, a conflict made it impossible for me to attend. A second conference was held at Santa Fe in January 1987 on techniques for the automation of processes related to DNA sequencing. A DOE subcommittee, headed by Professor Ignacio Tinoco of Berkeley, was established in 1986 to provide advice as to the feasibility of the human genome sequencing project and the outline of a plan as how best to proceed. I served on that committee.

We recommended that such a program be established and that the initial emphasis be on the establishment of genetic and "physical" maps—sequentially ordered collections of ten to twenty kilobase tracts for each chromosome—while the development of automated machines for the more laborious task of nucleotide sequencing proceeded. At the same time, development of computer programs for management of the vast amount of data to be gathered would proceed. We recommended an initial budget of forty million dollars a year to ramp up to some two hundred million dollars per year over five years. We projected that a further ten-year expenditure at that rate would complete the program and provide the sequence. We also proposed that some definite goals be set such as the sequence of one or two of the smaller human chromosomes by a definite date.

As this program moved forward, voices of opposition began to be heard. One faction argued against the introduction of Big Science into biology especially if it were to come at the expense of the current smaller-scale projects. The objection was in part self-interest, in part a conviction of the superiority of investigator-driven initiative, and in part a simple unfamiliarity with and fear of Big Science. A more glib objection raised was that much of the sequence reformation would be use-

less—that only a few percent of the human genome was meaningful and the great bulk was "garbage." Given our ignorance of so much of the genome, the evidence to support this position was limited; further, one person's garbage can be another's treasure. The potential utility of so-called "nonsense" DNA, for evolutionary or anthropological studies, or its role in control processes, is as yet quite unknown.

Still another objection related to the emphasis on human DNA. Admittedly, for the clarification of the present issues in biology, the complete sequence of E. coli DNA, drosophila DNA, or mouse DNA might be more useful, but to obtain a commitment of perhaps three billion dollars, the sequence of human DNA with its potential for medical insight was far more justifiable. And once the apparatus for the determination of the human DNA sequence was established, its application to the other genomes of interest would not be difficult.

The idea had an inherent natural appeal that has in fact swept all before it. The project is now underway. I merely provided the push to start the snowball rolling. It did not benefit UCSC as I had hoped, but it will surely benefit humanity and I am pleased about that. To have come from the nearly total ignorance of cellular substructure and molecular process in the 1930s to the prospect of a total knowledge of the human genome in the 1990s—what a remarkable journey of discovery.

The memorial that Mrs. Hoffman wanted to create for her husband was never realized, but from that thought so much has come. Perhaps it is sometimes truly "the thought that counts."