A NOVEL TECHNIQUE FOR TRANSFORMING THE THEFT OF MORTAL HUMAN CELLS INTO PRAISEWORTHY FEDERAL POLICY

Leonard Hayflick, Ph.D. . . . University of California, San Francisco Department of Anatomy P.O. Box 89 The Sea Ranch, CA 95497

E-mail: [email protected]

(Modified and updated from a lecture originally presented March 6, 1989 at the Seminar on Clinical and Research Applications of Human Cells and Tissues, American Association of Tissue Banks, Arlington, Virginia.)

Published in Experimental Gerontology 1998, 33, 191-207. Copyright l997, Leonard Hayflick

Abstract - A revolution has occurred in the attitude of biologists toward their intellectual property rights. What today is patentable and highly profitable was, twenty years ago, unpatentable and given away for nothing. The history of this revolution began in the early 1960's when we made the first effort to have self-duplicating cell strains patented. The application was denied because patent law at that time did not included living matter. Because of the demand for our normal human diploid cell strain, WI-38, by NIH grantees, NIH support was provided to distribute WI-38 gratis to hundreds of recipients. These included vaccine and cell manufacturers who profited enormously from the direct sale of WI-38 or it’s use as a substrate for many human virus vaccines. When federal support for the distribution of WI-38 ended, but demand did not, I continued to distribute it for costs similar to those made by the American Type Culture Collection. When I took the first initiative and asked NIH to have the then unique question of title to a self-duplicating system resolved, they sent an accountant who accused me of theft of government property. I replied with a lawsuit that, after six years of litigation, we won with an out-of-court settlement. During these six years the United States Supreme Court ruled that living matter could be patented. Also, the biotechnology industry was launched by biologists who, like me, started companies using cells or microorganisms developed with federal support. This use of intellectual property rights by the nascent biotechnology industry was ultimately embraced by the entire biological community and by a directive from the President of the United States. This revolution has now evolved to the point where government biologists themselves may profit from research in federal laboratories and the NIH itself aggressively seeks private commercial alliances. Universities have also pursued similar alliances to the extent that today the distinction between a research university and a commercial organization is only in the eyes of the Internal Revenue Service.

Key Words: Intellectual property rights, WI-38, theft, NIH, patents, profits INTRODUCTION

Alex Comfort played a crucial role in the events to be described. He did so because, like other colleagues, he was enraged by the enormity of an injustice that was being perpetrated by the administration of Stanford University and the National Institutes of Health (NIH). Without his clarion call for justice made to the editors of Science Magazine and to others who believed without question the version of events that came from the Public Relations Offices of these institutions, the events to be described would not have reached the happy conclusion that they did.

I dedicate this article to an uncommon man, Alex Comfort, physician, scientist, biogerontologist, novelist, essayist, poet, playwright, translator, raconteur, amateur radio operator, the Founding Editor of EXPERIMENTAL GERONTOLOGY, and magnificent iconoclast.

Twenty years ago a tenured medical school professor was accused of stealing government property, handed over to the local police by their university, investigated by the district attorney, shunned by his colleagues and illegally denied an NIH approved grant by the Department of Health and Human Services for doing what, today, is encouraged by all universities, ignored by the police and the district attorney, admired by their colleagues, championed by the NIH, and stated by the President of the United States to be Federal policy.

The act that I speak of is the sale, or commercial exploitation, of self-reproducing biological systems discovered by university biologists, partially or fully funded by the NIH. As the first, and only, American biologist ever to have experienced all of these events I believe that I can speak to the issues with some authority.

This episode, which began thirty-five years ago, should command the attention of all biologists for at least three compelling reasons. First, the matter of title, or ownership, of novel self-reproducing biological systems which is the sine qua non of the biotechnology industry has not been settled even after my experiences and that of other colleagues. Second, the consequence of this neglect is that all academic scientists engaged in the development of new biological systems with potential commercial value remain potential victims of charges of theft. The third reason why the scientific community should be interested in resolving this problem is that most of the attitudes surrounding this issue have changed so dramatically in the last thirty-five years years that it provides a monumental lesson in how fast the mores of thousands of previously apathetic scientists and their administrators can change when the interests of thousands transcend the identical interests of a single person.

Alex Comfort whose role in this issue will be discussed subsequently, was so distressed by the behavior of Stanford University and NIH officials that he chose to dedicate the 3rd edition of his landmark book, “The Biology of Senescence” (Comfort, 1979) to me with the latin inscription:

IN . CIVIVS . CALVMNIATORES . MINGIMVS a free translation of which is: “We piss on those who malign.”

GENESIS

This story began thirty years ago when Paul Moorhead and I described the finite replicative capacity of normal human fibroblasts and interpreted the phenomenon as aging at the cell level (Hayflick and Moorhead, 1961). We showed that when human embryonic cells are grown under the most favorable conditions, aging and death is the inevitable consequence after about fifty population doublings. We called this the Phase III phenomenon. We showed that, contrary to dogma of sixty years duration, the death of cultured normal human cells was not due to some trivial cause involving ignorance of proper medium components or culture conditions but was an inherent property of the cells themselves. The observation has since been confirmed in hundreds of laboratories world-wide(Hayflick, 1979; Norwood and Smith, 1985; Norwood et al., 1990).

At the time that our observation was made, the paramount dogma in cell culture biology since its development in the late 1800's was that the failure of cells to proliferate indefinitely in vitro must be attributable to errors in the “art" required to keep cells dividing forever. That dogma was so well entrenched that our original manuscript in which we described the Phase III Phenomenon, was rejected in 1960 by The Journal of Experimental Medicine with the statement that “The largest fact to have come out from tissue culture in the last fifty years is that cells inherently capable of multiplying will do so indefinitely if supplied with the right milieu in vitro." The letter was signed by Peyton Rous, soon to be awarded the Nobel Prize in Medicine or Physiology.

His belief, then universally accepted, was tantamount to the conviction that, given the right milieu in vivo, human beings also will live forever. Ponce de Leon called the right milieu in vivo “The Fountain of Youth" and those who believe that any cultured normal cell must be immortal if only the right medium can be found are, like Ponce de Leon, still searching for that fountain of youth even after 35 years of failed efforts (Rubin, 1997).

In our description of the human diploid cell strains we reported that they have several interesting properties (Hayflick and Moorhead, 1961):

First, if derived from human embryos, cell strains undergo about fifty population doublings. The potential cell yield from fifty population doublings is about twenty million metric tons.

Second, we found that human diploid cells undergo a number of population doublings inversely proportional to donor age. This suggested to us that the finite replicative capacity of cultured normal cells is an expression of aging at the cell level. This notion received considerable experimental support in subsequent years and became the basis for the burgeoning field of cell aging that we named "cytogerontology" (Hayflick, 1974).

Third, we showed that, if derived from normal tissue, cell strains have the diploid karyotype and, unlike immortal cell lines, normal cell strains are incapable of replication in suspension culture. Later this property was named anchorage dependence.

Fourth, we also demonstrated that human cell strains will not produce tumors when inoculated into the hamster cheek pouch or even when directly inoculated into terminal human cancer patients.

Fifth, we showed that human diploid cell strains can be cryogenically preserved. When, for example, our first widely distributed normal human diploid cell strain, WI-38, which we developed in 1962, is preserved at a particular doubling level and then reconstituted, the number of doublings remaining is equivalent to fifty minus the number of doublings spent prior to preservation. The cells have an extraordinary memory and “remember" at what doubling level they were preserved even after thirty-five years years of continuous storage in liquid nitrogen. WI-38 has been preserved longer than any other normal human or animal cell population.

As a result of this characterization we suggested that all cultured animal and human cells be classified into three groups:

First, the primary cell culture, derived from intact tissue and undergoing no subcultivations. Second, the cell strain which has (1) a finite capacity to replicate, (2) does not produce tumors when inoculated into experimental animals, (3) has the karyology of the tissue of origin and (4) is anchorage dependent.

The third class is the cell line which is (1) a population of immortal cells, that (2) may produce tumors when inoculated into laboratory animals, (3) does not have the karyology of the tissue of origin and (4) are usually anchorage independent.

We thus made the distinction, for the first time, that cultured cells were either mortal or immortal and that immortality resulted from the transformation of mortal normal cells (Hayflick and Moorhead, 1961 and Hayflick, 1965).

These distinctions, made thirty-five years years ago, have maintained their validity to this day when an understanding of the mechanisms of immortalization has become a major quest.

HUMAN VIRUS VACCINES

In our first report on the human diploid cell strains we demonstrated the broad human virus spectrum of these cells and suggested that human diploid cells could provide a superior substrate for the production of human virus vaccines. In 1962 we prepared the first vaccine produced in human diploid cells and showed this poliomyelitis vaccine to be safe and efficacious (Hayflick et al., 1962). We argued that a diploid cell strain was safer than the primary cell populations then used because of the ability to thoroughly test this class of cells before use. We introduced the concept of a master cell bank and a working cell bank now universally used in the biotechnology field (Hayflick and Jacobs, 1968).

These processes resulted for the first time in a reliable method for cell characterization based on one concept - standardization.

In spite of these obvious benefits the use of human diploid cell strains for the production of human virus vaccines met with enormous resistance. This resistance was led chiefly by the then Division of Biologics Standards (DBS), NIH (now called CBER and a part of the FDA) that controlled all vaccines licensed for use in the United States. After ten years of educational efforts and striking successes with diploid cell strain vaccines in Europe, the DBS finally licensed a poliomyelitis vaccine made in our human diploid cell strain WI-38 in 1972 - a decade after the original proposal was made (Hayflick, 1984).

Today, there are many licensed human virus vaccines produced in WI-38 or similar strains. These include polio, adenovirus types 4 and 7, rubella, rubeola, varicella and rabies. For example, all of the rubella vaccine used in the Western Hemisphere is produced in WI-38. Hundreds of millions of people throughout the world have been inoculated or fed vaccines produced in WI-38 and other human diploid cell strains with no reports of untoward effects traceable to the cell substrate itself.

TURNING THEFT INTO NATIONAL POLICY

In 1975 an incident involving WI-38 occurred that was to have a profound effect on our concept of intellectual property rights and the emerging biotechnology industry. That incident involved the ownership, or title, to WI-38 specifically. But generally, it involved title to all self-reproducing systems. When we first described the human diploid cells, efforts were made by the Wistar Institute, where I worked, to patent them. It was 1962 and the United States Patent Office held that no patent law covered living systems like these cells.

In 1962, because of the enormous demand for WI-38 starter cultures by NIH grantees, the NIH provided us with a contract to “Produce, Store and Distribute" it. In the spirit of the prevailing scientific attitudes in the 1960's, original ampules of WI-38 were given gratis to commercial cell culture manufacturers, pharmaceutical companies, and cell repositories worldwide including those in the U.S.S.R. and in Eastern Block countries.

In the decade after WI-38 was developed I have conservatively estimated that WI-38 starter cultures sold by cell culture manufacturers alone grossed well over twenty-five million dollars. No value has been put on the additional hundreds of thousands of WI-38 cultures used by vaccine manufacturers or cultures sold by third and fourth parties. No funds reverted to me, the Wistar Institute or to the Federal government.

The attitude during those years was that academic biologists had no intellectual property rights, nor should title be vested in them or their institutions for their development of new or unique life forms. Intellectual property was simply given away by starry-eyed biologists because the taint of commercialism could ruin an academic career. But, there was incredible irony and injustice in this. Commercial organizations, and even the Eastern Block countries could, and did, freely obtain WI-26 (an earlier human diploid cell strain that we developed) and WI-38 from me and sold or used them to produce enormous profits. Yet, the academic institutions, the federal government, and even we, the scientists who actually developed the cells, were forbidden from benefitting.

Our fellow academic scientists in electronics, physics, computer science and chemistry had long since learned that there was nothing unethical or wrong in turning their intellectual property rights into commercial products for the benefit of the public and they and their academic institutions benefited financially. Until 1975, the mentality of biological scientists was in the stone-age with respect to attitudes toward profiting from their discoveries, when, compared to colleagues in other sciences. Biologists simply gave away to others what they discovered and the recipients of their largesse often profited immensely. Recompense to the creative biologist often consisted of nothing more than a fine dinner. I know this to be true because a pharmaceutical company freely given WI-38 for vaccine manufacture invited me to one.

From the time that our NIH contract to distribute WI-38 ended in the early 1970's until today, WI-38 sales by commercial marketers of cell cultures have grossed well over 100 million dollars. In addition, vaccine manufacturers in many countries have used WI-38 obtained from me for the manufacture of millions of doses of human vaccines with a total value of well over one billion dollars.

Because of these events I began to realize in the late 1960's the great injustice caused by the official denial to biologists of what seemed to me to be their right to a share of some proportion of funds that might be realized from the commercial exploitation of their intellectual property. I felt that the exploitation of my discovery was not only commercially proper but also laudatory on grounds of the medical benefits that had accrued and continue to accrue to the hundreds of millions of recipients of vaccines produced in WI-38. However, the official position of the NIH that the inventors of something having commercial value should be denied any benefits was, I felt, not only unfair but logically absurd.

In 1975 in an effort to settle this then unique question of title to a self-duplicating system, I took the first initiative and asked the Director of the NIH to make a definitive determination of my title to the WI-38 cell strain. By that time my company, incorporated in 1972, and one of the first formed in the new biotechnology era, had sold starter cultures of the cells openly for more than five years - even to the NIH itself - in the honest belief that this was legal and fair. The distribution contract had ended and I had no support to store or distribute the cells. The costs of storage, packaging, distribution and record keeping were not trivial. I charged prices similar to those charged by the American Type Culture Collection.

Instead of sending a lawyer, and or a scientist, who might understand the complex and then unique circumstances of my claim, the NIH sent an accountant who, failing to understand the law, the science, or the larger issues of my uniqueness position, prepared a report in which he concluded that I had stolen government property and sold that property for personal gain. Worst of all the NIH released his damning report after a Freedom of Information Act request was made by a curious reporter who had heard some mischievous rumors (NIH Report, 1976).

In 1975 I decided to challenge the absurdity of the NIH’s report by filing a law suit against the then Department of Health, Education and Welfare and the NIH, in which I claimed title to WI-38 and all proceeds from sales of WI-38 made after our contract ended. My suit also claimed that the NIH, in releasing the accountants report without my rebuttal, had violated the Privacy Act of 1974.

CRUCIAL EVENTS

During the time that this litigation was underway several crucial events occurred that impacted on my lawsuit. First, in 1977, two years after I filed my suit, the U.S. Court of Customs and Patent Appeals reversed itself and ruled that even though microorganisms are alive, “we do not see any reason to deprive it, or its creator or owner, of the protection and advantages of the patent system."

Four years after I filed my suit and during my litigation in 1980, the patent laws dramatically changed with the Diamond vs Chakrabarty decision (447 US 303, 1980). This Supreme Court decision opened the way for the eventual patentability of microorganisms and cell populations that were then becoming the basis for the emerging biotechnology field. Most, if not all, were developed with full or partial federal grant or contract support. In the late 1970's a cell or microbial culture was simply taken from an academic institution to an emerging biotechnology company and utilized in industrial processes. There are dozens, if not hundreds, of examples of self-duplicating biological materials, produced in whole or in part with government funds and exploited commercially with no benefit to the government or, in most cases, to the inventor. One example of this generality, of many that could be given, are the cell populations currently sold by cell culture manufacturers. A glance at their product catalogues shows dozens of cell populations offered for sale that were derived by scientists supported with federal funds. There are even cells being sold, like the L cell, that was developed at the NIH itself.

Why are the companies that sell these cells not guilty of theft and sale of government property if the NIH believed, as it did, that all of WI-38 was NIH property?

Nevertheless the NIH and the scientific community did not anticipate, until quite recently, what we first pointed out in our suit in 1975. We argued, I believe for the first time, that not only did my former institution and I have a legitimate claim to the cells but a good case could be made for title to WI-38 to be vested in the parents or estate of the embryo from which WI-38 was derived. We had anticipated by more than a decade the current controversy over title to self-reproducing human cells by the donor patient. I refer here, for example, to the question of title to the Mo human cell line, established at UCLA, and which was in litigation for years.

A second example of controversy over title to a cell population is the human hybridoma made from the fusion product of the human cell line UC 729-6 and the lymphocytes of the mother of a Japanese post-doctoral student at the University of California, San Diego. The student wanted to use the hybridoma to treat his mother who was dying of cervical cancer. He was refused because his preceptor was a shareholder in Hybritech, who funded part of the research, and the student ultimately was forced to resign from the University. After some unpleasant publicity the matter was finally settled out-of-court. Nevertheless the question of ownership of cells based on familial ties has never been settled (Sun, 1983).

There is even a question of title to cells and their products when those cells are produced by commercial organizations, patented, deposited at the American Type Culture Collection (ATCC) and subsequently used by researchers in universities and at the NIH. The Johnson and Johnson Company sent about 25 letters to scientists in universities, other companies and to the NIH warning them that their use of the hybridoma cells deposited at the ATCC may infringe on the companies patent rights “... regardless of whether the thus-produced antibody is subsequently used or sold." The NIH patent attorney, Mr. Thomas Ferris, said, “We don't consider it an infringement (for researchers to use the cells) as long as it is experimental." But the Johnson and Johnson subsidiary, Ortho Diagnostics, is selling the antibody for research and diagnostic purposes; thus use of those antibodies by NIH or others clearly compromises potential Ortho sales to them. The NIH's patent attorney Mr. Ferris said, “...ultimately (the issue) can only be resolved in the courts (Fox, 1984)."

After six years of litigation my lawsuit was settled in 1981. During this period many scientists profited enormously from their intellectual property rights. I applaud this.

In 1983 title to the interferon producing KG-1 cell line, partly developed with NIH funds, was settled out of court by Hoffman-LaRoche and UCLA. Although the settlement terms were not made public, as mine were, Dr. David Golde, one of the cell lines developers said that the University received “what I consider to be a large sum." Yet the KG-1 cell line was produced in whole or in part with the support of NIH funding and the cells even passed through the NIH laboratories of Dr. Robert Gallo on their way to Hoffman-LaRoche. Never was UCLA or the developers of the KG-1 cell line accused by the NIH of theft and sale of government property. In fact, the NIH ignored the matter of title entirely (Budiansky, 1983).

Unlike the accusation of theft that was trumpeted by NIH in the press against me, Golde and Koeffler were not similarly accused for their role in an identical act. This is the result of the profound change in attitudes that has occurred in the biological community and the concomitant revolution in the NIH's thinking which began when they came to me in 1982 with a request for an out-of-court-settlement. Nevertheless the acrimony of the KG-1 case caused serious harm to the reputations of all the scientists involved and still the matter of ownership of the cells remains unsettled.

To do in the 1970's what is commonplace today would be to have had yourself characterized by the accountant-led NIH Office of Management Survey and Review, as I was, of having engaged in the theft of government property and its sale for personal gain (NIH Report, 1976).

Of the many ironies that occurred during this saga none is more astounding than the fact that after a decade of futile efforts by us to have WI-38 accepted for use in the production of human virus vaccines by what is now the FDA, those same public servants eventually wanted WI-38 so desperately that they publicly pronounced them to be “a national resource." Subsequently, in my absence, they entered my laboratory in 1975 and confiscated them!

A later irony appeared in 1988 in the Guide for Grants and Contracts published by the NIH. A new NIH policy was announced that revealed the extent to which the conversion of NIH thinking had evolved from what they formerly characterized as theft by me in 1975, to government policy in 1988: “It is the policy of the Public Health Service to make available to the public the results and accomplishments of the activities that it funds. Restricted availability of unique resources upon which further studies are dependent can impede the advancement of research and the delivery of medical care. In order to facilitate the availability of biological materials and resources to the scientific community, investigators may distribute the materials through their own laboratory or institution... Institutions and investigators may charge the requestor for the reasonable cost of production of unique biological materials, and for packaging and shipping. Such costs may include personnel, supplies, and other directly related expense (NIH Guide, 1988)."

WHEN ITS PROFITABLE LET ME KNOW

There are many other examples in science of an invention or resource that is recognized early to be valuable by its developer but, despite the claims, it is ignored by others.

An amusing example of this phenomenon which, for lack of a more succinct term, I will call the “I'm-not-interested-in-what-you -have-now-but-if-after-you-struggle-to-successfully-prove-that-it- is-valuable,-I-will-do-everything-possible-to-steal-it-from-you" phenomenon.

This attitude is wide-spread and of the many examples, other than my own, that I could give, one will suffice. The incident occurred at the University of Florida where Dr. Robert Cade, the inventor of Gatorade, came to University officials about 25 years ago and described his invention. He asked them to support marketing the drink since he developed it in his university laboratory. They refused. In 1972, after Cade risked the borrowed funds from his family and friends, Gatorade began to register millions of dollars in annual sales. Sensing that this was now a proven winner for which now they needn't take any risk, the University of Florida sued Cade for a piece of the action claiming, as Cade had originally told them, that it was developed in university laboratories. Ultimately an out-of- court settlement was reached in which the same university that originally laughed at Cade now reaps millions in annual royalties. Cade recalls, “They said it was a crazy idea, but when it was successful, they wanted it." (Flinchbaugh, 1987)

THE GOVERNMENT BACKS DOWN

In my case I am pleased to say that after seven years of litigation, the Justice Department, the NIH and the DHEW came to me in 1981 with an offer for an out-of-court settlement. The settlement finally agreed upon by me provided that (1) many of the original ampules of WI-38 confiscated from my laboratory would be returned to me, (2) all funds realized from the sale of WI-38, with interest, belonged to me, (3) WI-38 which until then could be sold by anyone except its inventor could now be sold by its inventor, and (4) title to WI-38 was not vested exclusively with the government, as the NIH had absolutely insisted was true, but that my claim to title had equal merit. The Justice Department, the NIH and the DHEW also agreed that the Privacy Act of 1974 had been violated by the NIH and they agreed to place a copy of the out-of-court settlement into the hands of everyone who asks for a copy of the damning report prepared by their accountant (NIH Report, 1976).

I should add that the funds won in this settlement, plus much more, were all consumed in payment of my costs of litigation.

Many believe that one compelling reason why the NIH came to me with the offer for an out-of-court settlement was because attitudes toward the intellectual property rights of biologists were then changing rapidly. This occurred because of the phenomenal growth of the biotechnology industry at that time and the general awareness of their heavy dependence on the exploitation of biological materials developed in universities with NIH funds and appropriated on a massive scale by these emerging companies.

Many believe that had we not prevailed in our litigation, the current status of title to new life forms developed in whole, or in part, with federal funds would be quite different. Title to hybridoma populations, DNA sequences, unique cell populations, plasmids, and life forms expressing new recombinant DNA properties is now vested in the institutions or the scientists who developed them regardless of federal support.

Attorneys representing scientists and nascent biotechnology companies claiming title to self-duplicating systems intended to provide legal briefs in our support if our case had ever gone to trial. If we had lost our suit it is probable that the assignment of patent and property rights by the government would have been quite different than it is today.

ENTER THE PRESIDENT

My position received its greatest support from action by the President of the United States. In 1983 President Reagan instructed federal agency heads that all businesses should be able to retain patent rights on inventions made in the course of government funded R&D work. He said that the administration takes the view that giving the private sector clear title to patents on inventions developed under federal contracts and grants will lead to more rapid commercialization of new products and processes and combat the slump in United States productivity and competitiveness (Walsh, 1983). In 1989, Senator Pete Domenici (R-N.M.) said, “I don’t see the problem. We’ll never make any progress in our economy unless someone can profit from a discovery. If I had to choose between holding back development, and letting an individual profit from publicly supported research, I’d opt for the profiting.” (The Scientist, 1989).

In the next year, 1984, I received a letter from Mr. Leroy B. Randall the Chief of the Patent Branch of NIH (Randall, 1984). He wrote, “Please be advised that your interpretation is correct. If the cell population is unpatentable or is not patented, (as WI-38 could not) the cell population is the property of the grantee institution or the contractor." I should also add that his statement came from Public Law 96-517 which specifically states that it is applicable to inventions made with public funds prior to July 1, 1981. WI-38 was developed in 1962, partly with public funds.

This official about-face and revolutionary government policy change which fully embraces my original position has evolved to the point where now, not only are businesses able to profit from Federally funded R & D work, but so also are government employees themselves!

This latest development could not have been dreamt of with the troglodyte mind-set that I encountered in the 1970's. The reaction then would have been that any government employee who profits from inventions made in government laboratories is asking for a penitentiary sentence. Today, these employees not only avoid prison but are celebrated by the government and entitled to a maximum of $100,000 annually in additional recompense over their regular salary for their intellectual property rights!

The same government that accused me of stealing its property and selling it for personal gain is now spending an enormous amount of energy and money to publicize the fact that government employees themselves are encouraged to profit from R&D work done in their federally owned and supported laboratories. In light of my experiences this development is almost beyond belief.

One of the best examples of this policy occurred in 1983 when Federal scientists began selling their research on the Strategic Defense Initiative (“Star Wars") for private gain. The White House strongly defended them by saying that it is legal, best serves the public interest, spurs scientific incentive, and encourages industrial productivity. The New York Times of November 4, 1985 reported that “Federal scientists are excitedly planning to capitalize on their Government research and in some cases have already made financial gains"(Broad, 1985).

In an article on the front page of the Sunday edition of this same newspaper in 1976, I was accused of stealing government property when, not as a government employee, I openly sold cultures of WI-38 cells for almost six years for use in biological research, human virus detection and the manufacture of human virus vaccines.

I was pilloried for facilitating the development of highly successful poliomyelitis, rubeola, rubella, adenovirus and rabies virus vaccines almost a decade after NIH partial support ended. Today, Federal space scientists are lauded by the same Government for selling the products of Star Wars. Furthermore, WI-38 cells were not developed in a Federal laboratory but in a private laboratory. Nevertheless the same government inferred that, unlike the Star Wars' federal scientists, my activities in assisting biomedical research and human virus vaccine development were illegal, did not serve the public interest, did not spur scientific incentive nor did it benefit industrial productivity. Nevertheless, it is common knowledge that several hundred million people throughout the world have benefitted from vaccines produced in WI-38.

Today, many scientists and their institutions legitimately profit from the sale of self-duplicating materials that they have developed with or without federal support (Nelkin, 1984). I support this. The attitude today is exactly opposite to what I experienced in 1976. In 1998, if you do not hold a patent on a cell population, plasmid or microorganism, or you are not a stockholder or scientific advisor to a company that exploits such materials, you are a failure in biology. Indeed, as of ten years ago more than one-third of the biomedical members of the U.S. National Academy of Sciences have formal ties to both corporate and academic institutions (Shulman, 1988). In a 1990 survey, from ten to over thirty percent of the biomedical faculty’s of this countries leading universities had formal commercial ties (Marshall, 1990). Surely these percentages must be greater today.

In Marcus Tullius Cicero's orations against Cataline he put it best when he said, “O Tempora! O Mores!” For those who have forgotten their Latin a loose translation would be, - Oh how much our mores change with time!

ENDURING STAINS

In spite of the profound changes that have taken place since my litigation ended, my reputation still bears the stains of having been charged by the NIH with theft of government property. The charges were made by a few bookkeeper-zealots from the NIH Office of Management Survey and Review with the complicity of several other NIH and DHEW public servants. The charges were made in a document (NIH, 1976), that was given to the press by the NIH in violation of the Privacy Act of 1974 which triggered my suit against them. These events caused the Dean of the School of Medicine at Stanford University, where I held a full professorship, to accept the charges made by the NIH bookkeeper without question and without the benefit of understanding the unique circumstances of my position. I am told that the Dean's reaction was based substantially on being advised by the bookkeeper that his cooperation was expected because 90% of his budget came from the NIH. I resigned from Stanford University to protest my unwillingness to be associated with an institution whose leadership behaved so reprehensibly.

Our eventual victory in the out-of-court settlement, with one exception, was ignored by both the popular and scientific press who had trumpeted the false charges on the front pages of many American and foreign newspapers and science magazines six years earlier. These included The New York Times, who published the false charges on the front page of their Sunday Edition and Science Magazine who published damning articles by Nicholas Wade. This publicity occurred because the NIH and Stanford University used their Public Relations and Press Departments to trumpet their false understanding of the situation. Individuals do not have this kind of organized and professional relationship with the media and are left helpless to effectively communicate protestations and to counter false charges.

The accused is often reluctant to refute his accusers because to do so will add to the list of his faults, a persecution complex or the belief by readers that “The dignity of truth is lost with much protesting” (Jonson, 1611). And so the poison is almost always fatal because even if the victim is ultimately vindicated completely, as I was, that uninteresting news will rarely be delivered as effectively as were the original sensational charges. Thus, tens of thousands of readers of the false charges were never informed by those publications that the lawsuit was settled in my favor. When we won the out-of-court settlement no press release was ever issued by the NIH or by Stanford University. Thus, it is not popularly known that our stand, originally viewed by the NIH as theft, actually set a precedent that is now not only vigorously encouraged by them but also by the entire biological academic community.

In 1996 Stanford officials fell victim to poetic justice when, after being vindicated on a government charge of fraud that was widely reported in the media, Gerhard Casper, University President said, “...the reputation and integrity of individuals and institutions have been sullied (by the) sensationalism that characterizes so much of our public life.” Donald Kennedy, the former Stanford President on whose watch the charges were first made said, “The fact of life is that settlements and ultimate judgments get carried on page 17 when the accusations get carried on page one” (Friedly, 1996).

There was only one publication that was embarrassed into publishing a short note about the resolution of these events. Science Magazine, which originally published many pages of erroneous information and opinions, reacted to our court victory by printing a one-eighth page news item, only because eighty- five of my colleagues had written a letter to Science Magazine in which they described their displeasure about the initial publicity and the enormity of the about-face performed by the NIH (Strehler, 1982).

ALEX COMFORT’S ROLE

It was Alex Comfort who rallied to my side when Science Magazine first published an article by Nicholas Wade in which Wade came as close as it is possible to come to accusing me of benefitting from the theft and sale of government property (Wade, 1976). My attempts to have Science Magazine publish my rebuttal to the Wade article was met with outright refusal. Alex Comfort, who was incensed with the injustice of this, wrote a scathing letter to Science Magazine demanding that I be given equal time. The weight of his reputation and the persuasive content of his letter caused Science Magazine to reverse itself and they reluctantly published my rebuttal (Hayflick, 1977). But, unlike the articles written by Wade, which were published unrefereed, the editors of Science Magazine demanded that my rebuttal be reviewed by two outside referees.

Many years later I sent to Nicholas Wade a copy of an article I wrote which contained the main points of the present article. He replied, “It’s certainly true that attitudes toward commercialization of research have changed in the last fifteen years. With Best wishes for the New Year, Nicholas Wade.”

To add further to the irony, in 1986 I was made a Fellow of the American Association for the Advancement of Science (publishers of Science Magazine) “for fundamental studies of the finite lifetime of cultured normal cells...”

It is not widely appreciated that, because of our out-of-court settlement many wrongly accused scientists have not, and in the future will not, suffer from violations of the Privacy Act of 1974 by the NIH. As a result of our litigation every federally funded scientist in this country is protected from defamation because when the NIH releases investigative reports they now cannot contain personal identifiers. This is extremely important because, again unknown to most scientists, anyone bent on ruining a reputation can anonymously accuse a federally funded scientist of wrongdoing and then enjoy the full cooperation of the NIH whose policy it is to investigate all such tips no matter how, or from whom, they are received. NIH inquisitors will then descend upon all of one's friends and colleagues asking the most intimate questions and arousing their darkest suspicions. When your innocence is discovered by the NIH investigators, that fact is not reported to the persons questioned, thus leaving them with their anxieties and you with your reputation to repair. A report always results from such an investigation and it can be released to the press or anyone else through a Freedom of Information Act inquiry.

Despite the favorable outcome of my experience, I cannot easily express the enormity of the emotional stress endured by me, my family and our friends because of a small NIH cabal who had formed opinions about title to a self-duplicating system that, until that time, had never been addressed by the law or by the biological community. As subsequent events proved, these public servants were forced to do an about face on their beliefs by edict from no less than their ultimate boss, the President of the United States, who completely embraced our position in 1983 (Walsh, 1983).

Although my suit had a happy ending, many of the early negative feelings directed towards me as a result of the initial tragic publicity have not changed. This can be attributed to the fact that individual scientists do not have public relations departments capable of overcoming negative information promulgated by similar departments at government and university facilities. THE REVOLUTION

The extent to which Universities, biologists and the Federal Government have embraced the principle that we advocated and defended, can be measured by the dramatic changes in Federal policy that have occurred over the past few years. I support all of these changes, not because I am envious of the benefactors or bitter about my experiences, but simply to point out the extent to which my position has been adopted by my accusers as their own philosophy.

The Federal Technology Transfer Act of 1986, (Public Law 99-502) requires federal agencies, including the NIH, to reward their scientists with not less than 15% of royalties arising from their work, and up to $100,000 per year. The more than 700 federally operated laboratories now are encouraged to undertake cooperative research with private companies, universities and state organizations and even to assign patent rights to them if that will accelerate technology transfer. Science fairs are held at the NIH and other government laboratories in an effort to court commercial interests (Byrne, 1988).

Before 1986 the attitude was that if the research was supported with public funds then it should be free for anyone to use. The result of this policy was that few if any entrepreneurs would want to exploit an invention because what is available to everyone is commercially worthless. The result was that what might become available to everyone became available to no one. A former physicist at the Oak Ridge National Laboratories who started two companies put it well when he said, “Twenty-years ago, any involvement with industry was considered unethical. Now it is enormously encouraged" (Charles, 1988)

Ronald Cape, then President and CEO of Cetus Corporation, one of the first biotechnology companies, also acknowledges that what was once characterized as the theft of government property for personal gain is now acknowledged as acceptable practice. In response to being asked about his strong support for academic research he candididly admitted that, “Biotech has grown in a unique way. It is built on the monumental investment of the American taxpayer over the last 40 to 45 years; an investment that has paid off handsomely. All the information deriving from it is public and has been extensively mined by the commercial sector." (Powledge, 1987)

As for universities like Stanford objecting to the use of their facilities for private gain by their faculty, as it did with me, the practice is so widespread that most current faculty would be dismissed if this notion was uniformly enforced. There is one example of many that could be given of using university facilities for personnel gain for which most faculty are guilty and, if enforced, would empty most universities of their staffs. Faculty members usually sign a patent and copyright waiver as a condition of employment. The conditions normally stipulate that all income produced when using university personnel, facilities or equipment for writing belongs to the university. If that rule was strictly enforced virtually every faculty member in this country would be found guilty of theft of university funds. Furthermore, any university employee who, in his or her capacity as a consultant, uses university equipment, personnel, typewriters or computers as part of their consulting duties is equally guilty of theft of university funds. That rule is honored more in the breach than in the observance.

The Vice President of Development at one of the most successful Silicon Valley start-up companies called MIPS, gave Stanford University 25,000 shares of stock and in doing so said, “A lot of the technology we use was developed at Stanford's Electrical Engineering and Computer Science departments. We just wanted to thank Stanford for helping us get started" (Stanford Campaign News, 1988). This is tantamount to admitting that Stanford facilities were put to good use by this company yet, since the discovery of “misuse" of its facilities was not made by the university when it occurred, the faculty members survived with their reputations intact and in Kafkaesque fashion received honors from the university for their thoughtfulness in making a contribution of stock.

With the development of the biotechnology industry a revolution occurred in the attitudes of university administrators and their biomedical faculties. What was previously regarded as the misuse of university facilities for personal gain has now become part of a frenzied effort by the same administrators to lease the use of their facilities and the intellectual property rights of their faculty members to the highest bidder. Many senior university officials have perplexed their speech writers by having them struggle with the nuances of convoluted language in order to escape from previous noble statements about the purity of their enterprises in order to justify their present anachronistic positions.

Major universities who previously condemned their faculty for profiting from their inventions find themselves a bit like the girl who turned to prostitution because she realized that she could command a good price for what she used to give away for nothing.

Today, most academic biomedical scientists are consultants, board members or shareholders in their own or other biotechnology companies. If not, they are considered to be failures. These new relationships are a part of what has been called the University-Industrial Complex (Kenney, 1986). In my view that term is an oxymoron because today's large research university is only distinguishable from an industrial enterprise because the Internal Revenue Service chooses to tax the profits of one and not the other. In fact, the phenomenon is well recognized by University leaders, one of whom is A. Bartlett Giametti, former President of Yale University, who characterizes it as the "corporatization" of the American University (Fiske, 1986).

In virtually all respects, universities are indistinguishable from commercial organizations. Today's large research university has taken on most of the trappings of the very institutions that, in the past, it tried so desperately not to emulate. The modern research university, like all successful commercial enterprises has, for example, a legal department, patent offices, business development offices and accounting practices that differ little from most commercial enterprises.

University Presidents have been reduced to fund raisers and the bottom line for a university is indistinguishable from that of any commercial enterprise. Columbia University has developed a formula used to browbeat its research faculty that measures the amount of grant money raised by each faculty member as a function of the square footage that they occupy. Universities, like department stores, now calculate the amount of gross sales (grant overhead) per square foot as a means of “motivating" their faculty and determining which department is more “productive."

Harvard University is one of many universities that have embarked on their own marketing ventures using a limited partnership established with a private investment consortium to profit directly from the labor of the research of it’s own faculty which, in turn, is supported in full, or in part, with taxpayers money (Shulman, 1988b).

The University of California started it’s own for-profit company, UC Technology Development Co., in 1992 to exploit faculty research and it’s new 1996 “STAR” project uses university and private company funds to support research by it’s faculty conducted on state property and with some direct or indirect federal support (Anderson, 1992). The objective, in part, “...is to build lasting linkages between California’s businesses and UC scientists...(and) to counteract well-funded efforts from other states to lure away California’s biotechnology firms and UC’s science base.”

The Johns Hopkins School of Medicine and Genetics Institute, Inc. have formed a new company, MetaMorphix, Inc., to develop and commercialize molecules regulating cell growth and differentiation (Genetic Engineering News, 1995). The MIT Industrial Liaison Program, half of whose member companies are foreign (fifty-two are Japanese), can for ten to fifty thousand dollars have easy access to the $300,000,000 a year of MIT research results, of which most is supported by the federal government (Anderson, 1989). These university-commercial alliances are only a few examples of many more that could be given.

The ultimate example of the profound reversal of position made after our pioneering efforts has been adopted by the NIH itself. It is not widely known that now investigator-initiated awards, commonly known as R01's, are available for use in commercial organizations. This tax-payer supported research may replace company supported research and result in a product beneficial to that company.

In the Federal Technology Transfer Act of 1986, federal laboratories are encouraged to enter into Cooperative Research and Development Agreements (CRADA’s) with industry to “hasten the process of getting discoveries out of the labs and into the marketplace” (Byrne, 1988). A CRADA allows a federal laboratory to provide personnel, services and property toward a joint research project and an exclusive product license with a commercial firm. The NIH scientist is entitled to a minimum share of fifteen percent of the royalties. This heretical concept which virtually mandates that NIH scientists form industrial partnerships (there were 200 commercial members in 1989) was so unthinkable in the 1960's and 1970's that an NIH scientist who did this at that time would have been committed to a federal penitentiary for using federal resources to benefit a commercial enterprise (Culliton, 1989).

As stated by Niels Reimers, director of technology licensing at Stanford University and generally regarded to be the dean of the revolution in university-commercial links, the name of the game is “marketing, marketing, marketing” (Buderi, 1988). SOLUTIONS

Meir Wilchek is a Professor at the Weizmann Institute of Science in Rehovoth, Israel. He is a victim of patent law as is Cesar Milstein, the Nobel Laureate who discovered how to make monoclonal antibodies using hybridomas. Many other scientist-victims could be named. Wilchek discovered affinity chromatography and its application to biomedical research. At least in respect to American patent law, appreciation of the discovery did not occur to Wilchek until more than one year after his publication, thus preventing United States patent protection. Like hybridoma technology, affinity chromatography has virtually revolutionized biotechnology.

Wilchek’s studies were partly conducted at the NIH and the technology has earned tens of millions of dollars for commercial companies. He has benefitted only trivially and takes home $1,200 a month at the Weizmann Institute. Wilchek is satisfied with this income but he feels that it is unfair, if not immoral, for commercial companies to be the sole beneficiaries of someone else's efforts, even if they are legally entitled to do so. He has proposed that such companies should voluntarily set aside one-half percent of their net earnings for research grants to scientists from whom they have “borrowed" the ideas or technology that have made them such handsome profits. This is much less than they would have to pay in royalties on a valid patent and it would encourage unconventional research to say nothing of being just. In my view the scientific community in this country, through their professional societies, should take the initiative in efforts to have legislation passed embodying the principles suggested by Professor Wilchek (Meyers, 1987). My purpose in describing these matters is to impress readers with the fact that despite the profound turnaround in attitudes and rules by scientists and by public servants, several of the fundamental issues of intellectual property rights have not been resolved.

Today, all federally supported university scientists are still at risk because of the apathy of the scientific community in resolving these important issues. In a more narrow sense the matter of title to the progeny of a self-duplicating biological system also needs to be settled.

ENVOI

In her book, published by the American Association for the Advancement of Science (publishers of Science Magazine) and titled "Science as Intellectual Property: Who Controls Scientific Research?" (Nelkin, 1984), Dorothy Nelkin writes:

“The rapidly changing viewpoints about individual entrepreneurial ventures in science are illustrated by the case of microbiologist Leonard Hayflick. In 1976 Hayflick, then at Stanford University, was embroiled in a conflict with NIH over the ownership of a cell line that he had developed in the 1960s. It was the first strain of normal human cells that could be established in a culture, and he formed a company to market the cells which were found to be useful in the production of vaccines. NIH publicly charged Hayflick with profiting from research conducted with federal support and claimed that the cells belonged to the government. “...(Hayflick) filed suit seeking title to the cells and the proceeds from sales. After a long, often acrimonious dispute, the case was settled out of court in 1981, with Hayflick retaining the money from sales but with the question of ownership of the cell line still unresolved.

“Today Hayflick's actions would not be controversial. It is now accepted practice for scientists and institutions to profit directly from the results of academic research through various types of commercial ventures."

Acknowledgments - I would like to thank the following individuals whose judgments and decisions on diverse subjects resulted in the circumstances portrayed herein and without whom, these interesting events would not have occurred and this article could not have been written: Dean Clayton Rich, Stanford University School of Medicine; John Schwartz, Legal Advisor to the Dean of the Stanford University Medical School; Richard Lyman, President, Stanford University; James W. Schriver, Director, Division of Management Survey Review, NIH, Bethesda, MD; Leon Jacobs, NIH; Hope Hopps, Center for Drugs and Biologics, FDA; Donald Murphy, NIA, NIH; Jack Gruber, Biological Carcinogenesis Branch, NCI, NIH; Ronald Lamont-Havers, Acting Director, NIH; Donald Fredrickson, Director, NIH; William Raub, NIH; Nicholas Wade, Science Magazine and Joseph Califano, Assistant Secretary of Health, Department of Health, Education and Welfare, Washington, D.C. (Affiliations apply to the time the events occurred.)

REFERENCES

ANDERSON, C. Congress asks “why Japan?”, Nature, 339, 568, 1989.

ANDERSON, C. UC Goes Where Harvard Feared to Tread, Science, 258, 1875, 1992.

BROAD, W.J. Space Arms Scientists in U.S. Selling Rights to Discoveries. The New York Times, November 4, p. 1., 1985.

BUDERI, R. Universities Buy into the Patent Chase, The Scientist, 2, 1-5, December 12, 1988.

BUDIANSKY, S. Roche Pays Up, Nature, 301, 6, 1983. BYRNE, G. NIH Holds a Science Fair, Science, 242, 661, 1988.

COMFORT, A., The Biology of Senescence, 3rd Edition, Elsevier North Holland, Inc., New York, 1979.

CHARLES, D. Oak Ridge Leads the Way, Science, 240, 875, 1988.

CULLITON, B.J. NIH, Inc.: The CRADA Boom, Science, 245, 1034, 1989.

FISKE, E.B. At 350, the U.S. University is Vast but Unfocused, The New York Times, September 7, p. 14, 1986.

FLINCHBAUGH, P. Dr. Cade of Gatorade, Gainesville (FL) Sun, No.261, p.1, 7a., 1987.

FRIEDLY, J. Judge Dismisses Suit Against Stanford, Science, 273, 1488, 1996.

FOX, J.L. Patents Encroaching on Research Freedom, Science, 224, 1080, 1984.

GENETIC ENGINEERING NEWS, Genetics Institute and Johns Hopkins form new company, May 1, 1995, page 41.

HAYFLICK, L. and MOORHEAD, P.S. (1961). The serial cultivation of human diploid cell strains. Experimental Cell Research 25, 585-621.

HAYFLICK, L., PLOTKIN, S. A., NORTON, T. N. and KOPROWSKI, H. Preparation of poliovirus vaccines in a human fetal diploid cell strain. Am. J. Hyg. 75, 240-158, 1962.

HAYFLICK, L. The limited in vitro lifetime of diploid cell strains, Exp. Cell Res. 37,614-636, 1965.

HAYFLICK, L.. Cytogerontology, in: Theoretical Aspects of aging, Rockstein, M. (Editor), Academic Press, New York, 1974.

HAYFLICK, L. Science, (To be obtained) 1977.

HAYFLICK, L. (1979). The cellular basis for biological aging.

In: Handbook of the Biology of Aging, Finch, C. and Hayflick, L. Editors), pp 159-186, Van Nostrand Reinhold, New York.

HAYFLICK, L. The coming of age of WI-38. In: Advances in Cell Culture, Karl Maramorosch, Editor, pp. 303-316, vol. 3, Academic Press, Inc. New York, 1984. HAYFLICK, L. and JACOBS, J.P. Suggested methods for the management and testing of a diploid cell culture used for virus vaccine production, In: Proceedings of a Symposium on Oncogenicity of Viral Vaccines, Yugoslav Academy of Sciences and Arts, Zagreb, Yugoslavia, pp 181-185, 1968.

JONSON, B. Cataline's Conspiracy, Act iii, Sc. 2., 1611.

KENNEY, M. Biotechnology: The University-Industrial Complex, Yale University Press, New Haven, Conn., 1986.

MARSHALL, E. When Commerce and Academe collide, Science, 248, 152-156, 1990.

MEYERS, N. Companies to Pay for Using Others' Ideas?, Nature, 325, 381, 1987.

NELKIN. D. Science as Intellectual Property: Who Controls Scientific Research? In: American Association for the Advancement of Science, Series on Issues In Science and Technology, Macmillan Publishing Co. pp 19-20, 1984.

NIH Report P-27-211, Available upon request under the Freedom of Information Act, 1976.

NIH Guide for Grants and Contracts, 17 (29) September 16, 1988.

NORWOOD, T.H.,and SMITH,J. R. The cultured fibroblast-like cell as a model for the study of aging in: Handbook of the Biology of Aging, Van Nostrand Reinhold Co. Inc., New York, Finch, C.E. and Schneider, E.L. (Editors) pp. 291-321, 1985.

NORWOOD, T.H., SMITH, J.R. and Stein, G.H. Aging at the Cellular Level: The human fibroblastlike cell model in: Handbook of the Biology of Aging, Academic Press, Inc. San Diego, CA, Schneider, E. L. and Rowe, J.W. (Editors) pp. 131-154, 1990.

POWLEDGE, T. Cape of Cetus Corp. on the NIH Budget and Competitiveness, The Scientist, 16-17, 1987.

RANDALL, L. B. Letter to the author from Chief, Patent Branch, National Institutes of Health, 1984.

RUBIN, H. Cell aging in vivo and in vitro. Mech. Aging Dev. 98, 1-35, 1997.

SHULMAN, S. U.S. Agencies Tighten Conflict-of-Interest Rules, The Scientist, p. 6.,1988.

SHULMAN, S. Harvard Starts it’s Own Marketing Venture at “Arms Length”, Nature, 335, 291, 1988b.

STANFORD CAMPAIGN NEWS Two More Gifts of Startup Stock: from Watts Family, MIPS Computer Systems, Spring, p 3.,1988.

STREHLER, B. et al., Hayflick - NIH Settlement, Science, 215, 240-241, 1982.

SUN, M. Scientists Settle Cell Line Dispute, Science, 220, 393, 1983. THE SCIENTIST, Did someone say profit? 3, 2, October 30, 1989.

WADE, N. The Rise and Fall of a Cell Line, Science, 192, 125- 127, 1976.

WALSH, J. Science, 219, 1408-1409, 1983.