Introduction

Except for Cassandra herself, prophets of doom have almost always turned out to be wrong, especially where scientific developments are concerned, and our remarks are not meant to discourage the great enthusiasm with which many molecular biologists are abandoning K12 for BALB C or some other mammal, such as a nematode. (F. Jacob and J. Monod. 1970, p. 3)

In the initial letter of invitation addressed to me two years ago, the Chairman of the Carter-Wallace Lectureship Committee explained that the purpose of these lectures was "to call the attention of students and faculty in biochemistry, biology, and chemistry to exciting developments in important areas of the life sciences." I assumed that the development to which I owed the invitation was hybridization of somatic cells, and suggested this title for my lectures; and I take the renewed invitation to lecture on this subject to mean that this theme had not come to be regarded meanwhile as less exciting, and hence, that the discouragement and pessimism which afflict nowadays so many biologists do not prevail at Princeton.

This pessimistic attitude was, as some of you may remember, signaled by Sol Spiegelman in the late fifties, when he stated that "the outlook is depressingly bright for the quick resolution of many interesting problems" and, as you know, reached its apogee in Gunther Stent's most articulate book "The Coming of the Golden Age: a View of the End of Progress" in which he claims that most of the essential principles of biology have been discovered and most of the essential problems solved; and that the few remaining ones are either not worth our bother or may not be solvable.

It appears to me true that, for the first time in the history of science, we have recently come to a point wherefrom one can see that science can eventually reach an end, but I do think that Stent's pessimism is premature, and I fully agree with the more constructive views recently expressed in two remarkable articles published in Nature: one entitled "Molecular Biology in the Year 2000" by Francis Crick, the other "Genes and Hereditary Characteristics" by Alfred D. Hershey. I highly recommend these two articles to those who are afraid that we shall soon run out of important problems, and I hope that they will feel somewhat reassured also by what I shall say in these lectures about the status of some fundamental biological questions.

Now, a few words about the plan of my lectures.

In the 10 years since its discovery in 1960, hybridization of somatic cells has grown from a biological curiosity into a method of analysis which is now so widely used in investigations of the genetic basis of a variety of biological phenomena, that an exhaustive review of the literature in a few lectures is no longer possible. I therefore think that it will be more rewarding if I limit my objectives: I shall first give you an historical account of the development of the method of somatic hybridization and of our knowledge of the properties of hybrid cells; and shall then speak in a somewhat more detailed way about three areas of biological research, presently investigated by means of somatic hybridization, which appear to me of particular importance or are of particular interest to me personally: formal genetics, cell differentiation, and cancer (Note 1).

History of Somatic Hybridization

I suspect that if we were honest we would have to admit that if any one of us had never been, our science would not have been quite the same; but it would be awfully hard to see the difference. (Sir Macfarlane Burnet. 1967, p. 4)

I chose to start with an historical account of somatic cell hybridization for two reasons.

First, in my opinion, an honest historical account by an eyewitness inevitably shows the respective roles, in any important scientific development, of deliberate, logical design and of "lucky accidents" and, hence, especially in periods of pessimism about the future which many biologists are going through right now, inspires confidence and hope that the unexpected will, again and again, bring unforeseeable solutions to what, on logical grounds, appear today to be insoluble problems.

The second, and much less important reason, is that a history of somatic hybridization has been written recently by Henry Harris, but his version is different from mine, and I may as well take this opportunity to present my own.

In presenting it to you, I shall assume that you are all acquainted, at least superficially, with the principles and techniques of cell culture in vitro on which hybridization of somatic cells relies, worked out chiefly by H. Eagle and T. T. Puck in this country. (The relevant references can be found in the excellent reviews by Green and Todaro and by Krooth et al., and in the book of Morgan Harris; a very brief account is given in Ref. 72. The definitions of some technical terms will be given in the Appendix.)

Since some of you may not be familiar with hybridization of somatic cells, I would like to begin by saying that the occurrence of this phenomenon was discovered in 1960 by a research team working in Paris under the leadership of Georges Barski, and not by me as has been often erroneously stated in reviews of the subject. I hasten to add that one person has not shared in this error: having made, in 1965, an important contribution to the field, Henry Harris, whose style sometimes makes one believe that he may be short on modesty, seems to ascribe the discovery of cell hybridization neither to Barski, nor to me, but to himself (Note 2).

The discovery of hybridization between cells of permanent lines

How was somatic hybridization discovered?

For several years, Barski had been studying two permanent, heteroploid lines of mouse cells growing in vitro and isolated many years earlier by Catherine Sanford and co-workers at N.I.H. (Note 3). These two cell lines were derived from the same initial culture, i.e. were very closely related, but, in the course of years, had become very different in the degree of their neoplasticity. Having observed that the cells of the two lines differed both in their morphology and in their karyotype, Barski decided to look for evidence of Pneumococcus-like transformation by growing the two cell types together: what he apparently was looking for were morphological changes of cells whose identity could be established by their unchanged karyotype. What he discovered was quite different, however. It was the appearance, after three months of mixed culture, of a new cell type which...