Response to letters fromSonnenschein and Capp

Sir,

The letter from Sonnenschein and Soto makes four

substantive points.

1. If Dr Sonnenschein cannot produce written evidence that

antedates 1958, he will eventually have to accept that the

view of cell multiplication outlined in my Bioessay does not

have its origin with him.

2. The published papers on cell multiplication by Steward

(sic), Bullough and Iversen do not antedate my article of

1958, nor do the schemes proposed by these authors

resemble the model I advocated then and continue to

advocate now.

3. Nowhere in myessay do I state or imply that ‘‘differentiated

cells do not proliferate.’’ As amatter of fact I cannot imagine

what is meant by the term ‘‘undifferentiated cell’’. I am

dealing with errors in differentiation, not absence of

differentiation.

4. ‘Field’ theories, of which the scheme proposed by

Sonnenschein and Soto is but a recent example, also have

a long history, but they have not been widely accepted

because they do not account for the demonstrable clonality

of many malignant tumours. I have no desire to belittle the

importance of the extracellular matrix, as one of my recent

papers(1) clearly shows. It is, however, difficult to see how

schemes that exclude a causal role for genetic changes at

the cellular level could explain the fact that somemalignant

tumours can be transmitted from host to host by the

passage of a single cell.

Capp acknowledges the stochastic nature of tumorigen-

esis, but seeks to accommodate the clonality of tumourswithin

the framework of a ‘field’ theory. In the early days of the lac

operon era in E. coli, Novik and Weiner showed that a stable

and heritable change in the mode of operation of a metabolic

pathway could be induced by fluctuation in the extracellular

concentration of the relevant metabolite. No doubt similar

stable adaptations can be produced in vertebrate cells. But in

E. coli these induced changes are not stochastic: they affect

the population as awhole, although, of course, the intracellular

concentration of any metabolite varies from cell to cell. Capp

proposes that induced changes in the extracellular environ-

ment might, without the intervention of mutation, generate

clones of malignant cells in which the malignancy is heritable.

I would regard this essentially Lamarckian scheme as rather

implausible, but I would not wish to argue that such a

phenomenon could not possibly occur. As it stands, however,

the idea is supported by little more than conjecture. Neither

Sonnenschein and Soto nor Capp appear to have taken on

board the implications of the Drosophila experiments. In

Drosophila, the tumours are indeed produced by recessive

mutations in the classical Mendelian sense (demonstrable

nucleotide changes in the DNA of specific genes), these

mutations do impair specific differentiation programmes at

specific times, and they produce tumours in a wide range of

different tissues. The real issue iswhetherwhatwehave learnt

from the fruit fly is applicable more widely in the animal

kingdom. I believe that it is, but I am happy to concede that the

evidence is, for the time being, largely circumstantial.

Reference1. Harris H. 2003. Is collagen XV a tumor suppressor? DNA and Cell Biol

22:225–226.

Henry HarrisSir William Dunn School of Pathology

University of Oxford

South Parks Road

Oxford OX1 3RE

DOI 10.1002/bies.20346

Published online in Wiley InterScience (www.interscience.wiley.com).

BioEssays 28:103, � 2005 Wiley Periodicals, Inc. BioEssays 28.1 103

Correspondence