An Open Letter to Armand Marie Leroi

Dear Armand,

I’ve recently been persuaded that I should stop identifying you as “Doctor X” and as “Reviewer Number One” of the rejected manuscript. Hence this Open Letter.

This will of necessity include material you may have read in my post-rejection email to the editor of Trends in Ecology and Evolution (TREE) and, perhaps, in prior posts to this site. Sorry, but some duplication cannot be avoided. After all, the prime purpose of an “open” communication is to reach other people, not the nominal addressee.

Parts of this message will be disrespectful. Sorry about that, but you’ve earned it.

Evaluating The Reviewer (Part Three)

In my last post I summarized the difference between me and the reviewer when it came to the question “Can jellyfish get cancer?” In this posting I will explain why that question is critically important, not to cancer researchers or to jellyfish enthusiasts, but to everyone who believes evolutionary theory ought to do what it now fails to accomplish: offer a reasoned mechanistic explanation for ~550 million years of Bilaterian evolution.

In the first paragraph of my peer-reviewed 1983 Letter “Cancer and Evolution: Synthesis” I made crystal clear what this reviewer completely ignores: the nucleus of my theory, its logical core. Here, with emphasis added, are the concluding sentences in that paragraph: 

“Although the precise cellular mechanisms involved in carcinogenesis are not considered here, it is assumed that within a target pre-mitotic cell the following sequence takes place: (a) the mutagen causes a mutational event and (b) oncogenes (Bishop, 1982) initiate transformation to the cancerous state following mitosis. It follows from this sequence that virtually all selected defenses against cancer would have enhanced the ability of the genomes to create organisms in which the genetic program is expressed with great fidelity in all somatic cells.” (1)

Evaluating the Reviewer (Part Two)

In “Cancer and Evolution: Amplification” my 1984 Letter in Journal of Theoretical Biology I make clear my conviction that cancer did not occur in every multicell lineage:

"[Oncogenes have] the potential for killing the organism in whose genetic program they are present, such deaths being initiated by the occurrence of a mutational event in a single somatic cell.  This theory states that oncogenes, thus defined, have been present in every cell of every specimen of every species of the Bilateria that ever existed, and that they have existed nowhere else in nature. " (Emphasis added)

The journal's Reviewer Number One takes a completely different view. As I wrote in my emailed letter to the journal’s editor:

“Reviewer #1 is clearly convinced that cancer can in principle occur in any multicell, that the initiation of the process does not require a specific triggering mechanism. He ignores the work of Varmus and Bishop (which earned a Nobel in 1985) and others in identifying cellular oncogenes, cancer-triggering mechanisms. I have already commented on the problems those discoveries create for conventional evolution theory.”

“Number One also suggests that if only they were examined more closely Cnidarians like jellyfish might exhibit cancer. My contrasting conclusion, inferred from their 500 million years of naked sun-bathing, is that death from carcinogenic UV radiation never threatened the jellyfish lineage. His preference for observational science and his rejection of inferential logic reminds me of the dozy bint I encountered who insisted that a certain 19th Century naturalist erred in concluding that direct observation was not a sufficient means of gaining insights into the history of extant animals.”

To summarize the critical distinction between me and the reviewer as to how the question “Was the jellyfish lineage influenced by cancer selection?” ought to be addressed:

James Graham: Using inferential logic, their ~500 million year history of unshielded exposure to carcinogenic UV radiation is sufficient to conclude that their evolution was unaffected by cancer.

Reviewer Number One: Ignore evolutionary history and do not use inferential logic. Simply observe enough extant jellyfish specimens long enough and cancer might be detected.

I have read enough of the writings of professionals in the biological sciences to know that many are convinced that there is only one scientific method; they seldom employ inferential logic and rely solely on laboratory investigation or direct observation in nature. But why would a scientist holding such narrow views undertake review of a paper submitted to a journal devoted to the historical science of evolution, a paper written by someone whose peer-reviewed published theory is the result of the same methodology he employs in the submitted manuscript?

Evaluating the Reviewer (Part One)

Although the disadvantages of my status as outsider heavily outweigh the advantages, occasionally a situation arises that gives me an opportunity to do something that would probably cause serious difficulties if I were on the faculty of a university or a member of an institutional research team. Perhaps the song "Freedom's just another word for nothing left to lose" exaggerates, but there are situations where the risk involved in reacting strongly to the incompetence of others is minimal and one is compelled to respond with frankness and vigor.

My idea—that lethal juvenile cancer played an essential role in the origin and evolution of complex animals—has gained some notice in journals; my two Journal of Theoretical Biology Letters and my amplifying book have been cited. But those citations appear in works devoted, not to Bilaterian evolution, which is the subject of my work, but to cancer. In an attempt draw the attention of the evolutionary community to my theory I recently submitted a manuscript to an evolution journal. Unfortunately, after review the journal rejected it. I then emailed the editor, telling him I accepted the finality of his decision, but that I found his reviewers' comments of poor quality. I went on to identify the principal reviewer's failings. My email to him was rather lengthy but I will summarize its major points in this and in subsequent postings.

Prior to sending my manuscript out for review the editor disclosed that he had contacted a few scientists about it, including “Doctor X,” who had previously offered me unsolicited (and unwelcome) advice which was the subject of this posting. In my letter to the editor I quoted  dismissive comments about me and my idea made by “X” in an interview with a journalist and in an email to a third party. I also told the editor that I believe his Reviewer #1 was actually “X” himself or his “intellectual, psychological and ethical clone.” I reached that conclusion because the reviewer’s comments reeked of the smugness “X” adopted in communicating with me.

What is most important in understanding what the reviewer did is that my manuscript contained nothing new; I made no original proposals. It is a concise, fact-based argument for the theory already published in the Journal of Theoretical Biology and in my Nature-reviewed book. By telling the editor that mine is a “dubious global theory” and taking the position that an argument in its favor doesn’t deserve publication in an evolution journal, “X” is implying that the following were wrong: the late James F. Danielli, FRS, founding editor of JTB and his co-reviewing member of that journal’s Editorial Board, Nature’s book reviewer and the Nature editor(s?) who decided, first, that my book was worthy of review and then approved publication of the (generally favorable) review. According to this single individual those biologists were all wrong to publish my ideas and he urged the editor not to allow the readers of his evolution journal to even learn of my theory’s existence.

To give some sense of the principal reviewer’s inaccuracies here’s a quote from my letter to the editor:

"Like [X], the reviewer is weirdly obsessed with “diversity.” In his relatively brief comments he mentions “diversity” or “diverse” thirteen times, giving the erroneous impression that my theory is all about (and only about) the number of extant species in Bilaterians versus the other multicells.

"He ignores what I emphasize: fundamental characteristics of Bilaterians…that distinguish them from cell colonies. To cite just one example, there is the matter of phenotypic uniformity in Bilaterians (to the point of eutely in nematodes and some insects). That widespread uniformity reflects a level of control over the precise construction of the entire soma, a degree of control not found in cell colonies. I think fundamental and obvious differences among multicells require solid theoretical explanation and in the historical science of evolution that means identifying explanatory events that occurred in the past. Reviewer #1 obviously does not. He is content with a theory that is silent on such important distinctions."        

This reviewer has read my book (as did “X”) so he knows that in addition to phenotypic uniformity I offer evolutionarily-effective mechanistic explanations (attributed to cancer selection’s postulated occurrence only in Bilaterians) for other fundamental differences between the Bilaterians and the cell colonies including the following:

UV radiation avoidance. The earliest Bilaterians burrowed in the sea bottom and their nearest descendants crawled on the bottom. The crawlers all possessed non-cellular external coverings and their marine descendants lived (for more than 300 million years) in the sea which itself affords environmental shielding from radiation. Of the terrestrial Bilaterians the only ones to shed external protection against radiation were vertebrates equipped with adaptive immune systems capable of killing cancer cells. Terrestrial invertebrate Bilaterians, which do not possess adaptive immune systems, all seem to have retained external non-cellular radiation shields.  In contrast, some cell colonies, notably jellyfish were not even provided external pigmentation which, like non-cellular shielding, would protect from the effects of mutagenic/carcinogenic radiation.

Flamboyant regeneration. With few exceptions (some annelids, echinoderms, salamanders) Bilaterians do not display the spectacular feats of regeneration found in other multicells.

Programmed senescence.  All Bilaterians display genetically-controlled senescence which I claim (on pages 82 and 83 of my book) is an anti-cancer mechanism. Not incidentally, an American biologist has reached an identical conclusion.

The reviewer does not even mention any of these four fundamental differences, all of which I identified in the peer-reviewed Letters and amplified in the Nature-reviewed book. He simply goes on and on (and on and on) about “diversity,” giving the editor the erroneous impression that because there are thousands of non-Bilaterian multicell species my theory is wrong.

Any student who submitted a paper containing such an egregious error would receive a failing grade. But this reviewer convinced the editor not to inform his readers of my published theory.

© 2013 by James Graham

Do Naked Mole Rats Confirm That Senescence is a Cancer Defense?

On page 83 of my 1992 book Cancer Selection I wrote: My theory thus explains the origin and function of [Bilaterian] aging. The programmed shutdown of the cell-renewal process was one of several mechanisms selected to avoid cancer in the earliest [Bilaterians.]

Although The New York Times reported in 2006 that Dr. Norman E. Sharpless of the University of North Carolina reached a similar conclusion (“I don’t think aging is a random process—it’s a program, an anticancer program …”) I am not aware of any published research that would directly confirm or refute this particular part of my theory. But researchers working with naked mole rats may have recently given it some — indirect and tentative — support.

As noted here, here, here and elsewhere these rodents seem to be exceptionally long-lived, with one specimen reaching 28 years. They are exceptional rodents for another reason: they do not get cancer. As reported in 2009 by researchers at the University of Rochester, “a naked mole rat has never been found with tumors of any kind.” More recently (and potentially more significantly) those researchers reported that they have “discovered the chemical that makes naked mole rats cancer-proof.”

So naked mole rats distinguish themselves from other rodents in two ways: they live much longer and they experience zero cancer. In comparison mice live about two years and seem highly susceptible to cancer; a 1962 examination of tumors in randomly gathered wild mice found an incidence of “… 121 neoplasms in 98 animals of a total 225,” an occurrence in forty-four percent of specimens.  (See reference.)

What then is the connection, if any, between the long lives of naked mole rats and their freedom from cancer? A mere coincidence or something more significant?

In Chapter Nine of Cancer Selection I offered a cancer-centered explanation for many fundamental differences between terrestrial vertebrates and terrestrial invertebrates: the vertebrates possess adaptive immune systems capable of killing cancer cells and invertebrates do not. Equipped with that “fail-safe” defense the vertebrate gene pools could produce animals no longer equipped with many preventive defenses against cancer.  In many vertebrate lineages the animals grew larger and lived longer. Larger sizes and longer lifespans required increased mitosis and, given the presence of oncogenes, greater risk of cancer initiation, but, with the presence of the adaptive immune system, no probable long-term increased risk of cancer death. (1)

Not equipped with an adaptive immune system capable of destroying cancer cells, the terrestrial invertebrates depended completely on defenses against cancer initiation. They avoided exposing somatic cells to carcinogenic radiation and eschewed those hallmarks of many vertebrate lineages: increased body sizes and extended lifespans.

If Sharpless and I are correct and Bilaterian senescence is a cancer defense mechanism, did something similar happen with naked mole rats? Did the presence of hyaluronan (HMW-HA), the chemical discovered by the Rochester investigators, reduce the risk of death from cancer to such an extent that it permitted lowering another defense, programmed senescence? Might molecular biologists one day determine that the origin of hyaluronan preceded the mole rats’ extension of lifespan far beyond that of other rodents? (2)

                                                                       *   *   *

Reference: Dawes, Clyde J., “Phylogeny and Oncogeny” pp 1-39 in Neoplasms and Related Disorders of Invertebrates and Lower Vertebrate Animals, National Cancer Institute Monograph 31, July 1969 (Dawes, C.J. and Harshbarger, J.C., eds.)

Notes 

1. A complete pdf of Chapter Nine is now available for downloading at www.jamesgraham.bz.

2.  I argue in Chapter Seven of my book that most Bilaterians do not regenerate damaged tissue as flamboyantly as non-Bilaterian multicells. After further thought, I now think that the exceptional regenerating capability of echinoderms may be related to their apparent immunity to cancer. See Starfish Secrets: Did Echinoderms Cure Cancer?

Comments and questions to the author are welcomed here.

At this site you will find links to additional material including my original Letters to the Journal of Theoretical Biology and  the 1992 Nature review of my book.
   

Copyright © 2013, 2014 by James Graham

This page was archived at The WayBack Machine on April 20, 2015.

Once in Galapagos a Lady ...

What follows is a re-posting of my initial (July 2009) entry to this blog. In it I suggest that perhaps scientists who fail to "see" cancer's role in Bilaterian evolution are emulating a woman who didn't approve of my airplane reading.  
  

This happened in the late 1970s or maybe in the early 1980s. I was returning to New York from a European business trip on a wide-body jet. As was my habit, I had a book with me and once we were airborne, I started to read it, a Penguin trade paperback entitled Evolution, its author, John Maynard Smith. 

In due course a meal was served and I placed the book in the pocket in front of me.

“I see you’re reading that book on evolution.”

It was the woman to my left. A fellow American, a dignified lady of a certain age who had the appearance and manner of someone who had the time (widow?) and money (life insurance proceeds?) to travel the world at her leisure and who spent her time and her money doing exactly that.

I glanced at her and saw from the unsmiling tightness of her mouth that this was not a pleasant query. Oh oh, I thought. Here it comes. 

“So, do you believe in it? In evolution?”

To have given a complete—and completely honest—answer I would have replied, Yes, I’m absolutely convinced that evolution did happen but the accepted theory fails to explain the existence of complex animals. It has a fatal flaw, but—not to worry—I’ve figured out how to fix it. Instead, I took the easy way out and, nodding my head and mumbling, let her know that I found it quite convincing but (the primary function of mumbling?) didn’t care to talk about it.

My fellow passenger then delivered what I am sure she considered the final word on the matter, a triumphant conclusion to our brief conversation.

Twenty-five Questions Not Solved by Conventional Evolutionary Theory

1. In all Bilaterian species individ­ual specimens are very similar to one another; they all have the same complex vital organs arranged in a virtually uniform manner. Some species of nema­todes and rotifers even exhibit eutely: each specimen consists of the identical number of cells arranged in precisely the same pattern. Such strict unifor­mity of entire phenotypes is not found in other multi­cel­ls (plants, Porifera and cnid­arians). In those phyla, plasticity reigns. How could the same mecha­nism, natural selection, possibly explain the emergence of both strict pheno­typic uniformity and wide­spread pheno­typic plasticity?

2. In cell colonies (plants, cnidarians, and Porifera) the most complex and highly organized tissues are those directly involved in sexual reproduc­tion. Natural selection ex­plains sex-organ complexity: if those organs had not functioned with exquisite precision the lineages would have perished. But Bilaterian complexity is different. In those animals vital organs located throughout the body perform func­tions not di­rectly involved in sexual repro­duction. How can the identical mechanism -- natural selection -- logically ac­count both for the existence of complex vital organs in ani­mals and their absence in cell colonies?

3. Among cnidarians, large organisms are found in sunny habitats; in the genus Cyanea some jellyfish grow to two meters in diameter. All jellyfish are comparatively simple organ­isms. However, among the later­ally symmetrical animals the combination of large size and exposure to sunny habi­tat is found only in the most transformed lineages, the terrestrial vertebrates. These animals are extremely complex. There seem to be no large, relatively simple animals (as simple, say, as annelids) living in sunny habitats. Why not?

 

4. Based on the fossil record the earliest Bilaterians all avoid­ed exposure to sunlight. Somatic cells were not directly exposed until about 400 mil­lion years after those ani­mals first appeared, and then only in lineages that produced animals with adaptive immune systems. In fact, most extant Bilaterians avoid expo­sing unprotected cells that divide. On the other hand, plants, Porif­era and most cnida­ria­ns do not avoid sun­light; many spend all their days bask­ing in it. What is the evolu­tion­ari­ly plausible expla­nation for this fundamental differ­ence in the life histo­ries and observed characteristics of the two groups of multicells?

5. Jellyfish fossils found in 2007 in Utah are estimated to be more than 500 million years old. According to University of Kansas investigators the ancient jellyfish were phenotypically very similar to present day jellyfish. It seems that, compared to Bilaterians, there has been little organismic transforma­tion in the cnidarians (and in the Porifera). What is the mechanistic expla­nation for such (what some might call) unpunct­uat­ed equilibrium? 

6. The theoretical problem of senescence, contrary to the opinion of some, has not been solved. Most plants, unlike all Bilaterians, do not exhibit programmed aging. An exception is found in certain bamboo species where all the individual plants live for a fixed number of years before they flower and reproduce. Then all the individual plants die. This is true aging -- the pro­grammed cessa­tion of mitosis following a fixed time period.

But programmed death dependent on cues from the environment which is exhibited by most plants (think of annual plants dying in the fall) is not aging; bring the geraniums inside before frost and they will survive to spring. Perhaps some annual plants do not survive indoors but with few exceptions plants do not undergo the temporal-sensitive slowdown in cell renewal that is the hallmark of aging in Bilaterians. Studies of Porifera and cnidarians indicate that they too do not age. 

All Bilaterians age and investigators have actually identified (in some species) genes "for" senescence.

How could the identical mechanism -- classic Darwinian selection -- possibly account for both the presence of such a fundamental character in all the Bilaterians and its absence in virtually all other multi­cells?