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The implications of Steele's soma-to-germline feedback for the safety of somatic gene therapy in humans.

by G. Korthof
20 Mar 1999
last update: 24 Sep 2002

    Scientists in the field of somatic and germline gene therapy in humans are either unaware of, or are silent about the fact that the Weismann Barrier could be permeable. They apparently don't know about the evidence supporting soma-to-germline gene flow.

Edward J. Steele, Robyn A. Lindley and Robert V. Blanden(1998) presented in their book Lamarck's Signature. How Retrogenes Are Changing Darwin's Natural Selection Paradigm evidence supporting the hypothesis that Weismann's Barrier (3) is selective permeable for DNA.
A couple of quotes from the Internet sites of the players in the field show the ignorance of the facts and the hypothesis. For example the document Germline Gene Therapy from the UCLA Center for the Study of Evolution and the Origin of Life :

"Somatic Cells make up the rest of the body. Changes to their genes do not pass to the next generation. Indeed, a central tenet of Mendelian genetics, the Weissman boundary, asserts that nothing that happens to the somatic cells or tissues of a mammal will have any effect whatsoever on the genetic information transmitted to its offspring."
Wilson Also Jim Wilson (see photo) from The Institute for Human Gene Therapy (IHGT) (4) from the University of Pennsylvania states:
Somatic gene therapy involves the manipulation of gene expression in cells that will be corrective to the patient but not inherited to the next generation.

And in Gene Therapy - An Overview we read:

The types of gene therapy described thus far all have one factor in common: that is, that the tissues being treated are somatic (somatic cells include all the cells of the body, excluding sperm cells and egg cells). In contrast to this is the replacement of defective genes in the germline cells (which contribute to the genetic heritage of the offspring). Gene therapy in germline cells has the potential to affect not only the individual being treated, but also his or her children as well.
In a report of the U.S. FOOD AND DRUG ADMINISTRATION we find a "Definition of transgenic animal":
A "transgenic animal" is defined as an animal which is altered by the introduction of recombinant DNA through human intervention. This includes two classes of animals; those with heritable germline DNA alterations, and those with somatic non-heritable alterations. Examples of the first class include animals with germline DNA altered through methods requiring ex vivo manipulation of gametes, early embryonic stages, or embryonic stem cell lines. Examples of the second class include animals with somatic cell DNA alterations achieved through gene therapy approaches such as direct plasmid DNA injection or virally-mediated gene transfer." "Transgene" refers to a segment of recombinant DNA which is either: 1) introduced into somatic cells, or 2) integrated stably into the germline of its animal host strain, and is transmissible to subsequent generations."
In Somatic vs. Germline Gene Therapy we read:
"Somatic cell gene therapy involved replacing a defective gene with a healthy gene in order to alleviate a disease. With this type of gene therapy the replaced gene would only affect the host because it would die when the host died. However, germ line gene therapy raised many more questions. This type of gene therapy concerned genetic changes which would be transmitted from the patient to their children because it affected the germ cells (sperm or eggs). "
On the Terminology Page of the American Society of Gene Therapy we read:
"Somatic Therapy: involves the manipulation of gene expression in cells that will be corrective to the patient but not inherited by the next generation. Somatic cells include all the non-reproductive cells in the human body."
The Internet sources can easily be extended with quotes from books on human genetics. For example Peter Sudbery(6) states:
"The crucial difference between somatic and germline gene therapy is that in the first, any genetic changes are restricted to the lifetime of the person treated, while in germline therapy any change is passed on to subsequent generations. Somatic gene therapy poses few ethical problems, but germline gene therapy represents a fundamentally new type of human activity whose consequences need to be thought through carefully before any experiments are attempted."
In the quoted articles no author considers the possibility that vectors targeted at somatic cells could end up in germline cells. The suggestion is that because somatic gene therapy is not inherited by definition, that's how gene therapy behaves in real-life. People writing about the safety and ethics of somatic gene therapy in humans, all assume somatic gene therapy does not and cannot have an effect on the germline. Apart from the first quote nobody explicitly states why there could not be such an effect. The effect on the germline could be viewed disadvantageous or advantageous. The point is that people in the gene therapy field assume that there is an ethical relevant difference between somatic and germline gene therapy, as can be concluded from their websites. The limited scope of somatic gene therapy, the individual, is contrasted with the effects for the human gene pool of germline therapy. However if Weismann's Barrier is permeable, this assumption is wrong. The more effective the soma-to-germline feedback system of Edward Steele is, the less relevant the ethical difference between somatic and germline gene therapy is. If somatic immuno-V-genes can find their way to the germline and can precisely replace germline V-genes, why not any other gene in a viral vector ?
"It is now generally accepted that the main limitations to widespread somatic gene therapy are simply the technical ones of devising effective vectors and transgenes. Most general reservations over safety and philosophical issues have now been satisfied."
From: UCLA Center for the Study of Evolution and the Origin of Life
   I don't know if the techniques used in human gene therapy promote gene transfer to the germline. However the point is that the websites of the organisations involved in human gene therapy do not tell us about the evidence for the permeability of the Weismann Barrier. There are two possible explanations for this omission. The first: they don't know the facts and in that case they are scientifically careless and possibly wrong. They are certainly wrong if Steele's hypothesis is right. The second: they do know about it, but are silent. In that case they are dishonest.

From an unexpected source and independent of Steele's line of research, for the first time evidence has been produced that a therapeutic gene used to treat a disease in animals found its way into sperm and eggs (1).
Mohan Raizada et al (2) at the University of Florida in Gainesville have delivered a therapeutic gene, inserted in a modified virus, into the hearts of rats that are predisposed to high blood pressure, and these rats and two subsequent generations were protected from hypertension.
Raizada: "Our data support the notion that the AT1R-AS is integrated into the parental genome and is transmitted to the offspring. The possibility that lack of a blood-gonadal barrier (3) and the presence of significant numbers of undifferentiated germ cells in the neonatal rat cannot be ruled out." According to Theodore Friedmann, director of the human gene therapy programme at the University of California in San Diego "this is a startling and very surprising result. It would have been impressive if even a few viruses travelled from the heart to the gonads, but the idea that all offspring inherited the therapeutic gene seems inconceivable".
Indeed inconceivable if one dogmatically accepts the Weismann Barrier and indeed surprising if one doesn't know about Steele's results.

Growing awareness?

A report Human Inheritable Genetic Modifications published Sep 2000 by the American Association for the Advancement of Science stated ('admitted') that it is very likely that some of the adult gene therapy trials in the US have had unintentional impacts on the germline. This is the first time that the idea of 'unintentional' germline effects is used in an official report, thereby blurring the distinction somatic/germline. Typically 'somatic' and 'germline' were separated literally by definition. A lot of what gene therapy institutes told (and tell?) the public on their websites is Public Relations stuff and propaganda. According to Norman Nevin, chair of he government's Gene Therapy Advisory Committee, "a proposal for in utero (fetal) gene therapy is unlikely to be approved, because of the risk of accidentally introducing germline changes". However Charles Coutelle (Imperial College School, London) says:"We should try to avoid germline gene transfer, but if it happens, it has to be balanced against the benefits. And that holds for all the gene therapy trials." Stuart Newman (New York Medical College) says: "Somatic modification in embryos is a grey area because there is a greater likelihood of germline modification." (5). Nobody mentioned the Weismann Barrier or Steele's work.
    On 13 Dec 2001 an article in Nature stated: "A patient in a gene-therapy trial has had the virus used to transfer the gene show up in his semen. The finding highlights the danger that gene therapy may inadvertently modify the genetic make-up of a patient's children." (7). Unexpectedly the gene was detected in the semen, but it was not detected in the sperm. "The FDA has said that no additional patient can be enrolled in the trial until each patient's semen tests negative for three months". A growing awareness in the end? Or do they still believe in the Weismann Barrier? A remark in the same article suggests this indeed: "researches suspect that evolution has devised ways of protecting the genetic cargo of eggs and sperm from viral onslaught."

    Feb 2002 the Food and Drug Administration FDA published a letter to Jim Wilson (10), from which I quote the part relevant for the effect on the germline (emphasis added):

"You failed to inform subjects that they should not donate blood or gametes, and you failed to inform subjects that gene transfer had potential to alter the genetic composition of reproductive cells. In FDA's letter dated June 13,1996, sent to you in your role as sponsor of the research, FDA requested that additional information be added to the informed consent document, including an instruction that subjects were not to donate blood or gametes, and a description of the potential germ-line effects of gene therapy. You expressly confirmed in writing, in your letter dated October 7, 1996, that you had added the instruction not to donate blood or gametes to the consent form. In fact, you did not add such wording to the consent form submitted to the IRBs at any time during the study, and you did not describe the potential effects of gene transfer on reproductive cells. This information was important to adequately inform the potential study subjects whose consent was sought."

In 2004 the CPMP Gene Therapy Expert Group of the European Medicine Agency, EMEA, published a report in which a discussion appeared about germline integration. By this they mean inadvertent germline integration of gene transfer vectors. "The possibility of exposure of gonadal tissue to gene transfer medicinal products raises safety concerns about vertical germline transmission of vector DNA." (11). It seems that the EMEA now acknowledges that DNA could pass the Weismann Barrier (without mentioning that name).

Horizontal Gene Transfer

[updated 15 June 2006]

Apart from the soma-to-germline feedback hypothesis, there is a group of phenomena that have implications for the Weismann Barrier. Horizontal Gene Transfer (Lateral Gene Transfer) is the natural transfer of DNA from one species to an unrelated species, especially interkingdom gene transfer. If a certain gene is present in the genome of all individuals of a species and if it is confirmed that it is a case of Horizontal Gene Transfer, then the gene must have passed the Weismann Barrier. So all cases of Horizontal Gene Transfer inevitably imply a passage of the Weismann Barrier. Direct uptake of foreign genetic material by the germ line is suggested by the evidence. Bushman (2002) uses the word 'germ-line tropism' (page 223), but he does not give any further details. In any case it seems that some retroviruses are able to insert themselves in the germline, while others such as HIV fail to do so and instead target immune cells (soma). Bushman notes also that nondestructive replication in germline is required (otherwise the sperm or egg will be destroyed and cannot participate in fertilisation). So a combination of 'germ-line tropism' and nondestructive replication is required for successful integration in the germline.
    Evidence for Horizontal Gene Transfer in bacteria, plants and animals has been collected in Syvanen and Kado (8). In another recent book Lateral DNA Transfer by Frederic Bushman (9) a magnificent overview is given of lateral gene transfer in all forms of life. Highly relevant is the topic "endogenous retroviruses". Endogenous retroviruses have been demonstrated in mice, pigs and humans. They originate from retroviral infection of germ-line cells (egg or sperm), followed by a stable integration in the genome of the species (p203).
"Humans harbor many endogenous retroviruses. Analysis reveals that the human genome contains fully 8% endogenous retroviral sequences, emphasizing the contribution of retroviruses to our genetic heritage" (p.204).
But again this means that all those sequences must have passed the Weismann Barrier. Isn't weird that the Weismann Barrier is not mentioned in both books? The word is not in the index of both books. This is even more bizarre because the authors are establishing a new paradigm in genetics and evolution. They are attacking Common Descent as the sole explanation of the genomes of species. One would have expected a discussion of the implications of their findings for the Weismann Barrier, but I did not find it. The Neo-Darwinian Evolutionary Synthesis excludes any form of Lamarckism from evolution. Lamarckism is the inheritance of acquired characteristics. Endogenous retroviruses are inherited acquired characteristics. So all Horizontal Gene Transfer is a form of Lamarckism. Could it be that Lamarckism is too heretical for these authors? end

References:

  1. Chance inheritance: has a gene therapy left its mark on the next generation?, New Scientist, 20 November 1999, p 7.
  2. Permanent Cardiovascular Protection From Hypertension by the AT1 Receptor Antisense Gene Therapy in Hypertensive Rat Offspring, Circulation Research 1999;85:e44. abstract; full text.
  3. Weismann Barrier proposed by August Weismann in 1885.
  4. 18-year-old Jesse Gelsinger was the first patient who died in a gene-therapy clinical trial (17 Sep 1999), which was conducted by the IHGT (see for example Nature 401, 517-518; 1999 and Nature 405, 497; 2000).
  5. As reported by Joanna Marchant in the New Scientist, 2 Dec 2000, p16-17.
  6. Peter Sudbery(1998) Human Molecular Genetics, p156.
  7. Nell Boyce(2001) "Trial halted after gene shows up in semen", Nature 414, 677 (13 Dec)
  8. Syvanen and Kado(2002): "Horizontal Gene Transfer", Second edition, Academic Press, 445 pages.
  9. Frederic Bushman(2002): "Lateral DNA Transfer. Mechanisms and consequences". Cold Spring Harbor Laboratory Press, 448 pages. Reviewed in: American Scientist July-August 2002 by Michael Syvanen.
  10. Letter from the FDA to Jim Wilson, the leader of the genetherapy clinical trial that resulted in the death of Jesse Gelsinger (FEB 2002) (big file)
  11. EMEA, EMEA/CPMP/1879/04/Final

Further Reading:


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Copyright ©1999-2002 Gert Korthof First published: 20 Mar 1999 updated: 9 Jan 2005