SECTION: CAPITOL HILL HEARING TESTIMONY

LENGTH: 2602 words

COMMITTEE: SENATE APPROPRIATIONS

SUBCOMMITTEE: LABOR, HEALTH AND HUMAN SERVICES, EDUCATION

HEADLINE: CLONING

TESTIMONY-BY: RUDOLF JAENISCH, PROFESSOR OF BIOLOGY AT THE

AFFILIATION: WHITEHEAD INSTITUTE

BODY:
Senate Hearing/

January 24th, 2002

Rudolf Jaenisch Whitehead Institute and Massachusetts Institute of Technology, Cambridge, MA 02142

I am a professor of biology at the Whitehead Institute and MIT, Boston. I am a basic scientist with a long-term interest in understanding the mechanisms of mammalian development. In recent years my research has focused on the cloning of mice with the goal to understand the reasons why the great majority of cloned animals are abnormal. Most of my funding comes from federal sources through peer reviewed grants from the NIH. My laboratory does not use human ES cells nor is it involved with the reproductive or therapeutic cloning of humans. These are, however, the two issues I want to address in my remarks. 1. REPRODUCTIVE CLONING

In March last year I gave testimony before the House Subcommittee on Energy and Commerce and before the Senate Subcommittee on Commerce, Science and Space: for scientific reasons I warned that any proposal to create humans by cloning would be irresponsible and reckless. Together with Ian Wilmut, who generated Dolly, I wrote an article for Science magazine where we summarized our concerns and I would like to submit that article for the records. Last year, no concrete evidence on gene expression in cloned animals was available and we could not base our opinion on hard molecular data. Since last year we and others have gathered hard molecular data and today we can state with certainty that there are widespread abnormalities in gene expression in cloned animals. For example, a recent study published in Science found that the expression patterns of a majority of the genes examined in the placentas of cloned mice were abnormal. These new data are entirely consistent with my belief that even without overt disease, virtually all cloned animals will have defects of one kind or another. Activists who push for human cloning at this point in time ignore the very worrisome scientific evidence that cloning is unsafe.

In summary, all evidence from animal experiments argues that reproductive cloning of humans is irresponsible and should not be pursued

My stance is clear: As a matter of science and as a personal conviction, I am opposed to human reproductive cloning. However, I am just as staunchly supportive of therapeutic applications of nuclear transfer, sometimes called therapeutic cloning. I believe it would be unfortunate if the door was closed to therapeutic cloning, as this would have grave consequences for an extremely promising new field of medical research. This is the topic I want to focus on.

11. THERAPEUTIC CLONING

The therapeutic cloning approach is based on embryonic stem cells as discussed below.

Embryonic Stem cells: these cells are derived from early embryos and they are cells capable of generating any cell type of the body. Discovered 20 years ago in mice and subject to extensive research, we can predict today with some confidence that these cells can provide unlimited number of cells of any tissue type that can be used for tissue replacement in conditions such as Parkinsons, diabetes, Alzheimers, liver cirrhosis etc. The available evidence suggests that human embryonic stem cells have a similar potential.

Therapeutic cloning: The technique of therapeutic cloning combines nuclear cloning and embryonic stem cell research, with the goal of creating a customized stem cell line for a needy patient. For instance, if one of you is severely diabetic, in this approach we would begin by taking one of your cells, perhaps from a skin biopsy or blood sample, and isolate its nucleus-the core of the cell that carries the chromosomes and all the genetic material. We would then inject your nucleus into an egg whose own nucleus, or genetic material, has been removed. The egg might come from a family member, a wife or daughter who would view the egg donation in the same light as a donation of an organ, a kidney or a liver or perhaps bone marrow or blood. When the nucleus of your skin or blood cell is exposed to signals in the egg, it reverts to its embryonic state-and your skin or blood cell begins to re-express the genes that it expressed when it was an embryo. Whether the cell that results from this process is your skin cell rejuvenated or a new embryo is as much a question of philosophy as of science. The methods are similar to the initial manipulations in reproductive cloning, but the intent is to generate cells for transplantation, not a human being. The cloned cells are grown in the petri dish for a few days, and instead of being implanted into the uterus of a woman, are cultured to generate an embryonic stem cell. This ES cell would match your body perfectly because it is your tissue. We would then coax the ES cells to differentiate in culture to insulin- producing cells, that we could then implant into you without fearing rejection and without the need to treat you with immune suppressive agents. Thus, the embryonic stem cells created by therapeutic cloning are of exclusive benefit to you--the nuclear donor and the recipient of the therapy patient. This contrasts with conventional organ transplantations where often poorly matched donors have to be used leading to major complications due to organ rejection and the use of immunosuppressive drugs.

Therapeutic cloning raises scientific and ethical concerns and I want to address some of these concerns that have been subject to a public debate that often ignores the underlying scientific and biological issues. The following questions are relevant for the potential use of the technology for tissue replacement in human patients.

1. An important issue in this debate is the concern of using embryos that have the potential to develop into a human being as a source for the generation of a cell line. I want, based upon biological facts, to emphasize a critical distinction between therapeutic cloning and the derivation of embryonic stem cells from a fertilized embryo derived by in vitro fertilization (IVF). All existing human embryonic stem cells have been derived from IVF embryos that were not implanted into the uterus. I want to stress two important differences between embryonic stem cells created by IVF or by therapeutic cloning.

a.) In IVF the embryo (i) has a unique combination of genes that has not existed before and (ii) has a high potential to develop into a healthy baby when implanted.

b.) l In therapeutic cloning the embryo (i) has the identical combination of genes as the donor. Therefore, the cloned embryo does NOT represent the creation of a unique new life but rather the reprogramming and rejuvenation of an existing cell from your body. One could argue that this is a special form of autologous transplantation-meaning derived from ones own tissues, which is already widely used in bone marrow, blood, and skin transplantation. (ii) The cloned embryo has a very low potential to ever develop into a normal person, because the overwhelming majority of clones do not gestate normally.

The majority of people in this country appear to accept the generation of embryonic stem cells from " left over" IVF embryos that are not implanted into the womb but would be destined for destruction. The generation of embryonic stem cells from cloned blastocysts for the purpose of therapeutic cloning would appear to pose fewer ethical problems than the generation of embryonic stem cells from IVF embryos.

2. Most animals cloned by nuclear transfer have serious abnormalities and die early in development. This begs the question: Would differentiated cells derived from embryonic stem cells that have been created by nuclear transfer cause similar abnormalities when transplanted into a human patient? Another question was raised by results from my laboratory showing that an important classes of embryonically regulated, imprinted genes are dysregulated in mouse embryonic stem cells, a condition termed epigenetic instability. This evoked an additional concern: Does the epigenetic instability of imprinted genes interfere with their potential use in tissue replacement?

The most serious abnormalities in cloned animals are caused by faulty reprogramming leading to abnormal regulation of genes that are important for the development of a whole embryo. In contrast, when an embryonic stem cell is differentiated in culture to functional tissue cells such as nerve cells, heart muscle cells or beta cells of the pancreas, these developmental genes need not be expressed (because no embryo is generated). Similarly, the faithful expression of imprinted genes is crucial for embryonic development but has probably little if any role for the proper functioning of adult somatic cells. Therefore, problems seen in cloned animals are not expected to affect the function of cells that are derived from cloned embryonic stem cells.

I want to emphasize the difference between generating a cloned animal from a embryonic stem cell nucleus by cloning and the transplantation of differentiated cells derived from the embryonic stem cells. In cloning, the donor nucleus must direct the development of an embryo and of all organs, and faulty reprogramming of the genome causes serious abnormalities in the cloned animal. This is not the case in tissue transplantation where the cells derived from the embryonic stem cell are introduced into a patient, i.e. in an organism that has been derived from a fertilized egg. The extensive experience with mouse embryonic stem cells over the last 20 years indicates that no abnormalities arise when ES cells are introduced into a normal embryo to form "chimeric mice" (as routinely used for gene targeting) or into an adult mouse. Therefore, it is not to be expected that epigenetic instability, if indeed found to be a property of human ES cells, would create a problem for transplantation.

In summary, I do not see Principal scientific reasons that would limit the use of ES cells for tissue repair.

Adult stem cells: An alternative to embryonic stem cells that has attained much attention are adult stem cells: can they provide another source for transplantation? Adult stem cells are isolated from a variety of tissues. They have the surprising ability to differentiate into functional cells such as nerve cells or heart muscle cells and even may have the potential to generate functional cells of tissue types other than that of their own origin. The hope is that such cells can be isolated from the adult and can serve as a source for transplantation. As with therapeutic cloning, the cells would be accepted by the patient but their generation would not involve the creation of a cloned embryo and thus would pose no ethical problems.

Clearly, the recent work on adult stem cells is very exciting and may even be revealing novel biological paradigms. Research on adult stem cells should be supported with great vigor. The question however, is whether the promise of adult stem cells to provide tissue repair is so great as to eliminate the need for research on embryonic stem cells. As a scientist with a broad perspective on these issues, let me give you my opinion.

The field of adult stem cell research is really very young. With the exception of bone marrow stem cells, which have been used for decades in bone marrow transplantation in the clinic, most adult somatic stem cells of other tissues were discovered only in the past few years and they remain poorly defined. Adult somatic stem cells for the brain, liver, pancreas, and skin among others are rare, difficult to purify and in most cases, are challenging to grow in culture. Adult stem cells have not been found in all tissues, and the clinical value of the ones we have at hand has not been established.

Embryonic stem cells have been intensively studied for more than 20 years. Embryonic stem cells, in contrast to adult stem cells, grow indefinitely in culture as homogeneous populations and have been shown to generate all tissue types of the body. Much progress has been made to direct differentiation to desired tissue types. Thus, we can be confident that embryonic stem cells represent the precursors of all tissues and that through research, tissue replacement will be realized in the future.

In conclusion, it would be unfortunate to stop research on embryonic stem cells because of the unrealized Potential of adult stem cells. Research in both fields should proceed with high Priority.

The British solution to embryonic stem cell work and therapeutic cloning is a reasonable one: Cloning of a human embryo for the purpose of creating a person (reproductive cloning) is criminal but cloning of an embryo for therapeutic purpose is permitted (therapeutic cloning). The dividing line between criminal and permitted cloning is a clear one: the implantation of the cloned embryo into the womb. Implantation of a cloned embryo is not permitted but explantation into a petri dish with the intent to derive an embryonic stem cell for therapeutic purpose is permitted. I believe that this dividing line between criminal and permitted manipulation of a human embryo is clearly defined and makes biological sense.

The main question you as legislators have to struggle with when making a decision is this one: do you want to close the door to the most advanced and promising research and deny the many now suffering patients a route for potential cure? To criminalize therapeutic cloning in this country poses serious ethical problems. Given that adult stem cell research is still in its infancy and it cannot be predicted what or when a therapeutic application will be delivered, can we afford to wait until this field has matured? Do you want to tell patients who suffer NOW of incurable and debilitating diseases that they will have to wait for an unspecified number of years until the technical problems of adult stem cells may have been resolved? In contrast, a patient with the same disease in Britain may be able to use a stem cell based therapy in a few years to come.

Unfortunately, the public discussion of therapeutic cloning suffers from serious misconceptions. Often, "reproductive cloning" is not differentiated from "therapeutic cloning". The word "cloning" provokes negative emotional reactions. I am concerned that the revulsion against "cloning" rather than objective reasons may lead to legislative actions that might impede potentially promising research. A case in point is "nuclear magnetic resonance imaging" or "NMRI". This technique, now known as "MRI", became widely used in the clinic as diagnostic procedure only after the word "nuclear" was dropped from its designation (because no radioactive substance is used). It would be unfortunate indeed if legislative decisions would be based on emotional rather than objective criteria.

I want to make a final point. In the 70s, when IVF became available as a reproductive technology, federally funded research was not permitted in this country in contrast to European countries. The result was that IVF was practiced in the private sector and lacked proper supervision. As a consequence, even today the activities of many fertility clinics are unsupervised and lack public scrutiny. It would be unfortunate if a similar mistake were made with therapeutic cloning. I believe we should proceed with this research under tight regulation. The work should be supported by federal funding, peer reviewed and be conducted in academic institutions of the highest standing that are bound to follow scientific and ethical standards and are subject to public scrutiny.



LOAD-DATE: January 24, 2002