Somatic cell nuclear transfer

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Somatic cell nuclear transfer can create clones for both reproductive and therapeutic purposes. The diagram depicts the removal of the donor nucleus for schematic purposes; in practice usually the whole donor cell is transferred.

In genetics and developmental biology, somatic cell nuclear transfer (SCNT) is a laboratory technique for creating an ovum with a donor nucleus (see process below). It can be used in embryonic stem cell research, or in regenerative medicine where it is sometimes referred to as "therapeutic cloning." It can also be used as the first step in the process of reproductive cloning.

[edit] The process

In SCNT the nucleus, which contains the organism's DNA, of a somatic cell (a body cell other than a sperm or egg cell) is removed and the rest of the cell discarded. At the same time, the nucleus of an egg cell is removed. The nucleus of the somatic cell is then inserted into the enucleated egg cell. After being inserted into the egg, the somatic cell nucleus is reprogrammed by the host cell. The egg, now containing the nucleus of a somatic cell, is stimulated with a shock and will begin to divide. After many mitotic divisions in culture, this single cell forms a blastocyst (an early stage embryo with about 100 cells) with almost identical DNA to the original organism.

[edit] SCNT in stem cell research

Some researchers use SCNT in stem cell research. The aim of carrying out this procedure is to obtain stem cells that are genetically matched to the donor organism. Presently, no human stem cell lines have been derived from SCNT research.

Human Embryonic Stem cell colony on mouse embryonic fibroblast feeder layer.

A potential use of genetically-customized stem cells would be to create cell lines that have genes linked to the particular disease. For example, if a person with Parkinson's disease donated his or her somatic cells, then the stem cells resulting SCNT would have genes that contribute to Parkinson's disease. In this scenario, the disease-specific stem cell lines would be studied in order to better understand the disease.^[1]

In another scenario, genetically-customized stem cell lines would be generated for cell-based therapies to transplant to the patient. The resulting cells would be genetically identical to the somatic cell donor, thus avoiding any complications from immune system rejection.^[1][2]

Only a handful of the labs in the world are currently using SCNT techniques in human stem cell research. In the United States, scientists at the Harvard University Stem Cell Institute, the University of California San Francisco, and possibly Advanced Cell Technology are currently researching a technique to use somatic cell nuclear transfer to produce embryonic stem cells.^[3] In the United Kingdom, the Human Fertilisation and Embryology Authority has granted permission to research groups at the Roslin Institute and the Newcastle Centre for Life.^[4] SCNT may also be occurring in China.^[5]

In 2005, a South Korean research team led by Professor Hwang Woo-suk, published claims to have derived stem cell lines via SCNT,^[6] but supported those claims with fabricated data.^[7] Recent evidence has proved that he in fact created a stem cell line from a parthenote.^{[8] [9]}

[edit] SCNT in reproductive cloning

Main article: cloning

This technique is currently the basis for cloning animals (such as the famous Dolly the sheep)^[10], and in theory could be used to clone humans. However, most researchers believe that in the foreseeable future it will not be possible to use this technique to produce a human clone that will develop to term.^[11][12]

[edit] Limitations

The stresses placed on both the egg cell and the introduced nucleus are enormous, leading to a high loss in resulting cells. For example, Dolly the sheep was born after 277 eggs were used for SCNT, which created 29 viable embryos. Only three of these embryos survived until birth, and only one survived to adulthood.^[10] As the procedure currently cannot be automated, but has to be performed manually under a microscope, SCNT is very resource intensive. The biochemistry involved in reprogramming the differentiated somatic cell nucleus and activating the recipient egg is also far from understood.

In SCNT, not all of the donor cell's genetic information is transferred, as the donor cell's mitochondria that contain their own mitochondrial DNA are left behind. The resulting hybrid cells retain those mitochondrial structures which originally belonged to the egg. As a consequence, clones such as Dolly that are born from SCNT are not perfect copies of the donor of the nucleus.

[edit] Controversy

Main article: stem cell controversy

Human Blastocyst, showing the inner cell mass (top, right).

Proposals to use Nucleus Transfer techniques in human stem cell research raise a set of concerns beyond the moral status of any created embryo. These have led to some individuals and organizations who are not opposed to human embryonic stem cell research to be concerned about, or opposed to, SCNT research. ^[13][14][15]

One concern is that blastula creation in human stem cell research will lead to the reproductive cloning of humans. Both processes use the same first step: the creation of a nuclear transferred embryo, most likely via SCNT. Those who hold this concern often advocate for strong regulation of SCNT to preclude implantation of any derived products for the intention of human reproduction. ^[16], or its prohibition.^[13]

A second important concern is the appropriate source of the eggs that are needed. SCNT requires human eggs, which can only be obtained from women. The most common source of these eggs today are eggs that are produced and in excess of the clinical need during IVF treatment. This is a minimally invasive procedure, but it does carry some health risks, such as ovarian hyperstimulation syndrome, and in very rare instances even death.

One vision for successful stem cell therapies is to create custom stem cell lines for patients. Each custom stem cell line would consist of a collection of identical stem cells each carrying the patient's own DNA, thus reducing or eliminating any problems with rejection when the stem cells were transplanted for treatment. For example, to treat a man with Parkinson's disease, a cell nucleus from one of his cells would be transplanted by SCNT into an egg cell from an egg donor, creating a unique lineage of stem cells almost identical to the patient's own cells. (There would be differences. For example, the mitochondrial DNA would be the same as that of the egg donor. In comparison, his own cells would carry the mitochondrial DNA of his mother.)

Potentially millions of patients could benefit from stem cell therapy, and each patient would require a large number of donated eggs in order to successfully create a single custom therapeutic stem cell line. Such large numbers of donated eggs would exceed the number of eggs currently left over and available from couples trying to have children through assisted reproductive technology. Therefore, healthy young women would need to be induced to sell eggs to be used in the creation of custom stem cell lines that could then be purchased by the medical industry and sold to patients. It is so far unclear where all these eggs would come from. The sale of human eggs is normally referred to as a "donation," but women who donate their eggs are often paid thousands of dollars.

Stem cell experts consider it unlikely that such large numbers of human egg donations would occur in developed country because of the unknown long-term public health effects of treating large numbers of healthy young women with heavy doses of hormones in order to induce hyperovulation (ovulating several eggs at once). Although such treatments have been performed for several decades now, the long-term effects have not been studied or declared safe to use on a large scale on otherwise healthy women. Longer-term treatments with much lower doses of hormones are known to increase the rate of cancer decades later. Whether hormone treatments to induce hyperovulation could have similar effects is unknown. There are also ethical questions surrounding paying for eggs. In general, marketing body parts is considered unethical and is banned in most countries. Human eggs have been a notable exception to this rule for some time.

To address the problem of creating a human egg market, some stem cell researchers are investigating the possibility of creating artificial eggs. If successful, human egg donations would not be needed to create custom stem cell lines. However, this technology may be a long way off.

[edit] Policies

SCNT is currently legal for research purposes in the United Kingdom, having been incorporated into the 1990 Human Fertilisation and Embryology Act in 2001.^[17] Permission must be obtained from the Human Fertilisation and Embryology Authority in order to perform or attempt SCNT.

In the United States, the practice remains legal, as it has not been addressed by federal law.^[18]

In 2005, the United Nations adopted a proposal submitted by Costa Rica, calling on member states to "prohibit all forms of human cloning inasmuch as they are incompatible with human dignity and the protection of human life." ^[19] This phrase may include SCNT, depending on interpretation.

The Council of Europe's Convention on Human Rights and Biomedicine and its Additional Protocol to the Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine, on the Prohibition of Cloning Human Being appear to ban SCNT. Of the Council's 45 member states, the Convention has been signed by 31 and ratified by 18. The Additional Protocol has been signed by 29 member nations and ratified by 14.^[20]

[edit] See also

• Stem cell research
• Stem cell controversy
• Embryogenesis
• In vitro fertilisation
• Cloning
• New Jersey legislation S1909/A2840
• Rejuvenation

[edit] References

1. ^ ^{a b} Semb H. "Human embryonic stem cells: origin, properties and applications." APMIS. 2005 Nov-Dec;113(11-12):743-50. PMID 16480446
2. ^ Hadjantonakis AK, Papaioannou VE. "Can mammalian cloning combined with embryonic stem cell technologies be used to treat human diseases? Genome Biol. 2002 Jul 30;3(8):REVIEWS1023. PMID 12186652
3. ^ Elizabeth Weise, "Cloning race is on again," USA Today (January 17, 2006, retrieved October 6, 2006)
4. ^ "Dolly scientists' human clone bid," BBC News (September 28, 2004, retrieved October 6, 2006)
5. ^ Charles C. Mann, "The First Cloning Superpower," Wired (January 2003, retrieved October 6, 2006)
6. ^ Hwang WS, Roh SI, Lee BC, Kang SK, Kwon DK, Kim S, Kim SJ, Park SW, Kwon HS, Lee CK, Lee JB, Kim JM, Ahn C, Paek SH, Chang SS, Koo JJ, Yoon HS, Hwang JH, Hwang YY, Park YS, Oh SK, Kim HS, Park JH, Moon SY, Schatten G. "Patient-specific embryonic stem cells derived from human SCNT blastocysts." Science. 2005 Jun 17;308(5729):1777-83. PMID 15905366
7. ^ Kennedy D. "Editorial retraction. of Hwang WS et al." Science. 2006 Jan 20;311(5759):335. PMID 16410485
8. ^ [1],Nature Stem Cell Blog.
9. ^ [2], The Scientist 19 June 2007
10. ^ ^{a b} Campbell KH, McWhir J, Ritchie WA, Wilmut I. "Sheep cloned by nuclear transfer from a cultured cell line." Nature. 1996 Mar 7;380(6569):64-6. PMID 8598906
11. ^ Revel M. "Research on animal cloning technologies and their implications in medical ethics: an update." Med Law. 2000;19(3):527-43. PMID 11143888
12. ^ Rhind SM, Taylor JE, De Sousa PA, King TJ, McGarry M, Wilmut I. "Human cloning: can it be made safe?" Nat Rev Genet. 2003 Nov;4(11):855-64. PMID 14634633
13. ^ ^{a b} Jeremy Rifkin. (February 18, 2002). "Fusion Biopolitics." The Nation. Retrieved on August 7, 2006.
14. ^ Sheryl Gay Stolberg, "Some for Abortion Rights Lean Right in Cloning Fight," New York Times (January 24, 2002)
15. ^ Lori B. Andrews, et al, Open Letter to US Senate on Human Cloning, (March 19, 2002)
16. ^ Lori B. Andrews et al. (March 19, 2002)."Open Letter to US Senators on Human Cloning and Eugenic Engineering." Retrieved on August 7, 2006
17. ^ Andy Coghlan, "Cloning opponents fear loopholes in new UK law," New Scientist (November 23, 2001, retrieved October 6, 2006)
18. ^ "Chapter 5: Legal and Policy Considerations. Cloning Human Beings" Report and Recommendations of the National Bioethics Advisory Commission, June 1997. Accessed 21 Oct 06
19. ^ United Nations, "General Assembly Adopts United Nations Declaration on Human Cloning By Vote of 84-34-37," press release (August 3, 2005, retrieved October 6, 2006)
20. ^ Council of Europe, Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine (April 4, 1997, retrieved October 6, 2006); Council of Europe, Additional Protocol to the Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine, on the Prohibition of Cloning Human Being (January 12, 1998, retrieved October 6, 2006)

[edit] Further reading

• Somatic cell nuclear transfer. Wilmut I, Beaujean N, de Sousa PA, Dinnyes A, King TJ, Paterson LA, Wells DN, Young LE. Nature. 2002 Oct 10;419(6907):583-6. PMID 12374931
• Reprogramming nuclei: insights from cloning, nuclear transfer and heterokaryons. (Free full text) Kikyo N, Wolffe AP. J Cell Sci. 2000 Jan;113 ( Pt 1):11-20.
• Cloning animals by somatic cell nuclear transfer--biological factors. (Free full text) Tian XC, Kubota C, Enright B, Yang X. Reprod Biol Endocrinol. 2003 Nov 13;1:98.
• Nuclear reprogramming and stem cell creation. (Free full text) Gurdon JB, Byrne JA, Simonsson S. Proc Natl Acad Sci U S A. 2003 Sep 30;100 Suppl 1:11819-22. Epub 2003 Aug 14.

[edit] External links

• Research Cloning: Medical and scientific, legal and ethical aspects
• The Basics: Stem Cells and Public Policy The Century Foundation, June 2005
• "Research Cloning Basic Science," Center for Genetics and Society, (Last modified October 4, 2004, retrieved October 6, 2006)
• Cloning: present uses and promises National Institutes of Health, Paper giving background information on cloning in general and SCNT from The Office of Science Policy Analysis.
• Nuclear Transfer -- Stem Cells or Somatic Cell Nuclear Transfer (SCNT) The International Society for Stem Cell Research
• The Hinxton Group: An International Consortium on Stem Cells, Ethics & Law