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Wednesday, June 27, 2018

Human cloning

From Wikipedia, the free encyclopedia

Diagram of the ways to reprogram cells along with the development of humans.

Human cloning is the creation of a genetically identical copy (or clone) of a human. The term is generally used to refer to artificial human cloning, which is the reproduction of human cells and tissue. It does not refer to the natural conception and delivery of identical twins. The possibility of human cloning has raised controversies. These ethical concerns have prompted several nations to pass laws regarding human cloning and its legality.

Two commonly discussed types of theoretical human cloning are: therapeutic cloning and reproductive cloning. Therapeutic cloning would involve cloning cells from a human for use in medicine and transplants, and is an active area of research, but is not in medical practice anywhere in the world, as of April 2017. Two common methods of therapeutic cloning that are being researched are somatic-cell nuclear transfer and, more recently, pluripotent stem cell induction. Reproductive cloning would involve making an entire cloned human, instead of just specific cells or tissues.

History

Although the possibility of cloning humans had been the subject of speculation for much of the 20th century, scientists and policy makers began to take the prospect seriously in the mid-1960s.

Nobel Prize-winning geneticist Joshua Lederberg advocated cloning and genetic engineering in an article in The American Naturalist in 1966 and again, the following year, in The Washington Post.[1] He sparked a debate with conservative bioethicist Leon Kass, who wrote at the time that "the programmed reproduction of man will, in fact, dehumanize him." Another Nobel Laureate, James D. Watson, publicized the potential and the perils of cloning in his Atlantic Monthly essay, "Moving Toward the Clonal Man", in 1971.[2]

With the cloning of a sheep known as Dolly in 1996 by somatic cell nuclear transfer (SCNT), the idea of human cloning became a hot debate topic.[3] Many nations outlawed it, while a few scientists promised to make a clone within the next few years. The first hybrid human clone was created in November 1998, by Advanced Cell Technology. It was created using SCNT - a nucleus was taken from a man's leg cell and inserted into a cow's egg from which the nucleus had been removed, and the hybrid cell was cultured, and developed into an embryo. The embryo was destroyed after 12 days.[4]

In 2004 and 2005, Hwang Woo-suk, a professor at Seoul National University, published two separate articles in the journal Science claiming to have successfully harvested pluripotent, embryonic stem cells from a cloned human blastocyst using somatic-cell nuclear transfer techniques. Hwang claimed to have created eleven different patent-specific stem cell lines. This would have been the first major breakthrough in human cloning.[5] However, in 2006 Science retracted both of his articles on clear evidence that much of his data from the experiments was fabricated.[6]

In January 2008, Dr. Andrew French and Samuel Wood of the biotechnology company Stemagen announced that they successfully created the first five mature human embryos using SCNT. In this case, each embryo was created by taking a nucleus from a skin cell (donated by Wood and a colleague) and inserting it into a human egg from which the nucleus had been removed. The embryos were developed only to the blastocyst stage, at which point they were studied in processes that destroyed them. Members of the lab said that their next set of experiments would aim to generate embryonic stem cell lines; these are the "holy grail" that would be useful for therapeutic or reproductive cloning.[7][8]

In 2011, scientists at the New York Stem Cell Foundation announced that they had succeeded in generating embryonic stem cell lines, but their process involved leaving the oocyte's nucleus in place, resulting in triploid cells, which would not be useful for cloning.[9][10][11]

In 2013, a group of scientists led by Shoukhrat Mitalipov published the first report of embryonic stem cells created using SCNT. In this experiment, the researchers developed a protocol for using SCNT in human cells, which differs slightly from the one used in other organisms. Four embryonic stem cell lines from human fetal somatic cells were derived from those blastocysts. All four lines were derived using oocytes from the same donor, ensuring that all mitochondrial DNA inherited was identical.[9] A year later, a team led by Robert Lanza at Advanced Cell Technology reported that they had replicated Mitalipov's results and further demonstrated the effectiveness by cloning adult cells using SCNT.[3][12]

In 2018, the first successful cloning of primates using somatic cell nuclear transfer, the same method as Dolly the sheep, with the birth of two live female clones (crab-eating macaques named Zhong Zhong and Hua Hua) was reported.[13][14][15][16][17]

Methods

Somatic cell nuclear transfer (SCNT)


Diagram of SCNT Process

In somatic cell nuclear transfer ("SCNT"), the nucleus of a somatic cell is taken from a donor and transplanted into a host egg cell, which had its own genetic material removed previously, making it an enucleated egg. After the donor somatic cell genetic material is transferred into the host oocyte with a micropipette, the somatic cell genetic material is fused with the egg using an electric current. Once the two cells have fused, the new cell can be permitted to grow in a surrogate or artificially.[18] This is the process that was used to successfully clone Dolly the sheep (see section on History in this article).[3]

Induced pluripotent stem cells (iPSCs)


Overview of iPS cells

Creating induced pluripotent stem cells ("iPSCs") is a long and inefficient process. Pluripotency refers to a stem cell that has the potential to differentiate into any of the three germ layers: endoderm (interior stomach lining, gastrointestinal tract, the lungs), mesoderm (muscle, bone, blood, urogenital), or ectoderm (epidermal tissues and nervous tissue).[19] A specific set of genes, often called "reprogramming factors", are introduced into a specific adult cell type. These factors send signals in the mature cell that cause the cell to become a pluripotent stem cell. This process is highly studied and new techniques are being discovered frequently on how to better this induction process.

Depending on the method used, reprogramming of adult cells into iPSCs for implantation could have severe limitations in humans. If a virus is used as a reprogramming factor for the cell, cancer-causing genes called oncogenes may be activated. These cells would appear as rapidly dividing cancer cells that do not respond to the body's natural cell signaling process. However, in 2008 scientists discovered a technique that could remove the presence of these oncogenes after pluripotency induction, thereby increasing the potential use of iPSC in humans.[20]

Comparing SCNT to reprogramming

Both the processes of SCNT and iPSCs have benefits and deficiencies. Historically, reprogramming methods were better studied than SCNT derived embryonic stem cells (ESCs).[9] However, more recent studies have put more emphasis on developing new procedures for SCNT-ESCs. The major advantage of SCNT over iPSCs at this time is the speed with which cells can be produced. iPSCs derivation takes several months while SCNT would take a much shorter time, which could be important for medical applications. New studies are working to improve the process of iPSC in terms of both speed and efficiency with the discovery of new reprogramming factors in oocytes. Another advantage SCNT could have over iPSCs is its potential to treat mitochondrial disease, as it utilizes a donor oocyte.[9] No other advantages are known at this time in using stem cells derived from one method over stem cells derived from the other.[21]

Uses, actual and potential


Stem cell treatments

Work on cloning techniques has advanced our basic understanding of developmental biology in humans. Observing human pluripotent stem cells grown in culture provides great insight into human embryo development, which otherwise cannot be seen. Scientists are now able to better define steps of early human development. Studying signal transduction along with genetic manipulation within the early human embryo has the potential to provide answers to many developmental diseases and defects. Many human-specific signaling pathways have been discovered by studying human embryonic stem cells. Studying developmental pathways in humans has given developmental biologists more evidence toward the hypothesis that developmental pathways are conserved throughout species.[22]

iPSCs and cells created by SCNT are useful for research into the causes of disease, and as model systems used in drug discovery.[23][24]

Cells produced with SCNT, or iPSCs could eventually be used in stem cell therapy,[25] or to create organs to be used in transplantation, known as regenerative medicine. Stem cell therapy is the use of stem cells to treat or prevent a disease or condition. Bone marrow transplantation is a widely used form of stem cell therapy.[26] No other forms of stem cell therapy are in clinical use at this time. Research is underway to potentially use stem cell therapy to treat heart disease, diabetes, and spinal cord injuries.[27][28] Regenerative medicine is not in clinical practice, but is heavily researched for its potential uses. This type of medicine would allow for autologous transplantation, thus removing the risk of organ transplant rejection by the recipient.[29] For instance, a person with liver disease could potentially have a new liver grown using their same genetic material and transplanted to remove the damaged liver.[30] In current research, human pluripotent stem cells have been promised as a reliable source for generating human neurons, showing the potential for regenerative medicine in brain and neural injuries.[31]

Ethical implications

In bioethics, the ethics of cloning refers to a variety of ethical positions regarding the practice and possibilities of cloning, especially human cloning. While many of these views are religious in origin, the questions raised by cloning are faced by secular perspectives as well. Human therapeutic and reproductive cloning are not commercially used; animals are currently cloned in laboratories and in livestock production.
Advocates support development of therapeutic cloning in order to generate tissues and whole organs to treat patients who otherwise cannot obtain transplants,[32] to avoid the need for immunosuppressive drugs,[33] and to stave off the effects of aging.[34] Advocates for reproductive cloning believe that parents who cannot otherwise procreate should have access to the technology.[35]

Opposition to therapeutic cloning mainly centers around the status of embryonic stem cells, which has connections with the abortion debate.[36]

Some opponents of reproductive cloning have concerns that technology is not yet developed enough to be safe - for example, the position of the American Association for the Advancement of Science as of 2014,[37] while others emphasize that reproductive cloning could be prone to abuse (leading to the generation of humans whose organs and tissues would be harvested),[38][39] and have concerns about how cloned individuals could integrate with families and with society at large.[40][41]

Religious groups are divided, with some[which?] opposing the technology as usurping God's (in monotheistic traditions) place and, to the extent embryos are used, destroying a human life; others support therapeutic cloning's potential life-saving benefits.[42][43]

Current law

In 2015 it was reported that about 70 countries had banned human cloning.[44]

Argentina

Human cloning is banned by the Presidential Decree 200/97 of 7 March 1997.[45]

Australia

Australia has prohibited human cloning,[46] though as of December 2006, a bill legalizing therapeutic cloning and the creation of human embryos for stem cell research passed the House of Representatives. Within certain regulatory limits, and subject to the effect of state legislation, therapeutic cloning is now legal in some parts of Australia.[47]

Canada

Canadian law prohibits the following: cloning humans, cloning stem cells, growing human embryos for research purposes, and buying or selling of embryos, sperm, eggs or other human reproductive material.[48] It also bans making changes to human DNA that would pass from one generation to the next, including use of animal DNA in humans. Surrogate mothers are legally allowed, as is donation of sperm or eggs for reproductive purposes. Human embryos and stem cells are also permitted to be donated for research.[citation needed]

There have been consistent calls in Canada to ban human reproductive cloning since the 1993 Report of the Royal Commission on New Reproductive Technologies. Polls have indicated that an overwhelming majority of Canadians oppose human reproductive cloning, though the regulation of human cloning continues to be a significant national and international policy issue. The notion of "human dignity" is commonly used to justify cloning laws. The basis for this justification is that reproductive human cloning necessarily infringes notions of human dignity.[49][50][51][52]

Colombia

Human cloning is prohibited in Article 133 of the Colombian Penal Code.[53]

European Union

The European Convention on Human Rights and Biomedicine prohibits human cloning in one of its additional protocols, but this protocol has been ratified only by Greece, Spain and Portugal. The Charter of Fundamental Rights of the European Union explicitly prohibits reproductive human cloning. The charter is legally binding for the institutions of the European Union under the Treaty of Lisbon and for member states of the Union implementing EU law.[54][55]

India

India does not have specific law regarding cloning but has guidelines prohibiting whole human cloning or reproductive cloning. India allows therapeutic cloning and the use of embryonic stem cells for research proposes.[56][57]

Russia

The Federal Assembly of Russia introduced the Federal Law N 54-FZ "On the temporary ban on human cloning" in April 19, 2002. On May 20, 2002 President Vladimir Putin signed this moratorium on the implementation of human cloning. On March 29, 2010 The Federal Assembly introduced second revision of this law without time limit.[58]

Serbia

Human cloning is explicitly prohibited in Article 24, "Right to Life" of the 2006 Constitution of Serbia.[59]

South Africa

In terms of section 39A of the Human Tissue Act 65 of 1983,[60] genetic manipulation of gametes or zygotes outside the human body is absolutely prohibited. A zygote is the cell resulting from the fusion of two gametes; thus the fertilised ovum. Section 39A thus prohibits human cloning.

United Kingdom

On January 14, 2001 the British government passed The Human Fertilisation and Embryology (Research Purposes) Regulations 2001[61] to amend the Human Fertilisation and Embryology Act 1990 by extending allowable reasons for embryo research to permit research around stem cells and cell nuclear replacement, thus allowing therapeutic cloning. However, on November 15, 2001, a pro-life group won a High Court legal challenge, which struck down the regulation and effectively left all forms of cloning unregulated in the UK. Their hope was that Parliament would fill this gap by passing prohibitive legislation.[62][63] Parliament was quick to pass the Human Reproductive Cloning Act 2001 which explicitly prohibited reproductive cloning. The remaining gap with regard to therapeutic cloning was closed when the appeals courts reversed the previous decision of the High Court.[64]

The first license was granted on August 11, 2004 to researchers at the University of Newcastle to allow them to investigate treatments for diabetes, Parkinson's disease and Alzheimer's disease.[65] The Human Fertilisation and Embryology Act 2008, a major review of fertility legislation, repealed the 2001 Cloning Act by making amendments of similar effect to the 1990 Act. The 2008 Act also allows experiments on hybrid human-animal embryos.[66]

United Nations

On December 13, 2001, the United Nations General Assembly began elaborating an international convention against the reproductive cloning of humans. A broad coalition of States, including Spain, Italy, the Philippines, the United States, Costa Rica and the Holy See sought to extend the debate to ban all forms of human cloning, noting that, in their view, therapeutic human cloning violates human dignity. Costa Rica proposed the adoption of an international convention to ban all forms of human cloning. Unable to reach a consensus on a binding convention, in March 2005 a non-binding United Nations Declaration on Human Cloning, calling for the ban of all forms of human cloning contrary to human dignity, was adopted.[67][68]

United States

The Patients First Act of 2017 (HR 2918, 115th Congress) aims to promote stem cell research, using cells that are “ethically obtained”, that could contribute to a better understanding of diseases and therapies, and promote the “derivation of pluripotent stem cell lines without the creation of human embryos…”.[69]

In 1998, 2001, 2004, 2005, 2007 and 2009, the US Congress voted whether to ban all human cloning, both reproductive and therapeutic (see Stem Cell Research Enhancement Act). Each time, divisions in the Senate, or an eventual veto from the sitting President (President George W. Bush in 2005 and 2007), over therapeutic cloning prevented either competing proposal (a ban on both forms or on reproductive cloning only) from being passed into law. On March 10, 2010 a bill (HR 4808) was introduced with a section banning federal funding for human cloning.[70] Such a law, if passed, would not have prevented research from occurring in private institutions (such as universities) that have both private and federal funding. However, the 2010 law was not passed.

There are currently no federal laws in the United States which ban cloning completely. Fifteen American states (Arkansas, California, Connecticut, Iowa, Indiana, Massachusetts, Maryland, Michigan, North Dakota, New Jersey, Rhode Island, South Dakota, Florida, Georgia, and Virginia) ban reproductive cloning and three states (Arizona, Maryland, and Missouri) prohibit use of public funds for such activities.[71]

In popular culture

Science fiction has used cloning, most commonly and specifically human cloning, due to the fact that it brings up controversial questions of identity.[72][73] Humorous fiction, such as Multiplicity (1996)[74] and the Maxwell Smart feature The Nude Bomb (1980), have featured human cloning.[75] A recurring sub-theme of cloning fiction is the use of clones as a supply of organs for transplantation. Robin Cook's 1997 novel Chromosome 6 and Michael Bay's The Island are examples of this; Chromosome 6 also features genetic manipulation and xenotransplantation.[76] There is also a series named Orphan Black which follows human clones' stories and experiences as they deal with issues and react to being the property of a chain of scientific institutions.
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Cloning

From Wikipedia, the free encyclopedia


Many organisms, including aspen trees, reproduce by cloning

Cloning is the process of producing genetically identical individuals of an organism either naturally or artificially. In nature, many organisms produce clones through asexual reproduction. Cloning in biotechnology refers to the process of creating clones of organisms or copies of cells or DNA fragments (molecular cloning). Beyond biology, the term refers to the production of multiple copies of digital media or software.

The term clone, invented by J. B. S. Haldane, is derived from the Ancient Greek word κλών klōn, "twig", referring to the process whereby a new plant can be created from a twig. In botany, the term lusus was traditionally used.[1] In horticulture, the spelling clon was used until the twentieth century; the final e came into use to indicate the vowel is a "long o" instead of a "short o".[2][3] Since the term entered the popular lexicon in a more general context, the spelling clone has been used exclusively.

Natural cloning

Cloning is a natural form of reproduction that has allowed life forms to spread for hundreds of millions of years. It is the reproduction method used by plants, fungi, and bacteria, and is also the way that clonal colonies reproduce themselves.[4][5] Examples of these organisms include blueberry plants, hazel trees, the Pando trees,[6][7] the Kentucky coffeetree, Myricas, and the American sweetgum.

Molecular cloning

Molecular cloning refers to the process of making multiple molecules. Cloning is commonly used to amplify DNA fragments containing whole genes, but it can also be used to amplify any DNA sequence such as promoters, non-coding sequences and randomly fragmented DNA. It is used in a wide array of biological experiments and practical applications ranging from genetic fingerprinting to large scale protein production. Occasionally, the term cloning is misleadingly used to refer to the identification of the chromosomal location of a gene associated with a particular phenotype of interest, such as in positional cloning. In practice, localization of the gene to a chromosome or genomic region does not necessarily enable one to isolate or amplify the relevant genomic sequence. To amplify any DNA sequence in a living organism, that sequence must be linked to an origin of replication, which is a sequence of DNA capable of directing the propagation of itself and any linked sequence. However, a number of other features are needed, and a variety of specialised cloning vectors (small piece of DNA into which a foreign DNA fragment can be inserted) exist that allow protein production, affinity tagging, single stranded RNA or DNA production and a host of other molecular biology tools.

Cloning of any DNA fragment essentially involves four steps[8]
  1. fragmentation - breaking apart a strand of DNA
  2. ligation - gluing together pieces of DNA in a desired sequence
  3. transfection – inserting the newly formed pieces of DNA into cells
  4. screening/selection – selecting out the cells that were successfully transfected with the new DNA
Although these steps are invariable among cloning procedures a number of alternative routes can be selected; these are summarized as a cloning strategy.

Initially, the DNA of interest needs to be isolated to provide a DNA segment of suitable size. Subsequently, a ligation procedure is used where the amplified fragment is inserted into a vector (piece of DNA). The vector (which is frequently circular) is linearised using restriction enzymes, and incubated with the fragment of interest under appropriate conditions with an enzyme called DNA ligase. Following ligation the vector with the insert of interest is transfected into cells. A number of alternative techniques are available, such as chemical sensitivation of cells, electroporation, optical injection and biolistics. Finally, the transfected cells are cultured. As the aforementioned procedures are of particularly low efficiency, there is a need to identify the cells that have been successfully transfected with the vector construct containing the desired insertion sequence in the required orientation. Modern cloning vectors include selectable antibiotic resistance markers, which allow only cells in which the vector has been transfected, to grow. Additionally, the cloning vectors may contain colour selection markers, which provide blue/white screening (alpha-factor complementation) on X-gal medium. Nevertheless, these selection steps do not absolutely guarantee that the DNA insert is present in the cells obtained. Further investigation of the resulting colonies must be required to confirm that cloning was successful. This may be accomplished by means of PCR, restriction fragment analysis and/or DNA sequencing.

Cell cloning

Cloning unicellular organisms


Cloning cell-line colonies using cloning rings

Cloning a cell means to derive a population of cells from a single cell. In the case of unicellular organisms such as bacteria and yeast, this process is remarkably simple and essentially only requires the inoculation of the appropriate medium. However, in the case of cell cultures from multi-cellular organisms, cell cloning is an arduous task as these cells will not readily grow in standard media.

A useful tissue culture technique used to clone distinct lineages of cell lines involves the use of cloning rings (cylinders).[9] In this technique a single-cell suspension of cells that have been exposed to a mutagenic agent or drug used to drive selection is plated at high dilution to create isolated colonies, each arising from a single and potentially clonal distinct cell. At an early growth stage when colonies consist of only a few cells, sterile polystyrene rings (cloning rings), which have been dipped in grease, are placed over an individual colony and a small amount of trypsin is added. Cloned cells are collected from inside the ring and transferred to a new vessel for further growth.

Cloning stem cells

Somatic-cell nuclear transfer, known as SCNT, can also be used to create embryos for research or therapeutic purposes. The most likely purpose for this is to produce embryos for use in stem cell research. This process is also called "research cloning" or "therapeutic cloning." The goal is not to create cloned human beings (called "reproductive cloning"), but rather to harvest stem cells that can be used to study human development and to potentially treat disease. While a clonal human blastocyst has been created, stem cell lines are yet to be isolated from a clonal source.[10]

Therapeutic cloning is achieved by creating embryonic stem cells in the hopes of treating diseases such as diabetes and Alzheimer's. The process begins by removing the nucleus (containing the DNA) from an egg cell and inserting a nucleus from the adult cell to be cloned.[11] In the case of someone with Alzheimer's disease, the nucleus from a skin cell of that patient is placed into an empty egg. The reprogrammed cell begins to develop into an embryo because the egg reacts with the transferred nucleus. The embryo will become genetically identical to the patient.[11] The embryo will then form a blastocyst which has the potential to form/become any cell in the body.[12]

The reason why SCNT is used for cloning is because somatic cells can be easily acquired and cultured in the lab. This process can either add or delete specific genomes of farm animals. A key point to remember is that cloning is achieved when the oocyte maintains its normal functions and instead of using sperm and egg genomes to replicate, the oocyte is inserted into the donor’s somatic cell nucleus.[13] The oocyte will react on the somatic cell nucleus, the same way it would on sperm cells.[13]

The process of cloning a particular farm animal using SCNT is relatively the same for all animals. The first step is to collect the somatic cells from the animal that will be cloned. The somatic cells could be used immediately or stored in the laboratory for later use.[13] The hardest part of SCNT is removing maternal DNA from an oocyte at metaphase II. Once this has been done, the somatic nucleus can be inserted into an egg cytoplasm.[13] This creates a one-cell embryo. The grouped somatic cell and egg cytoplasm are then introduced to an electrical current.[13] This energy will hopefully allow the cloned embryo to begin development. The successfully developed embryos are then placed in surrogate recipients, such as a cow or sheep in the case of farm animals.[13]

SCNT is seen as a good method for producing agriculture animals for food consumption. It successfully cloned sheep, cattle, goats, and pigs. Another benefit is SCNT is seen as a solution to clone endangered species that are on the verge of going extinct.[13] However, stresses placed on both the egg cell and the introduced nucleus can be enormous, which led to a high loss in resulting cells in early research. For example, the cloned sheep Dolly 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.[14] As the procedure could not be automated, and had to be performed manually under a microscope, SCNT was very resource intensive. The biochemistry involved in reprogramming the differentiated somatic cell nucleus and activating the recipient egg was also far from being well understood. However, by 2014 researchers were reporting cloning success rates of seven to eight out of ten[15] and in 2016, a Korean Company Sooam Biotech was reported to be producing 500 cloned embryos per day.[16]

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.

Organism cloning

Organism cloning (also called reproductive cloning) refers to the procedure of creating a new multicellular organism, genetically identical to another. In essence this form of cloning is an asexual method of reproduction, where fertilization or inter-gamete contact does not take place. Asexual reproduction is a naturally occurring phenomenon in many species, including most plants and some insects. Scientists have made some major achievements with cloning, including the asexual reproduction of sheep and cows. There is a lot of ethical debate over whether or not cloning should be used. However, cloning, or asexual propagation,[17] has been common practice in the horticultural world for hundreds of years.

Horticultural


Propagating plants from cuttings, such as grape vines, is an ancient form of cloning

The term clone is used in horticulture to refer to descendants of a single plant which were produced by vegetative reproduction or apomixis. Many horticultural plant cultivars are clones, having been derived from a single individual, multiplied by some process other than sexual reproduction.[18] As an example, some European cultivars of grapes represent clones that have been propagated for over two millennia. Other examples are potato and banana.[19] Grafting can be regarded as cloning, since all the shoots and branches coming from the graft are genetically a clone of a single individual, but this particular kind of cloning has not come under ethical scrutiny and is generally treated as an entirely different kind of operation.

Many trees, shrubs, vines, ferns and other herbaceous perennials form clonal colonies naturally. Parts of an individual plant may become detached by fragmentation and grow on to become separate clonal individuals. A common example is in the vegetative reproduction of moss and liverwort gametophyte clones by means of gemmae. Some vascular plants e.g. dandelion and certain viviparous grasses also form seeds asexually, termed apomixis, resulting in clonal populations of genetically identical individuals.

Parthenogenesis

Clonal derivation exists in nature in some animal species and is referred to as parthenogenesis (reproduction of an organism by itself without a mate). This is an asexual form of reproduction that is only found in females of some insects, crustaceans, nematodes,[20] fish (for example the hammerhead shark[21]), the Komodo dragon[21] and lizards. The growth and development occurs without fertilization by a male. In plants, parthenogenesis means the development of an embryo from an unfertilized egg cell, and is a component process of apomixis. In species that use the XY sex-determination system, the offspring will always be female. An example is the little fire ant (Wasmannia auropunctata), which is native to Central and South America but has spread throughout many tropical environments.

Artificial cloning of organisms

Artificial cloning of organisms may also be called reproductive cloning.

First steps

Hans Spemann, a German embryologist was awarded a Nobel Prize in Physiology or Medicine in 1935 for his discovery of the effect now known as embryonic induction, exercised by various parts of the embryo, that directs the development of groups of cells into particular tissues and organs. In 1928 he and his student, Hilde Mangold, were the first to perform somatic-cell nuclear transfer using amphibian embryos – one of the first steps towards cloning.[22]

Methods

Reproductive cloning generally uses "somatic cell nuclear transfer" (SCNT) to create animals that are genetically identical. This process entails the transfer of a nucleus from a donor adult cell (somatic cell) to an egg from which the nucleus has been removed, or to a cell from a blastocyst from which the nucleus has been removed.[23] If the egg begins to divide normally it is transferred into the uterus of the surrogate mother. Such clones are not strictly identical since the somatic cells may contain mutations in their nuclear DNA. Additionally, the mitochondria in the cytoplasm also contains DNA and during SCNT this mitochondrial DNA is wholly from the cytoplasmic donor's egg, thus the mitochondrial genome is not the same as that of the nucleus donor cell from which it was produced. This may have important implications for cross-species nuclear transfer in which nuclear-mitochondrial incompatibilities may lead to death.

Artificial embryo splitting or embryo twinning, a technique that creates monozygotic twins from a single embryo, is not considered in the same fashion as other methods of cloning. During that procedure, a donor embryo is split in two distinct embryos, that can then be transferred via embryo transfer. It is optimally performed at the 6- to 8-cell stage, where it can be used as an expansion of IVF to increase the number of available embryos.[24] If both embryos are successful, it gives rise to monozygotic (identical) twins.

Dolly the sheep


The taxidermied body of Dolly the sheep

Dolly clone

Dolly, a Finn-Dorset ewe, was the first mammal to have been successfully cloned from an adult somatic cell. Dolly was formed by taking a cell from the udder of her 6-year old biological mother.[25] Dolly's embryo was created by taking the cell and inserting it into a sheep ovum. It took 434 attempts before an embryo was successful.[26] The embryo was then placed inside a female sheep that went through a normal pregnancy.[27] She was cloned at the Roslin Institute in Scotland by British scientists Sir Ian Wilmut and Keith Campbell and lived there from her birth in 1996 until her death in 2003 when she was six. She was born on 5 July 1996 but not announced to the world until 22 February 1997.[28] Her stuffed remains were placed at Edinburgh's Royal Museum, part of the National Museums of Scotland.[29]

Dolly was publicly significant because the effort showed that genetic material from a specific adult cell, programmed to express only a distinct subset of its genes, can be reprogrammed to grow an entirely new organism. Before this demonstration, it had been shown by John Gurdon that nuclei from differentiated cells could give rise to an entire organism after transplantation into an enucleated egg.[30] However, this concept was not yet demonstrated in a mammalian system.

The first mammalian cloning (resulting in Dolly the sheep) had a success rate of 29 embryos per 277 fertilized eggs, which produced three lambs at birth, one of which lived. In a bovine experiment involving 70 cloned calves, one-third of the calves died young. The first successfully cloned horse, Prometea, took 814 attempts. Notably, although the first[clarification needed] clones were frogs, no adult cloned frog has yet been produced from a somatic adult nucleus donor cell.

There were early claims that Dolly the sheep had pathologies resembling accelerated aging. Scientists speculated that Dolly's death in 2003 was related to the shortening of telomeres, DNA-protein complexes that protect the end of linear chromosomes. However, other researchers, including Ian Wilmut who led the team that successfully cloned Dolly, argue that Dolly's early death due to respiratory infection was unrelated to deficiencies with the cloning process. This idea that the nuclei have not irreversibly aged was shown in 2013 to be true for mice.[31]

Dolly was named after performer Dolly Parton because the cells cloned to make her were from a mammary gland cell, and Parton is known for her ample cleavage.[32]

Species cloned

The modern cloning techniques involving nuclear transfer have been successfully performed on several species. Notable experiments include:

Human cloning

Human cloning is the creation of a genetically identical copy of a human. The term is generally used to refer to artificial human cloning, which is the reproduction of human cells and tissues. It does not refer to the natural conception and delivery of identical twins. The possibility of human cloning has raised controversies. These ethical concerns have prompted several nations to pass legislature regarding human cloning and its legality. As of right now, scientists have no intention of trying to clone people and they believe their results should spark a wider discussion about the laws and regulations the world needs to regulate cloning.[63]

Two commonly discussed types of theoretical human cloning are therapeutic cloning and reproductive cloning. Therapeutic cloning would involve cloning cells from a human for use in medicine and transplants, and is an active area of research, but is not in medical practice anywhere in the world, as of 2014. Two common methods of therapeutic cloning that are being researched are somatic-cell nuclear transfer and, more recently, pluripotent stem cell induction. Reproductive cloning would involve making an entire cloned human, instead of just specific cells or tissues.[64]

Ethical issues of cloning

There are a variety of ethical positions regarding the possibilities of cloning, especially human cloning. While many of these views are religious in origin, the questions raised by cloning are faced by secular perspectives as well. Perspectives on human cloning are theoretical, as human therapeutic and reproductive cloning are not commercially used; animals are currently cloned in laboratories and in livestock production.

Advocates support development of therapeutic cloning in order to generate tissues and whole organs to treat patients who otherwise cannot obtain transplants,[65] to avoid the need for immunosuppressive drugs,[64] and to stave off the effects of aging.[66] Advocates for reproductive cloning believe that parents who cannot otherwise procreate should have access to the technology.[67]

Opponents of cloning have concerns that technology is not yet developed enough to be safe[68] and that it could be prone to abuse (leading to the generation of humans from whom organs and tissues would be harvested),[69][70] as well as concerns about how cloned individuals could integrate with families and with society at large.[71][72]

Religious groups are divided, with some opposing the technology as usurping "God's place" and, to the extent embryos are used, destroying a human life; others support therapeutic cloning's potential life-saving benefits.[73][74]

Cloning of animals is opposed by animal-groups due to the number of cloned animals that suffer from malformations before they die,[75][76] and while food from cloned animals has been approved by the US FDA,[77][78] its use is opposed by groups concerned about food safety.[79][80][81]

Cloning extinct and endangered species

Cloning, or more precisely, the reconstruction of functional DNA from extinct species has, for decades, been a dream. Possible implications of this were dramatized in the 1984 novel Carnosaur and the 1990 novel Jurassic Park.[82][83] The best current cloning techniques have an average success rate of 9.4 percent[84] (and as high as 25 percent[31]) when working with familiar species such as mice,[note 1] while cloning wild animals is usually less than 1 percent successful.[87] Several tissue banks have come into existence, including the "Frozen Zoo" at the San Diego Zoo, to store frozen tissue from the world's rarest and most endangered species.[82][88][89]

In 2001, a cow named Bessie gave birth to a cloned Asian gaur, an endangered species, but the calf died after two days. In 2003, a banteng was successfully cloned, followed by three African wildcats from a thawed frozen embryo. These successes provided hope that similar techniques (using surrogate mothers of another species) might be used to clone extinct species. Anticipating this possibility, tissue samples from the last bucardo (Pyrenean ibex) were frozen in liquid nitrogen immediately after it died in 2000. Researchers are also considering cloning endangered species such as the giant panda and cheetah.

In 2002, geneticists at the Australian Museum announced that they had replicated DNA of the thylacine (Tasmanian tiger), at the time extinct for about 65 years, using polymerase chain reaction.[90] However, on 15 February 2005 the museum announced that it was stopping the project after tests showed the specimens' DNA had been too badly degraded by the (ethanol) preservative. On 15 May 2005 it was announced that the thylacine project would be revived, with new participation from researchers in New South Wales and Victoria.

In 2003, for the first time, an extinct animal, the Pyrenean ibex mentioned above was cloned, at the Centre of Food Technology and Research of Aragon, using the preserved frozen cell nucleus of the skin samples from 2001 and domestic goat egg-cells. The ibex died shortly after birth due to physical defects in its lungs.[91]

One of the most anticipated targets for cloning was once the woolly mammoth, but attempts to extract DNA from frozen mammoths have been unsuccessful, though a joint Russo-Japanese team is currently working toward this goal. In January 2011, it was reported by Yomiuri Shimbun that a team of scientists headed by Akira Iritani of Kyoto University had built upon research by Dr. Wakayama, saying that they will extract DNA from a mammoth carcass that had been preserved in a Russian laboratory and insert it into the egg cells of an African elephant in hopes of producing a mammoth embryo. The researchers said they hoped to produce a baby mammoth within six years.[92][93] It was noted, however that the result, if possible, would be an elephant-mammoth hybrid rather than a true mammoth.[94] Another problem is the survival of the reconstructed mammoth: ruminants rely on a symbiosis with specific microbiota in their stomachs for digestion.[94]

Scientists at the University of Newcastle and University of New South Wales announced in March 2013 that the very recently extinct gastric-brooding frog would be the subject of a cloning attempt to resurrect the species.[95]

Many such "de-extinction" projects are described in the Long Now Foundation's Revive and Restore Project.[96]

Lifespan

After an eight-year project involving the use of a pioneering cloning technique, Japanese researchers created 25 generations of healthy cloned mice with normal lifespans, demonstrating that clones are not intrinsically shorter-lived than naturally born animals.[31][97] Other sources have noted that the offspring of clones tend to be healthier than the original clones and indistinguishable from animals produced naturally.[98]

Dolly the sheep was created from a six year old cell sample from a mammary gland. Because of this, she aged quicker than other naturally born animals because she was started from already aging cells. She died prematurely at six years old, not only from her age but from respiratory issues and severe arthritis.

A detailed study released in 2016 and less detailed studies by others suggest that once cloned animals get past the first month or two of life they are generally healthy. However, early pregnancy loss and neonatal losses are still greater with cloning than natural conception or assisted reproduction (IVF). Current research is attempting to overcome these problems.[32]

In popular culture


In Jurassic Park (1993), dinosaurs are resurrected through cloning for entertainment

Sontarans in Doctor Who are a cloned warrior race

In Star Wars, clone troopers were genetically engineered to fight the Clone Wars

Discussion of cloning in the popular media often presents the subject negatively. In an article in the 8 November 1993 article of Time, cloning was portrayed in a negative way, modifying Michelangelo's Creation of Adam to depict Adam with five identical hands.[99] Newsweek's 10 March 1997 issue also critiqued the ethics of human cloning, and included a graphic depicting identical babies in beakers.[100]

The concept of cloning, particularly human cloning, has featured a wide variety of science fiction works. An early fictional depiction of cloning is Bokanovsky's Process which features in Aldous Huxley's 1931 dystopian novel Brave New World. The process is applied to fertilized human eggs in vitro, causing them to split into identical genetic copies of the original.[101][102] Following renewed interest in cloning in the 1950s, the subject was explored further in works such as Poul Anderson's 1953 story UN-Man, which describes a technology called "exogenesis", and Gordon Rattray Taylor's book The Biological Time Bomb, which popularised the term "cloning" in 1963.[103]

Cloning is a recurring theme in a number of contemporary science fiction films, ranging from action films such as Jurassic Park (1993), Alien Resurrection (1997), The 6th Day (2000), Resident Evil (2002), Star Wars: Episode II (2002) and The Island (2005), to comedies such as Woody Allen's 1973 film Sleeper.[104]

The process of cloning is represented variously in fiction. Many works depict the artificial creation of humans by a method of growing cells from a tissue or DNA sample; the replication may be instantaneous, or take place through slow growth of human embryos in artificial wombs. In the long-running British television series Doctor Who, the Fourth Doctor and his companion Leela were cloned in a matter of seconds from DNA samples ("The Invisible Enemy", 1977) and then — in an apparent homage to the 1966 film Fantastic Voyage — shrunk to microscopic size in order to enter the Doctor's body to combat an alien virus. The clones in this story are short-lived, and can only survive a matter of minutes before they expire.[105] Science fiction films such as The Matrix and Star Wars: Episode II – Attack of the Clones have featured scenes of human foetuses being cultured on an industrial scale in mechanical tanks.[106]

Cloning humans from body parts is also a common theme in science fiction. Cloning features strongly among the science fiction conventions parodied in Woody Allen's Sleeper, the plot of which centres around an attempt to clone an assassinated dictator from his disembodied nose.[107] In the 2008 Doctor Who story "Journey's End", a duplicate version of the Tenth Doctor spontaneously grows from his severed hand, which had been cut off in a sword fight during an earlier episode.[108]

After the death of her beloved 14-year old Coton de Tulear named Samantha in late 2017, Barbra Streisand announced that she had cloned the dog, and was now "waiting for [the two cloned pups] to get older so [she] can see if they have [Samantha's] brown eyes and her seriousness." [109] The operation cost $50,000 through the pet cloning company ViaGen.

Cloning and identity

Science fiction has used cloning, most commonly and specifically human cloning, to raise the controversial questions of identity.[110][111] A Number is a 2002 play by English playwright Caryl Churchill which addresses the subject of human cloning and identity, especially nature and nurture. The story, set in the near future, is structured around the conflict between a father (Salter) and his sons (Bernard 1, Bernard 2, and Michael Black) – two of whom are clones of the first one. A Number was adapted by Caryl Churchill for television, in a co-production between the BBC and HBO Films.[112]

In 2012, a Japanese television series named "Bunshin" was created. The story's main character, Mariko, is a woman studying child welfare in Hokkaido. She grew up always doubtful about the love from her mother, who looked nothing like her and who died nine years before. One day, she finds some of her mother's belongings at a relative's house, and heads to Tokyo to seek out the truth behind her birth. She later discovered that she was a clone.[113]

In the 2013 television series Orphan Black, cloning is used as a scientific study on the behavioral adaptation of the clones.[114] In a similar vein, the book The Double by Nobel Prize winner José Saramago explores the emotional experience of a man who discovers that he is a clone.[115]

Cloning as resurrection

Cloning has been used in fiction as a way of recreating historical figures. In the 1976 Ira Levin novel The Boys from Brazil and its 1978 film adaptation, Josef Mengele uses cloning to create copies of Adolf Hitler.[116]

In Michael Crichton's 1990 novel Jurassic Park, which spawned a series of Jurassic Park feature films, a bioengineering company develops a technique to resurrect extinct species of dinosaurs by creating cloned creatures using DNA extracted from fossils. The cloned dinosaurs are used to populate the Jurassic Park wildlife park for the entertainment of visitors. The scheme goes disastrously wrong when the dinosaurs escape their enclosures. Despite being selectively cloned as females to prevent them from breeding, the dinosaurs develop the ability to reproduce through parthenogenesis.[117]

Cloning for warfare

The use of cloning for military purposes has also been explored in several fictional works. In Doctor Who, an alien race of armour-clad, warlike beings called Sontarans was introduced in the 1973 serial "The Time Warrior". Sontarans are depicted as squat, bald creatures who have been genetically engineered for combat. Their weak spot is a "probic vent", a small socket at the back of their neck which is associated with the cloning process.[118] The concept of cloned soldiers being bred for combat was revisited in "The Doctor's Daughter" (2008), when the Doctor's DNA is used to create a female warrior called Jenny.[119]

The 1977 film Star Wars was set against the backdrop of a historical conflict called the Clone Wars. The events of this war were not fully explored until the prequel films Attack of the Clones (2002) and Revenge of the Sith (2005), which depict a space war waged by a massive army of heavily armoured clone troopers that leads to the foundation of the Galactic Empire. Cloned soldiers are "manufactured" on an industrial scale, genetically conditioned for obedience and combat effectiveness. It is also revealed that the popular character Boba Fett originated as a clone of Jango Fett, a mercenary who served as the genetic template for the clone troopers.[120][121]

Cloning has appeared in many video games. In Metal Gear Solid, the characters Solid Snake and Liquid Snake were born in a secret project as cloned soldiers. In Halo, cloning technology is shown to recreate organs. In addition, the Factions of Halo#United Nations Space Command uses cloning when it abducts children to train as supersoldiers. Here, non-clone children are trained as soldiers while the clones covertly replace the abducted children at home.

Cloning for exploitation

A recurring sub-theme of cloning fiction is the use of clones as a supply of organs for transplantation. The 2005 Kazuo Ishiguro novel Never Let Me Go and the 2010 film adaption[122] are set in an alternate history in which cloned humans are created for the sole purpose of providing organ donations to naturally born humans, despite the fact that they are fully sentient and self-aware. The 2005 film The Island[123] revolves around a similar plot, with the exception that the clones are unaware of the reason for their existence. In Raymond Han's 2017 novel, The Mind Clones Trilogy,[124] a dictator who suffered a terminal illness sought to implant his mind clone into his son's mind so that he could continue to rule the country. In another part of the trilogy, usurpers plotted to replace members of the Chinese Politburo Standing Committee using look-alike human clones.

The exploitation of human clones for dangerous and undesirable work was examined in the 2009 British science fiction film Moon.[125] In the futuristic novel Cloud Atlas and subsequent film, one of the story lines focuses on a genetically-engineered fabricant clone named Sonmi~451, one of millions raised in an artificial "wombtank," destined to serve from birth. She is one of thousands created for manual and emotional labor; Sonmi herself works as a server in a restaurant. She later discovers that the sole source of food for clones, called 'Soap', is manufactured from the clones themselves.[126]
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