Suicide gene

A suicide gene, in genetics, will cause a cell to kill itself through apoptosis. Activation of these genes can be due to many processes, but the main cellular "switch" to induce apoptosis is the p53 protein. Stimulation or introduction (through gene therapy) of suicide genes is a potential way of treating cancer or other proliferative diseases. Suicide genes form the basis of a strategy for making cancer cells more vulnerable, more sensitive to chemotherapy. The approach has been to attach parts of genes expressed in cancer cells to other genes for enzymes not found in mammals that can convert a harmless substance into one that is toxic to the tumor.[1] Most suicide genes mediate this sensitivity by coding for viral or bacterial enzymes that convert an inactive drug into toxic antimetabolites that inhibit the synthesis of nucleic acid. Suicide genes must be introduced into the cells in ways that ensure their uptake and expression by as many cancer cells as possible, while limiting their expression by normal cells. Suicide gene therapy for cancer requires the vector to have the capacity to discriminate between target and non target cells, between the cancer cells and normal cells.[2]

The ultimate goal of cancer therapy is the complete elimination of all cancer cells, while leaving all healthy cells unharmed. One of the most promising therapeutic strategies in this regard is cancer suicide gene therapy (CSGT), which is rapidly progressing into new frontiers.The therapeutic success, in CSGT, is primarily contingent upon precision in delivery of the therapeutic transgenes to the cancer cells only. This is addressed by discovering and targeting unique or / and over-expressed biomarkers displayed on the cancer cells and cancer stem cells. Specificity of cancer therapeutic effects is further enhanced by designing the DNA constructs, which put the therapeutic genes under the control of the cancer cell specific promoters. The delivery of the suicidal genes to the cancer cells involves viral, as well as synthetic vectors, which are guided by cancer specific antibodies and ligands. The delivery options also include engineered stem cells with tropisms towards cancers. Main mechanisms inducing cancer cells' deaths include: transgenic expression of thymidine kinases, cytosine deaminases, intracellular antibodies, telomeraseses, caspases, DNases. Precautions are undertaken to eliminate the risks associated with transgenesis. Progress in genomics and proteomics should help us in identifying the cancer specific biomarkers and metabolic pathways for developing new strategies towards clinical trials of targeted and personalized gene therapy of cancer.By introducing the gene into a malignant tumor, the tumor would reduce in size and possibly disappear completely, provided all the individual cells have received a copy of the gene.

When the DNA sample in the virus is taken from the patient's own healthy cells, the virus does not need to be able to differentiate between cancer cells and healthy ones. In addition, the advantage is that it is also able to prevent metastasis upon the death of a tumor.

Suicide genes are often utilized in biotechnology to assist in molecular cloning. Vectors incorporate suicide genes for an organism (such as E. coli). The cloning project focuses on replacing the suicide gene by the desired fragment. Selection of vectors carrying the desired fragment is improved since vectors retaining the suicide gene result in cell death.

Apoptosis

There are two ways that a cell can die: necrosis and apoptosis. Necrosis occurs when a cell is damaged by an external force, such as poison, a bodily injury, an infection or getting cut off from blood supply. When cells die from necrosis, it's a rather messy affair. The death causes inflammation that can cause further distress of injury within the body. Apoptosis, on the other hand, is relatively civil. Many cells undergo programmed cell death, or apoptosis, during fetal development. A form of cell death in which a programmed sequence of events leads to the elimination of cells without releasing harmful substances into the surrounding. Apoptosis plays a crucial role in developing and maintaining the health of the body by eliminating old cells, unnecessary cells, and unhealthy cells. The human body replaces perhaps one million cells per second. When a cell is compelled to commit suicide, proteins called caspases go into action. They break down the cellular components needed for survival, and they spur production of enzymes known as DNase, which destroy the DNA in the nucleus of the cell. The cell shrinks and sends out distress signals, which are answered by macrophages. The macrophages clean away the shrunken cells, leaving no trace, so these cells have no chance to cause the damage that necrotic cells do. Apoptosis also differs from necrosis in that it's essential to human development. For example, in the womb, our fingers and toes are connected to one another by a sort of webbing. Apoptosis is what causes that webbing to disappear, leaving us with 10 separate digits. As our brains develop, the body, the body creates millions more cells than it needs; the ones that don't form synaptic connections undergo apoptosis so that the remaining cells function well. Programmed cell death is also necessary to start the process of menstruation. That's not to say that apoptosis is a perfect process. Rather than dying due to injury, cells that go through apoptosis die in response to signals within the body. When cells recognize viruses and gene mutations, they may induce death to prevent the damage from spreading. Scientist are trying to learn how they can modulate apoptosis, so that they can control which cells live and which undergo programmed cell death. Anti-cancer drugs and radiation, for example, work by triggering apoptosis in diseased cells. Many diseases and disorders are linked with the life and death of cells—increased apoptosis is a characteristic of AIDS, Alzheimer's, and Parkinson's disease, while decreased apoptosis can signal lupus or cancer. Understanding how to regulate apoptosis could be the first step to treating these conditions.[3]

Too little or too much apoptosis can play a role in many diseases. When apoptosis does not work correctly, cells that should be eliminated may persist and become immortal, for example, in cancer and leukemia. when apoptosis works overly well, it kills too many cells and inflicts grave tissue damage. This is the case in strokes and neurodegenerative disorders such as Alzheimer's, Huntington's, and Parkinson's disease. Also known as programmed cell death and cell suicide.[4]

Cancer treatment

One of the challenges of cancer treatment is how to destroy malignant tumors without damaging healthy cells. A new method that shows great promise for accomplishing this employs the use of a suicide gene. A suicide gene is a gene which will cause a cell to kill itself through apoptosis. There are currently two methods of suicide gene therapy being used. Gene-directed enzyme-producing therapy (GDEPT) uses a gene taken from the cancer cell and then modified with other genes to form enzymes that are harmless to healthy cells.[5] This foreign enzyme is inserted into the tumor cells where it releases a prodrug, which is a small molecule harmless to healthy cells, but destructive to cancerous cells. The modified suicide gene converts the non-toxic prodrug into a cytotoxic substance. The second method of suicide gene therapy is called virus-directed enzyme-prodrug therapy. This uses a virus, such as herpes simplex or cold virus, as the carrier, or vector, to deliver the modified genes to the cancer cells. Suicide gene therapy is not necessarily expected to completely eliminate the need for chemotherapy and radiation treatment for all cancerous tumors. The damage inflicted upon the tumor cells, however, makes them more susceptible to the chemo or radiation. This approach has already proven effective against prostate and bladder cancers. The application of suicide gene therapy is being expanded to several other forms of cancer as well. Cancer patients often experience depressed immune systems, so they can suffer some side effects of the use of a virus as a delivery agent.

References

  1. ^ Karjoo, Zahra; Chen, Xuguang; Hatefi, Arash (2015-05-22). "Progress and problems with the use of suicide genes for targeted cancer therapy". Advanced Drug Delivery Reviews. 99 (Pt A): 113–28. doi:10.1016/j.addr.2015.05.009. ISSN 1872-8294. PMC 4758904. PMID 26004498.
  2. ^ "Suicide gene". MedicineNet. Retrieved 15 November 2014.
  3. ^ "What is apoptosis?". HowStuffWorks. 2010-03-31. Retrieved 15 November 2014.
  4. ^ "Apoptosis definition - Medical Dictionary: Definitions of Popular Terms Defined on MedTerms". Medicinenet.com. Retrieved 15 November 2014.
  5. ^ Karjoo, Zahra; Chen, Xuguang; Hatefi, Arash (2016). "Progress and problems with the use of suicide genes for targeted cancer therapy". Advanced Drug Delivery Reviews. 99: 113–28. doi:10.1016/j.addr.2015.05.009. PMC 4758904. PMID 26004498.
Algor mortis

Algor mortis (Latin: algor—coldness; mortis—of death), the second stage of death, is the change in body temperature post mortem, until the ambient temperature is matched. This is generally a steady decline, although if the ambient temperature is above the body temperature (such as in a hot desert), the change in temperature will be positive, as the (relatively) cooler body acclimates to the warmer environment. External factors can have a significant influence.

The term was first used by Dowler in 1849. The first published measurements of the intervals of temperature after death were done by Dr John Davey in 1839.

Dead on arrival

Dead on arrival (DOA), also dead in the field and brought in dead (BID), indicates that a patient was found to be already clinically dead upon the arrival of professional medical assistance, often in the form of first responders such as emergency medical technicians, paramedics, or police.

In some jurisdictions, first responders must consult verbally with a physician before officially pronouncing a patient deceased, but once cardiopulmonary resuscitation is initiated, it must be continued until a physician can pronounce the patient dead.

Death messenger

Death messengers, in former times, were those who were dispatched to spread the news that an inhabitant of their city or village had died. They were to wear unadorned black and go door to door with the message, "You are asked to attend the funeral of the departed __________ at (time, date, and place)." This was all they were allowed to say, and were to move on to the next house immediately after uttering the announcement. This tradition persisted in some areas to as late as the mid-19th century.

Death rattle

Terminal respiratory secretions (or simply terminal secretions), known colloquially as a death rattle, are sounds often produced by someone who is near death as a result of fluids such as saliva and bronchial secretions accumulating in the throat and upper chest. Those who are dying may lose their ability to swallow and may have increased production of bronchial secretions, resulting in such an accumulation. Usually, two or three days earlier, the symptoms of approaching death can be observed as saliva accumulates in the throat, making it very difficult to take even a spoonful of water. Related symptoms can include shortness of breath and rapid chest movement. While death rattle is a strong indication that someone is near death, it can also be produced by other problems that cause interference with the swallowing reflex, such as brain injuries.It is sometimes misinterpreted as the sound of the person choking to death, or alternatively, that they are gargling.

Dignified death

Dignified death is a somewhat elusive concept often related to suicide. One factor that has been cited as a core component of dignified death is maintaining a sense of control. Another view is that a truly dignified death is an extension of a dignified life. There is some concern that assisted suicide does not guarantee a dignified death, since some patients may experience complications such as nausea and vomiting. There is some concern that age discrimination denies the elderly a dignified death.

Dysthanasia

In medicine, dysthanasia means "bad death" and is considered a common fault of modern medicine.Dysthanasia occurs when a person who is dying has their biological life extended through technological means without regard to the person's quality of life. Technologies such as an implantable cardioverter defibrillator, artificial ventilation, ventricular assist devices, and extracorporeal membrane oxygenation can extend the dying process.

Dysthanasia is a term generally used when a person is seen to be kept alive artificially in a condition where, otherwise, they cannot survive; sometimes for some sort of ulterior motive. The term was used frequently in the investigation into the death of Formula One driver Ayrton Senna in 1994.

Fan death

Fan death is a well-known superstition in Korean culture, where it is thought that running an electric fan in a closed room with unopened or no windows will prove fatal. Despite no concrete evidence to support the concept, belief in fan death persists to this day in Korea, and also to a lesser extent in Japan.

Funeral director

A funeral director, also known as an undertaker (British English) or mortician (American English), is a professional involved in the business of funeral rites. These tasks often entail the embalming and burial or cremation of the dead, as well as the arrangements for the funeral ceremony (although not the directing and conducting of the funeral itself unless clergy are not present). Funeral directors may at times be asked to perform tasks such as dressing (in garments usually suitable for daily wear), casketing (placing the human body in the coffin), and cossetting (applying any sort of cosmetic or substance to the best viewable areas of the corpse for the purpose of enhancing its appearance). A funeral director may work at a funeral home or be an independent employee.

Gary Hudson (engineer)

Gary Hudson has been involved in private spaceflight development for over 40 years.

Hudson is best known as the founder of Rotary Rocket Company, which in spending ~$30 Million attempted to build a unique single stage to orbit launch vehicle known as the Roton. Rotary Rocket built a landing test simulator (the Roton ATV) which flew three successful test flights in 1999.

He also helped found Transformational Space T/Space in 2004.

He also helped found AirLaunch LLC which was awarded the DARPA/USAF FALCON project in 2003.Previous projects included designs of the Phoenix SSTO, the Percheron, and other rockets, founder of Pacific American Launch Systems, and various consulting projects.

Currently, he is the President and CEO of the Space Studies Institute.

Hudson appears as a character in the novel Fallen Angels, along with his Phoenix SSTO.

Hudson is also a founding partner of Oisin Biotechnologies, which is developing a liposomally-delivered suicide gene senolytic therapy (a treatment that removes senescent cells from the body). Hudson provided an initial seed donation to help fund the creation of the SENS Research Foundation.

Lazarus sign

The Lazarus sign or Lazarus reflex is a reflex movement in brain-dead or brainstem failure patients, which causes them to briefly raise their arms and drop them crossed on their chests (in a position similar to some Egyptian mummies). The phenomenon is named after the Biblical figure Lazarus of Bethany, whom Jesus raised from the dead in the Gospel of John.

Megadeath

Megadeath (or megacorpse) is one million human deaths, usually caused by a nuclear explosion. The term was used by scientists and thinkers who strategized likely outcomes of all-out nuclear warfare.

Necronym

A necronym (from the Greek words νεκρός, nekros, "dead" and ὄνομα ónoma, "name") is a reference to, or name of, a person who has died. Many cultures have taboos and traditions associated with referring to such a person. These vary from the extreme of never again speaking the person's real name, often using some circumlocution instead, to the opposite extreme of commemorating it incessantly by naming other things or people after the deceased.

For instance, in some cultures it is common for a newborn child to receive the name (a necronym) of a relative who has recently died, while in others to reuse such a name would be considered extremely inappropriate or even forbidden. While this varies from culture to culture, the use of necronyms is quite common.

Obituary

An obituary (obit for short) is a news article that reports the recent death of a person, typically along with an account of the person's life and information about the upcoming funeral. In large cities and larger newspapers, obituaries are written only for people considered significant. In local newspapers, an obituary may be published for any local resident upon death. A necrology is a register or list of records of the deaths of people related to a particular organization, group or field, which may only contain the sparsest details, or small obituaries. Historical necrologies can be important sources of information.

Two types of paid advertisements are related to obituaries. One, known as a death notice, omits most biographical details and may be a legally required public notice under some circumstances. The other type, a paid memorial advertisement, is usually written by family members or friends, perhaps with assistance from a funeral home. Both types of paid advertisements are usually run as classified advertisements.

Pallor mortis

Pallor mortis (Latin: pallor "paleness", mortis "of death"), the first stage of death, is an after-death paleness that occurs in those with light/white skin.

Rigor mortis

Rigor mortis (Latin: rigor "stiffness", mortis "of death"), or postmortem rigidity, is the third stage of death. It is one of the recognizable signs of death, characterized by stiffening of the limbs of the corpse caused by chemical changes in the muscles postmortem. In humans, rigor mortis can occur as soon as four hours after death.

Rosetta Martiniello-Wilks

Rosetta Martiniello-Wilks is an Australian cancer researcher and the current president of the Australasian Gene and Cell Therapy Society. She is a senior lecturer in the School of Medical and Molecular Biosciences at the University of Technology Sydney (UTS) in Ultimo, Sydney, Australia. Martiniello-Wilks is a core member of the Centre for Health Technologies at UTS and head of the Translational Cancer Research Group in the School of Medical and Molecular Biosciences, Faculty of Science, UTS.

Martiniello-Wilks' research includes searching for prostate cancer cures by developing gene and cell therapies and other innovative technologies:

New cancer hope (UTS website article) – "Prostate cancer (PCa) is the most commonly diagnosed cancer among men in Australia and many other western countries. If treated early with surgery, PCa has a cure rate of over 90 per cent. However, once advanced, it is incurable. Dr Martiniello-Wilks with Professor Pamela Russell, CSIRO lead scientists Dr Gerry Both, Dr Peter Molloy, Dr Trevor Lockett and their laboratories, have developed a cutting-edge 'direct delivery method' for advanced local PCa. This Gene Medicine for PCa uses a unique and safe virus to deliver a suicide gene, in a targeted manner, to prostate cells."

TK cell therapy

TK is an experimental cell therapy which may be used to treat high-risk leukemia. It is currently undergoing a Phase III clinical trial to determine efficacy and clinical usefulness.TK is currently being investigated in patients suffering from acute leukemia in first or subsequent complete remission and at high risk of relapse or in patients with relapsed disease who are candidates for haploidentical transplantation of hemopoietic stem cells (taken from a partially HLA-compatible family donor).

Thymidine kinase

Thymidine kinase is an enzyme, a phosphotransferase (a kinase): 2'-deoxythymidine kinase, ATP-thymidine 5'-phosphotransferase, EC 2.7.1.21. It can be found in most living cells. It is present in two forms in mammalian cells, TK1 and TK2. Certain viruses also have genetic information for expression of viral thymidine kinases.

Thymidine kinase catalyzes the reaction:

Thd + ATP → TMP + ADPwhere Thd is (deoxy)thymidine, ATP is adenosine triphosphate, TMP is (deoxy)thymidine monophosphate and ADP is adenosine diphosphate.

Thymidine kinases have a key function in the synthesis of DNA and therefore in cell division, as they are part of the unique reaction chain to introduce thymidine into the DNA. Thymidine is present in the body fluids as a result of degradation of DNA from food and from dead cells. Thymidine kinase is required for the action of many antiviral drugs. It is used to select hybridoma cell lines in production of monoclonal antibodies. In clinical chemistry it is used as a proliferation marker in the diagnosis, control of treatment and follow-up of malignant disease, mainly of hematological malignancies.

Virotherapy

Virotherapy is a treatment using biotechnology to convert viruses into therapeutic agents by reprogramming viruses to treat diseases. There are three main branches of virotherapy: anti-cancer oncolytic viruses, viral vectors for gene therapy and viral immunotherapy. These branches utilize three different types of treatment methods: gene overexpression, gene knockout, and suicide gene delivery. Gene overexpression adds genetic sequences that compensate for low to zero levels of needed gene expression. Gene knockout utilizes RNA methods to silence or reduce expression of disease-causing genes. Suicide gene delivery introduces genetic sequences that induce an apoptotic response in cells, usually to kill cancerous growths. In a slightly different context, virotherapy can also refer more broadly to the use of viruses to treat certain medical conditions by killing pathogens.

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