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Which cells will pass cancer to offspring?

Which cells will pass cancer to offspring?


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Each of these types below contains a DNA mutation. Which type(s) will affect the children of the individual whose cell it is.

  • Red blood cell
  • T cell
  • Skin (epithelial) cell
  • Neuron from the brain
  • Sperm cell
  • Cell from lining of the uterus
  • Placenta cell
  • Stem cell

My attempt: I think it's only a sperm cell, because that is the only cell to get passed on. Is this right?


Red blood cell

Will probably not. You inherit blood type, but not actual erythrocytes (though the mother's erythrocytes do interact with a fetus).

T cell

Will probably not. However, while in the uterus and for the first few weeks outside the uterus the Mother's immune system is effectively the newborn's immune system. While the mother doesn't pass on any myeloid progenitor cells, a disease affecting a leukocyte might also be passed on to the child (HIV).

Skin (epithelial) cell

Will not. You inherit many traits to do with skin (melanocyte activity resulting in melanin concentrations, for instance), but no skin cells are involved in the creation of the fetus.

Neuron from the brain

Will not. Neurons are the last time of cell I'd expect to vertically pass on a mutation, not only because their environment is usually tightly controlled (Schwann Cells, Blood-Brain Barrier, etc.), but also because the fetus will develop the beginnings of its nervous system very early on and I'm not aware of the mother's CNS or PNS interacting with the fetus in any significant way.

Sperm cell

Can certainly pass on a mutation as long as the mutation is part of the sperm's DNA. Though the particular gene the mutation exists on may be inactivated, it would still be passed on to the offspring and potential future generations.

Cell from lining of the uterus

I'm not positive on this one. The fertilized egg cell must implant itself in the lining of the uterus, and the landing location eventually becomes the umbilical cord. I suppose it's possible, particularly if the mutation occurs closer to the child's end - like the obliterated artery.

Placenta cell

Probably not, though like Cell from lining of the uterus I'm not super positive on this one. Given that the placenta is detached from both the mother and child soon after birth, a mutation in a placental cell that hasn't metasticized won't affect either. However, there may be interactions I'm not aware of.

Stem cell

"Stem cell" is a little vague. The body has many specific types of stem cells, and the fertilized egg itself basically turns into all of the stem cells the developing fetus will ever have. If it's referring to the daughter cells of a fertilized egg, then only the child will have the cancer, as the genetic inheritance is unidirectional (the mother's genome is not modified to resemble the child's in any way).

If someone has better knowledge on the interaction between the fetus and the uterus/mother or can come up with some references, listen to them. It's been a while since I've studied development.


Melanoma Cells Are More Likely to Spread after a Stopover in Lymph Nodes

Melanoma cells can spread from the primary tumor through the bloodstream and lymphatic system to form new tumors.

Melanoma, the most aggressive form of skin cancer, is often incurable once the cancer has spread from the original site of the tumor to distant organs and tissues.

Doctors have known for decades that melanoma and many other cancer types tend to spread first into nearby lymph nodes before entering the blood and traveling to distant parts of the body. But the implications of this detour through the lymph nodes have remained unclear.

Now, an NCI-funded study may provide some answers, raising the possibility of new treatment approaches that could help keep melanoma from spreading, or metastasizing, the study investigators said.

The study, published September 3 in Nature, shows that melanoma cells that pass through the lymphatic system before entering the bloodstream spread and form new tumors more readily than cells that directly enter the bloodstream.

In studies in mice, a team led by Sean Morrison, Ph.D., director of the Children’s Medical Center Research Institute at UT Southwestern, found that melanoma cells that travel through the lymphatic system are more resistant to a form of cell death called ferroptosis.

“This knowledge uncovers tremendous therapeutic potential, since enhancers and inhibitors of ferroptosis are being developed,” said Konstantin Salnikow, Ph.D., of NCI’s Division of Cancer Biology, who was not involved in the study.

However, further work is needed before such drugs could be tested in people with melanoma, Dr. Salnikow said.


Major Heritable Renal Cell Carcinoma Syndromes

Four major heritable renal cell carcinoma (RCC) syndromes (von Hippel-Lindau disease [VHL], hereditary leiomyomatosis and renal cell cancer [HLRCC], hereditary papillary renal carcinoma [HPRC], and Birt-Hogg-Dubé syndrome [BHD]) with autosomal dominant inheritance are listed in Table 1, along with their susceptibility genes. These syndromes are summarized in detail in the following PDQ summaries:

Table 1. Hereditary Renal Cell Cancer (RCC) Syndromes and Susceptibility Genes
Syndrome (Inheritance Pattern)Gene Locus, Gene Type (Protein)Renal Tumor Pathology Cumulative Cancer RiskNonrenal Tumors and Associated Abnormalities
AD = autosomal dominant ccRCC = clear cell renal cell carcinoma CNS = central nervous system.
von Hippel-Lindau disease (VHL) (AD) [1,2]VHL 3p26, tumor suppressor (pVHL) ccRCC (multifocal) 24%󈞙%CNS hemangioblastoma, retinal hemangioblastomas, pheochromocytoma, pancreatic neuroendocrine tumor, endolymphatic sac tumor, cystadenoma of the pancreas, the epididymis, and the broad ligament
Hereditary leiomyomatosis and renal cell cancer (HLRCC) (AD) [3-6] FH 1q42.1, tumor suppressor (fumarate hydratase) HLRCC-associated RCCUp to 32%Cutaneous leiomyomas, uterine leiomyomas (fibroids)
Hereditary papillary renal carcinoma (HPRC) (AD) [7,8]MET 7q34, proto-oncogene (hepatocyte growth factor receptor)Papillary type 1Approaching 100%None known
Birt-Hogg-Dubé syndrome (BHD) (AD) [9-12]FLCN 17p11.2, tumor suppressor (folliculin)Hybrid oncocytic, chromophobe, oncocytoma, papillary, clear cell 15%󈞊%Cutaneous: fibrofolliculomas/ trichodiscomas
Pulmonary: lung cysts, spontaneous pneumothoraces

Autosomal dominant mode of inheritance is the pattern of transmission reported within the families affected by these major RCC syndromes. Autosomal dominant means that it is sufficient for the altered gene to be present in one of the parents and that the chances of transmitting this gene and the disease to the offspring is 50% for each pregnancy. Genetic tests performed in Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories are available for the genes associated with VHL, HLRCC, HPRC, and BHD. Genetic counseling is a prerequisite for genetic testing. (Refer to the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)

References
  1. Choyke PL, Glenn GM, Walther MM, et al.: von Hippel-Lindau disease: genetic, clinical, and imaging features. Radiology 194 (3): 629-42, 1995. [PUBMED Abstract]
  2. Lonser RR, Glenn GM, Walther M, et al.: von Hippel-Lindau disease. Lancet 361 (9374): 2059-67, 2003. [PUBMED Abstract]
  3. Launonen V, Vierimaa O, Kiuru M, et al.: Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci U S A 98 (6): 3387-92, 2001. [PUBMED Abstract]
  4. Alam NA, Olpin S, Leigh IM: Fumarate hydratase mutations and predisposition to cutaneous leiomyomas, uterine leiomyomas and renal cancer. Br J Dermatol 153 (1): 11-7, 2005. [PUBMED Abstract]
  5. Toro JR, Nickerson ML, Wei MH, et al.: Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet 73 (1): 95-106, 2003. [PUBMED Abstract]
  6. Wei MH, Toure O, Glenn GM, et al.: Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer. J Med Genet 43 (1): 18-27, 2006. [PUBMED Abstract]
  7. Schmidt L, Duh FM, Chen F, et al.: Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet 16 (1): 68-73, 1997. [PUBMED Abstract]
  8. Schmidt LS, Nickerson ML, Angeloni D, et al.: Early onset hereditary papillary renal carcinoma: germline missense mutations in the tyrosine kinase domain of the met proto-oncogene. J Urol 172 (4 Pt 1): 1256-61, 2004. [PUBMED Abstract]
  9. Toro JR, Wei MH, Glenn GM, et al.: BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports. J Med Genet 45 (6): 321-31, 2008. [PUBMED Abstract]
  10. Toro JR, Glenn G, Duray P, et al.: Birt-Hogg-Dubé syndrome: a novel marker of kidney neoplasia. Arch Dermatol 135 (10): 1195-202, 1999. [PUBMED Abstract]
  11. Zbar B, Alvord WG, Glenn G, et al.: Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome. Cancer Epidemiol Biomarkers Prev 11 (4): 393-400, 2002. [PUBMED Abstract]
  12. Pavlovich CP, Walther MM, Eyler RA, et al.: Renal tumors in the Birt-Hogg-Dubé syndrome. Am J Surg Pathol 26 (12): 1542-52, 2002. [PUBMED Abstract]

Breast cancer brain metastases: biology and new clinical perspectives

Because of improvements in the treatment of patients with metastatic breast cancer, the development of brain metastases (BM) has become a major limitation of life expectancy and quality of life for many breast cancer patients. The improvement of management strategies for BM is thus an important clinical challenge, especially among high-risk patients such as human epidermal growth factor receptor 2-positive and triple-negative patients. However, the formation of BM as a multistep process is thus far poorly understood. To grow in the brain, single tumor cells must pass through the tight blood-brain barrier (BBB). The BBB represents an obstacle for circulating tumor cells entering the brain, but it also plays a protective role against immune cell and toxic agents once metastatic cells have colonized the cerebral compartment. Furthermore, animal studies have shown that, after passing the BBB, the tumor cells not only require close contact with endothelial cells but also interact closely with many different brain residential cells. Thus, in addition to a genetic predisposition of the tumor cells, cellular adaptation processes within the new microenvironment may also determine the ability of a tumor cell to metastasize. In this review, we summarize the biology of breast cancer that has spread into the brain and discuss the implications for current and potential future treatment strategies.

Figures

Schematic of tumor cell interactions…

Schematic of tumor cell interactions in the brain. An intensive direct and indirect…


Contents

Origins Edit

The inheritance of acquired characteristics was proposed in ancient times, and remained a current idea for many centuries. The historian of science Conway Zirkle wrote in 1935 that: [3]

Lamarck was neither the first nor the most distinguished biologist to believe in the inheritance of acquired characters. He merely endorsed a belief which had been generally accepted for at least 2,200 years before his time and used it to explain how evolution could have taken place. The inheritance of acquired characters had been accepted previously by Hippocrates, Aristotle, Galen, Roger Bacon, Jerome Cardan, Levinus Lemnius, John Ray, Michael Adanson, Jo. Fried. Blumenbach and Erasmus Darwin among others. [3]

Zirkle noted that Hippocrates described pangenesis, the theory that what is inherited derives from the whole body of the parent, whereas Aristotle thought it impossible but that all the same, Aristotle implicitly agreed to the inheritance of acquired characteristics, giving the example of the inheritance of a scar, or of blindness, though noting that children do not always resemble their parents. Zirkle recorded that Pliny the Elder thought much the same. Zirkle also pointed out that stories involving the idea of inheritance of acquired characteristics appear numerous times in ancient mythology and the Bible, and persisted through to Rudyard Kipling's Just So Stories. [4] Erasmus Darwin's Zoonomia (c. 1795) suggested that warm-blooded animals develop from "one living filament. with the power of acquiring new parts" in response to stimuli, with each round of "improvements" being inherited by successive generations. [5]

Darwin's pangenesis Edit

Charles Darwin's On the Origin of Species proposed natural selection as the main mechanism for development of species, but did not rule out a variant of Lamarckism as a supplementary mechanism. [6] Darwin called this pangenesis, and explained it in the final chapter of his book The Variation of Animals and Plants Under Domestication (1868), after describing numerous examples to demonstrate what he considered to be the inheritance of acquired characteristics. Pangenesis, which he emphasised was a hypothesis, was based on the idea that somatic cells would, in response to environmental stimulation (use and disuse), throw off 'gemmules' or 'pangenes' which travelled around the body, though not necessarily in the bloodstream. These pangenes were microscopic particles that supposedly contained information about the characteristics of their parent cell, and Darwin believed that they eventually accumulated in the germ cells where they could pass on to the next generation the newly acquired characteristics of the parents. [7] [8]

Darwin's half-cousin, Francis Galton, carried out experiments on rabbits, with Darwin's cooperation, in which he transfused the blood of one variety of rabbit into another variety in the expectation that its offspring would show some characteristics of the first. They did not, and Galton declared that he had disproved Darwin's hypothesis of pangenesis, but Darwin objected, in a letter to the scientific journal Nature, that he had done nothing of the sort, since he had never mentioned blood in his writings. He pointed out that he regarded pangenesis as occurring in protozoa and plants, which have no blood, as well as in animals. [9]

Lamarck's evolutionary framework Edit

Between 1800 and 1830, Lamarck proposed a systematic theoretical framework for understanding evolution. He saw evolution as comprising four laws: [10] [11]

  1. "Life by its own force, tends to increase the volume of all organs which possess the force of life, and the force of life extends the dimensions of those parts up to an extent that those parts bring to themselves"
  2. "The production of a new organ in an animal body, results from a new requirement arising. and which continues to make itself felt, and a new movement which that requirement gives birth to, and its upkeep/maintenance"
  3. "The development of the organs, and their ability, are constantly a result of the use of those organs."
  4. "All that has been acquired, traced, or changed, in the physiology of individuals, during their life, is conserved through the genesis, reproduction, and transmitted to new individuals who are related to those who have undergone those changes."

Lamarck's discussion of heredity Edit

In 1830, in an aside from his evolutionary framework, Lamarck briefly mentioned two traditional ideas in his discussion of heredity, in his day considered to be generally true. The first was the idea of use versus disuse he theorized that individuals lose characteristics they do not require, or use, and develop characteristics that are useful. The second was to argue that the acquired traits were heritable. He gave as an imagined illustration the idea that when giraffes stretch their necks to reach leaves high in trees, they would strengthen and gradually lengthen their necks. These giraffes would then have offspring with slightly longer necks. In the same way, he argued, a blacksmith, through his work, strengthens the muscles in his arms, and thus his sons would have similar muscular development when they mature. Lamarck stated the following two laws: [12]

  1. Première Loi: Dans tout animal qui n' a point dépassé le terme de ses développemens, l' emploi plus fréquent et soutenu d' un organe quelconque, fortifie peu à peu cet organe, le développe, l' agrandit, et lui donne une puissance proportionnée à la durée de cet emploi tandis que le défaut constant d' usage de tel organe, l'affoiblit insensiblement, le détériore, diminue progressivement ses facultés, et finit par le faire disparoître.[12]
  2. Deuxième Loi: Tout ce que la nature a fait acquérir ou perdre aux individus par l' influence des circonstances où leur race se trouve depuis long-temps exposée, et, par conséquent, par l' influence de l' emploi prédominant de tel organe, ou par celle d' un défaut constant d' usage de telle partie elle le conserve par la génération aux nouveaux individus qui en proviennent, pourvu que les changemens acquis soient communs aux deux sexes, ou à ceux qui ont produit ces nouveaux individus.[12]
  1. First Law [Use and Disuse]: In every animal which has not passed the limit of its development, a more frequent and continuous use of any organ gradually strengthens, develops and enlarges that organ, and gives it a power proportional to the length of time it has been so used while the permanent disuse of any organ imperceptibly weakens and deteriorates it, and progressively diminishes its functional capacity, until it finally disappears.
  2. Second Law [Soft Inheritance]: All the acquisitions or losses wrought by nature on individuals, through the influence of the environment in which their race has long been placed, and hence through the influence of the predominant use or permanent disuse of any organ all these are preserved by reproduction to the new individuals which arise, provided that the acquired modifications are common to both sexes, or at least to the individuals which produce the young. [13]

In essence, a change in the environment brings about change in "needs" (besoins), resulting in change in behaviour, causing change in organ usage and development, bringing change in form over time—and thus the gradual transmutation of the species. The evolutionary biologists and historians of science Conway Zirkle, Michael Ghiselin, and Stephen Jay Gould have pointed out, these ideas were not original to Lamarck. [3] [1] [14]

Weismann's experiment Edit

August Weismann's germ plasm theory held that germline cells in the gonads contain information that passes from one generation to the next, unaffected by experience, and independent of the somatic (body) cells. This implied what came to be known as the Weismann barrier, as it would make Lamarckian inheritance from changes to the body difficult or impossible. [15]

Weismann conducted the experiment of removing the tails of 68 white mice, and those of their offspring over five generations, and reporting that no mice were born in consequence without a tail or even with a shorter tail. In 1889, he stated that "901 young were produced by five generations of artificially mutilated parents, and yet there was not a single example of a rudimentary tail or of any other abnormality in this organ." [16] The experiment, and the theory behind it, were thought at the time to be a refutation of Lamarckism. [15]

The experiment's effectiveness in refuting Lamarck's hypothesis is doubtful, as it did not address the use and disuse of characteristics in response to the environment. The biologist Peter Gauthier noted in 1990 that: [17]

Can Weismann's experiment be considered a case of disuse? Lamarck proposed that when an organ was not used, it slowly, and very gradually atrophied. In time, over the course of many generations, it would gradually disappear as it was inherited in its modified form in each successive generation. Cutting the tails off mice does not seem to meet the qualifications of disuse, but rather falls in a category of accidental misuse. Lamarck's hypothesis has never been proven experimentally and there is no known mechanism to support the idea that somatic change, however acquired, can in some way induce a change in the germplasm. On the other hand it is difficult to disprove Lamarck's idea experimentally, and it seems that Weismann's experiment fails to provide the evidence to deny the Lamarckian hypothesis, since it lacks a key factor, namely the willful exertion of the animal in overcoming environmental obstacles. [17]

Ghiselin also considered the Weismann tail-chopping experiment to have no bearing on the Lamarckian hypothesis, writing in 1994 that: [1]

The acquired characteristics that figured in Lamarck's thinking were changes that resulted from an individual's own drives and actions, not from the actions of external agents. Lamarck was not concerned with wounds, injuries or mutilations, and nothing that Lamarck had set forth was tested or "disproven" by the Weismann tail-chopping experiment. [1]

The historian of science Rasmus Winther stated that Weismann had nuanced views about the role of the environment on the germ plasm. Indeed, like Darwin, he consistently insisted that a variable environment was necessary to cause variation in the hereditary material. [18]

The identification of Lamarckism with the inheritance of acquired characteristics is regarded by evolutionary biologists including Ghiselin as a falsified artifact of the subsequent history of evolutionary thought, repeated in textbooks without analysis, and wrongly contrasted with a falsified picture of Darwin's thinking. Ghiselin notes that "Darwin accepted the inheritance of acquired characteristics, just as Lamarck did, and Darwin even thought that there was some experimental evidence to support it." [1] Gould wrote that in the late 19th century, evolutionists "re-read Lamarck, cast aside the guts of it . and elevated one aspect of the mechanics—inheritance of acquired characters—to a central focus it never had for Lamarck himself." [19] He argued that "the restriction of 'Lamarckism' to this relatively small and non-distinctive corner of Lamarck's thought must be labelled as more than a misnomer, and truly a discredit to the memory of a man and his much more comprehensive system." [2] [20]

Context Edit

The period of the history of evolutionary thought between Darwin's death in the 1880s, and the foundation of population genetics in the 1920s and the beginnings of the modern evolutionary synthesis in the 1930s, is called the eclipse of Darwinism by some historians of science. During that time many scientists and philosophers accepted the reality of evolution but doubted whether natural selection was the main evolutionary mechanism. [21]

Among the most popular alternatives were theories involving the inheritance of characteristics acquired during an organism's lifetime. Scientists who felt that such Lamarckian mechanisms were the key to evolution were called neo-Lamarckians. They included the British botanist George Henslow (1835–1925), who studied the effects of environmental stress on the growth of plants, in the belief that such environmentally-induced variation might explain much of plant evolution, and the American entomologist Alpheus Spring Packard, Jr., who studied blind animals living in caves and wrote a book in 1901 about Lamarck and his work. [22] [23] Also included were paleontologists like Edward Drinker Cope and Alpheus Hyatt, who observed that the fossil record showed orderly, almost linear, patterns of development that they felt were better explained by Lamarckian mechanisms than by natural selection. Some people, including Cope and the Darwin critic Samuel Butler, felt that inheritance of acquired characteristics would let organisms shape their own evolution, since organisms that acquired new habits would change the use patterns of their organs, which would kick-start Lamarckian evolution. They considered this philosophically superior to Darwin's mechanism of random variation acted on by selective pressures. Lamarckism also appealed to those, like the philosopher Herbert Spencer and the German anatomist Ernst Haeckel, who saw evolution as an inherently progressive process. [22] The German zoologist Theodor Eimer combined Larmarckism with ideas about orthogenesis, the idea that evolution is directed towards a goal. [24]

With the development of the modern synthesis of the theory of evolution, and a lack of evidence for a mechanism for acquiring and passing on new characteristics, or even their heritability, Lamarckism largely fell from favour. Unlike neo-Darwinism, neo-Lamarckism is a loose grouping of largely heterodox theories and mechanisms that emerged after Lamarck's time, rather than a coherent body of theoretical work. [25]

19th century Edit

Neo-Lamarckian versions of evolution were widespread in the late 19th century. The idea that living things could to some degree choose the characteristics that would be inherited allowed them to be in charge of their own destiny as opposed to the Darwinian view, which placed them at the mercy of the environment. Such ideas were more popular than natural selection in the late 19th century as it made it possible for biological evolution to fit into a framework of a divine or naturally willed plan, thus the neo-Lamarckian view of evolution was often advocated by proponents of orthogenesis. [26] According to the historian of science Peter J. Bowler, writing in 2003:

One of the most emotionally compelling arguments used by the neo-Lamarckians of the late nineteenth century was the claim that Darwinism was a mechanistic theory which reduced living things to puppets driven by heredity. The selection theory made life into a game of Russian roulette, where life or death was predetermined by the genes one inherited. The individual could do nothing to mitigate bad heredity. Lamarckism, in contrast, allowed the individual to choose a new habit when faced with an environmental challenge and shape the whole future course of evolution. [27]

Scientists from the 1860s onwards conducted numerous experiments that purported to show Lamarckian inheritance. Some examples are described in the table.

Early 20th century Edit

A century after Lamarck, scientists and philosophers continued to seek mechanisms and evidence for the inheritance of acquired characteristics. Experiments were sometimes reported as successful, but from the beginning these were either criticised on scientific grounds or shown to be fakes. [45] [46] [47] [48] [49] For instance, in 1906, the philosopher Eugenio Rignano argued for a version that he called "centro-epigenesis", [50] [51] [52] [53] [54] [55] but it was rejected by most scientists. [56] Some of the experimental approaches are described in the table.

Early 20th century experiments attempting to demonstrate Lamarckian inheritance
Scientist Date Experiment Claimed result Rebuttal
William Lawrence Tower 1907 to 1910 Colorado potato beetles in extreme humidity, temperature Heritable changes in size, colour Criticised by William Bateson Tower claimed all results lost in fire William E. Castle visited laboratory, found fire suspicious, doubted claim that steam leak had killed all beetles, concluded faked data. [57] [58] [59] [46] [47]
Gustav Tornier 1907 to 1918 Goldfish, embryos of frogs, newts Abnormalities inherited Disputed possibly an osmotic effect [60] [61] [62] [63]
Charles Rupert Stockard 1910 Repeated alcohol intoxication of pregnant guinea pigs Inherited malformations Raymond Pearl unable to reproduce findings in chickens Darwinian explanation [64] [45]
Francis Bertody Sumner 1921 Reared mice at different temperatures, humidities Inherited longer bodies, tails, hind feet Inconsistent results [65] [66]
Michael F. Guyer, Elizabeth A. Smith 1918 to 1924 Injected fowl serum antibodies for rabbit lens-protein into pregnant rabbits Eye defects inherited for 8 generations Disputed, results not replicated [67] [68]
Paul Kammerer 1920s Midwife toad Black foot-pads inherited Fraud, ink injected or, results misinterpreted case celebrated by Arthur Koestler arguing that opposition was political [48] [69]
William McDougall 1920s Rats solving mazes Offspring learnt mazes quicker (20 vs 165 trials) Poor experimental controls [70] [71] [72] [73] [74] [75] [49]
John William Heslop-Harrison 1920s Peppered moths exposed to soot Inherited mutations caused by soot Failure to replicate results implausible mutation rate [76] [77]
Ivan Pavlov 1926 Conditioned reflex in mice to food and bell Offspring easier to condition Pavlov retracted claim results not replicable [78] [79]
Coleman Griffith, John Detlefson 1920 to 1925 Reared rats on rotating table for 3 months Inherited balance disorder Results not replicable likely cause ear infection [80] [81] [82] [83] [84] [85]
Victor Jollos [pl] 1930s Heat treatment in Drosophila melanogaster Directed mutagenesis, a form of orthogenesis Results not replicable [86] [87]

Late 20th century Edit

The British anthropologist Frederic Wood Jones and the South African paleontologist Robert Broom supported a neo-Lamarckian view of human evolution. The German anthropologist Hermann Klaatsch relied on a neo-Lamarckian model of evolution to try and explain the origin of bipedalism. Neo-Lamarckism remained influential in biology until the 1940s when the role of natural selection was reasserted in evolution as part of the modern evolutionary synthesis. [88] Herbert Graham Cannon, a British zoologist, defended Lamarckism in his 1959 book Lamarck and Modern Genetics. [89] In the 1960s, "biochemical Lamarckism" was advocated by the embryologist Paul Wintrebert. [90]

Neo-Lamarckism was dominant in French biology for more than a century. French scientists who supported neo-Lamarckism included Edmond Perrier (1844–1921), Alfred Giard (1846–1908), Gaston Bonnier (1853–1922) and Pierre-Paul Grassé (1895–1985). They followed two traditions, one mechanistic, one vitalistic after Henri Bergson's philosophy of evolution. [91]

In 1987, Ryuichi Matsuda coined the term "pan-environmentalism" for his evolutionary theory which he saw as a fusion of Darwinism with neo-Lamarckism. He held that heterochrony is a main mechanism for evolutionary change and that novelty in evolution can be generated by genetic assimilation. [92] [93] His views were criticized by Arthur M. Shapiro for providing no solid evidence for his theory. Shapiro noted that "Matsuda himself accepts too much at face value and is prone to wish-fulfilling interpretation." [93]

Ideological neo-Lamarckism Edit

A form of Lamarckism was revived in the Soviet Union of the 1930s when Trofim Lysenko promoted the ideologically-driven research programme, Lysenkoism this suited the ideological opposition of Joseph Stalin to genetics. Lysenkoism influenced Soviet agricultural policy which in turn was later blamed for crop failures. [94]

Critique Edit

George Gaylord Simpson in his book Tempo and Mode in Evolution (1944) claimed that experiments in heredity have failed to corroborate any Lamarckian process. [95] Simpson noted that neo-Lamarckism "stresses a factor that Lamarck rejected: inheritance of direct effects of the environment" and neo-Lamarckism is closer to Darwin's pangenesis than Lamarck's views. [96] Simpson wrote, "the inheritance of acquired characters, failed to meet the tests of observation and has been almost universally discarded by biologists." [97]

Botanist Conway Zirkle pointed out that Lamarck did not originate the hypothesis that acquired characteristics could be inherited, so it is incorrect to refer to it as Lamarckism:

What Lamarck really did was to accept the hypothesis that acquired characters were heritable, a notion which had been held almost universally for well over two thousand years and which his contemporaries accepted as a matter of course, and to assume that the results of such inheritance were cumulative from generation to generation, thus producing, in time, new species. His individual contribution to biological theory consisted in his application to the problem of the origin of species of the view that acquired characters were inherited and in showing that evolution could be inferred logically from the accepted biological hypotheses. He would doubtless have been greatly astonished to learn that a belief in the inheritance of acquired characters is now labeled "Lamarckian," although he would almost certainly have felt flattered if evolution itself had been so designated. [4]

Peter Medawar wrote regarding Lamarckism, "very few professional biologists believe that anything of the kind occurs—or can occur—but the notion persists for a variety of nonscientific reasons." Medawar stated there is no known mechanism by which an adaptation acquired in an individual's lifetime can be imprinted on the genome and Lamarckian inheritance is not valid unless it excludes the possibility of natural selection but this has not been demonstrated in any experiment. [98]

A host of experiments have been designed to test Lamarckianism. All that have been verified have proved negative. On the other hand, tens of thousands of experiments— reported in the journals and carefully checked and rechecked by geneticists throughout the world— have established the correctness of the gene-mutation theory beyond all reasonable doubt. In spite of the rapidly increasing evidence for natural selection, Lamarck has never ceased to have loyal followers. There is indeed a strong emotional appeal in the thought that every little effort an animal puts forth is somehow transmitted to his progeny. [99]

According to Ernst Mayr, any Lamarckian theory involving the inheritance of acquired characters has been refuted as "DNA does not directly participate in the making of the phenotype and that the phenotype, in turn, does not control the composition of the DNA." [100] Peter J. Bowler has written that although many early scientists took Lamarckism seriously, it was discredited by genetics in the early twentieth century. [101]

Studies in the field of epigenetics, genetics and somatic hypermutation [102] [103] have highlighted the possible inheritance of traits acquired by the previous generation. [104] [105] [106] [107] [108] However, the characterization of these findings as Lamarckism has been disputed. [109] [110] [111] [112]

Transgenerational epigenetic inheritance Edit

Epigenetic inheritance has been argued by scientists including Eva Jablonka and Marion J. Lamb to be Lamarckian. [113] Epigenetics is based on hereditary elements other than genes that pass into the germ cells. These include methylation patterns in DNA and chromatin marks on histone proteins, both involved in gene regulation. These marks are responsive to environmental stimuli, differentially affect gene expression, and are adaptive, with phenotypic effects that persist for some generations. The mechanism may also enable the inheritance of behavioral traits, for example in chickens [114] [115] [116] rats [117] [118] and human populations that have experienced starvation, DNA methylation resulting in altered gene function in both the starved population and their offspring. [119] Methylation similarly mediates epigenetic inheritance in plants such as rice. [120] [121] Small RNA molecules, too, may mediate inherited resistance to infection. [122] [123] [124] Handel and Romagopalan commented that "epigenetics allows the peaceful co-existence of Darwinian and Lamarckian evolution." [125]

Joseph Springer and Dennis Holley commented in 2013 that: [126]

Lamarck and his ideas were ridiculed and discredited. In a strange twist of fate, Lamarck may have the last laugh. Epigenetics, an emerging field of genetics, has shown that Lamarck may have been at least partially correct all along. It seems that reversible and heritable changes can occur without a change in DNA sequence (genotype) and that such changes may be induced spontaneously or in response to environmental factors—Lamarck's "acquired traits." Determining which observed phenotypes are genetically inherited and which are environmentally induced remains an important and ongoing part of the study of genetics, developmental biology, and medicine. [126]

The prokaryotic CRISPR system and Piwi-interacting RNA could be classified as Lamarckian, within a Darwinian framework. [127] [128] However, the significance of epigenetics in evolution is uncertain. Critics such as the evolutionary biologist Jerry Coyne point out that epigenetic inheritance lasts for only a few generations, so it is not a stable basis for evolutionary change. [129] [130] [131] [132]

The evolutionary biologist T. Ryan Gregory contends that epigenetic inheritance should not be considered Lamarckian. According to Gregory, Lamarck did not claim that the environment directly affected living things. Instead, Lamarck "argued that the environment created needs to which organisms responded by using some features more and others less, that this resulted in those features being accentuated or attenuated, and that this difference was then inherited by offspring." Gregory has stated that Lamarckian evolution in epigenetics is more like Darwin's point of view than Lamarck's. [109]

In 2007, David Haig wrote that research into epigenetic processes does allow a Lamarckian element in evolution but the processes do not challenge the main tenets of the modern evolutionary synthesis as modern Lamarckians have claimed. Haig argued for the primacy of DNA and evolution of epigenetic switches by natural selection. [133] Haig has written that there is a "visceral attraction" to Lamarckian evolution from the public and some scientists, as it posits the world with a meaning, in which organisms can shape their own evolutionary destiny. [134]

Thomas Dickens and Qazi Rahman (2012) have argued that epigenetic mechanisms such as DNA methylation and histone modification are genetically inherited under the control of natural selection and do not challenge the modern synthesis. They dispute the claims of Jablonka and Lamb on Lamarckian epigenetic processes. [135]

In 2015, Khursheed Iqbal and colleagues discovered that although "endocrine disruptors exert direct epigenetic effects in the exposed fetal germ cells, these are corrected by reprogramming events in the next generation." [137] Also in 2015, Adam Weiss argued that bringing back Lamarck in the context of epigenetics is misleading, commenting, "We should remember [Lamarck] for the good he contributed to science, not for things that resemble his theory only superficially. Indeed, thinking of CRISPR and other phenomena as Lamarckian only obscures the simple and elegant way evolution really works." [138]

Somatic hypermutation and reverse transcription to germline Edit

In the 1970s, the Australian immunologist Edward J. Steele developed a neo-Lamarckian theory of somatic hypermutation within the immune system and coupled it to the reverse transcription of RNA derived from body cells to the DNA of germline cells. This reverse transcription process supposedly enabled characteristics or bodily changes acquired during a lifetime to be written back into the DNA and passed on to subsequent generations. [139] [140]

The mechanism was meant to explain why homologous DNA sequences from the VDJ gene regions of parent mice were found in their germ cells and seemed to persist in the offspring for a few generations. The mechanism involved the somatic selection and clonal amplification of newly acquired antibody gene sequences generated via somatic hypermutation in B-cells. The messenger RNA products of these somatically novel genes were captured by retroviruses endogenous to the B-cells and were then transported through the bloodstream where they could breach the Weismann or soma-germ barrier and reverse transcribe the newly acquired genes into the cells of the germ line, in the manner of Darwin's pangenes. [103] [102] [141]

The historian of biology Peter J. Bowler noted in 1989 that other scientists had been unable to reproduce his results, and described the scientific consensus at the time: [136]

There is no feedback of information from the proteins to the DNA, and hence no route by which characteristics acquired in the body can be passed on through the genes. The work of Ted Steele (1979) provoked a flurry of interest in the possibility that there might, after all, be ways in which this reverse flow of information could take place. . [His] mechanism did not, in fact, violate the principles of molecular biology, but most biologists were suspicious of Steele's claims, and attempts to reproduce his results have failed. [136]

Bowler commented that "[Steele's] work was bitterly criticized at the time by biologists who doubted his experimental results and rejected his hypothetical mechanism as implausible." [136]

Hologenome theory of evolution Edit

The hologenome theory of evolution, while Darwinian, has Lamarckian aspects. An individual animal or plant lives in symbiosis with many microorganisms, and together they have a "hologenome" consisting of all their genomes. The hologenome can vary like any other genome by mutation, sexual recombination, and chromosome rearrangement, but in addition it can vary when populations of microorganisms increase or decrease (resembling Lamarckian use and disuse), and when it gains new kinds of microorganism (resembling Lamarckian inheritance of acquired characteristics). These changes are then passed on to offspring. [143] The mechanism is largely uncontroversial, and natural selection does sometimes occur at whole system (hologenome) level, but it is not clear that this is always the case. [142]

Baldwin effect Edit

The Baldwin effect, named after the psychologist James Mark Baldwin by George Gaylord Simpson in 1953, proposes that the ability to learn new behaviours can improve an animal's reproductive success, and hence the course of natural selection on its genetic makeup. Simpson stated that the mechanism was "not inconsistent with the modern synthesis" of evolutionary theory, [144] though he doubted that it occurred very often, or could be proven to occur. He noted that the Baldwin effect provide a reconciliation between the neo-Darwinian and neo-Lamarckian approaches, something that the modern synthesis had seemed to render unnecessary. In particular, the effect allows animals to adapt to a new stress in the environment through behavioural changes, followed by genetic change. This somewhat resembles Lamarckism but without requiring animals to inherit characteristics acquired by their parents. [145] The Baldwin effect is broadly accepted by Darwinists. [146]

Within the field of cultural evolution, Lamarckism has been applied as a mechanism for dual inheritance theory. [147] Gould viewed culture as a Lamarckian process whereby older generations transmitted adaptive information to offspring via the concept of learning. In the history of technology, components of Lamarckism have been used to link cultural development to human evolution by considering technology as extensions of human anatomy. [148]


Passaging Cells

Cell lines are frequently used in biomedical experiments, as they allow rapid culture and expansion of cell types for experimental analysis. Cell lines are cultured under similar conditions when compared to freshly-isolated, or primary, cells, but with some basic important differences: (i) cell lines require their own specific growth factor cocktails and (ii) their growth must be more closely monitored than primary cells, as the mutations that allow them to be grown indefinitely also can quickly lead to their overgrowth. Therefore, when a cell line reaches the point of growth in culture where it covers most of the bottom of the culture container, or about a 90% confluency, the cells must be resuspended, washed, used experimentally, frozen for later use, or re-seeded for further expansion in new culture containers.

This video will demonstrate how to use media indicators to determine cell culture health, which reagents and equipment are useful for safely removing adherent cell lines from culture, and various methods for transferring these robustly expanding cells into new cultures will be discussed. Also demonstrated are methods for how to culture feeder cells (important for providing essential growth factors to cell lines) and how to expand large numbers of cell line cultures at once.

Procedure

Passaging, or subculturing, of cells, is a common procedure wherein cells from a given culture are divided, or &ldquosplit&rdquo, into new cultures and fed with fresh media to facilitate further expansion. While the concept itself is relatively simple, in this video we will discuss some of the more important steps for the successful maintenance and expansion of cell lines.

Toxic metabolites accumulate in cell culture media over time. When expanding cells, it is particularly important to change the media regularly to maintain cell health and to monitor the cell expansion to avoid cell overgrowth.

Generally, two main types of cells are subcultured: immortalized cell lines and stem cell lines

Immortalized cell lines are cells that are derived from multicellular organisms that have experienced some type of mutation affecting their cell cycle regulation, allowing them to proliferate indefinitely. Perhaps the most famous immortalized cell line is the HeLa cell line, which was derived from a cervical cancer lesion found on a biopsy taken from Ms. Henrietta Lacks in 1951.

In contrast to cell lines immortalized by cancer, stem cell lines are generated by isolating self-renewing and multipotent cells from a variety of tissues both from adult and embryonic tissues. Under the right conditions these cells, like the human embryonic stem cells you see here, can be maintained in culture indefinitely.

Cells are either optimally cultured in suspension, like immortalized cells isolated from blood, or they grow best when adhered to a surface, as is the case for many tissue-derived cells.

The growth of these adherent cells must be closely monitored to ensure cell health. Depending on the cell type, most adherent cells need to be passaged when they are 70-90% confluent, that is, when they cover 70-90% of the culture container surface.

Bear in mind that cell lines retain many characteristics of the original cell culture, but with each successive passage they can also begin to acquire characteristics unique to the expanded culture. Therefore, consider limiting the number of times you continue to passage an individual cell culture.

When passaging cells, it is important to use sterile technique and the appropriate reagents and equipment.

It is essential to use the appropriate media for the optimal growth and expansion of your cell line. Each cell line will require a specific growth supplement cocktail, however, most cell lines at minimum require supplementation with the following: Serum, such as Fetal Bovine Serum, which must be heat-treated to inactivate the bovine complement and which provides vital growth factors for the cells, antibiotics, like penicillin and streptomycin, which help limit contaminating growth in the culture, and other growth factors, like fibroblast growth factor, to help prolong the growth and expansion of the cell lines. Store the supplemented, or 𠇌omplete”, cell culture media at 4 C when you’re not using it.

First, take note of the color of the tissue culture media. Fresh, cell culture media is rich in nutrients and appears a clear, orange color, partly due to the addition of the pH indicator, phenol red.

As cells begin to use up nutrients in the media, waste and acid begin to build up in the cell culture, lowering the pH. For this reason, many tissue culture medias contain phenol red, which turns the media from orange to yellow when cells turn the culture acidic. Change the media before it turns this color!

When the phenol red turns the media a pinkish color, indicating that the pH has become too basic for healthy cell growth, it may be time to change your CO2 tank as well as your media.

Most adherent cell lines attach naturally to uncoated plastic. Therefore plastic cell culture plates, like petri dishes or 6 well plates, are frequently used for subculturing cells.

Plastic cell culture flasks are also used. The T25 cell culture flask, for example, is often used to expand small cell line populations or to start the growth of a slowly expanding cell line. T75 culture flasks are commonly used for cell lines that proliferate more quickly or to generate larger numbers of cells than can fit in a T25 flask.

When removing adherent cells, the proteins that bind the cells to the plastic must first be cleaved. For this purpose, the digestive enzyme trypsin is frequently used. It is important to carefully time the trypsin exposure, as treatment for too long can result in damage to other cell surface proteins.

Cell culture media can contain trypsin neutralizers. Therefore, phosphate buffered saline, or PBS, is often used to wash the cells before trypsinization.

EDTA, a calcium chelator, is sometimes also used to enhance the proteolytic function of trypsin.

For expansion of the cell colony, the freshly-passaged cells are then grown in a cell culture incubator under the conditions appropriate to that cell line, typically at about 37 C, 5% CO2, and 95% humidity.

Before you begin, it is important to understand how frequently your cells should be monitored, which will depend on how fast your cells proliferate.

Now that your media is a happy orange color, observe the other culture conditions, such as whether or not the culture is cloudy – possibly indicating contamination -- the size and density of the cell colonies, and the overall quality of the cells.

If the cells have reached about 90% confluency, remove the tissue culture media and wash the cells with calcium- and magnesium-free PBS.

Now add trypsin to the cells and then incubate them at 37 C. After about 5 minutes, confirm that the cells have detached, and then stop the proteolysis by adding fresh tissue culture media.

Transfer the cell suspension into a conical tube for centrifugation. Then, after spinning down the cells, carefully remove the supernatant without disturbing the pellet and resuspend the cells in fresh media. Count how many cells you’ve collected and then seed the cells according to the density appropriate for immediate or later expansion.

Now that you know how to passage cells, let’s look at some different applications of the method.

As mentioned earlier, human embryonic stem cells are a type of cell that must be passaged. They are typically cocultured with mouse embryonic fibroblasts, or MEFs, which provide factors that help stem cells retain their pluripotent state.

Stem cell colonies grown on feeder cells need to be “picked” once they&rsquove reached the proper stage of development. They can be selected by micropipette or by gentle scraping with a glass picking tool and then plated in a new culture for expansion.

Some cell lines are sensitive to enzymatic digest or they are so tightly adherent they can’t be resuspended with trypsin treatment alone. A cell scraper can be used to gently remove the cells from the bottom of the culture plate. If the cells are particularly adherent, try moving a serological pipette in a firm scraping motion while rinsing the bottom of the cell container with media or another appropriate solution. Take care with this method, as delicate cells can be damaged by this mechanical method of dissociation.

To more quickly and reproducibly scale up the expansion of your cells than can be achieved in single layer flasks, multilayer flasks, which can expand cell cultures 3-5 fold compared to single layer flasks, can be used.

You&rsquove just watched JoVE&rsquos introduction to passaging cells. In this video we reviewed what a cell line is, how to subculture one, and some different applications of passaging cells. Thanks for watching and remember to keep your media fresh!


Contents

The word genetics stems from the ancient Greek γενετικός genetikos meaning "genitive"/"generative", which in turn derives from γένεσις genesis meaning "origin". [4] [5] [6]

The observation that living things inherit traits from their parents has been used since prehistoric times to improve crop plants and animals through selective breeding. [7] The modern science of genetics, seeking to understand this process, began with the work of the Augustinian friar Gregor Mendel in the mid-19th century. [8]

Prior to Mendel, Imre Festetics, a Hungarian noble, who lived in Kőszeg before Mendel, was the first who used the word "genetics." He described several rules of genetic inheritance in his work The genetic law of the Nature (Die genetische Gesätze der Natur, 1819). His second law is the same as what Mendel published. In his third law, he developed the basic principles of mutation (he can be considered a forerunner of Hugo de Vries). [9]

Other theories of inheritance preceded Mendel's work. A popular theory during the 19th century, and implied by Charles Darwin's 1859 On the Origin of Species, was blending inheritance: the idea that individuals inherit a smooth blend of traits from their parents. [10] Mendel's work provided examples where traits were definitely not blended after hybridization, showing that traits are produced by combinations of distinct genes rather than a continuous blend. Blending of traits in the progeny is now explained by the action of multiple genes with quantitative effects. Another theory that had some support at that time was the inheritance of acquired characteristics: the belief that individuals inherit traits strengthened by their parents. This theory (commonly associated with Jean-Baptiste Lamarck) is now known to be wrong—the experiences of individuals do not affect the genes they pass to their children, [11] Other theories included the pangenesis of Charles Darwin (which had both acquired and inherited aspects) and Francis Galton's reformulation of pangenesis as both particulate and inherited. [12]

Mendelian and classical genetics Edit

Modern genetics started with Mendel's studies of the nature of inheritance in plants. In his paper "Versuche über Pflanzenhybriden" ("Experiments on Plant Hybridization"), presented in 1865 to the Naturforschender Verein (Society for Research in Nature) in Brünn, Mendel traced the inheritance patterns of certain traits in pea plants and described them mathematically. [13] Although this pattern of inheritance could only be observed for a few traits, Mendel's work suggested that heredity was particulate, not acquired, and that the inheritance patterns of many traits could be explained through simple rules and ratios.

The importance of Mendel's work did not gain wide understanding until 1900, after his death, when Hugo de Vries and other scientists rediscovered his research. William Bateson, a proponent of Mendel's work, coined the word genetics in 1905 [14] [15] (the adjective genetic, derived from the Greek word genesis—γένεσις, "origin", predates the noun and was first used in a biological sense in 1860 [16] ). Bateson both acted as a mentor and was aided significantly by the work of other scientists from Newnham College at Cambridge, specifically the work of Becky Saunders, Nora Darwin Barlow, and Muriel Wheldale Onslow. [17] Bateson popularized the usage of the word genetics to describe the study of inheritance in his inaugural address to the Third International Conference on Plant Hybridization in London in 1906. [18]

After the rediscovery of Mendel's work, scientists tried to determine which molecules in the cell were responsible for inheritance. In 1900, Nettie Stevens began studying the mealworm. [19] Over the next 11 years, she discovered that females only had the X chromosome and males had both X and Y chromosomes. [19] She was able to conclude that sex is a chromosomal factor and is determined by the male. [19] In 1911, Thomas Hunt Morgan argued that genes are on chromosomes, based on observations of a sex-linked white eye mutation in fruit flies. [20] In 1913, his student Alfred Sturtevant used the phenomenon of genetic linkage to show that genes are arranged linearly on the chromosome. [21]

Molecular genetics Edit

Although genes were known to exist on chromosomes, chromosomes are composed of both protein and DNA, and scientists did not know which of the two is responsible for inheritance. In 1928, Frederick Griffith discovered the phenomenon of transformation (see Griffith's experiment): dead bacteria could transfer genetic material to "transform" other still-living bacteria. Sixteen years later, in 1944, the Avery–MacLeod–McCarty experiment identified DNA as the molecule responsible for transformation. [22] The role of the nucleus as the repository of genetic information in eukaryotes had been established by Hämmerling in 1943 in his work on the single celled alga Acetabularia. [23] The Hershey–Chase experiment in 1952 confirmed that DNA (rather than protein) is the genetic material of the viruses that infect bacteria, providing further evidence that DNA is the molecule responsible for inheritance. [24]

James Watson and Francis Crick determined the structure of DNA in 1953, using the X-ray crystallography work of Rosalind Franklin and Maurice Wilkins that indicated DNA has a helical structure (i.e., shaped like a corkscrew). [25] [26] Their double-helix model had two strands of DNA with the nucleotides pointing inward, each matching a complementary nucleotide on the other strand to form what look like rungs on a twisted ladder. [27] This structure showed that genetic information exists in the sequence of nucleotides on each strand of DNA. The structure also suggested a simple method for replication: if the strands are separated, new partner strands can be reconstructed for each based on the sequence of the old strand. This property is what gives DNA its semi-conservative nature where one strand of new DNA is from an original parent strand. [28]

Although the structure of DNA showed how inheritance works, it was still not known how DNA influences the behavior of cells. In the following years, scientists tried to understand how DNA controls the process of protein production. [29] It was discovered that the cell uses DNA as a template to create matching messenger RNA, molecules with nucleotides very similar to DNA. The nucleotide sequence of a messenger RNA is used to create an amino acid sequence in protein this translation between nucleotide sequences and amino acid sequences is known as the genetic code. [30]

With the newfound molecular understanding of inheritance came an explosion of research. [31] A notable theory arose from Tomoko Ohta in 1973 with her amendment to the neutral theory of molecular evolution through publishing the nearly neutral theory of molecular evolution. In this theory, Ohta stressed the importance of natural selection and the environment to the rate at which genetic evolution occurs. [32] One important development was chain-termination DNA sequencing in 1977 by Frederick Sanger. This technology allows scientists to read the nucleotide sequence of a DNA molecule. [33] In 1983, Kary Banks Mullis developed the polymerase chain reaction, providing a quick way to isolate and amplify a specific section of DNA from a mixture. [34] The efforts of the Human Genome Project, Department of Energy, NIH, and parallel private efforts by Celera Genomics led to the sequencing of the human genome in 2003. [35] [36]

Discrete inheritance and Mendel's laws Edit

At its most fundamental level, inheritance in organisms occurs by passing discrete heritable units, called genes, from parents to offspring. [37] This property was first observed by Gregor Mendel, who studied the segregation of heritable traits in pea plants. [13] [38] In his experiments studying the trait for flower color, Mendel observed that the flowers of each pea plant were either purple or white—but never an intermediate between the two colors. These different, discrete versions of the same gene are called alleles.

In the case of the pea, which is a diploid species, each individual plant has two copies of each gene, one copy inherited from each parent. [39] Many species, including humans, have this pattern of inheritance. Diploid organisms with two copies of the same allele of a given gene are called homozygous at that gene locus, while organisms with two different alleles of a given gene are called heterozygous.

The set of alleles for a given organism is called its genotype, while the observable traits of the organism are called its phenotype. When organisms are heterozygous at a gene, often one allele is called dominant as its qualities dominate the phenotype of the organism, while the other allele is called recessive as its qualities recede and are not observed. Some alleles do not have complete dominance and instead have incomplete dominance by expressing an intermediate phenotype, or codominance by expressing both alleles at once. [40]

When a pair of organisms reproduce sexually, their offspring randomly inherit one of the two alleles from each parent. These observations of discrete inheritance and the segregation of alleles are collectively known as Mendel's first law or the Law of Segregation.

Notation and diagrams Edit

Geneticists use diagrams and symbols to describe inheritance. A gene is represented by one or a few letters. Often a "+" symbol is used to mark the usual, non-mutant allele for a gene. [41]

In fertilization and breeding experiments (and especially when discussing Mendel's laws) the parents are referred to as the "P" generation and the offspring as the "F1" (first filial) generation. When the F1 offspring mate with each other, the offspring are called the "F2" (second filial) generation. One of the common diagrams used to predict the result of cross-breeding is the Punnett square.

When studying human genetic diseases, geneticists often use pedigree charts to represent the inheritance of traits. [42] These charts map the inheritance of a trait in a family tree.

Multiple gene interactions Edit

Organisms have thousands of genes, and in sexually reproducing organisms these genes generally assort independently of each other. This means that the inheritance of an allele for yellow or green pea color is unrelated to the inheritance of alleles for white or purple flowers. This phenomenon, known as "Mendel's second law" or the "law of independent assortment," means that the alleles of different genes get shuffled between parents to form offspring with many different combinations. (Some genes do not assort independently, demonstrating genetic linkage, a topic discussed later in this article.)

Often different genes can interact in a way that influences the same trait. In the Blue-eyed Mary (Omphalodes verna), for example, there exists a gene with alleles that determine the color of flowers: blue or magenta. Another gene, however, controls whether the flowers have color at all or are white. When a plant has two copies of this white allele, its flowers are white—regardless of whether the first gene has blue or magenta alleles. This interaction between genes is called epistasis, with the second gene epistatic to the first. [43]

Many traits are not discrete features (e.g. purple or white flowers) but are instead continuous features (e.g. human height and skin color). These complex traits are products of many genes. [44] The influence of these genes is mediated, to varying degrees, by the environment an organism has experienced. The degree to which an organism's genes contribute to a complex trait is called heritability. [45] Measurement of the heritability of a trait is relative—in a more variable environment, the environment has a bigger influence on the total variation of the trait. For example, human height is a trait with complex causes. It has a heritability of 89% in the United States. In Nigeria, however, where people experience a more variable access to good nutrition and health care, height has a heritability of only 62%. [46]

DNA and chromosomes Edit

The molecular basis for genes is deoxyribonucleic acid (DNA). DNA is composed of a chain of nucleotides, of which there are four types: adenine (A), cytosine (C), guanine (G), and thymine (T). Genetic information exists in the sequence of these nucleotides, and genes exist as stretches of sequence along the DNA chain. [47] Viruses are the only exception to this rule—sometimes viruses use the very similar molecule RNA instead of DNA as their genetic material. [48] Viruses cannot reproduce without a host and are unaffected by many genetic processes, so tend not to be considered living organisms.

DNA normally exists as a double-stranded molecule, coiled into the shape of a double helix. Each nucleotide in DNA preferentially pairs with its partner nucleotide on the opposite strand: A pairs with T, and C pairs with G. Thus, in its two-stranded form, each strand effectively contains all necessary information, redundant with its partner strand. This structure of DNA is the physical basis for inheritance: DNA replication duplicates the genetic information by splitting the strands and using each strand as a template for synthesis of a new partner strand. [49]

Genes are arranged linearly along long chains of DNA base-pair sequences. In bacteria, each cell usually contains a single circular genophore, while eukaryotic organisms (such as plants and animals) have their DNA arranged in multiple linear chromosomes. These DNA strands are often extremely long the largest human chromosome, for example, is about 247 million base pairs in length. [50] The DNA of a chromosome is associated with structural proteins that organize, compact, and control access to the DNA, forming a material called chromatin in eukaryotes, chromatin is usually composed of nucleosomes, segments of DNA wound around cores of histone proteins. [51] The full set of hereditary material in an organism (usually the combined DNA sequences of all chromosomes) is called the genome.

DNA is most often found in the nucleus of cells, but Ruth Sager helped in the discovery of nonchromosomal genes found outside of the nucleus. [52] In plants, these are often found in the chloroplasts and in other organisms, in the mitochondria. [52] These nonchromosomal genes can still be passed on by either partner in sexual reproduction and they control a variety of hereditary characteristics that replicate and remain active throughout generations. [52]

While haploid organisms have only one copy of each chromosome, most animals and many plants are diploid, containing two of each chromosome and thus two copies of every gene. [39] The two alleles for a gene are located on identical loci of the two homologous chromosomes, each allele inherited from a different parent.

Many species have so-called sex chromosomes that determine the gender of each organism. [53] In humans and many other animals, the Y chromosome contains the gene that triggers the development of the specifically male characteristics. In evolution, this chromosome has lost most of its content and also most of its genes, while the X chromosome is similar to the other chromosomes and contains many genes. This being said, Mary Frances Lyon discovered that there is X-chromosome inactivation during reproduction to avoid passing on twice as many genes to the offspring. [54] Lyon's discovery led to the discovery of other things including X-linked diseases. [54] The X and Y chromosomes form a strongly heterogeneous pair.

Reproduction Edit

When cells divide, their full genome is copied and each daughter cell inherits one copy. This process, called mitosis, is the simplest form of reproduction and is the basis for asexual reproduction. Asexual reproduction can also occur in multicellular organisms, producing offspring that inherit their genome from a single parent. Offspring that are genetically identical to their parents are called clones.

Eukaryotic organisms often use sexual reproduction to generate offspring that contain a mixture of genetic material inherited from two different parents. The process of sexual reproduction alternates between forms that contain single copies of the genome (haploid) and double copies (diploid). [39] Haploid cells fuse and combine genetic material to create a diploid cell with paired chromosomes. Diploid organisms form haploids by dividing, without replicating their DNA, to create daughter cells that randomly inherit one of each pair of chromosomes. Most animals and many plants are diploid for most of their lifespan, with the haploid form reduced to single cell gametes such as sperm or eggs.

Although they do not use the haploid/diploid method of sexual reproduction, bacteria have many methods of acquiring new genetic information. Some bacteria can undergo conjugation, transferring a small circular piece of DNA to another bacterium. [55] Bacteria can also take up raw DNA fragments found in the environment and integrate them into their genomes, a phenomenon known as transformation. [56] These processes result in horizontal gene transfer, transmitting fragments of genetic information between organisms that would be otherwise unrelated. Natural bacterial transformation occurs in many bacterial species, and can be regarded as a sexual process for transferring DNA from one cell to another cell (usually of the same species). [57] Transformation requires the action of numerous bacterial gene products, and its primary adaptive function appears to be repair of DNA damages in the recipient cell. [57]

Recombination and genetic linkage Edit

The diploid nature of chromosomes allows for genes on different chromosomes to assort independently or be separated from their homologous pair during sexual reproduction wherein haploid gametes are formed. In this way new combinations of genes can occur in the offspring of a mating pair. Genes on the same chromosome would theoretically never recombine. However, they do, via the cellular process of chromosomal crossover. During crossover, chromosomes exchange stretches of DNA, effectively shuffling the gene alleles between the chromosomes. [58] This process of chromosomal crossover generally occurs during meiosis, a series of cell divisions that creates haploid cells. Meiotic recombination, particularly in microbial eukaryotes, appears to serve the adaptive function of repair of DNA damages. [57]

The first cytological demonstration of crossing over was performed by Harriet Creighton and Barbara McClintock in 1931. Their research and experiments on corn provided cytological evidence for the genetic theory that linked genes on paired chromosomes do in fact exchange places from one homolog to the other. [59]

The probability of chromosomal crossover occurring between two given points on the chromosome is related to the distance between the points. For an arbitrarily long distance, the probability of crossover is high enough that the inheritance of the genes is effectively uncorrelated. [60] For genes that are closer together, however, the lower probability of crossover means that the genes demonstrate genetic linkage alleles for the two genes tend to be inherited together. The amounts of linkage between a series of genes can be combined to form a linear linkage map that roughly describes the arrangement of the genes along the chromosome. [61]

Genetic code Edit

Genes generally express their functional effect through the production of proteins, which are complex molecules responsible for most functions in the cell. Proteins are made up of one or more polypeptide chains, each of which is composed of a sequence of amino acids, and the DNA sequence of a gene (through an RNA intermediate) is used to produce a specific amino acid sequence. This process begins with the production of an RNA molecule with a sequence matching the gene's DNA sequence, a process called transcription.

This messenger RNA molecule then serves to produce a corresponding amino acid sequence through a process called translation. Each group of three nucleotides in the sequence, called a codon, corresponds either to one of the twenty possible amino acids in a protein or an instruction to end the amino acid sequence this correspondence is called the genetic code. [62] The flow of information is unidirectional: information is transferred from nucleotide sequences into the amino acid sequence of proteins, but it never transfers from protein back into the sequence of DNA—a phenomenon Francis Crick called the central dogma of molecular biology. [63]

The specific sequence of amino acids results in a unique three-dimensional structure for that protein, and the three-dimensional structures of proteins are related to their functions. [64] [65] Some are simple structural molecules, like the fibers formed by the protein collagen. Proteins can bind to other proteins and simple molecules, sometimes acting as enzymes by facilitating chemical reactions within the bound molecules (without changing the structure of the protein itself). Protein structure is dynamic the protein hemoglobin bends into slightly different forms as it facilitates the capture, transport, and release of oxygen molecules within mammalian blood.

A single nucleotide difference within DNA can cause a change in the amino acid sequence of a protein. Because protein structures are the result of their amino acid sequences, some changes can dramatically change the properties of a protein by destabilizing the structure or changing the surface of the protein in a way that changes its interaction with other proteins and molecules. For example, sickle-cell anemia is a human genetic disease that results from a single base difference within the coding region for the β-globin section of hemoglobin, causing a single amino acid change that changes hemoglobin's physical properties. [66] Sickle-cell versions of hemoglobin stick to themselves, stacking to form fibers that distort the shape of red blood cells carrying the protein. These sickle-shaped cells no longer flow smoothly through blood vessels, having a tendency to clog or degrade, causing the medical problems associated with this disease.

Some DNA sequences are transcribed into RNA but are not translated into protein products—such RNA molecules are called non-coding RNA. In some cases, these products fold into structures which are involved in critical cell functions (e.g. ribosomal RNA and transfer RNA). RNA can also have regulatory effects through hybridization interactions with other RNA molecules (such as microRNA).

Nature and nurture Edit

Although genes contain all the information an organism uses to function, the environment plays an important role in determining the ultimate phenotypes an organism displays. The phrase "nature and nurture" refers to this complementary relationship. The phenotype of an organism depends on the interaction of genes and the environment. An interesting example is the coat coloration of the Siamese cat. In this case, the body temperature of the cat plays the role of the environment. The cat's genes code for dark hair, thus the hair-producing cells in the cat make cellular proteins resulting in dark hair. But these dark hair-producing proteins are sensitive to temperature (i.e. have a mutation causing temperature-sensitivity) and denature in higher-temperature environments, failing to produce dark-hair pigment in areas where the cat has a higher body temperature. In a low-temperature environment, however, the protein's structure is stable and produces dark-hair pigment normally. The protein remains functional in areas of skin that are colder—such as its legs, ears, tail and face—so the cat has dark hair at its extremities. [67]

Environment plays a major role in effects of the human genetic disease phenylketonuria. [68] The mutation that causes phenylketonuria disrupts the ability of the body to break down the amino acid phenylalanine, causing a toxic build-up of an intermediate molecule that, in turn, causes severe symptoms of progressive intellectual disability and seizures. However, if someone with the phenylketonuria mutation follows a strict diet that avoids this amino acid, they remain normal and healthy.

A common method for determining how genes and environment ("nature and nurture") contribute to a phenotype involves studying identical and fraternal twins, or other siblings of multiple births. [69] Identical siblings are genetically the same since they come from the same zygote. Meanwhile, fraternal twins are as genetically different from one another as normal siblings. By comparing how often a certain disorder occurs in a pair of identical twins to how often it occurs in a pair of fraternal twins, scientists can determine whether that disorder is caused by genetic or postnatal environmental factors. One famous example involved the study of the Genain quadruplets, who were identical quadruplets all diagnosed with schizophrenia. [70] However, such tests cannot separate genetic factors from environmental factors affecting fetal development.

Gene regulation Edit

The genome of a given organism contains thousands of genes, but not all these genes need to be active at any given moment. A gene is expressed when it is being transcribed into mRNA and there exist many cellular methods of controlling the expression of genes such that proteins are produced only when needed by the cell. Transcription factors are regulatory proteins that bind to DNA, either promoting or inhibiting the transcription of a gene. [71] Within the genome of Escherichia coli bacteria, for example, there exists a series of genes necessary for the synthesis of the amino acid tryptophan. However, when tryptophan is already available to the cell, these genes for tryptophan synthesis are no longer needed. The presence of tryptophan directly affects the activity of the genes—tryptophan molecules bind to the tryptophan repressor (a transcription factor), changing the repressor's structure such that the repressor binds to the genes. The tryptophan repressor blocks the transcription and expression of the genes, thereby creating negative feedback regulation of the tryptophan synthesis process. [72]

Differences in gene expression are especially clear within multicellular organisms, where cells all contain the same genome but have very different structures and behaviors due to the expression of different sets of genes. All the cells in a multicellular organism derive from a single cell, differentiating into variant cell types in response to external and intercellular signals and gradually establishing different patterns of gene expression to create different behaviors. As no single gene is responsible for the development of structures within multicellular organisms, these patterns arise from the complex interactions between many cells.

Within eukaryotes, there exist structural features of chromatin that influence the transcription of genes, often in the form of modifications to DNA and chromatin that are stably inherited by daughter cells. [73] These features are called "epigenetic" because they exist "on top" of the DNA sequence and retain inheritance from one cell generation to the next. Because of epigenetic features, different cell types grown within the same medium can retain very different properties. Although epigenetic features are generally dynamic over the course of development, some, like the phenomenon of paramutation, have multigenerational inheritance and exist as rare exceptions to the general rule of DNA as the basis for inheritance. [74]

Mutations Edit

During the process of DNA replication, errors occasionally occur in the polymerization of the second strand. These errors, called mutations, can affect the phenotype of an organism, especially if they occur within the protein coding sequence of a gene. Error rates are usually very low—1 error in every 10–100 million bases—due to the "proofreading" ability of DNA polymerases. [75] [76] Processes that increase the rate of changes in DNA are called mutagenic: mutagenic chemicals promote errors in DNA replication, often by interfering with the structure of base-pairing, while UV radiation induces mutations by causing damage to the DNA structure. [77] Chemical damage to DNA occurs naturally as well and cells use DNA repair mechanisms to repair mismatches and breaks. The repair does not, however, always restore the original sequence. A particularly important source of DNA damages appears to be reactive oxygen species [78] produced by cellular aerobic respiration, and these can lead to mutations. [79]

In organisms that use chromosomal crossover to exchange DNA and recombine genes, errors in alignment during meiosis can also cause mutations. [80] Errors in crossover are especially likely when similar sequences cause partner chromosomes to adopt a mistaken alignment this makes some regions in genomes more prone to mutating in this way. These errors create large structural changes in DNA sequence—duplications, inversions, deletions of entire regions—or the accidental exchange of whole parts of sequences between different chromosomes (chromosomal translocation).

Natural selection and evolution Edit

Mutations alter an organism's genotype and occasionally this causes different phenotypes to appear. Most mutations have little effect on an organism's phenotype, health, or reproductive fitness. [81] Mutations that do have an effect are usually detrimental, but occasionally some can be beneficial. [82] Studies in the fly Drosophila melanogaster suggest that if a mutation changes a protein produced by a gene, about 70 percent of these mutations will be harmful with the remainder being either neutral or weakly beneficial. [83]

Population genetics studies the distribution of genetic differences within populations and how these distributions change over time. [84] Changes in the frequency of an allele in a population are mainly influenced by natural selection, where a given allele provides a selective or reproductive advantage to the organism, [85] as well as other factors such as mutation, genetic drift, genetic hitchhiking, [86] artificial selection and migration. [87]

Over many generations, the genomes of organisms can change significantly, resulting in evolution. In the process called adaptation, selection for beneficial mutations can cause a species to evolve into forms better able to survive in their environment. [88] New species are formed through the process of speciation, often caused by geographical separations that prevent populations from exchanging genes with each other. [89]

By comparing the homology between different species' genomes, it is possible to calculate the evolutionary distance between them and when they may have diverged. Genetic comparisons are generally considered a more accurate method of characterizing the relatedness between species than the comparison of phenotypic characteristics. The evolutionary distances between species can be used to form evolutionary trees these trees represent the common descent and divergence of species over time, although they do not show the transfer of genetic material between unrelated species (known as horizontal gene transfer and most common in bacteria). [90]

Model organisms Edit

Although geneticists originally studied inheritance in a wide range of organisms, researchers began to specialize in studying the genetics of a particular subset of organisms. The fact that significant research already existed for a given organism would encourage new researchers to choose it for further study, and so eventually a few model organisms became the basis for most genetics research. [91] Common research topics in model organism genetics include the study of gene regulation and the involvement of genes in development and cancer.

Organisms were chosen, in part, for convenience—short generation times and easy genetic manipulation made some organisms popular genetics research tools. Widely used model organisms include the gut bacterium Escherichia coli, the plant Arabidopsis thaliana, baker's yeast (Saccharomyces cerevisiae), the nematode Caenorhabditis elegans, the common fruit fly (Drosophila melanogaster), and the common house mouse (Mus musculus).

Medicine Edit

Medical genetics seeks to understand how genetic variation relates to human health and disease. [92] When searching for an unknown gene that may be involved in a disease, researchers commonly use genetic linkage and genetic pedigree charts to find the location on the genome associated with the disease. At the population level, researchers take advantage of Mendelian randomization to look for locations in the genome that are associated with diseases, a method especially useful for multigenic traits not clearly defined by a single gene. [93] Once a candidate gene is found, further research is often done on the corresponding (or homologous) genes of model organisms. In addition to studying genetic diseases, the increased availability of genotyping methods has led to the field of pharmacogenetics: the study of how genotype can affect drug responses. [94]

Individuals differ in their inherited tendency to develop cancer, [95] and cancer is a genetic disease. [96] The process of cancer development in the body is a combination of events. Mutations occasionally occur within cells in the body as they divide. Although these mutations will not be inherited by any offspring, they can affect the behavior of cells, sometimes causing them to grow and divide more frequently. There are biological mechanisms that attempt to stop this process signals are given to inappropriately dividing cells that should trigger cell death, but sometimes additional mutations occur that cause cells to ignore these messages. An internal process of natural selection occurs within the body and eventually mutations accumulate within cells to promote their own growth, creating a cancerous tumor that grows and invades various tissues of the body.

Normally, a cell divides only in response to signals called growth factors and stops growing once in contact with surrounding cells and in response to growth-inhibitory signals. It usually then divides a limited number of times and dies, staying within the epithelium where it is unable to migrate to other organs. To become a cancer cell, a cell has to accumulate mutations in a number of genes (three to seven). A cancer cell can divide without growth factor and ignores inhibitory signals. Also, it is immortal and can grow indefinitely, even after it makes contact with neighboring cells. It may escape from the epithelium and ultimately from the primary tumor. Then, the escaped cell can cross the endothelium of a blood vessel and get transported by the bloodstream to colonize a new organ, forming deadly metastasis. Although there are some genetic predispositions in a small fraction of cancers, the major fraction is due to a set of new genetic mutations that originally appear and accumulate in one or a small number of cells that will divide to form the tumor and are not transmitted to the progeny (somatic mutations). The most frequent mutations are a loss of function of p53 protein, a tumor suppressor, or in the p53 pathway, and gain of function mutations in the Ras proteins, or in other oncogenes.

Research methods Edit

DNA can be manipulated in the laboratory. Restriction enzymes are commonly used enzymes that cut DNA at specific sequences, producing predictable fragments of DNA. [97] DNA fragments can be visualized through use of gel electrophoresis, which separates fragments according to their length.

The use of ligation enzymes allows DNA fragments to be connected. By binding ("ligating") fragments of DNA together from different sources, researchers can create recombinant DNA, the DNA often associated with genetically modified organisms. Recombinant DNA is commonly used in the context of plasmids: short circular DNA molecules with a few genes on them. In the process known as molecular cloning, researchers can amplify the DNA fragments by inserting plasmids into bacteria and then culturing them on plates of agar (to isolate clones of bacteria cells—"cloning" can also refer to the various means of creating cloned ("clonal") organisms).

DNA can also be amplified using a procedure called the polymerase chain reaction (PCR). [98] By using specific short sequences of DNA, PCR can isolate and exponentially amplify a targeted region of DNA. Because it can amplify from extremely small amounts of DNA, PCR is also often used to detect the presence of specific DNA sequences.

DNA sequencing and genomics Edit

DNA sequencing, one of the most fundamental technologies developed to study genetics, allows researchers to determine the sequence of nucleotides in DNA fragments. The technique of chain-termination sequencing, developed in 1977 by a team led by Frederick Sanger, is still routinely used to sequence DNA fragments. [99] Using this technology, researchers have been able to study the molecular sequences associated with many human diseases.

As sequencing has become less expensive, researchers have sequenced the genomes of many organisms using a process called genome assembly, which utilizes computational tools to stitch together sequences from many different fragments. [100] These technologies were used to sequence the human genome in the Human Genome Project completed in 2003. [35] New high-throughput sequencing technologies are dramatically lowering the cost of DNA sequencing, with many researchers hoping to bring the cost of resequencing a human genome down to a thousand dollars. [101]

Next-generation sequencing (or high-throughput sequencing) came about due to the ever-increasing demand for low-cost sequencing. These sequencing technologies allow the production of potentially millions of sequences concurrently. [102] [103] The large amount of sequence data available has created the field of genomics, research that uses computational tools to search for and analyze patterns in the full genomes of organisms. Genomics can also be considered a subfield of bioinformatics, which uses computational approaches to analyze large sets of biological data. A common problem to these fields of research is how to manage and share data that deals with human subject and personally identifiable information.

On 19 March 2015, a group of leading biologists urged a worldwide ban on clinical use of methods, particularly the use of CRISPR and zinc finger, to edit the human genome in a way that can be inherited. [104] [105] [106] [107] In April 2015, Chinese researchers reported results of basic research to edit the DNA of non-viable human embryos using CRISPR. [108] [109]


Which cells will pass cancer to offspring? - Biology

Genes are in the DNA of each cell in your body. They control how the cell functions, including:

Researchers estimate that each cell contains 30,000 different genes. Within each cell, genes are located on chromosomes.

About chromosomes

Chromosomes are the thread-like structures in cells that contain genes. There are 46 chromosomes, arranged in 2 sets of 23.

You inherit one set from your mother and one from your father. One chromosome in each set determines whether you are female or male. The other 22 chromosome pairs determine other physical characteristics. These chromosome pairs are called autosomes.

How genes work

Genes control how your cells work by making proteins. The proteins have specific functions and act as messengers for the cell.

Each gene must have the correct instructions for making its protein. This allows the protein to perform the correct function for the cell.

All cancers begin when one or more genes in a cell mutate. A mutation is a change. It creates an abnormal protein. Or it may prevent a protein’s formation.

An abnormal protein provides different information than a normal protein. This can cause cells to multiply uncontrollably and become cancerous.

About genetic mutations

There are 2 basic types of genetic mutations:

Acquired mutations. These are the most common cause of cancer. They occur from damage to genes in a particular cell during a person’s life. For example, this could be a breast cell or a colon cell, which then goes on to divide many times and form a tumor. A tumor is an abnormal mass. Cancer that occurs because of acquired mutations is called sporadic cancer. Acquired mutations are not found in every cell in the body and they are not passed from parent to child.

Factors that cause these mutations include:

Germline mutations. These are less common. A germline mutation occurs in a sperm cell or egg cell. It passes directly from a parent to a child at the time of conception. As the embryo grows into a baby, the mutation from the initial sperm or egg cell is copied into every cell within the body. Because the mutation affects reproductive cells, it can pass from generation to generation.

Cancer caused by germline mutations is called inherited cancer. It accounts for about 5% to 20% of all cancers.

Mutations and cancer

Mutations happen often. A mutation may be beneficial, harmful, or neutral. This depends where in the gene the change occurs. Typically, the body corrects most mutations.

A single mutation will likely not cause cancer. Usually, cancer occurs from multiple mutations over a lifetime. That is why cancer occurs more often in older people. They have had more opportunities for mutations to build up.

Types of genes linked to cancer

Many of the genes that contribute to cancer development fall into broad categories:

Tumor suppressor genes. These are protective genes. Normally, they limit cell growth by:

Monitoring how quickly cells divide into new cells

Controlling when a cell dies

When a tumor suppressor gene mutates, cells grow uncontrollably. And they may eventually form a tumor.

Examples of tumor suppressor genes include BRCA1, BRCA2, and p53 or TP53.

Germline mutations in BRCA1 or BRCA2 genes increase a woman’s risk of developing hereditary breast or ovarian cancers and a man’s risk of developing hereditary prostate or breast cancers. They also increase the risk of pancreatic cancer and melanoma in women and men.

The most commonly mutated gene in people with cancer is p53 or TP53. More than 50% of cancers involve a missing or damaged p53 gene. Most p53 gene mutations are acquired. Germline p53 mutations are rare, but patients who carry them are at a higher risk of developing many different types of cancer.

Oncogenes. These turn a healthy cell into a cancerous cell. Mutations in these genes are not known to be inherited.

HER2, a specialized protein that controls cancer growth and spread. It is found in some cancer cells. For example, breast and ovarian cancer cells.

The RAS family of genes, which makes proteins involved in cell communication pathways, cell growth, and cell death.

DNA repair genes. These fix mistakes made when DNA is copied. Many of them function as tumor suppressor genes. BRCA1, BRCA2, and p53 are all DNA repair genes.

If a person has an error in a DNA repair gene, mistakes remain uncorrected. Then, the mistakes become mutations. These mutations may eventually lead to cancer, particularly mutations in tumor suppressor genes or oncogenes.

Mutations in DNA repair genes may be inherited or acquired. Lynch syndrome is an example of the inherited kind. BRCA1, BRCA2, and p53 mutations and their associated syndromes are also inherited.

Challenges in understanding cancer genetics

Researchers have learned a lot about how cancer genes work. But many cancers are not linked with a specific gene. Cancer likely involves multiple gene mutations. Moreover, some evidence suggests that genes interact with their environment. This further complicates our understanding of the role genes play in cancer.

Researchers continue to study how genetic changes affect cancer development. This knowledge has led to improvements in cancer care, including early detection, risk reduction, the use of targeted therapy, and survival.


Why fathers don't pass on mitochondria to offspring

Offering insights into a long-standing and mysterious bias in biology, a new study reveals how and why mitochondria are only passed on through a mother's egg - and not the father's sperm. What's more, experiments from the study show that when paternal mitochondria persist for longer than they should during development, the embryo is at greater risk of lethality. Harbored inside the cells of nearly all multicellular animals, plants and fungi are mitochondria, organelles that play an important role in generating the energy that cells need to survive. Shortly after a sperm penetrates an egg during fertilization, the sperm's mitochondria are degraded while the egg's mitochondria persist. To gain more insights into this highly specific degradation pattern, Qinghua Zhou et al. used electron microscopy and tomography to study sperm mitochondria (or paternal mitochondria) in Caenorhabditis elegans, a type of roundworm, during early stages of development. Intriguingly, the paternal mitochondria were found to partially self-destruct before the mitochondria were surrounded by autophagosomes, which target components within a cell and facilitate their degradation. This suggests that another mechanism, something within the paternal mitochondrion itself, initiates the degradation process. RNA analysis of paternal mitochondria during early stages of embryonic development hinted that it is the cps-6 gene that facilitates this process, which the team confirmed by studying sperm lacking cps-6 without it, paternal mitochondria remained significantly later into the development stage. Further investigation suggests that the enzyme that cps-6 encodes first breaks down the interior membrane of the paternal mitochondria before moving to the space within the inner membrane to breakdown mitochondrial DNA. When the researchers engineered paternal mitochondria to breakdown during later stages of development, this increased the chances that the embryo would not survive, suggesting that the transmission of paternal mitochondria is an evolutionary disadvantage. Collectively, results from this study suggest that cps-6 plays a key role in initiating the self-destruction of paternal sperm, which likely benefits the embryo.

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Mothers pass on allergies to offspring, Singapore preclinical study shows

SINGAPORE, 30 October 2020 - Mothers can pass allergies to offspring while they are developing in the womb, researchers from the Agency for Science, Technology and Research (A*STAR), KK Women's and Children's Hospital (KKH) and Duke-NUS Medical School in Singapore reported this week in the journal Science.

The study, which employed an animal model conducted according to the National Advisory Committee for Laboratory Animal Research (NACLAR) guidelines, shows that the key antibody responsible for triggering allergic reactions, immunoglobulin E (IgE), can cross the placenta and enter the foetus. When inside the foetus, the antibody binds to foetal mast cells, a type of immune cell that releases chemicals that trigger allergic reactions, from runny noses to asthma. After birth, newborn mice develop allergic reactions to the same type of allergen as their mothers at the time of first exposure - unlike adult mice, which require two exposures. Studies in the laboratory also showed that maternal IgE can bind to human foetal mast cells, indicating they might cross the placenta in humans in a similar way.

Dr Florent Ginhoux, Senior Principal Investigator at A*STAR's Singapore Immunology Network (SIgN), a senior co-author of the study, said, "There is currently a significant lack of knowledge on mast cells that are present early on in the developing foetus. Here, we discovered that foetal mast cells phenotypically mature through the course of pregnancy, and can be sensitised by IgE of maternal origin that cross the placental barrier. The study suggests that a highly allergic pregnant mother may potentially transfer her IgE to her baby that consequently develop allergic reactions when exposed to the first time to the allergen."

"Allergies begin very early in life," said Associate Professor Ashley St. John, an immunologist at Duke-NUS' Emerging Infectious Diseases Programme and a senior co-author of the study. "Infants experience allergic responses closely linked with the mother's allergic response in ways that cannot only be explained by genetics. This work emphasises one way that allergic responses can pass from the mother to the developing foetus, and shows how allergies can then persist after birth."

As part of the study, following NACLAR guidelines, researchers exposed mice to ragweed pollen, a common allergen, prior to pregnancy. Mice that developed a sensitivity to the pollen had offspring that also showed an allergic reaction to ragweed. The sensitivity is allergen-specific the offspring did not react to dust mites, another common allergen.

Notably, the transfer of sensitivity appears to fade with time. The newborn mice had allergic reactions when tested at four weeks, but less or none at six weeks.

The experimental studies were backed up with cellular tests and imaging, which showed maternal IgE bound to fetal mast cells, triggering the mast cells to release chemicals in reaction to an allergen, a process called degranulation.

This study further showed that the IgE transfer across the placenta requires the help of another protein, FcRN. Mice with FcRN knocked out lacked maternal IgE attached to their mast cells, and did not develop allergies after birth.

The study findings potentially open new intervention strategies to limit such transfer to minimise the occurrence of neonatal allergies. Currently, between 10 to 30 per cent of the world's population are affected by allergies. This number is set to continue rising and a solution preventing allergies being passed from mother to child could potentially bring those numbers down over time.

"Our research has really exciting findings that may explain the high incidence of early onset atopic dermatitis (eczema) in children of mothers with clinically proven eczema, which parallel findings in our local birth cohort findings," said Professor Jerry Chan, Senior Consultant, Department of Reproductive Medicine at KKH, Senior National Medical Research Council Clinician Scientist, and Vice Chair of Research with the Obstetrics and Gynaecology Academic Clinical Programme at the SingHealth Duke-NUS Academic Medical Centre. "From a clinical point of view, developing a further understanding in placental transfer of IgE, and the mechanism of foetal mast cell activation would be key to developing strategies to reduce the chance of eczema or other allergies from being transferred from mother to baby."

The authors next aim to better understand the mechanism of IgE transfer through the placenta, how IgE binding to mast cells in foetal skin modulate their functions and how it could affect skin physiology after birth.

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