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Human embryogenesis
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This article is about Human embryogenesis. For Embryogenesis in general, see Embryogenesis.
The initial stages of human embryogenesis.
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Human embryogenesis refers to the development and formation of the human embryo. It is characterised by the process of cell division and cellular differentiation of the embryo that occurs during the early stages of development. In biological terms, human development entails growth from a one-celled zygote to an adult human being. Fertilisation occurs when the sperm cell successfully enters and fuses with an egg cell (ovum). The genetic material of the sperm and egg then combine to form a single cell called a zygote and the germinal stage of prenatal development commences.[1] Embryogenesis covers the first eight weeks of development; at the beginning of the ninth week the embryo is termed a fetus. Human embryology is the study of this development during the first eight weeks after fertilisation. The normal period of gestation (pregnancy) is nine months or 38 weeks.
The germinal stage refers to the time from fertilization through the development of the early embryo until implantation is completed in the uterus. The germinal stage takes around 10 days.[2] During this stage, the zygote begins to divide, in a process called cleavage. A blastocyst is then formed and implanted in the uterus. Embryogenesis continues with the next stage of gastrulation, when the three germ layers of the embryo form in a process called histogenesis, and the processes of neurulation and organogenesis follow.
In comparison to the embryo, the fetus has more recognizable external features and a more complete set of developing organs. The entire process of embryogenesis involves coordinated spatial and temporal changes in gene expression, cell growth and cellular differentiation. A nearly identical process occurs in other species, especially among chordates.
Contents
1 Germinal stage
1.1 Fertilization
1.2 Cleavage
1.3 Blastulation
1.4 Implantation
1.5 Embryonic disc
2 Gastrulation
3 Neurulation
4 Development of organs and organ systems
4.1 Heart and circulatory system
4.2 Digestive system
4.3 Nervous system
4.4 Blood
5 Development of physical features
5.1 Face and neck
5.2 Eyes
5.3 Limbs
6 Clinical significance
7 See also
8 Additional images
9 References
10 External links
Germinal stage[edit]
Fertilization[edit]
Main article: Human fertilization
Fertilization takes place when the spermatozoon has successfully entered the ovum and the two sets of genetic material carried by the gametes fuse together, resulting in the zygote (a single diploid cell). This usually takes place in the ampulla of one of the fallopian tubes. The zygote contains the combined genetic material carried by both the male and female gametes which consists of the 23 chromosomes from the nucleus of the ovum and the 23 chromosomes from the nucleus of the sperm. The 46 chromosomes undergo changes prior to the mitotic division which leads to the formation of the embryo having two cells.
Successful fertilization is enabled by three processes, which also act as controls to ensure species-specificity. The first is that of chemotaxis which directs the movement of the sperm towards the ovum. Secondly there is an adhesive compatibility between the sperm and the egg. With the sperm adhered to the ovum, the third process of acrosomal reaction takes place; the front part of the spermatozoan head is capped by an acrosome which contains digestive enzymes to break down the zona pellucida and allow its entry.[3] The entry of the sperm causes calcium to be released which blocks entry to other sperm cells. A parallel reaction takes place in the ovum called the zona reaction. This sees the release of cortical granules that release enzymes which digest sperm receptor proteins, thus preventing polyspermy. The granules also fuse with the plasma membrane and modify the zona pellucida in such a way as to prevent further sperm entry.
Cleavage[edit]
Further information: Cleavage (embryo)
8-cell embryo, at 3 days
The beginning of the cleavage process is marked when the zygote divides through mitosis into two cells. This mitosis continues and the first two cells divide into four cells, then into eight cells and so on. Each division takes from 12 to 24 hours. The zygote is large compared to any other cell and undergoes cleavage without any overall increase in size. This means that with each successive subdivision, the ratio of nuclear to cytoplasmic material increases.[4] Initially the dividing cells, called blastomeres (blastos Greek for sprout), are undifferentiated and aggregated into a sphere enclosed within the membrane of glycoproteins (termed the zona pellucida) of the ovum. When eight blastomeres have formed they begin to develop gap junctions, enabling them to develop in an integrated way and co-ordinate their response to physiological signals and environmental cues.[5]
When the cells number around sixteen the solid sphere of cells within the zona pellucida is referred to as a morula[6] At this stage the cells start to bind firmly together in a process called compaction, and cleavage continues as cellular differentiation.
Blastulation[edit]
Further information: Polarity in embryogenesis
Blastocyst with an inner cell mass and trophoblast.
Cleavage itself is the first stage in blastulation, the process of forming the blastocyst. Cells differentiate into an outer layer of cells (collectively called the trophoblast) and an inner cell mass. With further compaction the individual outer blastomeres, the trophoblasts, become indistinguishable. They are still enclosed within the zona pellucida. This compaction serves to make the structure watertight, containing the fluid that the cells will later secrete. The inner mass of cells differentiate to become embryoblasts and polarise at one end. They close together and form gap junctions, which facilitate cellular communication. This polarisation leaves a cavity, the blastocoel, creating a structure that is now termed the blastocyst. (In animals other than mammals, this is called the blastula.) The trophoblasts secrete fluid into the blastocoel. The resulting increase in size of the blastocyst causes it to hatch through the zona pellucida, which then disintegrates.[7][4]
The inner cell mass will give rise to the embryo proper, the amnion, yolk sac and allantois, while the fetal part of the placenta will form from the outer trophoblast layer. The embryo plus its membranes is called the conceptus, and by this stage the conceptus has reached the uterus. The zona pellucida ultimately disappears completely, and the now exposed cells of the trophoblast allow the blastocyst to attach itself to the endometrium, where it will implant. The formation of the hypoblast and epiblast, which are the two main layers of the bilaminar germ disc, occurs at the beginning of the second week.[8] Either the embryoblast or the trophoblast will turn into two sub-layers.[9] The inner cells will turn into the hypoblast layer, which will surround the other layer, called the epiblast, and these layers will form the embryonic disc that will develop into the embryo.[8][9] The trophoblast will also develop two sub-layers: the cytotrophoblast, which is front of the syncytiotrophoblast, which in turn lies within the endometrium.[8] Next, another layer called the exocoelomic membrane or Heuser’s membrane will appear and surround the cytotrophoblast, as well as the primitive yolk sac.[9] The syncytiotrophoblast will grow and will enter a phase called lacunar stage, in which some vacuoles will appear and be filled by blood in the following days.[8][9] The development of the yolk sac starts with the hypoblastic flat cells that form the exocoelomic membrane, which will coat the inner part of the cytotrophoblast to form the primitive yolk sac. An erosion of the endothelial lining of the maternal capillaries by the syncytiotrophoblastic cells of the sinusoids will form where the blood will begin to penetrate and flow through the trophoblast to give rise to the uteroplacental circulation.[10][11] Subsequently new cells derived from yolk sac will be established between trophoblast and exocelomic membrane and will give rise to extra-embryonic mesoderm, which will form the chorionic cavity.[9]
At the end of the second week of development, some cells of the trophoblast penetrate and form rounded columns into the syncytiotrophoblast. These columns are known as primary villi. At the same time, other migrating cells form into the exocelomic cavity a new cavity named the secondary or definitive yolk sac, smaller than the primitive yolk sac.[9][10]
Implantation[edit]
Main article: Implantation (human embryo)
Trophoblast differentiation
After ovulation, the endometrial lining becomes transformed into a secretory lining in preparation of accepting the embryo. It becomes thickened, with its secretory glands becoming elongated, and is increasingly vascular. This lining of the uterine cavity (or womb) is now known as the decidua, and it produces a great number of large decidual cells in its increased interglandular tissue. The blastomeres in the blastocyst are arranged into an outer layer called Trophoblast.The trophoblast then differentiates into an inner layer, the cytotrophoblast, and an outer layer, the syncytiotrophoblast. The cytotrophoblast contains cuboidal epithelial cells and is the source of dividing cells, and the syncytiotrophoblast is a syncytial layer without cell boundaries.
The syncytiotrophoblast implants the blastocyst in the decidual epithelium by projections of chorionic villi, forming the embryonic part of the placenta. The placenta develops once the blastocyst is implanted, connecting the embryo to the uterine wall. The decidua here is termed the decidua basalis; it lies between the blastocyst and the myometrium and forms the maternal part of the placenta. The implantation is assisted by hydrolytic enzymes that erode the epithelium. The syncytiotrophoblast also produces human chorionic gonadotropin, a hormone that stimulates the release of progesterone from the corpus luteum. Progesterone enriches the uterus with a thick lining of blood vessels and capillaries so that it can oxygenate and sustain the developing embryo. The uterus liberates sugar from stored glycogen from its cells to nourish the embryo.[12] The villi begin to branch and contain blood vessels of the embryo. Other villi, called terminal or free villi, exchange nutrients. The embryo is joined to the trophoblastic shell by a narrow connecting stalk that develops into the umbilical cord to attach the placenta to the embryo.[9][13] Arteries in the decidua are remodelled to increase the maternal blood flow into the intervillous spaces of the placenta, allowing gas exchange and the transfer of nutrients to the embryo. Waste products from the embryo will diffuse across the placenta.
As the syncytiotrophoblast starts to penetrate the uterine wall, the inner cell mass (embryoblast) also develops. The inner cell mass is the source of embryonic stem cells, which are pluripotent and can develop into any one of the three germ layer cells,and which have the potency to give rise to all the tissues and organs.
Embryonic disc[edit]
The embryoblast forms an embryonic disc, which is a bilaminar disc of two layers, an upper layer called the epiblast (primitive ectoderm) and a lower layer called the hypoblast (primitive endoderm). The disc is stretched between what will become the amniotic cavity and the yolk sac. The epiblast is adjacent to the trophoblast and made of columnar cells; the hypoblast is closest to the blastocyst cavity and made of cuboidal cells. The epiblast migrates away from the trophoblast downwards, forming the amniotic cavity, the lining of which is formed from amnioblasts developed from the epiblast. The hypoblast is pushed down and forms the yolk sac (exocoelomic cavity) lining. Some hypoblast cells migrate along the inner cytotrophoblast lining of the blastocoel, secreting an extracellular matrix along the way. These hypoblast cells and extracellular matrix are called Heuser's membrane (or the exocoelomic membrane), and they cover the blastocoel to form the yolk sac (or exocoelomic cavity). Cells of the hypoblast migrate along the outer edges of this reticulum and form the extraembryonic mesoderm; this disrupts the extraembryonic reticulum. Soon pockets form in the reticulum, which ultimately coalesce to form the chorionic cavity or extraembryonic coelom.
Gastrulation[edit]
Main article: Gastrulation
Histogenesis of the three germ layers
Artificially colored - gestational sac, yolk sac and embryo (measuring 3 mm at 5 weeks)
Embryo attached to placenta in amniotic cavity

The primitive streak, a linear band of cells formed by the migrating epiblast, appears, and this marks the beginning of gastrulation, which takes place around the seventeenth day (week 3) after fertilisation. The process of gastrulation reorganises the two-layer embryo into a three-layer embryo, and also gives the embryo its specific head-to-tail, and front-to-back orientation, by way of the primitive streak which establishes bilateral symmetry. A primitive node (or primitive knot) forms in front of the primitive streak which is the organiser of neurulation. A primitive pit forms as a depression in the centre of the primitive node which connects to the notochord which lies directly underneath. The node has arisen from epiblasts of the amniotic cavity floor, and it is this node that induces the formation of the neural plate which serves as the basis for the nervous system. The neural plate will form opposite the primitive streak from ectodermal tissue which thickens and flattens into the neural plate. The epiblast in that region moves down into the streak at the location of the primitive pit where the process called ingression, which leads to the formation of the mesoderm takes place. This ingression sees the cells from the epiblast move into the primitive streak in an epithelial-mesenchymal transition; epithelial cells become mesenchymal stem cells, multipotent stromal cells that can differentiate into various cell types. The hypoblast is pushed out of the way and goes on to form the amnion.The epiblast keeps moving and forms a second layer, the mesoderm. The epiblast has now differentiated into the three germ layers of the embryo, so that the bilaminar disc is now a trilaminar disc, the gastrula.
The three germ layers are the ectoderm, mesoderm and endoderm, and are formed as three overlapping flat discs. It is from these three layers that all the structures and organs of the body will be derived through the processes of somitogenesis, histogenesis and organogenesis.[14] The embryonic endoderm is formed by invagination of epiblastic cells that migrate to the hypoblast, while the mesoderm is formed by the cells that develop between the epiblast and endoderm. In general, all germ layers will derive from the epiblast.[9][13] The upper layer of ectoderm will give rise to the outermost layer of skin, central and peripheral nervous systems, eyes, inner ear, and many connective tissues.[15] The middle layer of mesoderm will give rise to the heart and the beginning of the circulatory system as well as the bones, muscles and kidneys. The inner layer of endoderm will serve as the starting point for the development of the lungs, intestine, thyroid, pancreas and bladder.
Following ingression, a blastopore develops where the cells have ingressed, in one side of the embryo and it deepens to become the archenteron, the first formative stage of the gut. As in all deuterostomes, the blastopore becomes the anus whilst the gut tunnels through the embryo to the other side where the opening becomes the mouth. With a functioning digestive tube, gastrulation is now completed and the next stage of neurulation can begin.
Neurulation[edit]
Main article: Neurulation
Neural plate
Following gastrulation, the ectoderm gives rise to epithelial and neural tissue, and the gastrula is now referred to as the neurula. The neural plate that has formed as a thickened plate from the ectoderm, continues to broaden and its ends start to fold upwards as neural folds. Neurulation refers to this folding process whereby the neural plate is transformed into the neural tube, and this takes place during the fourth week. They fold, along a shallow neural groove which has formed as a dividing median line in the neural plate. This deepens as the folds continue to gain height, when they will meet and close together at the neural crest. The cells that migrate through the most cranial part of the primitive line form the paraxial mesoderm, which will give rise to the somitomeres that in the process of somitogenesis will differentiate into somites that will form the sclerotome, the syndetome,[16] the myotome and the dermatome to form cartilage and bone, tendons, dermis (skin), and muscle. The intermediate mesoderm gives rise to the urogenital tract and consists of cells that migrate from the middle region of the primitive line. Other cells migrate through the caudal part of the primitive line and form the lateral mesoderm, and those cells migrating by the most caudal part contribute to the extraembryonic mesoderm.[9][13]
The embryonic disc begins flat and round, but eventually elongates to have a wider cephalic part and narrow-shaped caudal end.[8] At the beginning, the primitive line extends in cephalic direction and 18 days after fertilization returns caudally until it disappears. In the cephalic portion, the germ layer shows specific differentiation at the beginning of the 4th week, while in the caudal portion it occurs at the end of the 4th week.[9] Cranial and caudal neuropores become progressively smaller until they close completely (by day 26) forming the neural tube.[17]
Development of organs and organ systems[edit]
The development of the organs starts during the third to eighth weeks of embryogenesis.
Heart and circulatory system[edit]
Main article: Heart development
Further information: Vascular remodelling in the embryo
The heart is the first functional organ to develop and starts to beat and pump blood at around 21 or 22 days.[18] Cardiac myoblasts and blood islands in the splanchnopleuric mesenchyme on each side of the neural plate, give rise to the cardiogenic region.[9]:165This is a horseshoe-shaped area near to the head of the embryo. By day 19, following cell signalling, two strands begin to form as tubes in this region, as a lumen develops within them. These two endocardial tubes grow and by day 21 have migrated towards each other and fused to form a single primitive heart tube, the tubular heart. This is enabled by the folding of the embryo which pushes the tubes into the thoracic cavity.[19]
Also at the same time that the endocardial tubes are forming, vasculogenesis (the development of the circulatory system) has begun. This starts on day 18 with cells in the splanchnopleuric mesoderm differentiating into angioblasts that develop into flattened endothelial cells. These join to form small vesicles called angiocysts which join up to form long vessels called angioblastic cords. These cords develop into a pervasive network of plexuses in the formation of the vascular network. This network grows by the additional budding and sprouting of new vessels in the process of angiogenesis.[19] Following vasculogenesis and the development of an early vasculature, a stage of vascular remodelling takes place.
The tubular heart quickly forms five distinct regions. From head to tail, these are the infundibulum, bulbus cordis, primitive ventricle, primitive atrium, and the sinus venosus. Initially, all venous blood flows into the sinus venosus, and is propelled from tail to head to the truncus arteriosus. This will divide to form the aorta and pulmonary artery; the bulbus cordis will develop into the right (primitive) ventricle; the primitive ventricle will form the left ventricle; the primitive atrium will become the front parts of the left and right atria and their appendages, and the sinus venosus will develop into the posterior part of the right atrium, the sinoatrial node and the coronary sinus.[18]
Cardiac looping begins to shape the heart as one of the processes of morphogenesis, and this completes by the end of the fourth week. Programmed cell death in the process of apoptosis is involved in this stage, taking place at the joining surfaces enabling fusion to take place.[19] In the middle of the fourth week, the sinus venosus receives blood from the three major veins: the vitelline, the umbilical and the common cardinal veins.
During the first two months of development, the interatrial septum begins to form. This septum divides the primitive atrium into a right and a left atrium. Firstly it starts as a crescent-shaped piece of tissue which grows downwards as the septum primum. The crescent shape prevents the complete closure of the atria allowing blood to be shunted from the right to the left atrium through the opening known as the ostium primum. This closes with further development of the system but before it does, a second opening (the ostium secundum) begins to form in the upper atrium enabling the continued shunting of blood.[19]
A second septum (the septum secundum) begins to form to the right of the septum primum. This also leaves a small opening, the foramen ovale which is continuous with the previous opening of the ostium secundum. The septum primum is reduced to a small flap that acts as the valve of the foramen ovale and this remains until its closure at birth. Between the ventricles the septum inferius also forms which develops into the muscular interventricular septum.[19]
Digestive system[edit]
Main article: Development of the digestive system
The digestive system starts to develop from the third week and by the twelfth week, the organs have correctly positioned themselves.
Nervous system[edit]
Main articles: Development of the nervous system in humans and Development of the human brain
Embryonic development
Development of brain in 8 week old embryo
Late in the fourth week, the superior part of the neural tube flexes at the level of the future midbrain—the mesencephalon. Above the mesencephalon is the prosencephalon (future forebrain) and beneath it is the rhombencephalon (future hindbrain).
Cranial neural crest cells migrate to the pharyngeal arches as neural stem cells, where they develop in the process of neurogenesis into neurons.
The optical vesicle (which eventually becomes the optic nerve, retina and iris) forms at the basal plate of the prosencephalon. The alar plate of the prosencephalon expands to form the cerebral hemispheres (the telencephalon) whilst its basal plate becomes the diencephalon. Finally, the optic vesicle grows to form an optic outgrowth.
Blood[edit]
Haematopoietic stem cells that give rise to all the blood cells develop from the mesoderm.
Development of physical features[edit]
Face and neck[edit]
This section needs expansion. You can help by adding to it. (November 2017)
Main article: Face and neck development of the embryo
From the third to the eighth week the face and neck develop.
Eyes[edit]
Main article: Eye development
The eye begins to develop from the third week to the tenth week.
Limbs[edit]
This section needs expansion. You can help by adding to it. (November 2017)
Main articles: Limb development and Limb bud
Further information: Zone of polarizing activity
In the fourth week limb development begins.
Clinical significance[edit]
Further information: Prenatal testing and Environmental toxicants and fetal development
See also: Obstetric ultrasonography
Toxic exposures during the germinal stage may cause prenatal death resulting in a miscarriage, but do not cause developmental defects. However, toxic exposures in the embryonic period can be the cause of major congenital malformations, since the precursors of the major organ systems are now developing.
Each cell of the preimplantation embryo has the potential to form all of the different cell types in the developing embryo. This cell potency means that some cells can be removed from the preimplantation embryo and the remaining cells will compensate for their absence. This has allowed the development of a technique known as preimplantation genetic diagnosis, whereby a small number of cells from the preimplantation embryo created by IVF, can be removed by biopsy and subjected to genetic diagnosis. This allows embryos that are not affected by defined genetic diseases to be selected and then transferred to the mother's uterus.
Sacrococcygeal teratomas, tumours formed from different types of tissue, that can form, are thought to be related to primitive streak remnants, which ordinarily disappear.[8][9][11]
First arch syndromes are congenital disorders of facial deformities, caused by the failure of neural crest cells to migrate to the first pharyngeal arch.
Spina bifida a congenital disorder is the result of the incomplete closure of the neural tube.
Vertically transmitted infections can be passed from the mother to the unborn child at any stage of its development.
Hypoxia a condition of inadequate oxygen supply can be a serious consequence of a preterm or premature birth.
See also[edit]
Aorta-gonad-mesonephros
CDX2
Development of the reproductive system
Development of the urinary system
Developmental biology
Drosophila embryogenesis
Embryomics
Gonadogenesis
Human tooth development
Potential person
Recapitulation theory
Additional images[edit]
Representing different stages of embryogenesis
Early stage of the gastrulation process
Phase of the gastrulation process
Top of the form of the embryo
Establishment of embryo medium
Spinal cord at 5 weeks
Head and neck at 32 days
List of human cell types derived from the germ layers
References[edit]
Jump up ^ Sherk, Stephanie Dionne. "http://www.healthline.com/galecontent/prenatal-development". Gale Encyclopedia of Children's Health, 2006. Gale. Archived from the original on 1 December 2013. Retrieved 6 October 2013. External link in |title= (help)
Jump up ^ "germinal stage". Mosby's Medical Dictionary, 8th edition. Elsevier. Retrieved 6 October 2013.
Jump up ^ "acrosome definition - Dictionary - MSN Encarta". Archived from the original on 2009-10-31. Retrieved 2007-08-15.
^ Jump up to: a b Forgács, G.; Newman, Stuart A. (2005). "Cleavage and blastula formation". Biological physics of the developing embryo. Cambridge University Press. p. 27. ISBN 978-0-521-78337-8.
Jump up ^ Brison, D. R.; Sturmey, R. G.; Leese, H. J. (2014). "Metabolic heterogeneity during preimplantation development: the missing link?". Human Reproduction Update. 20 (5): 632–640. doi:10.1093/humupd/dmu018. ISSN 1355-4786. PMID 24795173.
Jump up ^ Boklage, Charles E. (2009). How New Humans Are Made: Cells and Embryos, Twins and Chimeras, Left and Right, Mind/Self/Soul, Sex, and Schizophrenia. World Scientific. p. 217. ISBN 978-981-283-513-0.
Jump up ^ http://www.vanat.cvm.umn.edu/TFFLectPDFs/LectEarlyEmbryo
^ Jump up to: a b c d e f Carlson, Bruce M. (1999) [1t. Pub. 1997]. "Chapter 4: Formation of germ layers and initial derivatives". Human Embryology & Developmental Biology. Mosby, Inc. pp. 62–68. ISBN 0-8151-1458-3.
^ Jump up to: a b c d e f g h i j k l Sadler, T.W.; Langman, Jan (2012) [1st. Pub. 2001]. "Chapter 3: Primera semana del desarrollo: de la ovulación a la implantación". In Seigafuse, sonya. Langman, Embriología médica. Lippincott Williams & Wilkins, Wolters Kluwer. pp. 29–42. ISBN 978-84-15419-83-9.
^ Jump up to: a b Moore, Keith L.; Persaud, V.N. (2003) [1t. Pub. 1996]. "Chapter 3: Formation of the bilaminar embryonic disc: second week". The Developing Human, Clinically Oriented Embryology. W B Saunders Co. pp. 47–51. ISBN 0-7216-9412-8.
^ Jump up to: a b Larsen, William J.; Sherman, Lawrence S.; Potter, S. Steven; Scott, William J. (2001) [1t. Pub. 1998]. "Chapter 2: Bilaminar embryonic disc development and establishment of the uteroplacental circulation". Human Embryology. Churchill Livingstone. pp. 37–45. ISBN 0-443-06583-7.
Jump up ^ Campbell, Neil A.; Brad Williamson; Robin J. Heyden (2006). Biology: Exploring Life. Boston: Pearson Prentice Hall. ISBN 0-13-250882-6.
^ Jump up to: a b c Smith Agreda, Víctor; Ferrés Torres, Elvira; Montesinos Castro-Girona, Manuel (1992). "Chapter 5: Organización del desarrollo: Fase de germinación". Manual de embriología y anatomía general. Universitat de València. pp. 72–85. ISBN 84-370-1006-3.
Jump up ^ Ross, Lawrence M. & Lamperti, Edward D., ed. (2006). "Human Ontogeny: Gastrulation, Neurulation, and Somite Formation". Atlas of anatomy: general anatomy and musculoskeletal system. Thieme. ISBN 978-3-13-142081-7.|url=https://books.google.com/books?id=NK9TgTaGt6UC&pg=PA6
Jump up ^ "Pregnancy week by week". Retrieved 28 July 2010.
Jump up ^ Brent AE, Schweitzer R, Tabin CJ (April 2003). "A somitic compartment of tendon progenitors". Cell. 113 (2): 235–48. doi:10.1016/S0092-8674(03)00268-X. PMID 12705871. Retrieved 2014-04-20.
Jump up ^ Larsen, W J (2001). Human Embryology (3rd ed.). Elsevier. p. 87. ISBN 0-443-06583-7.
^ Jump up to: a b Betts, J. Gordon (2013). Anatomy & physiology. pp. 787–846. ISBN 1938168135.
^ Jump up to: a b c d e Larsen, W J (2001). Human Embryology (3rd ed.). Elsevier. pp. 170–190. ISBN 0-443-06583-7.
External links[edit]
Wikimedia Commons has media related to Human embryos.
Photo of blastocyst in utero
Slideshow: In the Womb
Online course in embryology for medicine students developed by the universities of Fribourg, Lausanne and Bern
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Human embryogenesis in the first three weeks
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The Binding of Isaac (video game)
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The Binding of Isaac
Publisher(s)
Edmund McMillen
Designer(s)
Edmund McMillen
Florian Himsl
Artist(s)
Edmund McMillen
Composer(s)
Danny Baranowsky
Engine
Adobe Flash
Platform(s)
Microsoft Windows, OS X, Linux
Release
September 28, 2011
Genre(s)
Roguelike, dungeon crawl, shooter, action-adventure
Mode(s)
Single-player
The Binding of Isaac is an indie roguelike video game designed by Edmund McMillen and Florian Himsl, initially released in 2011 for Microsoft Windows; the game was later ported for OS X, and Linux operating systems. The game's title and plot are inspired by the Biblical story of the Binding of Isaac: after Isaac's mother receives a message from God demanding the life of her son as proof of her faith, Isaac flees into the monster-filled basement of their home, where he must fight to survive. Players control Isaac or one of six other unlockable characters through a procedurally generated dungeon in a roguelike manner, fashioned after those of The Legend of Zelda, defeating monsters in real-time combat while collecting items and power-ups to defeat bosses and eventually Isaac's mother.
The game was the result of a week-long game jam between McMillen and Himsl to develop a The Legend of Zelda-inspired roguelike that allowed McMillen to showcase his feelings about both positive and negative aspects of religion that he had come to discover from conflicts between his Catholic and born-again Christian family members while growing up. McMillen had considered the title a risk but one he could take after the financial success of Super Meat Boy, and released it without much fanfare to Steam in September 2011, not expecting many sales. The game soon gained popularity partially as a result of various Let's Play videos showcasing the title. McMillen and Himsl released an expansion "Wrath of the Lamb" in May 2012, but were limited from further expansion due to limitations with the Flash platform. They had started working with Nintendo in 2012 to release a 3DS version, but Nintendo later backed out of the deal, citing controversy over the game's religious themes.
Developer Nicalis worked with McMillen in 2014 to complete a remake of the game, The Binding of Isaac: Rebirth, bringing additional features that McMillen had planned that exceeded Flash's limitation, as well as to improve the game's graphics and enable ports for other systems beyond personal computers, including PlayStation 4 and Vita, Xbox One, Wii U, Nintendo 3DS, and the Nintendo Switch. McMillen collaborated with James Id to release The Legend of Bum-bo in late 2017, which serves as a prequel to The Binding of Isaac.
The Binding of Isaac has been well-received, with critics praising the game's roguelike nature to encourage repeated playthroughs. By July 2014, McMillen reported over 3 million copies had been sold. The game has been said to contribute to renewed interest in the roguelike genre from both players and developers.
Contents
[hide]
1 Gameplay
2 Plot
3 Development and release
3.1 Soundtrack
3.2 Cancelled Nintendo 3DS port
3.3 Wrath of the Lamb
3.4 The Binding of Isaac: Rebirth
3.5 Other games
4 Reception
5 References
6 External links
Gameplay[edit]
Gameplay screenshot of The Binding of Isaac, showing Isaac attacking (center) and two enemies (top left and top right)
The Binding of Isaac is a top-down dungeon crawler game, presented using two-dimensional sprites, in which the player controls Isaac or other unlockable characters as they explore the dungeons located in Isaac's basement. The characters differ in speed, amount of health, amount of damage they deal, and other attributes.[1] The game's mechanics and presentation is similar to the dungeons of The Legend of Zelda, while incorporating random, procedurally-generated levels in the manner of a roguelike game.[2] On each floor of the basement dungeon, the player must fight monsters in a room before continuing onto the next room. This is most commonly done by the character's tears as bullets in the style of a twin-stick shooter, but the player can also use a limited supply of bombs to damage enemies and clear out parts of the room.[1] Other methods of defeating enemies become possible as the character gains power-ups, items that are automatically worn by the player-character when picked up that can alter the character's core attributes, such as increasing health or the strength of each tear, or cause additional side effects, such as for allowing charged tear shots to be fired after holding down a controller button for a short while, or a means to fire tears behind the character. Power-ups include passive items that improve the character's attributes automatically, active power-ups that can be used once before they are recharged by completing additional rooms in the dungeon, and single-use power-ups such as pills or Tarot cards that confer a one-time benefit when used, such as regaining full health, or increasing or decreasing all attributes of the character. The effect of power-ups stack, so that the player may come into highly-beneficial power-up combinations.[1][3]
Once a room is cleared of monsters, it will remain clear, allowing the player to re-trace their way through the level, though once they move onto the next level, they cannot return. Along the way, the player can collect money to buy power-ups from shopkeepers, keys to unlock special treasure rooms, and new weapons and power-ups to strengthen their chances against the enemies. The player's health is tracked by a number of hearts; if the character loses all their hearts, the game ends in permadeath and the player must start over from a freshly-generated dungeon. Each floor of the dungeon includes a boss which the player must defeat before continuing to the next level.[3] On the sixth of eight floors, the player fights Isaac's mother; after defeating her, Isaac crawls into her womb. Later levels are significantly harder, culminating in a fight against the heart of Isaac's mother on the eighth floor. An optional ninth floor, Sheol contains the boss Satan. Winning the game with certain characters or by certain conditions unlocks new power-ups that might appear in the dungeon or the ability to use one of the other characters. The game tracks the various power-ups that the player has found over time which can be reviewed from the game's menus.[1]
Plot[edit]
The Binding of Isaac's plot is very loosely inspired by the biblical story of the same name.[4] Isaac, a child, and his mother live in a small house on a hill, both happily keeping to themselves, with Isaac drawing pictures and playing with his toys, and his mother watching Christian broadcasts on television. Isaac's mother then hears "a voice from above", stating her son is corrupted with sin, and needs to be saved. It asks her to remove all that was evil from Isaac, in an attempt to save him. His mother obliges, taking away his toys, drawings, and even his clothes.
The voice once again speaks to Isaac's mother, stating that Isaac must be cut off from all that is evil in the world. Once again, his mother obliges, and locks Isaac inside his room. Once more, the voice speaks to Isaac's mother. It states she has done well, but it still questions her devotion, and tells her to sacrifice her son. She obliges, grabbing a butcher's knife from the kitchen and walking to Isaac's room. Isaac, watching through a sizable crack in his door, starts to panic. He finds a trapdoor hidden under his rug and jumps in, just before his mother opens his bedroom door. Isaac then puts the paper he was drawing onto his wall, which becomes the title screen.
During the game's loading points, Isaac is shown curled up in a ball, crying. His thoughts are visible, ranging among rejection from his mother and humiliation from his peers to a scenario involving his own death. The game features 13 possible endings, one after each major boss fight.
Development and release[edit]
The Binding of Isaac was developed following the release of Super Meat Boy, which McMillen considered a significant risk and a large time effort. When Super Meat Boy was released to both critical praise and strong sales, he felt that he no longer had to worry about the consequences of taking risks with his finances supported by its sales. He also considered he could take further risk with the concept.[4]
The Binding of Isaac's main concept was the result of a weeklong game jam that McMillen had with Florian Himsl; at the time, his co-contributor on Super Meat Boy, Tommy Refenes, was on vacation. The concept McMillen had was two-fold: to develop a roguelike title based on the first The Legend of Zelda game's dungeon structure, and to develop a game that addressed McMillen's thoughts on religion.[4] McMillen had been inspired by Shigeru Miyamoto, the designer of the original Zelda games.[5]
Random rooms were created for each floor of the dungeon by selecting ten to twenty rooms from a pre-built library of 200 layouts, adding in the monsters, items, and other features, and then including fixed rooms that would be found on each floor, such as a boss room and treasure room.[6] In expanding the gameplay, McMillen used the structure of Zelda's dungeons to design how the player would progress through the game. In a typical Zelda dungeon, according to McMillen, the player acquires a new item that helps them to progress farther in the game; he took the same inspiration to assure that each level in Isaac included at least one item and one bonus item on defeating the boss that would boost the character's attributes.[4] McMillen also wanted to encourage players to experiment to learn how things work within Isaac, mirroring how Miyamoto had done with the original Zelda game.[4] He designed the level progression to become more difficult with the player's progression in the game, as well as additional content that became available after beating the game as to make it feel like the game was long.[4] McMillen designed four of the selectable characters based on the main classes of Dungeons & Dragons—fighter, thief, cleric and wizard.[2][7][8]
On the story side, McMillen explained that the religious tone is based on his own experiences with his family, split between Catholics and born-again Christians.[4] McMillen noted that while both sides born out faith from the same Bible, their attitudes were different; he found some of the Catholic rituals his family performed inspiring, while other beliefs they had were condemning of several pastimes McMillen had participated in like Dungeons & Dragons.[4] He took inspiration from that duality to create Isaac's narrative, showing how religion can both instill harmful feelings while also bringing about dark creativity.[4] McMillen also considered the scare tactics used by the Christian right to condemn popular media of the 1980s, such as heavy metal and video games.[7] McMillen noted how many of the propaganda films from this period features satanic cults that would sacrifice children, and he noted how many Biblical stories mirrored these concepts, subsequently building the story around that.[6] He also stated that he also tended to like "really weird stuff" relating to toilet humor and similar types of off-color humor that did not sit well with his family and which he had explored in previous games before Super Meat Boy.[9] While Super Meat Boy helped to make his reputation (including being one of the featured developers in Indie Game: The Movie), he felt it was a "safe" game considering his preferred type of humor, and used Isaac to return to this form, considering that the game could easily be "career suicide" but would make a statement about what he really wanted to do.[9]
Within the week, they had a working game written in Adobe Flash's ActionScript 2. The two agreed to complete it out as a game they could release on Steam though with no expectations of sales. Completion of the game from the prototype to the finished state took about 3 months with part-time development.[4] During this time, they discovered there were several limitations on the size and scope of both Flash and ActionScript that limited how much they could do with the game, but continued to use the tools as to release the title.[4] McMillen said that because they were not worried about sales, they were able to work with Valve to release the game without fears of censorship or having to seek an ESRB rating. Releasing through Steam also enabled them to update the game freely, several times on its initial release, an aspect that they could not do with other consoles without significant cost to themselves.[4] They did release without significant end-user testing, as it would have taken several hundreds of users to go through all the various combinations of items that a player could collect, and McMillen recognized they had released the title with their buyers being playtesters for them.[4] A week after the Steam release, McMillen released a demo version via the website Newgrounds.[10] Merge Games produced a physical edition that included the game, soundtrack, and a poster, for stores in the United Kingdom in 2012.[11]
Soundtrack[edit]
Danny Baranowsky, the game's composer and who previously worked with McMillen on Super Meat Boy, was involved early on with the project shortly after the completion of the first prototype. McMillen and Baranowsky worked back and forth, with McMillen providing artwork from the game and allowing Baranowsky to develop the musical themes based on that; this would often lead to McMillen creating more art to support the music as it progressed. Baranowsky had been drawn to The Binding of Isaac as though the game puts forth a dark tone, he stated it had rather silly undertones underneath and such that one could not take it too seriously.[12] Some of the songs were inspired by classical choral music but modified to fit the theme of the game. Other works were inspired by boss fight songs composed by Nobuo Uematsu for the Final Fantasy series.[13] Baranowsky also had additional time after finishing the main songs for the game to craft short additional tracks that were used for special rooms like shops and secret areas.[13]
Cancelled Nintendo 3DS port[edit]
In January 2012, as the game has surpassed 450,000 units sold, McMillen stated that he was approached by a publisher that had interest in bringing the title to the Nintendo 3DS as a downloadable title through the Nintendo eShop, though McMillen had reservations given Nintendo's reputation for less risque content.[14] In late February, McMillen stated that Nintendo had rejected the game because of "questionable religious content". He believed this stemmed from Germany's classification board rating the existing Windows version of the game as "age 16+" due to potentially blasphemous content, the first such time a game was rated in that manner in the country.[15][4][16][17][18] McMillen noted that Nintendo executives he spoke to before this decision had noted some blasphemous content would have been acceptable, and were more concerned with overtly religious content. He also noted that he was approached about his willingness to make some changes to the game to make it more suitable for the 3DS, but never was given a list of specific changes. McMillen speculated that Nintendo was worried about its reputation; because of the game's resemblance to The Legend of Zelda, an unknowing child could potentially have downloaded the title and been shocked by the content, which would have reflected poorly on Nintendo.[19]
Several game websites were outraged at Nintendo's decision.[17][18] Though disappointed with Nintendo's decision, McMillen did not think the loss of the 3DS port was a major issue, and saw a brief sales burst on Steam as the news was covered in gaming website.[19] McMillen further praised the flexibility of the Steam platform, which does not require games to obtain ESRB ratings to be published on the service, and the freedom it gave to the publishers regardless of the game content.[17][18]
Nintendo would later allow the Rebirth remake to be released on both the New Nintendo 3DS and the Wii U in 2015; this came in part for three executives within Nintendo—Steve Singer, the vice president of licensing; Mark Griffin, a senior manager in licensing, and Dan Adelman, the head of indie development—that championed support for The Binding of Isaac.[20]
Wrath of the Lamb[edit]
"Wrath of the Lamb" redirects here. For the religious apocalypse, see Book of Revelation.
An expansion to the game, entitled Wrath of the Lamb, was released through Steam on May 28, 2012.[21] McMillen was inspired to create the expansion not only due to the success of the base game, but because his wife Danielle had fully completed the base game, the first game he had written in which she had shown significant interest.[4] The expansion adds 70% more content to the original, and contains more than 10 bosses, over 100 items, over 40 unlocks, two additional endings, and two additional optional levels.[22] This expansion added new "alternate" floors, which can replace the normal floors, creating an alternate route through the game. These floors contain harder enemies, and a different set of bosses. Other features include a new item type, Trinkets, which have a variety of passive or triggered effects when carried, as well as new room types.[23] McMillen had plans to release a second expansion beyond Wrath of the Lamb, but was constrained by the limits of Flash at this point.[4]
The Binding of Isaac: Rebirth[edit]
Main article: The Binding of Isaac: Rebirth
Sometime in 2012 after Isaac' release, McMillen was approached by Tyrone Rodriguez of Nicalis who asked if McMillen was interested in bringing the game to consoles. McMillen was interested, but insisted that they would have to reprogram the game to get around the limitations of Flash as to include "Wrath of Lamb" and the second planned expansion, remaking the game's graphics in 16-bit instead of 8-bit. Further, McMillen had wanted nothing to do with the business aspects of the game, having recounted the difficulties he had in handling this for Super Meat Boy.[4] Nicalis agreed to these, and began work in 2012 on what would become The Binding of Isaac: Rebirth, an improved version of the title.[4] It was released on November 4, 2014 for Microsoft Windows, OS X, Linux, PlayStation 4, and PlayStation Vita,[24] with versions for the Wii U, New Nintendo 3DS, and Xbox One released on July 23, 2015.[25] The game introduced numerous new playable characters, items, enemies, bosses, challenges, and room layout seeds for floors. A content pack, entitled "Afterbirth" was released for Rebirth starting October 2015, adding new alternate chapters, characters and items, as well as wave-based Greed mode.[26] A second update, "Afterbirth+", added further additional content and support for user-created modifications, and was released on January 3, 2017.[27]
Other games[edit]
McMillen is currently working with James Id to develop The Legend of Bum-bo, which McMillen expects to release in the first half of 2018. Bum-bo is described as a prequel to Isaac, and Isaac and Gish will appear as characters in the game.[28]
Reception[edit]
The Binding of Isaac
Aggregate score
Aggregator
Score
Metacritic 84/100[29]
Review scores
Publication
Score
Edge 8/10[31]
Eurogamer 9/10[30]
Game Informer 8/10[32]
GameSpot 8/10[1]
GameSpy [33]
IGN 7.5/10[34]
The Binding of Isaac received generally favorable reviews from game critics. On Metacritic, the game has an average of 84 out of 100 based on 30 reviews.[29]
The Binding of Isaac has been received by reviewers as a game with high replayability with the extensive range and combinations of power-ups that the player can encounter during a run-through, while providing an accessible Zelda-inspired framework that most video game players would recognize and easily come to understand.[30][35][33] John Teti for Eurogamer praised the game for its replayability through the randomization aspects, calling it "the most accessible exploration of the roguelike idea" that he had seen.[30] Edge's similarly commented on the lure to replay the game due to its short playthrough time, calling it "an imaginative and quick-witted arcade experience that manages to be both depraved and strangely sweet by turn".[31] GameSpot's Maxwell McGee stated that the game smartly has removed extraneous features such that "what remains is a tightly focused game that continues to feel fresh even after multiple completions".[1] Though the game is considered to be accessible to new players, reviewers found the game to be a difficult challenge, often set by the randomness of what power-ups the player happened to acquire during a single run.[35][33][32] Writers for The A.V. Club rated the game an A on a grading scale, and favorably compared the title to McMillen's Super Meat Boy, requiring the player to have "masochistic patience in the face of terrible odds".[36] This difficulty was considered mitigated by the large number of possible power-ups that the game offers, most would not be seen by players until they have replayed the game many times.[30] McGee noted that while players can review what items they have discovered prior to a run-through, this feature does not explain what each item does, leaving the effect to be determined by the player while in game.[1]
Game Informer's Adam Biessener noted that while The Binding of Isaac had a number of software bugs on release that may briefly detract from the experience, "McMillen’s vision shines through" in the game's playability, art style, and story.[32] Neilie Johnson for IGN found that some players may be put off by the game's crudeness but otherwise "it's totally random, highly creative and brutally unforgiving".[34] Similarly, Nathan Muenier for GameSpy noted the game had some shock value that one must work past, but otherwise was " imaginative" and "utterly absorbing".[33] Alternatively, Jordan Devore for Destructoid considered the visual style of the game one of its "biggest selling points", following from McMillen's past style of dark comedy from Super Meat Boy.[35] Baranowsky's soundtrack was found by reviewers to well-suit the themes of the game, and used appropriately to avoid extensive repetition during a playthrough.[1][35] Kirk Hamilton of Kotaku called the soundtrack as the combination of several genres and the musical styles of Danny Elfman, Muse, and Final Fantasy that created something "dark and unique".[13]
The Binding of Isaac was nominated in the Best Independent Game category at the 2011 Spike Video Game Awards, but lost to Minecraft.[37]
McMillen had only expected the game to sell a few hundred copies when he released it on Steam. For the first few months of its release, sales were roughly a few hundred per day, but shortly thereafter, McMillen found sales suddenly were boosted, a fact he attributed to numerous Let's Play videos that had been published by players to showcase the game and drove sales. By November 2012, the game sold over one million copies, with at least one-quarter of those having purchased the "Wrath of the Lamb" extension.[4] As of July 2014, the game has sold over 3 million copies.[38] By July 2015, following the release of Rebirth, the combined games had over 5 million units sold.[5] The Binding of Isaac is said to be a contributing factor towards the growth of the roguelike genre since around 2010, with its success paving the way for later games that used the roguelike formula, such as FTL: Faster Than Light and Don't Starve.[38][39]
References[edit]
^ Jump up to: a b c d e f g h McGee, Maxwell (November 21, 2011). "The Binding of Isaac Review". GameSpot. Retrieved April 14, 2016.
^ Jump up to: a b Scheirer, Jason (September 19, 2011). "Nightmarish Indie The Binding of Isaac Shooting Up Steam Next Week". Wired. Retrieved December 23, 2015.
^ Jump up to: a b Thursten, Chris (December 17, 2011). "The Binding of Isaac Review". PC Gamer. Retrieved April 25, 2016.
^ Jump up to: a b c d e f g h i j k l m n o p q r s McMillen, Edmund (November 28, 2012). "Postmortem: McMillen and Himsl's The Binding of Isaac". Gamasutra. Retrieved December 20, 2015.
^ Jump up to: a b Working, Sam (July 22, 2015). "The Binding of Edmund McMillen". Good Times. Retrieved February 11, 2016.
^ Jump up to: a b Jagielski, Rachel (September 2, 2011). "The Binding of Isaac: Interview with Team Meat's Edmund McMillen". VentureBeat. Retrieved April 25, 2016.
^ Jump up to: a b Holmes, Jonathan (July 21, 2011). "How a killer Christian shmup roguelike came to Steam". Destructoid. Retrieved April 25, 2016.
Jump up ^ McMillen, Edmund (September 17, 2011). "Progression?". Blogspot. Retrieved April 25, 2016.
^ Jump up to: a b Grayson, Nathan (June 26, 2012). "The Binding of Edmund McMillen". Eurogamer. Retrieved December 20, 2015.
Jump up ^ Haas, Pete (October 9, 2011). "The Binding Of Isaac Demo Released, Big Update On The Way". Cinema Blend. Retrieved December 23, 2015.
Jump up ^ Brown, Fraser (January 28, 2012). "The Binding of Isaac gets a grotesque retail edition". Destructoid. Retrieved May 10, 2016.
Jump up ^ Cooper, Hollander (October 24, 2011). "The Binding of Isaac, Cave Story 3D, and crying at poop: an interview with composer Danny B". Games Radar. Retrieved April 25, 2016.
^ Jump up to: a b c Hamilton, Kirk (December 22, 2011). "The Best Game Music of 2011: The Binding of Isaac". Kotaku. Retrieved May 10, 2016.
Jump up ^ O'Conner, Alice (January 6, 2012). "The Binding of Isaac 'mega expansion' incoming". Shacknews. Retrieved December 23, 2015.
Jump up ^ "16er-Einstufung wegen... Blasphemie" [16 rating because of... blasphemy] (in German). January 4, 2012. Retrieved February 9, 2012.
Jump up ^ Kollar, Phil (February 29, 2012). "Binding Of Isaac Blocked From 3DS Due To "Questionable Religious Content"". Game Informer. Retrieved March 1, 2012. In a follow-up tweet, McMillen confirmed that the decision was "due to the games [sic] 'questionable religious content.' He then took the opportunity to praise Steam for being such an open and supporting platform for independent and digitally distributed games.
^ Jump up to: a b c "Nintendo won't allow Binding of Isaac on the 3DS eShop". Destructoid. February 29, 2012. Retrieved February 29, 2012. It's a disgusting and sad situation, and I can only hope that something is done soon to change the way both Nintendo, and the industry in general, views the role between the hardware developers and software artists.(...)"All this stuff has opened my eyes so much more to the freedom devs have with Steam. Censorship like this doesn't pop up that often in games, and there are only a handful of "banned video games" or highly censored ones. It's nice to have the freedom to publish something that speaks its mind about religion on a platform like Steam."
^ Jump up to: a b c Groen, Andrew (February 29, 2012). "Nintendo blocks 3DS Binding of Isaac for "questionable religious content"". Ars Technica. Retrieved December 23, 2015.
^ Jump up to: a b Orland, Kyle (March 6, 2012). "Binding of Isaac creator: Nintendo rejection shows internal divisions over company's image". Ars Technica. Retrieved May 10, 2016.
Jump up ^ Crecente, Brian (April 3, 2015). "How a love of Nintendo opened the door for The Binding of Isaac and why it's only coming to New 3DS". Polygon. Retrieved February 7, 2016.
Jump up ^ Fletcher, JC (May 7, 2012). "The Binding of Isaac's Wrath of the Lamb begins May 28". Joystiq. Retrieved May 7, 2012.
Jump up ^ Marchiafava, Jeff (May 7, 2012). "The Binding of Isaac Expansion Dated". Game Informer. Retrieved May 7, 2012.
Jump up ^ Proctor, Lewie (January 30, 2012). "McMillen details The Wrath Of The Lamb, as Binding Of Isaac sells 450k". Gamasutra. Retrieved April 14, 2016.
Jump up ^ Hillier, Brenna (November 4, 2014). "The Binding of Isaac: Rebirth out now on Steam, PSN". VG247. Retrieved April 20, 2016.
Jump up ^ Machkovech, Sam (July 23, 2015). "Sacrilegious Binding of Isaac: Rebirth finally launches on Nintendo systems". Ars Technica. Retrieved April 20, 2016.
Jump up ^ Phillips, Tom (September 8, 2015). "The Binding of Isaac: Rebirth's meaty Afterbirth expansion pushes out a release date". Eurogamer. Gamer Network. Retrieved September 8, 2015.
Jump up ^ Matulef, Jeffrey (December 8, 2015). "The Binding of Isaac to receive mod tools DLC". Eurogamer. Retrieved December 8, 2015.
Jump up ^ Mersereau, Kevin (September 5, 2017). "Binding of Isaac prequel on target for a 2017 release". Destructoid. Retrieved September 5, 2017.
^ Jump up to: a b "The Binding of Isaac for PC Metacritic Score". Metacritic. CBS Interactive. Retrieved November 3, 2011.
^ Jump up to: a b c d Teti, John (October 7, 2011). "The Binding of Isaac Review". Eurogamer. Retrieved November 3, 2011.
^ Jump up to: a b "The Binding of Isaac Review". Edge. October 7, 2011. Archived from the original on October 8, 2011. Retrieved April 14, 2016.
^ Jump up to: a b c Biessener, Adam (October 3, 2011). "Equal Parts Gross, Disturbing, And Fun – The Binding of Isaac – PC". Game Informer. Retrieved November 3, 2011.
^ Jump up to: a b c d Meunier, Nathan (September 30, 2011). "GameSpy: The Binding of Isaac Review – Page 1". GameSpy. IGN Entertainment. Retrieved November 3, 2011.
^ Jump up to: a b Johnson, Neilie (October 11, 2011). "The Binding of Isaac Review – PC Review at IGN". IGN. IGN Entertainment. Retrieved November 3, 2011.
^ Jump up to: a b c d Devore, Jordan (October 2, 2011). "Review: The Binding of Isaac". Destructoid. Retrieved May 9, 2016.
Jump up ^ Anthony John Agnello, Noah Cruickshank, Russ Fischer, Steve Heisler, Rowan Kaiser, Gus Mastrapa, Samantha Nelson, Tasha Robinson, and John Teti (October 10, 2011). "Sawbuck Gamer, October 10, 2011". The A.V. Club. Retrieved April 14, 2016. CS1 maint: Uses authors parameter (link)
Jump up ^ Bradford, Matt (November 17, 2011). "2011 Spike VGA nominees announced, Zelda to become first Hall of Famer". GamesRadar. Retrieved May 10, 2016.
^ Jump up to: a b Mahardy, Mike (July 4, 2014). "Roguelikes: The Rebirth of the Counterculter". IGN. Retrieved December 23, 2015.
Jump up ^ Johnson, Mark (July 22, 2015). "Before Spelunky and FTL, There Was Only ASCII". Paste. Retrieved April 14, 2016.
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