Genetics Made Easy - Easy way to understand Birth...1

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1 - INTRODUCTION

Becoming a parent is a new and wonderful experience that will radically change your life, giving you a new dimension, meaning, and sense of responsibility.

Becoming a parent brings us to a many-sided and ambivalent situation, which rapidly takes us from feeling hilariously happy to being totally overwhelmed with worry, and vice versa, by a series of questions, doubts, and common affirmations, such as:will the baby be normal?", or the baby will be normal because we have never had any problems in our family".

However, this is not so, and reality tells us that each pregnancy is like a lottery that entails a certain risk for some sort of alteration or malformation in all families, being greater in some families and lesser in others. In the end, there is risk in all families, irrespectively of whether or not normal or abnormal children have been born previously.

If you have already fathered or mothered normal children, or children with some type of hereditary disorder, or this is your first time, and are considering the possibility of becoming pregnant in the future, or you are already pregnant, this web will help you find answers to some of your questions. 2 - THE ORIGIN OF LIFE Life begins when a spermatozoon (a mature male germ cell) and an ovum (a mature female germ cell) uniteto form one single cell called egg" or zygote", which as of that moment, will undergo a series of divisions that will ultimately result in the birth of an infant. This initial process is known as fertilisation, and it physiologically takes place in the female's uterine tubes. This process is initiated through sexual intercourse during the female's monthly ovulatory period. This is the period when a female is fertile and can become pregnant.  Once sexual intercourse has taken place, spermatozoa make their way through the female's reproductive tract towards the uterine tubes in search of the ovum - released by the ovary - to fertilise it. And voila! Fertilisation! One single sperm cell (spermatozoon) succeeds in entering the ovum and the miracle happens: a new life is created. From the Fallopian tubes, this new life reaches the uterus where it will lodge and continue to grow during nine months until birth. Growth takes place throughout a long stage of millions of cell divisions until a new being is totally formed. Nonetheless, for this long and complex process to become a reality, three previous stages are necessary: 1st STAGE: GAMETE PRODUCTION (OVA AND SPERMATOZOA) In the female, ova are produced in the ovary. Normally, each month, an ovum is released by one of the two ovaries and enters the Fallopian tube, a phenomenon known as ovulation. Next, the ovum migrates, that is, it makes its way down the uterine tube towards the uterus. During this journey, it will only be available for fertilisation during 24 hours. In the male, spermatozoa are continuously produced in the testis starting at puberty. The time required for their formation, from the start of development to the time a mature sperm cell with fertilising ability is obtained, is approximately 64 days. Once ejaculated, sperm cells will be capable of fertilisation for 48 hours. The adult male emits between 2 and 8 millilitres of semen in each ejaculation. And each millilitre can contain 20 million or more spermatozoa, under normal conditions. 2nd STAGE: UNION OF THE GAMETES 3rd STAGE: NESTING OR UTERINE IMPLANTATION The new life has to be embedded in the uterus in order to continue its growth and development. 3 - CELL SPECIALIZATION From the moment the egg or zygote is fertilised, it starts to divide, giving rise to new cells, which group together in an orderly fashion to form new organs in our body with specialised functions. Different sets of organs make up an interrelated ecosystem" so perfect and incredibly wonderful that it makes it possible for us to live, develop, and adapt to our environments. So it is then easy for us to figure out that such orderly fashion must be scrupulously directed and controlled And this is exactly the case, as all the instructions necessary for the development of the egg are contained in structures known as CHROMOSOMES that we all have inside our cells. Chromosomes are vase-like structures where all the genetic data or necessary instructions are contained for a given individual to develop. We could say that chromosomes are like our cook books, where all our cooking recipes are stored: Heart on the way! A kidney, please! A stomach coming! In one word, chromosomes contain our building blocks, that is to say our genetic heritage. We receive this genetic inheritance in two equal parts from our parents at the time of conception. In turn, and by the same method, it is transmitted to our offspring, and from our offspring, transmitted to their offspring, and so traits are derived from an earlier generation to another generation. Thus, chromosomes are responsible for the origin and continuity of life.  And, how do they do that? How can our organs be so different if all body cells contain exactly the same instructions? Let's see: In general terms, a cell is very much like an egg, and consisting of three major parts: a nucleus, a cytoplasm, and a cytoplasmatic membrane that encircles it. The answer is easy. They are able to do this through cell specialization. For the time being, let's just focus on the nucleus, as it is in its inner portion where chromosomes are found and which, in the human, total 46. Given that all cells in our body have developed from one single cell, the egg or ovum fertilised by one spermatozoon", all cells are identical, that is, they contain exactly the same instructions. However, depending on the organ they are to be part of, they will use a specific part of that information. This process is known as cell specialization. In this way, nerve cells contain the necessary information to form hair and the cells that make up hair have the necessary information to form nerves. However, once specialised, nerve cells will form nerve tissue and hair cells will form hair. And so, since different recipes" are used, cells will form different organs. A lung is, thus, different to a stomach because in the lung, the building blocks contained in the recipes" are designed to form cells that specialise in respiration, whereas, in the stomach, the recipes" that start operating are designed to form an organ that prepares the ingested food for subsequent absorption in the intestine. And, this process is repeated for each of the different parts that make up our body. Because of this, every human cell has 46 chromosomes containing all our cooking recipes" or building blocks. However, these recipes are not expressed at the same time in all cells. Some of these building blocks are expressed and function in certain cells, whereas in other cells, other buildings blocks come into play. As you can see, chromosomes that play a role in the formation of the stomach are at rest in the formation of the lung. 4 - CHROMOSOMES Chromosomes within a cell are arranged in sets. Each cell contains 46 chromosomes or 23 sets. Such sets of chromosomes are classified according to an international nomenclature: from the largest to the smallest, followed by sex-chromosomes. As you can see, we have: two number 1 chromosomes two number 2 chromosomes two number 3 chromosomes and so on for all sets. The first 22 sets are called AUTOSOMES, and are shared by both the male and the female. Chromosomes in set 23 are called GONOSOMES, or sex-chromosomes. These chromosomes can be X or Y, and constitute different sets depending on whether it is a man or a woman, for, as their name indicates, these chromosomes are concerned with thedetermination of sex and set the differences between a male and a female. A woman has two X sex-chromosomes and a man has one X sex-chromosome and one Y sex-chromosome. In other words, it is just ONE SIMPLE CHROMOSOME what makes us SO DIFFERENT from each other. Always remember that chromosomes are the same in all human races. Given that the number of chromosomes for everything to run smoothly should always be kept constant from generation to generation, each individual should only inherit 23 chromosomes from each progenitor at the time of conception. Thus, if a woman has 46 chromosomes and a man has 46 chromosomes, each one has to transmit to their unborn child half of that amount (23 chromosomes) at the time of fertilisation. And so the unborn child will receive 46 chromosomes, 23 from its female parent and 23 from its male parent = 46 in total. And, how is this possible? Let's go back a little bit. Every cell always results from the partition of one cell into two daughter cells. And so, from the moment in which the egg or zygote is formed, it undergoes division, producing two new cells. These, in turn, divide and each of them gives rise to two more cells, and this is successively repeated until the individual is formed. Given that nature is very wise, depending on whether it wants to keep the number of chromosomes constant or, alternatively, reduce it by one half, it has, at its convenience, two types of cell divisions, which it uses in a very specific and controlled manner. One is mitosis and the other is meiosis. The difference between both types of cell division lies in the way in which chromosomes are shared, that is the hereditary material at the moment of division. Thus, in the MITOSIS cell division, the two resulting daughter cells always contain the same number of chromosomes as the parent cell from which they derive. On the contrary, in the MEIOSIS cell division, the number of chromosomes is not kept constant, to the contrary, "it is reduced by one half". This is a reductional type of cell division, and so, at the end of the entire process, each resulting daughter cell contains only half the number of chromosomes from the parent cell. That is, from cells that contained 46 chromosomes grouped in 23 sets, cells that contain 23 chromosomes are derived, only taking one component from each set. It is on this type of meiotic cell division that we will be focusing. Please note that this is a very, very special type of cell division, and in the entire body, it is only used by germinal cells, that is, by cells located in the ovary in the woman and in the testis in the man. In other words, cells that are located in the organs involved in reproduction and whose function is to keep our number of chromosomes constant from generation to generation. Otherwise, the number of chromosomes would experience a two-fold increase in each generation, and this would be incompatible with life, endangering the preservation of specie. And, how is this distribution carried out? It is very easy. The original cell that contains the 46 chromosomes divides and splits into two new cells. Before they are separated, these two cells share the chromosomes in equal numbers and each of them takes one element from each set of chromosomes. Because they share the chromosomes between them, each of these two cells only contains 23 chromosomes, or one from each set. During this process, germinal cells start maturing and changingtheir form until they become the future gametes or cells withfertilising capacity. Please, note that these changes are extremely important. In the case of a male, a cell without a tail gives rise to cells with a tail that are called spermatozoa. This tail enables spermatozoa to swim from the time of ejaculation up the uterus and the uterine tubes in the female until they encounter an ovum which they fertilise. In the end, the percentage of spermatozoa that carry the X-chromosome is the same as the spermatozoa that carry the Y- chromosome. In the woman, after each meiotic cell division, one of the two resulting cells is sacrificed, giving to the other cell its energy reserves so that if the other cell is fertilised, it survives while it migratesdown the uterine tubes and implants in the uterus. The end result is that each month, the woman generates an ovumthat carries the X sex-chromosome, which can be fertilised by any of the millions of spermatozoa that are struggling to enter it, of which 50% carry the X-chromosome and the remaining 50% the Y-chromosome. Thus, the possibility of the new individual being a boy or a girl is always determined by the male, as it is the male who bears both types of spermatozoa, the X-bearing sex-chromosome and the Y-bearing sex-chromosome. In contrast, as thewoman only has two X sex chromosomes, she will always contribute with one ovum containing one X sex chromosome. In summary: From each male germinal cell, four spermatozoa are obtained, two of which are X-bearing sex-chromosome carriers, and two are Y-bearing sex-chromosome carriers. From the female germinal cell, one ovum carrying the X sex-chromosome is obtained. The possibilities of recombination at the time of fertilisation are as follows: And, what does a chromosome look like? A chromosome is a very complex chemical structure composed of proteins and DNA (desoxyribonucleic acid: a compound composed of nitrogenous bases, sugars and phosphates). When the chromosome is examined at a molecular level, the spatial shape it acquires resembles two strands twisted into a double helix (similar to a ladder suspended into space), where the steps correspond to the bases and the sugars and phosphates to the rail. There are four organic bases: GUANINE CYTOSINE ADENINE and THYMINE The steps of the ladder are always composed of sets of GUANINE and CYTOSINE, or alternatively ADENINE and THYMINE. The succession of these bases or steps forms a lineal coded message that contains all our recipes and that is decoded inside each cell through specific mechanisms. Let's see it: The spatial form DNA acquires is similar to a ladder suspended in space. The steps of the ladder are formed by pairs of Guanine and Cytosine, or by Adenine and Thymine. And the rail by sugars and phosphates. When it is necessary to use any of the recipes at cell level, the two DNA chains separate at this specific point and the gene or recipe is copied from beginning to end. This copy of the gene is called messenger RNA (messenger ribonucleic acid), during this process the Guanine is paired with Cytosine and Adenine instead of pairing with Thymine,does it with a new base called Uracil. Once the process is completed, the DNA closes again and this copy of messenger RNA leaves the nucleus and moves towards the cytoplasm to join the ribosomes. The function of the ribosomes is to read the message, and based on that information, to fabricate the proteins following a strict order. To carry out their function, ribosomes need amino acid transporters known as transfer RNA. Remember that proteins are formed by chains of amino acids, which play a very important function as they determine how all the molecules (sugars, fats, water, minerals, DNA, etc.) that conform our body must be arranged in order to function. The RNA message is written in a trinary code, that is, a specific amino acid is determined by a sequence of three bases. A codon is thus formed by a set of three bases. Given that we have four pairs of bases (Guanine, Cytosine, Adenine and Uracil), in total we have 64 possible combinations of codons to recall the 20 amino acids that conform our proteins. To make things easier, let's imagine that a chromosome is like a cassette tape, recorded over with cooking recipes one after another. In our case, the cooking recipes are the instructions for the structures in our body, such as the brain, heart, kidney, etc. to develop and function. 5 - HOW DO WE RECEIVE OUR GENETIC HERITAGE? Let's imagine a mother with her two daughters, who divides her belongings equally between them. The mother has two closets, two chairs, two beds, and she gives each of her daughters: one closet, one chair, one bed, etc. In our case, what we are dividing is the 23 sets of chromosomes that we have in each of our gonadal cells - that is the cells contained in the ovaries and the testis. Remember that the parent cell, both in the ovary and in the testis, contains 46 chromosomes arranged into 23 sets before it undergoes cell division. When meiotic division takes places, it divides the chromosomes equally between both daughter cells. Thus, from the two chromosomes contained in set 1, one is given to each daughter cell, and this process is repeated for each of the remaining sets. In the end, each daughter cell will have received 23 chromosomes, or what is the same, an element from each set. Subsequently, when the ovum and the spermatozoon unite, an individual with 46 chromosomes (23 from the mother + 23 from the father) is obtained. In this manner, the number of chromosomes in the human race is preserved. Let's also note that the information of the recipes contained in the chromosomes is copied twice (with the exception of sex-chromosomes in the male "XY"). From chromosome or cassette number 1, we have two copies: oneinherited from the father and one inherited from the mother. Simply because they are from the same cassette number, they must contain exactly the same recipes with exactly the same type of information, but with the specific variables that make up each individual. Suppose that recipe number 25, inherited from the maternal "cassette" number 2, contains information for blond hair, and that the one we have inherited exactly from the same place, but from the father's side, is for black hair. Both chromosomes or cassettes are giving us exactly the same information (HAIR COLOR), but with the traits or variables that each individual presents (BLOND hair or BLACK hair). Consequently, the instructions for hair are received twice. The new individual will on some occasions express the instructions given in both recipes, and on other occasions it will only express one set of instructions, despite having both sets, because one will dominate over the other. That is, it is easier for the dominant set of instructions to express or manifest itself than it is for the other. In our example, the individual will have black hair because black hair dominates over blond hair, but remember that the individual carries both recipes or sets of instructions: black hair and blond hair. This situation is repeated for all recipes over and over again. Nonetheless, in life anything can go wrong and this is also true for nature. Concerning our inheritance, these failures can be originated by; 6 - WHAT IS HEREDITY? Heredity is a set of chromosomes with their recipes that we have received or inherited from our parents and which we will pass on to our own children. As we mentioned before, chromosomes are classified in 23 sets. The first 22 sets are called AUTOSOMES and are the same in the man and in the woman. The components of set 23 are called GONOSOMES, or sex-chromosomes, and they are different in the man and in the woman. As their name indicates, they determine the sex of the human being. A woman has two sex-chromosomes "XX" while a man has one "X" chromosome and one "Y" chromosome. 7 - TYPES OF HEREDITY In terms of heredity, and following this classification, the recipes that determine the characteristics or traits for each person are divided into AUTOSOMAL characteristics, if they are contained in the first 22 sets of chromosomes, and SEX LINKED characteristics, if they are part of set 23. Within this group, we will only work with those recipes or traits that are "X"-chromosome dependent, as this chromosome is shared equally by the male and the female's sex-chromosomes. When discussing these recipes, we will refer to them as traits or characters linked to the X-chromosome. Conversely, traits that are "Y"-chromosome dependent are only transmitted from male to male, and will not be discussed here. This whole array of characteristics or traits can manifest or express in a dominant, recessive, co-dominant, or intermediate fashion. The terms "dominant and recessive" mean that we receive the information from a recipe twice, information from the father and information from the mother, as each of them contributes with one element from each set of their chromosomes. Then, and depending on how the information contained in those recipes manifests or is expressed, we can be faced with three different scenarios: A DOMINANT character or trait is when only one of the two recipes is expressed, be it the mother's or the father's, with one dominating over the other. The other recipe that is not being expressed at this moment but that belongs to the same chromosomal set (although it did not manifest in the presence of the other recipe) is called RECESSIVE character or trait because it is in RECESS, overlapping or hidden. In this case, for the character to manifest it is necessary for both progenitors to contribute with the same type of information. If only one of the progenitors provides the required information, the character does not manifest and then the individual is considered to be an asymptomatic carrier of such character or trait. When both recipes are expressed at the same time with the same intensity, they are called CO-DOMINANT CHARACTERS, as in the AB blood type. And, finally, when both recipes are expressed at the same time but the resulting character or trait is anintermediate expression of both, because neither dominates over the other; these characters are said to present an INCOMPLETE OR PARTIAL DOMINANCE, for instance if we cross-breed white flowers with red flowers, the descendants will have pink flowers. The pink flowers are the result of mixing up both pigments.

And do you want to know how this type of heredity was discovered?

It was Gregory Mendel, an Austrian Augustinian monk born in 1822, whom, while growing peas in his garden, discovered the laws that bear their last name and that constitute the corner stone of genetic science. Mendel crossed pure pea types that differed in one or more defined traits. Mendel followed for at least two generations the progenesis of this plant crossings.

In the year 1866 he had already published the results of the experiments that delineated the majority of the basic principles of classic genetics. However, at that time, the world was not yet ready to pay attention to Mendels great work. His discoveries were not recognised until much later after his death.

8 - WHY DO DISORDERS DEVELOP?

Well, it is very easy to explain.

When there are errors in these characters or recipes, the information they express or encode is also erroneous, and this more often than not, although not always- leads to malformations or disorders. Based on the chromosome where the anomalous gene or recipe is contained, we will have AUTOSOMAL DOMINANT DISORDERS and AUTOSOMAL RECESSIVE DISORDERS, and DISORDERS THAT ARE LINKED TO THE X-CHROMOSOME of a DOMINANT TYPE and of a RECESSIVE TYPE.

AUTOSOMAL DOMINANT AND RECESSIVE disorders, as their name indicates, refer to autosomes or chromosomes from set 1 to set 22, and these affect both man and woman alike.

SEX LINKED disorders refer to set 23. I would like to remind the reader that we will only be discussing those disorders that are linked to the X-chromosome. As we will be able to see, it makes a great difference whether it is the man or the woman who is carrying the defective gene.

Given that we have two chromosomes from each set, that is, one inherited from our mother and one inherited from our father,

for the same recipe or allele, within any set of our chromosomes, we may encounter any of the three following combinations:

• That both sets of information or alleles encoding for the same recipe are correct,

GOOD / GOOD = healthy individual

• That one recipe is correct and the other incorrect,

• Both recipes are incorrect.

This combination will always produce affected individuals, both for autosomal and for X sex-linked (X-chromosome) disorders, irrespectively of whether these are dominant or recessive.

At present, very few cases of autosomal dominant disorders and sex linked dominant disorders are known in which both alleles and recipes for the same character are defective or pathological and when this happens, the affected individuals tend to manifest the disorder or trait in a much more severe form, as both recipes are expressed together.

 Imagine a double portion of a bad tasting cake. Awful, isn't it?

9 - What happens when our recipes combine with our partner's recipes?

Well, each member of the couple, irrespectively of what their personal combination might be, will find that the other partner may express any of the previously mentioned combinations for any given recipe. Based on these recipes, at the time of fertilization, the different combinations, giving the different probabilities of presenting some trait or hereditary disorder, will be appear.

Let's get to the point and see what happens in practice.

As stated previously, in order for the number of chromosomes to remain constant and for germinal cells to be able to fertilise, a reductional division or meiosis has to occur. To explain the risk percentages in the different types of heredity, we will focus on the type of cells that are produced immediately after reductional division has taken place, as these are the only possible resulting combinations.

Under normal conditions in a woman, one of these cells is lost. Since we do not know which one of them will be lost, and one cell complements the other, both will be studied. These are the only two possible combinations and any of the two can occur.

From now on we will only refer to one single character encoded by the same chromosomal set, which will be represented as follows:

Given that each of us has two chromosomes from each set, our resulting gametes will be:

And our partner's gamete will be:

We will always be talking about the same recipe within the same chromosomal set, for both members of the couple.

And now let me give you a graphic representation of the different combinations that can result in reproduction.

If we pay close attention we will see that we are all a mixture of all the characters that run in our family. Our hair can be the same colour as that of our maternal grandfather and our eyes can be the same colour as our paternal grandfather's, the hands may resemble our maternal grandmother's and the teeth can be exactly like our father's.

For sure, you will ask yourselves: How is this mixture possible?

Well, it is extremely easy. Chromosomes of a same set exchange information between them before they undergo reductional division or meiosis. That is, recipe number 4 from chromosome number 1 is exchanged for recipe number 4 from the other chromosome number 1, and this same process is repeated in many other recipes.

In the end, the resulting chromosomes are a mixture of all the recipes or characters from our ancestors.

And it is thanks to this exchange that the variability of the species prevails, making each of us different from the other, unique and unrepeatable.

But, for every thing to come out right, each chromosome of the same set must contain the same recipes at the end of this process, irrespectively of whether they have been exchanged or not, so that each chromosome has all the recipes it needs, without a single one missing or in excess.

And now let's review the graphic representation of the different combinations that can result when we reproduce.

In this section, we are going to cover all possible combinations and it will be up to the reader to decide the preferred reading sequence. At your option, you can either:

a) Read through all the combinations, which will provide you with a global view. We recommend this option as it will enhance your overall understanding as to how we fight disorders today.

b) Read through only a few pages starting at the beginning, so that you become familiar with how these combinations give rise to disorders.

c) And if you are at specific risk, because you fall into any of the situations described, I suggest that you first read everything and then come back to the section that concerns your particular case.

As you can see, it is very easy 

Having seen how hereditary diseases are transmited, if you require specific information on a certain disease, the following links can help you:

• Genetic Alliance
• NOAH
• Orphanet
• Global TeleGenetics GeneScene
• Genetic and Rare Conditions Site
• Birth Defects-Genetics-Teratology-Foundations-Support-Organizations
• OMIM (Online Mendelian Inheritance in Man), this link includes the classification of all Mendelian hereditary diseases. The "Bible" of geneticists. A database for professionals. It is likely and completely understandable that you may not be familiar with some of the terminology used in the description of your review of the literature, but it will give you a good idea of the current status of the condition you may be looking for.

And please, regardless of all the information you get on the subject of your interest, do not forget that it is only an information service, containing data that must be interpreted by a specialist, so please before you make any decision, have a consultation with a Genetics department, where your individual case will be accurately assessed and where all your questions will be answered.

Where does all this take us?

Well, it is easy, when one of the progenitors is sick, or one or both of them are carriers of the same genetic disorder, they have a risk to produce affected children. The amount of risk and the sex of the affected individual is dependent on the type of inheritance.

For this reason, in case a malformation or a family disorder exists, the first thing to do is to study the family background and see which inheritance pattern runs in the family.

To this end, a genealogical tree is made using an international nomenclature  in which all the individuals appear, identifying those who are affected and once these are identified, to determine the degree of severity, because we know that, in some cases, this can vary among the particular individuals.

Remember that the final flavour depends on all the ingredients mixed in the pie:

In this case, the degree of severity for each individual depends on how all the recipes are assembled.

In case that the disorder or malformation is not diagnosed, appropriate exams must be performed to try and obtain a diagnosis, and on the basis of this diagnosis, the risk of the particular individual to produce children with the same problem is calculated.

Some of these disorders are very severe, so at the time of deciding on their reproductive future, couple may encounter the following situations:

1. They ACCEPT the prenatal diagnosis, if available for this particular disorder, regardless of whether they decide to terminate or go ahead with the pregnancy.
2. They DO NOT ACCEPT the prenatal diagnosis.

10 - How can all this knowledge be used to our benefit?

We know that there are hereditary disorders that can be transmitted to the offspring under a specific risk probability.

For many of these diseases, it is nowadays possible to determine which foetuses are healthy or affected, and if the unborn child is affected, we can give the couple the option to terminate the pregnancy.

We also know that in order for pregnancy to occur, the ovum and sperm cell that will fertilize must go through the phases ofPRODUCTION and UNION, and once the egg is fertilized by IMPLANTATION (or nesting).

Thus, we can conclude that when faced with a particular disorder, we have different options available:

One option is to establish a prenatal diagnosis, if such prenatal diagnosis is possible and accepted by the couple.

Or if this prenatal diagnos is not possible, or it is possible, but the couple refuses to undergo the tests, we can change or manipulate some aspect of the stages the fertilising cells will go through. This measure will lower the couple's risk to that of the general population, which is always below 1%. This procedure is called primary prevention.

How can we influence these stages? Let's see:

As you can see more and more solutions become available ! What must be clear is that, regardless of the technique used, the pregnancy in all these cases is carried by the woman of the couple. Only in some specific cases such as when the uterus of the woman does not exist or when it is not possible to use it due to the presence of prohibiting medical indications, a surrogate mother's uterus may be used instead, but only in those countries where this procedure is allowed by law.

Gamete donation always reduces the couple's theoretical risk of having a child affected with a particular disease to a general population risk, that is to a low risk, but never to a 0%. 0 and 100 do not exist in this field, so we always speak in terms of probabilities. Assisted reproduction techniques can be employed in disorders for which there is no prenatal diagnosis, or in disorders for which a prenatal diagnosis does exit, but the couple is against terminating a possible pregnancy or do not want to take the high risk of having an affected child if fertilization is performed with their own gametes. If they do not accept this option they can still adopt a child:

• Rainbow kids
• Association for Research in International Adoption

But, a word of cautiousness ...

It is clear that this technology is helping many couples to have children, but we must also be aware of the fact that these techniques are not free of risks. Some studies published in medical journals report that in vitro fertilisation and intracytoplasmic sperm injection(ICSI) imply a higher risk (9%) as compared to that of the general population (4.2%) to have children with congenital defects (diseases, malformations, etc.), or the possibility of multiple pregnancies, prematurity (infants born before their due date) and low birth weight (below 2.500gm). Some of these disorders include:

• Chromosomal alterations, mainly in the sex chromosomes.
• Cardiovascular problems.
• Gastrointestinal malformations.
• Urogenital problems.
• Musculoskeletal disorders and,
• Imprinting defects.

In simple terms, we know that each progenitor at the time of fertilisation contributes with one element of each pair of chromosomes or "books" so that at the time of fertilisation, when the 23 chromosomes from the mother + the 23 chromosomes from the father unite, an egg or embryo is formed containing 46 chromosomes. Ok, then. We have seen that in these books or chromosomes that contain all our recipes and during this period of chromosomal reduction (that is, cells that only contain 23 develop from cells that contain 46 chromosomes each), known as meiosis, some of the recipes are blocked or inactivated. In other words, the recipe will be expressed or not expressed (a process known as imprinting made throught a DNA methylation ) depending on whether this chromosomal reduction has taken place in the ovary or in the testicle.

We now know of some children being born with Angelmans syndrome and Beckwith-Wiedemanns syndrome, as a result of losing this differential expression in the recipes because the egg has been disturbed and is thus "unbalanced".

• Angelmans syndrome: Severe mental retardation, microcephalia (small head), intense seizures, abnormal gait, speech deterioration, trembling, inadequate behaviour patterns of happiness manifested by frequent laughing and excitability.
• Beckwith-Wiedemanns syndrome: Exopthalmos (a protrusion of the eye ball), Macroglosia (increased volume of the tongue), Gigantism (a growth disorder characterised by excessive growth of the body), Omphacele (umbilical hernia), Neonatal hypoglycaemia (decreased levels of blood glucose), Visceromegalia (large internal organs, liver, kidneys, spleen, and suprarenal glands).

7.5% of affected individuals have tumours, with most tumours appearing in the five years of life, including Wilms tumour (malignant tumour of the kidney), hepatoblastoma (liver tumour), neuroblastoma (tumour of the central nervous system, and rhabdomyosarcoma (malignant tumour of muscular tissue).

Why these congenital defects develop is not clear, but it could be due to:

In some cases, we are interfering with the natural selection process that takes place in each pregnancy, facilitating the union of gametes that would have never taken place otherwise.

The union of the gametes or "fertilisation", under normal or physiological conditions, occurs in one of the two Fallopian tubes (anatomical structures of the female's reproductive system or uterine tubes), a very special and well-nourished environment, characterised by a certain temperature, luminescence, oxygenation, and many other unknown parameters that are changed with the employment of these techniques.

What is the situation with ICSI (intracytoplasmic sperm injection)?

Under normal conditions, from all the ejaculated spermatozoa, only one spermatozoon succeeds in penetrating the ovum. From the time the spermatozoon is ejaculated to the time it encounters the ovum that is going to be fertilised, a series of recognition events and cell interactions take place that can lead to a series of changes in the cell and at molecular level of the DNA (deoxyribonucleic acid , or what's the same, changes in the books that contain our recipes) of the gametes or reproductive cells.

When the ICSI technique is used, this period of recognition and penetration does not exist, for the spermatozoon is introduced directly inside the ovum with the help of a probe needle. Thus, it is highly likely that in some cases these changes do no take place, consequently leading to the appearance of some sort of problem.

To make it simple, when someone rings the door bell, from the time we answer to the time we open the door, we have time to quickly fix our hair, tidy up the place, close the window, etc, but, if instead of ringing the bell, the person walks right in, we have no time to get ready, fix our hair, tidy up the place, or close the window.

Given that hereditary diseases and chromosomal alterations cause costly and long term health problems for the family, such as mental retardation or severe congenital alterations and anomalies, impossible to correct in some cases and prone to correction in others, this situation leads us to the next question.

11 - ORIGIN OF HEREDITARY DISORDERS

Our genetic heritage is contained in the genes or recipes inside the chromosomes. Chromosomes are not rigid structures, but totally the contrary; they are changeable and susceptible to mutation. This allows them to interact with the environment; being able to adapt due to their own evolution and reset mechanisms. Thus, any faulty or inappropriate changes affecting their number, structure, content or expression, can give rise to malformations or disorders.

Congenital disorders may be caused by any of the following alterations:

CHROMOSOMAL	when the chromosome is altered in either the number or structure.
MENDELIAN	when the alteration affects the chromosome contents or message, that is their genes or recipes.
MITOCHONDRIAL	our inheritance is not only in the chromosomes or nucleus DNA. A small amount of it is found in the mitochondria, a cellular structure located outside the nucleus, in a region called cytoplasm.
MULTIFACTORIAL	when the disorder or defect is the result of various genes acting together, plus the interaction of these genes with exogenous or environmental factors.
ENVIROMENTAL	produced by an external cause that affects the individual.

12 - PRENATAL DIAGNOSIS TECHNIQUES

If we are to perform this series of tests during the course of the pregnancy, we will logically have to employ techniques that will allow us to gain access into the foetus.

At present, these techniques are divided into invasive and non-invasive techniques of the foetal space.

Disorders can be diagnosed once we know what has caused them.

With a probable diagnosis, we must choose the most appropriate technique from all the techniques available, so our diagnosis can be demonstrated and confirmed and then proceed accordingly.

This is a hard task, as you can imagine !

Advances in the field of human genetics are spectacular as a result of integrating the different molecular biology techniques. New hereditary phenomena are being constantly discovered that must be taken into account and which were unimaginable a few years ago, such as:

• The genomic imprinting: This concept refers to a gamete, be it an ovum or a spermatozoon, which, depending on whether it has undergone a male or a female meiosis, the same recipe or gene in some chromosomes may be activated or deactivated. In other words, in normal conditions, we express the recipe of a progenitor and if this process of activation or deactivation has taken place incorrectly it could lead to problems.
• Nucleotide expansion: In some disorders, the gene or pathological recipe loses its stability, and somewhere along its information chain, it can undergo a mechanism of expansion or repetition. This would be the same as a word that is repeated several times in the same line, as if the gene "stuttered" and its message was not understood. If the "stuttering" became worse, that is, the word began to repeat itself from generation to generation, making it very unstable, we would be able to see that in that particular family the disorder would maniffest more and more in an earlier and more severe form.
• Uniparental dysomy: This concept refers to the fact that the same chromosomal set, or part of it, derives from the same progenitor as a result of some sort of error during meiotic division.

Once the situation is totally clear, we proceed to employ the most appropriate diagnostic techniques in each individual case. Please note that some of these techniques can be applied either during the prenatal or the post-natal period, that is, before or after the child is born.

At present, these techniques include:

13 - GENE THERAPY

We must remember that chromosomes are like cookbooks that contain our recipes. We receive these recipes in equal numbers from our progenitors at the time of fertilisation. These recipes contain all our genetic information. That is they express our traits. They specify the colour of our eyes, the colour of our skin, the colour of our hair, the shape of our nose or our teeth, ears, nails, the shape of our fingers, our toes, and each and every element that make us up. Sometimes the information we inherit is wrong and sometimes this can lead to an array of different pathological conditions that manifest as malformations or diseases. Sometimes, however, the information inherited is correct but for some reason throughout the course of our lives, it goes wrongending in disease such as cancer. Having clarified this point, we should now ask ourselves the question: What is gene therapy? Gene therapy is a laboratory procedure the aim of which is to repair wrong or incorrect recipes. And, how is this done? By correcting the error directly. By replacing the bad recipes for good recipes. By blocking the expression of the bad recipes. And, how can we repair the sick cells? Very easily, by using any of these strategies. Ex vivo strategy: Damaged cells are extracted from a patient and repaired in a laboratory setting; then, once repaired, the cells are reimplanted into the body of the affected individual. In situ strategy: The repairing gene or recipe is introduced directly in the actual defective organ of the affected individual. In vivo strategy: The repairing gene is administered to the patient so that it reaches the exact point to be treated. Why is gene therapy so important? Because it can help cure disease, regardless of whether or not these are hereditary. How far has gene therapy been developed? It is at an investigational stage. What are the problems faced by this technology? Transport method How can the genetic information contained in the recipes be transported until its final destination without being destroyed or damaged in the journey? We have to remember that nature is very wise and tends to destroy any thing that is unknown to it in order to protect us, so the trick is to bypass several cell recognition systems during the journey. To incorporate the recipes in the right place This means that once the recipe has reached its destination, that is the organ or part of the body that concerns us (lung, heart, brain, etc,) it must enter the organ and occupy the place where it should be. Submission Once the information or recipe has reached its destination within the cell, the information must undergo the established internal cell control for it to function properly. In other words, the recipes should only become expressed when due and only under certain stimuli. Any recipe acting on its own could alter the order and cause even further problems. When will this technology be ready for use? When we know how our recipes function and interact amongst themselves under normal conditions and how they act under altered conditions. When we know how to transport and insert them in the right place and how to maintain their stability and functions. Has this technique been tried on humans? Yes, the first experiments started back in 1989 and since then it has been tried in several different disorders. Why is this therapy allowed to be applied only in somatic cells and not in germinal cells? The answer is simple. Lets start by differentiating between somatic and germinal cells. Then, we will examine the exception. Somatic cells are those cell groups that form part of our body, with the exception of the cells involved in reproduction: the ovum and the spermatozoon. Germinal cells are cells that only take part in the reproductive process, namely the ovum in females and the spermatozoon in males. Gene therapy is only allowed to be applied in somatic cells. In doing this, the modification is born with and dies with the individual, preventing from being passed on to future generations. We have no right to modify the genetic heritage of future generations and even less through the use of new and advanced technologies, the effects of which are still not completely known, such as for instance the behavior of these recipes when they are transmitted from generation to generation. 14 - Cloning and stem cells vs. what is clonning? Cloning is a set of laboratory methods and techniques that allows us to reproduce any biological material as many times as we want, specifically cells, DNA, etc. We could say that cloning is the same as photocopying, that is, to make as many identical copies of something as we need. And, in our case, what do we want to clone or photocopy? Very easily, what we want to clone are very special cells called stem cells. What are stem cells? Stem cells are undifferentiated cells without a specific function because they have not yet changed into specific tissue cells. Stem cells are different to other body cells because during division they present the following characteristics: They produce new copies of themselves indefinitely. They produce new cells that under the right stimuli can develop into different tissues of which the human body is composed of. They can colonise and repair sick tissues or organs, replacing sick cells with healthy cells. Why is there so much interest in cloning stem cells? There is so much interest because stem cells, aided by genetic engineering, are to become two fundamental pillars in medicine in the very near future. Because when we achieve the appropriate combination of knowledge from genetics, medicine, physics, chemistry, molecular biology, cell and tissue engineering, biology, biochemistry, etc. from one or very few stem cells, we will be able to design and create cells and specific tissues to repair damaged organs or structures in our body and we will be able to produce therapeutic human proteins. This is known as regenerative medicine. For example in Parkinsons disease, it will be possible to replace damaged cells for new nerve cells and the affected individual will heal. For instance, it will be possible to replace cardiac cells that have been damaged by infarctions or cardiac insufficiency with new and healthy cells and the affected individual will heal. We will be able to repair medullary lesions caused by tumours or accidents. It will be possible for people suffering from diabetes to have insulin-producing cells transplanted into the pancreas and as a result and the affected individual will heal. The same will occur with many other diseases such as cancer, cystic fibrosis and degenerative diseases like Alzheimer's, etc. Where do we stand right now? We know that during their specialization or transformation, the cells in our body undergo specific cellular organ programming, but we don't know what kind it is, nor at what moment it functions! Let's remember that our body is formed by very different structures and organs: heart, liver, brain, lungs, bones, hair, stomach, etc. And that all the cells in our body have developed from one single cell, "the egg or ovum fertilized by a sperm cell", which is why all of them are identical, meaning they poses the same exact instructions, but, depending on the organ they belong to, they will use only some part or other of the information. This is known as cell specialization. In other words, all human cells possess 46 chromosomes engraved with all our kitchen recipes or "building blocks". However, these recipes are not manifested in all cells at the same time. Instead, some of the recipes are used on certain cells, and other recipes are used on other cells. Due to this, the lung is different to the eye because the recipes pertaining to the lung contain information for the formation of cells specialized in respiration, and the recipes in the eye give place to the formation of an organ that allows us to see. In other words, from an undifferentiated cell a complete individual has developed with millions of differentiated cells that make up different body structures. This means that during the development process the cells specialised. So, from the moment of fertilization to the birth of an individual and throughout his/her life, cells undergo a process of differentiation or cell specialization under the commands of specific cellular programming for each species. These cells in their early stages of embryonic development have the ability to produce a complete living being, meaning they are able to give origin to all the tissues of the new individual, including the extra-embryonic membranes that form the placenta. That is why they are called totipotential stemcells. Then, as gestation takes it course, they lose part of that potential because they become more and more specialized, and according to their transformation or differentiation possibilities they receive different names: Pluripotential stem cells are those capable of transforming themselves into all the tissues that compose a living being, except the extra-embryonic membranes (placenta). Multipotential stem cells are those that can be differentiated or that can be transformed into some tissues, but not all. Unipotential stem cells are those that can be transformed into just one type of cell tissue. If you wish to learn more information on the matter these links may be of use to you: International Groups European Council International Bioethics Committee (UNESCO) Ethics Committees Belgian Ethics Committee Danish Ethics Committee EEUU Ethics President Committee German Ethics Committee Italian Ethics Committee Portuguese Ethics Committee Spanish Ethics Committee Datasheets