Genetic Level Research
From Erin, Genetic Counselor
In every cell of our bodies, we have 46 chromosomes, having inherited 23 from each parent. Chromosomes are packages of genes, which are your body's "blueprints" or sets of instructions for how you grow, develop, function, learn, what you look like, etc. DNA is one of the chemicals that makes up the genes. The other chemical is RNA which will be discussed later. Imagine that each cell of your body has a set of instruction books for how to function. The actual books are the chromosomes, the instructions inside are the genes, and the letters which make up the words is the DNA. Our DNA is 6 billion letters long, in each cell of the body!
As a cell grows and divides into two daughter cells (this process is called mitosis), it has to replicate it's DNA in order to have two copies for each daughter cell. Remember that DNA is 6 billion letters....so imagine you had to take a 6 billion page book to the photocopier, you may make a mistake somewhere along the line. Well, our cells make mistakes too...a "spelling" mistake that occurs in the DNA of our genes is called a mutation. Mutations in a gene can affect the function of the gene. We have genes that regulate cell growth and proliferation. We have genes for apoptosis. Apoptosis is a fancy word for "programmed cell death." Our cells are "programmed" to die after a period of time; this helps to regulate cell growth. If aplastic anemia is thought to be caused by more cells undergoing programmed cell death, then there is probably a trigger that is inducing this death earlier. This may be due to a faulty gene instruction.
And in my case, there is a strong possibility that I am “predisposed” to having a problem with the gene responsible for creating healthy blood cells? (My father had Hodgkin’s)
So, there are 46 chromosomes - 23 pairs (is this the double helix?) in every cell in our body (except red blood cells – what is this about?) and they look like this:http://author.senescence.info/thoughts/karyotype.gif
The male has an x and y. The male has 2 x’s. The chromosome are made up of Genes
The very first cell (Mother’s fertilized egg) begins to divide (mitosis), becomes an embryo and from there on, each cell is told what it is supposed to become and do. You – become a brain cell. You – become a blood cell. You – become part of the lung, and so on. All cells are derived from stem cells which are the primitive types of cells from which a given organ or tissue arise.
Stem cells are unspecialized cells that have two important characteristics that distinguish them from other cells in the body. First, they can replenish their numbers for long periods through cell division. Second, after receiving certain chemical signals, they can differentiate, or transform into specialized cells with specific functions, such as a heart cell or nerve cell.
Stem cells can be classified by the extent to which they can differentiate into different cell types:
· Totipotent stem cells can differentiate into any cell type in the body plus the placenta, which nourishes the embryo. A fertilized egg is a type of totipotent stem cell. Cells produced in the first few divisions of the fertilized egg are also totipotent.
· Pluripotent stem cells are descendants of the totipotent stem cells of the embryo. These cells, which develop about four days after fertilization, can differentiate into any cell type, except for totipotent stem cells and the cells of the placenta.
· Multipotent stem cells are descendents of pluripotent stem cells and antecedents of specialized cells in particular tissues. For example, hematopoietic stem cells, which are found primarily in the bone marrow, give rise to all of the cells found in the blood, including red blood cells, white blood cells, and platelets. Another example is neural stem cells, which can differentiate into nerve cells and neural support cells called glia.
· Progenitor cells (or unipotent stem cells) can produce only one cell type. For example, erythroid progenitor cells differentiate into only red blood cells.
At the end of the long chain of cell divisions are "terminally differentiated" cells, such as a liver cell or lung cell, which are permanently committed to specific functions. These cells stay committed to their functions for the life of the organism or until a tumor develops. In the case of a tumor, the cells dedifferentiate, or return to a less mature state.
Haemopoietic stem cell
Cell that gives rise to distinct daughter cells, one a replica of the stem cell, one a cell that will further proliferate and differentiate into a mature blood cell.
Megakaryocytes - Giant polyploid cell of bone marrow that gives rise to 3-4,000 platelets.
Karyocyte – Any cell with a nucleus
Chromosomes – Chromosomes are the instructions resident in every cell
We have a set of instruction books in our cells 46 of them – 23 pairs
23 different instruction books but in pairs – 2 strands
One pair or strand is the “sense” and the other pair or strand is the “antisense”
Every single cell has this set of instructions
Each chromosome has short arms and long arms and kinks (the separator between the two arms and this kink is technically called the centromere
The two ends of the chromosomes are called the telomeres
Over time with multiple cell divisions (mitosis) these telomeres (tell-o-mears) become frayed (aging) In the case of some MDS and AA patients they are also prematurely shortened. There is current research at the NIH trying to understand why this occurs and what if anything can be done about it.
Pluripotent stem cells can give rise to all lineages, committed stem cells (derived from the pluripotent stem cell) only to some.
RBC’s do not have a nucleus and therefore do not have chromosomes, genes or DNA?
Each chromosome or book of instructions has a predetermined responsibility, e.g. Book number 1 or chromosome number 1 may be responsible creating brain cells, liver cells, skin cells and multiple other cells (100’s – 1000’s for each chromosome); book number 2 or chromosome number 2 may be responsible for creating bone cells, and hair and kidneys, etc. The stem cells are the karyocytes that
Each book may have 100’s of 1000’s of genes and each gene has a specific responsibility
Others have specific responsibilities and the human genome project was about trying to understand what each gene does – this was accomplished by “sequencing the genes because we can’t really see the genes yet.
Some of the genes are termed “junk” which probably means we don’t know what they do
Others have been sequenced so we know what they do.
The DNA are the words that make up the instructions
DNA Building block of the gene – the letters and the words
Another way to think of it:
Rope is the chromosome
Fiber is the Genes
Chemicals that make up the fiber are the DNA
DNA is the basic building block
DNA’s together make up the Gene
Bunch of genes and junk DNA make up the chromosome
Human Genome Project
Sequence of DNA _ Read all the letters
Much of it is junk
Now we’re trying to better understand what makes up the Genes
Humans have 25,000 genes (Same as a worm!)
How many genes do we have – Completed in 2001
Figured out the order of the letters
What do all the genes do?
Know what some do, others are still being researched.
Chromosomes are the packaged set of instructions
Some of the DNA is wound around proteins
A chromosome is made up of genes and proteins
Proteins are what your body is made up of
The instructions are how to make a protein
We have proteins that make skin color
We have proteins that make blood vessels
Proteins are part of a blood cell
Proteins do different things
Enzyme is a particular type of protein that helps chemical reactions occur
In biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific target molecules (substrates); the process is termed "phosphorylation". An enzyme that removes phosphate groups from targets is known as a phosphatase.
Generally, the purpose of phosphorylation is to "activate" or "energize" a molecule, increasing its energy so it is able to participate in a subsequent reaction with a negative free energy change. All kinases require a divalent metal ion such as Mg2+ or Mn2+ to be present, which stabilizes the high-energy bonds of the donor molecule and allows phosphorylation to occur.
The largest group of kinases is Protein kinases, which act on and modify the activity of specific proteins. These are used extensively to transmit signals and control complex processes in cells. Various other kinases act on small molecules (lipids, carbohydrates, aminio acids, nucleotides and more), either for signaling or to prime them for biochemical reactions in metabolism. These are named after their substrates and include:
Some proteins are in the membrane of the cell
Amino acids are the building block of the protein
They are the chemicals that form together to make a protein
Amino acid levels can change dramatically
We do amino acids on children and they change dramatically and taken by themselves are not very meaningful.
Metabolic physician should read those reports
PATTERNS of amino acids and that may reveal something
CD34 is a protein made up of amino acids
There are 20 amino acids in our body each protein is made up of various combinations of proteins.
Protein 1 may consist of amino acids 1, 3 ,5 , 7
Protein 2 could be 3, 3, 4, 3, 6
An antigen is simply another type of protein
There are thousands of classes of proteins – antigens, enzymes, antibodies
An antigen is a protein that sits on the surface of a cell and acts like a name tag for a cell
CD34 is a tag saying something is wrong with me – kill me
A Genotype is the actual instruction that is provide by DNA –and the phenotype is the physical characteristic or trait. So the DNA says give me blue eyes that’s the instruction The resulting blue eyes is the phenotype.
Phenotype The physical trait that you get as a result of the genotype
Some people with MDS have different genotypes (-5, -7) but have the same phenotype which is MDS.
Telomere – the tip of the chromosome – Prevents the chromosome from unraveling
The kink is the centromere ( in the middle)
Telomere is the aging process
Everytime a cell divides the telomere gets frayed
Telomorase is a little enzyme (protein) that rebuilds the telomere
If you have low amounts of telomorase you may end up with shortened telomeres
Current research at DNA is discovering that many people with AA have shortened telemeres.
Have known about telmorase for a long time but did not know how they related to various diseases
Scientists experiment with manipulating mice DNA and get predictable results – then go to clinical studies.
MDS – Treatment
Methylation – compounds (chemicals) in the body that surround DNA – bind to the gene and block them from working – Black piece of paper in front
People who have MDS, have too many Methyl groups – they are preventing the genes from doing what they are supposed to.
Is there a less invasive or more natural way to accomplish this methylation process than using invasive toxic drugs.
Herbal therapy? Chinese Medicines?
RNA is the intermediate between DNA and the protein
DNA makes RNA and RNA makes protein
Anti-sense therapy (From Leukemia Book)
Two strings – RNA Is one string
2 stranded DNA
1 strand codes for one
Sense and Antisense
When DNA makes RNA the 2 strands separate
Strand A makes RNA type 1
The sense strand is the strand that actually makes the protein
With antisense therapy – If someone is making a faulty protein, the antinsense strand can bind to the sense strand and prevent it from making the protein altogether.
Gene Therapy (From Leukemia Book)
Has not been as successful as had been hoped
Trying to correct the spelling errors
Whoever perfects the art of gene therapy will be the owner of the universe
Minor success on kids with metabolic diseases – missing certain chemical
Not sure about progress with Leukemia
Antigens block the name tag that says I am allergic to grass
The double helix of DNA has these features: View articel and picture here:http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/D/DoubleHelix.html
It contains two polynucleotide strands wound around each other.
The backbone of each consists of alternating deoxyribose and phosphate groups.
The phosphate group bonded to the 5' carbon atom of one deoxyribose is covalently bonded to the 3' carbon of the next.
The two strands are "antiparallel"; that is, one strand runs 5′ to 3′ while the other runs 3′ to 5′.
The DNA strands are assembled in the 5′ to 3′ direction and, by convention, we "read" them the same way.
The purine or pyrimidine attached to each deoxyribose projects in toward the axis of the helix.
Each base forms hydrogen bonds with the one directly opposite it, forming base pairs (also called nucleotide pairs).
Discussion of base pairing in DNA
3.4 Å separate the planes in which adjacent base pairs are located.
The double helix makes a complete turn in just over 10 nucleotide pairs, so each turn takes a little more (35.7 Å to be exact) than the 34 Å shown in the diagram.
There is an average of 25 hydrogen bonds within each complete turn of the double helix providing a stability of binding about as strong as what a covalent bond would provide.
The diameter of the helix is 20 Å.
The helix can be virtually any length; when fully stretched, some DNA molecules are as much as 5 cm (2 inches!) long.
The path taken by the two backbones forms a major (wider) groove (from "34 A" to the top of the arrow) and a minor (narrower) groove (the one below).
Link to John Kyrk's animations showing the structure of DNA.
Please let me know by e-mail if you find a broken link in my pages.)