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Transforming Blood Type
Transcript of Transforming Blood Type
Identifying an Efficient Enzyme
Evolution of More Efficient Enzyme
Most people, on average, will only need blood one time in their lives, to help fight a disease, restore blood lost during surgery or because of traumatic injury. But some patients, like sickle cell patients, may need blood many times during their lives. If the blood they receive is not a very close match, they will begin to reject transfusions. The evolution of stronger and more effective enzymes increase the promise of eventually chemically engineering strong matches for such patients.
Transforming A- and B-
Blood type transformation has been proposed by enzymatic removal of the terminal sugars of type A and B antigens. Through chemical engineering, an enzyme can be evolved to sever the terminal sugars of antigens, thus producing blood cells without the A or B antigen that could be classified as type O and be accepted by any patient, regardless of blood type.
Proposed enzymes only have the ability to snip the A and B antigens out of the hundreds of possible antigens on blood
Only A- and B- could be transformed into O- using current enzymes
Simon, Ravyn, Colman
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About 1 in 10 people entering a hospital need blood.
Approximately 32,000 pints of blood are used every day in US alone .
Thousands of lives are saved everyday by donated blood, but there are some limitations on donations.
Medical limitations on cross type blood transfusion restrict patients from receiving the donated blood they need.
For years scientists have been working on a method to transform blood types to O, the universal donor blood type. With the evolution of the enzyme, Sp3GH98, we are closer than ever to implementing blood type transformation.
GAVE syndrome patients are susceptible to gastrointestinal bleeding and lesions in the stomach
Many patients become dependent on blood transfusions
GAVE syndrome is just one of many various diseases that affect a patient's ability to produce and maintain sufficient quantities of certain blood components
The progress of this technology also shows promise in helping not just the engineering blood type matches, but also possibly in the engineering of organ donor matches.
For just kidney transplantation there are three tests to evaluate donors:
At the end of a year, 7% of kidney transplants are no longer working
Within three years, 17 % have failed
By 10 years, 46% have failed
What is an antigen
As stated by Linda J. Vorvick, MD, Medical Director, "An antigen is any substance that causes your immune system to produce antibodies against it."
In the case of blood antigens are attached to the outside of the blood cells and are naturally created by enzymes encoded by different alleles of the same gene. O blood type has no antigens because the enzyme code for a protein that is not functional.
Classification of blood all depends on the antigens
In total there are over 200 blood groups
33 major blood group systems
These include ABO and Rh
Blood is classified by through blood groups, collections and series
The different antigens are controlled by a single gene and are genetically distinct
Observed antigens are distinct but do not fall into blood groups until proven to be genetically different
If the antigen does not fit into either category it is placed in one of two series; rare antigens (<1%) are in the 700 series, the other commons ones are in the 901 series
The name of blood groups also tells us the antibodies the blood contains
The antigens on blood are associated with particular antibodies (A with A, B with B). The immune system sees the antigens as a threat and will attack it thus destroying the blood cell. However if the body has no antibodies to match the antigens the immune system can not react and nothing will happen.
Structural Basis of the ABO Blood Group Antigens
The immunodominant A and B trisaccharide epitopes are formed from the common H disaccharide substrate by alpha1,3-N-acetylgalactosaminyltransferase (GTA), defined by the blood group A gene, and alpha-galactosyltransferase (GTB), defined by the blood group B gene
First Enzyme Proposal
Nobel prizewinner Joseph L. Goldstein was the first to suggest the use of exoglycosdases for enzymatic conversion.
exoglycosdases would selectively remove αGalNAc and αGal from the A and B immunodominant trisaccharide antigens
α-galactosidase (derived from green coffee beans) would convert B antigens to the common H antigen
There is no conclusive evidence that about the origins of the antigens. However theories exist. For example the Smithsonian states that "People who are type A, for instance, seem more susceptible to smallpox, while people who are type B appear more affected by some E. coli infections". Meaning the different types could be due to evolutionary tracks. The different types could be a result of the immune response to the different infections
The study proved the enzymatic conversion of RBCs to be feasible, but required disproportionately large quantities of enzyme (1-2 g enzyme per unit of RBCs).
Bacterial Glycosidases Screening
In 2007, a study scanned 2,500 fungal and bacterial isolates for enzymes capable of severing A and B oligosaccharide substrates.
Most bacteria express high levels of α-galactosidases with acidic pH optima (a previous limitation to Goldstein's study)
Five isolates were found to be partially active with the B substrates, while only two were found to be active with both A substrates.
How they work and their origin
TLC assays preformed at a neutral pH
Flow Cytometry analysis
Immune system response
When blood with antigens is transfused with blood with A antibodies the immune system is alerted and takes action. The antibodies will attach to the bloods antigens which "hurts" the cell (smothers and disrupts the cells equilibrium). This is called agglutination. In a addition a cell covered in antibodies is a red flag for T-cells.
The search revealed activity similar to that of an Elizabethkingia meningosepticum
α-N-acetylgalactosaminidase. Its protein sequence was then used to identify a family of enzymes exclusively found in prokaryotes, GH109 (as classified by the carbohydrate-active enzyme database).
found to be only partially successful at cleaving antigen determining structures
structure determined by X-ray crystallography
Crystal Structure of the E. meningosepticum α-N-acetylgalactosaminidase
Test of Efficiency
Evaluated by sensitive FACS analysis using anti-A and anti-B reagants
Clear detection of low amounts of both A antigens and B antigens
Additional analysis with anti-H antibody demonstrated appropriate appearance of H antigen
On April 14th, a University of British Columbia research team at the Centre for Blood Research published the results of their work on the evolution of a more efficient enzyme for the transformation of RBCs. The team produced a significantly more effective mutant enzyme through several rounds of evolution. Their variants proved to be more effective at severing more resistant linkages than the wild-type enzyme.
Developed by directed evolution
Proved to be 170 times more effective after just five generations
Specifically more proficient at removing A- subtypes than parent enzymes
Method of protein engineering
Mimics natural evolution, but on a molecular level
Inserts mutations into the gene that codes for the enzyme
Selected mutants that proved more effective at cutting antigens
Blood type related complications in blood transfusion all has to do with agglutination. There are different degrees to which agglutination can occur. According to the CDC there are two different ways "Delayed hemolytic transfusion reaction (DHTR)" and "acute hemolytic transfusion reaction (AHTR)".
The recipient develops antibodies to red blood cell antigen(s) between 24 hours and 28 days after a transfusion. Mild to no symptoms
the rapid destruction of red blood cells that occurs during, immediately after, or within 24 hours of a transfusion when a patient is given an incompatible blood type. Symptoms include fever, pain and kidney failure
What are the complications
While O- is the most useful for blood donation, it is one of the
more rare blood types, and as supply cannot meet demand, blood centers often run short.
The possibility of generating more blood of the universal donor type is very promising, especially in emergency situations where
patients may be unresponsive and unidentified.
The attack and destruction of blood cells is called agglutination. Agglutination creates the symptoms and is the cause of the hazards of cross contaminating blood.
Gatric Antral Vascular Ectasia or GAVE Syndrome
Agglutination creates a
clot where it occurs which
can result in major consequence. According to Laura Dean, MD, "clotting system can cause shock, kidney failure, circulatory collapse, and death.
The official guidelines for emergency transfusions, according to the US National Library of Medicine, a part of the National Institutes of Health state:
If blood must be issued in an emergency and there is no time for cross-matching, group-specific blood can be issued. In extreme emergencies, when there is no time to obtain and test a sample, group ‘O’ Rh-negative packed red cells can be released.
HLA, the test representative of "tissue typing", stands for human leukocyte antigen. There are 6 antigens proven to be most important in organ transplantation. Ideal six-antigen matches are very rare except between identical twins and some siblings.
Karl Landstiener, an Austrian scientist descovered blood groups in 1901.
What was going on before 1901........?
The promise of engineering better blood matches and organ matches creates a whole new opportunity to possibly eliminate diseases such as Graft-versus-host.
But in the end what does it matter, all of its the same to him