Gene Therapy for "Bubble Boy" Disease

"Stem Cell Researchers Use Gene Therapy to Restore Immune Systems in 'Bubble Boy' Disease"

(ScienceDaily)

(credit: iStockphoto)
According to a recent ScienceDaily article, UCLA stem cell researchers have just completed an 11-year study which showed that gene therapy can be used to treat ADA-deficient severe combined immunodeficiency (SCID) or "Bubble Boy" disease. This disease is usually diagnosed when a child is six months old and can be fatal within one or two years. Children with SCID are very vulnerable to infectious diseases. This study looked at a combined gene therapy and chemotherapy treatment regimen, which restored the immune function in three out of the six children who received the treatment. The size of the study was very small; only ten children were involved. The study tested two different viral vectors to deliver healthy ADA genes into the bone marrow cells of the patients. This would then allow the enzyme to be produced in the body and, as the article says, "make up for the cells that don't have the gene." The patients who received the additional chemotherapy treatment had more success than the patients who did not and who continued with the enzyme therapy in addition to the gene therapy.

Before gene therapy became a possibility, the only treatment for ADA-deficient SCID is a very expensive and life-long regime of twice-weekly enzyme injections or, rarely, bone marrow transplants from matched siblings. So far, gene therapy treatment has been given to 40 children in the world.

Dr. Donald Kohn, a professor of pediatrics, microbiology, immunology, and molecular genetics in Life Sciences, who contributed to this study, says "We were very happy that in the human trials we were able to see a benefit in the patients after we modified the protocol. Doctors treating ADA-deficient SCID have had too few options for too long, and we hope this will provide them with an efficient and effective treatment for this devastating disease."

This study indicates that gene therapy is getting closer to saving the lives children suffering from ADA-deficient SCID.

Article: http://www.sciencedaily.com/releases/2012/09/120911111626.htm
Journal Article: http://bloodjournal.hematologylibrary.org/content/early/2012/09/10/blood-2012-02-400937

"Healing Broken Batteries"

"Regulator to consult public plans for new fertility treatments" (Ian Sample, The Guardian)

In the United Kingdom, 1 in every two hundred people are affected by diseases caused by glitches in the genetic material in the mitochondria.  These diseases most often affect the brain, heart and muscle function.  

Mitochondria, often thought of as the batteries for they provide energy, are composed of 37 genes.  The genes contribute to 0.2% of the genetic makeup.  Mitochondria are only passed down from mothers. 

The Welcome Trust Centre for Human Genetics at the University of Oxford would like to reduce, and ultimately end, the number of diseases caused by glitches in the genetic material in the mitochondria.  

To do so, the Centre has been developing two processes of genetic modification; maternal spindle transfer and pronuclear transfer.  Of the two processes, maternal spindle transfer is the more developed of the two.


During maternal spindle transfer, the nucleus of the mother's egg is removed and inserted into a healthy female donor's egg.  Thus, the egg has the mother's chromosome (held inside the nucleus) and the donor's healthy mitochondria.  This new egg is then fertilized by the father's sperm, and the resulting offspring contains the DNA of both parents and the mitochondria of the healthy female donor.  

Pronuclear transfer is essentially the same process, but is performed on an early-stage embryo as opposed to an egg.  

This form of genetic modification is not yet legal or public.  It is rather controversial, for it is yet another step using genetic modification.  Jeremy Hunt, the Health Secretary, is to be informed of public opinion and of the process by the Human Fertilization and Embryology Authority.  A parliamentary debate will be held to consult Jeremy Hunt and HFEA to determine the legality.  

There is great controversy surrounding the work of the Welcome Trust Centre.  How far will genetic modification go?  Will we eventually be creating "ideal" offspring by using different parts of cells?  Should the donor be anonymous?  These questions are all of great concern in determining whether this form of genetic modification will be approved.  

Interacting Mutations Promote Diversity

Genetic diversity is maintained through the balance of mutation, genetic drift, and selection. This evolutionary biology study from Mac Planck Institute explores the competition between mutations within a population and how it promotes diversity. To do so, the study analyzes the fitness value of a gene and uses evolutionary game theory principles to come to the conclusion that the fitness of a mutation depends on its frequency. Fitness is a measure of success for a given gene, i.e. the number of offspring produced in the next generation that survive and reproduce. Basic evolutionary theory states that a single allele must compete with other alleles in a given gene pool and either become established or die out. The emergence of a mutation within a gene pool, in particular, creates diversity because it increases the number of phenotype possibilities for offspring (see above figure, a). This same reasoning can also be applied to competition between different mutations. Therefore, evolutionary competition between mutations has produced "stable polymorphisms." This study is significant in that it helps us develop a greater understanding of population genetics and the inheritance of genes.

News Article: http://phys.org/news/2012-06-interacting-mutations-diversity.html

Primary Research Article: http://www.nature.com/ncomms/journal/v3/n6/full/ncomms1930.html

Other Sources: http://www.uic.edu/classes/bms/bms655/lesson13.html

Reversible Epigenetic Changes in Honey Bees

 

In a study by researchers from Johns Hopkins University and Arizona State University, the first evidence of reversible epigenetic changes associated with behavior in any organism is observed in honey bees.

Bees are born into specific castes based on the kind of treatment they received as larvae. While the distinctions between say, a queen bee and a worker bee are fixed for life, the subcastes of worker bee are more flexible. For example, a nurse bee (a type of worker bee who stays in the hive to take care of the queen) usually becomes a forager bee (a worker bee who gathers pollen) later in life. The differences between these two types of worker bee can be seen be seen in their respective patterns of methylation.

In the study, "Reversible switching between epigenetic states in honeybee behavioral subcastes", researchers removed all of the nurse bees from a hive while the forager bees were out collecting honey. When the forager bees returned, 50% of them became nurse bees. However, this change was not only limited to behavior - the methylation patterns of DNA in their brain cells had reversed to those seen in nurse bees.

As Andrew Feinberg of Johns Hopkins explains, "What is exciting is that the genes that change back are the same genes that changed in the other direction initially — and the same ones that would regulate epigenetic behaviour"

However, the implications go far beyond just bees. In the following excerpt from a recent Nature article Andrew Feinberg and fellow researcher Gro Andam explain the relevance for human biology:

A greater understanding of how epigenetics affects behaviour may lead to insights into human biology, Feinberg says, noting that epigenetic effects on human behaviour might express themselves in addiction, learning and memory. If the link between behaviour and methylation patterns “is true in a bee, it is likely to also be true in us”, he says.

This does not mean that artificially changing the methylation pattern of DNA would result in a desired behaviour, but “it would be great if that was feasible”, says Amdam. “Reversing possible ‘bad’ epigenetic marks in human physical and psychological diseases is already a big research interest in biomedicine. Perhaps bees can be used to figure out how it could be done.”

Sources:
http://dx.doi.org/10.1038/nn.3218
http://www.nature.com/news/job-swapping-makes-its-mark-on-honeybee-dna-1.11418#/b1
http://articles.latimes.com/2012/sep/17/science/lat-sci-sn-worker-bees-switch-jobs-via-their-epigenomes-20120917
http://www.guardian.co.uk/environment/2012/sep/16/bee-study-behaviour