Some students I was teaching thought that this might be possible: to engineer the insulin-producing cells with a correctly functioning gene, a type of gene therapy.  While this has been a goal for researchers, and they have successfully made insulin-producing cells in the lab from embryonic stem cells, they are not appropriate for transplant because they do not release the insulin in response to glucose levels.  Plus, the immune system might still recognize these cells as foreign and destroy them.

So a new study is looking at transforming cells of the gut that don’t have a specific job yet.  These cells receive signals throughout the life of an individual to become many different types of cells that are used for normal gut function.  So could they engineer these cells to receive the signals to become insulin-producing cells?  Also, would the cells only release the insulin in response to blood glucose levels?

Two Columbia University researchers have started finding possible answers to these questions.  Once they turned off a gene that normally plays a key role in the fate of a cell, insulin-producing cells were generated.  Having cells in the gut that make insulin can be dangerous if they did not release insulin in response to blood glucose levels, but these “new” gut cells have glucose-sensing receptors to allow them to do just that. Another remarkable feature was that the gene could be turned off either early on in development, or later on in adulthood, so it wouldn’t matter how old the patient was.

The next step is to take the research that has been done on mice so far, and see if they can mimic this in humans with the use of a drug or chemical.  This method will also need to prove to be safe and more effective than current methods of treatment, not just to avoid the burden of daily injections.

While most students don’t fully grasp this idea, there are a few examples we can use that can help to explain this.  I have always used examples of giraffes and the development of long necks, or antibiotic resistance in bacteria, but these seem to be a bit out of the realm of many 5^th grade students.  So what better example than ourselves!

During another lesson, I introduced the development of lactase persistence, or having the ability to drink and eat dairy products past infancy.  Digesting the sugar in milk (lactose) is dependent on whether or not the cells of your small intestine are producing the enzyme lactase.  Lactase is responsible for breaking lactose into smaller components that then get absorbed into the bloodstream.  For mammals that get milk from mother early in life, this enzyme is essential.  Would a mutation in the DNA that would allow a cell to continue to make lactase past infancy be beneficial?  It all depends on which population of humans you ask.

If it is a population of humans that began drinking the milk of other animals after the development of agriculture, like those of Northern European descent, it would be selected for.  These populations now show the highest frequency of lactase persistence among all human populations.  If dairy was not a part of your diet after infancy, this mutation wouldn’t be considered beneficial and would not have been selected for, such as in African, Asian and South American populations.

So, when teaching evolution and the changes that we see in species over time, it is nice to be able to give an example that we can see in humans.  Using an example that is a recent development in humans over the last 10,000 years, may help students to understand this concept better, and apply it across any species.

This may help to answer many questions.  How can we have so many different types of cells and they all carry the same genetic information?  How is it possible for one identical twin to develop cancer while the other does not?  Can we use this control of the gene expression to help cells that may have lost their way?

It is amazing to think that just about all of the cells of the human body has the same DNA.  The full genetic profile with all of the instructions on how to make a human is in almost every cell.  When most students come through the DNA Learning Center, many of them think that there is different DNA inside of these cells.  That red blood cells have different DNA than bone cells and nerve cells.  One way this is done is through the interaction of small methyl groups (-CH₃) that get added to the DNA molecule, which can help to silence a gene that is not needed in some type of cell or at some point of development.  This is a epigenetic “tag” because there is no change to the sequence of DNA, it is just whether or not there is access to the DNA.  The methyl groups that get added make the cell unable to activate that gene.

This addition of methyl groups, called methylation, also can change throughout the course of our life.  So as we get older the interaction of these groups with our DNA can change.  So even with identical twins, who are born with the same DNA, their epigenetic “tags” can vary and occur independent of one another.  And even more, certain lifestyle choices and experiences throughout the life of a person can change the epigenetic profile of an individual.  And then this gets passed on to our children.  So even what a mother eats while pregnant can affect the tags that get passed to their child.  This ultimately will affect the expression of genes in the child.

And now we are using this information to help treat disease, such as cancer.  So if a gene is turned on that shouldn’t be, could we add methyl groups to that section of the DNA to turn it off?  This has started being used as a new therapy for the treatment for certain cancers.

This has recently been reported for patients with Hemophilia B.  Hemophilia B, also known as Christmas disease, is due to a deficiency of the clotting factor IX (FIX).  The first reported case of Hemophilia B due to a decrease in FIX was in 1952, and was called “Christmas Disease” after the first patient diagnosed was named Stephen Christmas.  Without this clotting factor, the blood does not form clots and results in severe bleeding episodes, especially in the joints and muscles.

Bettert reatment for this disorder began back in the 1960’s where they would inject FIX concentrates into the blood of patients with hemophilia B.  This increased the average age of death of 24 to a median lifespan of 63 years of age.  So with the success of the protein therapy, why try to fix the genes?  With each treatment costing $150,000 to $300,000, a patient needing clotting factors for hemophilia could incur a lifetime cost of $20 million.

So there needs to be a way that a patient can have a more effective treatment option that will cost less.  This new treatment option offers some hope.  Using a new virus for the administration of the gene, patients have seen an increased production of FIX protein for longer periods of time, and were able to stop or decrease the amount of concentrate injections they would need.  With one injection of the virus only costing about $30,000, dramatic cost savings have already been seen.  While this does offer new hope for the treatment of clotting disorders, follow-up with a larger number of patients and for longer periods of time will be needed to fully weigh the benefits and risks of this technique.  Once this has been done, hopefully we will see gene therapy used more in practice and maybe even for more than just clotting disorders.

Ponder, Katherine P.  Merry Christmas for Patients with Hemophilia B. The New England Journal of Medicine 10.1056; December 10, 2011.  Nathwani A.C., Tuddenham E.G.D., Rangarajan S., et al.

Pharmacogenomics is the ability to study the differences in the DNA of a person to see how they are going to respond to a certain drug.  The DNA contains instructions on how to make proteins.  These proteins then go on to carry out life’s basic functions.  A disorder that may result because of changes in the production of these proteins resulting from mutations in the DNA has been a major area of research for some time.  But now we have to look into how some of these proteins are interacting with the medications that we are taking to treat the disorder.  It is a major shift in the way many people think about DNA and how it affects our health.

Pharmacogenomics is a relatively new area of science that is now looking into these differences in the DNA that cause a person to respond to a drug in a certain way, if at all.  There are a whole group of proteins that are in charge of metabolizing, or breaking down, the medications we take into their active forms.  The instructions in the DNA that make these proteins are different from person to person, so it is these variations that will either make a person make more of the proteins, less, or none at all.  These different levels then cause a person to respond to a drug in a certain way.

For example, if a patient is taking the blood thinner Warfarin to treat blood clots, and they are making too much of the protein that metabolizes this drug, they will break it down too fast and this could possibly thin the blood too much.  If they are a patient that either makes less or none of this protein, the clots will still form, which could still cause serious problems for that patient.  So if we could gather all of the variations in the DNA that lead to certain reactions to drugs, we could use this information to better treat future patients.

A DNA test could be done before the medication is prescribed.  If a patient is showing a similar variation in the DNA to a previous patient that was not able to metabolize a drug, the doctor may want to think twice about prescribing that drug to their patient.  Since we now know that one size does NOT fit all, studying the variations in the DNA to see how their patients will respond to certain drugs will help in prescribing the correct drug and at the right dose.

Featured image from: http://www.genomicslawreport.com/index.php/tag/personalized-medicine/

So we got into a discussion about model organisms, those that are used as a good system to be able to compare back to human beings, and in what ways they are being used.  That we have to even figure out whether or not something has a genetic basis.  Or maybe a good treatment option for a genetic disease.  If an organism shows similar symptoms as a human disease, this will give us a better understanding on when and how the disease progresses, causes and possible treatment options.

This allowed one student to immediately jump into what causes Autism.  We talked about the controversy that surrounds the disorder, and ways scientists are trying to figure out the genetic basis of the disease, and how much the environment can play a role.  In our current discussion, it was a perfect way for me to bring an actual example of how other organisms are being used to find out more about a specific disorder.

It was shown by a group of researchers at Cold Spring Harbor Laboratory that a deletion of a group of genes on chromosome number 16 causes autism-like symptoms.  They used mouse models with the same genetic alteration to show that when fewer copies of these genes are inherited, it leads to features resembling those that are used to diagnose autism.  Changes were seen in the structure of the mouse brain (see image below) and in their overall behavior of the mice.  Using the mouse model, they are able to mimic the disease to better understand what causes it, better diagnose it, and a new possible target for intervention and treatment.

Image from http://www.cshl.edu/Article-Mills/cshl-team-finds-evidence-for-the-genetic-basis-of-autism

Image from Nature Reviews Genetics 3, 941-955 (December 2002)

While this technology offers the hope to increase the success of IVF, it does raise some concerns about choosing a child in order to meet the needs and desires of parents. While most cases seem to have parents that are trying to increase their chances of having a viable pregnancy, some have raised some major ethical dilemmas. For example, two parents with achondroplasia, a disorder of bone growth that causes the most common form of dwarfism , is caused by having only one mutated copy of a gene. These parents might want to avoid an embryo that receives a mutated copy from both parents, which would be lethal. Instead, would they possibly choose an embryo that only has one affected copy, which would result in a child with achondroplasia, instead of an unaffected embryo? Would an unaffected child suffer more in an achondroplastic family than an affected child in such an environment?

This technique can be applied in a variety of ways, but I wonder if there are more ethical concerns than anything else. With any new technology, just because we can, should we? Are parents going to do this just to have a child free of genetic disease? Or is the future of “designer babies” closer than we think?

Among other uses, we finally get to the idea that these bacterial cells can be used as factories to make any protein you want, even human proteins.  It all depends on what recipe, or gene, you give them.  If you give them the recipe to make human insulin, they will. And then this insulin can be used to treat diabetes.

They can see the benefits when discussing bacteria, but once I show them a picture of a multicellular organism that has been engineered with this protein, such as a pig or monkey, the debate begins to heat up. That while the protein is harmless to the organism, they don’t feel it is necessary to make pigs glow.  While this may be true, many researchers would beg to differ.

Researchers use this protein in many studies that were once invisible. If they are studying the production of a protein, maybe when the protein gets produced during development, or in what type of cell it gets made, they can visualize this process with the help of the green fluorescent protein. This will hopefully give insight to many disorders that result from the faulty production of a protein.  We need to see how and when the process works normally to gain more information about when it does not work. Then we can hopefully use this information to fix it.

Many debates arise during discussions involving genetic research because of the potential benefits that could arise from the study, while disturbing a few people or groups along the way. These are good discussions to have with students though, as they may be faced with decisions in the future about potential career choices or matters that will affect them on a more personal level.

It has been amazing to see what we have learned since then, but even more interesting to think of where this could go in the future.  Hopefully soon we will be able to apply this on a more individual basis, with people being able to identify potential risk factors for certain diseases at their primary care physician.  This then will lead to new developments for drug therapy, having a drug that will be able to target a certain pathway that is specific to that patient.  I can only wonder and look forward to what will come next.

Undergraduate students are now being challenged during the International Genetically Engineered Machine (iGEM) competition at MIT to take this very common tool and apply it to a new field called Synthetic Biology. They can order different pieces of DNA to string together and function inside of living cells, almost like LEGO pieces being built up together to form a castle. There is actually a catalog of different types of gene segments, such as promoters, terminators and primers. Organizers of the competition are striving to go beyond simple gene transfer, by making new synthetic pieces of DNA that can be attached together to form a new set of instructions that can be taken up by a living cell, such as bacteria. Projects ranged from banana and wintergreen smelling bacteria, to an arsenic biosensor, to Bactoblood, and buoyant bacteria.