Category: Disease

Ok, let’s start off with the basics:

Parkinson’s disease is a neurological disorder where nerve cells that make dopamine are destroyed. Dopamine is an important neurotransmitter and without it, nerve cells are unable to properly send messages to other parts of the body. Eventually, the destruction of dopamine-producing cells leads to a loss of muscle function that gets worse over time. The typical symptoms of Parkinson’s are shaking and difficulty with walking, movement, and muscle coordination.  Unfortunately, not a lot is known about why these nerve cells waste away in the first place.

In gene therapy, a gene variant is used to alter the function of a cell or an organ. The way that genes are transferred into cells is pretty interesting: the gene is put into an inert virus, which is then injected into the target cell to deliver the gene.

Now, a new large-scale study suggests that a type of gene therapy (called NLX-P101) may be able to improve Parkinson’s symptoms. The gene that was targeted is called GAD (stands for glutamic acid decarboxylase). This gene produces a chemical called GABA (stands for Gamma-aminobutyric acid), which is a neurotransmitter than inhibits the excessive firing of neurons seen among Parkinson’s patients. From an interview in ScienceDaily with one of the researchers, Dr. Matthew During:

“In Parkinson’s disease, not only do patients lose many dopamine-producing brain cells, but they also develop substantial reductions in the activity and amount of GABA in their brains. This causes a dysfunction in brain circuitry responsible for coordinating movement,” explains Dr. During.

So, what they’ve done is inject a fully-functioning GAD gene into the brains of Parkinson’s patients. Those that were injected showed substantial improvement compared to individuals that did not receive the treatment.  


LeWitt, P.A. et al. (2011). AAV2-GAD gene therapy for advanced Parkinson’s disease: a double-blind, sham-surgery controlled, randomised trial. Lancet Neurology in press.


Continuing with our exploration of the vignettes in Science’s 10th anniversary celebration of the human genome project, we run across an interview with Eric Green, who just recently became the director of the National Human Genome Research Institute. As with all of these pieces, there’s lots of interesting stuff here. A couple of highlights from the interview:

Q: Why did you set 2020 for when genomics will begin affecting health care? Why is it going to take so long?

Eric Green: When we talk to people who have a historic view of medical advances, they have pointed out that truly changing medical care takes a substantial amount of time. Often decades. And I’ve grown sensitive to the criticisms of genomics by some who believe that since 2003, when the genome project ended, we haven’t sufficiently improved human health 7 years later. So part of the reason is just to be a little bit more realistic and a little more cautious.  

Q: Where are you hoping we will be by 2020?

Eric Green: I’m hoping that by 2020 we will have this incredible mountain of information about how genetic variants play a role in disease, that it will just provide an entirely new venue for really thinking about how to both predict disease, maybe prevent disease, and certainly treat disease.

Notice that Dr. Green seems pretty confident in our ability to use genomics to predict and treat disease, but puts a “maybe” in front of prevention.


Kaiser, J., Green, E. (2011). The genome project: what will it do as a teenager? Science 331: 660.

There is a gene, with the exciting name of Tp53, that, among other things, regulates apostosis (programmed cell death). Apostosis is actually good for a number of reasons, but one thing that it does is get rid of damaged cells before they cause problems. There are, however, two variants of this gene: one has the amino acid arganine, in which apostosis proceeds normally, and the other, which has the amino acid proline, where apostosis is curtailed. The arganine variant has been shown to protect individuals from the development and spread of cancer cells. This is a good thing, of course. However, apostosis of brain cells occurs in the aftermath of a stroke, and if it is not checked, this can delay or prevent an individual’s recovery. You can imagine, then, that a new study finds that people with the arginine variant do not recover as well from strokes as those with the proline variant. From a summary in ScienceNews:

Of people who had a poor prognosis after a stroke, about 81 percent carried two copies of the arginine variant. About 91.5 percent of people with a poor outcome after a hemorrhage had the arginine variant. None of the people with two copies of the proline variant had bad outcomes after either stroke or hemorrhage. People with one copy of each variant tended to have good prognosis after either type of brain injury.

One commentator suggests that his may not apply equally well across racial groups. Again, from the summary:

“We know already that there’s no way this is going to hold up in African Americans,” says Maureen Murphy, a cancer biologist at the Fox Chase Cancer Center in Philadelphia. African Americans tend to have the proline version of p53, but also have high rates of stroke, often with very poor outcomes, she says. It will be important to repeat the study in other ethnic groups to determine the variants are good predictors of stroke outcome for everyone.


Gomez-Sanchez, J.C., et al. (2011). The human Tp53 Arg72Pro polymorphism explains different functional prognosis in stroke. Journal of Experimental Medicine. 209: online.

We’re starting to go through some of the interesting vignettes in Science’s 10th anniversary celebration of the human genome project. One of these papers takes a realistic view of how genomic research has benefited human health over the past 10 years. A few areas that the authors touch on:

1. Identifying risk:  The predictive power of most genetic variants associated with diseases is not very high. This means that the potential benefits of separating patients even into gross categories such as “high” and “low” risk based on the presence/absence of disease-risk genes are in many cases outweighed by the cost of potentially misclassifying (and thus mistreating) them.

2. The difficulty of changing behavior: When someone is told they are at a genetically higher risk of developing a particular disease, there is really no evidence to indicate that they change their dietary or exercise habits (see also this post on the blog). Altering an individual’s environment (regardless of the presence/absence of disease-risk genes) is probably a better, and more lasting, way of convincing them to be less lazy, or to eat better and not smoke.    

3. False hope: Scientists and the press are both responsible for creating false hopes for genomic research in human health.

The authors do suggest that the following are realistic expectations:

1. The genes responsible for most Mendelian disorders will be identified. This will permit quick diagnoses, particularly for diseases that are caused by a single gene. 

2. Pharmacogenomics (the study of the influence of genetic variation on drug response) will enhance the safety and efficacy of treatments. However, because a lot of variability in drug response is tied to non-genetic factors, we can’t expect genomics to completely solve this issue.    

They make the interesting suggestion that because most mortality in high-income countries results from things like smoking, sedentary behavior, and excessive food and alcohol consumption, the diseases associated with these factors are best (or at least as effectively) researched via the social and behavioral sciences (i.e., how do we change these behaviors?) rather than through genomics (i.e., how do we identify individuals at genetic risk for these diseases?).  


Evans, J.P., Meslin, E.M., Marteau, T.M., Caufield, T. (2011). Deflating the genomic bubble. Science 331: 861-862.

UPDATE 2.23.2011. Dr. Hawks blogs about this issue here.

Ok, so we all know what the genome is: the entire sequence of As, Ts, Gs, and Cs (all 6 billion or so of them) that make up the DNA sequence in each of our cells. As you all now know, we’ve had the complete human genome mapped out for ten years now (of course, we’re still trying to figure out what it all does). We also know that whenever there is a change in the DNA molecule (a mutation), that change can become permanent and, in some cases, will be passed down to offspring.  

Well, there are ways that changes can be heritable WITHOUT actually changing the underlying DNA sequence…which is where the epigenome comes into play (“epi” comes from the Greek for “above” or “over”). The epigenome is the host of non-genetic factors that cause genes to change the way that they behave. The classic example is cell differentiation: how is it that a single fertilized egg can differentiate into heart cells, liver cells, skin cells, etc., even though the DNA molecule remains the exact same in all the cells? What happens is that epigenetic factors turn on only the genes that are needed for each cell type to carry out their specific functions. 

Now, most of these epigenetic changes occur only within an individual’s lifetime and are thus only passed from one cell to the next as they divide. However, and this is where it gets really cool, if these changes occur in a sperm or egg cell, then some could be inherited from one generation to the next. This should sound familiar because, in effect, this would be the inheritance of acquired characteristics, which is Jean-Baptiste Larmarck’s oft-ridiculed mechanism for evolution!

Scientists are now on the hunt for a map of the epigenome. For starters, they have been mapping the relatively small epigenomes of the fruit fly and the round worm, and an ongoing study now has a basic epigenomic map for both species. What can this tell us? From an interview with one of the team leaders on the project, Dr. Sarah C.R. Elgin (Washington University, St. Louis), from ScienceDaily:

“We learned many things from the Human Genome Project,” Elgin says, “but of course it didn’t answer every question we had!

“Including one of the oldest: We all start life as a single cell. That cell divides into many cells, each of which carries the same DNA. So why are we poor, bare, forked creatures, as Shakespeare put it, instead of ever-expanding balls of identical cells?

“This work,” says Elgin, “will help us learn the answer to this question and to many others. It will help us to put meat on the bones of the DNA sequences.”

There is actually a conference on human epigenetics, Environmental Epigenetics and Disease Susceptibility, March 27-April 1 in Asheville, NC. Just a smattering of the papers that will be given:

“Epigenetics, Brain Evolution and Behavior”; “Transgenerational Epigenetic Inheritance”; “Epigenetics at the Interface of Genetic and Environmental Risk Factors for Autism Spectrum Disorders”; “The Imprinted Brain Theory: How Genes Set the Balance between Autism and Psychosis”

Laron syndrome (also referred to as Growth Hormone Insensitivity Syndrome, Pituitary Dwarfism II, and Growth Hormone Receptor Deficiency) is an autosomal recessive disorder (i.e., you have to have two copies of the mutated gene–one from mom and one from dad) caused by a mutation on chromosome 5 that results in an individual being non-responsive to growth hormone. Those that are non-responsive fail to produce insulin-like growth factor I, which ultimately leads to short stature.

Jaime Guevara-Aguirre stands with some of the people who took part in his study of Laron syndrome in Ecuador. Photo credit: Valter Longo.

NPR reports on a study in Ecuador that shows that this mutation, while causing Laron syndrome,  seems to prevent diseases such as diabetes and cancer (diseases typically, though not exclusively, associated with ageing). What is super interesting is that a mutation similar to Laron syndrome is known to extend lifespans in other organisms like yeast and worms. From the interview with researcher Valter Longo:

The mutation seems to prevent diabetes by allowing people to get by on very low levels of insulin, Longo says. It wards off cancer by reducing DNA damage in cells, and helping to eliminate abnormal cells. You might expect all this protection would allow the small people in Ecuador to live longer than their taller relatives, Longo says. But that’s not what he found. “The majority of them die of strange causes,” he says, including alcohol abuse and accidents. These are things that are preventable and not caused by a disease, Longo says. Subtract these deaths, he says, and it looks like people with Laron syndrome really would live longer than their relatives. Longo says his study suggests that a whole group of people might be able to lower their risk of cancer and diabetes if they could lower their levels of growth hormone, or change the body’s response to it. The benefit would probably be greatest in people who have unusually high levels of the hormone, he says.

Connecting to a previous post on the blog, scientists also suggest that people with pituitary tumors (a similar situation to these growth hormone abnormalities) may also be at greater risk for cancer (see Irish giants and DNA)

We’ve talked about SNPs (single nucleotide polymorphisms) before on the blog. These are mutations in single bases along the DNA molecule. Because it has been found that some SNPs are associated with particular diseases, geneticists scan genomes to identify SNPs that may either explain a disease or at least identify individuals that may be at risk for a disease. As described in a recent report in Reuters, one unintended consequence of these genome scans has been the identification of incest. As many of you know, the development of abnormalities in offspring is more common in incestuous (i.e., mating with a close relative–how “close” is “close” varies by culture)  matings. Because closely related individuals share a greater proportion of their genes, the chances are greater that deleterious recessive genes (genes that are only expressed when an individual has two copies, one from either parent) will pair up in their offspring and cause problems.

Although this new information of course has important legal implications, in most cases the physicians were already aware of the incestuous relationship.


Schaaf, C.P., Scott, D.A., Wiszniewska, J., Beaudet, A.L. (2011). Identification of incestuous parental relationships by SNP-based DNA microarrays. Lancet 377: 555-556.

As many of you know, some of the best evidence for natural selection comes from viruses and bacteria, which always seem to be adapting to the newest vaccine. Well, a new study published in Science shows just how adaptable some of these little critters can be. As summarized in ScienceNews, an international team has sequenced the genomes from 240 individuals of a particularly nasty strain of pneumonia-causing bacteria (Streptococcus pneumoniae). These guys have been found to be resistant to multiple drugs, and this study shows why:

1. Since the strain’s emergence (estimated to be around 1970 or so), it has changed one of its DNA bases (called a “point mutation”) about once every 15 weeks.

2. This strain (just like other species of bacteria) swaps genetic material (called “recombination”) with other strains.   

Put these things together, and…voila! You get the relatively rapid introduction of new gene variants or, in some cases, entirely new genes. The most important ones seem to be genes that code for a sugar coating that makes the bacteria difficult for the immune system to neutralize. The irony here, of course, is that the driving force behind the evolution of this and other strains is the development of vaccines meant to identify these different sugar coatings. Rapid mutation rates and recombination in these bacterial strains allows their populations to come up with new variants that are immune to the latest vaccines. 


Croucher, N.J. et al. (2011). Rapid pneumococcal evolution in response to clinical interventions. Science 331: 430-434.

Genetic screening for diseases

What would you do if a genetic screening indicated that you had a 70% chance of developing Alzheimer’s? Well, a recent study published in the New England Journal of Medicine suggests that people really don’t seem to care. From a summary in the New York Times:

…the Scripps Translational Science Institute followed more than 2,000 people who had a genomewide scan by the Navigenics company. After providing saliva, they were given estimates of their genetic risk for more than 20 different conditions, including obesity, diabetes, rheumatoid arthritis, several forms of cancer, multiple sclerosis and Alzheimer’s. About six months after getting the test results, delivered in a 90-page report, the typical person’s level of psychological anxiety was no higher than it had been before taking the test.

Although they were offered sessions, at no cost, with genetic counselors who could interpret the results and allay their anxieties, only 10 percent of the people bothered to take advantage of the opportunity. They apparently didn’t feel overwhelmed by the information, and it didn’t seem to cause much rash behavior, either.

Would you want to be screened for diseases? What would you do with the information once you had it?


Bloss, C.S., Schorck, N.J., Topol, E.J. (2011). Effect of direct-to-consumer genomewide profiling to assess disease risk. New England Journal of Medicine

Irish giants and DNA

As reported in the New York Times and published in the New England Journal of Medicine, researchers have successfully extracted DNA from the skeleton of Charles Byrne, who was known during his lifetime (1761-1783) as the “Irish Giant.” Measuring in at a towering 7’7″, he apparently died of the combined effects of tuberculosis and “an excessive love of gin.” His body was purchased soon after his death, after which it was boiled in acid and put on display at a museum in London. Some years later, after the removal of the top of his skull, it was determined that he suffered from a pituitary tumor. The pituitary gland sits at the base of the brain and regulates, among other things, the release of growth hormone. So, Byrne essentially suffered from growth hormone gone haywire.

The skeleton of Charles Byrne (Photo credit: Ronan McCloskey)

What’s interesting (at least for our purposes here) is that DNA analysis discovered that Byrne had a genetic mutation in his AIP gene.  These sorts of mutations are rare: only about 5% of people with pituitary tumors inherited them via a mutated gene. This particular mutation is so rare that when researchers found the same mutation among four families from Northern Ireland, they determined that these families are in fact related to Byrne (they shared a common ancestor 55 to 67 generations ago, or about 1,500 years ago).

The mutation probably occurs in other populations, either through shared ancestry or spontaneous mutation. Cool stuff.


Chahal, H.S., Stals, K., Unterländer, M., Balding, D.J., Thomas, M.G., Kumar, A.V., Besser, M.G., Atkinson, B.A., Morrison, P.J., M.D.; Howlett, Trevor A. M.D.; Levy, Miles J. M.D.; Orme, Steve M. M.D.; Akker, Scott A. M.B., B.S., Ph.D.; Abel, Richard L. Ph.D.; Grossman, A.B., Burger, J., Ellard, S., Korbonits, M. (2011). AIP mutation in pituitary adenomas in the 18th Century and today. New England Journal of Medicine 364: 43-50.