The Question of Fragile X

Geneticists really need to work on naming their genes. Drosophila geneticists are the worst - we give genes names such as Grunge, grim reaper, and swiss cheese (see a great link here), but sometimes the human geneticists can slip as well. One example - the fragile X syndrome. The name fragile X suggests that this version of the X chromosome is like a Ming vase...delicate and susceptible to fragmenting. But in reality, it causes a much worse condition.

What happens in fragile X is that there has been a duplication in a portion of the DNA on the X chromosome. Duplications happen all of the time, but unfortunately, this one happens to occur within the coding region for a gene. This gene is FMR-1, and it appears to be a very important gene for humans. FMR-1's gene product, the fragile X mental retardation protein (FMRP)is responsible for development of the neurons - the cells that conduct billions of electronic messages in our bodies, and brains, per second. In the mutated form of FMRP, there has been a repeat in one of the instructions, commonly called a codon. The repeat, called a trinucleotide repeat since it adds three new "letters" to the DNA message, causes the resulting protein to fold incorrectly. Proteins are all about folding, it is their three-dimensional shape that gives them their unique function. Imagine if you needed a wrench for a certain repair job, and the manufacturer mistakenly bent the top of the wrench at a 45 degree angle... it would make it very difficult to complete the task at hand. Proteins operate in much the same manner.

Another interesting aspect of repeats is the fact that they have the ability to increase in size from generation to generation. During the production of egg and sperm cells in humans (called meiosis), similar chromosomes line up with one another. The repeats can cause a misalignment, which can increase the size of the repeat. More repeats means a more severe form of the disorder. That is why everyone with fragile X does not have the same symptoms (what us geneticists call a phenotype).

Since Fragile X is on one of the sex-chromosomes, males (who are XY) are definitely more susceptible to its effects, since females (XX) at least have the chance to have a second, good copy of the chromosome. Fragile X syndrome can result in both mental retardation and a form of autism. In fact the recent attention to autism has resulted in some interesting discoveries about fragile X, specifically its relationship with a group of receptors on the cells in the brain called mGluR5. Identification of a receptor is a big deal, since drugs can be developed to interact directly with the receptor. Individuals with fragile-X also sometimes display aggressive behavior, but that is most likely believed to be a secondary result of the disease, probably brought on by speech difficulties, frustration, and anxiety - complications of the effects of mental retardation.

While drug studies are promising, a "repair" of fragile X is unlikely. Since the repeats in fragile X can be very large (200+ copies sometimes) it is unlikely, at least in 2008, that the defect could be repaired using any form of biotechnology, including gene therapy. Furthermore, since the gene product, FMRP, has already caused problems in the cells, it would probably not be possible to reverse the influence on the person. We should be able to treat the symptoms, and it appears that we are getting better at understanding how to do this, but this may be a good example of where our genetic limitation lie.

What is LRRK2?

The recent announcement that Sergey Brin, the multibillionaire co-founder of Google, has discovered that he possesses a genetic mutation that predisposes him to a form of Parkinson's disease has resulted in multiple stories in the news on the "genetic basis" of Parkinson's and the candidate gene LRRK2.

But what exactly is LRRK2? The fact that we now have names for so many of these genes signifies one of the true advances in modern medicine - the fact that we actually know the location, but not necessarily the function, of most genes in humans. But we often forget that these genes themselves are very interesting. LRRK2 stands for leucine-rich repeat kinase 2, which means about nothing to most people. This means that the gene encodes for a protein that has within it a leucine-rich regions, and some sort of kinase function. Still mean nothing? Well, leucine-rich regions tend to be associated with proteins that interact with one another. This is common in many metabolic pathways. In fact, we know that the dardarin protein (the protein encoded for by LRRK2) is actively involved in the mitochondria of the cell - the energy powerhouses that burn carbohydrate fuel to produce energy. And the term kinase indicates that this protein is basically a form of cellular "on-off' switch. Kinases add phosphates to other molecules, effectively turning them on or off. So dardarin turns on and off other proteins.

So what does this tell us? Well, by dissecting the name we can see that this gene, and its gene product (the dardarin protein) are most likely a component of a much larger, protein activation pathway. From a cellular perspective, these pathways can be, and usually are, very complex, with defects at many locations possible. Any of these defects may cause Parkinson's. The disease may also be caused by mutations in genes that have nothing to do with dardarin or LRRK2. So, it is unlikely that the discovery of Mr Brin's mutation will be the silver bullet in the fight against Parkinson's disease. Mutations in this gene account for only a small percentage of Parkinson's cases. However, Mr Brin's announcement will serve to increase awareness, and hopefully funding, of research to better understand the chemical pathways that LRRK2 is part of. But we can add dardarin to the diseasome, or those proteins that are known to cause disease. And once we understand the function, we may be able to start talking about gene therapy and drug development.

The Reality of Race

What really makes us different? As the father of two young children, I am constantly amazed at how my children begin to distinguish themselves from others in their class. At a very young age, they barely recognized that not all people were the same, and what differences they did note were more of a curiosity to them than a type of distinction.

Now, however, as they exit middle school, they are well aware that some people are "different" from them. Sure, some of it is their social environment — we all know that middle schools are not the model of social integration. But as a scientist, I always have been intrigued by the apparent need to define ourselves as unique, even when it is clear from a scientific perspective that the majority of these differences are due to very minor variations in our genetic makeup.

Despite the ongoing "nature versus nurture" argument between the social scientists and geneticists, as scientists we always have suspected that our underlying differences would have to be controlled by genetics and the biochemical pathways that those genes regulate. While we now recognize that the environment does play a role in gene expression, and few of us believe that we are genetic automatons, barely a week goes by when we are not made aware of a new discovery on the genetic basis of a behavior or a disease. Genes control phenotypes. If race is such an important aspect of our society, as is clearly demonstrated by the latest political cycle, why has it taken us so long to really take a good look at the "phenotype" of race, and determine whether race is genetic?

Over the past several years there have been a number of articles that address the concept of race. One of my favorites is "Does Race Exist?" by Michael Bamshad and Steve Olson, from the Nov. 10, 2003, issue of Scientific American. I make this a required reading article for all of my science classes, from non-scientists to future geneticists.

The basic premise of this article is that the pigmentation level of an individual's skin is a poor criteria to use to identify them as belonging to a specific race, and that the use of these phenotypic races in medicine is bound to create problems.

The authors give an example of African Americans, who are typically identified as being of African descent. However, Africa is not home to a group of genetically identical individuals. Sub-Saharan Africans are genetically different from those from South Africa and the Mediterranean regions.

What is really important is how these populations of humans have historically adapted to selective forces including disease and the environment. Groups that have responded to similar selective forces are more correctly classified as a "race" than those with similar skin colors.

A recent NewScientist article, "Watson vs Venter: the loser is race-based medicine," brings two of biotech's big names to center stage on the discussion of race. James Watson and Craig Venter have made their genomes available publically. (For details see Venter and Watson.)

As Ewen Callaway reports in the article, an analysis of Watson's genome indicates that Watson, a phenotypic Caucasian, possesses a number of mutations that are found most commonly in populations from East Asia.

What this means is that Watson's doctor may prescribe him codeine or antidepressant drugs based upon his Caucasian phenotype, without realizing that at the metabolic level, Watson's cells are operating as if he is Asian.

The same thing is probably happening in each of us. Now that the two big boys, and their associated financial clout, are involved in the discussion, maybe we can really start to talk about what race means.

I, for one, am encouraged that these discussions are starting to gain momentum. At a time when humanity appears to be obsessed in establishing differences based upon race, sexual orientation, ethnicity and religious preference, it is promising to see that the scientific community is working to dispel these notions.

Research into the genetic basis of race needs to continue, not only for the development of new drugs, but to break down society's stereotypes of race. We need to recognize that while the person next to us may look different than we do, he or she may have more in common with us as an individual than a person of our perceived "race." I have a hard time seeing how anything negative can come from this realization.

This entry was originally published as "The Differences Within Us: The Latest Scientific Discussions on Race and Medicine" in the Sept 11, 2008 volume of Bioworld Perspectives. It is reprinted here by permission of AHC Media.

Synthetic Life Makes Synthetic Proteins

The genetic code is the metabolic instructions by which the genetic information in the DNA is translated into a protein. The fact that almost all organisms use the same code is prime evidence that all life is related in its evolutionary past. The code is considered to be "conserved" and "universal". Of course, the concept of universality may be challenged by exobiology's explorations of Mars, Europa, and Titan, but the conservative nature of the genetic code, with the exception of a few Archaebacteria, has always been a cornerstone of biological science.


But the reality of course is that the Genetic Code is like the Cobal language of computer science. The Genetic Code is old (over 3.5 billion years). Of course life on this planet is not going to update the genetic code anytime soon - it is thriving using the old code, but evolution is a weird thing, if something better comes along, and a mechanism to adapt to that change exists, the out with the old and in with the new. Until recently it appeared to be metabolically impossible to "update" the code. But one species, Homo sapiens, may have discovered a way to fast-track the process.

The basic tenants of the genetic code is that the information coming from the DNA, in the form of messenger RNA, is "read" by a ribosome three units (also called a codon) at a time. Each codon codes for an amino acid, the building blocks of a protein. Proteins are the workhorses of the cell - everything depends on them. In other words, genes code for proteins. While we have had the ability to change genes for some time, using recombinant DNA technology and genetic engineering, until recently we were always confined to the use of the same old programming language.

Earlier this year, independent teams of researchers at Harvard University and the University of Cambridge have found ways to alter not only the genetic code, but also the cellular machinery responsible for deciphering the code - the ribosome. (see Synthetic biology: Rewriting the code for life by Linda Geddes, 2008). This process is called synthetic biology, and due to the efforts of biotech giants such as Craig Venter, this is no longer science fiction. We now have at our fingertips the technology to create new forms of life that are designed for specific missions and environments.

These advances open up unbelievable possibilities, and the potential for unimaginable nightmares. It may soon be possible to manufacture proteins that were not possible from a biochemical perspective just a few years ago. This could create new drugs that could finally eradicate some of our specie's biggest problems, such as cancer and HIV. It could also allow us to develop plants that tolerate salt water, or grow on toxic waste. A new programming language means endless possibilities. It also could spell our demise as a species. After all, the evolutionary history of life on this planet tells us that if something better comes along, the old is replaced... even if it is us. Let us not be so egocentric to think that we are special from an evolutionary perspective. Unless of course, you believe that our purpose on Earth is to generate our own successors.

Nondisclosure Agreements for First Dates

Michael Creighton's latest thriller, Next, presents all sorts of what-if scenarios for the genetic community. While most of us will not have to deal with foul-mouthed orangutans or smart-ass parrots, a recent report published in the Proceedings of the National Academy of Sciences suggests that there may be a genetic factor contributing to fear of commitment in males. As reported today by the BBC ("Commitment phobes can blame genes", Sept 2, 2008), this gene is called AVPR1A. Males with a certain allele for this gene (allele 334)have an aversion to commitment, and are less likely to have happy, fulfilled marriages.

Maybe this is not a surprise...but it could be a problem for some males. In a Creighton-world scenario, a male goes out for a date with an attractive women. As he excuses himself to go use the restroom, the woman quietly swabs the inside of his glass, removing a few epithelial cells. She then sends these off to a genetic screening lab where she finds out that the male possesses two copies of AVPR1A allele 334. The next day she ends the relationship and then publishes his name on her blog to warn her friends that he is a hopeless cause. If you think that these tests do not exist - click here.

Why would she do this? Because there are evolutionary differences between the ways that men and women view relationships. Like it or not, in the animal kingdom (to which humans belong), women often form long-term relationships for the purpose of rearing young. Men, on the other hand, are more likely to seek multiple, short-term relationships. So back to humans.... why should the female invest valuable time and energy in a relationship that is genetically bound for failure? No longer do women have to contemplate whether he will "change" - the genetic evidence will tell them. Anyone else hear warning sirens?


So guys, the next time you go out on that first date, make sure that you have your partner sign a non-disclosure agreement stating that any genetic information that she obtains as a result of your date is to remain your legal property unless you consent to its release. Of course, that type of conversation will probably also stop you from getting a second date, but at least your little genetic secret may remain private.