Wednesday, June 18, 2008

Men: The Next Endangered Species?

Men, have you recently had one of those feelings that something was not exactly right? A sense of impending doom? An uneasiness with the state of the world? While it was not exactly front-page news, an article by Nick Lane in the June 7th issue of New Scientist (One Baby, Two Moms) should have all men worried. Lane’s article has to do with the generation of a embryonic cell that is basically a hybrid of three parents. The purpose was to transfer mitochondria from one cell to another to potentially prevent disease. The implications for men in general may be much more severe.

Mitochondria are the powerhouses of your cells. These small internal compartments are where your body converts food, usually carbohydrates, into the energy that runs all cellular processes. They use lots of oxygen in the process. In fact, if it wasn’t for mitochondria, the oxygen that you breathe would be lethal.

Mitochondria are interesting for several other reasons. One is the fact that they really don’t belong to us. If you take a good look at the genetics of the mitochondria you will quickly discover that they closely resemble those of the bacteria. The mitochondrial chromosome is circular, just like those of a bacterium, and the structure of the genes on the chromosome is very similar as well. Creationists absolutely hate mitochondria since they provide strong evidence of a major evolutionary event (over 600 million years ago) in the formation of modern cells. Each of our cells contains the remnants of a bacterial infestation hundreds of millions of years ago. But that fact has very little to do with the extinction of males.

What is more important is that we get our mitochondria from our mother. When a sperm cell fertilizes an egg, only the mitochondria in the egg survive. Thus, the mitochondria in my cells are all derived from my mother, who in turn got them from her mother, etc, etc. In fact, our mitochondria provide a history of our heritage. (For excellent coverage of this topic, read Brian Sykes book The Seven Daughters of Eve). But there is a flaw in this process. If there is a defect in a woman’s mitochondria, then she will pass that defect on to her offspring. Since the male doesn’t contribute mitochondria, then there is no chance of getting a “normal” mitochondria from the male. Mitochondria disorders are associated with a number of neurological disorders. Women with a history of these disorders have always been concerned about reproduction.

To bypass this problem, scientists have recently developed a procedure to produce embryos from three parents – two females and one male. This process allows a woman with a known mitochondrial disorder to produce a healthy embryo by using her DNA, mitochondria from another woman, and DNA from a man. The result is a child with the same genetic make-up as would be produced by any normal fertilization event between a man and a woman, but minus the mitochondrial disorder.

Sounds good right? Well, what this has done is place us one step closer to the ability to combine two eggs to produce an embryo. And once that happens men, there will be little reason to keep us around anymore.

Females reproducing without males is nothing new to the animal world. There are several species can either reproduce without males (called parthenogenesis). But until recently, it appeared that males were absolutely necessary for reproduction in mammals. There are several important genetic reasons for this, and the information in Nick Lane’s article does not necessarily indicate that men are doomed – yet. But it does indicate that scientists have overcome another hurdle in their ability to manipulate cells. Soon, perhaps sooner than we think, it will be possible to merge two eggs to form a zygote.

With the news being presented in this article, men are one step closer to joining the dodo bird and passenger pigeons. Author Bryan Sykes has already foretold this in another of his books - Adam’s Curse: A Future Without Men. This should be required reading for all men. For now we are one step closer to that reality. And if the guy at the top of this post is an endangered species… in general are doomed.

Friday, June 6, 2008

The Latest Evolution of the -Omes: The Diseasome Comes to Life

In 1988 if you had told most scientists that the human genome would be sequenced within 20 years, and that the resulting genome would turn out to be the least complicated of the –omes, most of them (including this one) would have said that you had been reading too much science fiction.

I distinctly remember discussions in graduate school about how the human genome probably contained around 150,000 genes. As the years progressed, techniques improved and research continued ... and the size of the human genome began to collapse quickly. At one point I remember hearing a colleague comment on how humans appeared to be "de-evolving" at a record pace! By the year 2000 the human genome had shrunk to around 50,000 genes, and over the next eight years it continued to contract. Recent estimates place the number of genes at around 24,000–30,000.

What had happened was not some major evolutionary genomic constriction event; rather, it was a greater understanding of how genes interacted and were processed by the metabolic machinery of the cell. Scientists began to think that it was not the genes themselves that were important; it might be the gene products that truly mattered.

For many molecular biologists, and probably most of the biotechnology community, the genome turned out to be somewhat of a bust. A disease is a phenotype, an outward portrayal of a trait, which in the case of most diseases has an underlying cause in the genome, but not in all cases. Creutzfeldt-Jakob disease is a nice example of a condition that is caused not by a defect in a gene (although there is some suggestion of genetic susceptibility), but rather by a malfunctioning protein called a prion. In fact, most diseases are caused by protein-related problems. Thus, in order to understand human disease it was necessary to take a good look at the proteome, or the sum of the proteins within a cell.

The size of the proteome appears to be even more elusive than the size of the genome. Estimates range from between 90,000 to more than 400,000 proteins in the human proteome. Of course this number is dependent on a number of items, including cell type, influence of external stimuli, cell age, nutritional state, etc. The proteome is the cell's response to its environment, and therefore it is expected that it will fluctuate depending on the needs of the cell.

So while some still work to identify the entire proteome, attention has shifted to what the proteome can tell us about the health of a cell. To do that, it was necessary to understand interactions within the proteome. This is called the interactome and it encompasses the study of all interactions at the molecular level within cells. The interactome is based primarily on protein-protein interactions. This led to amazing breakthroughs in systems biology, which integrated biochemistry, molecular genetics and cell biology to more fully understand how cells work.

Something very interesting occurred at this point. When studying protein interactions it is often useful to go back and identify the genes that code for each protein. Advances in biotech have made this a relatively easy process, and it was only a matter of time before scientists began to uncover some intriguing connections. In a New York Times article by Andrew Pollack, the author interviews scientists who have used studies of the proteome and interactome to reveal genes common to both heart attacks and muscular dystrophy — two seemingly unrelated conditions.

In other words, molecular science has come full circle. An understanding of the genome is once again important, but so is an understanding of the interactome and proteome. Together, these items are sometimes called the diseasome. The diseasome represents the latest evolution of the -ome; it fully integrates all information to understand factors that may cause a disease.

If you are having a hard time visualizing the diseasome, then a quick visit to an interactive graphic on a portion of the diseasome prepared by The New York Times will help immensely. If you notice, there are connections in this diagram that seem to be impossible if you think only about the disease, such as genes linking myocardial infarctions and Alzheimer's disease. But if you step back from the disease for a second, and integrate the information, it starts to make sense. At the cellular level, metabolic activities are directed by genes and proteins interacting in complex manners. Since there are a limited number of genes and proteins, but a seemingly unlimited number of diseases, then there must be common factors that we have previously missed.

So what does all of this mean? The ability to visualize these interactions may allow medical researchers to develop innovative methods of detecting and treating disease states. Some, such as Dr. Albert-László Barabási at The New England Journal of Medicine and Northeastern University, have called this network medicine.

In the very near future, as more of these interactions are mapped out, doctors may begin to prescribe unique combinations of drugs that would have not even been considered 10, or even five, years ago.

Diseases that previously were thought to be too complex to cure, such as muscular dystrophy and diabetes, may very soon be things of the past.

Note: this article first appeared in the June 5, 2008 issue of BioWorld Perspectives, and is reproduced here by permission of AHC Media, LLC