The hottest news in science today is an announcement by J. Craig Venter, founder of Celera Genomics, itself in the news today for announcing its acquisition of Berkely HeartLab, Inc. Of course, Celera is the company which was the first group to map the entire human genome while in competition with a U.S. government funded program to do the same. Venter announced after completing the project that the largest portion of the map was derived from sequencing parts of his own DNA, along with DNA material from four other individuals. Today he announced that he and his colleagues at J. Craig Venter Institute have completed the work to map a single individual's entire genome and that the resulting data would be made available to the public via the World Wide Web. The genome is his.
Their research article is titled The Diploid Genome Sequence of an Individual Human and is published on the PLoS Biology web site, a peer-reviewed open-access journal published by the Public Library of Science. The actual map of the genome can be viewed as an interactive poster but the reader is forewarned that a very fast computer and connection are required to look through the data. The poster is also available for download as an 88 MegaByte Adobe Reader file (.PDF).
If one has read my previous posts about genetics and genetic engineering for treatment therapies then one can readily understand that the following quote from the article can be considered to be very timely:"Clearly, to enable the forthcoming field of individualized genomic medicine, it is important to represent and understand the entire diploid genetic component of humans, including all forms of genetic variation in nucleotide sequences, as well as epigenetic effects."
The estimated cost of the effort to map Craig Venter's genome is something over $60 million. It is projected that within the near future genome mapping will cost about $100 thousand per individual and it is foreseen that when the practice becomes fairly routine that the cost will be reduced drastically to about $1,000 per individual.
The article can be an interesting read even to the layman. There are some intriguing links, like that to the Ensembl website, which "maintains automatic annotation on selected eukaryotic genomes". For example, click on the species Chimpanzee in the Popular Genomes sidebar and "click on chromosome for a closer view" etc. Other links to companies under the Materials and Methods section of the paper provide information on the products and technologies used in the mapping project. All in all, even a superficial perusal of the paper can provide a rudimentary yet informative background in genomics.
Tuesday, January 22, 2008
Craig Venter's Genome
We're a long way from effective gene therapy
It seems that the more we learn the more we need to learn. Life appears to be far more complicated than we know. We like to think that we understand the DNA molecule and the transcription process which leads to protein synthesis. We've sequenced the entire human genome and we now know which genes are responsible for many inheritable diseases yet we appear to be far short of the ability to apply our knowledge of genetics to developing effective gene therapies. Ideally, we would like to be able to introduce a drug therapy which actually invades those target cells which harbour the mutant genes and actually rebuild the DNA so that the defective gene becomes normal. I've already explained in my post titled Rethinking genetic engineering why simply addressing a single genetic component could not present an effective gene therapy because the process of protein synthesis involves far greater complexity than merely changing one suspect gene. Other genes and even non-genetic sequences of the DNA molecule are included in the assembly of the RNA template for the purpose of synthesising a single protein. For that matter, the root of some problems may very well not lie with the DNA molecule itself but the methyl groups on the histone proteins within which the DNA is embedded, and to which some of the DNA material is bonded.
Unfortunately, we must admit that the extent of our current knowledge of gene therapy is limited to our ability to actually effect a genetic change in the DNA molecule but that this falls far short of our ability to apply in any practical sense an actual procedure which cures the patient. Furthermore, we are discovering that the idea that just because something seems to work in mice that it should work in humans is essentially flawed. Mice don't always live long enough to present the adverse reactions to gene therapies that are thought to be effective. This reflects the tragic case of two young girls with a severe immune deficiency who were subjects in an experimental protocol and who developed leukemia as a direct result of their treatment. As a result of this event investigating researchers transplanted the treated cells of the first series mice into healthy mice and eventually those mice developed leukemia. The entire process from the treatment of the first group of mice to the manifestation of disease in the second group spanned more than two years.
These reports follow the tragic death of an 18 year old patient who was suffering from arthritis but who was otherwise young and healthy and whose condition was being treated effectively by drug therapies. He took part in an experimental protocol which involved infusion of a gene repair kit via an adenoviral vector. His is the first death attributed to gene therapy.
The community must now sit back and rethink gene therapy strategies. It is clearly apparent that our knowledge at present is incomplete. Only when the entire process leading to synthesis of a defective protein is known and fully understood can we apply effective treatments to eradicate the corresponding disease. And even then the treatment that works for one patient may not be the right treatment for another, even though the same root gene is responsible. When all the factors are known it may be that the vector for treatment involving all of the RNA's components might very well already exist in the form of "smart nanoparticle" carrier bacteria, as discussed in paragraph five of my post titled Bacteria can make us better. These carrier bacteria would in all likelihood need to be custom-made for the patient.
Monday, January 21, 2008
The ENCODE project: beyond the genome project
"The human genome is an elegant but cryptic store of information."
In 2001 the project to catalog the human genome was completed. Embedded in the DNA molecule are genes and what were once believed to be "junk DNA", noncoding portions of the DNA that represented fully 98.8% of the entire genome. It has been found that some of these noncoding portions are shared among mammals. This suggests that they play some crucial role as yet undetermined. Information contained herein is partially derived from a June 13, 2007 Scientific American article.
In 2003 a new project involving 35 research groups was undertaken to create the encyclopedia of DNA elements (ENCODE). The pilot phase of the project targeted 1% of the human genome (roughly 30Mb of data).
All species have been found to transcribe large portions of "noncoding" DNA for some unapparent reason, and in addition to the role that RNA plays in protein synthesis, some RNA's play roles by themselves.
The ENCODE consortium selected 44 separate sections of the genome for study of which 3% make up genes, yet 93% of the material was transcribed and extensive overlapping in the noncoding portions was discovered when transcription was compared with any of the 399 ENCODE genes. 65% of the gene transcription process also involved selected portions of other genes as well as pieces of DNA far outside of the target genes [distal regions]. ENCODE findings confirm reports from other sources that often a protein is synthesized from exons (cleaved gene portions) of different genes.
23% of mammals share 5% of the studied sequence. Of these 5% approximately 60% show evidence of function. Evaluation from a purely scientific point of view would suggest that evolution has preserved these DNA portions as species have diverged. Yet it is not untoward to suggest that they would exist even from separate evolutionary beginnings based on the premise that there is a very distinct progression that the evolution of life takes when it does manifest - an intelligent design principle based on the natural anthropocentric process. Either suggestion is speculative, although I personally believe the latter one.
What is known is that we are just analysing the tip of the iceberg with respect to the full extent of the knowledge that we require to fully understand the code that DNA represents and the processes which interpret that code to produce life. But we are already far ahead of that day in 2001 when it was announced that the complete human genome had been sequenced.
Genome biologist George Weinstock of the Baylor College of Medicine in Houston says, "this study shows us how far we are from a comprehensive understanding of the human genome."
