Science and Medicinie: Rewriting Genetics

David Brown
Washington Post Staff Writer
Tuesday, November 13, 2007; 11:00 AM

Washington Post science writer David Brown and genetics researcher Joshua Mendell of Johns Hopkins University were online Tuesday, Nov. 13 at 11 a.m. ET to discuss how scientists are revising what were once canonical rules of genetics.

Read more in Monday's Science Page story: How Science Is Rewriting the Book on Genes (Post, Nov. 12)

A transcript follows.


David Brown: Greetings geno-chatters! This is the place for a discussion about some of the new developments and insights in genetics in recent years. More than can be covered in an hour, that's safe to say. We are lucky and privileged today to be joined by a leading explorer of this frontier, Joshua Mendell of Johns Hopkins School of Medicine. His particular research interest is "post-transciptional regulation of gene expression"---basically, the editing of the message after it is transcribed from DNA into RNA. I realize this may already be a bit technical; we will try to keep it simple and understandable to everyone. Dr. Mendell has an MD and a PhD and will probably be answering most of the questions. So let's begin.


New York, N.Y.: What is RNA and what is the research about at the University of Pennsylvania where they are injecting RNA into cancel cells and supposedly they hope it will fight cancer?

Joshua Mendell: RNA is a molecule that is similar to DNA. All organisms use DNA to store genetic information. When a cell needs to utilize the instructions stored in DNA, it first makes a copy as RNA. Cells use RNA for many purposes. For example, RNA carries the instructions to make proteins (called messenger RNA). There are other forms of RNA that function to regulate messenger RNAs (for example, a type of RNA called microRNAs). Over the last 5 years, cancer researchers have become increasingly interested in microRNAs because these molecules exist at abnormal levels in cancer cells. This causes abnormal amounts of other proteins to be made that can promote tumor formation. Several labs are indeed trying to restore normal microRNA levels to tumor cells as an experimental therapy. These approaches have shown early promise in the lab, but they are still years away from being used in actual patients.


Baltimore, Md.: Don't definitions in science change constantly as there are new discoveries? And since genetics seems to be constantly evolving, can you explain what's new or surprising in this field?

Joshua Mendell: Absolutely. One of the most exciting things about being a scientist is that it is always a learning process. All fields are constantly evolving.

This is a particularly exciting time in genetics, especially now that we know the sequence of the human genome. I think one of the most surprising things that has emerged over the last 5 years is the importance of sequences in the genome that do not encode proteins. Until recently, it was generally believed that the protein-coding genes were key to understanding the genome. We now appreciate that sequences that do not encode proteins are at least as important. One major function of these so-called non-coding genes is to regulate protein coding genes. Elucidation of the mechansisms utilized to control gene expression is one of the hottest areas of biology now.


Silver Spring, Md.: David & Joshua,

Have you thought about the impact these of genetically based and developed drugs currently approved, in the market, in use and under various stages of research test and development?

Regardless of their value, and clinical trials test conducted, and studies results, if there is such a great percent of unknown protein activity there is a greater exponential risk involved in the use of these drugs for test or otherwise. Activity, Effective and Adverse Events might differ for subjects involved, possibly demographically. Given latest DNA High Throughput Sequencing (454) Screening processes, microarray and genomic platform opportunities; Have Bio-Pharmaceutical Companies, Academic/Medical/Research Organizations (JHU) and Regulatory Agencies a safety retro-active re-assessment plan and approach?



David Brown: There is always the chance that a drug will have unintended consequences (which, of course, is why they are tested so extensively before they can be approved for general use). We now are able to figure out that some of these adverse events are the result of the drug acting on a gene. The flip side is that some entirely unexpected uses of drugs are being found, thanks to the ability to screen drugs (and chemical compounds in general) for gene effects. The best example of that is the unexpected effect of a blood pressure drug, losartan. One of Dr. Mendell's colleagues, Hal Dietz, has discovered that losartan turns down a gene that is very important in Marfan syndrome, a disease that sometimes leads to the rupture of the aorta. Losartan may be able to treat the underlying defect in this genetic disease. Clinical studies to try to answer that are underway.

Joshua Mendell: I'd also like to add that genetic research has actually dramatically improved our ability to design drugs with fewer side effects. Before our current understanding of molecular biology, drugs were developed using random screening approaches. Drug companies now are able to rationally design drugs to modulate specific cellular pathways. The results are much more specific drugs with fewer side effects (although all drugs can have unanticipated effects).

Another important impact of genetics on this area is the field of "pharmacogenetics". This is where scientists examine the genetic make-up of patients to identify in advance who is likely to experience side effects. This approach will very likely revolutionize the use of medicines in the next decade.


Washington, D.C.: Besides research for new medicines, what else does Genetic research help with?

Joshua Mendell: Genetic research is impacting virtually all aspects of our understanding of basic biology as well as the practice of medicine. In addition to leading to the development of new therapies, genetic research also helps better diagnose disease, better choose existing therapies to tailor the conditions of specific patients, and especially better counsel patients to make wise lifestyle decisions to prevent disease.

David Brown: There are all kinds of insights from genetics--and the related field, genomics--that don't involve medicine and health. It is giving us an unbelievably clear view of the process of evolution. By comparing the genomes of different species, we can see what processes direct basic things like the development of "body plan" in embryonic life, what species are related to each other but may not appear to be, etc. Comparitive genomics also gives us insight into the movement of human populations, even in historical times.


Washington, D.C.: I know that genes mutate, but are there ever any NEW genes? Or did the decoding of the human genome really detect everything?

Joshua Mendell: Evolution is an ongoing experiment. Due to random events that occur in individuals in a large population, genomic rearrangements or mutation can produce produce genes with new function. It is important to note that it takes a very long time for these new genes to have any measurable impact on a species (thousands to millions of years).

Regarding your second question, we do continue to discover new genes in the human genome. Most (but probably not absolutely all) protein coding genes have been identified. But we now appreciate that there are many genes that produce functional RNA molecules that do not encode proteins. We are still not very good at identifying them just by looking at the genome sequence. So many more will be discovered.


Fairfax, Va.: Are there other revisions to genetics that you didn't have space to include in the paper?

David Brown: There were many examples I did not have space to mention. For example, regulation of genes by micro-RNAs (miRNA) is a huge field that is providing a lot of insights about many different things. For example, some cancers appear to be augmented by the action of miRNAs (by helping tumors grow blood vessels, for example), while other miRNAs do the opposite, they help suppress tumor growth. It is also clear that some of the visible differences between individuals, so-called "phenotypic differences", are the product of actions of micro-RNAs. In other words, it is the regulation of the genes, not mutations in the gene itself, that can make all the difference in the world.

Another area I didn't have a chance to get into is the growing realization that the genes in the mitochondria, the cell's power plant, have a huge effect on many other genes by establishing different energy states (a little like the charge in a battery) that have an important environmental effect on the entire organism and on the activities of many, many genes. The mitochondria has fewer than 50 genes, but they are very important in establishing the potency and, in some cases, the disease potential, of many of the 22,000 genes outside the mitochondria.


Rockville, Md.: Junk DNA?

How far afield do you have to go to imagine we have some shared "memories" stored in our DNA? There is evidence of past memories. I have no idea about a mechanism or storage system. But there could be a lot of "data" stored there.

Joshua Mendell: The genome is a record of a sort that reflects the experiences of our species through history. For example, a major environmental event (such as an ice age) will lead to the selection of specific traits in a species. An interesting result of this is that we are currently living in an environment that is not necessarily optimal for our selected biology. For example, having access to a high fat diet (which was not usually available thousands of years ago) predisposes human to cardiovascular disease.

David Brown: This is a very interesting question, in my opinion. The phenomenon of "instinct" is one that, I think, has not been adequately explained but that is almost entirely genetic in origin. Instincts function as a form of pre-existing memory in the individual. What genes are involved in establishing instincts--a mother duck feigning a broken wing in order to distract a predator from her chicks, a newborn antelope getting on its feet and walking within an hour of birth--will be very, very interesting to figure out over the coming decades.


David Brown: I think I am going to ask Dr. Mendell a question I got about other hot issues and open questions. What are the current thoughts about so-called "junk DNA"? This is the DNA that doesn't code for proteins and doesn't appear to have been conserved in unchanged form over evolutionary time. Errors creep in, it gets duplicated, etc etc and that doesn't seem to have a great effect on an organism. Is it doing important things we don't know about?


Columbia, Md.: Are you by any chance related to Gregor Mendel?

Also, do you have any concerns for the GMOs that are already in the market and in our fields around the world, since many of them were created before these new findings came out about the so-called "junk" DNA?

Joshua Mendell: I am not to my knowledge related to Gregor Mendel.

I do not believe that GMOs pose any specific risk that is different from any highly selected agricultural product. Remember that selective breeding has been modulating the genomes of organisms for thousands of years. In my opinion, genetic engineering may be able to produce more specific effects than these breeding strategies.


Joshua Mendell: The function of "junk DNA" is a very exciting and mysterious area of genetics. Undoubtedly, some of this non-conserved sequence has important function. Scientists have demonstrated that some nonconserved sequences have important roles in regulating protein coding genes. In fact, the differences between species many be in part due to these types of sequence elements. Their specificity for a given species by definition makes them nonconserved.

Another type of nonconserved element are "transposons". These are selfish, parasitic sequences that jump around the genome, making copies of themselves. Whether there are advantages to a species to have these types of sequences is an area of active investigation.


Joshua Mendell: Another new and very exciting area of genetics has come from the discovery of common "copy number variation" in the human genome. It was known that throughout human populations, specific nucleotides vary from individual to individual. It has been hypothesized that these differences are responsible for the differences among individuals (for example, height, weight, hair color, build, etc.). We now know that large regions of the human genome may exist in different copies in different people and this may contribute to normal variation in populations and also disease. This is a very exciting new area of research.


David Brown: I think we are out of time. It was a small but interesting group---a 300-level seminar! Thanks for listening. And thank you, Dr. Mendell, for joining me.


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