So we got into a discussion about model organisms, those that are used as a good system to be able to compare back to human beings, and in what ways they are being used.  That we have to even figure out whether or not something has a genetic basis.  Or maybe a good treatment option for a genetic disease.  If an organism shows similar symptoms as a human disease, this will give us a better understanding on when and how the disease progresses, causes and possible treatment options.

This allowed one student to immediately jump into what causes Autism.  We talked about the controversy that surrounds the disorder, and ways scientists are trying to figure out the genetic basis of the disease, and how much the environment can play a role.  In our current discussion, it was a perfect way for me to bring an actual example of how other organisms are being used to find out more about a specific disorder.

It was shown by a group of researchers at Cold Spring Harbor Laboratory that a deletion of a group of genes on chromosome number 16 causes autism-like symptoms.  They used mouse models with the same genetic alteration to show that when fewer copies of these genes are inherited, it leads to features resembling those that are used to diagnose autism.  Changes were seen in the structure of the mouse brain (see image below) and in their overall behavior of the mice.  Using the mouse model, they are able to mimic the disease to better understand what causes it, better diagnose it, and a new possible target for intervention and treatment.

Image from http://www.cshl.edu/Article-Mills/cshl-team-finds-evidence-for-the-genetic-basis-of-autism

Well, it could be your family and it could be your environment. Studies have shown that addictions run in families. In fact, if a parent has an addiction, the child is 4 to 8 times more likely to have an addiction as well. It doesn’t necessarily have to be the same addiction, but an addiction nonetheless. Those with other family members with an addiction are more susceptible to the disease, but that also doesn’t mean that the disease is inevitable.

Saying that addiction runs in the family would speculate a possible genetic component. In fact, researchers are currently trying to link addiction to a cluster of genes in the human genome. Scientists are looking for “addiction genes” that are biologically different from others that might make someone prone to addiction. It also might affect the severity of withdrawals.

For example, in humans, a candidate gene for addiction includes the A1 allele of dopamine receptor gene DRD2 which is common in those with alcohol and cocaine addictions. Also, non-smokers are more likely to carry a protective gene, CYP2A6, which causes them to feel more nausea and dizziness from smoking.

Mice have been a model for studies on human addiction because the reward pathway functions in mice are very similar to those in the human brain.

Mice bred to lack serotonin receptor gene Htr1b are more attracted to cocaine and alcohol. Those with low levels of neuropeptide Y drink more alcohol while those with higher levels tend to abstain from alcohol.

It mainly all comes down to the reward pathway in our brains. The reward pathway is in the center of our brain and connects to other areas such as those controlling memory and behavior. It’s responsible for driving our feelings of motivation, rewards and behavior. The main job of the pathway is to make us feel good when we engage in behaviors essential to survival such as eating and drinking. Places in the brain gather information about what’s happening outside of our body and then strengthen circuits within the brain that control desirable behavior.

For instance, say you’re thirsty and someone hands you a cold water bottle. The brain will tell you that there’s cold water in front of you. Stored in your brain is a memory that says “if you drink that water, you won’t be thirsty anymore and you’ll feel good!” So you’ll drink the water. While drinking, you’re 5 senses will send a single to your brain about drinking the water. The brain, in response will release dopamine, giving you a jolt of pleasure which is your instant reward. The reward pathway will make you repeat the behavior for the same dopamine reward, like a dog doing a trick for a dog biscuit. The wiring in your brain for that particular activity has been strengthened.

Despite the genetic link, it’s not all due to our DNA makeup. Essentially, addiction is the combination of the interaction of several genes (not just a single gene) with social and environmental factors. Also, just because someone has all that’s necessary for an addiction doesn’t mean they’ll have an addiction problem. For example, I know I have an addictive personality but I look for other ways to expel or sedate the addiction and to put that addictive capability to better use.

Researchers have been searching for ways to treat and prevent addictions. One way is the identification of genes. The genes can become “drug targets,” in which researchers can work to modify the gene product’s activity resulting in stabilizing or reversing pathways to restore the brain to proper function.

Earlier this year, researchers at UT Southwestern Medical Center have a new hypothesis. They hope that by increasing a process known as neurogenesis it might prevent or treat addiction. Neurogenesis is a normally occurring process of making nerve cells in the brain. In previous studies, blocking neurogenesis had increased a rodent’s vulnerability for cocaine addiction and relapse. They hope that by stimulating the increase of neurogenesis, it might combat addiction. Another application is to use this increased neurogenesis in situations where a patient is required to use a potentially addicted medication such as Vicodin, a severe pain killer with a high addiction rate. Perhaps this treatment may be used in those who have quit their addiction in order to prevent a relapse.

Recently, new research focusing on microRNA (miRNA) and gene expression might also have a potential effect on the fight with addiction. miRNAs are used in gene expression regulation and gene silencing. They bind to complementary mRNA strands and prevent translation to a protein. Raising the levels of miR-212, an miRNA, in the brains of cocaine-using rats have caused the rodents to take in less of the drug. Completely blocking the miRNA, and allowing full gene expression, increased the drug use. This would suggest a new drug target- a medication to raise miR-212 levels or at least creating something to mimic the miRNA’s function. Liked to miR-212 is an increase in the protein CREB. CREB holds promise in fighting drug addiction by decreasing the reward response, sometimes actually creating an aversion to it all together. The only obstacle with CREB drug targets is the regulation of it. The level cannot become too low (where the rewards are increased) because it can lead to addiction and anxiety, but it cannot become too high (where nothing is rewarding) which can lead to depression. This study has only been done with cocaine and is currently under investigation for the applications in nicotine and alcohol addictions.

Someday, possibly, there will be ways for those suffering from addictions, whether they be chemical addictions, which is heavily mentioned here, or an addiction to more physical things to overcome that addiction and lead healthier lives.

It has been amazing to see what we have learned since then, but even more interesting to think of where this could go in the future.  Hopefully soon we will be able to apply this on a more individual basis, with people being able to identify potential risk factors for certain diseases at their primary care physician.  This then will lead to new developments for drug therapy, having a drug that will be able to target a certain pathway that is specific to that patient.  I can only wonder and look forward to what will come next.

Neandertals, the extinct species of what are most likely our closest relatives, lived on earth at the same time as our human ancestors but died out about 30,000 years ago. With the sequence of their genome now complete, we can compare the DNA to humans and chimpanzees to learn more about what makes humans unique as a species.

The discovery of fossils is an exciting link to our past. Although the fossil bones do contain DNA, much of it is contaminated. Dr. Emily Hodges at the Cold Spring Harbor Laboratory developed a technique to quickly identify and amplify specific portions of contaminated DNA accurately. Referred to by her team as ‘array capture re-sequencing’, the procedure uses regions of human exons (lengths of DNA that code for proteins) to probe for (or fish out) the Neandertal exons from contaminated DNA samples.

Through the technique they were able to identify 88 differences (in a total of only 83 proteins) between human and Neandertal protein sequences. Amazing!

Go to the following links to access both papers:

The Draft Sequence of the Neandertal Genome:

http://www.sciencemag.org/cgi/reprint/328/5979/710.pdf

Targeted Investigation of the Neandertal Genome by Arrary-Based Sequence Capture:

http://www.sciencemag.org/cgi/reprint/328/5979/723.pdf

For addition information on Neandertals:

Science Magazine:

http://www.sciencemag.org/special/neandertal/feature/index.html

DNA Interactive:
http://www.dnai.org/ (under applications>human origins)

Interviews with Svante Paabo:

DNA From the Beginning:
http://www.dnaftb.org/30/concept/index.html (under audio/video)

Of course, everyone asks me what I think about National DNA Day, to which I usually reply, “Every day is DNA Day at the DNA Learning Center.”

DNA is business as usual for me and legions of genetic researchers and counselors, but its also becoming business as usual for a lot of average people who are interested in their health or genealogy.

People also often ask me how I feel about all the personal DNA data that is becoming available. To which I usually reply, “I’d be a lot more concerned about losing a credit card or my social security number than having someone look at my DNA.”

An amazing amount of personal DNA information is becoming affordable to the interested person willing to provide a saliva sample by mail. With the tag line “genetics just got personal,” the company called 23 and Me will provide a sophisticated scan of DNA extracted from saliva for less than $500. The company uses research-grade methods to scan more than 600,000 DNA variations to provide risk information about 150 diseases and health-related traits – as well as genetic ancestry. Several other companies will do a similar analysis at a competitive price. So far, only several tens of thousands of people have actually taken these companies up on their offer of a (relatively) cheap gene scan, messing up their business plans.

It may be that people are holding out to get the whole ball of wax. DNA sequencing is becoming so inexpensive – forget the gene scan – it is becoming trivial to determine a person’s entire DNA code, or genome. To date, whole genome sequences have been published for only about 20 humans, but the 1,000 Genomes Project will increase that number 50-fold. We are only a year or two away from the day when an entire human genome sequence can be generated a cost of $1,000 – the price of a middling refrigerator.

Ethicists, who tend to be people who worry a lot, have done a lot of worrying about the consequences of such genetic knowledge. On a personal level, will a gene scan take on the aspect of genetic tarot, predicting the future course of our lives? What will it be like when we have a precise catalog of all the good, bad, and middling genes—and the wherewithal to determine who has which? In the face of such knowledge, will society continue to acquiesce to those who prefer to let nature take its course or will we gravitate toward a prescribed definition of the “right” genetic stuff? Heavy stuff for sure if you or your family is facing a life-threatening disease or if you think hard about the sort of genetically stratified world envisioned in Brave New World, GATTACA, or The Island.

These scenarios aside, the truth is that, for most people, all this DNA data may be more banal than anyone could ever have imagined. (What, no ethical dilemma?) The original human genome sequence was a composite from several anonymous individuals, for which an extensive informed consent protocol had been followed. However, on becoming the first known individual to have his entire genome sequenced, Nobel Laureate James D. Watson promptly released it all online – with the exception of the ApoE gene that estimates his risk of Alzheimer’s disease. Watson’s sequence has been available for public examination since 2007, with no ill effect to him.

About 400 letters of my genetic code has been in an anonymous online database for several years now, and it hasn’t caused me any grief either. We have the same DNA sequences from about 50,000 students stored in the same anonymous database, and they haven’t caused any alarm. At least I haven’t gotten a single phone call from an irate parent in the 10 years since we started putting the sequences online.

That doesn’t mean we should be cavalier about what we do with our personal health information, including certain DNA data. But I think we’re pretty well covered by the Genetic Nondiscrimination Act of 2008, which prohibits insurance companies or employers from using personal genetic information against us. Besides, there’s just so much DNA data becoming available, no one has time to look at it all – any more than anyone has enough time to keep up with their emails. There’s just too much stuff in cyberspace.

So, I’m not being flippant when I say that I’m not very worried about the proliferation of DNA data. It’s only that there are plenty of other types of data that are more readily available and can hurt us more directly.

That’s why I always carry my wallet in my front pocket.

Cancer cells have mutations in their genes that render them unable to respond to signals that regulate cell division. These cells grow uncontrollably and can invade normal tissue in other locations of the body and cause disrupted functions of major organs. This is why cancer is so deadly.

A mutagen is a physical or chemical substance that can alter genetic material in cells. DNA can be damaged or changed (mutated). Cancer cells have changes in the genes themselves. These changes can include mutations , deletions of part or whole genes or even the addition of extra copies of genes.

There are many mutagens that can cause cancer in cells. These are called carcinogens. Two of the most common and most deadly cancers, lung and skin are caused by two well known carcinogens, cigarette smoke and sunlight. Some studies suggest when 15 cigarettes are smoked, an error in DNA occurs.

Now the UK’s Wellcome Trust Sanger Institute has cracked the code for the mutations within DNA that can cause tumors that lead to these two devastating types of cancers.

This new information can open the door to major advancements in treatment, medication and maybe even cures in the future of skin and lung cancers.

Especially in the United States, eugenics was firmly grounded in agriculture. Many of the leaders of the American movement had backgrounds in plant and animal breeding. For example, prior to becoming superintendent of the Eugenics Record Office (ERO) at Cold Spring Harbor, Harry Laughlin had corresponded with Davenport about their shared interest in breeding fancy chickens. During the first decade of the 20^th century, Davenport was secretary of the eugenics section of the American Breeders Association, and his slight book made clear the agricultural connection, “Eugenics: The Science of Human Improvement by Better Breeding.”

Another of Davenport’s Cold Spring Harbor institutions, the Carnegie Station for Experimental Evolution, also followed an agricultural bent. Its researchers used domestic plants and animals to set up controlled experiments to test evolutionary theory. At the same time that Laughlin and Davenport were establishing the ERO in 1910, Carnegie researcher George Harrison Shull was finishing a series of experiments on hybrid vigor in corn. For several generations he bred individual corn plants against themselves, watching as each inbred line grew less productive and more susceptible to disease. However, crossing two inbred lines maximized heterozygous traits and produced vigorous, highly productive offspring.

Shull’s work on hybrid vigor flew in the face of the eugenic pronouncement of “like with like” and the ERO’s campaign against inter-racial marriages. Race Crossing in Jamaica, published in 1929, was Davenport’s final attempt to provide a scientific rationale for racial purity. After more than 400 pages of data and analysis the best he could conclude was that that race mixing produced  “physical, mental, and instinct disharmonies.” On mental tests, he judged a higher proportion of  “browns” in Jamaica were “muddled and wuzzle-headed,” whatever that means. Eugenicists extended the concept of race to different ethnic and religious groups, so eugenics provided the Nazis a “scientific” justification for their ban on inter-racial marriages between Germans and Jews that began the march to the Holocaust.

Ultimately, Shull’s method was used to increase corn yield five-fold in the U.S., whereas the restrictive marriage laws promulgated in the U.S. and Germany led to heartbreak. Of course, Shull’s method of crossing inbred lines could not actually be applied to humans. However, his sense of hybrids accentuating the fundamental qualities of two different biological lines has actually been born out by centuries of harmonious cross-cultural and cross–racial marriages. There never was any biological basis for restricting mixed-race marriages, and eugenicists’ “data” on this subject was colored by bigotry.  People, like corn or any other organism, benefit from gene mixing that increases heterozygous traits.

Just recently, a group of researchers at the University of Maryland School of Medicine have identified a variant of a gene that is believed to play a major role in determining why people do not respond to a popular anti-clotting medication. This gene variant, carried by as many as a third of the general population can put patients at increased risk for subsequent heart attacks, strokes and other serious cardiovascular problems. The interesting thing is, that this increased risk is not due to patients genetic predisposition for these disorders, but because it renders their medication ineffective.

Medicines that we introduce into our bodies often require one or several important mechanisms to unfold their intended effects: they may have to be actively transported into our cells, biochemically altered and thereby activated, or they may require deactivation and/or removal in order to not do more harm then good. Any of these processes may involve proteins on one level or another and, therefore, depend on genes. Thus, as we have maps that indicate the loci associated with genetic disorders (visit Tour > genome spots in DNA Interactive), we will soon have maps that tell us where to look if we wish to know our predisposition to the medications we use to cure ailments: whether they will do us any good, are totally useless or, in a worst case scenario, can even harm us.