Genetics For The Rest Of Us: July 2015

Thursday, July 23, 2015

New genetic clues for depression

Current estimates for depression from the National Institute of Mental Health (NIMH) indicate that in any given year, 6.7% of the American population has the disease. To put that statistic in terms that are easier to grasp, that means that over 21,000,000 people have the disease in this country alone. It’s been hard to nail down what could be causing it, however.

Finally, scientists think they’ve finally found the first hard genetic links to major depressive disorder (MDD).

Depression, like most complex diseases that result from a combination of both genes and environment (e.g. diabetes, heart disease, etc.), is a difficult disease to study. For a long time, we’ve known that many people with depression have family members who also suffer from the disease and that stress or other traumatic events can intensify the disorder.

For the longest time, though, searches for genetic variants that could cause the disease came up empty. Learning from the difficulties experienced by other groups of researchers, the CONVERGE consortium (a group of scientists based in both China and the UK¹) used a different approach from previous attempts to study the genome of Han Chinese women. When they did this, they found variants in two genes, SIRT1 and LHPP².

Finding the first genetic clues for what causes depression is an enormous breakthrough to say the least. Figuring out how these genes help to cause depression in the first place is the next step. Thankfully, one of the genes that may help cause the disease in Chinese women may give us a clue about what could be causing depression in patients from other parts of the world.

SIRT1 is involved in maintaining the health of mitochondria³, which is the “power plant” of the cell. Mitochondria are instrumental in producing adenosine triphosphate (ATP), the usable form of energy for cells that we produce by breaking down sugars in food. When the mitochondria don’t function properly, the cell is in serious trouble because it doesn’t have the energy to do what it needs.

The fact that depressed individuals may have problems with mitochondria fits nicely with ideas that have been discussed by biologists and psychiatrists for a while.

The brain is highly demanding when it comes to energy production. As an organ, the brain only weighs about three pounds, but it consumes about one-fifth of the body’s energy⁴. In order to keep up with demand, the mitochondria have to be working non-stop at peak efficiency. So, if a gene variant makes the mitochondria less fit to produce energy the brain needs, it stands to reason that things like mood could be affected.

New brain imaging techniques show us regions of the brain that aren’t working normally in people with depression⁵. We know that serotonin, a chemical that helps cells in the brain communicate with one another, is also important in how the disease works. For example, selective serotonin reuptake inhibitors (SSRIs) make up a major class of medications used to treat depression and related diseases⁶, and they all work by targeting serotonin.

So are SIRT1 and LHPP the entire story when it comes to genetic links to depression? I highly doubt it.

Mitochondria and brain function are controlled by a multitude of genes, but the fact that diseases like depression could be caused in part by problems with energy production in the brain opens new avenues for research, treatments, and ultimately, cures. Findings like these are probably only the tip of the iceberg.

References

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387371/
http://www.nature.com/nature/journal/vaop/ncurrent/full/nature14659.html
http://www.nature.com/nature/journal/vaop/ncurrent/full/nature14635.html
http://www.scientificamerican.com/article/why-does-the-brain-need-s/
https://www.sciencemag.org/content/317/5839/757.full
http://stke.sciencemag.org/content/5/244/pe45.full

Monday, July 13, 2015

Mail-to-order genomics--worthwhile?

NPR recently ran an article discussing why mail-to-order genomic analysis may not be all it’s cracked up to be, and I thought it would be worthwhile to continue that discussion. Companies offering this service are advertising promises that I feel they are often unable to deliver, and I think people should know why scientists like me should be wary of these promises.

In this post, I’ll explain what mail-to-order genomic analysis is, what the genome is made up of, why the genome can be difficult to interpret, and why the genome doesn’t provide the whole picture of human health.

What is mail-to-order genomic analysis?

Many of you have probably seen ads for these services. In a nutshell, companies sell kits so you can learn more about your genome. You can order these kits online, and a company mails you a tube to spit in so you can send it back for analysis. A few weeks later, they give you the results.

One such company, 23andMe, first started selling their kits to customers in 2007, the company was primarily providing novelty genetic information¹. For example, they would look your genome for variants associated with dry earwax or whether your urine was likely to smell particularly bad after eating asparagus.

A few years later, 23andMe got in trouble with the U.S. Food and Drug Administration (FDA), the federal agency that oversees food safety and pharmaceutical drug approval, when they started providing health information in their analysis reports^2,3.

What the FDA was concerned about was that patients would use 23andMe’s genome analysis to make their own health decisions instead of talking to a physician^2,3. This is a problem because genome analysis is relatively new compared to a lot of biology, so scientists and physicians are still don’t understand how variants relate to many diseases.

What exactly makes up the genome?

The human genome is over 3 billion nucleotides (letters that make up the genome, abbreviated as A, C, T, and G) long and split into 23 separate chunks called chromosomes.

Genes in the genome provide instructions for individual components of the cell. Simply put, the genome is the entire instruction set for making an organism. The genome is housed in the cell’s nucleus, the “command center of the cell,” and the cell is constantly referring to it in order to do things it needs.

To relay the necessary information in the genome to the rest of the cell, a gene is transcribed into ribonucleic acid (RNA) and exported from the nucleus. That RNA can encode a message for a protein, an extremely large molecule that performs a given function in the cell, to be made. Outside the nucleus, ribosomes translate the RNA message into a protein.

For decades, we thought each gene made a single protein and RNA was nothing more than a message. We thought that if we sequenced the human genome and found what all the genes were, we’d have a mostly complete understanding of the cell and what makes us human.

Why can the genome be difficult to interpret?

When we first sequenced the human genome, we were surprised to find only 3% of it was made of genes⁴. Moreover, we were expecting to find around 100,000 genes, and we found only around 26,000-30,000. Now, some scientists are the count is even lower, maybe even less than 20,000⁵.

What this basically meant was that 97% of the genome was a mystery.

Around the same time, other biologists were figuring out that RNA did a lot more than we thought, maybe just as many different things as proteins could. Looking at the genome again, we found well over 9,000 genes that didn’t make proteins and instead made RNA with unknown function⁶.

Also, we started learning that each gene could be read in multiple ways to produce slightly different proteins that could have very different functions in the cell⁷. So, the idea that one gene was supposed to make only one protein, was also wrong.

So, saying the genome is complicated is a major understatement.

Why is the genome not the whole picture?

As it turns out, the DNA making up the genome itself can be modified to affect how the cell reads the genome⁸ in response to environmental changes (like if rat mother doesn’t lick her babies enough, certain genes don’t get turned on properly; you can pretend to be a rat mother here). Traditional genome sequencing doesn’t catch these modifications.

We also found out that the way the genome was packed into the nucleus was important. Take progeria, for example, a disease that causes rapid aging (like in the movie Jack with Robin Williams). A few years ago, we found an error in tethering the genome to the nucleus can cause a form of the disease⁹. We’re still trying to figure out how genome packing can affect health and disease, but genome sequencing doesn’t really help us understand it.

Alone, the genome sequence is just one piece of a giant puzzle, which is why the got in trouble with the FDA. It’s misleading to say we can know a lot about your future health by looking at the genome. 23andMe is still a successful company, but they’ve had to scale back on what they way they can and can’t do¹⁰.

So is mail-to-order genomics worthwhile?

Companies like 23andMe certainly told customers genomic analysis was worthwhile.

Doctors already routinely screen for errors in single genes, so genetic information does have real, practical uses. Medicine is certainly heading in the direction of whole genome analysis. The National Institutes of Health (NIH) is pouring money into it, and at some point, genome sequencing will be an everyday part of our lives. But that time is a long way off, I think.

So is mail-to-order genome analysis worthwhile? Not yet, in my opinion.

References

Friday, July 3, 2015

Why should we care about genetics, anyway?

So why should we care about [blank], anyway?

If any of you are anything like me, that’s a question you asked yourself throughout school more times than you can count while filling in the blank with whatever subject you were supposed to be studying. For me, the blank was filled with subjects like physical chemistry. For my wife, it was subjects like art history.

I mean, we all have reasons for caring on some level or another. If nothing else, we at least needed to get a decent grade on whatever we were studying so we wouldn’t have to take it again. But for most of us, once we turned in the final exams and got grades good enough to go onto the next thing, we forgot about them.

But for those people who end up working in those subjects we hate and block out of our memories, that question matters, especially when they’re mostly funded by taxpayer money. When people lose a significant chunk of their paycheck to taxes, they wonder—rightly—if that money is going to things that are worthwhile or if it’s just being wasted. If it’s worthwhile, we’re usually okay with it. If it isn’t, we get angry.

So how do we decide what’s worthwhile?

The answer to that question can be easy to answer a lot of the time. Things like building roads and curing diseases are important and are easy for most people to understand. The problem comes when these important things get obscured by jargon that isn’t easy for most people to understand.

I remember first becoming aware of this problem during the campaign for the 2008 United States presidential election. I was visiting my parents, and we were keeping track of the election coverage (because we’re nerds) when Sarah Palin, then running mate for John McCain, was launching a tirade against wasteful government spending. On that particular day, she was criticizing a $200,000 earmark for basic research studying fruit flies (link at the end of the post).

During her speech, Palin said, “[…] some of these pet projects, they really don’t make a whole lot of sense and sometimes these dollars go to projects that have little or nothing to do with the public good. Things like fruit fly research in Paris, France. I kid you not.”

The problem, aside from the fact that it only took her a few seconds to align the entire research community against her, was that the study she was talking about mattered to the American public for several reasons.

First, the scientists studying that particular fruit fly were trying to prevent the spread of an invasive species that was destroying millions of dollars worth of crops in California; the farmers and businesses relying on the olive trees being attacked by that fruit fly were taking serious financial damage. Second, this funded research project was taking place in the United States, not France (to this day, I have no clue where she got the idea this project was in Paris). Third, fruit flies help form the foundation of modern genetics.

Believe it or not, fruit flies (e.g. Drosophila melanogaster) carry variants of the same genes that humans have with the added benefit of being less complex so we have a better chance of understanding what they do. The human genome is complicated, and studying fruit flies provides an incredible amount of insight into how humans work, especially with respect to diseases like autism (which Palin’s nephew has).

Obviously, Palin was hoping to generate anger to score political points in an election she and her running mate were horribly losing. Also, Palin neither knows nor in all likelihood cares about how important fruit flies are to our understanding of humans. What I saw as the primary problem with her political stunt was the fact that people were listening. Some in the audience laughed at the audacity of studying fruit flies for any reason. Others were probably thinking that research like this had to be stopped because they couldn’t see why studying genetics in fruit flies was worth anyone’s time.

The thing was, though, I felt that I couldn’t really blame Palin for what she was doing. After all, she wouldn’t even be able to do it if scientists could actually explain why fruit flies were important in the first place. If scientists could better communicate with the public, maybe we wouldn’t be facing draconian budget cuts every few years.

The point I’m trying to make is that, as scientists, we get frustrated at the public for not understanding what we’re doing when we only have ourselves to blame for many incidents like the one with Palin. It’s true that most people don’t study science after leaving high school, but we shouldn’t equate that with an unwillingness to learn. Other people just earn their livings through something other than science. Some people fix cars, draw blood from patients, or teach kids in school. I can’t do any of those things. That doesn’t mean I don’t think these things are important or don’t want to know about them.

Speaking from my own personal experience, most people are willing to show an interest in what we study so long as we explain it to them in a simple, friendly, and uncondescending way. Most people are open-minded if you give them a chance to be.

So, with that in mind, that’s the goal for this blog. I want to be able to explain things that are happening in genetics research so the average person can understand them. As much as scientists might like to think themselves immune from public opinion and pop culture, we’re very much dependent on continued interest in the topics we study.

To do that, I have two kinds of posts I’d like to start doing. The first would involve me translating jargon from the latest hot research in my field so people can stay current with what’s going on without having to study genetics for ten years. I would also like to take questions that people might have about basic biology or what they hear about in the news so I can clarify anything that seems archaic.

I’d like this to be as interactive as possible, so if anyone has any questions about biology, genetics, medicine, etc., just let me know!

References

http://news.sciencemag.org/policy/2008/10/french-fruit-fly-fracas