The Thousand Dollar Genome Has Arrived!

The first human genome was sequenced about a decade ago, at a cost of around four billion dollars. The results were amazing, showing us that people have a paltry twenty some thousand total genes. We thought we were a lot more complicated than that. We also found that chimps have DNA sequence about 99% identical to ours. Ouch again! We thought we were more special than that.

OK, we sequenced the human genome, and learned some cool stuff. So, you might think, end of story, now let’s do something else.

But the sequencing of one human genome is really just the beginning of the story. Different people have DNA sequences that are about 0.1% different. Unless they are twins. And twins are remarkably alike, in appearance and just about everything else, exactly because they share the same DNA sequence. The obvious conclusion is that your DNA sequence is really important in defining your many traits.

We’d like to be able to unravel the very complicated relationship between your DNA sequence and your traits. Many diseases have a foundation in DNA sequence. If we knew which of your genes contributed to your disease then we might be able to devise more effective therapies, designed to work best for you.

We’d like to sequence the DNAs of lots of people, with many different illnesses, to better understand the genetic basis of disease. But at four billion dollars per sequence that’s not going to happen.

Enter the DNA sequencing revolution! The cost of sequencing a person’s DNA has been plummeting. A year ago it cost only about four thousand dollars, down a million fold from the original four billion dollars. But even four thousand dollars is still a lot of money.

But, Illumina has just announced a new machine, the HiSeqX Ten, capable of sequencing a person’s DNA for only 800 dollars. Further, it offers staggering throughput, capable of sequencing tens of thousands of genomes per year.

The thousand dollar genome has long been considered the cost point at which genome sequencing can become a standard diagnostic procedure. We are now entering an era where everyone will have their DNA sequenced, and the resulting data will become a key part of our medical records.

As we collect thousands, and then millions of DNA sequences, and correlate them with the corresponding medical records, we will figure out how the different sequences contribute to disease. Medicine is about to take a giant step forward.

And, in a similar manner, we will begin to better understand how DNA sequences impact our other traits, including intelligence, appearance and athletic ability. When this new understanding is combined with our increasing power to manipulate our DNA sequences it opens up some fascinating, and perhaps frightening, possibilities. We will be the first species able to dictate our own evolution.

The term eveloce refers to a singularity boundary point in our evolution, where each generation is more intelligent, and better technologically equipped, to genetically design the next generation. A literal evolutionary explosion results.

And where this will take us, nobody knows. It could well mean the end of the human race as we know it, but perhaps the beginning of something better.

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A Genome Without the Junk Proves that ENCODE Conclusions are Garbage

One of the shocking results of the Human Genome Project was the finding that we only have about 20 thousand genes. This seemed a ridiculously small number to encode an organism as complex as a person. How does a fertilized egg turn itself into an adult human being when it is only equipped with some 20 thousand genes in its nucleus to guide the process??

You might think that if people have 20 thousand genes then other organisms must have far fewer. We’re better than them, right? You’d think it would take more genes to make a person than a mouse, or a frog, or a fruit fly. But it turns out that all mammals have pretty much the same number of genes. And many amphibians have more genes than us. And fruit flies have about 15 thousand genes, a number not way different from us. It is clear that we are not at the apex of the chart when it comes to gene number.

It turns out that only about one percent of our DNA is encoding protein, the prime function of genes. The proteins are the workers, making muscles move, breaking down food, creating energy, and building the backbones of our cells. DNA is the sacred data storage unit, passed from one generation to the next, carrying the code that tells cells how to make proteins. But if genes make up only one percent of our DNA, then what does the rest of the DNA do??

There are competing theories. Some scientists say most of this extra DNA is just junk. It exists, but it does no harm, and we live with it. It is excess baggage that we carry around. But others contend that most DNA actually has function, perhaps in creating very fine regulatory networks to make sure that the genes are properly expressed.

To better understand the function of the noncoding DNA the US National Institutes of Health funded the ENCODE project, the Encyclopedia of DNA Elements. Hundreds of scientists were put on the job, hundreds of millions of dollars were spent, and some of the results have now been published in the most prestigious journals. They were looking for the function of this extra DNA, and they loudly proclaimed that they had indeed found it. And it was not junk! Indeed, based on their studies they concluded that at least 80% of the DNA, not just the 1% encoding proteins, has important function in at least some cell type.

So, one might think, problem solved.

But then an international consortium of 29 scientists published a study of a rather remarkable plant, U. gibba. They are bladderworts, often compared to snapdragons and orchids, and they are carnivorous, trapping and digesting prey organisms. It turns out that U. gibba has a very surprising genome, with almost no junk DNA. The results were so unexpected that the paper was published in Nature (June 2013), one of the most prestigious journals. It turns out that the U. gibba DNA has 28,500 genes, significantly more than human DNA, but the total amount of DNA per cell is only 77 megabases, about 40 times smaller than ours. So, while there are far more protein encoding genes, there is far less DNA. There is almost no junk!

And it is not something peculiar to plants. Most plant DNAs are like most animal DNAs, with only a very small percentage consisting of genes. An evolutionary comparison of the U. gibba DNA with DNAs from related plants, including tomatoes and snapdragons, shows that the U. gibba has somehow figured out how to eliminate the excess DNA. And yet is does just fine! It doesn’t need the junk!

The unavoidable conclusion is that the extra DNA is not required. It has no essential function. It is really just junk. And ENCODE is wrong.

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Is it OK to have three parents??

We all have two parents, a mom and a dad, and they each contributed half of our genes. We all learned this in high school biology. It’s that meiosis thing, with reduction divisions making sperm and eggs with only half the normal number of genes, and then their union restoring the full number.

But that isn’t the whole story. Our cells have mitochondria, little energy factories, that have their own genes. Not very many genes, just a few. There are thirty seven mitochondrial genes, compared to about 23 thousand in the nucleus. But these mitochondrial genes have very important functions. Defects in these genes can cause a number of diseases, including mitochondrial myopathy (with muscle problems), Leber’s hereditary optic neuropathy, which can cause blindness, and Leigh’s disease, which results in degradation of motor skills and eventual death.

Interestingly, the mitochondrial genes are quite exceptional, since they are only inherited from the mother. I actually showed this as a graduate student, way back in the early seventies. I analyzed the mitochondrial DNAs from horses and donkeys, and their mixed progeny, mules (male donkey and female horse parents) and hinnies (male horse and female donkey parents). The results showed that the mitochondrial DNA just came from mom. This turns out to be true in all mammals.

Now suppose that mom has a severe mitochondrial gene mutation that she’d rather not pass to her children. Normal procreation would result in all of her children receiving her mitochondrial DNA, with the mutation. But there is a way to fix that. We can give the fertilized egg a cytoplasm transplant from a donor egg without the mitochondrial DNA mutations.

The simplest way to achieve this would be to transfer the nucleus of the fertilized egg to a new egg from a healthy mother. The resulting child would have three parents. Half of the nuclear genes would come from mom, and half from dad. And all of the mitochondrial genes would come from the second mother that donated the egg with the healthy mitochondria.

This is very different from nuclear transfer cloning, where an adult nucleus is placed into a surrogate fertilized egg. Cloning is very inefficient, usually succeeding for only about one percent of nuclear transfers. And even then there is question about the health of the progeny.

In contrast, the three parent scheme, with the nucleus of the fertilized egg moved to the donor egg with the nucleus removed, requires no fancy reprogramming to turn an adult nucleus into an embryonic one. It would work extremely well, with no obvious consequences, except the resulting child would have healthy mitochondria.

And what is wrong with that??

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Poop is more therapeutic than antibiotic

In a recent study appearing in the New England Journal of Medicine it was shown that in some cases swallowing some poop can actually do you more good than taking a powerful antibiotic.

Els van Nood and colleagues were studying patients suffering gut infections caused by a nasty bacteria, Clostridium difficile. These bacteria release toxins that can cause severe abdominal pain, intestinal inflammation, bloating and diarrhea. They produce spores that are fairly widespread. Indeed many people catch the bug while in the hospital (how convenient!), resulting in an estimated 14 thousand deaths per year in the US (http://www.economist.com/news/science-and-technology/21565586-bacterial-medicine-starting-emerge-bugs-system).

Unfortunately, about 20 percent of people treated with powerful antibiotics respond poorly, suffering recurrent infections. So, someone came up with a brilliant idea. What if we treat them with poop instead of antibiotic??

At first glance this might not seem so smart. After all, they are already infected, and isn’t poop full of germs? How could that make them better?

Well, it can.

In fact our intestines are indeed normally full of bacteria. In fact they are so small and numerous that, in the end, our bodies actually have more bacterial cells in them than human cells. But these bacteria normally do no harm. Not all bacteria are bad. And the good bacteria in the gut actually compete with the bad ones, keeping down their population. So a proper intestinal flora mix, with a strong population of good bacteria is actually important for health.

It turns out that sometimes people with intestinal infections actually just need a good stool transplant. Perhaps their good bacteria have been killed off by a previous treatment with antibiotics, or such, leaving the bad guys free to ravage the gut unchallenged.

So in this study it was shown that stool infusion into the intestine, (probably better than drinking it), from a healthy donor, was actually far superior in treating patients than antibiotics. Indeed the results were so dramatic that they ethically had to stop the study midway. The control patients that had been receiving antibiotics were given stools instead, so they would have a better chance of recovery.

I’m wondering if those of us with especially good poop will now be able to patent it, turn it into pills, and make a fortune. Sounds like easy money to me.

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Chronic Inflammation: The Rich Guy Disease

Chronic inflammation is the modern day silent killer. It promotes the development of many deadly diseases, including cancer (http://www.scientificamerican.com/article.cfm?id=chronic-inflammation-cancer), heart disease, stroke, Alzheimer’s disease and diabetes (http://www.lef.org/protocols/health_concerns/chronic_inflammation_01.htm).

So, what is inflammation? Acute, or short term, inflammation is our normal response to an infection. The infected area becomes red, swollen and inflamed. We bring our innate immune system arms to bear, knocking holes in the bacterial cells, spewing out chemical poisons, and actually eating the enemy. A war against the infection is waged, and when it is won everything returns to normal.

Chronic, or long term, low level inflammation is, however, quite a different beast. The body is acting like it is constantly battling a low grade infection, even though generally none is present. And the effects can be lethal, as mentioned, promoting a host of diseases.

What causes chronic inflammation? There are several likely causes, including stress, obesity, diet, and in some cases actual chronic infection. But recent studies suggest a surprising correlation between an affluent lifestyle and chronic inflammation.

It has been known for some time that “being too clean can sometimes lead to disease.” (http://www.pbs.org/wgbh/rxforsurvival/series/diseases/polio.html). Polio, for example, existed for many centuries as a common virus, but rarely causing disease. Polio virus normally infects out intestinal tracts. It is transmitted by the “fecal-oral route”, when our poop contaminates our food. Before good sanitation procedures became common almost everyone carried the polio virus and infants would be infected at an early age. But the virus is quite benign when infecting infants, probably because of partial protection from the mother’s antibodies. So the severe form of the disease, where the nervous system is attacked resulting in paralysis, was uncommon. But in the 1900s, as the water supplies and sewage disposal systems became more sanitary, fewer people became infected with the virus, so sometimes the mother did not transmit protective antibodies, and infections at a much later age became more frequent. FDR was not infected until he was 39 years old. And at this age the paralytic form of polio is much more likely. So we paid a price for our improved hygiene.

A similar story might hold true for chronic inflammation. McDade et al (http://www.ncbi.nlm.nih.gov/pubmed/22639072) recently published a study in the American Journal of Human Biology where they examined chronic inflammation levels in the hinterlands of Ecuador, where very primitive living conditions prevailed. It is possible to quantitate chronic inflammation by measuring the blood levels of a protein, CRP, produced by the liver. They followed the CRP levels of the Ecuadorians for many weeks, finding that they have remarkably low levels of chronic inflammation. Of course their CRP levels went up when they had an infection, but their background CRP levels were about four times lower than what is seen in America. None of the Ecuadorians had CRP concentrations that would classify them as having chronic inflammation. This is in sharp contrast to America, where one third of adults have chronic inflammation, with CRP levels above 3 mg/l.

MacDade et al state that “infectious microbes have been part of the human ecology for millennia, and it is only recently that more hygienic environments in affluent industrialized settings have substantially reduced the level and diversity of exposure.” They suggest that natural exposure to microbes at an early age helps to fine tune our immune systems, “and in the absence of such inputs, poorly regulated or self-directed inflammatory activity may be more likely to emerge.”

So, when our immune systems aren’t presented with enough other things to attack, they might decide to attack us! It is probably not appropriate to start feeding our kids dirt, but it might be time to develop a safe soup of microbes, a kind of probiotic for infants, that could help them to mold their immune systems, and to reduce the levels of chronic inflammation in coming generations.

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Genetic Determinism, Indeed!

Genetic determinism, according to Wikipedia, is the belief that genes, along with environmental conditions, determine morphological and behavioral phenotypes. It does not mean that genes totally rule, and will decide your preferred political party, your religion, and your love of carrots. It just means that genes are really important in shaping who you are.

So how much is decided by genes, and how much by environment? How much nature and how much nurture? Studies of identical twins have helped us answer this question. Identical twins are the result of an early split of an embryo, thereby giving two people instead of one, but with exactly the same set of genes.

Below is a picture of my grandmother, Martha, and her identical twin Mary. In the small town where they grew up they were known as the Sin Twisters. No one could tell them apart. They’d often swap out for taking tests in high school, and even on dates. And no one was the wiser. Shades of the movie The Parent Trap, but they turned out better than Lindsey Lohan.

 

twins smallest Genetic Determinism, Indeed!

So, give two people the same set of genes and they’ll look pretty much identical. It is easy to conclude that genes are extremely important in determining appearance. But what about other things, like intelligence, athletic ability, and health? Twins can also help us figure out the genetic contribution for these features. The key is to study twins that were for some reason separated at birth and raised in different environments. If genes are really important in defining characteristics then one would predict that identical twins raised by different families would still show significant similarities, above and beyond their physical appearance.

Sir Francis Galton was the first to use twins to study the genetic contribution to traits. He was a cousin of Charles Darwin’s and was very much taken by the theory of evolution and interested in studying the inheritance of characteristics, including intelligence. He coined the term “nature versus nurture” and concluded from his work that nature was more important than nurture.

The modern day Minnesota Twins Study is one of the most comprehensive investigations of nature versus nurture. They have analyzed hundreds of identical and fraternal twins, raised in the same or different environments. It turns out that environment has relatively little effect on physical features. If you take identical twins and rear them apart they still look identical. And if you take fraternal twins and raise them together they still don’t look the same, although there will be similarities, in part because they do share half of their genes.

IQ also showed strong heritability, with the results indicating that about 70 to 80 percent of a person’s IQ is determined by genes. There were also some surprising results to come from the study, showing genetic contribution to unexpected psychological attributes. For example, there seem to be happy and sad genes. Identical twins, even when raised apart, scored more alike in measures of happiness than fraternal twins. And another surprise was the connection between genes and the level of religiosity. One might think that family environment in this case would be particularly important, with children exposed to religion on a weekly basis much more likely to become religious. But if one identical twin was religious, then the other was more likely to be as well, even when raised separately. Of course genes did not pick the faith. One twin might be a devout Protestant, while the other twin, raised by a different family, would be a devout Jew. And what about health? Genes are clearly important here as well, with hundreds of diseases now known to have a genetic component.

Of course genes are also important in defining our athletic ability. As an example of the relationship between genes and athleticism consider the dogs shown below. They are both female whippets of about the same age. But one has a mutation in the myostatin gene, and as a result her muscles have grown to rather enormous proportions. She is one very strong and very fast whippet. It turns out that some human body builders have natural occurring mutations in the same gene. They were born to body build.

wendy smallest Genetic Determinism, Indeed!

 

So genes play an important role in defining both our physique and our psyche. But it is also important to note that they don’t completely define us. Identical twins are certainly similar, but they are not the same. Although our genes establish limits, within those limits there exist a wide range of possibilities, determined by chance and our environment.

Finally, there is the question of how much we currently understand about the relationship between genes and traits. Suppose that we could completely control the genetic makeup of our offspring. Perhaps shockingly, this possibility is not as far-fetched as you might think. Could me create children that are incredibly smart, healthy, good looking and athletic? The truth is that right now we understand very, very little about the genetic equations that define these traits. And it is clear that the answers are going to be, in general, extremely complicated.

But there is currently a revolution going on in the world of DNA sequencing. The price continues to plummet. We are now sequencing the DNAs of tens of thousands of people, and in the near future it will be millions. We will then be able to connect the dots, and relate the different orders of the G,A,T,C bases to the different traits of the people that carry them.

The future of our species could get very interesting.

About the Author: Eveloce was an undergraduate at UCLA, received his PhD from the University of North Carolina at Chapel Hill and was a postdoctoral research fellow at Harvard Medical School. He has published over one hundred research articles, co-authored the third edition of the medical school textbook Larsen’s Human Embryology, and serves on the editorial board of the science journal Developmental Biology. He wrote the book “Designer genes: A new era in the evolution of man” published by Random House and available at Amazon.

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All about flesh eating bacteria

The 24 year old graduate student Aimee Copeland fell when a homemade zip line over the Little Tallapoosa River broke. She hit the rocks below, suffering deep cuts that became infected with flesh eating bacteria. And the horror began, with doctors forced to amputate both feet, both hands, all of one leg, and part of her body, in an effort to save her life. When told they would remove her hands she reportedly looked up and mouthed the words “Let’s do this”, appreciating that her purple hands would have to go.

So, what is flesh eating bacteria? The condition can be caused by many different kinds of bacteria, including Streptococcus pyogenes, Staphylococcus aureus and Clostridium perfringens. In the case of Aimee the culprit appears to be Aeromonas hydrophila, found in warm climates and fresh or brackish water. Like the antibiotic resistant strains of Staphylococcus aureus (MRSA), it is resistant to most antibiotics. It produces a toxin (poison) called Aerolysin Cytotoxic Enterotoxin that damages tissue.

How do you catch it? It can infect cuts, as was the case for Aimee, or you can even get it from a bruise (about one third of cases), and sometimes there is no evidence of an injury at all. You can also get it through foods, including seafood, meats and some vegetables.

The bacteria that cause it are fairly common, so the question is why do some people get it and others not? People with compromised immune systems are susceptible, as you might expect. But there is also increasing evidence that some people are genetically predisposed to get certain infections, even if their immune systems are otherwise perfectly fine. For some reason their immune systems are particularly prone to invasion by certain strains of bacteria. It also appears that the bacteria can make toxins that disable the immune system.

How do you treat it? The Aeromonas bacteria encode a protein called beta lactamase that degrades penicillin and the penicillin derivative antibiotics. Despite antibiotic resistance most strains will respond to so-called third generation agents. The other treatment is surgical removal of the most infected areas (surgical debridement).

What are the symptoms? The first symptom is usually pain at the site of a wound. Then the pain gets worse and the tissue around the wound swells and can change in color. As the infection spreads there are flu like symptoms with fever, nausea and diarrhea. It is important to get treatment early. Death can result within 24 hours, and even with high-dose antibiotic treatment about 25% of patients die.

The technical term for flesh eating bacteria is necrotizing fasciitis, which is a fancy way of saying dying tissue. It is generally relatively rare, with about 4 cases per 100,000 people (http://www.bioedonline.org/news/news.cfm?art=1234). So don’t panic, but be careful!
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