Today, genomic interpretation can be like looking at tea leaves, but the CLARITY Challenge is hoping to change that. (Image: micahb37/flickr)

Children’s Hospital Boston recently announced a $25,000 competition for the development of an interpretation and communication system that can deliver genomic information from the lab to physicians and patients. As the cost of genome sequencing continues to fall and may break the $1,000 barrier soon, the issue is no longer about acquiring genetic data but about what all the data means. Scientists around the world have been making progress interpreting the molecular language of DNA but, as the Human Genome Project revealed, the human genome contains at least 25,000 genes, so research can be slow going. Furthermore, what information is obtained and published in journals has a hard time finding its way into practices for physicians to understand and apply toward patient care.

At the heart of the challenge is a rather simple question: can genomic information be analyzed effectively and presented to a doctor in a way that helps the patient?

While the hospital could have just tossed more money at genetic research to promote advances, it’s chosen to host a competition to drive innovation. The CLARITY Challenge, which stands for the Children’s Leadership Award for the Reliable Interpretation and appropriate Transmission of Your genomic information, directs research groups and companies to focus on major bottlenecks in genomic medicine. Competitors will receive raw DNA sequence data from three de-identified children with confirmed, unknown genetic diseases and their families. The challenge is to develop a system to root out the underlying genetic basis for the disease and communicate that information in a way that guides physicians in caring for their patients.

The winner is scheduled to be announced in October.

Frankly, in the healthcare world, $25,000 is really not that much money, considering that research grants frequently are in the millions of dollars. But the prize that awaits the group that wins the CLARITY Challenge is what every researcher on the frontier of medicine can claim and reap the rewards from: being first. For something this significant in genomic medicine, odds are that whoever claims the prize will be winning for years to come.

[Media: micahb37/flickr]

[Sources: PR Newswire, Vector, WSJ]

New study shows that blood-based gender tests performed in medical labs are 95% accurate, but says nothing about direct-to-consumer testing.

Want to find out if your baby is going to be a boy or a girl but aren’t sure about what test to use? A new study shows that simple, non-invasive blood tests are highly accurate as early as seven weeks of pregnancy. By comparison, ultrasound requires at least 13 weeks to reach the same level of accuracy. But don’t go and grab the first blood test you find online. The study evaluated tests performed in medical labs, and even though companies typically use the same methods, the accuracy of direct-to-consumer tests have yet to be evaluated.

Fetal sex determination is typically determined with a quick and noninvasive ultrasound. But at 11 weeks ultrasounds get it wrong 40 percent of the time, although by 13 weeks its accuracy approaches 100 percent. The current study, led by Tufts University’s Diana Bianchi and published this month in the Journal of the American Medical Association, sought to determine how blood-based gender tests measured up. The results were impressive. They compiled data from 57 studies that measured the accuracy of lab-based gender testing. Of the over 6,500 pregnancies included in the studies, the tests determined sex with an accuracy of 95 percent at 7 weeks and 99 percent at 20 weeks. The researchers also evaluated the accuracy of urine-based tests. With inaccuracy rates as high as 24 percent, they concluded that urine-based tests were unreliable.

How can a baby’s gender be detected in the mother’s blood? During gestation, some of the baby’s DNA will mix into the mother’s blood. After isolating the DNA, technicians can test for the male-specific Y-chromosome. Because the mother doesn’t carry a Y-chromosome herself, detecting one would indicate she’s carrying a boy. One source of inaccuracy, however, are cases in which no Y-chromosome is detected and it’s concluded that the baby is a girl. But absence of proof is not proof of absence – failure to detect a Y-chromosome could simply mean sufficient amounts of the baby boy’s DNA is not present in the mother’s bloodstream. The baby’s DNA collects in the bloodstream over time, accounting for increased gender-test accuracy at later weeks of gestation.

The study comes at a time when online genetics test are a burgeoning industry. Since the human genome was sequenced in 2003 companies peddling at-home genetics tests have exploded onto the scene that claim to read our DNA and give us information on our ethnic heritage, family tree, what foods we should eat to stay healthy – even the sport we’re best fit to play. Not to be left behind during the genomics boom, many companies are also spinning out tests to reveal to excited parents just what to expect. Then they can tell their friends, think of a name, buy trucks instead of dolls and paint the room blue.

Except, it doesn’t always work out as planned.

After spending $300 on a screen, Rohit and Geeta Jain were told to expect a baby boy. The testing company claimed to be 95 percent accurate. When their precious little baby girl was born six months later they were stunned. Rohit told the LA Times, “There’s only two choices – either it’s a boy or a girl. I couldn’t fathom how it could be wrong.”

One could fathom how it could be wrong, were it wrong only 5 percent of the time. But while the direct-to-consumer gender testing business as a whole hasn’t undergone the sort of evaluation that Bianchi’s group performed, there are signs abound that parents-to-be may just want to hold off on painting that nursery just yet. Cases like the Jains’ are all too common. In 2005 Acu-Gen Biolab offered the Baby Gender Mentor test. Featured on the Today Show and Newsweek, the company claimed that their test was 99.9 percent accurate. In 2009 the company filed for bankruptcy as a result of a class action lawsuit against hundreds of women who had been refused a refund after the test turned out to be wrong.

The Federal Trade Commission has issued a warning to consumers to be skeptical of at-home genetics tests in general, as “some of these tests lack scientific validity.” LA Times science writer Karen Kaplan mentions that scientists view the tests as “the latest incarnation of old wives’ tales about salty food cravings, hairy legs and belly shapes denoting the sex of the impending baby. This time, the predictions are being sold with the patina of cutting-edge genetic technology.”

Blood-based gender testing is already being performed routinely by doctors in the Netherlands, the UK, France, and Spain use the tests routinely to determine if the baby needs to be tested further for gender-linked disorders. For example, Duchenne muscular dystrophy, a genetic disorder that results in the rapid weakening of muscles, overwhelmingly affects males. If it is determined that the baby is a girl then the costly genetic test for muscular dystrophy can be ruled out.

But some countries don’t look at gender testing as a convenience or health measure. Research has shown that in both India and China the tests are increasingly being used to select for males – baby girls are being aborted. Consumer Genetics Inc., the makers of the blood test “Pink or Blue” requires women to sign a consent form agreeing not to use the tests for gender selection. Also, the company refuses to sell its kits to customers in China or India.

Direct-to-consumer genetic tests, including gender tests, will continue to multiply as the genomics boom continues. As of 2008 there were approximately 1,400 tests on the market. Still none of them are regulated by the FDA, which means the buyer better beware. Even the relatively simple detection of a Y-chromosome can go awry. Although the overall accuracy of the tests included in the current study was very high, the researchers saw a lot of variability. Despite the tests being carried out in bona fide medical labs there were still some that were simply not as accurate as others. The technology is there and the study shows that on average the professionals know how to use it. With blood tests, parents eager to have their baby’s sex don’t have to wait 13 weeks. But until governments formulate a plan to evaluate and regulate direct-to-consumer tests, it’s probably best to have that test in the clinic.

[image credits: Healthfiend]
image: Healthfiend

Belgian Blues, the Schwarzeneggers of cows.

It’s been more than a decade since humans have cracked their own genetic code, but we’ve yet to wake up to a world of engineered lifeforms on the Island of Dr. Moreau. While we’re waiting for genetic science to mature maybe we should take a good long look at cows. Specifically, the Belgian Blue. This muscle bound meathead is a monument to the genetic power of selective breeding. A single genetic defect, a faulty myostatin gene, is responsible for its enormous bulk, and that defect was carefully passed on through the breed for more than a century before it was even known what was causing the cattle’s impressive ‘double muscling.’ Watch the introduction to life of the modern Belgian Blue in the video from National Geographic below. Before we dive into modifying the human gene pool, we better learn the lessons that working with the Belgian Blue has taught us: even the most primitive genetic tools are immensely powerful, they raise serious ethical concerns, and their results are so impressive as to almost guarantee their use. With genetic testing on the rise, and artificial insemination more prevalent, sex is primed to undergo a major renaissance in the years before it’s outdone by genetic engineering.

For those who have never seen a Belgian Blue in person, the experience is…dramatic. Imagine walking past a dozen or so regular bulls and being intimidated by their sheer size and strength. Then imagine passing a bull so heavily laden with muscle it makes all those scary bulls look like cupcakes. That’s the Belgian Blue, and despite the breeds docility, it never fails to impress onlookers as a very frightening animal.

In the clip above we hear about some of the amazing advantages associated with the Belgian Blue strain. They can have 40% or more additional edible muscle mass, most of which is lean meat! They gain weight well, and quickly, and produce high protein milk for their young. While they comprise a relatively small percentage of the international market, the meat itself is highly prized as its lean nature makes it healthier (and some say more tender and juicy as well). Unless you’ve specially requested it, I doubt most of you have tasted Belgian Blue, but if you are interested here’s a listing of where you can find it offered in the US and Canada.

What the breeder in the National Geographic video doesn’t have time to outline is the physical problems associated with uninhibited muscle growth. The Belgian Blue and the Piedmontese, another breed with myostatin problems, are viable farm strains of cattle. They can live, reproduce, give milk, and be consumed with no risk to humans. To themselves, however, these Conan-looking cows are less friendly. They experience a wide range of health risks associated with their muscle – calves can develop enlarged tongues and stiff legs which make it difficult, if not impossible, to feed, leading to early death. Many of the cattle develop cardio-respiratory ailments. In almost all modern herds, Caesarean sections are common due to complications in pregnancy, and in some cases C-section rates have climbed to nearly 90% of all births!

Caesarean scars are clear on this cow, and are common in most herds.

Both the impressive bulk and health issues of the Belgian Blue have been maintained through the relatively simple technology of line breeding. Essentially, a very few bulls are selected to be the fathers for calves in all of the females. By choosing those bulls which clearly demonstrate the myostatin defect phenotype, breeders can make more and more of the muscled cattle. Once semen is collected from bulls (as the video so graciously shows us – eww) it can be tested and then used to impregnate cows through artificial insemination. Anecdotally it is suggested that most of the world’s current Belgian Blue herds were derived from just three bulls and their descendants. While that may be an exaggeration, the truth is certainly that in efforts to perfect the breed very few male genetic lines are allowed to continue.

When shaved, the muscle of the Belgian Blue is even more obvious.

That’s true for all types of cattle and livestock, really. Traditional selective breeding pushes us towards a narrower gene pool. It’s unclear if that is going to get much worse or much better as modern genetic testing takes hold. We’ve already discussed how cheaper DNA tests are allowing cattle breeders to choose the absolute best bulls for line breeding. Those cheap tests mean that any rancher can now see if they have a prize bull. That may open up breeders to using new fathers, or it may simply replace the very small number of current stud bulls with a new, but equally small, generation of replacements.

Either way, what’s good for cattle is slowly becoming good for humans. Though no one seems to want to phrase it in this way, humans are starting to adopt selective breeding habits and technologies. There are now several companies that sell genetic tests in association with in vitro fertilization (IVF) clinics. With good cause, I might add. Successful testing for Tay-Sachs has helped dramatically reduce the occurence of that disease in the US. Most of these newer genetic testing companies are looking to repeat that success for more than a hundred other genetic conditions. Wouldn’t you want to know before you got pregnant if your children would be at high risk for crippling ailments? If you are a genetic carrier for such a disease then Preimplantation Genetic Diagnosis (PGD) can allow you to select fertilized embryos without the disease. IVF and PGD are giving us the tools necessary to, at least in terms of our own gametes, become selective breeders. Breeders informed with rudimentary genetic information, which is a step up from those Belgian farmers who first started propagating their mutant cows.

(Left) Trout given a mutant gene from the Belgian Blue are notably more muscular than regular trout (right).

We’ve discussed before how genetically engineered animals are on the horizon and could be on our plates in the near future. The Belgian Blue’s mutant myostatin gene variation has even been spliced into rainbow trout to give them more bulk (and thus more more worth as food). Animals are already being genetically engineered, and if work in primates is any indication, we’re slowly approaching the time when scientists will be able to waltz inside a human embryo, tinker with its DNA, and get the child to come to term. That possibility, however, scares the sh*t out of most people, and angers the rest. The chances that human genetic engineering is going to have a smooth transition into becoming a popular technology is almost nil. Expect legal and social hurdles to abound. Hell, I wouldn’t be surprised if armed conflict arose around this controversy as well. It could take decades before we accept such technology, though my bet is eventually that we will.

Meanwhile, modern sex powers on. PGD and IVF aren’t universally excepted, but they aren’t fueling riots either. Morally, they are a much more widely acceptable technology. Personally, I know a few IVF (possibly even PGD) kids and my world would be a lot poorer if they weren’t around. I’m glad it’s an option for parents.

But that doesn’t keep it from being a stepping stone to some pretty amazing selective breeding opportunities that could give us the equivalent of designer babies even without genetic engineering. See the Belgian Blue? That’s a single mutant gene that turned out to be helpful, and that simple breeding habit was propagated for more than a century. We’ve already seen human children who were born with the equivalent of the myostatin defect seen in the monstrous cattle. Picture a time when we discover other, relatively rare but potentially advantageous, genetic mutations. Imagine if everyone had the ability to comb through their sperm and find those mutant gametes with the desired traits you want. You could optimize your offspring – give yourself super babies with no genetic tampering required. Long before genetics is ready to replace it with something better, sexual reproduction is going to get more and more impressive thanks to modern technology.

I look forward to seeing all your Belgian Blue-like children in the future.

...this was not what I had in mind.

[image credit: via the Built Report, Terry Bradley via National Geographic, renatothally via DeviantArt, Barbarossa via Wikicommons]
[video credit: National Geographic]
[table via BelgianBlue.org with sources as listed]
[sources: BelgianBlue.org, Hubpages]

By giving neurons bacterial light-responsive genes, neuroscientists are now able to control the activity of neurons using a laser.

More and more neuroscientists are using a new tool to shed light–literally–on the brain to uncover its secrets.

The brain is the most complex object in the known universe. It weighs only about 3 pounds but is packed with 100 billion neurons, each of which sends out intertwining processes and forms thousands of connections to other neurons. How to disentangle the brain’s complexity to uncover the specific neurons and patterns of activity that give us memory, fear, self-awareness, and love? What is the ideal approach to identifying the brain circuits that have gone awry in depression and schizophrenia? Nobel laureate Francis Crick addressed these questions in 1979, writing in Scientific American that neuroscientists needed a method by which “all neurons of just one type could be inactivated, leaving the others more or less unaltered.” The answer to Crick’s scientific prayer is called optogenetics–a technology in which lasers and genes converge to enable neuroscientists to turn off neurons–and turn them on–with unprecedented control.

It’s one of those inventions that brings two facets of nature’s ingenuity together in an unnatural way. Green algae microbes make a protein called channelrhodopsin that allows them to detect sunlight. Channelrhodopsin is a channel that opens when activated by sunlight and allows positively-charged ions into the algae. When neurons communicate, they are similarly activated by positively-charged ions. The ions cause the neuron to fire an action potential–the electrical activity that’s behind brain function. By inserting algae’s channelrhodopsin gene into neurons, scientists have produced neurons that are activated by light.

Normal neurons fire action potentials on a millisecond timescale. Because the lasers themselves can be flashed at a millisecond timescale, researchers can program the laser to induce the neurons to exhibit activity behavior that is very close to their normal behavior in the brain. Different types of activity that neurons normally exhibit–such as steady, tonic firing or firing in bursts–can be induced and the impact on brain processing can be assessed.

Scientists have been scouring nature for more genes like channelrhodopsin in an effort to expand the optogenetic toolset. Halorhodopsin, a protein found in halobacteria is a channel for, not cations, but negatively-charged anions. When these proteins are activated by light they inhibit the neuron rather than activate it. And it just so happens that these two proteins are activated by different wavelengths of light. Channelrhodopsin is activated by blue light while halorhodopsin is activated by green light, so scientists can inject the two genes into the same group of neurons and turn them on or off at will. The versatility of optogenetics is also strengthened by the ability to insert the genes into specific cell types. Channelrhodopsin has been expressed exclusively in the inhibitory cells of the mouse cortex. The ability to activate specific cell types in different brain regions is a powerful method by which to parse out the different functions of neuronal subtypes in brain circuits.

Before optogenetics, neuroscientists used electricity and drugs to tamper with and study neuronal circuits. But these are comparatively crude probes. Activating neurons by current injection suffers from low spatial resolution, as the current will spread to neurons surrounding the targeted area. Drugs spread too and are often administered systemically. Not only does this reduce spatial resolution and complicate data analysis, it also makes side effects unavoidable. These issues are overcome by the precision of optogenetic’s pinpoint laser.

The video below is a TED Talks seminar in which MIT’s Ed Boyden discusses the latest in optogenetics research. He describes how the technique is being eagerly adopted by labs across the world to advance the study of post-traumatic stress disorder and addiction, and how it might one day be used to treat seizures and macular degeneration. The overactive neurons of a seizure patient could be quieted using inhibitory halorhodopsins. Boyden is himself involved in using optogenetics to treat macular degeneration. In macular degeneration the light-sensitive tissue of the retina die, resulting in vision loss. But the neurons that transmit the visual information from that tissue, however, are still intact. Boyden suggests that the disease might be treated by giving those intact neurons channelrhodopsin and making them responsive to light. He likens it to putting solar panels on a house. He’s already begun testing this idea in mice. In a fascinating demonstration, he shows a blind mouse swimming aimlessly around a pool searching for a platform to stand on. The location of the platform is cued by a light signal that the blind mouse cannot see. After injecting the mouse’s retina with the channelrhodopsin gene it swims right over to the light.

In the manner that polymerase chain reaction (PCR) revolutionized the way we study genes, optogenetics continues the scientific tradition of ingenious new tools leading us to new insights. We owe our debt of gratitude to Karl Deisseroth and his group at Stanford University for bringing us this wonderful tool. Deisseroth was the first to introduce channelrhodopsin into the brains of mice in 2005. Today, thousands of scientists across the world have adopted the technique to study the brain. In 2010 optogenetics was dubbed Method of the Year by the journal Nature Methods. That same year the journal Science listed it among the breakthroughs of the decade. One of the most exciting facets of science is revisiting old problems with new perspectives and new tools. Optogenetics is still in its early days. As more neuroscientists adopt the technique and push it as far as they can, one can only guess what mysteries of brain function and disease will be brought to light.

[image credit: New York Times]
[video credit: TEDtalksDirector via YouTube]
image: Optogenetics
video: Ed Boyden

If asking nicely doesn't work, maybe science can reveal the secrets of the immortal jellyfish!

The search for the fountain of youth has been ongoing ever since man decided that dying wasn’t all that appealing. And now, it appears that this elusive holy grail has been found, albeit by a species that is not ours! So who is the lucky winner of the everlasting life sweepstakes? None other than the humble and dime-sized jellyfish known as Turritopsis nutricula. This creature has accomplished what no other biological being on our planet has ever been known to do: reverse it’s aging to become young again after reaching full maturity! As early as 1992, scientists had observed this phenomenon in Turritopsis and research into its secrets was ongoing. However, a recent spike in the numbers and geographic distribution of this species has once again brought it to the attention of the greater scientific community because of the many important breakthroughs we have witnessed in stem cell research in the past decade. As regenerative medicine continues to grow into the future of medicine, it’s clear that this tiny jellyfish may hold the answers to not only addressing the many aging-related ailments we face, but also our own mortality!

In the picture below, you can see the typical lifecycle of a jellyfish. It starts out as a larva that eventually sinks to the bottom of the ocean and attaches to a sturdy substrate and continues development into a polyp that resembles a sea plant. The polyp then matures to become a free-floating medusa, what we commonly recognize as jellyfish resembling an upside down saucer with tentacles. Not much excitement so far, but Turritopsis has put an interesting twist to this process. It undergoes development much like what I’ve described above and what many of its relatives go through. However, during times of stress like a shortage of food, Turritopsis responds by beginning to reverse the process before eventually becoming a polyp again. From this point then, it can again develop into a sexually mature medusa when conditions become more favorable. Theoretically, it can repeat this process indefinitely as its cells undergo a process called transdifferentiation, a rare biological process whereby any non-stem cell can become a different cell entirely. It is still unclear whether only specific cells can only become other specific cells or if any cell in Turritopsis has the potential to become any other cell.

The typical lifecycle of a jellyfish. Exciting, isn't it?

Ok, what Turritopsis does is admittedly cool, but why would we care? As you know, here at the Hub, one of our favorite topics are stem cells and all the promise they hold for regenerating tissue and treating a vast array of ailments. And while stem cells are one avenue to reach the goal of regenerating damaged or diseased tissues, transdifferentiation is another option that can get us to that goal.

Allow me to digress here and clarify the difference between these two systems (also see the below figure). Stem cells are cells that can differentiate into any type of cell. They can be isolated from a natural state i.e. embryonic stem cells (ESCs), or created by taking already differentiated cells and coaxing them to undifferentiate into stem cells, becoming induced pluripotent stem cells (iPSCs). These stem cells can then differentiate into another type of cell. On the other hand, transdifferentiation doesn’t require the middle step of becoming a stem cell. Any differentiated cell can become any other differentiated cell, given of course that it receives the correct signals.

If transdifferentiation can be harnessed in the lab, we may be able to avoid using stem cells altogether.

Much of the advances in stem cell technology have come from having an understanding of how stem cells naturally develop into different cell types. Thus, nature’s methods are teaching us how to manipulate stem cells and turn them into the desired cell type. And when it comes to transdifferentiation, the hope is that we will eventually be able to learn how creatures like Turritopsis skip the stem cell step and go directly from one cell type to another. As such, a recent breakthrough in using transdifferentiation for therapeutic purposes was reached in the laboratory of Dr. Deepak Srivastava of the Gladstone Institute of Cardiovascular Disease at the University of California, San Francisco. In a recent article in the journal Cell, Dr. Srivastava’s group describes their success in getting architectural cells in the heart called fibroblasts to differentiate into cardiomyocyte-like cells. In case you’re rusty on your cardiac anatomy, cardiomyocytes are the cells in the heart that contract and result in it’s rhythmic beating. And as Dr. Srivastava explains in the video below, it is the loss of these cells and the development of scar tissue that is debilitating to those fortunate enough to survive a heart attack. So by just switching on three genes in the fibroblasts, the researchers were able to coax them to transdifferentiate into cardiomyocyte-like cells that looked and behaved like cardiomyocytes. Taking it one step further, they implanted these cells into the hearts of mice and found that they behaved just as one would expect them to. In a previous post, we had described similar results, but in that work, the researchers had to first produce stem cells from skin cells before producing the cardiomyocytes. Clearly, Dr. Srivastava’s group has taken this to another level.

So while we still have some hurdles to overcome before this type of treatment is available for use in humans, it is indeed on its way. The amazing work being done in laboratories such as Dr. Srivastava’s are inching us closer to the day when perhaps we’ll be able to not only treat various ailments, but also to turn back the hands of time and reverse our aging like Turritopsis has been able to do. A recent press release by Advanced Cell Technology (ACT) hints at some potentially new technologies they are developing to take advantage of transdifferentiation. While most of their work thus far has focused on stem cell-based treatments, it’s encouraging to see companies like ACT put time and money into exploring transdifferentiation-based treatments as well. Sure everyone is working to get to the same goal, but there may be more than one way to get there!

[Sources: Cell, National Geographic, Wikipedia, Advanced Cell Technology, Gladstone Institute of Cardiovascular Disease, Nature Reviews Genetics, KQED TV]
[Image Credits: Russel McAvoy, Nature Reviews Genetics]
[Video Credit: KQED TV]

As published in the Public Library of Science One, the cows were cloned by somatic cell nuclear transfer–the same method Ian Wilmut used to clone Dolly–in which the nucleus of a somatic (body) cell is transferred into an egg that has had its nucleus removed. Prior to inserting the somatic nucleus into the enucleated egg, Dr. Li’s group infected it with a virus carrying the human gene for lysozyme. Lysozyme is an enzyme found in large quantities in human breast milk that can lyse–or split open–the cell walls of harmful bacteria in the gut. In addition to its antibacterial effects, lysozyme works to boost the body’s immune response to infection. The immunological benefits imparted by lysozyme is an important reason why breast milk is so healthy for developing babies. It’s absent in most of the baby formulas commonly-used to supplement or substitute breast milk. Compared with the 200-400 μg/ml concentration found in human breast milk, cow milk normally contains lysozyme at 0.05-0.22 μg/ml. The milk from Dr. Li’s cows increased their lysozyme concentrations more than a hundred-fold to 26 μg/ml.

In addition to lysozyme, Dr. Li’s group successfully cloned cows that produce milk containing two additional human proteins, called lactoferrin and alpha-lactalbumin, both of which strengthen the baby’s immune system. Like lysozyme, these proteins are found in normal cow milk but increasing their amounts will provide a further boost to the baby’s immune system. On top of that the cow benefits as well. The human genes will help protect the cow’s udder from infection, possibly decreasing the need for feeding the animals antibiotics, a major contributor to the harrowing pattern of antibiotic resistance that is spreading worldwide.

In addition, the SKYLAB scientists made the cow milk more human-like in other ways. They increased milk fat content by about 20 percent and changed the concentrations of certain milk solids to more closely match the concentrations found in human milk. The group victoriously proclaimed that their demonstration proves that it is possible to “humanize” cow milk.

So when should we expect to find the cow-produced, human-like milk to show up at a supermarket near us? Dr. Li, collaborating with a Beijing company called GenProtein Biotechnology Company, projects it’ll take about ten years until the milk is made available to the public. How palatable consumers find the humanized milk is anybody’s guess at this point. The ChinaDaily reported that Dr. Li describes the milk as having a “stronger” taste than normal milk–but he didn’t specify normal cow milk or normal breast milk. We’ll just have to wait and see, I guess.

The researchers claim that the Holstein cows used in the study produced "humanized" milk but were otherwise normal.

Probably more important than taste, much of the West is still weary–if not outright hostile–to the idea of GM foods. Countries of the European Union are especially incensed–61% of Europeans are opposed to GM foods. As suggested by the Wall Street Journal, however, the increasing costs of non-GM food imports may cause Europeans to soon change their tune. Obviously, GM foods don’t face the same opposition in China which is moving rapidly towards the commercial use of genetically-modified foods such as rice and corn. The fact that they were able to combine two techniques that are still controversial in the West–GM and animal cloning–with the public visibility that they did is indicative of a country that is ready to take the lead on this area of research, and reap all of the economic benefits that will inevitably follow. Dr. Li alludes to this in the paper, saying, “Thus, our study not only describes transgenic cattle whose milk offers the similar nutritional benefits as human milk but also reports techniques that could be further refined for production of active human lysozyme on a large scale.”

If you’re totally grossed out by the idea of putting human genes into animals you should know that Dr. Li’s cows are far from the first organisms to have human genes and produce human proteins. Since the 1980s we’ve cultured the bacteria, E. coli, carrying the human gene for insulin (a protein). The easily mass-produced and purified insulin from bacteria was an improvement over the purified cow insulin we’d been using up until then to treat persons suffering from type 2 diabetes. Soon thereafter we enlisted the help of E. coli to produce human growth hormone. But bacterial systems are limited in their capacity to correctly fold and modify the comparably complex proteins produced by mammals. Because of this mammalian systems have been developed to express our mammalian genes. Human antithrombin III has been grown up and purified from farm animal milk; the human antibody interferon β1a has been grown up in chicken egg whites. To date the list of human genes grown in these and other mammalian systems includes monoclonal antibodies, blood factors, hormones, growth factors, cytokines, enzymes, milk proteins, collagen and fibrinogen.

Add to the list human lysozyme produced in cow milk. If we’re already growing it in cow milk, and we’re already drinking cow milk, is it really that much of a stretch to combine the two in a nice, refreshing, frothy cup?

Or baby bottle?

Dr. Li and his research team hopes that their readily available “humanized” milk will provide an option for women who can’t breast feed or don’t want to breast feed their child. Unfortunately it seems that fear-mongering, anti-GM groups often cause the benefits of GM to get overlooked, this despite the majority of American citizens eating GM foods without even realizing it. My guess is that when GM foods bear fruit that is both more plentiful and more resilient, sticking with non-GM foods will become an increasingly pricey proposition. The EU is finding this out right now. Will they relax their restrictions on GM, or will China be left to move easily forward into this as-yet unexploited market?

[image credits: supercoolbaby.com, Maksim via wikicommons]

image 1: supercoolbaby
image 2: wikicommons

Scientists were finally able to grow sperm in the lab–from mice. It still remains to be shown if the same procedure can be used for humans.

In an amazing technical feat researchers in Japan have accomplished something that has stymied the field for the past half century: they successfully grew sperm in the lab. They then used the sperm to impregnate female mice and produce a healthy litter. The breakthrough holds promise for millions of men worldwide with infertility.

Published recently in Nature, the work was pioneered by Takehiko Ogawa and colleagues at Yokohama City University. The procedure involves taking biopsies of mouse testes, breaking them up into 1 to 3 mm pieces, placing them on agarose that has been partially soaked with a special medium, and letting them be for two months. If all goes according to plan, the chemicals in the medium would induce the gonadal stem cells to differentiate into mature sperm. Getting the ingredients of that medium right has been the major confound since efforts to produce sperm in the lab began in the 1960s.

To make their lives easier they used mice genetically modified with green fluorescence protein (GFP) that would only become activated in cells that had differentiated into viable sperm. The researchers could then just look through the microscope and all of the stem cells that had successfully differentiated to sperm would glow green.

Imagine, after years of frustration, peering into the microscope and seeing a lovely field of glowing green. But Ogawa and his crew didn’t pop the champagne just yet. The ultimate proof was then to see if their homegrown sperm was healthy and functional–could they be used to successfully fertilize an egg and produce normal, healthy offspring. Using two different methods they fertilized 23 and 35 oocytes, respectively. The dams gave birth to 7 and 5 live offspring who survived to adulthood and were able to produce offspring of their own.

Now it’s time to break out the champagne.

Sperm is often stored frozen in sperm banks for future use. To simulate this scenario Ogawa’s team cryopreserved the sperm in liquid nitrogen for 4 to 25 days. When the cells were thawed and cultured, expression of the GFP marker confirmed that they resumed full spermatogenesis in culture. They have yet to demonstrate that the freeze-thaw cycle leaves their cultured sperm intact well enough to produce healthy offspring that are in turn able to produce healthy offspring. It remains possible that freezing and thawing the cells left some as yet undetected structural damage, for example, or caused some epigenetic changes–changes in the molecules bound to genetic material that affects gene expression. Nevertheless, their demonstration is already an amazing accomplishment.

After 50 years of effort researchers have finally discovered a way to grow sperm in the lab. Swapping out a commonly-used culture ingredient may be the key.

Given the increasing number of successfully grown tissues and stem cell acrobatics flipping one type of cell to another, we may be getting the impression that simply growing sperm in a dish isn’t all that groundbreaking. You half expect those rambunctious miniature tadpoles to will themselves alive on their own. But growing sperm–a gamete–is much more complicated than growing somatic—rest of the body–cells. It is a sequential, multistep process involving a complex list of players named primordial germ cell, spermatogonium, primary spermatocyte, secondary spermatocyte, spermatid and mature sperm. Each of these stages requires an equally complex battery of signals provided by the non-germ cells that surround them. The whole process of going from stem to sperm cell takes over 60 days in humans; in mice (and most other mammals) it takes over a month. Successfully commanding a month long differentiation is a daunting challenge. We’d been trying since the 1960s but, until Ogawa’s study, we’d failed every time.

Through much trial and error, the researchers happened upon a key modification to their protocol that seemed to make all the difference. When trying to grow sperm in a dish a researcher would typically use fetal bovine serum (FBS), serum from the blood of newborn calves. FBS is a widely-used supplement in mammalian tissue cultures. Ogawa’s group had had some success with FBS in the past, but they decided to try replacing their FBS with what’s called knockout serum replacement (Ko-SR). This was a strange move, as Ko-SR is essentially FBS with most of the ingredients that promote the differentiation of cells removed. It’s typically used by stem cell researchers who want their stem cells to remain in an undifferentiated state. Surprisingly, and to the delight of Ogawa and colleagues, the Ko-SR had just the opposite effect: it promoted the differentiation of the sperm stem cells into mature sperm. It’s still unclear why the Ko-SR worked, but Ogawa suspects it’s due to one of the differentiation-inducing ingredients that still remains, called parvalbumin. If this turns out to be true, not only would the study give us a new tool to treat infertility, it will teach us something new about the basic biology of sperm maturation.

The team’s 12 newborn mice mark the triumph of a half a century’s effort. When you’re dealing with biological complexity slow and incremental is not only the pace of progress, it’s safer. It would be a tragedy if we were to give a man who had already conquered cancer the hope of having children, only to hand him the devastation of an unhealthy child. Taking genes into our own hands is risky business (let’s not forget that Dolly had progressive lung disease) and it remains to be seen whether or not the strategy can be used to make human sperm and to make human beings. Nevertheless, the team’s 12 newborn mice are a testament to power of relentless tinkering. And as they continue to tinker I don’t expect we will have to wait another sixty years to hear their good news.

[image credit: Rama and pdimages.com/web9 via wikicommons]

image 1: wikicommons_mouse

image 2: wikicommons_sperm

Detecting this extra chromosome responsible for Down syndrome just got a whole lot easier

Things are definitely on the move in the field of fetal screening. Researchers at the Cyprus Institute of Neurology and Genetics have developed a test that analyzes maternal blood between 11 to 14 weeks of gestation for the presence of fetal trisomy 21, the occurrence of an extra chromosome primarily responsible for Down syndrome. Not only is it an improvement on other methods, it is noninvasive, eliminates screening by amniocentesis, and is 100% accurate. If the results of an early trial can be replicated, a commercial test may be available in a couple of years. This is a welcome addition to the growing arsenal of technologies aimed at turning the tide against genetic disease.

Thankfully, we’re getting closer to the day when those 5-inch needles can be a thing of the past.

Genetic disorders are a broad and complex set of abnormalities in an individual’s DNA that can be evident in the womb or lay hidden until a later point in life. Down syndrome is one of the former and is the most common chromosomal condition, affecting one in every 691 babies. While it is most commonly associated with a characteristic physical appearance, other aspects of the syndrome can vary significantly from one individual to another, such as developmental delays, impairments in physical growth, and a range of other health issues, some life threatening. Nowadays, expectant mothers are warned about the possibility of Down syndrome especially because the risk for Down syndrome rises abruptly with age. In fact, the incidence rate increases from 1 in 1,250 at age 25 to 1 in 106 at age 40, and by age 49, that risk is 1 in 11.

It is now standard to recommend midtrimester amniocentesis for women over the age of 35 and some doctors are urging all pregnancies to be screened for trisomy 21. And that’s where the problem comes in. Inserting a needle into the amniotic sac to withdraw fluid turns out to be kind of risky (who would have thought?). Infection can occur, the fetus could be punctured, or labor could be induced. These risks accumulated into a miscarriage rate of about 1 out of every 200 pregnancies, although current studies suggest that improvements in procedure and the use of ultrasound has lowered that number to 1 in 1,600 pregnancies. Still, everyone can agree that a screening procedure shouldn’t be as risky as the condition it is testing for.

Clearly, Dr. Philippos Patsalis and his colleagues in Cyprus felt that there was a better way, so they started with a discovery 15 years ago that significant amounts of fetal DNA (3-6%) circulates within a pregnant woman’s blood. The presence of an extra 21^st chromosome could be important if they could find signatures within it that could be contrasted against the mother’s DNA. Fortunately, the researchers found eight sites on the extra chromosome that have higher degrees of cytosine methylation. By amplifying the fetal DNA, screening for the higher methylation and running statistical analysis, they were able to detect trisomy 21 in maternal blood in two groups (one control and one blind) of 40 pregnant women with 100% sensitivity and 100% specificity. Additionally, the blood was obtained between 11 and 14 weeks of gestation, which is up to a month earlier than a reliable amniocentesis can be performed. And here’s another cool thing: the methodology uses techniques that are common to many diagnostic laboratories, and that means a low implementation and a low cost. Admittedly, this was a small trial and Dr. Patsalis has stated that a larger clinical trial is needed, but clearly this is moving in the right direction.

The day is approaching when prenatal screening will answer all of an expectant mother's questions

This new methodology not only reflects the power and potential of genetics screening, but it adds to the arsenal of prenatal knowledge that healthcare professionals and parents are gaining access to and at an earlier stage in gestation. A few years ago, we highlighted some of this progress with preimplantation genetic diagnosis for IVF embryos, but for parents who’ve gone about making babies the low tech way, earlier detection is important for making decisions about lifestyles. Let’s face it: raising a child with a genetic disorder can be daunting and many who discover the presence of trisomy 21 opt to terminate the pregnancy, as much as 92 percent in the UK. Ethics aside, this new test for Down syndrome will hopefully become part of the multitude of prenatal genetic conditions that are currently part of standard screens. Considering that 1 in 5 women have their first children after age 35, a new test can’t come soon enough.

[Image: National Institute of General Medical Sciences]

[Source: March of Dimes, National Down Syndrome Society, Nature Medicine, NY Times]

Dr. Sheng Ding pioneered a method by which skin cells are converted to heart cells without going through an induced pluripotent stem cell state.

It’s faster, more powerful, and user-friendly. No, I’m not talking about the latest generation tablet, I’m talking about the latest upgrade in stem cell research. The transformation of adult cells from one type to another is common enough. We’ve reported on researchers successfully transforming skin cells into heart, blood, and intestinal cells. This process typically involves converting the adult cell to a pluripotent, stem cell state, from which it can differentiate into one of the specialized forms. As if the cell one day realized that it never really wanted to grow up to be a skin cell, scientists could help revert it back to its infant—or, embryonic—state so it could have another go at life. A recent study by scientists at the Scripps Research Institute in La Jolla, California showcases a different method that bypasses this initial transformation to the stem cell state. Apparently you can teach an old dog new tricks.

Over the last decade scientists have had increasing success in converting skin cells and other types of cells into something different, including heart and blood cells. Efforts are underway across the world to improve the techniques and clinical viability of these cell conversions. The work by Dr. Sheng Ding and his colleagues at Scripps qualifies as a major improvement. The road ahead still requires much work, but it’s clear that each day mankind moves closer to producing cells of every type, custom made for your body.

Faster

The novelty of the new research coming out of Scripps is not going from skin cells to heart cells beating in a dish—that stuff’s becoming old hat—but that they accomplished it in just 11 days. It is normally a two step process that requires four to five weeks. It also requires a lot more work, owing to the step where the skin cells are converted to induced pluripotent stem cells (iPS). This is done by introducing four genes recently discovered to reprogram differentiated adult cells to embryonic stem cell-like pluripotency. The four genes encode transcription factors, proteins in the cell nucleus that regulate the expression of other genes. Typically the four genes are active for two to four weeks before the differentiated cell is converted to an iPS cell. Ding’s group modified this protocol by allowing the genes to work for as little as four days before deactivating them. The result are skin cells “pushed” in the direction of the induced stem cell state without actually becoming iPS cells. Turns out that’s enough, which, aside from saving time, reveals something new about stem cell biology. The current work was performed using skin cells from mice and it remains to be seen if the shortcut can be applied to human skin cells. Nevertheless, to render the iPS cell stage unnecessary is a major paradigm change for the field and it will be interesting to see if the new paradigm bolsters progress in the near future.

You can see the beating cells in a video below from newsy.com’s coverage of the study:

More Powerful

In addition to being faster, Ding’s protocol boosts efficiency. The old protocol yields an estimated maximum of approximately 0.2 heart cells for every skin cell plated. Skipping the iPS cell stage yields a whopping 1.2 heart cells per skin cell. In the paper the team speculates that the increased efficiency is due to the generation of mitotically active cells which are able to divide and multiply. Resembling heart precursor cells, they speculate further that “these intermediate cells, if successfully isolated and stabilized in culture, could become an expandable and renewable source for not just cardiomyocytes, but many other terminally differentiated cardiovascular cells as well.” In the paper they extend this thought, suggesting that the principle of a versatile intermediate might be important, not only for creating the numerous types of cells that go into making a heart, but for stem cell applications in all tissues.

Scientists at the Scripps Research Institute needed just eleven days to convert skin cells in beating heart cells.

User Friendly

The four genes that researchers use to produce the iPS cells is risky because these same genes can turn cells into tumors. Inactivating them after only a few days instead of a couple weeks reduces this risk. And, like any self-respecting technology, an upgrade is in the making. Because they can turn cells cancerous, stem cell researchers have been searching for a way to reprogram differentiated cells into iPS cells without using the four genes altogether. Demonstrating that the genes are only needed for a few days instead of weeks simplifies the problem and makes the genes easier to replace.

To be sure, stem cell research has a lot of ground to cover before it becomes an effective treatment for disease. For example, the current study was done in mice and it remains to be seen whether or not the shortened protocol produces the same results in human cells. I find it impressive, however, that the four genes widely used by researchers to convert fully-differentiated, adult cells into embryonic-like, pluripotent stem cells were discovered less than five years ago. Since then iPS cells have been gotten by converting other cells besides skin, including cells from the stomach and liver. The current study was the first that we are aware of to bypass the iPS cell stage for differentiation to heart cells, but this shortcut has already been taken for differentiation into blood cells. It is exciting to note that human cells were used in that study.

But in case you hadn’t heard, stem cells have already been used in tissue replacement therapies. We’ve previously reported on tracheal transplants of two women. This involved a donor trachea (from a cadaver) that was coated with a layer of the patients’ stem cells which fostered regrowth of the trachea. Because the new layer of cells originated from the patient the risk of an immune response against the new trachea was minimized.

From my vantage point, it seems that stem cell therapies are inevitable. I also believe that the day is long in coming. Unfortunately it seems that many people have been set up to hope for miracles after the hyperbolic political battles over stem cell research in the past. But therapies rarely come from sudden miracles. Instead it is the incremental advances and shifts in paradigm, such as that achieved by Ding and his colleagues, that will bring us the stem cell therapies we are hoping for.

[image credit: The Scripps Research Institute]

[video credits: newsy.com]

Will mammoths walk the earth again?

For as long as life has been a feature of this planet, natural selection has been wiping out species with subpar adaptive strategies. Among the casualties: dinosaurs, mammoths, Neanderthals, and all manner of megafauna that we’d all love to see first-hand. Alas, mother nature hasn’t been particularly forgiving of species selected against: for four billion years, extinction meant extinction. That is, until last year.

The exception to this sobering evolutionary rule? The Pyrenean ibex, a kind of goat native to the Pyrenees Mountains between Spain and France. For a century, this subspecies of Spanish ibex had been living on the brink of extinction; on January 6, 2000, the last surviving Pyrenean ibex (named Celia) was naturally selected against via a falling tree. Fast forward to 2009, when scientists used frozen tissue to successfully clone Celia, making the ibex the first species (or subspecies) to become un-extinct. Well, for seven minutes.

Celia’s second incarnation died shortly after birth due to physical defects in her lungs, one of a variety of problems common to cloned mammals (other defects include malformed hearts, compromised immune systems, and developmental delays). Cloning is generally accomplished by somatic cell nuclear transfer (SCNT), a process by which a surrogate egg is implanted with the nuclear DNA of the organism to be cloned. But the process is terribly inefficient: Celia’s DNA was implanted into 439 eggs to form embryos, only 57 of which were implanted into surrogate goats, only 5 of which were born, and only one of which was born alive. And that’s what happens with a good genetic sample.

Cloning requires high quality DNA, which is generally in short supply for extinct species. When an organism dies, its cells release enzymes that break down the nuclear chromosomes into short strands of DNA. Over time, this genetic material gets mixed in with bacterial DNA and other life forms that invade the tissue. Nucleotides can also change over time, swapping A’s for T’s and G’s for C’s. By the time we dig up bones of extinct species, they are often too genetically noisy to pick out the original genome. So what options are there?

There are two potential ways to bring long-extinct species back to the present day, and both involve injecting a surrogate egg with the target species’ DNA. The first method is in vitro fertilization of the egg using frozen sperm. This method produces a hybrid between two species (e.g. an elephant and mammoth) and it is only a viable option if the target species’ and the egg donor species’ DNA are similar enough to produce a viable embryo (you can’t implant a dog with a dinosaur). By backcrossing hybrid offspring, breeders could then produce a more pure lineage over time.

The second method of resurrecting ancient species is by pure cloning: emptying the surrogate egg of its own DNA, and injecting it with a copy of the target species’ genome. There are two potential sources of such a genome: researchers can use well preserved (e.g. frozen) somatic cells, as in Celia’s case, or they can build the genome up themselves. No species has yet been cloned with reconstructed DNA, but for long-gone species it might be our best shot.

The mammoth is probably the most likely species to go un-extinct anytime soon. While most researchers feel that frozen mammoths’ DNA is too damaged for cloning, we are close to having sequenced their entire genome (it will be the first completed genome for a long-dead species). Penn State University’s Mammoth Genome Project has sequenced roughly 85% of the mammoth’s DNA; once the MIT/Harvard Broad Institute’s Elephant Genome Project is completed, cross-comparison will allow PSU to close in on that final 15%. But knowing a species’ sequence doesn’t mean it could be cloned: we would either need to stitch together a synthetic version, or alter an elephant’s genome at the relevant sites. We can’t do either yet.

A mouse cloned from damaged frozen tissue (pictured) at the RIKEN Institute

That’s why some ambitious Japanese scientists are betting on frozen tissue instead. The privately funded Mammoth Creation Project aims to resurrect the long-dead species by retrieving frozen sperm from the tundra and creating an elephant/mammoth hybrid. They even plan to make a Critchon-esque “Pleistocene Park” in Siberia to show off their creation to the world. Not much news has emerged on the efforts’ progress, though the theoretical basis of deep freeze resurrection did get a recent boost. In 2008, researchers at Japan’s RIKEN Institute successfully cloned a mouse whose cells had been damaged from 16 years of sub-freezing temperatures – the technique could potentially translate to mammoth tissue as well.

While mammoths often died and froze in the tundra, Neanderthals have (thus far) left us mostly bones. But that hasn’t stopped progress in the Neanderthal Genome Project, a collaborative effort between Max Planck Institute and 454 Life Sciences. Just this May, an initial draft of the Neanderthal genome was published in Science – and it revealed the widely reported gene swapping (i.e. interbreeding) between their lineage and ours. As with the mammoth, the genetic samples were noisy: fragments of Neanderthal genes were mixed in with bacterial and fungal DNA, as well as the human DNA of the scientists who dug it up (in fact, over 90% of the DNA in the samples were contaminant, i.e. non-Neanderthal).  To distinguish which genetic material in bone samples were Neanderthal and which were not, researchers cross compared the samples with both human and chimp genomes.

As with mammoths, there’s a big difference between sequencing a Neanderthal genome and actually cloning one. A synthetically produced genome would need to be packaged into chromosomes that can be replicated in a cell, which we don’t know how to do yet. George Church has suggested that a technique invented in his lab, called MAGE, could be used to alter an induced pluripotent stem cell into the genome of a Neanderthal. The stem cell could then be induced to grow into a heart, arm, or brain of a Neanderthal for research purposes. And what about cloning a whole organism? It’s conceivable, but raises some rather sticky ethical concerns among the public and scientists alike.

In case you hadn’t guessed, dinosaurs are quite a ways off (just try a googling “Tyrannosaur Genome Project”). Ancient species have fewer close extant relatives which we can use for comparison, and their samples are worse for wear. Still, sequencing is getting faster and faster, and we seem to be doing better with noisy and damaged DNA. If we can iron out the difficulties of chromosome packing and clone viability, we can expect more species to join the un-extinct list. And for the roughly 100 species that go extinct every day?  Well, besides slowing human-caused extinction with animal and environmental conservation, we can always put them on ice in a frozen zoo.

[image credit: Steven W Marcus, ExhibitEase LLC; RIKEN Institute]

[source note: some of the Neanderthal cloning progress came from an excellent article written recently for Archaeology, "Should we clone Neanderthals" by Zach Zorich]

As we previously reported, the International Open Facility Advancing Biotechnology (BIOFAB) is a project to produce thousands of standardized genetic “parts” for researchers to use in the pioneering work of synthetic biology. Started with a seed grant from the National Science Foundation (NSF), BIOFAB is the world’s very first biological design-build facility. They will be providing bioparts to researchers gratis to speed along national research into new drugs, biofuels, chemicals, you name it – all the promising frontiers of synthetic biology. And they should be open for business within 6 months.

So what exactly is a synthetic biology “part”? Good question – that was exactly the topic of the project’s first human practices report (found here). The short answer is that biological parts are small snippets of DNA with basic, well-understood functions (e.g. the production of a certain protein). Building a microbe from scratch is no easy task, especially if you have to identify and characterize all of these building blocks yourself. That’s exactly what synthetic biologists have been doing – it costs millions of dollars and takes years of legwork.

Synthetic biology is an emerging field that combines biology and engineering to reconfigure DNA into desirable results, generally microorganisms that can be used to produce drugs, perform chemical reactions, or work as fuels. But because the field is so new, there haven’t yet been standards set for what works and what doesn’t. Characterizing these basic components (and providing them) will give a common engineering language for researchers working on very different problems. It will also make potential progress faster and cheaper.

BIOFAB director Drew Endy (Stanford) and co-director Adam Arkin (UC Berkeley)

But researchers will still have their work cut out for them. One of the most problematic issues for synthetic biology – and one that BIOFAB deals with regularly – is that DNA snippets are only “parts” in the context of some “whole.” Genes work in complex networks, altering one another’s expression in interdependent ways; removed from the context of a larger genome, the function of any particular genetic strand changes. This makes the issue of isolating concrete characteristics to each part a difficult task: it acts differently depending on the surrounding DNA. It’s significant that this difficulty is precisely what has been a major road block for post-Genome Project genetics more generally.

So who sets the standards? Consider it Biology 2.0. Collaborative, open source efforts from many different labs have resulted in the emergence of what are called BioBrick standard parts. Many of these have been collected and housed at the Registry for Standard Biological Parts, founded in 2003 at MIT (we ran a story on this last year). The director of BIOFAB, Drew Endy of Stanford, was instrumental in shaping BioBrick part standards – and now his team is building a factory to provide them to the research world.

BIOFAB was launched in January of this year, and is currently a small scale operation (they have about 10 staff members total). The project is housed in a Lawrence Berkeley National Labs building in Emeryville, CA, and is a collaboration between researchers from UC Berkeley and Stanford (apparently despite the football rivalry). Perhaps a dubious award to some, BIOFAB was named “Best Local Innovator” by the East Bay Express, a Bay Area paper which also recommends the taco truck near my house. Suffice to say I trust their opinion.

Gene mutations can tell us our personal disease susceptibilities. Are we ready?

If you were going to get Alzheimer’s disease, would you want to know? Or is genetic ignorance bliss? The new era of commercial genetics is putting all sorts of predispositions right at peoples’ fingertips, and not all of it is good news. As more people are genotyped in both research and commercial settings, a new ethical question emerges: are people ready to face their own DNA? One study at Boston University says – with a few important qualifiers – yes.

The BU School of Medicine ran a multi-year psychological review of peoples’ emotional reactions to learning their susceptibility to Alzheimer’s disease (AD). The Risk Evaluation and Education for Alzheimer’s Disease (REVEAL) study genotyped the adult children of AD patients for the gene ApoE, one variant of which increases an individual’s chances of developing the disease by 10 to 30 times. They then looked at how the disclosure of this information affected levels of anxiety, depression, and test-related distress. The group found no significant short-term psychological fallout of delivering bad news, at least compared to subects’ emotional baselines and a control group. Most people accept the news and move on.

The study was highlighted in a recent Wired feature on Google co-founder Sergey Brin which documents his discovery of a mutated LRRK2 gene within his own genome. Brin, whose wife Anne Wojcicki cofounded 23andMe, has a genetic polymorphism that puts him at a significant risk for Parkinson’s disease. Not everyone has the resources to mount a full-scale assault on their genetic predisposition – Brin has thrown $50 million at Parkinson’s research – but most of us would react as he has: by educating ourselves, weighing our options, and getting on with our lives.

Led by primary investigator Dr. Robert Green, the REVEAL study recruited 162 subjects whose parents have Alzheimer’s disease but who themselves are asymptomatic. All the subjects underwent genetic counseling during which they discussed their family history, learned about the gene in question, and took initial psychological surveys. Subjects were then randomly assigned to one of two groups: a disclosure group which received their genotypes, and a control nondisclosure group whose blood was not analyzed.

Within the disclosure group, 53 subjects tested positive for the ε4 variation of the gene, which is implicated in AD susceptibility. A major theory of Alzheimer’s disease is that it results from excessive amyloid plaque deposits in the brain. ApoE codes for a protein that helps to break down these deposits; the ε4 variant is thought to make the body less efficient at clearing the plaque, putting a carrier at greater risk. All subjects were tested for three psychological factors – anxiety, depression, and test-related distress – 6 weeks, 6 months, and 1 year following the tests. ε4 carriers reported higher test-related distress at the 6 week mark, but otherwise emotional states did not differ significantly from either the ε4-negative or the nondisclosure groups. Most subjects said that given the chance, they would undergo the test again.

Unfortunately, it’s hard to say whether these results could be generalized to the general population. For one thing, all the subjects were people willing or curious to know their own genotype; the study even found that those subjects who self-referred (i.e. sought the study out) had lower anxiety and depression levels in the first place. Researchers also specifically excluded participants whose baseline anxiety or depression were above a certain threshold. Arguably, these are the subjects most likely to undergo significant emotional distress at the bad news. Finally, the researchers acknowledge their results could have been different if their subjects weren’t well educated on the gene and disease (i.e. genetic counseling and family histories with AD).

This final question of education gets to the heart of most concerns about genetic knowledge. Just how well educated is the public when it comes to their genes? Media outlets (but certainly never this one) constantly report genetic research in ways that are both sensationalist and overdeterministic. “Scientists discover the gene for alcoholism!” tends to make a better (and shorter) headline than “Scientists discover gene polymorphism is statistically more prevalent in alcoholics than in control groups!” The difference is important. Too often, people perceive genes as having clearly understood, direct causation with their phenotypes, which is frankly a flattering but misinformed picture of the current state of most genetic science. We haven’t reached GATTACA just yet.

That being said, assuming people can’t handle their own genetic susceptibilities seems (to quote 23andMe’s Esther Dyson on a related issue) “appallingly paternalistic.” Genetics is already becoming ubiquitous, both in medical and commercial sectors. We can’t (and shouldn’t) be protected from our genomes; we should be educated about them. Most of our genetic knowledge regarding disease is probabilistic anyway, so learning about predispositions can help people make smarter preventative dietary or medical decisions (e.g. as with news of high cholesterol). And that’s what I call personalized medicine.

[image credit: Davidson College Dept of Biology; Stanford University]

FDA = Big Brother

The New York Times reports that last week the FDA announced plans to regulate commercial genetics companies like 23andMe and deCODE. The agency sent (and posted) letters to five major genetics companies, claiming their services fall under the FDA designation of a “medical device” and must therefore be regulated federally. The FDA is calling on each company to either apply for federal approval or explain why they are exempt, igniting debates over how the dawning age of personal genetics will fit into existing structures of medical regulation.

Among the letter recipients are 23andMe, deCODE, and NaviGenetics, all companies that test for genetic variations linked to ancestry, disease susceptibility, and potential drug responses. Also tapped was Illumina Inc., a company that sells DNA chips for other companies to use (e.g. 23andMe uses customized versions of their chips), and Knome Inc., which offers complete genome sequencing and has scanned more genomes than any other company in the world. This round of letters wasn’t exactly unprecedented; last month, Pathway Genomics Corp., which markets an at-home saliva genetic test, received a similar letter.

We often report about new frontiers in the genetics revolution – the amazing success of prenatal screening, the dawn of synthetic genomics, chasing the causes of autism and developing new cancer treatments. The acceleration of discoveries in genetic technology is dizzying, and not just for the curious layperson. Legal and legislative institutions have faced the new challenge of making unprecedented decisions about how to regulate these emerging technologies. Can you patent a gene? Can employers or insurance companies peek at your genome? Or, in the present case, does a DNA kit count as a diagnostic tool? These are social, ethical, and political questions that didn’t exist twenty years ago, and our government has been scrambling to address them as they emerge.

The issue at the center of the FDA’s crackdown – what qualifies for federal regulation – has traditionally been determined by how widespread a device or service is.  Generally, FDA approval is required for any medical device that is widely distributed for use in laboratories, doctor’s offices, or sold in stores (Pathway was attempting to sell saliva kits – which we previously described in detail here at the Hub – at Walgreen drug stores).  Companies like 23andMe argue that their genotyping takes place in-house, and should therefore be exempt from federal red tape (the FDA pointed out that the company’s saliva kits are sold on Amazon). Esther Dyson, a board member at the company, has even called the FDA’s position “appallingly paternalistic.”

But distribution isn’t the only issue at stake.  A more interesting question is whether your personal genome is currently a tool for diagnosis – and if not, when it will be. As we’ve covered recently, the state of the union is less than perfect. Commercial genetics companies interpret their customers’ genomes by means of correlation studies; any particular genotype is “associated” with a disease because it is found in higher proportions within diseased populations. This kind of probabilistic genetics isn’t the same as understanding the molecular mechanisms by which genes act, much less the environmental factors involved in a final phenotype. Today, with a few exceptions, a genome scan cannot diagnose much more than statistical likelihoods.

But this will change. As genetic testing gets cheaper, research will accelerate and begin to unlock how gene expression contributes to certain diseases. As a genome scan becomes a real diagnostic tool, it will need to be regulated just as other medical devices are. In this sense, the FDA’s move is preemptive to the changes which will come. I’m tempted to think that 23andMe’s resistance has more to do with the open-source philosophy it shares with its partner, Google. It’s your genome, you should have unregulated access to it, etc. Putting peoples’ health into their own hands resonates well with the brave new world these companies envision: less top-down control, no Microsoft-esque middle man, don’t be evil, all that. The FDA here plays the part of big brother, prying into what is frankly between you and your commercial genetics provider.

Do we want a wild zone of laissez-faire freedom when it comes to genetic technology? Probably not. The industry is changing so rapidly, and in such unpredictable ways, that regulation will be essential to addressing the emerging ethical and social concerns that accompany such powerful technology. But the danger is that regulatory systems are inherently conservative, notoriously slow to adapt to rapidly changing fields – information technology and biotechnology being prime examples. Outdated and sluggish regulation will restrict innovation, slow progress, and increase costs in a tangle of decades-old red tape.  The FDA must coevolve to meet the unprecedented needs of regulating a fledgling market without clipping its wings.

Even if a genome scan can’t currently determine very much, that doesn’t mean people aren’t already making medical decisions based on their results. This trend will increase as our understanding of gene expression gets better. The accuracy of these tests should come under closer scrutiny as they become more and more instrumental to our diagnostic processes and healthcare decisions. Commercial testing will need to be regulated eventually – what remains to be seen is whether the FDA can adapt to this new landscape as fast as it changes.

A researcher at the Autism Genome Project

Autism remains one of the most poorly understood and troubling developmental disorders of modern medicine. But the genetic revolution could turn that around. Recent research by the groundbreaking Autism Genome Project has identified key mutations and susceptibility genes involved in the disorder. Down the road, this could pave the way for new treatments.

Autism is a poorly understood developmental disorder that can cause impaired social interaction, poor communication skills, repetitive behaviors, and a variety of other symptoms. Cases differ in both the degree of severity and particular symptoms, and include three subtypes along what is called the autism spectrum: Autism, Asperger’s syndrome, and Pervasive Developmental Disorder. Symptoms usually appear before a child is three years old, and the disorder is four times more common in boys than in girls. The National Institute of Health estimates that three to six children in every 1,000 will have some type of autism spectrum disorder.

The cause of autism is notoriously elusive, and has been the focus of extensive research over the past few decades. Because disorders along the autism spectrum are diagnosed behaviorally, they exhibit variable symptoms (thus, the “spectrum”) and aren’t the result of any single cause. Controversies over autism’s causes have debated whether its roots are biological or environmental (see, for example, the debunked vaccine theory). Recent research is showing that like most psychological disorders, autism is linked to a combination of genetic, epigenetic, and environmental factors. However, the emerging consensus is that autism is primarily genetically mediated, with high rates of heritability for both autism (0.7) and Asberger’s syndrome (0.9). Until recently, the actual genetic mutations responsible for autism’s heritability have remained unclear.

Enter the Autism Genome Project (AGP). A large-scale collaborative research project of 120 scientists from 60 different institutions, the AGP aims to identify the genetic architecture involved in susceptibility to autism and spectrum disorders. This month, the AGP reported in Nature its findings that strengthen a growing consensus about the role of genetic mutations called copy number variations (CNVs) in the autism spectrum. Because we all inherit 23 chromosomes from each parent, most folks have two copies of each gene or DNA segment – one from mom, one from dad. A copy number variation is when a particular stretch of base pairs (sometimes encompassing whole genes) differs from the expected number of two. Sometimes a deletion leaves one set, and sometimes a duplication gives three or more sets.

The AGP research found a higher prevalence of CNVs in autistic populations than in controls, which are thought to disrupt genetic mechanisms important for neuronal and intellectual development. Only about 1% of the general population has these CNVs, and they are only present in 3.3% of autism cases. The AGP study also identified four susceptibility genes involved in cellular proliferation, synapse development, and signaling between neurons – but again, mutations on these genes are rare and aren’t common to all individuals with autism. These findings support a growing consensus that autism is caused by a multitude of “rare variants,” none of which directly cause the disorder but which collectively increase an individual’s susceptibility.

AGP started in 2002 and has undergone two major phases of research. Phase One concluded in 2007 and identified two genes involved in autism susceptibility.  Phase Two – the research presented here – compared the genomes of 996 people with autism against those of 1,287 control subjects, including many family studies. Future research at AGP will focus on identifying further CNVs within the population by increasing the sample sizes for comparison.

It’s important to recognize the complexity of factors that lead to autism, as well as our limited understanding of these relationships. Autism is not caused by just a few genes or mutations, and we aren’t going to find a “smoking gun” cause anytime soon. In many ways, autism research exemplifies the growing recognition that genetic determinants are messy and complex (recently covered here at the Hub). Instead of straightforward common genetic causes, the susceptibility to autism is linked to unique combinations of mutations, only some of which show significant overlap between individuals.

This recent AGP research is promising in two ways. First, it opens up new avenues for further research, showing scientists where to look to more clearly understand the causal mechanisms that underlie autism’s genetic component. Second, it paves the way for new treatment options by clarifying which molecular mechanisms are broken in the autistic genome – malfunctions we can develop drugs to counteract. This research is most valuable within the broader context of autism’s epigenetic and environmental factors, and its implications for treatment should be combined with equally important therapy-based approaches.

Autism remains one of the most troubling and elusive psychiatric disorders in the modern age. There is still a great deal we don’t know. Is the disorder becoming more common, or is it being diagnosed more consistently? What environmental factors increase the risk of autism, and how do they interact with genetic components? There are many avenues for further research, and it is promising to see such massively collaborative efforts as the AGP. Slowly, as we shed more light on the autistic genome, we can develop treatments more appropriate to the disorder and the individual patient. And because the costs of genetic testing are dropping rapidly, research should continue to accelerate and put new therapeutic options within reach. Maybe someday, we can look back on this pioneering research as the foundations for a cure.

Check out this short video from ABC covering the recent findings:

[image credit: Autism Genome Project]