WHO Issues Update on Polio in Central Africa

On March 17, 2014, the World Health Organization (WHO) elevated the risk assessment of international spread of polio from central Africa, particularly Cameroon, to very high. A new exportation event from Equatorial Guinea demonstrates that the risk of international spread from central Africa remains very high. On June 18, 2014, Brazil reported that wild poliovirus type 1 (WPV1) had been detected in a sewage sample collected in March 2014 at Viracopos International Airport in Sao Paolo state. Genetic sequencing indicates that this virus is most closely related to the virus that is circulating in Equatorial Guinea.

Four wild poliovirus type 1 (WPV1) cases have been reported in Equatorial Guinea in 2014. The index case – Equatorial Guinea’s first case to be reported since 1999 – had onset of paralysis on Jan. 28, 2014; the country’s most recent case occurred on April 3, 2014. Genetic sequencing indicates these cases are linked to an ongoing WPV1 outbreak in Cameroon (Cameroon’s most recent case was on Jan. 31, 2014). Equatorial Guinea is implementing outbreak response activities, with three National Immunization Days (NIDs) with bivalent oral polio vaccine (OPV) in April and May, and plans for further NIDs in July and August. NIDs are deemed essential to stop the outbreak as an estimated 40 percent of children are fully immunized against polio through the routine immunization program in the country.

No one in Brazil has been paralyzed by the virus nor is there evidence of transmission within the population of that country. This importation event in Brazil demonstrates that all regions of the world continue to be at risk of exposure to wild poliovirus until polio eradication is completed globally. It is important that all countries, in particular those with frequent travel and contacts with polio-affected countries and areas, strengthen surveillance for polioviruses (especially through the detection and investigation of Acute Flaccid Paralysis or AFP cases) in order to rapidly detect any new virus importations and to facilitate a rapid response. Uniformly high routine immunization coverage should be maintained at the district level to minimize the consequences of any new virus introduction.

An analysis of immunity levels across central Africa found important immunity gaps in most countries in 2014, prompting the large-scale polio immunization campaigns that are ongoing in the area. In Gabon, a nationwide immunization campaign was held in June (with a further round planned for July), and in the Republic of Congo, a nationwide activity was conducted in May (another round is planned for June). Polio vaccination campaigns have been conducted where possible in the Central African Republic (May to June), with another round planned for accessible areas in July.

The WHO says there is no evidence to date that Brazil was re-infected by the poliovirus of Equatorial Guinea origin that was detected in a sewage sample collected in Sao Paolo State in March 2014; to date there has been no evidence of transmission of the virus in Brazil following this exposure.

Given Brazil’s high levels of population immunity, reflected in the high routine immunization coverage (>95 percent) and periodic vaccination campaigns, the lack of evidence so far of WPV1 transmission and the response being implemented, WHO assesses the risk of spread of this virus within or from Brazil as low.

WHO’s International Travel and Health recommends that all travelers to and from polio-affected areas be fully vaccinated against polio.

Source: WHO

US company in Iowa churns out 100 cloned cows a year

In the meadow, four white-haired Shorthorn heifers peel off from the others, raising their heads at the same time in the same direction. Unsettling, when you know they are clones. 

Four white heifers, "genetic twin sisters" produced using cloning technology, from a very elite Shorthorn cow in the US, are pictured at the headquarter of Trans Ova Genetics in Sioux Center, Iowa, on June 16, 2014 - by Juliette Michel

From their ears dangle yellow tags marked with the same number: 434P. Only the numbers that follow are different: 2, 3, 4 and 6.

The tag also bears the name of the company that bred them and is holding them temporarily in a field at its headquarters in Sioux Center, Iowa: Trans Ova Genetics, the only large US company selling cloned cows.

A few miles away, four Trans Ova scientists in white lab jackets bend over high-tech microscopes in the company's laboratories. They are meticulously working with the minute elements of life to create, in Petri dishes, genetically identical copies of existing animals.

Each year, the company gives birth, using the cloning technique, to about 100 calves. It also clones pigs and horses.

The specialist in reproductive technologies for livestock began to become interested in the 1990s in cloning, a niche market.

The birth of Dolly the sheep in 1996 -- the first clone of an adult mammal -- had seemed at the time like something straight out of science fiction.

And the advanced technology raised ethical concerns because it deviates from normal reproduction that marries genetic material from two parents.

Still, the controversial technique has spread and is used in a number of countries, including the United States.

In 2008, the agency charged with US food safety, the Food and Drug Administration, approved consumption of meat and milk from cloned cows, pigs and goats.

But on the other side of the Atlantic, just last December, the European Commission, the European Union's executive, proposed a ban on the cloning of animals used for food and their import. That has yet to be decided.

The commission, however, did not seek a ban on the sale of products from the descendants of cloned animals or insist on the traceability of their origin, actions that were pushed by the European Parliament.

The idea of tracking such animals elicits a shrug from Blake Russell, who heads Trans Ova's animal cloning division ViaGen.

"There are cattle in the thousands globally now", and their offspring and descendants are "going to multiply every year," Russell said.

"It would be next to impossible to go backwards."

Cloning can boost the production of animal protein to feed the world's growing population, said Mark Allan, Trans Ova's director of marketing and genomics.

The technique allows the preservation of desirable characteristics in the cloned animal, such as leaner meat, higher milk production and disease resistance, he noted.

- Bonanza for breeders -

Cloning is a bonanza for owners of elite cows or bulls, who sell the animals' sperm or eggs at a premium price but face the extinction of that income flow when the animal dies. By paying $20,000 to Trans Ova for a cloned animal, the owner can keep on reaping profits into the future.

Opponents of the practice say dangers loom.

The US authorities have made a major mistake by not regulating it, and allowing consumption of cloned meat before long-term studies of its impact on human health, said Jaydee Hanson, senior policy analyst at the non-profit Center for Food Safety.

Mortality rates are higher than for non-cloned animals at all stages of development, and surrogate cows carrying the cloned egg have more problems during pregnancy and delivery, said Hanson.

He said that of the millions of cows produced every year, the number that are cloned is "overall pretty insignificant." 

"But the bottom line is you do not want large numbers of these animals for a number of reasons, number one being that cloned animals are generally unhealthy."

"Any time you take the natural process and you bring change, there's always a learning curve," said Trans Ova's Russell.

Fish found common genetic ground to develop electric organs

The work published this week was led by Michael Sussman, director of the Biotechnology Center at the University of Wisconsin-Madison.

Charles Darwin specifically cited fish as important models for understanding the principles of evolution, the researchers wrote. In the new study, they looked at six different lineages of fish, all of which evolved independently and sometimes in vastly different environments, and found that each used essentially the same genes and developmental and cellular pathways to make electric organs.

The ability to obtain and compare genomic sequences is further validation for evolution, Phillips said. “The interesting thing about this article is not the technology or the genome assembly stuff but the biology, the observation that these different animals all converted their muscle cells to electric cells by turning down the things that muscle cells normally do and turning up the parts that make electricity.”

Phillips’ part began while he was a professor at Madison, where he spent 12 years before he returned to Rice.

“I helped provide the computational infrastructure to do the assembly of the genomic DNA and the transcriptomic RNA,” he explained. “There’s a lot of nucleic acid sequencing involved in this work. It comes off in short bits that are pretty worthless until they’re assembled into at least a first draft of the entire genome.” Phillips’ team also helped with the RNA transcriptomes.

“We mapped them onto the genomic DNA in order to see what cellular components have been up- or down-regulated through evolution,” he said. “It’s a good bit of computational work putting those sequences together before you even get to any biological questions.”

Electric organs are found only in fish, the researchers noted, but they’re in a lot of fish. They’re found all around the world in six broad lineages and are, in Darwin’s view, a great example of convergent evolution: Unrelated organisms indRice University computational biologist George Phillips is co-author on a new paper in Science detailing a 10-year effort that determined a variety of fish with electric organs evolved those organs by similar means.

The researchers found that over time, a genetic toolbox used by independently evolved fish turned muscles into electric organs able to deliver shocks to enemies, navigate and even communicate.ependently evolve similar traits to adapt to their environments or a particular ecological niche.

Some deliver a more powerful jolt than a wall socket through a cascade of electrical activity that moves from cell to cell much like power flows serially through batteries in a flashlight, the researchers wrote.

The new work started with the South American electric eel. The team compiled the first draft assembly of its complete genome and compared it with data from other lineages. That allowed them to trace common genomic pathways that led the fish to ramp up the native voltage in cells that enables muscle to contract.

Millions of such cells in a six-foot electric eel help it deliver a jolt of about 600 volts, Sussman said, making it a top predator. It is “in essence, a frog with a built-in five-and-a-half-foot cattle prod,” he said.

“I consider ’exotic’ organisms such as the electric fish to be one of nature’s wonders and an important ‘gift’ to humanity,” Sussman said. “Our study demonstrates nature’s creative powers and its parsimony, using the same genetic and developmental tools to invent an adaptive trait time and again in widely disparate environments.

“By learning how nature does this, we may be able to manipulate the process with muscle in other organisms and in the near future, perhaps use the tools of synthetic biology to create electrocytes for generating electrical power in bionic devices within the human body or for uses we have not thought of yet.”

“The technology for doing this kind of work has been around for a while,” said Phillips, who has advised researchers on the project since returning to Houston. “Mike Sussman, my buddy and our ringleader, has been a pioneer in recognizing the important biological problems to which we can apply these technologies.

“I’m a general computational biologist and this work sits in my realm. I’m sort of agnostic, many times, about what it gets used for,” he said. “Biology is so diverse, there’s no end to things you can apply this to. It just so happened that electric eels captured Sussman’s attention awhile back.”

The National Science Foundation, the W.M. Keck Foundation and the National Institutes of Health funded the research.

Overall Survival “Significantly Higher” After Second-Line Chemotherapy

Researchers in a country especially prone to mesothelioma say second-line chemotherapy with a drug called gemcitabine can significantly improve survival.

Turkey is home to several cities with some of the highest rates of mesothelioma in the world. It is also the site of aggressive mesothelioma research. Doctors in the Department of Medical Oncology at Acibadem Kayseri Hospital in Kayseri, Turkey, have just released their findings on second-line treatment with gemcitabine (Gemzar) and the results contain some encouraging news for patients struggling with malignant pleural mesothelioma.

A total of 73 mesothelioma patients from four different Turkish institutions were evaluated based on whether or not they had second-line chemotherapy with gemcitabine, an antimetabolite that prevents cancer cells from making new DNA and RNA. All of the mesothelioma patients in the study had first-line chemotherapy with a pemetrexed-based regimen, the most popular treatment for mesothelioma.

On average, the patients who received second-line chemotherapy with gemcitabine survived for a median of two months longer than those who received no second-line chemotherapy. In addition, when the researchers looked at the rates of survival among the two groups at 6, 12, 18, 24, and 36 months, there were significantly more patients in the gemcitabine group alive at 36 months than there were in the first-line chemotherapy-only group.

For patients who had pemetrexed-based chemotherapy followed by gemcitabine-based treatment, the median overall survival was 20.8 months from diagnosis. In contrast, patients who only had first-line chemotherapy followed by palliative care to manage their symptoms had an overall survival of just one year and one month from diagnosis.

“According to our results, we may consider gemcitabine-based regimens as a second-line chemotherapy after treatment with pemetrexed plus platinum in patients with malignant pleural mesothelioma,” concludes lead researcher Hasan Mutlu, a medical oncologist with Acibadem Kayseri Hospital.

The high rates of mesothelioma in certain Turkish cities are blamed on high levels of erionite, a mineral similar to asbestos, in the soil. Rocks containing erionite have traditionally been used to build homes and public buildings in these cities. Elsewhere in the world, most cases of mesothelioma are due to occupational or environmental asbestos exposure.

Source:

Mutlu, H et al, “Second-line gemcitabine-based chemotherapy regimens improve overall 3-year survival rate in patients with malignant pleural mesothelioma: a multicenter retrospective study”, August 3, 201, Medical Oncology, Epub ahead of print

Why Does Biology Still Have the Ability to Surprise Us?

About forty years ago, a biochemistry professor told my class that now that the genetic code had been worked out and the lac operon discovered, the only thing left for us students was to work out the details. Boy, was he wrong!

If there's one thing I've learned over the last forty years, it is that every ten years or so the biological apple cart is upset, and a long-established "fact," an assumption based on incomplete knowledge, is proven to be wrong.

I am sure you can find textbooks that still include some of these old "facts." Below is a partial list of those assumptions that have had to be revised, and some that are still under discussion.

1. Old fact: DNA is stable and genes don't hop around.

New discovery: Mobile genetic elements can hop from place to place in the DNA, duplicating themselves and changing gene expression. Sometimes they carry surrounding genes with them.

2. New "old" fact: Mobile genetic elements are selfish DNA that replicate themselves without benefit to the organism, thus cluttering the genome with garbage.

New discovery: Mobile genetic elements appear to be involved in the regulation of many important genes, and their distribution in the genome is nonrandom.

3. Old fact: A gene is an uninterrupted stretch of DNA that encodes a single protein. Genes are arranged like beads on a string.

New discovery: Genes in eukaryotes are interrupted, sometimes multiple times, by non-coding sequences called introns. The introns get spliced out of the messenger RNA before the message is translated. Because of splicing, one gene can produce many different but related proteins.

New discovery: Genes can overlap one another on the same stretch of DNA, on the same strand or on opposite strands. Thus one piece of DNA can produce multiple different proteins.

Take home message: 1 stretch of DNA ≠ 1 gene ≠ 1 protein

4. Old fact: There are only 3 forms of RNA: messenger RNA, transfer RNA, and ribosomal RNA.

New discovery: New classes of short and long RNA transcripts serve to regulate gene expression.

5. Old fact: Pseudogenes are useless broken remnants of former genes.

New discovery: Not all pseudogenes are useless. Pseudogenes can be transcribed, and their products can be used to regulate the expression of their full-length sister genes. Related to #4.

6. Old fact: The genome is full of junk, the remnants of wasteful evolutionary processes and selfish DNA (see #1, #2 and #5 above).

New discovery: "Junk" DNA isn't junk after all. It has many important regulatory functions in the cell.

Revolutionary discoveries like these often happen when someone tries something new, stumbles across some contrary evidence, and begins to question the validity of an established "fact." The results have been astonishing -- and have even won the Nobel Prize. Because of these discoveries we have gained a new and better, though still imperfect understanding of biology.

Why should we still have the "facts" wrong? After all, we've been studying biology for sixty years after the discovery of DNA's structure, and 50 years after the code was worked out.

Perhaps a better question would be, "Why does biology have the ability to surprise us?" It's because life is much more sophisticated than anything we can imagine. We look at biology from our very limited perspective, and at almost every turn we are puzzled or amazed. You can even read it in the understated, carefully couched language of published articles, where words like "surprising" or "unexpected" appear often.

Remember that biochemistry professor who claimed that all the important work in biology was done? He also said we'd never find gears or wheels in biology. Poor guy!

You'd think that scientists would be more cautious about our pronouncements if we can be so wrong. But we are only human, like everyone else, and our accepted "facts" are often deeply entrenched in our thinking. In truth, though, only one rock solid "fact" exists -- that some time in the not too distant future a strongly held "fact" will be proven mistaken.

Like Darwinian evolution, perhaps?

UCSB researchers explore genetic underpinnings of nerve-cell spacing

The functional organization of the central nervous system depends upon a precise architecture and connectivity of distinct types of neurons. Multiple cell types are present within any brain structure, but the rules governing their positioning, and the molecular mechanisms mediating those rules, have been relatively unexplored.

A new study by UC Santa Barbara researchers demonstrates that a particular neuron, the cholinergic amacrine cell, creates a "personal space" in much the same way that people distance themselves from one another in an elevator. In addition, the study, published in the Proceedings of the National Academy of Sciences, shows that this feature is heritable and identifies a genetic contributor to it, pituitary tumor-transforming gene 1 (Pttg1).

Patrick Keeley, a postdoctoral scholar in Benjamin Reese's laboratory at UCSB's Neuroscience Research Institute, has been using the retina as a model system for exploring such principles of developmental neurobiology. The retina is ideal because this portion of the central nervous system lends itself to such spatial analysis.

"Populations of neurons in the retina are laid out in single strata within this layered structure, lending themselves to accurate quantitation and statistical analysis," explained Keeley. "Rather than being distributed as regular lattices of nerve cells, populations in the retina appear to abide by a simple rule, that of minimizing proximity to other cells of the same type. We would like to understand how such populations create and maintain such spacing behavior."

To address this, Keeley and colleagues quantified the regularity in the population of a particular type of amacrine cell in the mouse retina. They did so in 26 genetically distinct strains of mice and found that every strain exhibited this same self-spacing behavior but that some strains did so more efficiently than others. Amacrine cells are retinal interneurons that form connections between other neurons and regulate bipolar cell output.

"The regularity in the patterning of these amacrine cells showed little variation within each strain, while showing conspicuous variation between the strains, indicating a heritable component to this trait," said Keeley.

"This itself was something of a surprise, given that the patterning in such populations has an apparently stochastic quality to it," said Reese, a professor in the Department of Psychological and Brain Sciences. Stochastic systems are random and are analyzed, at least in part, using probability theory.

This strain variation in the regularity of this cellular patterning showed a significant linkage to a location in the genome on chromosome 11, where the researchers identified Pttg1, previously unknown to play any role in the retina.

Working in collaboration with colleagues at the University of Tennessee Health Science Center in Memphis, Keeley's team demonstrated that the expression of this gene varies across the 26 strains of mice and that there was a positive correlation between gene expression and regularity. They then identified a mutation in this gene that itself correlated with expression levels and with regularity. Working with colleagues at Cedars-Sinai Medical Center in Los Angeles, the team also demonstrated directly that this mutation controlled gene expression.

"Pttg1 has diverse functions, being an oncogene for pituitary tumors, and is known to have regulatory functions orchestrating gene expression elsewhere in the body," explained Keeley. "Within this class of retinal neurons, it should be regulating the way in which cells integrate signals from their immediate neighbors, translating that information to position the cell farthest from those neighbors." Future studies should decipher the genetic network controlled by Pttg1 that mediates such nerve-cell spacing.

Keeley, who completed his bachelor of science degree in the Department of Psychological and Brain Sciences, went on to complete his Ph.D. in the Department of Molecular, Cell and Developmental Biology, both at UCSB. Each program has provided complementary training for his research interests. He acquired an appreciation for behavioral and systems neuroscience during his undergraduate training, then turned his attention to the molecular and genetic underpinnings of the nervous system.

Scientists Discover How the Shocking Electric Eel Evolved its Jolt to Stun Prey

The electric eel is an unusual creature with the ability to create a potent electric field that it uses to hunt its prey. Now, scientists have uncovered the evolutionary origins of this electric field and have found that the eel's charge actually evolved from a muscle. (Photo : Jason Gallant, Michigan State University)

The electric eel is an unusual creature with the ability to create a potent electric field that it uses to hunt its prey. Now, scientists have uncovered the evolutionary origins of this electric field and have found that the eel's charge actually evolved from a muscle.

The electric organ is an anatomical feature that's found only in fish. Over the course of history, though, this feature evolved independently about half a dozen times in environments ranging from the flooded forests of the Amazon to marine environments. In fact, worldwide there are hundreds of electric fish in six broad lineages. The fact that all of these fish are so widely dispersed and unrelated means that electric fish are a perfect example of convergent evolution.

While the fish may be different, though, their electric organ is somewhat similar. The researchers sequenced and assembled DNA from the electric eel genome and then produced protein sequences from the cells of the electric organs and skeletal muscles of three other electric fish lineages using RNA sequencing and analysis. In the end, they found that electric organs in fish worldwide us the same genetic tools and cellular and developmental pathways to independently create the electric organ.

So how does this "charge" work? All muscle cells have electric potentially. In fact, a simple muscle contraction will release small amounts of voltage. The fish amplified this ability by evolving another type of cell called electrocytes, which are larger cells organized in sequence and capable of generating much higher voltages.

"What is amazing is that the electric organ arose independently six times in the course of evolutionary history," said Lindsay Traeger, one of the researchers, in a news release.

Not only did this organ arise independently, though; the fish also used the same "genetic toolbox" in order to create their electric organ. This organ is usually used by fish in murky environments in order to communicate with mates, navigate, stun prey and defend against other predators.

"I consider 'exotic' organisms such as the electric fish to be one of nature's wonders and an important 'gift' to humanity," said Michael Sussman, one of the researchers, in a news release. "Our study demonstrates nature's creative powers and its parsimony, using the same genetic and developmental tools to invent an adaptive trait time and again in widely disparate environments. By learning how nature does this, we may be able to manipulate the process with muscle in other organisms and, in the near future, perhaps use the tools of synthetic biology to create electrocytes for generating electric power in bionic devices within the human body or for uses we have not thought of yet."

Integrating Clinical Genomics Data into Standard Medical Practice

While the utilization of NGS is going to be a routine part of clinical practice within five years, the ability to make sense of genomic data will take many more years.

Dr. David Smith believes that in five years about 90% of upper-tier hospitals in the U.S. will be doing genomic and transcriptomic sequencing of the type of cancer with which a patient presents. [© kentoh - Fotolia.com]

• Consider this scenario:

  “In five or ten years, you will show up at your doctor’s office, not feeling well, with a thumb drive that contains all your important health-related information, including a copy of your entire genome. Your physician will run the disk through a sophisticated computer and, after studying the results, prescribe a treatment, maybe even a form of genetic engineering or gene therapy, based on the genomic components of your disease, not just your symptoms.”

• Fact or Fiction?

  Click Image To Enlarge +

  David Smith, Ph.D.

  “The full-blown version of this five-year scenario is fiction,” says David Smith, Ph.D., professor of laboratory medicine and pathology at the Mayo Clinic. “Now having your genome on a disk in five years will very likely be a reality but being able to fully interpret your genome’s data and make a clinically important decision remains more in the realm of fiction.”

  Dr. Smith’s lab relies on cutting-edge genomic technologies to better understand the molecular alterations that underlie cancer development. He is also chairman of the technology assessment committee, which works for the Center for Individualized Medicine at the Mayo Clinic. The committee’s goal is to evaluate new technologies that could have a significant impact on research and its clinical translation.

  The most exciting technology has been the recent advancements in DNA sequencing, which now make it possible to sequence a person’s entire genome for just a few thousand dollars, according to Dr. Smith.

  “The reality is that in five years the clinical utilization of next-gen sequencing is going to be all pervasive and a routine part of clinical practice,” he predicts. “But it is going to be many years to come before we will be able to successfully untangle a lot of the actual genomic data and decide what it all means.”

  Looking at cancer, his lab’s focus, Dr. Smith believes that in five years about 90% of the upper-tier hospitals in the U.S. will be doing genomic and transcriptomic sequencing of the type of cancer with which a patient presents. “The medical team will compare the genetic fingerprint of the patient’s cancer with that of his or her normal cells. That comparison will become part of the clinical diagnosis,” he says, adding that deciding on the best therapy based on the genomic data will probably have to wait for another ten years or so.

  This therapeutic challenge arises from the well-known “big data” issue, notes Dr. Smith. “Over time we are going to have collected genetic patterns from thousands and thousands of human genomes. Our task will be to figure out which patterns are real and which are just noise,” he says.

  Another challenge, he suggests, is the need for standardization of the data. Not for gene sequencing which is a straight base call but definitely for “gene expression and RNA-Seq data because there is variability and uncertainty involved here,” maintains Dr. Smith.

  “For example, if I do an RNA-Seq in Minnesota on an Illumina platform and then do another in California on an Ion Torrent instrument, against what do I standardize the results,” he asks. “I think we should start taking a DNA sample and send it out to ten different groups for DNA and RNA analysis. Then we will be able to see what kind of variability exists and then be in a better position to establish some type of standards for the data.”

• Detecting and Repairing DNA Errors

  Click Image To Enlarge +

  Elaine Mardis, Ph.D.

  Elaine Mardis, Ph.D., agrees that genetic engineering therapy for people is not arriving anytime soon. Dr. Mardis, the co-director at The Genome Institute of Washington University and a professor of genetics, believes that researchers will probably have the ability to detect and repair DNA errors at the preimplantation embryo stage in about ten years.

  “We can genotype embryos right now that do or don’t carry mutations such as in cystic fibrosis. But mutation repair is still far off,” she says. “And trying to repair DNA mutations in a grown adult is even more problematic.”

  She points out that we know that BRCA1 and BRCA2 are prognostic for women to develop breast and ovarian cancer.

  “But there is a mystery here in that if the same mutated form of DNA is carried in every cell, why does cancer only appear in breast and ovarian tissues?” asks Dr. Mardis. “We still don’t fundamentally understand how to specifically target the appropriate tissues in adults with, for example, gene therapy or with another gene repair technique.”

  Dr. Mardis strongly believes that next-gen sequencing is the major driver of clinical genomics.

  “Baseline research in the basic science arena is establishing methodologies for up-front preparation of libraries for next-gen sequencing and for downstream analytical processes that are critical for coming to more precise genomic interpretation in the clinic,” she explains. “This constitutes 99% of the battle for clinical translation of genomic data.”

  Dr. Mardis adds that supporting technologies such as computer science and computational pipelines are also necessary for the successful integration of clinical omics into standard medical practice.

  Dr. Mardis notes that another key clinical genomics driver is the fact that many children who currently come to a medical genetics clinic with an uncertain diagnosis immediately undergo some type of sequencing, primarily exome sequencing to aid in the diagnosis. Establishing clinical utility, i.e., how fast you can get an answer about the child’s condition, is enhanced by exome sequencing rather than single gene-by-gene testing, according to Dr. Mardis.

  “Exome sequencing is less expensive than multiple single gene tests and insurance companies recognize that,” said Dr. Mardis. “The burden of clinical utility falls on the clinical genomics lab. Payers want to know if they pay for a genomics test, will the patient have a path to a solution that is better than the current standard of care? They [the payers] ask questions like how much does this test cost in comparison to another test? If it costs more why is the new test better?”

  Dr. Mardis stresses that big data analytics will address some of the cost equation. “Most of the cost is not in the DNA sequencing process but in analyzing the data,” she points out. In general, she finds no problem with data standardization as currently practiced. “Most large-scale sequencing teams use the bam file format to align reads to the genome. You can run bam files through any predictor program to come up with your own variant calls,” she says.

  In storing variant calls, you might run into trouble because definitions about what you consider and call variants and actually put into a variant file can themselves vary, according to Dr. Mardis.

  “We either need to warehouse genomic data as bam format files or throw all the data away and keep the biological samples in a biobank,” she says. “Data storage is becoming more expensive than data production. And regarding data production, competition will come in the future with new DNA sequencing platforms that will drive the costs down further.

A CRISPR Way To Fix Faulty Genes

• 

  The CRISPR enzyme (green and red) binds to a stretch of double-stranded DNA (purple and red), preparing to snip out the faulty part.

  Illustration courtesy of Jennifer Doudna/UC Berkeley

Scientists from many areas of biology are flocking to a technique that allows them to work inside cells, making changes in specific genes far faster — and for far less money — than ever before.

"It's really powerful, it's a really exciting development," says Craig Mello of the University of Massachusetts Medical School. He won the Nobel Prize in 2006 for a different technique that also lets scientists modify how genes work. But, Mello says, this new genetic tool – known as CRISPR for clustered regularly interspersed short palindromic repeats — is more powerful, "because now you can essentially change a genome at will to almost anything you want. The sky's the limit."

Sure, scientists previously have made enormous strides in their ability to do things with genes: modifying them, moving them from cell to cell, even animal to animal.

But doing these things has been time consuming and expensive. It looks like CRISPR will change all that.

Mello thinks medical applications for CRISPR are not far off. He's formed a company,CRISPR Therapeutics, to develop therapies for people with genetic blood diseases likesickle cell and thalassemia. He says it's been possible, in theory, to treat these diseases by removing a patient's bone marrow, repairing the damaged gene, and then returning the repaired cells to the patient. In practice, Mello says, succeeding with that approach has been nearly impossible.

"But now, the cost for that has come down to where it's really feasible to tailor therapies using the patient's own cells," he says, "essentially correcting their genetic disease." Though a lot of testing still needs to be done before doctors can say the CRISPR technique is safe and effective enough for use in treating patients, even many scientists not directly involved in the research are enthusiastic about its possibilities.

CRISPR is one of those interesting inventions that comes, not from scientists explicitly trying to cure a disease, but from researchers trying to understand something fundamental about nature.

Jennifer Doudna's research at the University of California, Berkeley has focused on how bacteria fight the flu. It turns out bacteria don't like getting flu any more than the rest of us do. Doudna says the way bacteria fight off a flu virus gave her and her colleagues an idea.

Bacteria have special enzymes that can cut open the DNA of an invading virus and make a change in the DNA at the site of the cut — essentially killing the virus.

Doudna and other scientists figured out how this defense system works in bacteria; that was interesting all by itself. But then they realized that they could modify these enzymes to recognize any DNA sequence, not just the DNA sequence of viruses that infect bacteria.

"So this is now enabling researchers to introduce changes into the genetic code of cells and organisms at essentially any site," she says.

Doudna realized from the start that she was on to something big. "I remember really feeling ... the hairs on the back of my neck," she recalls. "Because I thought, wow, if this could work in animal or plant cells, this could be a very, very useful and very powerful tool. Honestly, I didn't even realize at the time how powerful."

Like Craig Mello, Doudna also foresees medical applications for CRISPR, and she is a co-founder of a biotech company that hopes to use the technology to develop new therapies.

Copyright 2014 NPR. To see more, visit http://www.npr.org/.

Transcript

MELISSA BLOCK, HOST:

Biologists are pretty excited about a new technique they've started using. It goes by the acronym, CRISPR. That's C-R-I-S-P-R. It allows them to manipulate genes and cells in a way they've never been able to do in the past. As part of his series, "Joe's Big Idea," NPR's Joe Palca has been exploring inventions that can change the world. Today he tells us why scientists think CRISPR could launch a new era in biology and medicine. And yes, he'll tell us what CRISPR stands for eventually.

JOE PALCA, BYLINE: Sure, scientists have made enormous strides in their ability to do things with genes - modifying them, moving them from cell to cell, even animal to animal. But doing these things is time-consuming and expensive. It looks like CRISPR will change all that.

CRAIG MELLO: It's really powerful. It's a really exciting development.

PALCA: That's Craig Mello of the University of Massachusetts medical school. He won the Nobel Prize for a technique that also lets you modify how genes work, but he says CRISPR is more powerful.

MELLO: Because now you can essentially change a genome at will to almost anything you want, the sky's the limit.

PALCA: Not only is CRISPR less expensive to use, but making precise genetic changes in cells now takes hours instead of days or weeks. Mello thinks medical applications for CRISPR are not far off. He's formed a company to develop therapies for people with genetic blood diseases like sickle-cell and thalassemia. He says it's been possible, in theory, to treat these diseases by removing a patient's bone marrow, repairing the damaged gene, and then transplanting the repaired cells back to the patient. Mello says in practice it's been nearly impossible to accomplish this.

MELLO: But now, the cost for that has come down to where it's really feasible to tailor-make therapies using the patient's own cells and essentially correcting their genetic disease.

PALCA: CRISPR is one of those interesting inventions that didn't come from scientists who were explicitly trying to cure a disease, but who wanted to understand something fundamental about nature.

JENNIFER DOUDNA: How to bacteria fight the flu?

PALCA: Jennifer Doudna is at the University of California, Berkeley. Turns out bacteria don't like getting flu any more than the rest of us. Doudna says the way bacteria fight off a flu virus gave her and her colleagues an idea. Bacteria have special enzymes that can cut open the DNA of an invading virus and make a change in the DNA at the site of the cut, essentially killing the virus. Doudna and her colleagues figured out how this defense system works in bacteria - something that was interesting all by itself. But then they realized that they could modify these enzymes to recognize any DNA sequence, not just the DNA sequence of viruses that infect bacteria.

DOUDNA: So this is now enabling researchers to introduce changes into the genetic code of cells and organisms at essentially any site that they might wish to do so.

PALCA: Doudna realized from the start that she was onto something big.

DOUDNA: I remember really feeling sort of the hairs on the back of my neck, you know, because I thought, wow, you know, if this could work in animal or plant cells, this could be a very, very useful and very powerful tool. Honestly I didn't even realize at the time how powerful. I was really thinking, boy, if it works even at all it will be very interesting.

DOUDNA: Doudna is also involved in a biotech company that hopes to exploit CRISPR for medical technologies. Scientists have just started exploring what they can do with CRISPR. The first applications may be in the field of medicine, but when scientists get their hands on any new tool it's usually best to expect the unexpected. Stay tuned. Oh, and by the way if you're interested in what CRISPR is an acronym for, don't ask Craig Mello.

MELLO: It stands for clustered regularly interspersed - wait a second (Laughing). Clustered regularly interspersed...

PALCA: He got it eventually. It stands for clustered regularly interspersed short palindromic repeats. So now you know. Joe Palca, NPR News.

V.N. Anisimov: Russian Optimist on Longevity

Last March, I wrote a column entitled Reality Check, featuring the work of Stephen Spindler.  Spindler is a veteran researcher at UC Riverside, and perhaps the world’s foremost expert in the design and execution of longevity studies in mice.  But Steve is a glass-half-empty kind of guy.  And ever since I wrote that column, I’ve been thinking that I need to write about Spindler’s opposite number in Russia:  Vladimir Anisimov is a veteran gerontologist at the Petrov Institute in St Petersburg, who has also been testing longevity potions on mice through a long career.  Anisimov is a glass-half-full kind of guy.  His best contribution to anti-aging medicine may be epithalamin, a treatment that has been hiding in plain sight for over thirty years.

An innovator with a deep knowledge of biochemistry, Anisimov has published theoretical as well as practical science.  His lab has tested biochemical ideas about aging, as well as doing many studies on genetics and longevity in rodents and flies.  He has reported and summarized results of other Russian labs in English-language journals.

Some of Anisimov’s findings are well-known to me, and therefore to followers of this blog and of my Aging Advice web site.  Metformin reduces mortality and slashes cancer risk in people who take it as a medication for diabetes.  Metformin increases life span of ordinary non-diabetic mice.  Anisimov thinks it will do the same for non-diabetic humans, and I agree it’s a good bet.  Melatonin, the hormone that regulates our daily cycle, is also found to prolong life span in mice.   Melatonin in the blood is very sensitive to light exposure, and melatonin disappears with the dawn’s early light   Anisimov found that sleeping in total darkness is better for longevity than exposure to light during the night.  Here are two reviews by Anisimov of mostly Russian work on life extension with melatonin [2003, 2006].

(Unrelated to melatonin and to Anisimov: A recent study also suggests sleeping in the cold helps preserve insulin sensitivity.)

Another of Anisimov’s lines of research is less well-known to me, and I report here my first impressions.  He has worked with “short peptides”, strings of less than 10 amino acids, that can act as signals or switches that control body chemistry globally.  Short peptides are small enough to pass easily through the skin or through the blood-brain barrier.  Unlike full-size proteins, short peptides tend to resist dismemberment by stomach enzymes.  Carnosine and carnitine are familiar examples of di-peptides, consisting of 2 amino acids.

Here’s the theory:  We know that gene expression is quite different in old and young people.  In the literature, you find various interpretations and explanations why this might be true.  But my interpretation is clear and simple:  The body times its life cycle using gene expression.  When we’re young, we express genes that make us grow.  When we’re middle-aged, we express genes that keep us healthy.  When we’re old, we express genes that destroy us.

“Gene expression” is the translation of DNA into proteins.  Proteins are the signals and the workhorses of body chemistry.  The translation is well understood since Francis Crick discovered the Genetic Code in the 1960s.  But the language for determining which gene gets expressed when is apparently much more complicated, and it is just beginning to be decoded in the 21st Century.  This is the science of epigenetics.

Among the signals that can locate a particular stretch of DNA, and turn it ON or OFF are short stretches of RNA called pi-RNAs, methyl transferases and histone de-acetylases.  (I’m sorry to throw biochem jargon at you, but I’m excited to have just barely begun to educate myself about the fundamentals of epigenetics with a Coursera course this spring.)  But the point is that these short peptides that Anisimov has been studying for 20 years work also as gene promoters and repressors – epigenetic signals that are more specific than the methyl transferases and less specific than pi-RNAs.  Apparently they can affect whole categories of genes [ref].

Here’s a paper in which Anisimov summarizes 35 years’ experience with animal experiments, and some tantalizing human results as well.  (One of the differences in Russian bio-medicine, for better and for worse, is that regulations about experiments on humans are more relaxed than in the US.)   Here’s a table summarizing results in mice and rats.  (As usual, life extension in flies is more dramatic, but less indicative of human benefits.)  As you can see, this is a science that goes back to the 1970s, when the top two preparations were purified from epithalamus and thymus glands.

The thymus is a gland in the upper chest that trains the immune cells in our blood to attack invading cells, but to lay off our own body’s cells.  As we get older, the thymus shrinks, and I believe this to be a basic cause of aging immune function, auto-immune disease, and increased susceptibility to infection.  Thymalin was found to stimulate thymus re-growth and to rejuvenate immune function.

Epithalamin is also called epitalon or epithalon, and was discovered in extacts from a region of the brain called the epithalamus.  This region contains the pineal gland, or “third eye”, which controls wake/sleep cycles and is the body’s source of melatonin.  Like thymalin, epithalamin is a string of four amino acids.  Thymalin generated excitement in the 1980s, until epithalamin stole its thunder.  Not only did it extend life more consistently, but its effect on thymic growth was found to be superior to thymalin.

In the table, epithalamin has been the best-studied short peptide, and it has the best record for life extension in rodents.  In a separate table, the same paper shows that epithalamin and thymalin suppress cancer in rodents.  There is also evidence of large reductions in mortality when epithalamin was given to older human subjects:

In addition, it has recenty been reported (2003, 2004) that epithalamin is a telomerase activator.  Skeptics (Spindler in particular) point out that caloric restriction is such a strong influence on life span that many treatments will appear to show benefit only because they affect appetite.  Some of the studies do measure food intake, and find that epithalamin is able to increase lifespan without decreasing food consumption.

(Epitalon is available commercially, but not from most supplement sources.  Recommended dosage is usually less than 10mg, but experience with different dosages is very limited.)

Reference: a crash course in mid-brain anatomy

Here’s a picture of the human brain, courtesy of Wikipedia.  The mid-brain is the endocrine function, where computations made with neurons are translated into prescriptions for internal secretion.

The epithalamus is shown in cherry.  It includes the pineal gland, the so-called “third eye” which is responsible for the body’s light-sensitive clock, and where melatonin comes from.  The hypothalamus is shown in lime.  It includes various “nuclei”, notably the suprachiasmatic nucleus, which is the closest thing science has found to a developmental clock.  The pituitary is also part of the hypothalamus, and secretes hormones involved in the life cycle and the menstrual cycle: HGH, LH, FSH, TSH and sex hormones.

Conclusions

All of this looks so promising that I wonder why there hasn’t been more follow-up, and why American researchers haven’t built on the Russian results.  Russian science tends to be more adventurous than American science.  That doesn’t mean they make more mistakes.  The problem with American science is that it is too rigidly institutionalized and controlled within an establishment.  It is usually not possible to get funding to ask a question to which you do not already know the answer.  So the mistakes of American science are more likely to be under the header “confirmation bias”, while Russian science is more likely to be offering results that may not pan out.  This seems to be a well-established field, with positive results that have been affirmed over decades in different labs with flies, rodents, and humans.  My web search identified no dangers or reports of toxicity.  I’d say it’s high time the American and European gerontology communities picked up this thread.  In the mean time, please comment if you have any experience with epitalon or other short peptides.

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This article originally appeared on Josh's blog here: http://joshmitteldorf.scienceblog.com/2014/06/26/v-n-anisimov-russian-optomist-on-longevity/