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### Gene Drives Could Wipe Out Insect-Borne Disease — But What’s the Price?

In 2014, a few days after Christmas, Dr. Valentino Gantz walked into his lab at the University of California, San Diego to check on some newly hatched fruit flies.

With a single look, he knew he had shattered the laws of evolution.

It was supposed to be an unremarkable quick in-and-out. Gantz and his advisor Dr. Ethan Bier were trying to develop a way to spread certain genes through a large population — a mutagenic chain reaction popularly known as a “gene drive.”

The head and eye of a fruit fly.

Gantz bred the larvae — thousands of them — from an albino mother. According to classical rules of inheritance, only one out of four young flies should carry the mutation.

Instead, one after another, Gantz saw nothing but pale, albino flies.

“We were stunned,” said Bier, “it was like the sun rose in the west rather than the east.”

Locked behind five security doors, sealed in a biosafety containers, was a tool that could forever end insect-borne diseases — and in the process, wipe out entire species, reengineer life and perhaps topple ecosystems.

#### The genius of gene drives

What the team painstakingly discovered was a new incarnation of an old idea: using CRISPR, the gene editing technique, to construct “selfish gene” mutations that insert themselves into the genome and transmit down generations with nearly 100% efficiency.

Genes normally go from parent to child like shuffling a deck of cards. Take a physical trait like red eyes in mosquitos. Mosquitos (and humans) carry two copies of almost every gene. Red eyes is a dominant trait in mosquitos, which means it only takes one copy of the red-eye gene for it to appear.

A mosquito stands on a leaf.

Now, say a mother mosquito has one red-eye and one black-eye gene variant at analogous positions on two separate DNA bundles. The bundle that carries the red-eye gene has a near 50/50 chance of getting passed on to her offspring. Fair and square.

Nature, however, evolved a way to cheat the system. A group of selfish genes encode an enzyme that homes in on one of the DNA bundles — the one that doesn’t carry the desired gene variant. There, it makes a cut. This triggers the cell’s DNA repair system, which uses the other DNA bundle — the one with the red-eye gene — as a template to repair the other bundle, effectively copying the red-eye gene. Now, unless it mutates, the red-eye gene has a near 100% chance of getting passed on to baby mosquitos.

The result? When released in sufficient quantity, a single inserted gene could spread through an entire population in roughly a dozen generations, or a single season.

In 2003, in a seminal paper Dr. Austin Burt laid out the possibility of building artificial gene drives to control the spread of blood-borne diseases like malaria. It’s an intriguing idea: spread a “suicide gene” to wipe out the entire species, or add in disease-resistant genes to entire populations.

A big hurdle? Gene drives were tough to make with traditional molecular genetics methods. That is, until CRISPR came along.

#### Malaria-resistant mosquitos

Easy, cheap and highly effective, CRISPR lets scientists make precise cuts almost anywhere along the genome and works in a large number of species. Linked to a gene drive, the cut also defines where artificial selfish genes get copied in. Once they’re in, they spread through natural procreation.

Working with Dr. Anthony James, Gantz added a gene that makes malaria antibodies in mama mosquitos whenever they drink. These antibodies tightly grab onto the parasite and stop it from developing any further, preventing its deadly effects.

Since the gene adds no benefit to the mosquitos, normally it would get diluted by the gene pool and eventually peter out. With gene drive, however, it gets passed through generations with 99% efficacy.

Although the researchers stopped short of confirming that the mosquitos were resistant to malaria, they did show that they expressed the antibody genes.

“It’s completely outstanding,” said Dr. Kevin Esvelt, a gene drive researcher at Harvard.

Burt agrees, but says long-term studies are needed to see how long the effects can last. Modeling studies show that it takes roughly 20 generations for the new gene to spread wide enough to make a difference.

So far we haven’t done cage experiments to assess long-term efficiency and mutation rates, but it’s one of our next steps, Gantz told Singularity Hub.

I think far more pressing are larger questions that need to be addressed before we can even contemplate field studies, Gantz said. Now that technology is no longer a limitation, should we — for the greater good — dictate the fate of entire species?

#### Driving forward

Earlier this year, the National Academies of Sciences, Engineering and Medicine hosted a workshop to begintackling the thorny issue of playing god.

For one, the technology isn’t quite there yet. How specific is the gene manipulation? How long can it last? Can we make it somewhat reversible? What are the ecological effects of gene drives?

“We know so little,” said Dr. Zach Adelman, a molecular geneticist at Virginia Polytechnic Institute.

And it’s not just transmissible diseases. In theory, gene drives could give nearly extinct animals an edge up and save them from extinction.

Even when the science part gets figured out, should we tamper with Mother Nature? Essentially, we need to balance immediate humanitarian concerns with potential global ecological effects, said Burt. Since animals roam far and wide, unheeding of national boundaries, multiple countries will have to work together to develop regulatory guidelines and establish governing agencies.

“We have time to figure it out though,” said Burt.

In the meantime, gene drive researchers are taking extra precautions to avoid accidentally contaminating the environment with lab-grown mutants.

Our experiments were conducted in high-security labs, explained Gantz. We also worked with tropical mosquitos that can’t survive in the California climate. Even if they somehow got out, they wouldn’t be able to sustain their life cycle or find mates, he said.

Yet some experts are still concerned.

Dr. George Church, a pioneer in gene drives at Harvard, calls for failsafe mechanisms to stop the gene drive from propagating if anything went wrong. His proposal, though elegant, is not a simple fix. Long story short, it involves adding in another gene drive, a “reversal” one so to speak, to balance out the effects of the first drive.

So far, the mechanism was only shown to work in yeast.

We need some serious soul searching before we can move on to field applications, said Gantz. With this study, we did go for a slightly less risky route: compared to other gene drive approaches that wipe out entire species, ours — population modification — should in theory have a smaller impact on an ecosystem, explained Gantz.

The team — Gantz, James and Bier — believes it’ll take about a year to prepare mosquitoes for field tests. Although eager to test drive population modification, they are going slow and careful.

“It’s not going to go anywhere until the social science advances to the point where we can handle it,” saidJames. “We’re not about to do anything foolish.”

RELATED TOPICS:

 Palabra(s) clave: ANTHONY JAMESAUSTIN BURTBLOOD-BORNE DISEASECRISPRCRISPR/CAS9ETHAN BIERGENE DRIVESGENETIC ENGINEERINGGEORGE CHURCHKEVIN ESVELTMALARIATRANSGENIC MOSQUITOSUNIVERSITY OF CALIFORNIA SAN DIEGOVALENTINO GANTZWYSS INSTITUTE

### Gene Editing Is Now Cheap and Easy—and No One Is Prepared for the Consequences

In April 2015, a paper by Chinese scientists about their attempts to edit the DNA of a human embryo rocked the scientific world and set off a furious debate. Leading scientists warned that altering the human germ line without studying the consequences could have horrific consequences. Geneticists with good intentions could mistakenly engineer changes in DNA that generate dangerous mutations and cause painful deaths. Scientists — and countries — with less noble intentions could again try to build a race of superhumans.

Human DNA is, however, merely one of many commercial targets of ethical concern. The DNA of every single organism — every plant, every animal, every bacterium — is now fair game for genetic manipulation. We are entering an age of backyard synthetic biology that should worry everybody. And it is coming about because of CRISPRs: clustered regularly interspaced short palindromic repeats.

Discovered by scientists only a few years ago, CRISPRs are elements of an ancient system that protects bacteria and other single-celled organisms from viruses, acquiring immunity to them by incorporating genetic elements from the virus invaders. CRISPRs evolved over millions of years to trim pieces of genetic information from one genome and insert it into another. And this bacterial antiviral defense serves as an astonishingly cheap, simple, elegant way to quickly edit the DNA of any organism in the lab.

Until recently, editing DNA required sophisticated labs, years of experience, and many thousands of dollars. The use of CRISPRs has changed all that. CRISPRs work by using an enzyme — Cas9 — that homes in on a specific location in a strand of DNA. The process then edits the DNA to either remove unwanted sequences or insert payload sequences. CRISPRs use an RNA molecule as a guide to the DNA target.  To set up a CRISPR editing capability, a lab only needs to order an RNA fragment (costing about $10) and purchase off-the-shelf chemicals and enzymes for$30 or less.

Because CRISPR is cheap and easy to use, it has both revolutionized and democratized genetic research. Hundreds, if not thousands, of labs are now experimenting with CRISPR-based editing projects. A race is on between the major research institutions to file CRISPR-technique patents. Research dollars, both public and private, are pouring into CRISPR projects. Meanwhile, a panoply of leading geneticists — including one of the developers of the CRISPR technology — has urged for a moratorium on alterations to the human germ line until the implications of messing with human DNA are further studied and safeguards put in place.

Changing human DNA creates, for scientists and humanity, a frightening ethical grey zone. On the one hand, for the many millions of poor souls suffering from diseases arising from genetic defects, CRISPR and the research it fuels could mean finding a cure for their problem in their lifetimes. On the other hand, changing the human germ line is incredibly risky without much better knowledge of how our DNA actually works.

Though scientists now commonly sequence human DNA, they still struggle to understand how the different pieces of the human genome work together. For example, until recently, scientists thought that much of our genetic material was useless and served no purpose. They called it “junk” DNA. In a previous era, they might have considered editing the junk out of our genes.

Now, research is emerging showing that junk DNA plays a key role in regulating genetic expression (effectively turning various genes on and off), regulation that is fundamental to the biological processes that govern our bodies and our endocrine systems. What if a well-intentioned researcher develops a cure for one of these diseases and shares it with thousands of sufferers before realizing that the cure is far worse than the disease and that the side effects are painful — or even deadly — and easily spread from person to person?

Such a scenario could arise through good intent. But in the hands of evil biohackers, these powerful and simple tools are a cause for alarm. A smart biohacker could alter the influenza genome, for example, to make it more potent, setting off an epidemic that kills hundreds of millions of people.  Though a nuclear weapon can cause tremendous long-lasting damage, the ultimate biological doomsday machine is bacteria, because they can spread so quickly and quietly.

No one is prepared for an era when editing DNA is as easy as editing a Microsoft Word document. The government does not have any regulations on editing human DNA. The ethical concerns have not been fleshed out. There is no centralized risk-management inventory, listing which labs are doing what with CRISPR. It’s all rather terrifying.

Rarely do I argue that a moratorium on technological progress is the prudent course. But the stakes in the case of CRISPR are so high that I believe a blanket moratorium is the only course. Yes, rogue scientists may nonetheless continue working at modifications on the human germ line; and that could endow them with a first-mover advantage and unfair knowledge. But such a moratorium could be as effective as the global moratorium on the cloning of humans has been: at the least, scientists such as those who engineered the human embryos in China would become international pariahs rather than being celebrated for publishing papers in prestigious publications.

Image Credit: Shutterstock.com

 Palabra(s) clave: biohackerscrisprCRISPR/Cas9dnadna editinggene editinggenetic diseasegenetic engineeringsynthetic biology

#### Gene Editing [1052]

Insight & Intelligence™

### Gene Editing Will Change Everything—Just Not All at One Time

#### Transformative technology is still in its infancy but great things are expected in human health and industrial and agbio markets.

by Harry Glorikian

From the discovery in the late 1980s by researchers at Osaka University of strange repeat DNA sequences sitting beside a gene in a common bacterium, to the frenzied deals and financings over CRISPR technology today, gene editing has taken firm hold in the worlds of basic and applied life science. In fact, the variety of gene-editing technologies goes way beyond CRISPR, and its commercial applications go beyond human therapeutics to encompass agriculture, both plants and animals, and a broad array of high-margin industrial products. In short, gene editing holds the promise of transforming the way R&D is conducted and products developed across major sectors of the global life science economy.

Gene editing broadly refers to a suite of methods that use site-specific endonucleases to first target a double-stranded break in the genome and then to repair that gene by disrupting it or by rewriting its sequence. Over the course of the past few decades, the technology has progressed through the use of meganucleases (MEGAs), zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspersed short palindromic repeats (CRISPRs). Each specific iteration of the technology has been easier to design and has brought gains in speed and ease-of-use.

Thus far, Sangamo Biosciences is the only company to have applied one of these technologies —ZFNs—to the development of clinical-stage human therapeutics. Other companies such as the start-ups CRISPR Therapeutics and Editas Medicine have focused on CRISPR and have attracted eye-opening investments by elite early-stage VCs. In December, Editas completed multiple licensing deals on the same day for the gene-editing technologies TALEN and CRISPR/Cas9 (Cas9 refers to the protein that binds to RNA molecules which guide it to a specific location on the genome where it triggers a double-stranded break).

And recently, big pharma has entered the field. Last June, Pfizer inked a deal with Paris-based Cellectis to harness the biotech’s gene-editing capabilities to the development of CART-T (chimeric antigen receptor T-cell) anticancer immunotherapies.

Nonetheless, CRISPR, whose relative ease of use has made it the research tool of choice for achieving specific genomic modifications, is overwhelmingly finding use in academic laboratories. By contrast, Sangamo, which controls patents around ZFNs, is in Phase II with SB-728, a ZFN-based approach to modifying the gene encoding CCR5, the major co-receptor used by HIV to infect cells of the immune system. Moreover, Sangamo has entered into collaborative partnerships with Shire International and Biogen Idec, for human therapeutics; and it has licensed its technology to Dow AgroSciences and Sigma-Aldrich for agricultural and research applications.

Editas and the other product-focused start-ups are still years, if not decades, from bringing a product to market. It is also still not clear that CRISPR technology will prove suitable for human therapeutics. Fundamental challenges yet to be worked out include its degree of specificity and the potential of single-guide RNAs to cause off-target effects in the human genome.

However, while human therapeutic applications of gene editing steal the limelight, there are other sectors, including agriculture and specialty chemicals, in which the technology has advanced beyond the laboratory into product development and even onto the market.

#### Gene Editing Poised to Transform Agriculture

In fact, gene editing is closer to transforming agricultural markets than human medical markets. To understand what is driving its application in agriculture, a few statistics are in order. The world’s population is set to grow from nearly 7 billion today to over 9 billion by 2050. The problem of overpopulation will be exacerbated by rising world food prices, by famines caused by both natural and political forces, by the overdevelopment of arable land, and by changing climate patterns. The Food and Agriculture Organization estimates the need for a 70% increase in crop production to simply maintain nutrition at today's levels.

Gene editing offers the ability to modify critical traits in crops and animals: boosting food crop yields and nutrient quotients and making crops able to withstand blights, pests, or climatic extremes; and breeding hardier, disease-resistant farm animals with improved nutritional profiles. Moreover, food staples such as bananas, cassava, plantain, or potatoes, which are currently impervious or for which conventional breeding techniques are glacially slow, stand to benefit from gene editing.

Other factors favoring the early adoption of gene editing in agriculture include the regulatory standards governing it. Gene editing has the potential of enabling a faster, less costly path to market. In the U.S., the U.S. Department of Agriculture (USDA) has recently ruled that some mutations made by MEGAs, ZFNs (e.g., Dow AgroSciences’ ZFN-derived maize lines) and TALEN (Cellectis plant sciences uses TALEN to improve potatoes, soybean, and other agricultural commodities) do not come under their regulatory authority. Therefore the preparation of a costly and time-consuming data package is not required. USDA expects to announce its position on the use of CRISPR/Cas9 to create new plant traits in the near future.

Cibus, a San Diego-based agbio firm with a proprietary gene-editing platform, had its sulfonylurea herbicide tolerant canola approved first in the U.S. and more recently in Canada, making it the only example of a company founded on genomic editing to have reached market. Regulatory bodies in the U.S. and Europe consider its technology, Rapid Trait Development System (RTDS™), to be a natural form of targeted mutagenesis, and as such, excluded from an onerous and costly approval process. Cibus, which claims itsRTDS platform is proven and reproducible, has other products in its pipeline.

That distinction between the older, transgenic forms of breeding, in which foreign genetic material is introduced into the plant or animal, and on the other hand gene editing in which the native gene is modified in situ, involves more than just regulatory red tape. The older forms of transgenic genetic modification carry the status of genetically modified organism, or GMO, a politically controversial label that has hobbled the commercial development of agbio markets and, along with costly regulatory requirements, actually added to the cost of transgenic crop production. Although global transgenic crop acreage has seen 131% CAGR from 1996 to 2012 according to the International Service for the Acquisition of Agri-Biotech Applications (ISAAA), as of 2012 meaningful penetration into Europe, China, and other regions remains elusive because of GMO issues.

Transgenic techniques have other drawbacks: the trait that is conferred might not be stable, are randomly inserted and thus may unintentionally disrupt native genes or may have linkage drag or reduced recombination rates near the inserted transgene which might take years of plant breeding to fix.

By contrast, gene editing enables stable and heritable genomic changes quickly and easily without introducing foreign DNA. And although the patent situation particularly for CRISPR/CAS9 is still in the first inning and will likely take years to sort out.  Private companies like Cibus with proprietary technology have been able to build a patent estate permitting it to press ahead with product development. Unlike transgenesis, gene editing will enable researchers to modify genetic information in a natural way to bring out of the existing genome entirely new traits. And best of all, regulators have given it the green light to position its products as the non-GMO alternative.

#### An Agricultural Ecosystem Emerges

Companies competing in the agricultural gene -editing space include firms providing tools and services, and those focused on product development and commercialization. The former group is composed of companies like Transposagen Biopharmaceuticals that serve both medical and agricultural markets with a broad variety of molecular biology products and services including gene editing. Examples of the latter group include Cibus, Precision Biosciences, Caribou Biosciences, Nova Synthetix, Cellectis, and Recombinetics. Only St. Paul, MN-based Recombinetics, which applies TALENs to the improvement of livestock, is a pure play agbio company. The others focus their gene-editing technology on various combinations of human therapeutics, agriculture, research use, and industrial products. Cibus, for instance, while primarily invested in agricultural gene editing, also applies its RTDS platform to the production of squalane.

In addition, large, multinational chemical and life science companies have agricultural divisions that employ gene-editing technology acquired mostly through licensing arrangements with small specialist companies. Examples include Dow AgroSciences, DuPont Pioneer, Bayer CropSciences, and BASF Plant Sciences. Indeed, these global companies play a similar role to big pharma by providing funding, expertise, and geographic reach to small, innovative firms.

Not far behind agricultural applications for gene editing are the industrial applications. Companies like Nucelis, Sigma Aldrich, and Precision Biosciences are working on high-performance oils for use in cosmetics and lubricants, biofuels, flavorings, and other high-margin specialty chemicals. In June 2013, Cellectis reported that its scientists, using MEGAs and TALENs, successfully engineered the genome of single-celled photosynthetic algae called diatoms for the purpose of producing biofuel. Nucelis is close to market with its squalane oil, a fully hydrogenated form of squalene, the natural compound, which it can scale to commercial quantities using a microbial production platform.

Gene editing has surely arrived. Despite the majority of media attention and investment dollars going to applications in human therapeutics, which no doubt promise the greatest return, the first commercial products will be agricultural and industrial. That’s where scientists and entrepreneurs are pioneering the production, the regulatory science, and the commercialization of products derived from gene editing.

 Palabra(s) clave: Gene EditingTransformative technology

### The Gene Engineering eBook

Hemos escrito un eBook que contiene una visión completa de la ingeniería genética y una guía con toda la gama de productos que ofrecemos para ayudarle con su investigación.
Las tecnologías incluyen:

• Las últimas tecnologías de edición del genoma: GeneArt® Precision TALs y vectores CRISPR
• RNAi con siRNA y miRNA para modular la expresión génica
• Sistemas de expresión de proteínas Flp-In™ y Jump-In™

 Palabra(s) clave: Gene EngineeringeBook

### Gene Engineering flip book

#### Genome Engineering Workflow: Editing and Modulation

At Life Technologies, we have developed a complete suite of products for the genome engineering workflow, from cell culture and sample preparation to genome modification, to detection and analysis of known genetic variants. Our featured technologies include Flp-In™ and Jump-In™ protein expression systems, RNAi with siRNA and miRNA for gene expression modulation, and the newest technologies, GeneArt® Precision TALs and CRISPR (see the selection table on page 8).

Identification: The Ion Proton® system is a reliable sequencing platform to identify and elucidate variants important for the heritability of cancer, as well as Mendelian and complex disorders. Our bioinformatics package, the Ion Reporter™ Server System, is a combined hardware and software solution for automatically analyzing and annotating human sequence variants.

Detection and analysis: Subsequent to the identification of functional variants and to create cell models to study these variants, quantitative gene expression studies using TaqMan® and SYBR® reagents can be performed on trusted real time PCR instruments to validate functional variants. Protein expression levels can also be confirmed using our extensive western analysis platforms and reagents.Genome engineering and model creation: To further delineate functionality of variants, our genome engineering tools and services include RNAi, GeneArt®  CRISPR vectors, GeneArt® Precision TALs, and the creation of cell model systems. Additionally, to assess the cleavage efficiency of genome editing tools at a given locus, we offer the GeneArt®

Genomic Cleavage Detection Kit. We even offer a complete service for engineering your cell of choice to produce custom-designed, stable cell lines that meet your requirements.

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 Palabra(s) clave: Gene Engineeringflip book

## Gene-Edited Pets

By Karen Zusi

In 2014, China’s BGI reported the creation of genetically-engineered Bama pigs that grow to be 15 kilograms, or 33 pounds. Last week (September 23), at the Shenzhen International Biotech Leaders Summit in China, the company announced plans to sell these “micro-pigs” as pets for approximately $1,600 each. Originally, the micro-pigs were crafted for use in research labs. Pigs are more similar to humans than rats and mice are, making them better candidates for drug development tests and other projects eventually intended for human clinical trials. However, keeping a full-size adult pig for lab work is costly and resource-heavy, regardless of the breed. BGI’s solution was to take cells from a Bama pig fetus, disable the growth hormone receptor protein using the gene-editing technology TALENs, and then clone the pig. After a careful breeding program, BGI had a set of tiny pigs that would remain small as they matured, making them appropriate for research labs. The micro-pigs have since been used in studies of stem cells and the gut microbiome, Yong Li, technical director of BGI’s animal-science platform, told Nature. The company’s latest pet-selling venture is intended to fund research on gene-editing regulation, Nature reported—and BGI was turning heads at the Shenzhen summit with their pigs. “We had a bigger crowd than anyone,” Lars Bolund, a medical geneticist from Aarhus University in Denmark who helped BGI develop the pig gene-editing program, told Nature. “People were attached to them. Everyone wanted to hold them.” But researchers elsewhere remain cautious about the endeavor and the ethical questions it might raise. “I just hope we establish a regulatory framework—guidelines for the safe and ethical use of this technology—that allows the potential to be realized,” Daniel Voytas, a geneticist at the University of Minnesota, told Nature. “I worry that pet mini-pigs distract and add confusion to efforts to achieve this goal.”  Palabra(s) clave: TALENspigsgenetically engineeredgene editingbiotechBGI #### Genetic Repression Boosts Memory [1474] EUREKALERT, UNIVERSITY OF CAMBRIDGE ## Genetic Repression Boosts Memory By Kate Yandell #### Expression or translation of some genes must be turned off in the mouse hippocampus for memories to form. For decades, researchers have known that forming memories requires that the expression and translation of some genes be upregulated in the brain. Unexpectedly, the mouse hippocampus also has an extensive program of genetic downregulation that is required for memory to function properly, according to a paper published today (October 1) in Science. “This is a breakthrough, because we are now introducing new pathways that seem to be important in memory formation,” said study coauthor V. Narry Kim, who studies RNA biology at the Institute for Basic Science and Seoul National University in Korea. “By studying these pathways, we will be able to have a much better clue in understanding memory formation and the molecular mechanisms behind it.” “It provides a fresh concept,” said Mauro Costa-Mattioli, who studies learning and memory at Baylor College of Medicine in Houston, Texas, and was not involved in the study. “Essentially, not only do you need translation stimulation, but you also need translational repression.” Prior studies on memory were designed to detect proteins that must be upregulated for memories to form. “A lot of these studies have been done by essentially blocking either gene transcription or translation with drugs, with genetics, sometimes even with behavior, and looking at what the effects are on memory formation,” said Charles Hoeffer, who studies protein synthesis and memory at the University of Colorado, Boulder, and was not involved in the research. Kim and her colleagues produced a more comprehensive profile of gene expression and protein production. The researchers put mice through contextual fear conditioning, a process that involves shocking the animals in a specific chamber so that they learn to fear it. They removed the animals’ hippocampi—centers of spatial memory—either five minutes, 10 minutes, 30 minutes, or four hours after putting them through conditioning. They then analyzed the hippocampi using RNA-sequencing and ribosome profiling, a technique that reveals whether RNAs are being translated into proteins. The researchers identified 104 genes whose transcription or translation deviated significantly from control mice at some point in the hours immediately following the contextual fear conditioning. Exactly how gene activity changed at each time point varied. During the first 10 minutes after fear conditioning, genes showed relatively few changes in transcription into mRNA. Instead, whether mRNA was translated into protein was altered. “There are cases where translational control is much more fast that transcriptional control,” explained Kim. Early on, cells can alter the rate of protein synthesis more easily than they can turn transcription off and on. By the time 30 minutes passed, cells had made changes to transcription as well as translation. Even after five minutes, the researchers began to see translational repression, with more than half of altered genes showing downregulation by that time. By 30 minutes, 31 of 42 altered genes were repressed, and at four hours, 48 of 55 altered genes were downregulated. Many of the genes that were repressed at 30 minutes remained repressed at four hours, the researchers observed. Strikingly, at four hours, half of the repressed genes likely depended on inhibition of one protein: estrogen receptor alpha (ESR1). When the researchers activated ESR1 in mice by giving them a drug, the mice partly lost their ability to learn from contextual fear conditioning. The researchers additionally overexpressed one of the genes that was translationally repressed immediately following contextual fear conditioning, Nrsn1. Although the exact role of this tubulin-related gene in memory is unknown, overactivating this gene in mice also led to trouble forming memories. The researchers emphasized that much work remains to figure out how networks of repressed genes advance memory formation. “We don’t know why this . . . gene network should be deactivated during memory consolidation,” said study coauthor Bong-Kiun Kaang of Seoul National University. “I don’t think anybody in our field would have said, oh yeah, there’s going to be ESR1 downregulation that’s critical for memory formation,” said Eric Klann, who studies learning and memory at New York University’s Center for Neural Science and was not involved in the research. That is why it is so valuable to broadly screen genes without being guided by preconceived notions, he added. Klann hypothesized that this repressive program could be the brain’s way of turning off safeguards that ordinarily prevent people from remembering too much. “If you remembered everything, your brain would turn to mush,” he said. When it is time to form a memory, the brain must downregulate genes that are actively suppressing memory, he proposed. Klann and Costa-Mattioli pointed out that the methodology of the study might even have led the team to underestimate the degree of changes to gene expression and translation during memory formation. Only a small proportion of hippocampal neurons are involved in this process. The researchers analyzed the whole hippocampus, possible diluting larger changes in small groups of memory-forming neurons. Memory consolidation is “more complex than we expected,” said Kaang. “There’s a balance between inhibition and activation of genes to make long-lasting and long-term memory.” J. Cho et al., “Multiple repressive mechanisms in the hippocampus during memory formation,” Science, 350:82-87, 2015.  Palabra(s) clave: translation, RNA-seq, mice, memory, hippocampusgene expressionfear conditioning #### Genomic Elements Reveal Human Diversity [1340] ### Genomic Elements Reveal Human Diversity By Anna Azvolinsky Duplication of copy number variants may be the source of greatest diversity among people, researchers find. World map with geographic coordinates of populations sampled in the study. PETER H. SUDMANT Genetic differences among ethnically diverse individuals are largely due to structural elements called copy number variants (CNVs), according to a study published today (August 6) in Science. Compared with other genomic features, such as single nucleotide variants (SNVs), CNVs have not previously been studied in as much detail because they are more difficult to sequence. Covering 125 distinct human populations around the world, geneticist Evan Eichler at the University of Washington in Seattle and an international team of colleagues studied the genomes of 236 people—analyzing both SNVs and CNVs. “The take-home message is that we continue to find a lot more genetic variation between humans than we appreciated previously,” Eichler told The Scientist. “This is a really exciting study of CNVs in worldwide human populations and has a much finer resolution than what had been done before,” said Kirk Lohmueller, who studies human genetic variation at the University of California, Los Angeles, and was not involved in the work. Classified as deletions or duplications, CNVs are genomic loci that can greatly vary in the number of copies, and are often located in regions of highly repetitive content, making them more difficult to sequence compared to SNVs. Thus far, the vast majority of human genome analyses—including from the Human Genome Project and the 1,000 Genomes Project—have focused on SNVs and CNV deletions; these studies largely overlooked CNV duplications because of technology limitations. In the present study, the median size of CNVs identified was 7,396 base pairs. “Here, [the authors] put in an extra effort, sequencing each genome much more deeply—about 10 times more than what was done in the 1,000 Genomes Project,” said Alexander Urban a geneticist at the Stanford School of Medicine, who was also not involved in the study. “That is a massive achievement in genomic data generation.” From their dataset, the researchers were able to reconstruct the organization of an ancestral human genome—around 200,000 years old—and compare it to the chimpanzee and orangutan reference sequences. This comparative analysis revealed at least 40 million base pairs of additional DNA in the ancestral human genome reconstruction that are not found in the current human reference genome. A portion of this sequence was retained in the genomes of several modern African people, suggesting the loss of this additional sequence as humans migrated away from the continent. Eichler and his colleagues compared the modern human genomes to genomes of three ancient human lineages as well as two extinct lineages—Neanderthal and Denisova. The researchers found that CNVs were a source of seven times greater diversity compared to SNVs. “While there are fewer CNV events, the number of base pairs that are different between two individuals are largely dictated by CNVs, especially within the duplicated regions,” Eichler explained. This difference between CNVs and SNVs is likely to grow much larger as new sequencing platforms are used to understand human genetic variation, he added. Specifically, CNV duplications were the source of the greatest diversity; these features were four times more likely to affect genes compared to CNV deletions across all populations, suggesting that selection of the duplications and deletions differed throughout evolution. The researchers also found that CNVs had the greatest effect on genomic diversity among non-African human genomes. The implication, said Eichler, is that during “the last 80,000 years, the genomes of our ancestors that left Africa have gone through much more remodeling by CNVs compared to SNVs,” said Eichler. Next, Eichler’s team would like to compare specific CNV loci among different modern populations to ascertain positive versus negative selection as well as correlations with disease risk. The study provides clues on how evolution may have acted on different genomic elements, but there’s a lot more to learn, said Lohmueller. “This is a great step in that direction but it’s not the last part of the story on understanding which CNVs in our genomes are neutral or deleterious.” P.H. Sudmant et al., “Global diversity, population stratification, and selection of human copy number variation,” Science, doi:10.1126/science.aab3761, 2015.  Palabra(s) clave: single-nucleotide polymorphismhuman researchhuman geneticshuman evolutiongenetics & genomicsevolutionary genomicscopy number variants #### Genomics & Insurance: The Rising Tide of Genetic Data [1700] ### Genomics & Insurance: The Rising Tide of Genetic Data by Sabine VanderLinden Blog: Genomics & Insurance: what does the rising tide of genetic data mean for insurance? by Sabine VanderLinden Click to Tweet As genome sequencing is made available to everyone and the insights from the data is used to forecast, pre-empt and prevent health risks, what does all this mean for insurance customers and insurers alike? In 2003, the human genome was mapped. It took 13 years and$3 billion. Today any human genome can be sequenced for \$1,500 in 15 minutes. Click to Tweet

As this cost continues to drop, we’re likely to see genome sequencing for nearly everything, including  unborn and newborn child. This gives us the ability to spot gene mutations that could lead to future illnesses and medical conditions.

With such new reality, we now face two significant questions: Who should be allowed to access such genetic information? And what could or should be done with it?

“When talking about life insurance, it’s going to be difficult to ignore genomic data. Your DNA is your medical future. It’s predictive of what’s likely to afflict or kill you.”Peter Diamandis

#### Promising means to identify health risks

Genetic information is one of the most promising means for addressing potential health risks and avoiding those all together. But leveraging such source of insight may also bring genetic discrimination. This is a central concern for individuals and the government.

Such scenarios are neither hypothetical nor do they sit in a far future reality. There are, already, companies using genetic information as part of the screening process for job applicants. And most countries do not have yet in place comprehensive regulations or rules to prevent institutions to use such information or ensure the secure usage of such information.

Before we delve into the future implications of genetic testing for business and technology, let’s look at what genetic information means to the basic concept of insured risk. Insurance is based on shared knowledge related to potential risks that have not yet happened. By assessing an individual’s health risks, an insurer can pool that individual with others at a similar risk level, or allow the worst risk types to be pooled with the best risk types to optimise price and future claims costs. This way, medical costs are equitably distributed throughout that specific risk pool. This system only works when both insurer and insured share the same information. When one side has additional information the other isn’t privy to, it’s a little like insider trading which puts one party at an advantage over the other.

We are today gaining access to an enormous volume and variety of data sets—individually and collectively—that can be used to evaluate health risk. While we attempt to use that data to improve people’s health and longevity, we will need to figure out a fair way to spread insurance risks across health groups where more genetic information is available, whilst not being unduly unfair.

These two things require a tricky balance.

#### Where are we today in terms of policy?

Current regulatory and ethical policies encourage a system “Where we are better off not knowing”. As long as neither the applicant nor the insurer is aware of any genetic abnormalities, there can be no discrimination based on the knowledge of pre-existing genetic information.

Two key questions come to mind: How can we keep this information secret and only use the relevant bits to save life? If we know of the existence of a piece of information which may potentially occur in the future should insurers have the right to request and use it?

“Genetic screening data could be misused, by those people who might gain benefits on the expense of those whose genetic screening results revealed that they are under risk of some diseases, it is important to ensure that if the application of any new technology leads to negative impacts on the members of the society, then this new technology will be unaccepted by the majority.” Human Genetic Screening, Firas M Abu-El Samem

There is a voluntary code set down by many national insurance associations. The United States has a specific federal law addressing the issue of genetic discrimination. France also prevents doctors from sharing that information and requires data providers to keep any illnesses and diseases secret. The Genetic Information Non-disclosure Act (GINA) prohibits employers from using genetic information for hiring or compensation purposes. It also prevents insurance companies from using genetic information when underwriting health insurance. This does not, however, apply to life, disability or long-term care insurance. Nor does it apply to banks that may wish to know genetic information before approving mortgages or loans.

The more genetic information we acquire, the greater ability we have to prevent or minimise long-term illnesses and live healthier lives. Insurers also benefit by being able to more accurately pool client premiums. And researchers can develop new medicines and treatments based on improved genetic information. But how do we take full advantage of this information without creating a system in which many people become uninsurable or afraid to undergo genetic testing?

The solution relies on a partnership between businesses, the government, genomic researchers and technological innovators. Breaking down or disintermediating the value chain and ensuring that key parties actually use the health information they hold within the constraints of data laws. We are only in the rudimentary stages of this cooperation. The challenge is finding new, innovative ways to manage and disseminate this rising tide of genetic data.

#### Startups in the genomic space

You have a great opportunity to help healthcare, life, long term care, disability and indemnity insurers. Please think of the ways you can drive the right level of transparency across the health and life insurance value chains, without making at risk customers uninsurable.

 Palabra(s) clave: Startupsgenomic spaceGenomics & Insurance

#### Gente nueva [1364]

Las nuevas relaciones entre la genética y la vida de las personas en un libro apasionante

### Gente nueva

Un nuevo libro de Viviana Bernath que encarna en intensas historias de vida las nuevas posibilidades que la genética humana pone a disposición de las personas.

Por Daniel Flichtentrei | Fuente: IntraMed

#### Sinopsis

Título: Gente nueva
Autor (es): Viviana Bernath
Sello: SUDAMERICANA
ISBN: 9789500753142
EAN: 9789500753142

Los entrecruzamientos entre la diversidad sexual, la diversidad genética y la diversidad funcional son el eje de este texto. Qué es la identidad, qué define la maternidad o la paternidad, cuál es la importancia de los genes en la filiación, cuál es el rol de la ciencia, la tecnología y la medicina en la detección y diagnóstico de enfermedades genéticas.

Los avances de la ciencia genética y la tecnología nos brindan recursos antes impensados tanto para generar vida humana como para detectar enfermedades futuras. Estamos en condiciones de afirmar que el uso de estas herramientas está produciendo una verdadera revolución social.

A través de quince historias reales, Viviana Bernath profundiza con agudeza en estos cambios acontecidos en apenas cuatro décadas: las nuevas familias y, en consecuencia, la gente nueva que se multiplica a partir de la donación de gametas, la fecundación in vitro, la selección embrionaria, el alquiler de vientres, y que se suman al diagnóstico de patologías genéticas, y a la posibilidad de decidir y lograr que los hijos nazcan libres de síntomas. La autora indaga sobre qué es la identidad, qué define la maternidad o la paternidad, cuál es la importancia de los genes en la filiación, cuál es el rol de la ciencia, la tecnología y la medicina en la detección de enfermedades y, esencialmente, si estamos construyendo una sociedad dispuesta a no discriminar e incluirnos a todos.

GenTe nueva nos interpela, individual y colectivamente, acerca de estos y muchos otros dilemas a los que la ciencia y nuestros propios deseos nos enfrentan a cada paso.

#### Acerca de la autora

Pasaje a la India

Ese lunes por la mañana, Carlos llegó de su consultorio algo más temprano que de costumbre....abrió la bandeja de entrada del Outlook y vio la notificación...¿qué diría esta vez? ¿el intento habría fracasado de nuevo?....

No, esta vez lo habían logrado! antes de fin de año serían padres, los embriones habían prendido. De inmediato llamó a Agustín para darle la noticia...

Mariana y Gabriela son dos mujeres como cualesquiera, con los mismos sueños y las mismas dificultades que todas; mujeres casadas, profesionales, que trabajan, que son madres y se esfuerzan y hacen malabares para tratar de cumplir con todos los roles lo mejor posible...Claro que su historia no es igual a la de la mayoría; lo que las distingue, aunque no sean las únicas, es que son madres de la misma hija y que están casadas entre sí...

Cuando Guido era muy pequeño, su madre María Silvia, notó que su hijo no se comportaba tal cual indicaba la literatura pediátrica. No se sentó a la edad promedio ni tampoco empezó a caminar cuando le correspondía.

Tuvieron que pasar varios años y visitar diferentes médicos hasta que finalmente a Guido le diagnosticasen que tenía X- Frágil. A partir de entonces la vida de toda la familia cambió para siempre.

Palabras del Dr. Mario Sebastiani en la presentación del libro

Los libros pueden ser muy importantes para algunos, o para otros, un arte pobre. De hecho hay gente que lee, pero porqué no ser respetuosos con la gente que no lee.

Pueden ser importantes para quien los escribe y en este caso en particular y sin duda, merece un homenaje la Dra. Viviana Bernath, dado que no sólo nos deleita con su tercer entrega escrita sino que además, vuelve a poner en palabras sencillas las dificultades propias que tenemos al comprender una especialidad, que como la genética, constituye un paradigma fundamental en nuestra esencia. Pensamos que es algo por momentos lejano, pero curiosameinte, donde hay un ser viviente, hay una genética.

El otro homenaje debe darse a los que, con generosidad particular, le ofrecieron a Viviana sus vivencias y sus experiencias para lograr un hijo. Desde hace años guardo una posición muy crítica hacia el nacer a punto tal que algunos pares de la obstetricia y la ginecología me han apodado como un obstetra “antinatalista¨. Asimismo he osado preguntarme ¿porqué tenemos hijos? y suelo desplegar una crítica importante sobre la temática de los nacimientos en el sentido que los hijos no me parecen que sean la consecuencia del amor sino meramente, una consecuencia del deseo. Sin embargo encuentro en las parejas que deben recurrir a los distintos métodos de fertilización asistida una especial estima y admiración.

Mis pensamientos son obviamente y como no podría ser de otra manera, contradictorios: no es necesario tener hijos pero por otro lado veo que el no tenerlos constituye de manera marcada una fuente de sufrimiento para las personas. Los humanos , seres distintos a los animales por nuestra particular inteligencia, sin embargo, nos comportamos de manera muy similar que a las otras especies puesto que necesitamos reproducirnos a los efectos de perpetuarnos en el tiempo. Unos lo hacen inconcientemente, los animales, y los humanos concientemente, por lo menos en la mayoría de los casos. La necesidad de reproducirnos cruza nuestra existencia en algun momento. Estas personas que deben recurrir a estos métodos o a estudios genéticos contrastan con aquellos que logran un embarazo de manera inesperada, y muchas veces, particularmente, irresponsable.

Como se nota a través de las distintas historias, nuestras gametas pueden ser muy importantes, pero cuando nos convertimos en personas, quedó muy atrás lo que se expresaba en los genes que estaban incluidos en cada gameta . Dicho de otra manera es más divertido ser persona que ser gameta. A punto tal que si deseamos perpetuarnos a través de un hijo, los 46 cromosomas y los millares de genes, no alcanzan. La complejidad de la existencia no se juega solamente en las mitocondrias o en la expresión de los genes sino en una diversidad de situaciones propias de la vida nuestra de cada día, que, si bién, está elegida por cada uno de nostros, en gran parte, está mediada por el medio externo o los demás.

Muchas de las historias que se incluyen en Gente Nueva se logran a través del deseo, del miedo, de la incertidumbre, del desconocimiento, pero logran expresarse gracias a un evento tecnológico-cientifico. Artesanía y emociones; Alma y ciencia unidas dan lugar a Gente Nueva.

Nuevamente quienes disfrutarán del libro son el escritor y los que vean reflejada su historia en estas páginas….pero quiero jerarquizar ahora a los lectores puesto que seguramente tendrán la oportunidad de emocionarse, reflexionar, aprender una vez más de los demás, aprender a ser mejores, a ser más tolerantes, menos burdamente críticos, menos emocionales. Y aquí es donde los libros les pertenecen más a los lectores que al escritor o a los protagonistas, y es bueno que así sea.

Por ello el libro me ha gustado de manera especial y de manera utilitarista al decir de la ética. Me resultó útil, atractivo, interesante, por momentos emotivo, por momentos muy emotivo, y además esclarecedor. La gente será nueva, pero a la larga deberá lidiar con las mismas problemáticas de la gente vieja: origenes, dificultad con sus padres y madres, dificultad con los que van a compartir la vida, y buscarán una identidad más dificil de lograr que la genética. La anatomía o la genética no es nuestro destino sino tan solo valijas que llevamos. Por ello es cierto que son Gente Nueva, pero es nuestro deber verlos como Gente Igual. O bien tan solo podríamos decir que son gente con una manera distinta de ser concebidos. Este libro no resuelve los problemas de la gente nueva sino que los ubica en una escenografía real y menos emocional.

Viviana gracias por esta nueva entrega. Ocupás un lugar de privilegio en ese rincón donde los científicos logran contar con simpleza y emoción el puente que se tiende entre la ciencia y la vida común.

 Palabra(s) clave: genéticala vida de las personas

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