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Why Myriad Genetics Stock Rocketed 26.3% Higher in June — The … – Motley Fool

Posted: July 11, 2017 at 12:40 pm

What happened

Shares of Myriad Genetics (NASDAQ:MYGN), a company focused on genetic testing, rose more than 26% in June, according to data fromS&P Global Market Intelligence.

Investors can credit the gains to a trio of positive announcements.

First, Myriad announced results from a 2,000-patient study using its myRisk Hereditary cancertest. Data from the study showed that 50% of breast cancer mutationsare missed with current testing guidelines and that 34% of these mutations were notpredicted by family history. This data helped to demonstrate the clinical advantages of the using company's test and could help to spur demand.

Image source: Getty Images.

Second, Myriad said that 17 health insurance plans have decided to cover the company's EndoPredict breast cancer test. Those 17 plans represent more than 35 million lives and bring the company's private pay coverage total up to109 million lives.

Finally, the company reported clinical results from its phase 3 OlympiAD trial with partner AstraZeneca. Data from the trial showed that Myriad's BRACAnalysis CDx companion test helped to identify patients with BRCA-mutated HER2-metastatic breast cancer. Physicians then used that identification to treat patients with either AstraZeneca's drug olaparib or standard chemotherapy. The data showed that using olaparib led to a meaningfulgain in progression-freesurvival. Myriad plans on using the data to seek FDA approval for this new test, which, if approved, could triple its addressable market.

Myriad's stock continues to climb back from the drubbing that it took last year. That beating was caused by falling profits due to pricing pressure in the company's corehereditary cancer testing business. Given the declines, it is easy to understand why the company is putting an emphasis on its other fast-growing testing products.

In spite of the advances, Wall Street doesn't have a lot of hope for this company's long-term profit growth potential. In fact, current estimates call for Myriad's profits to decline by more than 7% annually over the next five years. For that reason, I think that investors would probably be best served by looking elsewhere for investment opportunities.

Brian Feroldi has no position in any stocks mentioned. The Motley Fool has no position in any of the stocks mentioned. The Motley Fool has a disclosure policy.

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Is There a Genetic Limit to Milk Production? – Dairy Herd Management

Posted: July 11, 2017 at 12:40 pm

With herd averages approaching 40,000 lb of milk per cow and the single lactation record nearly double that, it begs the question: Are we approaching the genetic limits of milk production.

In a word: No, say Kent Weigel, a geneticist with the University of Wisconsin and Chad Dechow, a geneticist with Pennsylvania State University.

We really arent, says Weigel. The same question was asked 40 years ago when Beecher Arlinda Ellen produced 55,561 lb of milk in a 365-day lactation. That record wasnt broken for 19 years. But then, the record toppledagain and again and again. Last year, Ever-Green-View My Gold-ET, set a new single lactation milk production record with 77,480 lb in 365 days. In percentage terms, My Gold out-did Ellen by nearly 40%!

I think we have a little way to go before we reach the limit, says Dechow. If you look at the Predicted Transmitting Ability for milk on these record cows, theyre just slightly above average.

The other way to look at, says Weigel, is to consider feed intake as a multiple of the maintenance requirement. In the 1980 and 1990s, top cows were producing maybe five times their body maintenance levels. We didnt have any cows at 6 or 7X maintenance; now we do, he says.

So theres no evidence were hitting a limit, but at some time, we might simply reach the physical capacity of the udder, I guess.

To me, it more a question of cost, says Weigel. Is the extra pound of milk worth the cost of producing it, and is it my best strategy for profitability? If I have to spend 99 to get $1 back, is it worth it? Is increasing production per cow the lowest hanging fruit on my farm?

Selecting for larger cows, with bigger frames and more rumen capacity, is not the answer, say both Weigel and Dechow. Larger is not more efficient; larger is actually less efficient, says Dechow. We actually need smaller cows to be more efficient at current levels of milk production.

Look at Jerseys. Some Jerseys are making 40,000 lb of milk, and they dont have nearly the size and scale of Holsteins.

Health traits are becoming a larger proportion of selection indexes, which is a good thing. Unhealthy cows simply burn through calories to power their immune system. Healthy cows produce more, says Weigel

A bigger issue might be that farmers are placing less urgency on reproduction than they were a decade ago, says Dechow. Many herds are now reliant on reproductive hormone protocols to get cows bred. But if those tools are ever lost, it could become a problem.

Inbreeding is also a concern, and it continues to increase. Bull studs are doing a good job of weeding out detrimental genetic recessives. The real issue, says Dechow, is that the industry is likely weeding out just the worst recessive genes with obvious problems. The ones that we dont see as major recessives may be causing more subtle problems, he says.

Still, both Weigel and Dechow say industry selection indexes do a pretty good job of balancing production, health traits and conformation. While every herd doesnt need a customized index, the geneticists say each dairy owner should think about what he or she is trying to accomplish with the genetics they buy. If there are a diversity of goals, there will be diversity of selection and inbreeding wont be as big of a concern, says Weigel.

Genetics isnt really the issue limiting production and efficiency, he says. The limiting factors in most herds are cow comfort and herd management.

Most herds are doing 70% to 80% of things right, and are getting good production. But if they can get 99% right, wow! Thats when you see production jump.

Note: This story appears in the July 2017 issue of Dairy Herd Management.

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Research on Stem Cell Therapy | Liveyon Regenerative Medicine

Posted: July 10, 2017 at 6:48 am

Liveyon LLC is the exclusive worldwide distributor of a regenerative medicine product that is derived from umbilical cord. This product contains cells, stem cells and growth factors which may serve as a therapy for various degenerative diseases/disorders.

Stem cells and cell based therapies have shown tremendous promise; yet controlled studies are still needed in order to confirm its efficacy. Professional judgment and expertise is needed in using these therapies for any therapeutic use, and we urge anyone embarking on the use of stem cell therapies or any regenerative medicine product to consult the national health data bases to evaluate current information from clinical trials. The FDA websites on human tissue should also be consulted to get its current evaluation of any regenerative therapy.

Stem cells, like other medical products that are intended to treat, cure or prevent disease, generally require FDA approval before they can be marketed. FDA has not approved any stem cell-based or regenerative medicine products for use, other than cord blood-derived hematopoietic progenitor cells (blood forming stem cells) for certain indications.

http://www.fda.gov/AboutFDA/Transparency/ Basics/ucm194655.htm

844-548-3966 support@liveyon.com

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‘Stem-cell tourism’ needs tighter controls, say medical experts – The … – Washington Post

Posted: July 10, 2017 at 6:48 am

By Reuters By Reuters July 8

Stem cell tourism in which patients travel to developing countries for unproven and potentially risky therapies should be more tightly regulated, according to a group of international health experts.

With hundreds of medical centers around the world claiming to be able to repair tissue damaged by conditions such as multiple sclerosis and Parkinsons disease, tackling unscrupulous advertising of such procedures is crucial.

These therapies are advertised directly to patients with the promise of a cure, but there is often little or no evidence to show they will help or that they will not cause harm, the 15 experts wrote in the journal Science Translational Medicine.

Some types of stem cell transplant mainly using blood and skin stem cells have been approved by regulators after full clinical trials found they could treat certain types of cancer and grow skin grafts for burn patients.

But many other potential therapies are only in the earliest stages of development and have not been approved by regulators.

Stem cell therapies hold a lot of promise, but we need rigorous clinical trials and regulatory processes to determine whether a proposed treatment is safe, effective and better than existing treatments, said one of the 15, Sarah Chan of Britains University of Edinburgh.

The experts called for global action, led by the World Health Organization, to introduce controls on advertising and to agree on international standards for the manufacture and testing of cell- and tissue-based therapies.

The globalization of health markets and the specific tensions surrounding stem cell research and its applications have made this a difficult challenge, they wrote. However, the stakes are too high not to take a united stance.

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Chemotherapy before breast cancer surgery might fuel metastasis – STAT

Posted: July 10, 2017 at 6:48 am

W

hen breast cancer patients get chemotherapy before surgery to remove their tumor, it can make remaining malignant cells spread to distant sites, resulting in incurable metastatic cancer, scientists reportedlast week.

The main goal of pre-operative (neoadjuvant) chemotherapy for breast cancer is to shrink tumors so women can have a lumpectomy rather than a more invasive mastectomy. It was therefore initially used only on large tumors after being introduced about 25 years ago. But as fewer and fewer women were diagnosed with large breast tumors, pre-op chemo began to be used in patients with smaller cancers, too, in the hope that it would extend survival.

But pre-op chemo can, instead, promote metastasis, scientists concluded from experiments in lab mice and human tissue, published in Science Translational Medicine.

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The reason is that standard pre-op chemotherapies for breast cancer paclitaxel, doxorubicin, and cyclophosphamide affect the bodys on-ramps to the highways of metastasis, said biologist John Condeelis of Albert Einstein College of Medicine, senior author of the new study.

Called tumor microenvironments of metastasis, these on-ramps are sites on blood vessels that special immune cells flock to. If the immune cells hook up with a tumor cell, they usher it into a blood vessel like a Lyft picking up a passenger. Since blood vessels are the highways to distant organs, the result is metastasis, or the spread of cancer to far-flung sites.

Depending on characteristics such as how many tumor cells, blood vessel cells, and immune cells are touching each other, the tumor microenvironment can nearly triple the chance that a common type of breast cancer (estrogen-receptor positive/HER2 negative) that has reached the lymph nodes will also metastasize, Condeelis and colleagues showed in a 2014 studyof 3,760 patients. The discovery of how the tumor microenvironment can fuel metastasis by whisking cancer cells into blood vessels so impressed Dr. Francis Collins, director of the National Institutes of Health, that he featured it in his blog.

The new study took the next logical step: can the tumor microenvironment be altered so that it promotes or thwarts metastasis?

To find out, Einsteins George Karagiannis spent nearly three years experimenting with lab mice whose genetic mutations make them spontaneously develop breast cancer, as well as mice given human breast tumors. In both cases, paclitaxel changed the tumor microenvironments in three ways, all more conducive to metastasis: the microenvironment had more of the immune cells that carry cancer cells into blood vessels, it developed blood vessels that were more permeable to cancer cells, and the tumor cells became more mobile, practically bounding into those molecular Lyfts.

As a result, the mice had twice as many cancer cells zipping through their bloodstream and in their lungs compared with mice not treated with paclitaxel. Two other neoadjuvants, doxorubicin and cyclophosphamide, also promoted metastasis by altering the tumor microenvironment. This showed that the tumor microenvironment is the doorway to metastasis, Condeelis said.

The scientists also analyzed tissue from 20 breast cancer patients who had undergone pre-op chemo (12 weeks of paclitaxel and four of doxorubicin and cyclophosphamide). Compared to before the chemo, the tumor microenvironment after treatment was more conducive to metastasis in most patients. In five, it got more than five times worse. No patients microenvironment got less friendly to metastasis.

Pre-op chemo may have unwanted long-term consequences in some breast cancer patients, the Einstein researchers wrote.

That finding is fascinating, powerful, and very important, said Julio Aguirre-Ghiso of Mount Sinai School of Medicine, an expert in metastasis who was not involved in the study. It raises awareness that we might have to be smarter about how we use chemotherapy.

Dr. Julie Gralow, a medical oncologist at the University of Washington, said that if pre-op chemo promoted metastasis, that should have shown up in studies that compared it to post-op chemo, but for the most part it hasnt. However, that could be because only tumor cells containing certain proteins that make them especially mobile are affected in this way. This is an interesting study, to say the least, Gralow said. I am willing to keep my mind open to the possibility that there are some breast cancer patients in whom things get worse with pre-op chemo.

One reason to question the findings, however, is that if pre-op chemo promotes metastasis in some patients, that might be expected to have shown up in studies of the therapy. Overall, in fact, those studies showthat neoadjuvant chemotherapy does not seem to improve overall survival, as the authors of an editorial in the Journal of Clinical Oncology wrote.

Thats not as bad as decreasing survival, of course. But Einsteins Dr. Maja Oktay, a co-author of the new research, cautioned that the typical length of the studies six or so years is too short to assess the risk of metastasis, which can take more than 20 years to appear, she said. Such patients might never be flagged as having metastatic cancer, let alone having it linked to pre-op chemo decades earlier, said Aguirre-Ghiso.

On a brighter note, not all breast cancer patients have the kind of tumor microenvironment in which pre-op chemo can promote metastasis. Whether they do or not can be determined by a simple lab test, but one that is not routinely done, Condeelis said.

Serendipitously, an experimental compound called rebastinib, being developed by Deciphera Pharmaceuticals, seems to be able to block the on-ramp to the metastasis highway. In a study currently recruiting patient volunteers, the Einstein scientists (who have no financial relationship with Deciphera) are studying whether rebastinib can improve outcomes in metastatic breast cancer.

Sharon Begley can be reached at sharon.begley@statnews.com Follow Sharon on Twitter @sxbegle

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genetic engineering | Definition, Process, & Uses …

Posted: July 10, 2017 at 6:46 am

Genetic engineering, the artificial manipulation, modification, and recombination of DNA or other nucleic acid molecules in order to modify an organism or population of organisms.

The term genetic engineering initially referred to various techniques used for the modification or manipulation of organisms through the processes of heredity and reproduction. As such, the term embraced both artificial selection and all the interventions of biomedical techniques, among them artificial insemination, in vitro fertilization (e.g., test-tube babies), cloning, and gene manipulation. In the latter part of the 20th century, however, the term came to refer more specifically to methods of recombinant DNA technology (or gene cloning), in which DNA molecules from two or more sources are combined either within cells or in vitro and are then inserted into host organisms in which they are able to propagate.

The possibility for recombinant DNA technology emerged with the discovery of restriction enzymes in 1968 by Swiss microbiologist Werner Arber. The following year American microbiologist Hamilton O. Smith purified so-called type II restriction enzymes, which were found to be essential to genetic engineering for their ability to cleave a specific site within the DNA (as opposed to type I restriction enzymes, which cleave DNA at random sites). Drawing on Smiths work, American molecular biologist Daniel Nathans helped advance the technique of DNA recombination in 197071 and demonstrated that type II enzymes could be useful in genetic studies. Genetic engineering based on recombination was pioneered in 1973 by American biochemists Stanley N. Cohen and Herbert W. Boyer, who were among the first to cut DNA into fragments, rejoin different fragments, and insert the new genes into E. coli bacteria, which then reproduced.

Most recombinant DNA technology involves the insertion of foreign genes into the plasmids of common laboratory strains of bacteria. Plasmids are small rings of DNA; they are not part of the bacteriums chromosome (the main repository of the organisms genetic information). Nonetheless, they are capable of directing protein synthesis, and, like chromosomal DNA, they are reproduced and passed on to the bacteriums progeny. Thus, by incorporating foreign DNA (for example, a mammalian gene) into a bacterium, researchers can obtain an almost limitless number of copies of the inserted gene. Furthermore, if the inserted gene is operative (i.e., if it directs protein synthesis), the modified bacterium will produce the protein specified by the foreign DNA.

A subsequent generation of genetic engineering techniques that emerged in the early 21st century centred on gene editing. Gene editing, based on a technology known as CRISPR-Cas9, allows researchers to customize a living organisms genetic sequence by making very specific changes to its DNA. Gene editing has a wide array of applications, being used for the genetic modification of crop plants and livestock and of laboratory model organisms (e.g., mice). The correction of genetic errors associated with disease in animals suggests that gene editing has potential applications in gene therapy for humans.

Genetic engineering has advanced the understanding of many theoretical and practical aspects of gene function and organization. Through recombinant DNA techniques, bacteria have been created that are capable of synthesizing human insulin, human growth hormone, alpha interferon, a hepatitis B vaccine, and other medically useful substances. Plants may be genetically adjusted to enable them to fix nitrogen, and genetic diseases can possibly be corrected by replacing dysfunctional genes with normally functioning genes. Nevertheless, special concern has been focused on such achievements for fear that they might result in the introduction of unfavourable and possibly dangerous traits into microorganisms that were previously free of theme.g., resistance to antibiotics, production of toxins, or a tendency to cause disease. Likewise, the application of gene editing in humans has raised ethical concerns, particularly regarding its potential use to alter traits such as intelligence and beauty.

In 1980 the new microorganisms created by recombinant DNA research were deemed patentable, and in 1986 the U.S. Department of Agriculture approved the sale of the first living genetically altered organisma virus, used as a pseudorabies vaccine, from which a single gene had been cut. Since then several hundred patents have been awarded for genetically altered bacteria and plants. Patents on genetically engineered and genetically modified organisms, particularly crops and other foods, however, were a contentious issue, and they remained so into the first part of the 21st century.

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Stanford’s Final Exams Pose Question About the Ethics of Genetic Engineering – Futurism

Posted: July 10, 2017 at 6:46 am

In BriefThe age of gene editing and creation will be upon us in thenext few decades, with the first lifeform having already beenprinted. Stanford University questions the ethics of prospectivestudents by asking a question we should all be thinking about. Stanfords Moral Pickle

When bioengineering students sit down to take their final exams for Stanford University,they are faced with a moral dilemma, as well as a series of grueling technical questions that are designed to sort the intellectual wheat from the less competent chaff:

If you and your future partner are planning to have kids, would you start saving money for college tuition, or for printing the genome of your offspring?

The question is a follow up to At what point will the cost of printing DNA to create a human equal the cost of teaching a student in Stanford? Both questions refer to the very real possibility that it may soon be in the realm of affordability to print off whatever stretch of DNA you so desire, using genetic sequencing and a machine capable of synthesizing the four building blocks of DNA A, C, G, and T into whatever order you desire.

The answer to the time question, by the way, is 19 years, given that the cost of tuition at Stanford remains at $50,000 and the price of genetic printing continues the 200-fold decrease that has occurred over the last 14 years. Precursory work has already been performed; a team lead by Craig Venter created the simplest life form ever known last year.

Stanfords moral question, though, is a little trickier. The question is part of a larger conundrum concerning humans interfering with their own biology; since the technology is developing so quickly, the issue is no longer whether we can or cant,but whether we should or shouldnt. The debate has two prongs: gene editing and life printing.

With the explosion of CRISPR technology many studies are due to start this year the ability to edit our genetic makeup will arrive soon. But how much should we manipulate our own genes? Should the technology be a reparative one, reserved for making sick humans healthy again, or should it be used to augment our current physical restrictions, making us bigger, faster, stronger, and smarter?

The question of printing life is similar in some respects; rather than altering organisms to have the desired genetic characteristics, we could print and culture them instead billions have already been invested. However, there is theadditional issue of playing God by sidestepping the methods of our reproduction that have existed since the beginning of life. Even if the ethical issue of creation was answered adequately, there are the further questions ofwho has the right to design life, what the regulations would be, and the potential restrictions on the technology based on cost; if its too pricey, gene editing could be reserved only for the rich.

It is vital to discuss the ethics of gene editing in order to ensure that the technology is not abused in the future. Stanfords question is praiseworthy because it makes todays students, who will most likely be spearheading the technologys developments, think about the consequences of their work.

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America’s First Free-Roaming Genetically Engineered Insects Are … – Gizmodo

Posted: July 10, 2017 at 6:46 am

Diamondback moths may be a mere half-inch in length, but their voracious appetite for Brussels sprouts, kale and cauliflower make them a major pain for farmers. This week, the U.S. Department of Agriculture approved a potential solution: moths genetically engineered to contain a special gene that makes them gradually die off. A field trial slated to take place in a small area of upstate New York will become the first wild release of an insect modified using genetic engineering in the US.

The moths have been engineered by the British biotech firm Oxitec, the same company that last year caused a stir with its plans to release genetically modified, Zika-fighting mosquitoes in the Florida Keys. The diamond back moths take a similar approach to the mosquitoes, modifying male mosquitoes to limit the population over time by passing on a gene to offspring when it mates with wild females that causes female moths to die before they reach maturity.

The technique is a riff on an approach used to manage agricultural pests since the 1950s, known as sterile insect technique. Using radiation, scientists made insects like the screwworm unable to produce viable offspring. By 1982, screwworm was eradicated from the US using this alternative to pesticides. In Silent Spring Rachel Carson suggested this approach was the solution to the dangers of harmful pesticides agricultural producers required to protect their crops. The problem was that it did not work on every insectin many cases, it simply left irradiated insects too weak to compete for mates with their healthier kin.

Diamondback moths are a sizable problem for farmers, and a problem thats growing as the moths develop resistance to traditional pesticides. They do about $5 billion in damage to cruciferous crops worldwide every year. In the upcoming trial, a team at Cornell University will oversee the release of the genetically engineered moths in a 10-acre field owned by Cornell in Geneva, New York.

After a review found that the field trial is unlikely to impact either the environment or humans, the USDA issued a permit that allows for the release of up to 30,000 moths per week over several months. It is caterpillars that damage crops, so the plan to release adult males that produce unviable offspring should not cause any additional crop damage. And any surviving moths will likely be killed off by pesticides or upstate New Yorks frigid winter, according to the report submitted to the USDA.

The plan to release modified mosquitoes in the Keys attracted much local ireafter initially getting the greenlight from the FDA, the project was ultimately stalled by a local vote and forced to find a new location for a trial.

In upstate New York, too, the moths have stirred up a debate over GMOs for the past several years, though the plan has not been met with quite the same level of opposition. The approval process through the USDA rather than the FDA, too, was much swifter.

In laboratory and greenhouse trials, the modified mosquito was reportedly effective in decreasing the overall population. But tests still need to determine how it will fare in open air.

Oxitec has released its engineered mosquitoes Brazil, Grand Cayman, and Panama, and still plans to go ahead with a field trial in the Keys. In December, the company announced plans for field trials of a genetically modified Mediterranean fruit fly in Western Australia. It is also working on genetically engineering several other agricultural pests, including Drosophila suzukii and the Olive fly.

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Writing the human genome – The Biological SCENE

Posted: July 10, 2017 at 6:46 am

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Synthetic biologists have been creating the genomes of organisms such as viruses and bacteria for the past 15 years. They aim to use these designer genetic codes to make cells capable of producing novel therapeutics and fuels. Now, some of these scientists have set their sights on synthesizing the human genomea vastly more complex genetic blueprint. Read on to learn about this initiative, called Genome Project-write, and the challenges researchers will faceboth technical and ethicalto achieve success.

Nineteenth-century novels are typically fodder for literature conferences, not scientific gatherings. Still, at a high-profile meeting of about 200 synthetic biologists in May, one presenter highlighted Mary Shelleys gothic masterpiece Frankenstein, which turns 200 next year.

Frankensteins monster, after all, is what many people think of when the possibility of human genetic engineering is raised, said University of Pennsylvania ethicist and historian Jonathan Moreno. The initiative being discussed at the New York City meetingGenome Project-write (GP-write)has been dogged by worries over creating unnatural beings. True, part of GP-write aims to synthesize from scratch all 23 chromosomes of the human genome and insert them into cells in the lab. But proponents of the project say theyre focused on decreasing the cost of synthesizing and assembling large amounts of DNA rather than on creating designer babies.

The overall project is still under development, and the projects members have not yet agreed on a specific road map for moving forward. Its also unclear where funding will come from.

What the members of GP-write do agree on is that creating a human genome from scratch is a tremendous scientific and engineering challenge that will hinge on developing new methods for synthesizing and delivering DNA. They will also need to get better at designing large groups of genes that work together in a predictable way, not to mention making sure that even larger assembliesgenomescan function.

GP-write consortium members argue that these challenges are the very thing that should move scientists to pick up the DNA pen and turn from sequence readers to writers. They believe writing the entire human genome is the only way to truly understand how it works. Many researchers quoted Richard Feynman during the meeting in May. The statement What I cannot create, I do not understand was found on the famed physicists California Institute of Technology blackboard after his death. I want to know the rules that make a genome tick, said Jef Boeke, one of GP-writes four coleaders, at the meeting.

To that end, Boeke and other GP-write supporters say the initiative will spur the development of new technologies for designing genomes with software and for synthesizing DNA. In turn, being better at designing and assembling genomes will yield synthetic cells capable of producing valuable fuels and drugs more efficiently. And turning to human genome synthesis will enable new cell therapies and other medical advances.

In 2010, researchers at the Venter Institute, including Gibson, demonstrated that a bacterial cell controlled by a synthetic genome was able to reproduce. Colonies formed by it and its sibling resembled a pair of blue eyes.

Credit: Science

Genome writers have already synthesized a few complete genomes, all of them much less complex than the human genome. For instance, in 2002, researchers chemically synthesized a DNA-based equivalent of the poliovirus RNA genome, which is only about 7,500 bases long. They then showed that this DNA copy could be transcribed by RNA polymerase to recapitulate the viral genome, which replicated itselfa demonstration of synthesizing what the authors called a chemical [C332,652H492,388N98,245O131,196P7,501S2,340] with a life cycle (Science 2002, DOI: 10.1126/science.1072266).

After tinkering with a handful of other viral genomes, in 2010, researchers advanced to bacteria, painstakingly assembling a Mycoplasma genome just over about a million bases in length and then transplanting it into a host cell.

Last year, researchers upped the ante further, publishing the design for an aggressively edited Escherichia coli genome measuring 3.97 million bases long (Science, DOI: 10.1126/science.aaf3639). GP-write coleader George Church and coworkers at Harvard used DNA-editing softwarea kind of Google Docs for writing genomesto make radical systematic changes. The so-called rE.coli-57 sequence, which the team is currently synthesizing, lacks seven codons (the three-base DNA words that code for particular amino acids) compared with the normal E. coli genome. The researchers replaced all 62,214 instances of those codons with DNA base synonyms to eliminate redundancy in the code.

Status report International teams of researchers have already synthesized six of yeast's 16 chromosomes, redesigning the organism's genome as part of the Sc2.0 project.

Bacterial genomes are no-frills compared with those of creatures in our domain, the eukaryotes. Bacterial genomes typically take the form of a single circular piece of DNA that floats freely around the cell. Eukaryotic cells, from yeast to plants to insects to people, confine their larger genomes within a cells nucleus and organize them in multiple bundles called chromosomes. An ongoing collaboration is now bringing genome synthesis to the eukaryote realm: Researchers are building a fully synthetic yeast genome, containing 17 chromosomes that range from about 1,800 to about 1.5 million bases long. Overall, the genome will contain more than 11 million bases.

The synthetic genomes and chromosomes already constructed by scientists are by no means simple, but to synthesize the human genome, scientists will have to address a whole other level of complexity. Our genome is made up of more than 3 billion bases across 23 paired chromosomes. The smallest human chromosome is number 21, at 46.7 million baseslarger than the smallest yeast chromosome. The largest, number 1, has nearly 249 million. Making a human genome will mean making much more DNA and solving a larger puzzle in terms of assembly and transfer into cells.

Today, genome-writing technology is in what Boeke, also the director for the Institute of Systems Genetics at New York University School of Medicine, calls the Gutenberg phase. (Johannes Gutenberg introduced the printing press in Europe in the 1400s.) Its still early days.

DNA synthesis companies routinely create fragments that are 100 bases long and then use enzymes to stitch them together to make sequences up to a few thousand bases long, about the size of a gene. Customers can put in orders for small bits of DNA, longer strands called oligos, and whole geneswhatever they needand companies will fabricate and mail the genetic material.

Although the technology that makes this mail-order system possible is impressive, its not prolific enough to make a human genome in a reasonable amount of time. Estimates vary on how long it would take to stitch together a more than 3 billion-base human genome and how much it would cost with todays methods. But the ballpark answer is about a decade and hundreds of millions of dollars.

Synthesis companies could help bring those figures down by moving past their current 100-base limit and creating longer DNA fragments. Some researchers and companies are moving in that direction. For example, synthesis firm Molecular Assemblies is developing an enzymatic process to write long stretches of DNA with fewer errors.

Synthesis speeds and prices have been improving rapidly, and researchers expect they will continue to do so. From my point of view, building DNA is no longer the bottleneck, says Daniel G. Gibson, vice president of DNA technology at Synthetic Genomics and an associate professor at the J. Craig Venter Institute (JCVI). Some way or another, if we need to build larger pieces of DNA, well do that.

Gibson isnt involved with GP-write. But his research showcases what is possible with todays toolseven if they are equivalent to Gutenbergs movable type. He has been responsible for a few of synthetic biologys milestones, including the development of one of the most commonly used genome-assembly techniques.

The Gibson method uses chemical means to join DNA fragments, yielding pieces thousands of bases long. For two fragments to connect, one must end with a 20- to 40-base sequence thats identical to the start of the next fragment. These overlapping DNA fragments can be mixed with a solution of three enzymesan exonuclease, a DNA polymerase, and a DNA ligasethat trim the 5 end of each fragment, overlap the pieces, and seal them together.

To make the first synthetic bacterial genome in 2008, that of Mycoplasma genitalium, Gibson and his colleagues at JCVI, where he was a postdoc at the time, started with his eponymous in vitro method. They synthesized more than 100 fragments of synthetic DNA, each about 5,000 bases long, and then harnessed the prodigious DNA-processing properties of yeast, introducing these large DNA pieces to yeast three or four at a time. The yeast used its own cellular machinery to bring the pieces together into larger sequences, eventually producing the entire Mycoplasma genome.

Next, the team had to figure out how to transplant this synthetic genome into a bacterial cell to create what the researchers called the first synthetic cell. The process is involved and requires getting the bacterial genome out of the yeast, then storing the huge, fragile piece of circular DNA in a protective agarose gel before melting it and mixing it with another species of Mycoplasma. As the bacterial cells fuse, some of them take in the synthetic genomes floating in solution. Then they divide to create three daughter cells, two containing the native genomes, and one containing the synthetic genome: the synthetic cell.

When Gibsons group at JCVI started building the synthetic cell in 2004, we didnt know what the limitations were, he says. So the scientists were cautious about overwhelming the yeast with too many DNA fragments, or pieces that were too long. Today, Gibson says he can bring together about 25 overlapping DNA fragments that are about 25,000 bases long, rather than three or four 5,000-base segments at a time.

Gibson expects that existing DNA synthesis and assembly methods havent yet been pushed to their limits. Yeast might be able to assemble millions of bases, not just hundreds of thousands, he says. Still, Gibson believes it would be a stretch to make a human genome with this technique.

One of the most ambitious projects in genome writing so far centers on that master DNA assembler, yeast. As part of the project, called Sc2.0 (a riff on the funguss scientific name, Saccharomyces cerevisiae), an international group of scientists is redesigning and building yeast one synthetic chromosome at a time. The yeast genome is far simpler than ours. But like us, yeasts are eukaryotes and have multiple chromosomes within their nuclei.

Synthetic biologists arent interested in rebuilding existing genomes by rote; they want to make changes so they can probe how genomes work and make them easier to build and reengineer for practical use. The main lesson learned from Sc2.0 so far, project scientists say, is how much the yeast chromosomes can be altered in the writing, with no apparent ill effects. Indeed, the Sc2.0 sequence is not a direct copy of the original. The synthetic genome has been reduced by about 8%. Overall, the research group will make 1.1 million bases worth of insertions, deletions, and changes to the yeast genome (Science 2017, DOI: 10.1126/science.aaf4557).

So far, says Boeke, whos also coleader of Sc2.0, teams have finished or almost finished the first draft of the organisms 16 chromosomes. Theyre also working on a neochromosome, one not found in normal yeast. In this chromosome, the designers have relocated all DNA coding for transfer RNA, which plays a critical role in protein assembly. The Sc2.0 group isolated these sequences because scientists predicted they would cause structural instability in the synthetic chromosomes, says Joel Bader, a computational biologist at Johns Hopkins University who leads the projects software and design efforts.

The team is making yeast cells with a new chromosome one at a time. The ultimate goal is to create a yeast cell that contains no native chromosomes and all 17 synthetic ones. To get there, the scientists are taking a relatively old-fashioned approach: breeding. So far, theyve made a yeast cell with three synthetic chromosomes and are continuing to breed it with strains containing the remaining ones. Once a new chromosome is in place, it requires some patching up because of recombination with the native chromosomes. Its a process, but it doesnt look like there are any significant barriers, Bader says. He estimates it will take another two to three years to produce cells with the entire Sc2.0 genome.

So far, even with these significant changes to the chromosomes, the yeast lives at no apparent disadvantage compared with yeast that has its original chromosomes. Its surprising how much you can torture the genome with no effect, Boeke says.

Boeke and Bader have founded a start-up company called Neochromosome that will eventually use Sc2.0 strains to produce large protein drugs, chemical precursors, and other biomolecules that are currently impossible to make in yeast or E. coli because the genetic pathways used to create them are too complex. With synthetic chromosomes well be able to make these large supportive pathways in yeast, Bader predicts.

Whether existing genome-engineering methods like those used in Sc2.0 will translate to humans is an open question.

Bader believes that yeast, so willing to take up and assemble large amounts of DNA, might serve as future human-chromosome producers, assembling genetic material that could then be transferred to other organisms, perhaps human cells. Transplanting large human chromosomes would be tricky, Synthetic Genomics Gibson says. First, the recipient cell must be prepped by somehow removing its native chromosome. Gibson expects physically moving the synthetic chromosome would also be difficult: Stretches of DNA larger than about 50,000 bases are fragile. You have to be very gentle so the chromosome doesnt breakonce its broken, its not going to be useful, he says. Some researchers are working on more direct methods for cell-to-cell DNA transfer, such as getting cells to fuse with one another.

Once the scientists solve the delivery challenge, the next question is whether the transplanted chromosome will function. Our genomes are patterned with methyl groups that silence regions of the genome and are wrapped around histone proteins that pack the long strands into a three-dimensional order in cells nuclei. If the synthetic chromosome doesnt have the appropriate methylation patterns, the right structure, it might not be recognized by the cell, Gibson says.

Biologists might sidestep these epigenetic and other issues by doing large-scale DNA assembly in human cells from the get-go. Ron Weiss, a synthetic biologist at Massachusetts Institute of Technology, is pushing the upper limits on this sort of approach. He has designed methods for inserting large amounts of DNA directly into human cells. Weiss endows human cells with large circuits, which are packages of engineered DNA containing groups of genes and regulatory machinery that will change a cells behavior.

In 2014, Weiss developed a landing pad method to insert about 64,000-base stretches of DNA into human and other mammalian cells. First, researchers use gene editing to create the landing pad, which is a set of markers at a designated spot on a particular chromosome where an enzyme called a recombinase will insert the synthetic genetic material. Then they string together the genes for a given pathway, along with their regulatory elements, add a matching recombinase site, and fashion this strand into a circular piece of DNA called a plasmid. The target cells are then incubated with the plasmid, take it up, and incorporate it at the landing site (Nucleic Acids Res. 2014, DOI: 10.1093/nar/gku1082).

This works, but its tedious. It takes about two weeks to generate these cell lines if youre doing well, and the payload only goes into a few of the cells, Weiss explains. Since his initial publication, he says, his team has been able to generate cells with three landing pads; that means they could incorporate a genetic circuit thats about 200,000 bases long.

Weiss doesnt see simple scale-up of the landing pad method as the way forward, though, even setting aside the tedium. He doesnt think the supersized circuits would even function in a human cell because he doesnt yet know how to design them.

The limiting factor in the size of the circuit is not the construction of DNA, but the design, Weiss says. Instead of working completely by trial and error, bioengineers use computer models to predict how synthetic circuits or genetic edits will work in living cells of any species. But the larger the synthetic element, the harder it is to know whether it will work in a real cell. And the more radical the deletion, the harder it is to foresee whether it will have unintended consequences and kill the cell. Researchers also have a hard time predicting the degree to which cells will express the genes in a complex synthetic circuita lot, a little, or not at all. Gene regulation in humans is not fully understood, and rewriting on the scale done in the yeast chromosome would have far less predictable outcomes.

Besides being willing to take up and incorporate DNA, yeast is relatively simple. Upstream from a yeast gene, biologists can easily find the promoter sequence that turns it on. In contrast, human genes are often regulated by elements found in distant regions of the genome. That means working out how to control large pathways is more difficult, and theres a greater risk that changing the genetic sequencesuch as deleting what looks like repetitive nonsensewill have unintended, currently unpredictable, consequences.

Gibson notes that even in the minimal cell, the organism with the simplest known genome on the planet, biologists dont know what one-third of the genes do. Moving from the simplest organism to humans is a leap into the unknown. One design flaw can change how the cell behaves or even whether the cells are viable, Gibson says. We dont have the design knowledge.

Many scientists believe this uncertainty about design is all the more reason to try writing human and other large genomes. People are entranced with the perfect, Harvards Church says. But engineering and medicine are about the pretty good. I learn much more by trying to make something than by observing it.

Others arent sure that the move from writing the yeast genome to writing the human genome is necessary, or ethical. When the project to write the human genome was made public in May 2016, the founders called it Human Genome Project-write. They held the first organizational meeting behind closed doors, with no journalists present. A backlash ensued.

In the magazine Cosmos, Stanford University bioengineer Drew Endy and Northwestern University ethicist Laurie Zoloth in May 2016 warned of unintended consequences of large-scale changes to the genome and of alienating the public, potentially putting at risk funding for the synthetic biology field at large. They wrote that the synthesis of less controversial and more immediately useful genomes along with greatly improved sub-genomic synthesis capacities should be pursued instead.

GP-write members seem to have taken such criticisms to heart, or come to a similar conclusion on their own. By this Mays conference, human was dropped from the projects name. Leaders emphasized that the human genome would be a subproject proceeding on a conservative timescale and that ethicists would be involved at every step along the way. We want to separate the overarching goal of technology development from the hot-button issue of human genome writing, Boeke explains.

Bringing the public on board with this kind of project can be difficult, says Alta Charo, a professor of law and bioethics at the University of Wisconsin, Madison, who is not involved with GP-write. Charo cochaired a National Academy of Sciences study on the ethics and governance of human gene editing, which was published in February.

She says the likelihood of positive outcomes, such as new therapies or advances in basic science, must be weighed against potential unintended consequences or unforeseen uses of genome writing. People see their basic values at stake in human genetic engineering. If scientists achieve their goalsmaking larger scale genetic engineering routine and more useful, and bringing it to the human genomemajor changes are possible to what Charo calls the fabric of our culture and society. People will have to decide whether they feel optimistic about that or not. (Charo does.)

Given humans cautiousness, Charo imagines in early times we might have decided against creating fire, saying, Lets live without that; we dont need to create this thing that might destroy us. People often see genetic engineering in extreme terms, as a fire that might illuminate human biology and light the way to new technologies, or one that will destroy us.

Charo says the GP-write plan to keep ethicists involved going forward is the right approach and that its difficult to make an ethical or legal call on the project until its leaders put forward a road map.

The group will announce a specific road map sometime this year, but it doesnt want to be restrictive ahead of time. You know when youre done reading something, Boeke said at the meeting in May. But writing has an artistic side to it, he added. You never know when youre done.

Katherine Bourzac is a freelance science writer based in San Francisco.

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Smelling your food makes you fat – UC Berkeley

Posted: July 10, 2017 at 6:45 am

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Our sense of smell is key to the enjoyment of food, so it may be no surprise that in experiments at the University of California, Berkeley, obese mice who lost their sense of smell also lost weight.

Whats weird, however, is that these slimmed-down but smell-deficient mice ate the same amount of fatty food as mice that retained their sense of smell and ballooned to twice their normal weight.

In addition, mice with a boosted sense of smell super-smellers got even fatter on a high-fat diet than did mice with normal smell.

The findings suggest that the odor of what we eat may play an important role in how the body deals with calories. If you cant smell your food, you may burn it rather than store it.

These results point to a key connection between the olfactory or smell system and regions of the brain that regulate metabolism, in particular the hypothalamus, though the neural circuits are still unknown.

This paper is one of the first studies that really shows if we manipulate olfactory inputs we can actually alter how the brain perceives energy balance, and how the brain regulates energy balance, said Cline Riera, a former UC Berkeley postdoctoral fellow now at Cedars-Sinai Medical Center in Los Angeles.

Humans who lose their sense of smell because of age, injury or diseases such as Parkinsons often become anorexic, but the cause has been unclear because loss of pleasure in eating also leads to depression, which itself can cause loss of appetite.

The new study, published this week in the journal Cell Metabolism, implies that the loss of smell itself plays a role, and suggests possible interventions for those who have lost their smell as well as those having trouble losing weight.

Sensory systems play a role in metabolism. Weight gain isnt purely a measure of the calories taken in; its also related to how those calories are perceived, said senior author Andrew Dillin, the Thomas and Stacey Siebel Distinguished Chair in Stem Cell Research, professor of molecular and cell biology and Howard Hughes Medical Institute Investigator. If we can validate this in humans, perhaps we can actually make a drug that doesnt interfere with smell but still blocks that metabolic circuitry. That would be amazing.

Riera noted that mice as well as humans are more sensitive to smells when they are hungry than after theyve eaten, so perhaps the lack of smell tricks the body into thinking it has already eaten. While searching for food, the body stores calories in case its unsuccessful. Once food is secured, the body feels free to burn it. Zapping olfactory neurons The researchers used gene therapy to destroy olfactory neurons in the noses of adult mice but spare stem cells, so that the animals lost their sense of smell only temporarily for about three weeks before the olfactory neurons regrew.

After UC Berkeley researchers temporarily eliminated the sense of smell in the mouse on the bottom, it remained a normal weight while eating a high-fat diet. The mouse on the top, which retained its sense of smell, ballooned in weight on the same high-fat diet.

The smell-deficient mice rapidly burned calories by up-regulating their sympathetic nervous system, which is known to increase fat burning. The mice turned their beige fat cells the subcutaneous fat storage cells that accumulate around our thighs and midriffs into brown fat cells, which burn fatty acids to produce heat. Some turned almost all of their beige fat into brown fat, becoming lean, mean burning machines.

In these mice, white fat cells the storage cells that cluster around our internal organs and are associated with poor health outcomes also shrank in size.

The obese mice, which had also developed glucose intolerance a condition that leads to diabetes not only lost weight on a high-fat diet, but regained normal glucose tolerance.

On the negative side, the loss of smell was accompanied by a large increase in levels of the hormone noradrenaline, which is a stress response tied to the sympathetic nervous system. In humans, such a sustained rise in this hormone could lead to a heart attack.

Though it would be a drastic step to eliminate smell in humans wanting to lose weight, Dillin noted, it might be a viable alternative for the morbidly obese contemplating stomach stapling or bariatric surgery, even with the increased noradrenaline.

For that small group of people, you could wipe out their smell for maybe six months and then let the olfactory neurons grow back, after theyve got their metabolic program rewired, Dillin said.

Dillin and Riera developed two different techniques to temporarily block the sense of smell in adult mice. In one, they genetically engineered mice to express a diphtheria receptor in their olfactory neurons, which reach from the noses odor receptors to the olfactory center in the brain. When diphtheria toxin was sprayed into their nose, the neurons died, rendering the mice smell-deficient until the stem cells regenerated them.

Separately, they also engineered a benign virus to carry the receptor into olfactory cells only via inhalation. Diphtheria toxin again knocked out their sense of smell for about three weeks.

In both cases, the smell-deficient mice ate as much of the high-fat food as did the mice that could still smell. But while the smell-deficient mice gained at most 10 percent more weight, going from 25-30 grams to 33 grams, the normal mice gained about 100 percent of their normal weight, ballooning up to 60 grams. For the former, insulin sensitivity and response to glucose both of which are disrupted in metabolic disorders like obesity remained normal.

Mice that were already obese lost weight after their smell was knocked out, slimming down to the size of normal mice while still eating a high-fat diet. These mice lost only fat weight, with no effect on muscle, organ or bone mass.

The UC Berkeley researchers then teamed up with colleagues in Germany who have a strain of mice that are supersmellers, with more acute olfactory nerves, and discovered that they gained more weight on a standard diet than did normal mice.

People with eating disorders sometimes have a hard time controlling how much food they are eating and they have a lot of cravings, Riera said. We think olfactory neurons are very important for controlling pleasure of food and if we have a way to modulate this pathway, we might be able to block cravings in these people and help them with managing their food intake.

Co-authors of the paper are Jens Brning, director of the Max Planck Institute for Metabolism Research in Cologne, Germany, and his colleagues Eva Tsaousidou, Linda Engstrm Ruud, Jens Alber, Hella Brnneke and Brigitte Hampel; Jonathan Halloran, Courtney Anderson and Andreas Stahl of UC Berkeley; Patricia Follett and Carlos Daniel de Magalhaes Filho of the Salk Institute for Biological Studies in La Jolla, California; and Oliver Hahn of the Max Planck Institute for Biology of Ageing in Cologne.

The work was supported by the Howard Hughes Medical Institute, the Glenn Center for Research on Aging and the American Diabetes Association.

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Smelling your food makes you fat - UC Berkeley

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