CHICAGO – Small RNA molecules originally developed as a tool to study gene function trigger a mechanism hidden in every cell that forces the cell to commit suicide, reports a new Northwestern Medicine study, the first to identify molecules to trigger a fail-safe mechanism that may protect us from cancer.
The mechanism — RNA suicide molecules — can potentially be developed into a novel form of cancer therapy, the study authors said.
Cancer cells treated with the RNA molecules never become resistant to them because they simultaneously eliminate multiple genes that cancer cells need for survival.
“It’s like committing suicide by stabbing yourself, shooting yourself and jumping off a building all at the same time,” said Northwestern scientist and lead study author Marcus Peter. “You cannot survive.”
The inability of cancer cells to develop resistance to the molecules is a first, Peter said.
“This could be a major breakthrough,” noted Peter, the Tom D. Spies Professor of Cancer Metabolism at Northwestern University Feinberg School of Medicine and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Peter and his team discovered sequences in the human genome that when converted into small double-stranded RNA molecules trigger what they believe to be an ancient kill switch in cells to prevent cancer. He has been searching for the phantom molecules with this activity for eight years.
“We think this is how multicellular organisms eliminated cancer before the development of the adaptive immune system, which is about 500 million years old,” he said. “It could be a fail safe that forces rogue cells to commit suicide. We believe it is active in every cell protecting us from cancer.”
This study, which will be published Oct. 24 in eLife, and two other new Northwestern studies in Oncotarget and Cell Cycle by the Peter group, describe the discovery of the assassin molecules present in multiple human genes and their powerful effect on cancer in mice.
Looking back hundreds of millions of years
Why are these molecules so powerful?
“Ever since life became multicellular, which could be more than 2 billion years ago, it had to deal with preventing or fighting cancer,” Peter said. “So nature must have developed a fail safe mechanism to prevent cancer or fight it the moment it forms. Otherwise, we wouldn’t still be here.”
Thus began his search for natural molecules coded in the genome that kill cancer.
“We knew they would be very hard to find,” Peter said. “The kill mechanism would only be active in a single cell the moment it becomes cancerous. It was a needle in a haystack.”
But he found them by testing a class of small RNAs, called small interfering (si)RNAs, scientists use to suppress gene activity. siRNAs are designed by taking short sequences of the gene to be targeted and converting them into double- stranded RNA. These siRNAs when introduced into cells suppress the expression of the gene they are derived from.Peter found that a large number of these small RNAs derived from certain genes did not, as expected, only suppress the gene they were designed against. They also killed all cancer cells. His team discovered these special sequences are distributed throughout the human genome, embedded in multiple genes as shown in the study in Cell Cycle.
When converted to siRNAs, these sequences all act as highly trained super assassins. They kill the cells by simultaneously eliminating the genes required for cell survival. By taking out these survivor genes, the assassin molecule activates multiple death cell pathways in parallel.
The small RNA assassin molecules trigger a mechanism Peter calls DISE, for Death Induced by Survival gene Elimination.
Activating DISE in organisms with cancer might allow cancer cells to be eliminated. Peter’s group has evidence this form of cell death preferentially affects cancer cells with little effect on normal cells.
To test this in a treatment situation, Peter collaborated with Dr. Shad Thaxton, associate professor of urology at Feinberg, to deliver the assassin molecules via nanoparticles to mice bearing human ovarian cancer. In the treated mice, the treatment strongly reduced the tumor growth with no toxicity to the mice, reports the study in Oncotarget. Importantly, the tumors did not develop resistance to this form of cancer treatment. Peter and Thaxton are now refining the treatment to increase its efficacy.
Peter has long been frustrated with the lack of progress in solid cancer treatment.
“The problem is cancer cells are so diverse that even though the drugs, designed to target single cancer driving genes, often initially are effective, they eventually stop working and patients succumb to the disease,” Peter said. He thinks a number of cancer cell subsets are never really affected by most targeted anticancer drugs currently used.
Most of the advanced solid cancers such as brain, lung, pancreatic or ovarian cancer have not seen an improvement in survival, Peter said.
“If you had an aggressive, metastasizing form of the disease 50 years ago, you were busted back then and you are still busted today,” he said. “Improvements are often due to better detection methods and not to better treatments.”
Cancer scientists need to listen to nature more, Peter said. Immune therapy has been a success, he noted, because it is aimed at activating an anticancer mechanism that evolution developed. Unfortunately, few cancers respond to immune therapy and only a few patients with these cancers benefit, he said.
“Our research may be tapping into one of nature’s original kill switches, and we hope the impact will affect many cancers,” he said. “Our findings could be disruptive.”
Northwestern co-authors include first authors William Putzbach, Quan Q. Gao, and Monal Patel, and coauthors Ashley Haluck-Kangas, Elizabeth T. Bartom, Kwang-Youn A. Kim, Denise M. Scholtens, Jonathan C. Zhao and Andrea E. Murmann.
The research is funded by grants T32CA070085, T32CA009560, R50CA211271 and R35CA197450 from the National Cancer Institute of the National Institutes of Health.
Nathan Treff was diagnosed with type 1 diabetes at 24. It’s a disease that runs in families, but it has complex causes. More than one gene is involved. And the environment plays a role too.
So you don’t know who will get it. Treff’s grandfather had it, and lost a leg. But Treff’s three young kids are fine, so far. He’s crossing his fingers they won’t develop it later.
Now Treff, an in vitro fertilization specialist, is working on a radical way to change the odds. Using a combination of computer models and DNA tests, the startup company he’s working with, Genomic Prediction, thinks it has a way of predicting which IVF embryos in a laboratory dish would be most likely to develop type 1 diabetes or other complex diseases. Armed with such statistical scorecards, doctors and parents could huddle and choose to avoid embryos with failing grades.
IVF clinics already test the DNA of embryos to spot rare diseases, like cystic fibrosis, caused by defects in a single gene. But these “preimplantation” tests are poised for a dramatic leap forward as it becomes possible to peer more deeply at an embryo’s genome and create broad statistical forecasts about the person it would become.
The advance is occurring, say scientists, thanks to a growing flood of genetic data collected from large population studies. As statistical models known as predictors gobble up DNA and health information about hundreds of thousands of people, they’re getting more accurate at spotting the genetic patterns that foreshadow disease risk. But they have a controversial side, since the same techniques can be used to project the eventual height, weight, skin tone, and even intelligence of an IVF embryo.
In addition to Treff, who is the company’s chief scientific officer, the founders of Genomic Prediction are Stephen Hsu, a physicist who is vice president for research at Michigan State University, and Laurent Tellier, a Danish bioinformatician who is CEO. Both Hsu and Tellier have been closely involved with a project in China that aims to sequence the genomes of mathematical geniuses, hoping to shed light on the genetic basis of IQ.
The company’s plans rely on a tidal wave of new knowledge showing how small genetic differences can add up to put one person, but not another, at high odds for diabetes, a neurotic personality, or a taller or shorter height. Already, such “polygenic risk scores” are used in direct-to-consumer gene tests, such as reports from 23andMe that tell customers their genetic chance of being overweight.
For adults, risk scores are little more than a novelty or a source of health advice they can ignore. But if the same information is generated about an embryo, it could lead to existential consequences: who will be born, and who stays in a laboratory freezer.
“I remind my partners, ‘You know, if my parents had this test, I wouldn’t be here,’” says Treff, a prize-winning expert on diagnostic technology who is the author of more than 90 scientific papers.
Genomic Prediction was founded this year and has raised funds from venture capitalists in Silicon Valley, though it declines to say who they are. Tellier, whose inspiration is the science fiction film Gattaca, says the company plans to offer reports to IVF doctors and parents identifying “outliers”—those embryos whose genetic scores put them at the wrong end of a statistical curve for disorders such as diabetes, late-life osteoporosis, schizophrenia, and dwarfism, depending on whether models for those problems prove accurate.
The company’s concept, which it calls expanded preimplantation genetic testing, or ePGT, would effectively add a range of common disease risks to the menu of rare ones already available, which it also plans to test for. Its promotional material uses a picture of a mostly submerged iceberg to get the idea across. “We believe it will become a standard part of the IVF process,” says Tellier, just as a test for Down syndrome is a standard part of pregnancy.
Some experts contacted by MIT Technology Review said they believed it’s premature to introduce polygenic scoring technology into IVF clinics—though perhaps not by very much. Matthew Rabinowitz, CEO of the prenatal-testing company Natera, based in California, says he thinks predictions obtained today could be “largely misleading” because DNA models don’t function well enough. But Rabinowitz agrees that the technology is coming.
“You are not going to stop the modeling in genetics, and you are not going to stop people from accessing it,” he says. “It’s going to get better and better.”
Testing embryos for disease risks, including risks for diseases that develop only late in life, is considered ethically acceptable by U.S. fertility doctors. But the new DNA scoring models mean parents might be able to choose their kids on the basis of traits like IQ or adult weight. That’s because, just like type 1 diabetes, these traits are the result of complex genetic influences the predictor algorithms are designed to find.
“It’s the camel’s nose under the tent. Because if you are doing it for something more serious, then it’s trivially easy to look for anything else,” says Michelle Meyer, a bioethicist at the Geisinger Health System who analyzes issues in reproductive genetics. “Here is the genomic dossier on each embryo. And you flip through the book.” Imagine picking the embryo most likely to get into Harvard like Mom, or to be tall like Dad.
For Genomic Prediction, a tiny startup based out of a tech incubator in New Jersey, such questions will be especially sharply drawn. That is because of Hsu’s long-standing interest in genetic selection for superior intelligence.
In 2014, Hsu authored an essay titled “Super-Intelligent Humans Are Coming,” in which he argued that selecting embryos for intelligence could boost the resulting child’s IQ by 15 points.
Genomic Prediction says it will only report diseases—that is, identify those embryos it thinks would develop into people with serious medical problems. Even so, on his blog and in public statements, Hsu has for years been developing a vision that goes far beyond that.
“Suppose I could tell you embryo four is going to be the tallest, embryo three is going to be the smartest, embryo two is going to be very antisocial. Suppose that level of granularity was available in the reports,” he told the conservative radio and YouTube personality Stefan Molyneux this spring. “That is the near-term future that we as a civilization face. This is going to be here.”
The fuel for the predictive models is a deluge of new data, most recently genetic readouts and medical records for 500,000 middle-aged Britons that were released in July by the U.K. Biobank, a national precision-medicine project in that country.
The data trove included, for each volunteer, a map of about 800,000 single-nucleotide polymorphisms, or SNPs—points where their DNA differs slightly from another person’s. The release caused a pell-mell rush by geneticists to update their calculations about exactly how much of human disease, or even routine behaviors like bread consumption, these genetic differences could explain.
Armed with the U.K. data, Hsu and Tellier claimed a breakthrough. For one easily measured trait, height, they used machine-learning techniques to create a predictor that behaved flawlessly. They reported that the model could, for the most part, predict people’s height from their DNA data to within three or four centimeters.
Height is currently the easiest trait to predict. It’s determined mostly by genes, and it’s always recorded in population databases. But Tellier says genetic databases are “rapidly approaching” the size needed to make accurate predictions about other human features, including risk for diseases whose true causes aren’t even known.
Tellier says Genomic Prediction will zero in on disease traits for which the predictors already perform fairly well, or will soon. Those include autoimmune disorders like the illness Treff suffers from. In those conditions, a smaller set of genes dominates the predictions, sometimes making them more reliable.
A report from Germany in 2014, for instance, found it was possible to distinguish fairly accurately, from a polygenic DNA score alone, between a person with type 1 diabetes and a person without it. While the scores aren’t perfectly accurate, consider how they might influence a prospective parent. On average, children of a man with type 1 diabetes have a one in 17 chance of developing the ailment. Picking the best of several embryos made in an IVF clinic, even with an error-prone predictor, could lower the odds.
In the case of height, Genomic Prediction hopes to use the model to help identify embryos that would grow into adults shorter than 4’10”, the medical definition of dwarfism, says Tellier. There are many physical and psychological disadvantages to being so short. Eventually the company could also have the ability to identify intellectual problems, such as embryos with a predicted IQ of less than 70.
The company doesn’t intend to give out raw trait scores to parents, only to flag embryos likely to be abnormal. That is because the product has to be “ethically defensible,” says Hsu: “We would only reveal the negative outlier state. We don’t report, ‘This guy is going to be in the NBA.’”
Some scientists doubt the scores will prove useful at picking better people from IVF dishes. Even if they’re accurate on the average, for individuals there’s no guarantee of pinpoint precision. What’s more, environment has as big an impact on most traits as genes do. “There is a high probability that you will get it wrong—that would be my concern,” says Manuel Rivas, a professor at Stanford University who studies the genetics of Crohn’s disease. “If someone is using that information to make decisions about embryos, I don’t know what to make of it.”
Efforts to introduce this type of statistical scoring into reproduction have, in the past, drawn criticism. In 2013, 23andMe provoked outrage when it won a patent on the idea of drop-down menus parents could use to pick sperm or egg donors—say, to try to get a specific eye color. The company, funded by Google, quickly backpedaled.
But since then, polygenic scores have become a routine aspect of novelty DNA tests. A company called HumanCode sells a $199 test online that uses SNP scores to tell two people about how tall their kids might be. In the dairy cattle industry, polygenic tests are widely used to rate young animals for how much milk they’ll produce.
“At a broad level, our understanding of complex traits has evolved. It’s not that there are a few genes contributing to complex traits; it’s tens, or thousands, or even all genes,” says Meyer, the Geisinger professor. “That has led to polygenic risk scores. It’s many variants, each with small contributions of their own, but which have a significant contribution together. You add them up.” In his predictor for height, Hsu eventually made use of 20,000 variants to guess how tall each person was.
Around the world, a million couples undergo IVF each year; in the U.S., test-tube babies account for 1 percent of births. Preimplantation genetic diagnosis, or PGD, has been part of the technology since the 1990s. In that procedure, a few cells are plucked from a days-old embryo growing in a laboratory so they can be tested.
Until now, doctors have used PGD to detect embryos with major abnormalities, such as missing chromosomes, as well as those with “single gene” defects. Parents who carry the defective gene that causes Huntington’s disease, for instance, can use embryo tests to avoid having a child with the fatal brain ailment.
The obstacle to polygenic tests has been that with so few cells, it’s been difficult to get the broad, accurate view of an embryo’s genome necessary to perform the needed calculations. “It’s very hard to make reliable measurements on that little DNA,” says Rabinowitz, the Natera CEO.
Tellier says Genomic Prediction has developed an improved method for analyzing embryonic DNA, which he says will first be used to improve on traditional PGD, combing many single-gene tests into one. Tellier says the same technique is what will permit it to collect polygenic scores on embryos, although the company did not describe the method in detail. But other scientists have already demonstrated ways to overcome the accuracy barrier.
In 2015, a team led by Rabinowitz and Jay Shendure of the University of Washington did it by sequencing in detail the genomes of two parents undergoing IVF. That let them infer the embryo’s genome sequence, even though the embryo test itself was no more accurate than before. When the babies were born, they found they’d been right.
“We do have the technology to reconstruct the genome of an embryo and create a polygenic model,” says Rabinowitz, whose publicly traded company is worth about $600 million, and who says he has been mulling whether to enter the embryo-scoring business. “The problem is that the models have not quite been ready for prime time.”
That’s because despite Hsu’s success with height, the scoring algorithms have significant limitations. One is that they’re built using data mostly from Northern Europeans. That means they may not be useful for people from Asia or Africa, where the pattern of SNPs is different, or for people of mixed ancestry. Even their performance for specific families of European background can’t be taken for granted unless the procedure is carefully tested in a clinical study, something that’s never been done, says Akash Kumar, a Stanford resident physician who was lead author of the Natera study.
Kumar, who treats young patients with rare disorders, says the genetic predictors raise some “big issues.” One is that the sheer amount of genetic data becoming available could make it temptingly easy to assess nonmedical traits. “We’ve seen such a crazy change in the number of people we are able to study,” he says. “Not many have schizophrenia, but they all have a height and a body-mass index. So the number of people you can use to build the trait models is much larger. It’s a very unique place to be, thinking what we should do with this technology.”
This week, Genomic Prediction manned a booth at the annual meeting of the American Society for Reproductive Medicine. That organization, which represents fertility doctors and scientists, has previously said it thinks testing embryos for late-life conditions, like Alzheimer’s, would be “ethically justified.” It cited, among other reasons, the “reproductive liberty” of parents.
The society has been more ambivalent about choosing the sex of embryos (something that conventional PGD allows), leaving it to the discretion of doctors. Combined, the society’s positions seem to open the door to any kind of measurement, perhaps so long as the test is justified for a medical reason.
Hsu has previously said he thinks intelligence is “the most interesting phenotype,” or trait, of all. But when he tried his predictor to see what it could say about how far along in school the 500,000 British subjects from the U.K. Biobank had gotten (years of schooling is a proxy for IQ), he found that DNA couldn’t predict it nearly as well as it could predict height.
Yet DNA did explain some of the difference. Daniel Benjamin, a geno-economist at the University of Southern California, says that for large populations, gene scores are already as predictive of educational attainment as whether someone grew up in a rich or poor family. He adds that the accuracy of the scores has been steadily improving. Scoring embryos for high IQ, however, would be “premature” and “ethically contentious,” he says.
Hsu’s prediction is that “billionaires and Silicon Valley types” will be the early adopters of embryo selection technology, becoming among the first “to do IVF even though they don’t need IVF.” As they start producing fewer unhealthy children, and more exceptional ones, the rest of society could follow suit.
“I fully predict it will be possible,” says Hsu of selecting embryos with higher IQ scores. “But we’ve said that we as a company are not going to do it. It’s a difficult issue, like nuclear weapons or gene editing. There will be some future debate over whether this should be legal, or made illegal. Countries will have referendums on it.”
What does it really cost to bring a drug to market?
The question is central to the debate over rising health care costs and appropriate drug pricing. President Trump campaigned on promises to lower the costs of drugs.
But numbers have been hard to come by. For years, the standard figure has been supplied by researchers at the Tufts Center for the Study of Drug Development: $2.7 billion each, in 2017 dollars.
Yet a new study looking at 10 cancer medications, among the most expensive of new drugs, has arrived at a much lower figure: a median cost of $757 million per drug. (Half cost less, and half more.)
Following approval, the 10 drugs together brought in $67 billion, the researchers also concluded — a more than sevenfold return on investment. Nine out of 10 companies made money, but revenues varied enormously. One drug had not yet earned back its development costs.
The study, published Monday in JAMA Internal Medicine, relied on company filings with the Securities and Exchange Commission to determine research and development costs.
“It seems like they have done a thoughtful and rigorous job,” said Dr. Aaron Kesselheim, director of the program on regulation, therapeutics and the law at Brigham and Women’s Hospital.
“It provides at least something of a reality check,” he added.
The figures were met with swift criticism, however, by other experts and by representatives of the biotech industry, who said that the research did not adequately take into account the costs of the many experimental drugs that fail.
“It’s a bit like saying it’s a good business to go out and buy winning lottery tickets,” Daniel Seaton, a spokesman for the Biotechnology Innovation Organization, said in an email.
Dr. Jerry Avorn, chief of the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, predicted that the paper would help fuel the debate over the prices of cancer drugs, which have soared so high “that we are getting into areas that are almost unimaginable economically,” he said.
A leukemia treatment approved recently by the Food and Drug Administration, for example, will cost $475,000 for a single treatment. It is the first of a wave of gene therapy treatments likely to carry staggering price tags.
“This is an important brick in the wall of this developing concern,” he said.
Dr. Vinay Prasad, an oncologist at Oregon Health and Science University, and Dr. Sham Mailankody, of Memorial Sloan Kettering Cancer Center, arrived at their figures after reviewing data on 10 companies that brought a cancer drug to market in the past decade.
Since the companies also were developing other drugs that did not receive approval from the F.D.A., the researchers were able to include the companies’ total spending on research and development, not just what they spent on the drugs that succeeded.
One striking example was ibrutinib, made by Pharmacyclics. It was approved in 2013 for patients with certain blood cancers who did not respond to conventional therapy.
Ibrutinib was the only drug out of four the company was developing to receive F.D.A. approval. The company’s research and development costs for their four drugs were $388 million, the company’s S.E.C. filings indicated.
Accurate figures on drug development are difficult to find and often disputed. Although it is widely cited, the Tufts study also was fiercely criticized.
One objection was that the researchers, led by Joseph A. DiMasi, did not disclose the companies’ data on development costs. The study involved ten large companies, which were not named, and 106 investigational drugs, also not named.
But Dr. DiMasi found the new study “irredeemably flawed at a fundamental level.”
“The sample consists of relatively small companies that have gotten only one drug approved, with few other drugs of any type in development,” he said. The result is “substantial selection bias,” meaning that the estimates do not accurately reflect the industry as a whole.
Ninety-five percent of cancer drugs that enter clinical trials fail, said Mr. Seaton, of the biotech industry group. “The small handful of successful drugs — those looked at by this paper — must be profitable enough to finance all of the many failures this analysis leaves unexamined.”
“When the rare event occurs that a company does win approval,” he added, “the reward must be commensurate with taking on the multiple levels of risk not seen in any other industry if drug development is to remain economically viable for prospective investors.”
Cancer drugs remain among the most expensive medications, with prices reaching the hundreds of thousands of dollars per patient.
Although the new study was small, its estimates are so much lower than previous figures, and the return on investment so great, that experts say they raise questions about whether soaring drug prices really are needed to encourage investment.
”That seems hard to swallow when they make seven times what they invested in the first four years,” Dr. Prasad said.
The new study has limitations, noted Patricia Danzon, an economist at the University of Pennsylvania’s Wharton School.
It involved just ten small biotech companies whose cancer drugs were aimed at limited groups of patients with less common diseases.
For such drugs, the F.D.A. often permits clinical trials to be very small and sometimes without control groups. Therefore development costs may have been lower for this group than for drugs that require longer and larger studies.
But, Dr. Danzon said, most new cancer drugs today are developed this way: by small companies and for small groups of patients. The companies often license or sell successful drugs to the larger companies.
The new study, she said, “is shining a light on a sector of the industry that is becoming important now.” The evidence, she added, is “irrefutable” that the cost of research and development “is small relative to the revenues.”
When it comes to drug prices, it does not matter what companies spend on research and development, Dr. Kesselheim said.
“They are based on what the market will bear.”
Correction: September 14, 2017
An earlier version of this article incorrectly identified the company that acquired a drug maker. It was AbbVie, not Janssen Biotech (which jointly develops the drug). Additionally, the article incorrectly described what AbbVie acquired. It was the company Pharmacylics, which developed the drug Imbruvica, not the drug itself.
NASA researchers have found large quantities (2.8 parts per billion) of acrylonitrile* (vinyl cyanide, C2H3CN) in Titan’s atmosphere that could self-assemble as a sheet of material similar to a cell membrane.
Acrylonitrile (credit: NASA Goddard)
Consider these findings, presented July 28, 2017 in the open-access journal Science Advances, based on data from the ALMA telescope in Chile (and confirming earlier observations by NASA’s Cassini spacecraft):
Azotozome illustration (credit: James Stevenson/Cornell)
1. Researchers have proposed that acrylonitrile molecules could come together as a sheet of material similar to a cell membrane. The sheet could form a hollow, microscopic sphere that they dubbed an “azotosome.”
A bilayer, made of two layers of lipid molecules (credit: Mariana Ruiz Villarreal/CC)
2. The azotosome sphere could serve as a tiny storage and transport container, much like the spheres that biological lipid bilayers can form. The thin, flexible lipid bilayer is the main component of the cell membrane, which separates the inside of a cell from the outside world.
“The ability to form a stable membrane to separate the internal environment from the external one is important because it provides a means to contain chemicals long enough to allow them to interact,” said Michael Mumma, director of the Goddard Center for Astrobiology, which is funded by the NASA Astrobiology Institute.
Organic rain falling on a methane sea on Titan (artist’s impression) (credit: NASA Goddard)
3. Acrylonitrile condenses in the cold lower atmosphere and rains onto its solid icy surface, ending up in seas of methane liquids on its surface.
Illustration showing organic compounds in Titan’s seas and lakes (ESA)
4. A lake on Titan named Ligeia Mare that could have accumulated enough acrylonitrile to form about 10 million azotosomes in every milliliter (quarter-teaspoon) of liquid. Compare that to roughly a million bacteria per milliliter of coastal ocean water on Earth.
Chemistry in Titan’s atmosphere. Nearly as large as Mars, Titan has a hazy atmosphere made up mostly of nitrogen with a smattering of organic, carbon-based molecules, including methane (CH4) and ethane (C2H6). Planetary scientists theorize that this chemical make-up is similar to Earth’s primordial atmosphere. The conditions on Titan, however, are not conducive to the formation of life as we know it; it’s simply too cold (95 kelvins or -290 degrees Fahrenheit). (credit: ESA)
6. A related open-access study published July 26, 2017 in The Astrophysical Journal Letters notes that Cassini has also made the surprising detection of negatively charged molecules known as “carbon chain anions” in Titan’s upper atmosphere. These molecules are understood to be building blocks towards more complex molecules, and may have acted as the basis for the earliest forms of life on Earth.
“This is a known process in the interstellar medium, but now we’ve seen it in a completely different environment, meaning it could represent a universal process for producing complex organic molecules,” says Ravi Desai of University College London and lead author of the study.
* On Earth, acrylonitrile is used in manufacturing of plastics.
NASA Goddard | A Titan Discovery
Abstract of ALMA detection and astrobiological potential of vinyl cyanide on Titan
Recent simulations have indicated that vinyl cyanide is the best candidate molecule for the formation of cell membranes/vesicle structures in Titan’s hydrocarbon-rich lakes and seas. Although the existence of vinyl cyanide (C2H3CN) on Titan was previously inferred using Cassini mass spectrometry, a definitive detection has been lacking until now. We report the first spectroscopic detection of vinyl cyanide in Titan’s atmosphere, obtained using archival data from the Atacama Large Millimeter/submillimeter Array (ALMA), collected from February to May 2014. We detect the three strongest rotational lines of C2H3CN in the frequency range of 230 to 232 GHz, each with >4σ confidence. Radiative transfer modeling suggests that most of the C2H3CN emission originates at altitudes of ≳200 km, in agreement with recent photochemical models. The vertical column densities implied by our best-fitting models lie in the range of 3.7 × 1013 to 1.4 × 1014 cm−2. The corresponding production rate of vinyl cyanide and its saturation mole fraction imply the availability of sufficient dissolved material to form ~107 cell membranes/cm3 in Titan’s sea Ligeia Mare.
Pronounced ‘crisper’, the technique stands for Clustered Regularly Interspaced Short Palindromic Repeat and refers to the way short, repeated DNA sequences in the genomes of bacteria and other microorganisms are organised.
Inspired by how these organisms defend themselves from viral attacks by stealing strips of an invading virus’ DNA, the technique splices in an enzyme called Cas creating newly-formed sequences known as CRISPR. In bacteria, this causes RNA to make copies of these sequences, which help recognise virus DNA and prevent future invasions.This technique was transformed into a gene-editing tool in 2012 and was named Science magazine’s 2015 Breakthrough of the Year. While it’s not the first DNA-editing tool, it has piqued the interest of many scientists, research and health groups because of its accuracy, relative affordability and far-reaching uses. The latest? Eradicating HIV.
At the start of May, researchers at the Lewis Katz School of Medicine at Temple University (LKSOM) and the University of Pittsburgh demonstrated how they can remove HIV DNA from genomes of living animals – in this case, mice – to curb the spread of infection. The breakthrough was the first time replication of HIV-1 had been eliminated from infected cells using CRISPR following a 2016 proof-of-concept study.
In particular, the team genetically inactivated HIV-1 in transgenic mice, reducing the RNA expression of viral genes by roughly 60 to 95 per cent, before trialling the method on infected mice.
“During acute infection, HIV actively replicates,” Dr. Khalili explained. “With EcoHIV mice, we were able to investigate the ability of the CRISPR/Cas9 strategy to block viral replication and potentially prevent systemic infection.”
Since the HIV research was published, a team of biologists at University of California, Berkeley, described 10 new CRISPR enzymes that, once activated, are said to “behave like Pac-Man” to chew through RNA in a way that could be used as sensitive detectors of infectious viruses.
These new enzymes are variants of a CRISPR protein, Cas13a, which the UC Berkeley researchers reported last September in Nature, and could be used to detect specific sequences of RNA, such as from a virus. The team showed that once CRISPR-Cas13a binds to its target RNA, it begins to indiscriminately cut up all RNA making it “glow” to allow signal detection.
Two teams of researchers at the Broad Institute subsequently paired CRISPR-Cas13a with the process of RNA amplification to reveal that the system, dubbed Sherlock, could detect viral RNA at extremely low concentrations, such as the presence of dengue and Zika viral RNA, for example. Such a system could be used to detect any type of RNA, including RNA distinctive of cancer cells.
This piece has been updated to remove copy taken from WIRED US.
Artificial intelligence algorithms are being taught to generate art, human voices, and even fiction stories all on their own—why not give them a shot at building new ways to treat disease?
Atomwise, a San Francisco-based startup and Y Combinator alum, has built a system it calls AtomNet (pdf), which attempts to generate potential drugs for diseases like Ebola and multiple sclerosis. The company has invited academic and non-profit researchers from around the country to detail which diseases they’re trying to generate treatments for, so AtomNet can take a shot. The academic labs will receive 72 different drugs that the neural network has found to have the highest probability of interacting with the disease, based on the molecular data it’s seen.
Atomwise’s system only generates potential drugs—the compounds created by the neural network aren’t guaranteed to be safe, and need to go through the same drug trials and safety checks as anything else on the market. The company believes that the speed at which it can generate trial-ready drugs based on previous safe molecular interactions is what sets it apart.
Atomwise touts two projects that show the potential of AtomNet, drugs for multiple sclerosis and Ebola. The MS drug has been licensed to an undisclosed UK pharmacology firm, according to Atomwise, and the Ebola drug is being prepared for submission to a peer-reviewed publication.
Alexander Levy, the company’s COO and cofounder, said that AtomNet learns the interactions between molecules much like artificial intelligence learns to recognize images. Image recognition finds reduces patterns in images’ pixels to simpler representations, teaching itself the bounds of an idea like a horse or a desk lamp through seeing hundreds or thousands of examples.
“It turns out that the same thing that works in images, also works in chemistry,” Levy says. “You can take an interaction between a drug and huge biological system and you can decompose that to smaller and smaller interactive groups. If you study enough historical examples of molecules … and we’ve studied tens of millions of those, you can then make predictions that are extremely accurate yet also extremely fast.”
One of Atomwise’s advantages, Levy says, is that the network works with 3D models. To generate the drugs, the model starts with a 3D model of a molecule—for example a protein that gives a cancer cell a growth advantage. The neural network then generates a series of synthetic compounds (simulated drugs), and predicts how likely it would be for the two molecules to interact. If a drug is likely to interact with the specific molecule, it can be synthesized and tested.
Levy likens the idea to the automated systems used to model airplane aerodynamics or computer chip design, where millions of scenarios are mapped out within software that accurately represents how the physical world works.
“Imagine if you knew what a biological mechanism looked like, atom by atom. Could you reason your way to a compound that did the thing that you wanted?” Levy says.
Every once in a while someone in Silicon Valley brings up the possibility of living forever, or at least a really long time, but first we’re going to need to figure out a way to enjoy all those extra years. Unity Biotechnology is a startup focusing on medicines to help us do that by slowing the effects of age-related diseases. And the company announced it has pulled in a whopping $116 million in Series B financing today — some of which came from Amazon’s Jeff Bezos.
Sometimes your body keeps aging cells around longer. These cells stop dividing after some form of stress,which is an anti-cancer mechanism that keeps damaged cells from dividing and growing out of control. But too much build-up of those types of cells leads to other problems as we age. Unity looks for ways to help your body shed older cells causing inflammation and other diseases linked to aging.
Unity holds a great amount of potential in preventing our bodies from aging as fast and that has perked some of the top investors in science and medicine and is one of the larger private financings in biotech history.
But it’s not the first time Bezos has invested in biotech. The Amazon CEO placed his bets on Juno Therapeutics back in 2014, through his venture capital arm Bezos Expeditions. Juno is one of the IPO success stories in the biotech world for its breakthrough discoveries in cancer medicine.
The Scottish-based mutual fund Baillie Gifford, which has also invested in several biotech companies, also invested in this round — as did Venrock, ARCH Venture Capital, Mayo Clinic and WuXi Pharmaceuticals.
The company also announced it would be placing Keith Leonard — the former CEO of KYTHERA Biopharmaceuticals — in the role of CEO and that previous CEO and co-founder Nathaniel “Ned” David will now be Unity’s president.
2016 was an incredible year for technology, and for humanity.
Despite all the negative political-related news, there were 10 tech trends this year that positively transformed humanity.
For this “2017 Kick-Off” post, I reviewed 52 weeks of science and technology breakthroughs, and categorized them into the top 10 tech trends changing our world.
I’m blown away by how palpable the feeling of exponential change has become.
I’m also certain that 99.99% of humanity doesn’t understand or appreciate the ramifications of what is coming.
In this post, enjoy the top 10 tech trends of the past 12 months and why they are important to you.
Let’s dive in…
1. We Are Hyper-Connecting the World
In 2010, 1.8 billion people were connected. Today, that number is about 3 billion, and by 2022 – 2025, that number will expand to include every human on the planet, approaching 8 billion humans.
Unlike when I was connected 20 years ago at 9,600 baud via AOL, the world today is coming online at one megabit per second or greater, with access to the world’s information on Google, access to the world’s products on Amazon, access to massive computing power on AWS and artificial intelligence with Watson… not to mention crowdfunding for capital and crowdsourcing for expertise.
a) Google’s 5G Solar Drones Internet Service: Project Skybender is Google’s secretive 5G Internet drone initiative. News broke this year that they have been testing these solar-powered drones at Spaceport America in New Mexico to explore ways to deliver high-speed Internet from the air. Their purported millimeter wave technology could deliver data from drones up to 40 times faster than 4G.
b) Facebook’s Solar Drone Internet Service: Even before Google, Facebook has been experimenting with a solar-powered drone, also for the express purpose of providing Internet to billions. The drone has the wingspan of an airliner and flies with roughly the power of three blowdryers.
c) ViaSat Plans 1 Terabit Internet Service: ViaSat, a U.S.-based satellite company, has teamed up with Boeing to launch three satellites to provide 1 terabit-per-second Internet connections to remote areas, aircraft and maritime vehicles. ViaSat is scheduled to launch its satellite ViaSat2 in early 2017.
d) OneWeb Raises $1.2B for 900 Satellite Constellation: An ambitious low-Earth orbit satellite system proposed by my friends Greg Wyler, Paul Jacobs and Richard Branson just closed $1.2 billion in financing. This 900-satellite system will offer global internet services as soon as 2019.
e) Musk Announces 4,425 Internet Satellite System: Perhaps the most ambitious plan for global internet domination was proposed this year by SpaceX founder Elon Musk, with plans for SpaceX to deploy a 4,425 low-Earth orbit satellite system to blanket the entire planet in broadband.
In December, the World Economic Forum reported that solar and wind energy is now the same price or cheaper than new fossil fuel capacity in more than 30 countries.
“As prices for solar and wind power continue their precipitous fall, two-thirds of all nations will reach the point known as ‘grid parity’ within a few years, even without subsidies,” they added.
This is one of the most important developments in the history of humanity, and this year marked a number of major milestones for renewable energy.
Here’s 10 data points (stories) I’ve hand-picked to hammer home the historic nature of this 2016 achievement.
a) 25 percent of the World’s Power Comes From Renewables: REN21, a global renewable energy policy network, published a report showing that a quarter of the world’s power now comes from renewable energy. International investment in renewable energy reached $286 billion last year (with solar accounting for over $160b of this), and it’s accelerating.
e) Coal Will Never Recover: The coal industry, once the backbone of U.S. energy, is fading fast on account of renewables like solar and wind. Official and expert reports now state that it will never recover (e.g., coal power generation in Texas is down from 39% in early 2015 to 24.8% in May 2016).
j) Tesla’s Gigafactory: Tesla’s $5 billion structure in Nevada will produce 500,000 lithium ion batteries annually and Tesla’s Model III vehicle. It is now over 30 percent complete… the 10 million square foot structure is set to be done by 2020. Musk projected that a total of 100 Gigafactories could provide enough storage capacity to run the entire planet on renewables.
3. Glimpsing the End of Cancer and Disease
Though it may seem hard to believe, the end of cancer and disease is near.
Scientists and researchers have been working diligently to find novel approaches to combating these diseases, and 2016 saw some extraordinary progress in this regard.
Here’re my top 10 picks that give me great faith about our abilities to cure cancer and most diseases:
a) Cancer Immunotherapy Makes Strides (Extraordinary Results): Immunotherapy involves using a patient’s own immune system (in this case, T cells) to fight cancer. Doctors remove immune cells from patients, tag them with “receptor” molecules that target the specific cancer, and then infuse the cells back in the body. During the study, 94% of patients with acute lymphoblastic leukemia (ALL) saw symptoms vanish completely. Patients with other blood cancers had response rates greater than 80%, and more than half experienced complete remission.
b) In China, CRISPR/Cas9 used in First Human Trial: A team of scientists in China (Sichuan University) became the first to treat a human patient with an aggressive form of lung cancer with the groundbreaking CRISPR-Cas9 gene-editing technique.
c) NIH Approves Human Trials Using CRISPR: A team of physicians at the University of Pennsylvania’s School of Medicine had their project of modifying the immune cells of 18 different cancer patients with the CRISPR-Cas9 system approved by the National Institute of Health. Results are TBD.
f) New Treatment Causes HIV Infected Cells to Vanish: A team of scientists in the U.K. discovered a new treatment for HIV. The patient was treated with vaccines that helped the body recognize the HIV-infected cells. Then, the drug Vorinostat was administered to activate the dormant cells so they could be spotted by the immune system.
g) CRISPR Cures Mice of Sickle Cell Disease: CRISPR was used to completely cure sickle cell by editing the errant DNA sequence in mice. The treatment may soon be used to cure this disease, which affects about 100,000 Americans.
h) Eradicating Measles (in the U.S.): The World Health Organization (WHO) announced that after 50 years, they have successfully eradicated measles in the U.S. This is one of the most contagious diseases around the world.
i) New Ebola Vaccine Proved to be 100% Effective: None of the nearly 6,000 individuals vaccinated with rVSV-ZEBOV in Guinea, a country with more than 3,000 confirmed cases of Ebola, showed any signs of contracting the disease.
j) Eradicating Polio: The World Health Organization has announced that it expects to fully eradicate polio worldwide by Early 2017.
4. Progress on Extending Human Life
I am personally convinced that we are on the verge of significantly impacting human longevity. At a minimum, making “100 years old the new 60,” as we say at Human Longevity Inc.
This year, hundreds of millions of dollars were poured into research initiatives and companies focused on extending life.
Here are five of the top stories from 2016 in longevity research:
a) 500-Year-Old Shark Discovered: A Greenland shark that could have been over 500 years old was discovered this year, making the species the longest-lived vertebrate in the world.
b) Genetically Reversing Aging: With an experiment that replicated stem cell-like conditions, Salk Institute researchers made human skin cells in a dish look and behave young again, and mice with premature aging disease were rejuvenated with a 30% increase in lifespan. The Salk Institute expects to see this work in human trials in less than 10 years.
d) Funding for Anti-Aging Startups: Jeff Bezos and the Mayo Clinic-backed Anti-Aging Startup Unity Biotechnology with $116 million. The company will focus on medicines to slow the effects of age-related diseases by removing senescent cells (as mentioned in the article above).
e) Young Blood Experiments Show Promising Results for Longevity: Sakura Minami and her colleagues at Alkahest, a company specializing in blood-derived therapies for neurodegenerative diseases, have found that simply injecting older mice with the plasma of young humans twice a week improved the mice’s cognitive functions as well as their physical performance. This practice has seen a 30% increase in lifespan, and increase in muscle tissue and cognitive function.
Could lead to an anti-aging drug that counters damage from old age, cancer, and radiation.
A research team led by Harvard Medical School professor of genetics David Sinclair, PhD, has made a discovery that could lead to a revolutionary new drug that allows cells to repair DNA damaged by aging, cancer, and radiation.
In a paper published in the journal Science on Friday (March 24), the scientists identified a critical step in the molecular process related to DNA damage.
The researchers found that a compound known as NAD (nicotinamide adenine dinucleotide), which is naturally present in every cell of our body, has a key role as a regulator in protein-to-protein interactions that control DNA repair. In an experiment, they found that treating mice with a NAD+ precursor called NMN (nicotinamide mononucleotide) improved their cells’ ability to repair DNA damage.
“The cells of the old mice were indistinguishable from the young mice, after just one week of treatment,” said senior author Sinclair.
Disarming a rogue agent: When the NAD molecule (red) binds to the DBC1 protein (beige), it prevents DBC1 from attaching to and incapacitating a protein (PARP1) that is critical for DNA repair. (credit: David Sinclair)
Human trials of NMN therapy will begin within the next few months to “see if these results translate to people,” he said. A safe and effective anti-aging drug is “perhaps only three to five years away from being on the market if the trials go well.”
What it means for astronauts, childhood cancer survivors, and the rest of us
The treatment could also help travelers aboard aircraft flying across the poles. A 2011 NASA study showed that passengers on polar flights receive about 12 percent of the annual radiation limit recommended by the International Committee on Radiological Protection.
The other group that could benefit from this work is survivors of childhood cancers, who are likely to suffer a chronic illness by age 45, leading to accelerated aging, including cardiovascular disease, Type 2 diabetes, Alzheimer’s disease, and cancers unrelated to the original cancer, the researchers noted.
For the past four years, Sinclair’s team has been working with spinoff MetroBiotech on developing NMN as a drug. Sinclair previously made a link between the anti-aging enzyme SIRT1 and resveratrol. “While resveratrol activates SIRT1 alone, NAD boosters [like NMN] activate all seven sirtuins, SIRT1-7, and should have an even greater impact on health and longevity,” he says.
Sinclair is also a professor at the University of New South Wales School of Medicine in Sydney, Australia.
Abstract of A conserved NAD+ binding pocket that regulates protein-protein interactions during aging
DNA repair is essential for life, yet its efficiency declines with age for reasons that are unclear. Numerous proteins possess Nudix homology domains (NHDs) that have no known function. We show that NHDs are NAD+ (oxidized form of nicotinamide adenine dinucleotide) binding domains that regulate protein-protein interactions. The binding of NAD+ to the NHD domain of DBC1 (deleted in breast cancer 1) prevents it from inhibiting PARP1 [poly(adenosine diphosphate–ribose) polymerase], a critical DNA repair protein. As mice age and NAD+ concentrations decline, DBC1 is increasingly bound to PARP1, causing DNA damage to accumulate, a process rapidly reversed by restoring the abundance of NAD+. Thus, NAD+ directly regulates protein-protein interactions, the modulation of which may protect against cancer, radiation, and aging.