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Mapping the Human Exposome: Understanding the “E” after the “G”

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By: Bryan Bassig, Ph.D.

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Source: Pixabay

 

Current efforts to maximize our understanding of the known interplay between genetic and environmental factors in disease etiology have the potential to inform future research priorities and disease management and prevention

Defining the concept of the ‘exposome’

It is now commonly accepted that the etiology of most chronic diseases is a combination of genetics and environmental exposures, and most likely the interaction of these factors (“G” x “E”). The breadth of environmental exposures that have been implicated in chronic disease risk is substantial and includes personally modifiable factors including smoking and dietary choices as well as exposures that likely require policy interventions on a more universal scale, such as reducing air pollution. Substantial investments to map and characterize the human genome have led to an explosion of population-based studies that seek to understand the specific genetic variants that are associated with a wide variety of disease phenotypes. This in turn has generated great enthusiasm in applying these identified variants to personalized disease risk management and treatment. Whereas current discussion of the role of genetics in population-based health has already begun to move from discovery to translation with ongoing personalized medicine initiatives, our understanding of how to comprehensively measure the totality of environmental factors (broadly defined as non-genetic factors) that shape disease risk at a population-based level has generally lagged behind that of genetics.

Given the interplay and contributions of both “G” and “E” in disease processes, research and financial investments in one component but not the other likely lead to less efficiency in capturing the interindividual variation that exists in disease etiology and treatment and survival. An increasing recognition of this point over the last decade has propagated several research initiatives aimed at greater understanding of environmental factors in disease etiology, including efforts to understand the human “exposome.” Investment in these initiatives from a scientific funding standpoint has the potential to significantly improve exposure science and may in theory inform population-based health research strategies.

The concept of the human exposome was first conceived by epidemiologist Dr. Christopher Wild, a former director of the International Agency for Research on Cancer, in 2005. The concept has since gained traction within the research community. The idea behind the exposome is to complement the advances that have been made in understanding the human genome by characterizing the full spectrum of environmental exposures that occur from conception to death with an understanding that these exposures are both dynamic in nature and broad in scope. Indeed, a full “mapping” of the exposome as originally conceived by Dr. Wild and subsequently by others would include an ability to measure all internal (e.g. endogenous hormones and metabolites) factors as well as exogenous exposures that are either specific to the individual (e.g. smoking/alcohol, diet) or more universal in nature (e.g. built environment, climate). These exposures would be captured or measured at various “snap shots” throughout life, ideally corresponding to key time points of biological development such as in utero, childhood, and early adulthood. In contrast to traditional exposure assessment in population-based studies, which rely on questionnaires or targeted biological measurements of a limited number of chemicals that have been selected a priori, innovative technologies that take an agnostic and more comprehensive approach to measuring internal biomarkers (e.g. “omics”) or lifestyle-related factors (e.g. using smart phones to log physical activity patterns) would be needed for full characterization. Ideally, this would represent the “cumulative level of all cumulative exposures” in the human body.

Implementation: Progress, Potential, and Challenges

Implementation of the exposome paradigm is still in its relative infancy and current discussions are primarily focused on the scope of the initiative that is achievable within the parameters of scientific funding and infrastructure. For instance, in the absence of large prospective cohort studies that include collection of repeated samples or exposure information from people over multiple timepoints, application of the exposome paradigm is still possible but may be limited to fully characterizing the internal and external environment using samples or measurements taken at a single timepoint. While the current focus is on scientific implementation of this paradigm, the potential long-term translatable implications of exposome research can be imagined. From the standpoint of environmental regulation, agencies that conduct risk assessments of environmental exposures evaluate a series of questions including the dose-response relationship of these exposures with biologic effects or disease risk, and whether certain factors like age at exposure influence susceptibility. Application of the exposome framework provides a mechanism to potentially better characterize these questions as well as to evaluate multiple exposures or “mixtures” when making regulatory decisions. This potential however would need to be balanced in view of the existing regulatory framework and the need to develop guidelines for interpreting the expansive and complex datasets.   

While any application of the exposome paradigm to public health or clinical utilization would be an incredibly daunting challenge, a 2012 study published in Cell described this theoretical potential. The case study presented findings from a multiomic analysis of a single individual over 14-months in which distinct biologic changes and omic profiles were observed during periods when the individual was healthy relative to periods when he developed viral illness and type 2 diabetes. The authors concluded that the observed profiles were a proof of principle that an integrative personal omics profile could potentially be used in the future for early diagnostics and monitoring of disease states. While the study did not integrate data on external environmental exposures, further incorporation of these factors into the omic framework may provide evidence of distinct signatures that differ according to exposure status.

Current efforts to advance the exposome field have been bolstered by several initiatives including a 2012 report by the National Academies that described the future vision and strategy of exposure science in the 21st Century. Exposome-related research is also a major goal of the 2018-2023 strategic plan offered by the National Institute of Environmental Health Science (NIEHS), and the agency has supported two exciting exposome research initiatives. These include the HERCULES (Health and Exposome Research Center: Understanding Lifetime Exposures Center) research center at Emory University that is on the front lines of developing new technologies for evaluating the exposome, and the Children’s Health Exposure Analysis Resource (CHEAR) to encourage the use of biological assays in NIH-funded studies of children’s health.

As the field of exposomics matures, there will undoubtedly be several issues that arise that intersect both scientific and policy-related considerations as described by Dr. Wild and others involved in this field. These include but are not limited to:

  1. a) Cross-discipline education and training opportunities: The exposome paradigm encompasses multiple scientific disciplines, including laboratory sciences, bioinformatics, toxicology, and public health. Given the traditional model of graduate programs in science, which generally focus on distinct subfields, new educational and/or training programs that provide cross-disciplinary foundations will be critical in training the next-generation of scientists in this field.
  2. b) Data accessibility and reproducibility: Given its expansive nature and the inherent interindividual variation of non-genetic factors, full characterization of the exposome and associations between exposures and disease may require large international teams of researchers that have central access to the expansive, complex datasets that are generated. Unlike the human genome, the dynamic nature of the internal and external environment will require extensive reproduction and validation both within and across different populations.
  3. c) Funding and defining value: Fully implementing the exposome paradigm from an epidemiological research perspective would likely require profound investments in study infrastructure and laboratory technology. The discontinuation of the National Children’s Study, which originally intended to enroll and follow 100,000 children from birth to 21 years of age in the United States, illustrates the challenges associated with conducting large longitudinal research projects. These demands would need to be balanced with justifying the added value and potential for future utility along the same lines as genomics. The comprehensive understanding of non-genetic determinants of disease risk from a research standpoint, however, is the natural precursor to any discussion of utility.
  4. d) Communication of research findings: The field of genomics has matured to the point that consumers can now obtain personalized reports and risk profiles of their genome from companies like 23andMe and Ancestry.com. It is theoretically possible that this commercial model could be extended in the future to other types of biomarkers such as the metabolome, yet the dynamic nature and current lack of clarity regarding the disease relevance of most non-genetic biomarkers would create considerable challenges in interpreting and conveying the data.

Conclusions

The underlying principles of the exposome were originally conceived by Dr. Wild as a mechanism to identify non-genetic risk factors for chronic diseases in epidemiologic studies. While the increasing number of exposome research initiatives are primarily focused on this scientific goal, challenges remain in the implementation. It is likely too early to project what the future public health and/or clinical utility of this paradigm, if any, may be. Nevertheless, continued investments in this area of research are critical to understand the “missing pieces” of disease etiology and to ideally inform preventive measures and/or disease management in the future.  

 

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Written by sciencepolicyforall

November 21, 2018 at 9:55 pm

Insect Allies and the role of DARPA in scientific research

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By: Ben Wolfson, Ph.D.

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Source: Pixabay

 

Last month, a Pentagon research program called Insect Allies burst into the public conversation after a team of research scientists and legal scholars published an article detailing their concerns and critiques of the project in Science magazine. Insect Allies is run by the Defense Advanced Research Projects Agency (DARPA), and was announced in 2016 with the stated goal of “pursuing scalable, readily deployable, and generalizable countermeasures against potential natural and engineered threats to the food supply with the goals of preserving the U.S. crop system”. As indicated by its eponymous project name, the Insect Allies research program seeks to develop insects that carry gene editing viruses, allowing for rapid genetic modification of plant food sources. The Insect Allies program exemplifies both the pros and cons of DARPA work. The described project leapfrogs current technological paradigms, promoting a next stage of synthetic biology work. However at the same time, it seeks to create a technology with problematic potential military applications. The battle between basic research and the development of military technologies is one that has dogged DARPA since its inception. As the theoretical and empirical knowledge in the fields of genetic modification and synthetic biology improve, it is imperative that novel technologies are developed with the appropriate ethical and moral oversight and that scientists consider the ramifications of their work.

Origins and Changes of DARPA

Science and the military have long been interwoven, a process that was formalized in the U.S. in the past century. In 1947, President Truman created the Department of Defense, in part to fund scientific research. A decade later President Eisenhower highlighted the importance of science in national defense with the creation of the Advanced Research Projects Agency (renamed DARPA in 1972). DARPA’s creation was in direct response to the launch of Sputnik by the Soviet Union, and given the mission statement of “preventing technological surprises like Sputnik, and developing innovative, high-risk research ideas that hold the potential for significant technological payoffs”.

In its early years, DARPA funded significant amounts of basic and foundational research that did not have immediate applications. However, in 1973 Congress passed the Mansfield Amendment, preventing the Defense Department from funding any research without “a direct and apparent relationship to a specific military function or operation”. The amendment was contentious at the time of its passing, with Presidential Science Advisor Lee DuBridge telling a congressional subcommittee that the amendment had negatively affected the quality of research projects because it is not possible to prove the relevance of a project, and therefore it is wrong to prevent an agency from funding basic research it sees as valuable. Passage of the amendment fundamentally reshaped the U.S. research funding landscape, and projects consisting of upwards of 60% of DOD research funds were cancelled or moved to other agencies. In place of basic research DARPA has shifted to funding research with direct military applications. These projects have often fallen into the realm of “dual-use” technologies, having both civilian and military uses. Successful examples of this strategy include funding projects that evolved into the internet and Global Positioning Systems (GPS). Current research span from projects with clear civilian applications, such as a multitude of projects researching the next generation of medical technologies, to those that are weapons research with purely military potential.

The Insect Allies program

Agriculture is one of the predominant industries in the U.S., making the U.S. a net exporter and world’s largest supplier of a variety of agricultural products including beef, corn, wheat, poultry and pork. The importance of American agriculture to both national security and the security of its global allies and trade partners is well recognized by national security officials, especially in the context of climate change and the potential for growing scarcity. The primary threats to agriculture are disease and weather related events. While these can be mitigated through pesticides, clearing of crops, quarantine, and selective breeding, current strategies are both destructive and time consuming.

The Insect Allies program has three focus areas; viral manipulation, insect vector optimization, and selective gene therapy in mature plants. Through application and combination of these technologies Insect Allies would function by genetically modifying already growing plants through utilization of “horizontal environmental genetic alteration agents (HEGAAs). Traditionally, genetic modification involves changing the genes of a parent organism and propagating its offspring. This process is essentially the same as the selective breeding practiced in agriculture for generations. While this is effective, it is a time-consuming practice as you must breed successive generations of your population of interest.

Through HEGAAs, Insect Allies completely revamp the process. Instead of creating a population of interest from scratch, HEGAAs allow scientists to modify an existing population. If you wanted to create a pesticide-resistant crop, the traditional strategy would be to insert the gene for pesticide resistance into one plant and then collect its seeds and use them to grow an entire field of pesticide resistant plants. With HEGAA technology, farmers could make an already grown field resistant by modifying each individual plant on a broad scale.

Criticism of the Insect Allies program

The authors of the Science article critique the Insect Allies program over a variety of issues, ranging from biological to ethical or moral dilemmas. The article raises issue with both the use of wide-scale genetic modification technologies as well as with the application of insects as vectors as opposed to already existing technologies such as overhead spraying. The use of wide-scale genetic modification is a line which has yet to be crossed, and currently lacks a regulatory path. While research into gene modifying technology is ongoing and real-world tests inevitable, these tests are a contentious issue that is currently being debated. Moreover, agricultural products modified by HEGAAs have no current path to the market. The combination of seemingly little thought in the program towards the regulation that would be necessary for the described application of their technology as well as the existence of lead the authors to suspect that Insect Allies is being developed for other means. While a population of gene-modifying insects could be used to help U.S. crops survive weather-changes or pesticides, they could also potentially be applied to crops of other nations in war. Biological Weapons were banned in 1972, and currently no nations have (publicly) developed them.While the technologies being developed by Insect Allies are described as “for peaceful means”, the stated goals are achievable through already existing technologies. Furthermore, international competition with Insect Allies may accelerate crossing the line between wartime and peacetime technology.

Soon after publication of the Science article, Dr. Blake Bextine, program manager for Insect Allies, released a statement refuting many of these points. He stated that DARPA moved into agricultural work as it is an important aspect of both national and international security, and that the work falls under DARPA’s charter to develop fundamentally new technologies that leapfrog existing capabilities. Moreover, he affirmed that Insect Allies has no plan for open release, and that regulatory systems would be developed and had been planned since the start of the program.

What does the future hold

The Science article’s authors note that they would be worried about Insect Allies whether it was under a civilian or military purview, but it is impossible to ignore the implications of synthetic biology and genetic modification research to the military. DARPA’s strategy of generating high-risk, high-reward research is both effective and engrained into the DNA of the organization, however so is the fact that DARPA is a defense organization.

When DARPA was founded (as ARPA), it was to promote high-risk scientific research that would increase U.S. soft power internationally. After the Mansfield amendment, these goals were shifted towards applied research instead of basic, and with them a focus on defense-oriented research. An advantage of basic research is that it takes time to develop, allowing the findings, and their ramifications, to percolate throughout the global scientific community. The quintessential example of this is regulation of recombinant DNA technologies. Soon after recombinant DNA technology was developed, the 1975 Asilomar Conference was held to establish voluntary guidelines that would ensure the safety of a game-changing scientific technology. As synthetic biology technological development has accelerated, the discussion around the regulation of synthetic biology and genetic modification technology has also begun, and is currently ongoing.

While it is impossible to argue with the massive benefits that civilian applications of DARPA developed technologies have provided, synthetic biology and genetic modification technologies have the potential to enact immense changes globally. The environment and application of a technology has a huge potential to influence its use and the way it is viewed by the public for generations. Insect Allies program states that it is focusing on developing insect-based HEGAAs technologies as a means of pushing development of gene-editing technologies to increase food security in a transparent manner that promotes open published research. It is critical that the Insect Allies program is held to this standard, and that regulation by the global scientific community is allowed to impact the direction and application of these potentially game-changing technologies.

 

 

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November 15, 2018 at 11:22 am

Unlinking databases is not enough to unlink identity from genetic profiles

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By: Allison Dennis B.S.

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Source: Pixabay

 

The efficacy of law enforcement is an issue of public safety. Advances in medicine are a matter of personal wellbeing. Knowing more about one’s unique genetic heritage is a point of curiosity. As all of these spheres delve further and further into DNA sequencing, the ubiquity of personal genetic information is increasingly becoming an issue of privacy. The emerging nature of DNA technology has left us with three major types of DNA databases separated by their use: medical, forensic, and recreational. Each is governed by its own sets of rules, set by federal law, state law, and user agreements. Under specific circumstances data can be intentionally shared for other uses. However, the technological limitations that kept these databases separated in the past may be nearing erosion.

Medical

By congregating and comparing the genomes of people with and without a specific disease through DNA databanks, researchers can discover small glitches in the DNA of affected patients. Identifying the genetic changes that disrupt the normal functions of the body allows researchers to begin designing therapeutics to correct deficiencies or developing genetic tests to diagnose specific diseases, possibly before symptoms have appeared. The potential for medical databases have prompted government led initiatives such as All of Us to amass genetic information from a diverse group of 1 million Americans, which will be queried for medical insights. Already, the Cancer Genome Atlas, maintained by the US National Institutes of Health, contains deidentified genetic data from tumor and normal tissues from 11,000 patients and is openly searchable for research purposes. Foundation Medicine, a private company that provides doctors and patients with genomic profiles of tumor samples to inform treatment options, has stockpiled data from over 200,000 samples. Foundation Medicine shares these data through collaborative agreements and business partnerships with members of the oncology research community and pharmaceutical companies.

Medical DNA databanks, while masking a patient’s name, may link to an individual’s medical history. Because researchers often do not know what parts of the genome will reveal key clues, the genetic data contained in these databases is rich. Often researchers look at how the frequency of single nucleotide changes at hundreds of thousands of places in the genome differ between people affected and unaffected by a particular disease.

The medical benefit of compiling and sharing genomic information is carefully balanced against privacy concerns by Federal regulation. The Genetic Information and Nondiscrimination Act of 2008 (GINA) prohibits employers and health insurers from requesting access to an individual’s or family’s genetic information. The Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule mandates that health-care providers not disclose an individual’s genetic information. The NIH Genomic Data Sharing Policy limits access to individual-level genetic information held in their databases, including the Cancer Genome Atlas, to approved scientific researchers. Despite these safeguards, genetic information contained within medical databases can be identified and provided to law enforcement following a court order in extreme cases.

Forensic

Forensic DNA databases contain searchable genomic profiles for the critical task of identification by law enforcement and military experts. U.S. Federal law allows law enforcement officers to collect and store DNA profiles on anyone they arrest, including those detained by immigration enforcement. Since 1998, the Federal Bureau of Investigation has hosted the national Combined DNA Index System (CODIS), which currently contains 16.8 million offender and arrestee profiles. Unlike medical databases, which can contain a wealth of information, CODIS profiles are limited to a set of 20 places in the genome where the number of times a small sequence of DNA is repeated varies between individuals. The unique combination of these 20 lengths place the probability of two unrelated people sharing a profile at roughly 1 in 1 septillion, and were intentionally selected to not reveal any medically relevant parts of the genome.

The creation of CODIS was authorized by Congress through the DNA Identification Act of 1994, which mandated privacy protection standards. As a safeguard, the database profiles are associated with specimen identification numbers rather than any personal information. The system can only be accessed in physically secure spaces and is restricted to use by criminal justice agencies specifically for the purpose of law enforcement. Only after a match has been found from a query and the candidate match has been confirmed by an independent laboratory will the identity of the suspected perpetrator be revealed, and even then only to the agencies involved in the cases. The Scientific Working Group on DNA Analysis Methods (SWGDAM) continues to recommend revisions to these standards for security and confidentiality issues. Despite housing a relatively unrevealing type of genetic information, CODIS goes above and beyond the privacy protections provided by many recreational and medical databases.

Recreational

Individuals are increasingly turning to direct-to-consumer genetics testing, driven by their curiosity to discover their genetic heritage and to gain some insight into their genetic traits. These tests contain a wealth of information drawn from single nucleotide changes across more than 500,000 parts of the genome. The most popular tests are offered by AncestryDNA and 23andMe, who manage data according to Privacy Best Practices established by the industry. These practices include removing names and demographic identifiers from genomic records, storing identifying information separately if retained, using encryption, limiting access, and requiring consent for third party sharing. As the records are presumed to contain medically relevant information, all identified samples are governed by the same HIPAA and GINA regulations that govern medical tests. 23andMe has amassed a database of over 5 million genetics profiles. AncestryDNA has over 10 million, greatly rivaling the size of forensic and medical databases.

Direct-to-consumer genetics testing companies often sell de-identified genetic data to pharmaceutical and diagnostic development companies for research purposes. Those that follow the Privacy Best Practices established by the industry only do so for users who have consented to participate in research, and GINA expressly prohibits these companies from sharing an individual’s genetic information with potential employers or health insurers.

There are also limits to prevent law enforcement from abusing recreational genetics testing companies. While there is the potential for someone to submit a sample that is not their own, the AncestryDNA service agreement stipulates that users only provide their own sample, and 23andMe expressly disallows “law enforcement officials to submit samples on behalf of a prisoner or someone in state custody.” Moreover, their tests have been specifically designed to make collection of a third parties’ sample difficult. For instance, the 23andMe test requires an amount of saliva needing 30 minutes to generate, preventing illicit collection.

While companies go to great lengths to protect the information contained in their databases, most companies will provide individuals with their own complete profiles when requested. The allure of mapping family connections has lead millions of genealogical hobbyists to openly contribute their re-identified genomic DNA to searchable online databases. The most famous searchable database is GEDmatch, which currently contains about one million profiles. The platform allows users to upload their own genome to retrieve high probability matches of other user’s profiles. A level of privacy is maintained by only sharing small pieces of the genome, allowing complete profiles to remain obscured. However, GEDmatch’s user agreement emphasizes that rather than use encryption, they store data in a format that “would be very difficult for a human to read” and allow volunteers access to the data. Additionally, they specifically welcome “DNA obtained and authorized by law enforcement” for inclusion in their database. The wealth of information publicly hosted on sites like GEDmatch have provided a unique opportunity for other types of DNA databanks to share information and blur the lines of privacy.

Database Cross-Linking

The use of GEDmatch by law enforcement marks an important seachange in genetic privacy. In the past, medical and recreational databases were only occasionally queried by law enforcement, who were seeking specific profiles. However in April 2018, in a desperate search for leads to solve a cold case, law enforcement officers utilized a nearly 40-year old rape-kit to develope a genetic profile. While previous searches over the decades had been limited to the FBI database and the perpetrator’s 20 CODIS loci law enforcement officials were able to undertake a blind and expansive search by uploading the complete profile to the GEDmatch database, which ultimately lead to a third cousin of the man who would be charged with 12 murders.

These types of searches have the power to exonerate or implicate criminals, as a 100% match is undeniable. While only just starting to be used, for someone of European ancestry living in the United States the odds are as high as 60% that a genetic relative can be identified from a database similar to GEDmatch. A public opinion poll conducted shortly after April 2018, revealed that the majority of respondents approved of searches of recreational databases by law enforcement, especially to identify perpetrators of violent crimes.

Scientists have already laid the theoretical groundwork that could allow law enforcement to link a suspect’s profile in a medical or recreational database using the limited 20 CODIS markers from a crime-scene sample. Portions of the genome that share close physical proximity along a chromosome are more likely to be inherited together, allowing statistical predictions to be made about which pieces are most likely to occur together. Although the two types of profiles do not contain the same markers, scientists can predict which marker profiles most likely came from the same individual.

While the use of these tactics might be supported for the purpose of identifying violent criminals, it also puts medical privacy at risk. Despite the de-identification of genomic profiles, scientists have demonstrated reasonable success in tracking down a person’s identity given a genetic profile, a genealogical database such as GEDmatch, and information on the internet.

As DNA databases develop in their depth of information and coverage of individuals, the ability to link records to individuals grows. A lack of compatibility will not be enough to keep medical genomic information sequestered from criminal profiles. Industry standards and user agreements must be discussed and strengthened to safeguard the genetically curious.

 

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November 8, 2018 at 10:14 am

Science Policy Around the Web – July 7, 2017

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By: Liu-Ya Tang, PhD

Source: pixabay

Autism

Is There Such a Thing as an Autism Gene?

Autism has become a global burden of disease. In 2015, it was estimated to affect 24.8 million people globally. Significant research efforts are underway to investigate the causes of autism. Autism is highly heritable – there is an 80 percent chance that a child would be autistic if an identical twin has autism. The corresponding rate is about 40 percent for fraternal twins.

However, is there such a thing as a single autism gene? Researchers haven’t found one specific gene that is consistently mutated in every person with autism. Conversely, 65 genes are strongly linked to autism and more than 200 others have weaker ties, many of which are related to important neuronal functions. Mutations in a variety of these genes can collectively lead to autism. The mutations could be from single DNA base pair, or copy number variations, which are deletions or duplications of long stretches of DNA that may involve many genes. Most mutations are inherited, but some mutations could also happen in an egg or sperm, or even after conception.

Besides genetic factors, maternal lifestyle and environmental factors can also contribute to autism. Exposure to air pollution during pregnancy or a maternal immune response in the womb may increase the risk of autism. While there is speculation on the link between vaccines and autism, it is not backed by scientific evidence.

Since both genetic and non-genetic factors play a role in the development of autism, establishing the underlying mechanism is complicated. There is no single specific test that can be used for screening autism. However, some tests are available to detect large chromosomal abnormalities or fragile X syndrome, which is associated with autism. (Nicholette Zeliadt, Washington Post)

STEM Education

New Florida Law Lets any Resident Challenge What’s Taught in Science Classes

A new law was signed by Florida Gov. Rick Scott (R) last week, and has taken effect starting July 1. The law requires school boards to hire an “unbiased hearing officer” to handle complaints about teaching materials that are used in local schools. Any county resident can file a complaint, and the material in question will be removed from the curriculum if the hearing officer thinks that the material is “pornographic,” or “is not suited to student needs and their ability to comprehend the material presented, or is inappropriate for the grade level and age group.”

There are different voices in the new legislation, which affects 2.7 million public school students in Florida. Proponents argue that it gives residents more right in participating in their children’s education. A sponsor, state Rep. Byron Donalds (R-Naples), said that his intent wasn’t to target any particular subject. However, Glenn Branch, deputy director of the National Council for Science Education, is worried that science instruction will be challenged since evolution and climate change have been disputed subjects. A group called Florida Citizens for Science asked people to pay close attention to classroom materials and “be willing to stand up for sound science education.”

Like the new law in Florida, the legislature in Idaho rejected several sections of the state’s new public school science standards related to climate change and requested a resubmission for approval this fall. Since the Trump administration began, there has been “a new wave of bills” targeting science in the classroom. To protect teacher’s “academic freedom,” Alabama and Indiana adopted non-binding resolutions that encourage teachers to discuss the controversy around subjects such as climate change. A supporter of the resolution, state Sen. Jeff Raatz (R-Centerville), told Frontline, “Whether it be evolution or the argument about global warming, we don’t want teachers to be afraid to converse about such things”. (Sarah Kaplan, Washington Post)

 

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July 7, 2017 at 1:32 pm

Is the human germline off limits?

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By: Thomas Calder, Ph.D.

Licensed via Creative Commons

A new genetic engineering technology, known as CRISPR-Cas9, is allowing scientists to edit the human genome faster and easier than ever thought possible. This technology has the potential to treat and even cure several major diseases such as sickle-cell anemia, HIV, and many forms of cancer. As a result, many labs around the world are rushing to better understand the CRISPR-Cas9 system so they can eventually advance the technology into the clinic. However, such unparalleled potential comes with a risk. CRISPR-Cas9 could be used to alter the genetic code of germline cells, which are reproductive cells that could then pass these alterations onto further generations. This has scientists and the public asking the controversial question: is editing the human germline ethical?

This controversy is not new, as genetic engineering technologies have been around since the 1980’s. Zinc-finger nucleases (ZFNs) were discovered in the 1980’s and were determined to have genome-editing capabilities during 1996-2003. ZFNs are DNA cutting enzymes that can be engineered to target specific segments of DNA, and can thus alter sections of the human genome. Designing ZFNs proved to be difficult, so many scientists were excited when different genome-editing enzymes, TAL effector nucleases (TALENs), were found in 2009-2010 to be easier to engineer than ZFNs. Both ZFNs and TALENs have the same shortcoming though. They require scientists to design proteins specifically for a targeted segment of DNA, which then requires validation of each newly designed protein. Thus, these technologies are highly impractical for editing the genome on a large-scale.

The CRISPR-Cas9 system was first discovered in 1987 by a Japanese lab, but it was not well understood until recent years. Scientists determined in 2005-2007 that bacteria harbor this DNA editing system to digest foreign viral DNA. In 2011-2012, scientists began to understand the basic essentials of this system so they could utilize it for genetic engineering. They discovered that Cas9 is a DNA cutting enzyme that can be targeted to specific DNA fragments with the help of a specially designed guide-RNA molecule. This system proved to be much easier to use that ZFNs and TALENs, because scientists did not have to design different enzymes for each targeted DNA fragment. Instead, they only had to engineer RNA molecules to match with targeted DNA fragments. With this approach, CRISPR-Cas9 can be used to target and alter any gene based on its genetic code, and it can even be used for genome-wide studies.

With the recent characterization of CRISPR-Cas9, a new frontier in science has begun. Scientists have designed guide-RNA molecules for every gene in the genome to determine which genes are essential for various diseases, such as many forms of cancer. This approach is exciting because it may lead to the discovery of new targets for drug-based therapy. Scientists are also creating animal models of various genetic diseases by causing disease-specific alterations in the genome of animals such as mice and monkeys. For humans, this research has focused on non-reproductive cells, but the efficacy of this technology is making the human germline a tempting target. Theoretically, scientists could use CRISPR-Cas9 in an embryo to remove a disease-causing gene and replace it with a healthy version of the gene. This approach has the potential to ward off deadly diseases—but is it ethical? Most importantly, is it safe?

Both questions are controversial. In terms of safety, many scientists currently agree that it is not safe to create a permanent genetic alteration that can be passed onto future children. One concern is that Cas9 could have off-target effects that could damage the human genome in unpredictable ways. Another concern is that scientists do not understand the genome well enough to start making changes to the code. According to a Perspective article in the journal Science, by scientists that attended an ethics discussion in January on the topic of editing the human germline, “there are limits to our knowledge of human genetics, gene-environment interactions, and the pathways of diseases (including the interplay between one disease and other conditions or diseases in the same patient).” Also, side-effects from altering the genetic code of an embryo might not be noticeable until that embryo turns into a grown child, many years into the future. Therefore, more information on the human genome is necessary before genetic engineering of the human germline can be considered safe.

These safety concerns factor into the ethics debate, but other concerns are also drawing attention. While CRISPR-Cas9 is currently being proposed to prevent debilitating diseases, the use of this technology might start a slippery slope that could lead to the creation of “designer-babies.” For example, the genome of an embryo could be altered to impart a different eye color, hair color, or higher level of intelligence. These changes are certainly not worth the risk of side-effects, but some parents might pursue these options to provide their child with a “leg up”. Other ethical questions include:

  • Would the use of this technology be regulated?
  • Would a child be monitored if he/she was genetically modified as an embryo? Would the child’s future offspring be monitored?
  • Which parts of society would have access to this technology? Would use of this technology lead to a greater divide between the poor and wealthy?

The CRISPR-Cas9 technology is advancing quickly, so scientists need to act now to reach a consensus on these ethical issues. Many scientists have already called for a moratorium on editing the human germline in the short-term. This would provide time for scientists to engage with the bioethics community and the public to discuss the ethical, social, and legal implications of altering the human genome.

The genetic engineering capabilities of CRISPR-Cas9 is exciting. Millions of lives could benefit from this new technology. It could cure certain cancers, prevent diabetes, ward of many age-related diseases, and even stop HIV from causing AIDS. But scientists must use extra caution when editing the human germline, because any negative effects that arise could last for many generations into the future.

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Written by sciencepolicyforall

April 15, 2015 at 11:02 am