The concept of a “third eye” is usually associated with perception beyond the physical world, but in a new scientific case, it provides insight into evolutionary development.
Researchers have intentionally genetically modified a common beetle to develop a third functional eye, right in the middle of its forehead.
It builds on previous research in which they caused a beetle to grow a third eye accidentally. Both studies were led by Indiana University postdoctoral researcher Eduardo Zattara.
“Developmental biology is beautifully complex in part because there’s no single gene for an eye, a brain, a butterfly’s wing or a turtle’s shell,” explained researcher Armin Moczek of Indiana University.
“Instead, thousands of individual genes and dozens of developmental processes come together to enable the formation of each of these traits. We’ve also learned that evolving a novel physical trait is much like building a novel structure out of Lego bricks, by re-using and recombining ‘old’ genes and developmental processes within new contexts.”
This means that evolving new features may not be as complicated as scientists previously thought, requiring fewer genetic changes.
The beetles lost their horns – and developed a compound eye in the middle of their heads. Moreover, it only worked in horned beetles, not other kinds.
“We were amazed that shutting down a gene could not only turn off development of horns and major regions of the head, but also turn on the development of very complex structures such as compound eyes in a new location,” Zattara said last year.
“The fact that this doesn’t happen in Tribolium is equally significant, as it suggests that orthodenticle genes have acquired a new function: to direct head and horn formation only in the highly modified head of horned beetles.”
The development of organs in an abnormal place – called ectopic organs – is a technique scientists use to try and understand how new physical traits evolve.
This has been done in fruit flies – in 1995, a team of scientists published a paper that described how they’d managed to grow ectopic eyes on the wings and legs of fruit flies.
The work of Zattara’s team, by comparison, was much simpler. They set out to intentionally grow a third eye in two types of scarab beetle, Onthophagini and Oniticellini, by wiping out just a single gene, the same head development gene from their earlier research.
The third eyes the beetles developed actually resulted from fused pairs of eyes. They also lost their horns, or grew much smaller horns, consistent with the earlier research.
The team then conducted multiple tests to confirm that the new eye had the same cell types, genes, nerve connections and behavioural responses as a normal eye.
“This study experimentally disrupts the function of a single, major gene. And, in response to this disruption, the remainder of head development reorganizes itself to produce a highly complex trait in a new place: a compound eye in the middle of the head,” Moczek said.
“Moreover, the darn thing actually works!”
The research could help understand how organs develop and become part of a body – which knowledge, in turn, could prove useful in the development of artificial lab-grown organs, for both research and medical purposes.
The team’s paper has been published in the journal PNAS.
Genetically Engineered Eggs are Better than Golden Eggs
People often warn about the amount of cholesterol you get from eating too many eggs. But what if there were health benefits to eggs as well — like drugs that fight cancer, hepatitis, and other diseases? Japanese researchers from the National Institute of Advanced Industrial Science and Technology (AIST) did just that when they successfully genetically engineered chickens to lay eggs that contain a special pharmaceutical agent.
According to a report by The Japan News, the researchers at AIST genetically modified precursor cells of chicken sperm to produce a type of protein that’s related to the immune system called interferon beta.
This protein has been found to be effective in treating malignant skin cancer and hepatitis. The modified cells were used to fertilize eggs that produced male chicks. A few rounds of cross-breeding the male chicks resulted in chickens that inherited the genes with interferon beta.
Reagent import and sales firm Cosmo Bio Co. in Tokyo, which developed the method together with the AIST researchers and the the National Agriculture and Food Research Organization in Ibaraki Prefecture, now has three hens that lay eggs every one or two day. The egg whites from those eggs contain interferon beta.
Why go through such a tedious process? The project’s goal was to potentially reduce the costs of making drugs. “This is a result that we hope leads to the development of cheap drugs,” Hironobu Hojo, professor at Osaka University, told The Japan News. “In the future, it will be necessary to closely examine the characteristics of the agents contained in the eggs and determine their safety as pharmaceutical products.”
This is just one example of how gene editing methods can reshape industries, especially healthcare. Others have worked on applying gene editing such as CRISPR directly into cancer cells or to a patient. Producing cheap drugs from chicken eggs is another possibility — and a rather creative one, at that.
Moving forward, the researchers plan to work on stabilizing the interferon beta contents of the eggs to produce some a dozen milligrams to 100 milligrams from a single egg.
“It’s time we provided some critical scrutiny and stopped parroting the gospel of medical progress at all costs,” writes former molecular biologist Dr. David King in a recent Guardian editorial. “…we must stop this race for the first GM baby.”
King wrote in response to the announcement earlier this month that doctors had successfully altered the genomes of single-cell human embryos. Using CRISPR, the doctors removed a gene for hypertrophic cardiomyopathy (HCM), a common heart disease that can cause sudden cardiac arrest and death. Their results are described in Nature.
King is the founder of Human Genetics Alert, an independent watchdog group opposed to certain outcomes of genetic engineering. He argues that genome editing of the type in Nature is not a justified use of medical research dollars, given the ability to avoid the birth of children with such conditions through testing.
“In fact, the medical justification for spending millions of dollars on such research is extremely thin: it would be much better spent on developing cures for people living with those conditions,” King says. He argues that inevitably, even if pioneered for medical reasons, market forces will inevitably push genome editing towards creating “designer babies,” allowing the very wealthy to program desired traits into their unborn children.
King, and others, see this application as unethical and akin to eugenics.
“Once you start creating a society in which rich people’s children get biological advantages over other children, basic notions of human equality go out the window,” King writes. “Instead, what you get is social inequality written into DNA.”
“We are still a long way from serious consideration of using gene editing to enhance traits in babies,” Janet Rossant, co-author of a report on human genome editing for the National Academy of Sciences (NAS), told the Guardian. “We don’t understand the genetic basis of many of the human traits that might be targets for enhancement.”
If this changes in the future, King argues that it will be impossible to keep the influence of money from directing how that knowledge is used. He bases this prediction of market-based inequality on existing practices — such as the high price tag of ova donated by “tall, beautiful Ivy League students” and the popularity of the international surrogacy market among those with the means to travel for a baby.
Yet existing regulatory systems may be enough to prevent the future King predicts.
In their report for NAS, Rossant and her co-authors emphasized that while caution and ethical oversight are necessary, the US Food and Drug Administration’s system for evaluating medical products could, too, assess potential uses of genome editing. The authors predict that editing for purposes of enhancement — as they put it, “not clearly intended to cure or combat disease and disability” — would not pass muster.
Additionally, King’s argument largely overlooks the potential of gene editing to help children whose conditions are unlikely to have a cure, or whose parents are unwilling to reject a pregnancy.
For Lee and many others suffering from genetic disease, even a selective regulatory establishment may spell collateral damage for the rest of their lives. But the fact stands: caution and oversight will be paramount when playing with the very means nature gave us for life.
When bioengineering students sit down to take their final exams for Stanford University, they are faced with a moral dilemma, as well as a series of grueling technical questions that are designed to sort the intellectual wheat from the less competent chaff:
If you and your future partner are planning to have kids, would you start saving money for college tuition, or for printing the genome of your offspring?
The question is a follow up to “At what point will the cost of printing DNA to create a human equal the cost of teaching a student in Stanford?” Both questions refer to the very real possibility that it may soon be in the realm of affordability to print off whatever stretch of DNA you so desire, using genetic sequencing and a machine capable of synthesizing the four building blocks of DNA — A, C, G, and T — into whatever order you desire.
The answer to the time question, by the way, is 19 years, given that the cost of tuition at Stanford remains at $50,000 and the price of genetic printing continues the 200-fold decrease that has occurred over the last 14 years. Precursory work has already been performed; a team lead by Craig Venter created the simplest life form ever known last year.
The Ethics of Changing DNA
Stanford’s moral question, though, is a little trickier. The question is part of a larger conundrum concerning humans interfering with their own biology; since the technology is developing so quickly, the issue is no longer whether we can or can’t,but whether we should or shouldn’t. The debate has two prongs: gene editing and life printing.
The question of printing life is similar in some respects; rather than altering organisms to have the desired genetic characteristics, we could print and culture them instead — billions have already been invested. However, there is the additional issue of “playing God” by sidestepping the methods of our reproduction that have existed since the beginning of life. Even if the ethical issue of creation was answered adequately, there are the further questions of who has the right to design life, what the regulations would be, and the potential restrictions on the technology based on cost; if it’s too pricey, gene editing could be reserved only for the rich.
It is vital to discuss the ethics of gene editing in order to ensure that the technology is not abused in the future. Stanford’s question is praiseworthy because it makes today’s students, who will most likely be spearheading the technology’s developments, think about the consequences of their work.
There’s a glimmer of hope, though: scientists at the Lewis Katz School of Medicine at Temple University (LKSOM) and the University of Pittsburgh published a study in the journal Molecular Therapyshowing it’s possible to surgically remove HIV DNA from a living animal genome. This is the first time that such a method was demonstrated to be possible, and it could increase the chances of eliminating HIV infection.
The secret is in CRISPR/Cas9, the world’s most efficient and effective gene editing tool, which made it possible to delete targeted HIV-1 fragments from the infected animal tissue genome. “CRISPR-associated protein 9 (Cas9)-mediated genome editing provides a promising cure for HIV-1/AIDS,” the study’s abstract notes. This research built on a proof-of-concept study that the same team of researchers conducted last year.
“Our new study is more comprehensive,” LKSOM’s Wenhui Hu explained. “We confirmed the data from our previous work and have improved the efficiency of our gene editing strategy. We also show that the strategy is effective in two additional mouse models, one representing acute infection in mouse cells and the other representing chronic, or latent, infection in human cells.”
Search and Destroy
The researchers used CRISPR/Cas9 to shut down HIV on three sets of animal models: one performed on transgenic mice with HIV-1, another with mice acutely infected with the mouse equivalent of human HIV (ecoHIV), and a third group of mice that had human immune cells with latent HIV-1 embedded into their tissues and organs.
In all three animal models, the researchers were able to successfully render HIV inactive via gene editing, reducing the RNA expression of viral genes by up to 95 percent in the first model, and up to 96 percent in the second. For the third model, they were able to remove viral fragments from the latently infected human cells in the mouse organs after only a single CRISPR/Cas9 treatment.
Now, researchers need to make the treatment more viable for humans: “The next stage would be to repeat the study in primates, a more suitable animal model where HIV infection induces disease, in order to further demonstrate elimination of HIV-1 DNA in latently infected T cells and other sanctuary sites for HIV-1, including brain cells,” said researcher Kamel Khalili. “Our eventual goal is a clinical trial in human patients.”
As this is the first time gene editing was demonstrated to work on HIV in animals, this method could prove to be a game changer in treating the elusive virus: it’s a crucial step in, eventually, creating a cure.
From tackling cancer to eradicating single-gene mutations, the CRISPR/Cas9 gene editing tool is often portrayed as the eighth wonder of the world by many. We look to CRISPR regarding how it affects us as a species, but the implications of the CRISPR Cas-9 system extend far beyond just humanity. The gene editing tool’s precision and efficacy can be implemented in manipulating the genetics of our agriculture as well as animals. It would be wrong, however, to think that this is humanity’s first attempt at the genetic manipulation of crops and pets alike—to be fair, we have been doing it since the inception of human civilization itself.
Thirty thousand years ago, our ancestors were the first individuals to manufacture genetically modified organisms (GMOs) before it was cool. Through selective breeding or artificial selection, wild wolves in East Asia were selected for docility. With more obedient animals at their side, humans from 32,000 BCE could optimize their hunter/gatherer lifestyles. After several millennia, the artificially-selected wolves began to resemble the dogs we see today. Crops weren’t spared from our genetic coercion either. In fact, humans had domesticated several forms of wheat since 7800 BCE. However, our greatest success in genetic modification through artificial selection comes from corn. Corns is derived from a wild grass known as teosinte, which only occurred when humans at the time selectively planted corn kernels that displayed desirable traits. Over time, this behavior reconciled the five-gene difference between corn and teosinte and led to the desirable crop that we use to this day.
So how does CRISPR work? Unlike other gene editing tools in the past, CRISPR works to propagate sequences through generations at a 97% effectiveness rate. The system is naturally found in viruses, but researchers were able to manipulate the tool to essentially work as a copy and paste function for any desirable genetic information. The advent of CRISPR is revolutionizing business, with corporations taking advantage of the easy-to-use genetic engineering to even edit pets to sell. However, while CRISPR does essentially accelerate mankind’s ability to artificially select traits for organisms that we find beneficial, people like David Ishee, a Mississippi kennel operator, believe that we can reverse the negative side effects of artificial selection—particularly hyperuricemia (an abnormally high level of uric acid in the blood) in Dalmatians. While David feels that it’s a relatively simple request to utilize gene editing in the hopes of ameliorating a human-caused condition in the breed of dogs, the U.S. Food and Drug Administration (FDA) feels differently.
Ishee, and many others like him who wish to genetically modify animals, face the FDA’s newly drafted regulations from January 2017. While Ishee’s plan to modify the malfunctioning genes of Dalmatians and re-insert them into healthy sperm before fertilization isn’t outlawed by the FDA, its distribution is.
If Ishee manages to produce healthy Dalmatians without the disease, he would not be able to sell or distribute them for breeding purposes, according to the FDA. With that said, Ishee’s hope of spreading his movement far and wide might just be curtailed by government regulation.
The new measures by the FDA might just be a response to the emerging fear that CRISPR and other gene editing techniques can be utilized as weapons of mass destruction. While there are those who don’t intend on adhering to the regulations, hoping the new administration would absolve them entirely, there are others like Ishee who are stonewalled against even starting their projects. However, the benefits of being able to use CRISPR on animals’ DNA could be huge; just looking at dogs and cats alone, selective breeding has introduced some unfortunate side effects. We could help our pets live longer, more comfortable lives in the future. Dalmatians shouldn’t have to suffer because humans wanted a dog that had spots, and perhaps we can undo some of the damage we’ve done in the name of purebred dogs and cats. Scientists and others who want to use this technology also argue that doing this is completely different than splicing two animals’ DNA together, for example.
What about you? Do you feel this is the FDA’s responsibility?
While most of the proposed CRISPR applications are focused on editing somatic (non-reproductive) cells, altering germline (reproductive) cells is also a very real possibility. This prospect of editing germline cells and making changes that would be passed on from generation to generation has sparked a heated ethical debate.
The potential to change someone’s DNA even before they are born has led to claims that CRISPR will be used to create “designer babies.” Detractors were appalled at the hubris of science being used to engineer the human race. Supporters, on the other hand, are saying this ability should be a human right.
Rigging the Game
To be fair, most advocates of genetic editing aren’t rallying for support so CRISPR can be used to create a superior human race. Rather, they believe people should have free access to technology that is capable of curing diseases. It’s not about rigging the genetic game — it’s about putting the technique to good use while following a set of ethical recommendations.
To that end, a panel made up of experts chosen by the National Academy of Sciences and the National Academy of Medicine released a series of guidelines that essentially gives gene editing a “yellow light.” These guidelines supports gene editing on the premise that it follows a set of stringent rules and is conducted with proper oversight and precaution.
Obviously, genetic enhancement would not be supported under these guidelines, which leaves some proponents miffed. Josiah Zaynor, whose online company The ODIN sells kits allowing people to conduct simple genetic engineering experiments at home, is among those who are adamant that gene editing should be a human right. He expressed his views on the subject in an interview with The Outline:
We are at the first time in the history of humanity where we can no longer be stuck with the genes we are dealt. As a society we have begun to see how choice is a right, but for some reason when it comes to genetics, some people think we shouldn’t have a choice. I can be smart and attractive, but everyone else should be ugly, fat, and short because those are the genes they were dealt and they should just deal with it.
The immense potential of gene editing to change humanity means the technology will continue to be plagued by ethical and philosophical concerns. Given the pace of advancement, however, it’s good that we’re having this debate on what and who it should be used for right now.
Genetically modifying (GM) animals to ensure the survival of a species is not a new concept. Last year, a biotech company announced their plans to edit certain genes in cattle that would enable them to produce plasma. The plasma would be used in humans to fight disease, which could potentially prevent outbreaks.
Now, a group of researchers wants to genetically modify chicks to support the survival of several different subspecies. These GM chicks would act as surrogates, laying an assortment of eggs that contain rare varieties of chicken species from all over the world.
The team responsible for this feat includes scientists working at the University of Edinburgh’s Roslin Institute. They’ve stated that in order for this all to work, the GM chicks have to be sterilized, meaning they will never be able to hatch eggs that are biologically their own. Sterilization in these chicks occurs through the deletion of a gene called DDX4, which is necessary to produce primordial follicles (the very beginnings of fetus formation). Their findings are published in the journal Development.
In 2016, a group of sterile GM chicks hatched at the Roslin Institute, making this the first time anyone has ever genetically engineered birds in Europe. In their next step, they will transplant follicles of the rare chicken species into the surrogate before they are even born.
Why Does This Matter?
The team has concluded that their ultimate goal is to create a complete gene bank of rare chicken breeds. One important reason for this involves the diversity that they’d bring into the gene pool. This genetic variation could potentially lead scientists to uncover a variant that is resistant to new forms of avian flu. “It’s not what we’re protecting in the breeds that’s important, it’s what those breeds represent in their genes,” stated Richard Broad, a field officer for the Rare Breeds Survival Trust.
This gene bank, dubbed the ‘Frozen Aviary,’ will contain the frozen primordial follicles of rare birds that are readily available and could easily be inseminated into GM eggs. With this gene bank, scientists could bring extinct subspecies back to life, or even provide insurance for the survival of commercial breeds that are so quickly consumed by humans.
“We’re interested in chicken because that is the animal which is the most consumed animal on the planet and we want to protect all the different breeds of chickens that we have,” said Michael McGrew, an author of the study.
The Frozen Aviary currently contains the preserved genetic material of 25 different breeds and over 500 samples from individual chickens. The team hopes to expand their work in the future to involve different breeds of ducks, geese, quail, and possibly the endangered golden eagle. Unfortunately, their GM chicks cannot lay eggs containing a completely different species, so they would all have to find their own suitable surrogates. However, the basic principles of this study could, theoretically, be used with all of these different species.
Genetic engineering is proving to be an increasingly useful tool, effective at everything from protecting plant species to helping humans battle disease. It’s also getting progressively easier to harness, which is why we’re seeing a quickly growing community of do-it-yourself genetic engineers (or biohackers) emerge. Many of these DIY scientists are focused on improving animal species for better breeding, but some skeptics are afraid some well-intentioned scientist somewhere might accidentally home-brew a deadly pathogen or open some other sort of Pandora’s box of genetic devastation.
“This guidance addresses animals whose genomes have been intentionally altered using modern molecular technologies, which may include random or targeted DNA sequence changes including nucleotide insertions, substitutions, or deletions, or other technologies that introduce specific changes to the genome of the animal,” the draft reads. “This guidance applies to the intentionally altered genomic DNA in both the founder animal in which the initial alteration event occurred and the entire subsequent lineage of animals that contains the genomic alteration.”
As expected, this isn’t sitting well with DIY geneticists. Biohacker David Ishee uses genetic engineering to attempt to rid dogs of many of the disorders that go along with high-end breeding. In an interview with Gizmodo, he said that he knows that what genetic hobbyists like him do is actually beneficial. Plus, it’s not that complicated. “It should be straightforward,” he said. “The animals just get molecular surgery to fix a broken gene that causes their bladders to explode. Then those animals can become the founders on a healthy generation of Dalmatians and breed the disease away in a few years.”
The new FDA rule, however, makes it difficult for Ishee and his fellow biohackers to continue with their efforts. Granted, the proposed regulation by the FDA would allow them to keep working in their make-shift labs, but they would be required to have their genetically modified products vetted by the FDA in the same way that the agency regulates new drugs. Scientists are worried that this might make animal genomics feasible only for large, cash-rich corporations and thus limit innovation. “It’s regulation to control who can use these new technologies and how much money they need to have to use them, not regulation to mitigate any risks,” Ishee said.
The FDA, on the other hand, argues that what it’s doing isn’t meant to hinder the work done by these biohackers. “The FDA has made a continuous effort to better understand the needs of the developer community and has instituted a number of activities aimed at providing assistance to regulated small businesses,” according to an emailed statement sent by the agency to Gizmodo.
But it isn’t like these DIY geneticists have been doing things however they want. They practice self-regulation, with strong ethics and safety policies that make sure none of their experiments harm people or the environment. Now, with the FDA involved in home-based genetic engineering, biohackers like Ishee can’t help but feel uneasy. “If [the FDA] was organized for accessibility, smaller organizations could get involved,” he said. “But I don’t have half a million dollars for an expert to help me through that process.”
American chestnut trees were once among the most majestic hardwood trees in the eastern deciduous forests, many reaching 80 to 120 feet in height and eight feet or more in diameter.
The “then boundless chestnut woods” Thoreau wrote about in Walden once grew throughout the Appalachian mountains. They provided habitat and a mast crop for wildlife, a nutritious nut crop for humans and a source of valuable timber. Because of their rapid growth rate and rot-resistant wood, they also have significant potential for carbon sequestration, important in these days of climate change.
The species has a sad story to tell. Of the estimated four billion American chestnut trees that once grew from Maine to Georgia, only a remnant survive today.
The species was nearly wiped out by chestnut blight, a devastating disease caused by the exotic fungal pathogen Cryphonectria parasitica. This fungus was accidentally introduced into the United States over a century ago as people began to import Asian species of chestnut. It reduced the American chestnut from the dominant canopy species in the eastern forests to little more than a rareshrub.
After battling the blight for more than a century, researchers are using the modern tools of breeding, bio-control methods that rely on a virus that inhibits the growth of the infecting fungus, and direct genetic modification to return the American chestnut to its keystone position in our forests.
To restore this beloved tree, we will need every tool available. It’s taken 26 years of research involving a team of more than 100 university scientists and students here at the not-for-profit American Chestnut Research and Restoration Project, but we’ve finally developed a nonpatented, blight-resistant American chestnut tree.
One genetic tweak
My research partner, Dr. Chuck Maynard, and I work with a team at the SUNY College of Environmental Science and Forestry (ESF) that includes high school
students, undergraduate and graduate students, postdoctoral fellows, colleagues from other institutions and volunteers. Our efforts focus on direct genetic modification, or genetic engineering, as a way to bring back the American chestnut.
We’ve tested more than 30 genes from different plant species that could potentially enhance blight resistance. To date, a gene from bread wheat has proven most effective at protecting the tree from the fungus-caused blight.
This wheat gene produces an enzyme called oxalate oxidase (OxO), which detoxifies the oxalate that the fungus uses to form deadly cankers on the stems. This common defense enzyme is found in all grain crops as well as in bananas, strawberries, peanuts and other familiar foods consumed daily by billions of humans and animals, and it’s unrelated to gluten proteins.
We’ve added the OxO gene (and a marker gene to help us ensure the resistance-enhancing gene is present) to the chestnut genome, which contains around 40,000 other genes. This is a minuscule alteration compared to the products of many traditional breeding methods. Consider the techniques of species hybridization, in which tens of thousands of genes are added, and mutational breeding, in which unknown mutations are induced. Genetic engineering allows us to produce a blight-resistant American chestnut that’s genetically over 99.999 percent identical to wild-type American chestnuts.
There is another logical question: what about unintended consequences? Of course undefined questions are impossible to answer, but logically the method producing the smallest changes to the plant should have the fewest unintended consequences. We have not observed nontarget transgene effects – that is, changes that we didn’t intend – on our trees or on other organisms that interact with our trees, for example with beneficial fungi.
And at any rate, unintended consequences aren’t constrained to the genetics lab. Chestnut growers have seen unintended consequences resulting from their hybrid breeding of chestnuts. One example is the internal kernel breakdown (IKB) seen in chestnut hybridization, caused by crossing a male sterile European/Japanese hybrid (“Colossal”) with Chinese chestnut. By mixing tens of thousands of genes with unknown interactions through traditional breeding, occasionally you get incompatible combinations or induced mutations that can lead to unintended outcomes like IKB or male sterility.
One of the key advantages of genetic engineering is that it’s far less disruptive to the original chestnut genome – and thus to its ecologically important characteristics. The trees remain more true to form with less chance of unforeseen and unwanted side effects. Once these genes are inserted, they become a normal part of the tree’s genome and are inherited just like any other gene. They have no more chance of moving to other species than do any of the approximately 40,000 genes already in chestnut.
Next steps for the blight-resistant American chestnut
One of the challenges of genetic engineering that is not faced by any other methods of genetic modification also serves as a safeguard. We must shepherd these trees through federal regulatory review by the U.S. Department of Agriculture, the Environmental Protection Agency and the Food and Drug Administration. Our plan is to submit these applications as we finish collecting the necessary data; we expect the process to take three to five years. Once we receive (anticipated) approval, we will quickly make the trees available to the public.
This project is unique because it is the first to seek approval of a transgenic plant to help save a species and restore a forest’s ecology. Our forests face many challenges today from exotic pests and pathogens such as Emerald Ash Borer, Hemlock Wooly Adelgid, Sudden Oak Death, Dutch Elm Disease, and many more. The American chestnut can serve as a model system for protecting our forest’s health.
Direct genetic modification will likely not be used in isolation. Integration might improve the outcomes of both the conventional hybrid/backcross breeding program of the American Chestnut Foundation and our genetic engineering program. Allowing crosses between the best trees from both programs will allow gene stacking – having multiple and diverse resistance genes in a single tree – with each working in a different way to stop the blight. This would significantly decrease the chances that the blight could ever overcome the resistance. The two programs working together would also allow the addition of resistance genes for other important pests, such as Phytophthora, which causes a serious root rot in the southern part of the chestnut range. And combining methods increases the chances that the resistance will be long-lasting and reliable, which is very important for a tree that in good health can live for centuries.
A unique aspect of the genetically engineered American chestnut trees is their ability to rescue the genetic diversity in the small surviving population of American chestnut trees. When we cross our blight-resistant transgenic trees to these surviving “mother” trees, directly in the wild or from nuts gathered from them and grown in orchards, we’re helping preserve the remaining wild genes.
Half the resulting offspring will be fully blight-resistant, while also containing half the genes from the mother tree. By making these crosses, the restoration trees will be ecologically adapted to the diverse environments in which they’ll grow. These trees could also be used to boost the genetic diversity of the hybrid/backcross breeding program, or used directly for restoration and left to fend for themselves, allowing natural selection to make the final determination of the effectiveness of our efforts.
The American chestnut was one of the most important hardwood tree species in the eastern forests of North America, and it can be again. This tiny change in the genome will hopefully be a huge step toward putting the American chestnut on a path to recovery.
The potential of stem cells for various treatments keeps scientists, like a team at the Salk Institute, to continually develop ways to produce human/animal (chimera) stem cells. Now, the chimera that these researchers are developing is not the multi-headed, fire-breathing monster of Greek mythology, but rather a genetic chimera. A genetic chimera is simply a singular organism made up of cells coming from different zygotes.
This team of Salk Institute researchers, led by Juan Carlos Izpisua Belmonte, are aiming to develop a chimera made of both human and pig stem cells. “The ultimate goal is to grow functional and transplantable tissue or organs, but we are far away from that,” said Izpisua Belmonte, researcher and author of the study published in the journal Cell. “This is an important first step.”
As expected, developing fully grown three-dimensional tissues and organs from stem cells in a petri dish wasn’t easy. “It’s like when you try to duplicate a key. The duplicate looks almost identical, but when you get home, it doesn’t open the door. There is something we are not doing right,” Izpisua Belmonte said. “We thought growing human cells in an animal would be much more fruitful. We still have many things to learn about the early development of cells.”
Izpisua Belmonte and Salk scientist Jun Wu’s experiment began with the production of a rat/mouse chimera, something that’s already been done by other scientists in 2010. They introduced rat cells into mouse embryos and allowed these to mature. They then proceeded to introduce human cells into an organism, opting for cows and pigs because their organs more closely resemble human organs in terms of size. They experimented with about 1,500 pig embryos over a four-year period.
Several different forms of human stem cells were injected into pig embryos to determine which could best survive. Of these, those that showed a high survival rate and the most potential to continually develop were “intermediate” pluripotent stem cells. “Intermediate cells are somewhere in between” the two cell types, “naive” cells and “primed” cells, Wu explained. The former have unrestricted development and resemble cells in an earlier developmental origin. The later have already developed further but remain pluripotent.
The human cells that survived formed a human/pig chimera embryo. These were implanted into sows and were allowed to develop for three to four weeks. “This is long enough for us to try to understand how the human and pig cells mix together early on without raising ethical concerns about mature chimeric animals,” Izpisua Belmonte said.
However, even with the best-performing human stem cells, Wu stated that the level of contribution to the chimeric embryo was low. But this isn’t necessarily a bad thing. One concern about human/animal chimera embryos is that they would develop to be too human. “At this point, we wanted to know whether human cells can contribute at all to address the ‘yes or no’ question,” said Izpisua Belmonte. “Now that we know the answer is yes, our next challenge is to improve efficiency and guide the human cells into forming a particular organ in pigs.” The researchers are now relying on CRISPR to do this, editing pig genomes to open gaps that the human cells can fill in.
The goal of growing fully functional and transplantable tissue or organs is still far away. Thankfully, this team is not intending to create fully grown chimera organisms (the ethical issues of this “mad science” would be too difficult). For now, the researchers are happy that this study can help scientists understand how human stem cells grow and specialize. The human/pig chimera embryos could also give insights into early human development and disease onset.
Microelectronics has transformed our lives. Cellphones, earbuds, pacemakers, defibrillators – all these and more rely on microelectronics’ very small electronic designs and components. Microelectronics has changed the way we collect, process and transmit information.
Such devices, however, rarely provide access to our biological world; there are technical gaps. We can’t simply connect our cellphones to our skin and expect to gain health information. For instance, is there an infection? What type of bacteria or virus is involved? We also can’t program the cellphone to make and deliver an antibiotic, even if we knew whether the pathogen was Staph or Strep. There’s a translation problem when you want the world of biology to communicate with the world of electronics.
The research we’ve just published with colleagues in Nature Communications brings us one step closer to closing that communication gap. Rather than relying on the usual molecular signals, like hormones or nutrients, that control a cell’s gene expression, we created a synthetic “switching” system in bacterial cells that recognizes electrons instead. This new technology – a link between electrons and biology – may ultimately allow us to program our phones or other microelectronic devices to autonomously detect and treat disease.
Communicating With Electrons, Not Molecules
One of the barriers scientists have encountered when trying to link microelectronic devices with biological systems has to do with information flow. In biology, almost all activity is made possible by the transfer of molecules like glucose, epinephrine, cholesterol and insulin signaling between cells and tissues. Infecting bacteria secrete molecular toxins and attach to our skin using molecular receptors. To treat an infection, we need to detect these molecules to identify the bacteria, discern their activities and determine how to best respond.
Microelectronic devices don’t process information with molecules. A microelectronic device typically has silicon, gold, chemicals like boron or phosphorus and an energy source that provides electrons. By themselves, they’re poorly suited to engage in molecular communication with living cells.
Free electrons don’t exist in biological systems so there’s almost no way to connect with microelectronics. There is, however, a small class of molecules that stably shuttle electrons. These are called “redox” molecules; they can transport electrons, sort of like wire does. The difference is that in wire, the electrons can flow freely to any location within; redox molecules must undergo chemical reactions – oxidation or reduction reactions – to “hand off” electrons.
Turning Cells On and Off
Capitalizing on the electronic nature of redox molecules, we genetically engineered bacteria to respond to them. We focused on redox molecules that could be “programmed” by the electrode of a microelectronic device. The device toggles the molecule’s oxidation state – it’s either oxidized (loses an electron) or reduced (gains an electron). The electron is supplied by a typical energy source in electronics like a battery.
We wanted our bacteria cells to turn “on” and “off” due to the applied voltage – voltage that oxidized a naturally occurring redox molecule, pyocyanin.
Electrically oxidizing pyocyanin allowed us to control our engineered cells, turning them on or off so they would synthesize (or not) a fluorescent protein. We could rapidly identify what was happening in these cells because the protein emits a green hue.
In another example, we made bacteria that, when switched on, would swim from a stationary position. Bacteria normally swim in starts and stops referred to as a “run” or a “tumble.” The “run” ensures they move in a straight path. When they “tumble,” they essentially remain in a one spot. A protein called CheZ controls the “run” portion of bacteria’s swimming activity. Our electrogenetic switch turned on the synthesis of CheZ, so that the bacteria could move forward.
We were also able to electrically signal a community of cells to exhibit collective behavior. We made cells with switches controlling the synthesis of a signaling molecule that diffuses to neighboring cells and, in turn, causes changes in their behavior. Electric current turned on cells that, in turn, “programmed” a natural biological signaling process to alter the behavior of nearby cells. We exploited bacterial quorum sensing – a natural process where bacterial cells “talk” to their neighbors and the collection of cells can behave in ways that benefit the entire community.
Perhaps even more interesting, our groups showed that we could both turn on gene expression and turn it off. By reversing the polarity on the electrode, the oxidized pyocyanin becomes reduced – its inactive form. Then, the cells that were turned on were engineered to quickly revert back to their original state. In this way, the group demonstrated the ability to cycle the electrically programmed behavior on and off, repeatedly.
Interestingly, the on and off switch enabled by pyocyanin was fairly weak. By including another redox molecule, ferricyanide, we found a way to amplify the entire system so that the gene expression was very strong, again on and off. The entire system was robust, repeatable and didn’t negatively affect the cells.
Sensing and Responding on a Cellular Level
Armed with this advance, devices could potentially electrically stimulate bacteria to make therapeutics and deliver them to a site. For example, imagine swallowing a small microelectronic capsule that could record the presence of a pathogen in your GI tract and also contain living bacterial factories that could make an antimicrobial or other therapy – all in a programmable autonomous system.
This current research ties into previous work done here at the University of Maryland where researchers had discovered ways to “record” biological information, by sensing the biological environment, and based on the prevailing conditions, “write” electrons to devices. We and our colleagues “sent out” redox molecules from electrodes, let those molecules interact with the microenvironment near the electrode and then drew them back to the electrode so they could inform the device on what they’d seen. This mode of “molecular communication” is somewhat analogous to sonar, where redox molecules are used instead of sound waves.
These molecular communication efforts were used to identify pathogens, monitor the “stress” in blood levels of individuals with schizophrenia and even determine the differences in melanin from people with red hair. For nearly a decade, the Maryland team has developed methodologies to exploit redox molecules to interrogate biology by directly writing the information to devices with electrochemistry.
Perhaps it is now time to integrate these technologies: Use molecular communication to sense biological function and transfer the information to a device. Then use the device – maybe a small capsule or perhaps even a cellphone – to program bacteria to make chemicals and other compounds that issue new directions to the biological system. It may sound fantastical, many years away from practical uses, but our team is working hard on such valuable applications…stay tuned!
As the culprit behind one million cases of food poisoning and 380 deaths every year, Salmonella is definitely bad news for the stomach. But what if it’s possible to turn Salmonella into one of the good guys? That’s exactly what researchers from Duke University wanted to achieve when they genetically engineered a strain of Salmonella into brain tumor munchers.
In a study published in the journal Molecular Therapy – Oncolytics, the Duke researchers genetically modified the bacterium Salmonella typhimurium not to attack the gastrointestinal tract, but to instead fight one of the most aggressive forms of brain cancer known to humankind. Glioblastoma holds a record median survival time of only 15 months, and that’s even with the best care currently available. Those who survive, just about 10 percent, manage to prolong their lives for only five years once diagnosed.
Furthermore, the blood-brain barrier makes it impossible for drug-based treatment to attack glioblastoma. Surgery doesn’t quite cut it, either. So, an aggressive attacker deserves an equally intense fighter. Hence, the researchers made an unlikely ally out of Salmonella. With a few genetic tweaks to its DNA, they were able to turn Salmonella into a sort of cancer-seeking missile that self-destructs deep inside tumors. Lab tests in rats with extreme cases of glioblastoma showed an astonishing 20 percent survival rate, with the tumors going into remission over a period of 100 days — roughly equal to 10 human years.
“Since glioblastoma is so aggressive and difficult to treat, any change in the median survival rate is a big deal,” said researcher Johnathan Lyon. “And since few survive a glioblastoma diagnosis indefinitely, a 20 percent effective cure rate is phenomenal and very encouraging.”
The tweaks made the Salmonella into Purine-deficient bacteria. Purine is an amino-acid that’s abundantly found in tumors. So, once these modified Salmonella were injected into the brain, they dug deep into the tumors and started rapidly multiplying. At the same time, they have also been designed to produce two compounds in low-oxygen environments, such as the inside of tumors. These added compounds, Azurian and p53, cause cells to self destruct, killing both the tumors and the Salmonella bacteria.
As Ravi Bellamkonda, co-author of the study and Vinik Dean of Duke’s Pratt School of Engineering, put it:
[D]esigning bacteria to actively move and seek out these distributed tumors, and express their anti-tumor proteins only in hypoxic, purine rich tumor regions is exciting. And because their natural toxicity has been deactivated, they don’t cause an immunological response. At the doses we used in the experiments, they were naturally cleared once they’d killed the tumors, effectively destroying their own food source.
As with most experimental therapy, it isn’t clear yet when it will move out of the lab and into clinical trials. But this certainly gives hope for combatting one of the world’s deadliest diseases — thanks to genetic engineering. Treatments that use genetic engineering are certainly changing the world of medicine. From the most effective gene editing tool to modifying mosquitoes to fight dengue fever, genetic engineering seems to be leading us steadily into a disease-free future.
Each year, mosquitos carrying the dengue fever virus (DENV) infect about 390 million people across the world. Symptoms of the fever are often similar to other viral infection (headaches, nausea, fatigue, etc.) but can develop into more serious issues such as massive bleeding, shock, and death. The virus is responsible for the deaths of nearly 25,000 people worldwide, each year.
Researchers have been working painstakingly to develop ways to combat the mosquitos that carry the virus. Now, researchers from Johns Hopkins University have published their work on how mosquitos can be genetically engineered to resist DENV. The study has been published in PLOS Neglected Tropical Diseases.
Mosquitos’ own immune systems also try to fight the virus off upon infection. There are specific proteins known as ‘Dome’ and ‘Hop’ that activate after infection to kickstart the immune process. The new work shows how the researchers were able to turn on this immune response as soon as the would-be host ingests infected blood, much sooner than the natural response.
Scientists engineered the bugs to express either Dome or Hop sooner and the results were very promising. The viral counts of DENV were reduced by 78.18 percent for those engineered to express Dome, and a remarkable 83.63 percent for Hop.
Engineering the Resistance
The rise of the gene editing technique known as CRISPR has given epidemiologists new hope that many of these mosquito-borne illnesses can be combatted on a molecular level. Other diseases, such as malaria, are currently being targeted by genetic engineers. However, genetic engineering brings about its own set of ethical and practical concerns.
Extra diligence must be exhibited if researchers want to both prove the effectiveness of these and similar methods, as well as convince the public of their safety. Just this past election, Florida voters passed a resolution to allow the release of genetically modified mosquitos to combat the Zika virus.
As stated by the researchers of the dengue fever study, there is hope in genetic engineering, “Recently developed powerful mosquito gene-drive systems that are under development are likely to make it possible to spread pathogen resistance in mosquito populations in a self-propagating fashion, even at a certain fitness cost.”
The transition from one year to the next is always a little uncertain – an uneasy blend of anxiety and optimism, it’s also a time of retrospection, introspection, and even a little tentative prognostication. And since the latter is our stock-in-trade at Futurism, we believe now is the perfect time to look ahead at what 2017 has in store for us.
Here’s our list of some of the many wonderful advances in medicine we can look forward to in 2017.
Sophisticated technologies have always had an important role to play in medicine, with each year adding extraordinary new tools to the physician’s medicine bag—2017 will be no exception.
We can, for instance, expect further improvements in the technology of robotic surgery. In addition to the currently available da Vinci Surgical System, look to see competition from the new surgical robot system developed by the partnership of Google and Johnson & Johnson. These new systems will parlay advances in software, miniaturization, and robotics to allow for minimally invasive surgeries on the most delicate elements of human anatomy.
We can expect the application of AI to medicine to only increase in the coming year, when the need to cull through and assimilate enormous quantities of medical data—whether on an individual or large-scale, societal basis—will become critical. Meanwhile, the danger that potentially flawed machine learning programs will supplant rather than merely supplement human medical judgment will also become much more than just an abstruse, academic question for medical ethicists.
A Pharmacological Revolution
But 2017 won’t be just about robots and artificial intelligence. It’s likely that some of the less visually spectacular medical technologies will yield the most astonishing medical breakthroughs. Drug research, for instance, is poised to take off in 2017—especially with immunotherapeutic treatments for cancer.
According to Stanley Marks, chairman of the UPMC CancerCenter, it is these treatments—which marshal the body’s immune system to attack and destroy cancerous cells—that represent the single most promising new front in the war on cancer. Using checkpoint inhibitor drugs and CAR (chimeric antigen receptor) T-cell therapies, it’s become possible to mobilize the body’s own immune system to fight the cancer.
The method involves extracting T-cells from the patient’s own blood, and genetically engineering them to recognize, attach to, and neutralize tumorous cells. It’s already had promising results in fighting some leukemias, so we can look forward to more research on these remarkable “living drugs” in 2017.
The revolutionary CRISPR/Cas-9 gene-editing technology has disrupted biology like nothing else—and bids fair to transform it from a slow, imprecise science to something approaching the precision of the physical sciences. What 2017 holds for gene-editing technology is anyone’s guess—it’s even possible that the Chinese, or some other nation with laxer standards than are currently permitted in the U.S., might begin a more widespread use of the technique in human subjects.
But expect passive measures, too, such as simply learning how Alzheimer’s and other neurodegenerative diseases progress, or even non-medical agricultural and industrial uses for the technology. As Nicola Patron of the Earlham Institute sagely observes, “Understanding what DNA sequences do is what enables us to solve problems in every field of biology from curing human diseases, to growing enough healthy food, to discovering and making new medicines, to understanding why some species are going extinct.”
The bottom line: 2017 is looking to be an exciting year, in all avenues of research and discovery, but particularly in medicine. And if all the above wasn’t exciting enough for you—you can look forward to capping it off with what might be the world’s first head transplant.
Disembodied heads or not, you can read all about the latest developments here at Futurism.