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Synthetic Genetic Shakespeares

Examining the implications of science and technology

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Synthetic Genetic Shakespeares

The personal blog of Tyler Kokjohn. A partial list of my scientific publications may be found on PubMed. The opinions expressed in these posts are my own. I declare I have no competing scientific or financial interests regarding the topics examined in this blog.

Apocalypse-ology – Imagining the Unthinkable

Picture some scientists and philosophers brainstorming end-of-the-world scenarios.  This is not an exercise to create new show concepts for the History Channel, the University of Cambridge Centre for the Study of Existential Risk is supporting efforts to identify emerging technological advances with a potential to terminate civilization (1).   One of the goals of the work is to reveal ways to prevent disasters.

Nuclear annihilation, rogue artificial intelligence and synthetic pathogen pandemics mixed with asteroid collision or volcanic eruption suggest the list of calamities that could harm humankind is long.  Add in the reality that not even the most expert scientists will be able to foresee all the implications of their discoveries (2) and the future seems grim.  However, despite the fact that many potential threats can be envisioned clearly, undertaking a proactive program to study the general area has critics.  One concern is the events are so improbable.  Another worry is that arousing public fears over “Frankensteinian fantasies” might be counterproductive (1).

Aud

 

Are apocalypse-ology programs wasting time worrying about wildly improbable incidents?  What is improbable today may not necessarily remain so in the future.  Estimates of probabilities for adverse events must take account of the fact that technologies are evolving rapidly.  Experience teaches us activities that are limited to expert teams with specialized equipment now may be conducted with less trouble and skill in the future. The distinguished scientist Martin Rees has noted that technological advances have been empowering and will endow individuals with vast destructive powers (1).  This idea is alarming because outcomes subject to personal whims and eccentricities will be inherently unpredictable.    

One suggestion offered to avoid the disaster of a malevolent AI system is simple – “Don’t build one” (1).  A sound strategy until someone decides to deliberately do just such a thing.  Although it is not common, scientists have broken rules or threatened to violate them in an apparent pique of anger.  One investigator seeking ways to control Dutch elm disease released genetically modified bacteria into the environment without following the necessary evaluation protocols (3).  In addition, to facilitate his work he introduced the disease agent into a geographic location in which it had not yet been detected (3).  Another scientist who had conducted gain-of-function experiments with H5N1 avian influenza threatened to submit his work for publication without required approvals (4).  This particular investigation was controversial because some scientists, concerned the information could provide a model for (unspecified) nefarious actors to create dangerous flu viruses, advised the study not be published.  Ultimately, this scientist did not act on his threat and a scientific advisory panel consented to publish the work in full.  Will we always be as fortunate in the future if someone empowers themselves to ignore the rules and cut corners?  What if technological barriers fall far enough to enable many others to act with true premeditated malice as was the case with the U.S. anthrax attacks of 2001 (5)?     

In addition to the potential for deliberate acts of defiance or malevolence, the possibility for error exists when working with biological agents.  Dr. Malcolm Casadaban died after he became infected working with a strain of plague bacteria that was thought to be harmless (6).  Plague is typically transmitted by flea bite and the exact circumstances that caused Dr. Casadaban’s infection are mysterious, although he did have a medical condition that may have made him more susceptible once the bacteria entered his body.  Errors, procedural violations and escapes have been documented regularly in laboratories conducting work with high risk biological agents (7, 8).  At least one escape may have had global consequences – genomic analyses have revealed a high likelihood the 1977 Russian influenza pandemic was sparked by release of the virus from a laboratory (8).  However, the exact circumstances that enabled Russian flu viruses to escape control and spread across the world have never been explained.    

Is apocalypse-ology a productive use of scientific brainpower or is it idle ivory tower fear mongering?  Risk analysis is an integral part in the decision-making processes regarding the approval of research proposals involving recognized high-risk agents or situations.  Assessing the benefits of gain-of-function research on potentially dangerous viruses must be balanced by examining hypothetical nightmare scenarios.  What happens if this virus gets out of the lab?  Could it be stopped?  Let’s consider the case of a new, lab-manufactured influenza virus.  If this new virus was Tamiflu sensitive, could an epidemic following an accident or release be suppressed by supplying the drug?  Now run through the realities – how fast could you recognize an escape, how far would it extend geographically before you could distribute Tamiflu, how much Tamiflu would you need and how would it be delivered where it was needed to stay ahead of the epidemic?  This is not an idle thought experiment exercise, but an important means to identify which actions are feasible and which are futile.  Forearmed with the information, reason-based decisions may be reached and effective safeguards put in place before a disaster occurs.   It is true predictive capacities are sometimes limited.  However, for those situations in which we can foresee certain possibilities it would be irresponsible not to explore them.

Will envisioning “Frankensteinian fantasies” take us anywhere?  The key point is that it might help us avoid ending up somewhere we very much wish we had never gone in the first place.   

Jeff Future of Life       

                         

(1) Kai Kupferschmidt.   Taming the Monsters of Tomorrow.  Science, 11 January 2018.  http://www.sciencemag.org/news/2018/01/could-science-destroy-world-these-scholars-want-save-us-modern-day-frankenstein

(2) Heidi Ledford.   CRISPR, the Disruptor.  Nature, 3 June 2015.    https://www.nature.com/news/crispr-the-disruptor-1.17673

(3) Mark Crawford.   Researcher Flouts Gene-splicing Rules.  Science 237:838-839.  http://science.sciencemag.org/content/237/4817/838.2/tab-pdf

(4) Declan Butler.   Mutant-flu Researcher Plans to Publish Even Without Permission.  Nature, 17 April 2012.  http://www.nature.com/news/mutant-flu-researcher-plans-to-publish-even-without-permission-1.10469

(5) Greg Gordon and Mike Wiser.   New Report Casts Doubt on FBI Anthrax Investigation.  PBS.org, 19 December 2014.  https://www.pbs.org/wgbh/frontline/article/new-report-casts-doubt-on-fbi-anthrax-investigation/

(6) Emma Graves Fitzsimmons.   Researcher Had Bacteria for Plague at his Death.  The New York Times, 21 September 2009.  http://www.nytimes.com/2009/09/22/us/22chicago.html

(7) Jocelyn Kaiser.   Accidents Spur Closer Look at Biodefense Labs.    Science 317:1852-1854, 28 September 2007.  http://science.sciencemag.org/content/317/5846/1852.full

(8) Martin Furmanski.   Threatened Pandemics and Laboratory Escapes: Self-Fulfilling Prophesies.  Bulletin of the Atomic Scientists, 31 March 2014.  https://thebulletin.org/threatened-pandemics-and-laboratory-escapes-self-fulfilling-prophecies7016

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Tiny Change, Big Trouble

Has a Food Additive Promoted a Clostridium difficile Disease Epidemic?

Levels of obesity, depression and addiction to opioids appear to be increasing in the United States.  However, even when statistics confirm such suspicions are correct, identifying a root cause(s) producing the new situations may be tricky.  Clearly, Americans are more obese than ever, but should we blame that on not getting as much exercise as past generations, eating too much fast food or a combination of factors?  Although we may not often view it as dangerous, the health consequences of increasing obesity levels are so potentially significant they may signal an impending decline in average life expectancy (1).  Taking effective action to combat trends like increasing obesity hinges on being able to discover the critical factor(s) which foster them.

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An Emerging Disease

Scientists may have exposed a factor promoting an emerging increase in serious inflammatory gastrointestinal disease caused by the bacterium, Clostridium difficile (2).  The U. S. Centers for Disease Control and Prevention (CDC) estimates this pathogen is now responsible for a half million infections and tens of thousands of deaths annually (3).  This unfortunately common infection adds billions of dollars to annual U.S. health care costs (3).

Is a Food Additive Involved?

The new findings suggest the presence of trehalose, a now widely used food additive, favors the growth of the two strains of C. difficile most associated with fatal disease (2).  Following cost reductions due to changes in production methods, trehalose was approved as a food additive.  Outbreaks of highly pathogenic C. difficile strains appeared shortly after the addition of trehalose to a wide variety of foods (2).  This apparent link suggests dietary trehalose reaches levels in some human subjects high enough to aid colonization by the C. difficile strains most likely to produce serious disease.  Disease due to C. difficile infections often follows a disturbance of the normal balance of gastrointestinal tract bacteria by antibiotic treatment or cancer chemotherapy.  Subjects harboring highly pathogenic C. difficile strains and/or following diets that promote the growth of such strains may be at elevated risk for serious illness after such medical interventions.  If this hypothesis is correct the emergence of grave C. difficile infections in the last 20 years was boosted by something trivial – adding trehalose to our diets.

War You3

The Mad Cow Disease Experience

It will be important to confirm these findings.  Multiple lines of evidence are bolstering the notion that the microbial flora of the gastrointestinal tract is dynamic, sensitive to change and plays big, sometimes surprising roles, in our health and wellbeing (4).  Perhaps what the C. difficile epidemic will ultimately reveal is that even apparently trivial alterations may have enormous downstream implications.  We have seen something similar before when an apparently trivial change in food production methods driven by economic factors led to disaster.  Re-feeding meat bone meal wastes to cattle produced a massive common source epidemic of bovine spongiform encephalopathy (BSE), sometimes known as mad cow disease (5).  This simple decision to supplement cattle feed possibly coupled with a change in how those materials were rendered created a situation that led to the explosive amplification and transmission of the infectious proteins (prions) that cause mad cow disease.  The near simultaneous emergence of an analogous neurologic disease of humans known as new variant Creutzfeldt-Jakob disease (vCJD) in the same geographic location suggests mad cow prions also invaded humans through a dietary route.  The BSE epidemic in cattle was halted by destroying herds and changing rules regarding the preparation and use of meat bone meal animal feed supplements.  However, because the incubation periods of prion diseases are long, it remains unknown how many persons will ultimately develop vCJD.

The mad cow disease epidemic reminds us that trivial changes may sometimes have dramatic consequences.  Perhaps further studies will confirm a small change in food additives facilitated C. difficile epidemics.  Could alterations and additions to our diets we believed had no health implications be causing or contributing to other maladies?  Perhaps, as might be the case with C. difficile, our diets set us up for diseases to appear when the proper circumstances are present.

(1) S. Jay Olshansky et al. 2005. A Potential Decline in Life Expectancy in the United States in the 21st Century.  The New England Journal of Medicine 352(11)”1138-1145.  http://www.nejm.org/doi/full/10.1056/NEJMsr043743

(2) Jimmy D. Ballard.  2018.  Pathogens Boosted by Food Additive.  Nature, 3 January 2018.  https://www.nature.com/articles/d41586-017-08775-4

(3) The Centers for Disease Control and Prevention.  2015.    https://www.cdc.gov/media/releases/2015/p0225-clostridium-difficile.html

(4) Gretchen Reynolds.  2018.  Exercise Alters Our Microbiome.  Is That One Reason it’s so Good for Us?  The New York Times, 3 January 2018.  nyti.ms/2ELYACS

(5) U.S. Food and Drug Administration.  Bovine Spongiform Encephalopathy.  https://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/ComplianceEnforcement/BovineSpongiformEncephalopathy/default.htm

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Will Scientific Research Validate the “Twinkie Defense”?

The murders of San Francisco mayor George Moscone and city supervisor Harvey Milk by Dan White created a media sensation 40 years ago.  Part of the public uproar involved a diminished capacity alibi employed by Mr. White’s lawyers that was repackaged by others as the captivating “Twinkie defense” (1).  The central tenet of the alleged Twinkie defense was that consumption of sugary junk foods impaired the defendant’s mental capacity.  Although the actual legal defense revolved around the consequences of Mr. White’s untreated depression, part of the evidence brought forth was his switch to an unhealthy diet.  The mis-characterized trial strategy provoked public outrage and was established as an urban legend (1). 

Not long after this shocking trial had concluded I was a graduate student being introduced to the biochemistry of neuronal cells by Professor Michael Collins.  I recall Dr. Collins discussing the Twinkie defense, indicating that although the public perceptions about it may not have been completely accurate, neurons were sensitive to their environments.  Although not much direct evidence was in hand at that time, Dr. Collins did not dismiss the possibility dietary choices might substantially impact human behavior.  Science may soon have a great deal more to say about such matters.

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Researchers are now tracing out the complex biochemical transactions that take place between human beings and the invisible microbes living in and on us (2).  It turns out that the benefits of a healthy, high fiber diet actually reach us indirectly through the metabolic transformations produced by a diverse community of active microorganisms.  Gut microbes, our personal gastrointestinal microbiomes, are influenced by diet and, in turn, feed back essential, health-maintaining signals to our cells.  Evidence is accumulating that gut bacteria may synthesize or regulate the levels of key neurotransmitters such as serotonin that are known to play important roles in disorders such as depression (3).

The discoveries revealing the intricate interactions between gut bacteria and the brain hint we may see new ways to mitigate some significant human health issues.  If such notions are validated, could the findings herald the transformation of the Twinkie defense from inaccurate legend into a compelling, scientifically-grounded legal strategy? 

Then again, perhaps the lawyers of the future will never need it.  If we comprehend how dietary choices influence behavior, scientist-nutritionists of the future might devise new foods (4) and probiotic programs to keep us all happy and well-behaved in a brave new world.  

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(1) David Mikkelson.   The Twinkie Defense.  Snopes.com, 27 August 2009.  https://www.snopes.com/legal/twinkie.asp

(2) Carl Zimmer.   Fiber is Good for You.  Now Scientists May Know Why.  The New York Times, 1 January 2018.  https://t.co/tCfReMWXaj

(3) David Kohn.   When Gut Bacteria Change Brain Function.  The Atlantic, 24 June 2015.   https://t.co/XpU4K5PMug

(4) Barbara J. King.   Clean Meat, Via Lab, Is On the Way.  NPR, 2 January 2018.  https://t.co/UJ71m9B9Eo

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Will Genetic Engineering Enable Us to Retrieve Lost Ecosystems?

At one time in recent history an estimated 4 billion American chestnut trees thrived in the Eastern U.S. (1).  The vast and productive stands were almost exterminated by a fungal blight disease and only a few remnants exist today.  The deadly fungal disease agent, Cryphonectria parasitica, was accidentally introduced when Asian chestnut species were imported into the country.  This simple action ended up completely changing the species composition and physical structure of American forests.  The full ecological consequences of the change have never been documented.

Chestnut

 

A Repeating Tale of Woe

The sad story of the American chestnut has been and is being repeated today as other invasive exotic disease agents and hundreds of other insect species have reached the U.S. (2).  Decades after the mass die-off of chestnuts, American elm trees were done in by Dutch elm disease and today ash trees are being destroyed by emerald ash borer beetles from Asia (2, 3).

Efforts to genetically engineer chestnut trees to resist blight seem successful and projects to restore the species are now being proposed (1).  Perhaps this will be a model for future undertakings to reverse plant losses due to the invasive species and exotic disease agents introduced by humans.  However, this is still a research project and although promising, the genetic engineering approach has been criticized (4).  In addition, anything involving releasing genetically engineered organisms into the environment seems to generate controversy (5).

Can Lost Ecosystems be Recovered?

Is the dream of restoring Eastern American forest ecosystems to their former glory – before human actions destroyed the chestnuts – possible?  In one sense, it might be if genetically engineering or plant breeding efforts produce viable trees that resist disease and propagate successfully.  The unstated question is if humans successfully restore this keystone species, will all then be as it once was?  Or will we have created a simulacrum of a vanished ecosystem; one good enough to fool us into believing we have reversed the damage that cannot be undone?  Perhaps if chestnut populations are re-established the full range of species that once thrived with and on them will rebound as well.  And perhaps some of the life forms that once depended on chestnut trees have disappeared forever, never to return.  The fact is we are unable to tally the full species losses that followed the destruction of the chestnut forests and can never be assured we can make our way back to a lost ecology of the past.

De-extinction of species such as wolly mammoths and the passenger pigeon has been proposed as a remedy for human-caused losses (6, 7).  Perhaps these schemes will succeed in cobbling together un-natural hybrids such as mammophants (6) or something reminiscent of passenger pigeons in the laboratory.  Maybe the final products will be such good imitations they will even fool experts in taxonomy.  As is the case with the American chestnut, releasing these facsimiles, even close ones, into the world is not fully restoring lost ecological systems.  The unknown and uncounted species that once existed in, on and with these species may have been lost forever, possibly never to return.  If we seek to do more than save a few charismatic species, genetic engineering efforts may be helpful in salvaging ecosystems threatened by exotic diseases or invasive species.  However, this may require interventions before the keystone species vanish and take along all the living beings that depend on them.

Perhaps science will be able synthesize passenger pigeon look-alikes, is that a prelude to recovering wild flocks so vast they will awe future birdwatchers?  Again, things may not be so simple (8), our understanding of ecosystem-species dynamics is still limited.  In addition, the environments conservationists will attempt to release these creations into are not the same the original versions they once dominated.  Vast tracts of the U.S. have been turned over to human purposes.  Still, the choices available may hinge on some remarkably simple questions.  Will we be able to find room for passenger pigeons?  We are having trouble sharing our environment with Monarch butterflies and other less demanding species.

Monarch

(1) William Powell.   New Genetically Engineered American Chestnut Will Help Restore the Decimated, Iconic Tree.   The Conversation, 19 January 2016.  http://theconversation.com/new-genetically-engineered-american-chestnut-will-help-restore-the-decimated-iconic-tree-52191

(2) Deborah G. McCullough.   Will We Kiss Our Ash Goodbye?  American Forests, Winter 2013.   http://www.americanforests.org/magazine/article/will-we-kiss-our-ash-goodbye/

(3) Tina Casagrand.   Millions of Ash Trees are Dying, Creating Huge Headaches for Cities.  National Geographic, 4 December 2014.    https://news.nationalgeographic.com/news/2014/12/141202-emerald-ash-borer-forestry-trees-environment/

(4) Cici Zhang.   The American Chestnut Tree Has a Good Shot at Making a Comeback.  Scienceline, 25 January 2017. http://scienceline.org/2017/01/american-chestnut-tree-good-shot-making-comeback/

(5) Anne Petermann. Why We Must Say No to GMO Chestnuts.  The Campaign to Stop GE Trees, 7 March 2017.  https://stopgetrees.org/must-say-no-gmo-chestnuts/

(6) Hannah Devlin.    Wolly mammoth on Verge of Resurrection, Scientists Reveal.  The Guardian, 16 February 2017.   https://www.theguardian.com/science/2017/feb/16/woolly-mammoth-resurrection-scientists

(7) David Biello.   Ancient DNA Could Return Passenger Pigeons to the Sky.  Scientific American, 29 August 2014.  https://www.scientificamerican.com/article/ancient-dna-could-return-passenger-pigeons-to-the-sky/

(8) Elizabeth Pennisi.   Four Billion Passenger Pigeons Vanished.  Their Large Population May Have Been What Did Them In.  Science, 16 November 2017.  http://www.sciencemag.org/news/2017/11/four-billion-passenger-pigeons-vanished-their-large-population-may-have-been-what-did

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Preserving Odd Connections

Years ago, during the Christmas season, I would often find my way to a used bookstore in Cedar Falls, Iowa.  It was a delightful jumble – all sorts of pearls scattered here and there, each embedded with a not-so-faint cigarette odor that came home with them.  It took a long time to go through the place, but I was usually rewarded with finding something I had no idea I wanted until I actually laid eyes on it.  Until recently I did not comprehend the full value of the service this little used bookstore had provided me.            

A story in The New York Times today noted the passing of Book World, the 4th largest U.S. bookstore chain with over 40 stores (1).  These are hard times for retail in general and book sellers in particular.  The depressing truth be told, these losses confirm it is tough to compete with the internet merchandizers these days.

This story reminded me of an article I first noticed on Twitter a few days earlier about the joys and difficulties of finding books that fall outside personal experience (2).  True enough, the software enabling us to browse Amazon or other internet sites is helpful, but these wonderful tools may also be inadvertently constricting.  It can be tough to discover something really novel when you have no idea of what items to search or rely on suggestions based on items purchased by others who bought the same book.  Maybe the current software workaround for persons determined to expand their horizons is to enter in some random words and just see what pops up.        

Although some programs are better than others (2), suffocation by search algorithm is one facet of emerging changes that collectively diminish the chances we will stumble on unanticipated gems while shopping.  Making the effort to get to local retail outlets is not always the final solution because stores must organize their stocks in some manner and, as noted by Ms. Schwab, “… the more we categorize, the less we are likely to discover.”  However, pacing a real bookstore does at least give more opportunity for fully serendipitous discoveries.  Mulling over this situation it finally dawned on me how that dusty, smoke-laden and rather wonderfully disorganized used book store was actually a well disguised treasure filled with unique opportunities for discovery.

Will finding mind-bending reading become tougher in the future as bookstores vanish?  Maybe Amazon will find a way to devote a corner of their new bricks-and-mortar stores to used books.  If we are really lucky they will allow them to be kept in an untidy fashion unsupervised with powerful computer algorithms or curated by neatness-obsessed managers.  Nature preserves for untrammeled explorers trapped in a homogenized world, the magic of odd connections might still occur in such places.

 

Books

 

(1) David Streitfeld.   Bookstore Chains, Long in Decline, Are Undergoing a Final Shakeout.  The New York Times, 28 December 2017.  nyti.ms/2lePwhN

(2) Victoria Schwab.    Just Trust Me:  In Praise of Strange Books.  NPR, 23 December 2017.  twitter.com/npr/status/945…

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Will Silence Rule the Nights?

Rachel Carson opens her book, Silent Spring, with a haunting fictional fable in which people awakened too late to an ecological disaster of their own making.  Seeing themselves in this vivid story readers knew instinctively a world so poisoned the songbirds fell quiet and died could not be safe for them or their children.  Silent Spring shocked the public and spurred corrective actions to prevent that terrible vision from ever coming true.

Silent1

What Isn’t on the Windshields

Noting that vehicle windshields stayed much cleaner than they used to may have revealed some insect populations have undergone startling declines (1).  Systematic trapping studies confirm that the deductions based on clean windshields were correct; many sites harbor significantly fewer bugs than they did thirty years ago.  Alarms have been sounded about honeybee deaths and Monarch butterfly declines, but the most recent observations suggest that general losses of insect abundance could be widespread.  Habitat destruction, invasive species, climate change (2) and agricultural practices, alone or in combination, may be driving the declines.  Because insects represent around 70% of all known species (2) and are major components of food webs, large scale losses will produce cascades of significant ecological consequences. 

Large-scale Declines

The world is in the midst of the 6th mass extinction (2).  Catastrophic regional losses of tree species such as the American Elm and global declines affecting an entire class of living organisms, the amphibians, have been documented.  However, while we recognize the passing of a handful of charismatic species, more obscure living organisms may die off without attracting any notice.  A recent story about disappearing sword ferns highlights the challenges in simply recognizing the occurrence and full extent of slowly evolving environmental transformations (3).

No One Gets Out of Here Alive?             

The preface to Silent Spring features a statement by E. B. White noting the inclination of humans to dominate Nature.  We certainly are clever and have had tremendous accomplishments, but are we too ingenious for our own good?  Perhaps vanishing species are the silent signs of emerging ecological trouble.  Could the increased use of chemicals like glyphosate be changing the microbial balance and fertility of soils?  Is it possible that being awash in a complex brews of herbicides, pesticides and an army of chemicals has decimated our own health-giving normal microbial flora and upset our physiology?  It is unlikely human beings will continue to thrive if the functionality of our living world is poisoned to the point of ecosystem malfunction.  If we are unwise the Singularity envisioned by futurists may not be a renaissance, but a harsh awakening to a silent Spring. 

Awake well before dawn a few days ago I heard particularly enthusiastic choruses of hooting by great horned owls and howling by coyotes.  It is comforting to think my small part of the world is still a safe haven for top predators, but will the collective impacts of development, climate change and invasive species finally throttle these voices?  Will we sense what is happening before silence rules the nights?   

Silent2

 

 

To Ed Fortner – teacher, bio-acoustics researcher and mentor

 

(1) Gretchen Vogel.  2017.  Where Have All the Insects Gone?  Science, 10 May 2017.  http://www.sciencemag.org/news/2017/05/where-have-all-insects-gone

(2) Jacob Mikanowski.  2017.  ‘A Different Dimension of Loss’: Inside the Great Insect Die-off.  The Guardian, 14 December 2017.  https://www.theguardian.com/environment/2017/dec/14/a-different-dimension-of-loss-great-insect-die-off-sixth-extinction

(3) Sarah Deweerdt.  2017.  The Mystery of the Missing Ferns. Sierra, 17 August 2017.    https://www.sierraclub.org/sierra/mystery-missing-ferns?utm_source=twitter&utm_campaign=sierramag&utm_medium=national_social

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JASONs’ Nightmare – DARPA Prepares to Ride the Tiger

CRISPR – clustered regularly interspaced short palindromic repeats are the unusual DNA sequence patterns discovered in bacteria which were later recognized to serve as part of a highly specific search-and-destroy system targeting viruses.  Scientists have adapted the CRISPR system to enable them to edit the DNA of living organisms with great precision.

Gene drives – a CRISPR-based genome editing technology which may enable the genetic alteration of entire species.  Once released into the environment gene drives will spread autonomously through populations like an infection.

Extinction drives – gene drives designed to prevent the reproduction of a target species.  In theory, the unrestricted spread of such constructs would cause the ultimate extinction of the target species.

The JASONs – a longstanding U. S. government advisory group providing analyses on a range of emerging scientific/technical issues having implications for national security.

 

The Defense Advanced Research Projects Agency (DARPA) is supporting a range of research on gene editing and other biotechnologies (1).  The agency’s significant involvement in gene drive development was highlighted recently by the release of communications obtained through a Freedom of Information Act (FOIA) request (2, 3).  The information may have shocked some, but DARPA has already been acknowledged publicly as the most significant funding source for gene drive research and development (4).  The reason is simple – gene drives have clear and direct national security implications.  

Gene Drives Are Promising and Controversial

Some gene drives have been tested in the laboratory (5) and efforts are underway to obtain approvals to field test one designed to combat human malaria.  This particular gene drive, if it works as planned, will decrease disease transmission by inhibiting the reproduction of mosquito vectors.  In principle, once released the continued autonomous spread of an extinction drive like this could eliminate the entire target mosquito species.  Although sometimes touted as a sure solution to tough human health problems like malaria, how gene drives will perform in complex natural ecosystems and their impacts against disease are unknown.   

The idea of controlling malaria by wiping out a mosquito species sounds good, but the ultimate ecological consequences of an extinction drive are also unknown.  For example, could exterminating mosquitoes have adverse impacts on food webs?  If an extinction drive seems to be creating havoc, is there any way to stop it after release?  Dr. Kevin Esvelt, a pioneering gene drive inventor, has become concerned some plans to eradicate invasive species using extinction drives might backfire (6).  The open questions and worries about potential irreversible impacts have prompted calls to limit gene drive research and testing (7).  Whether the scientific community and private investors in gene drive technology development will embrace the proposed restraints remains to be seen (8). 

CRISPR-based technologies have evolved so quickly that even the scientific community has been compelled to react to unfolding events (9, 10).  That the new capabilities have outrun experience, norms and guidelines is revealed by the repeated calls for suspension of activities (6, 9) issued by the scientists themselves.  This discomfort among the experts is a clear red flag.

Containment Concerns

A big concern with gene drive research is containment since escapes from the laboratory might have potentially disastrous consequences.  DARPA insists investigators working under its patronage follow strict safety rules (4), but not everyone is funded, i.e., controlled, by this agency.  Will effective containment measures be adopted and employed faithfully by all workers?  Potentially dangerous pathogens, agents posing well-known risks and with well-developed procedures to contain them safely, have escaped and spread across the world (11).  Deficiencies in laboratory operating procedures continue to come to light (12), suggesting we cannot assume all is necessarily secure with gene drive work.               

The Biotechnology Tsunami

DARPA is trying to keep pace with fast advances across the extremely diverse field known loosely as biotechnology.  New information combined with improvements in technology have improved the diagnosis and treatment of certain cancers.  However, the ability to synthesize long strands of DNA routinely might also make it possible an extinct scourge like smallpox virus could be resurrected.  Such situations where developments have obvious benefit combined with a potential for harm occur commonly enough to have been given a special designation – dual use research of concern (DURC).  Because the problems have been recognized and steps can be taken to minimize them, DURC situations in one sense are simpler than what may be coming.

Tidal wave

The JASONs’ Nightmare Calculation – Proliferation Probability = 1

Concerns over nuclear weapons led to efforts to limit their spread through a formal non-proliferation treaty.  The nations seeking to control such weapons had something important going for them; building the devices were challenging and expensive enterprises largely limited to nation-states.  The non-proliferation treaty has achieved some degree of success for 50 years, perhaps it will successfully weather the currently difficult situations.

There will be no non-proliferation treaty that contains the spread of all potentially dangerous biotechnology applications.  The entry barriers are nowhere near as daunting or expensive as those impeding nuclear weapons ambitions and the specialized knowledge necessary to proceed is widely distributed.  This combined with prior history suggests along with nation-states, small groups like Aum Shinrikyo or perhaps single persons could be significant future actors.  To get a sense of how fast things have evolved, Google ‘CRISPR home kit.’  Although these educational kits have little or no potential for dangerous misuse, it is interesting to consider that 5 years or so ago only researchers at the cutting edge were using CRISPR.  In biotechnology the transition from far-out idea to routine practice is swift and empowering.

Hydra 

The democratization of biotechnology is beneficial because it enables more creative persons to participate in scientific research and discovery.  A diversity of approaches may yield a novel insight that produces a torrent of new advances.  However, varied applications and approaches may also yield unexpected issues.  Have a look at this article (10) in which a leading CRISPR genetic editing technology developer describes a sudden, frightening revelation about an experiment utilizing this powerful tool.  Proliferation happened a long time ago and even the experts will have difficulty anticipating what might come next. 

Avoiding grassroots jungle

Imagine the dilemma facing those tasked with identifying and mitigating threats to national security emerging from biotechnology research.  Barriers to participation are falling steadily while technical capabilities expand and build exponentially.  Under these circumstances it has become critical for DARPA to investigate the full range of developments like gene drives and proactively develop tools to control them, if possible.  Maybe this situation will turn out to be the biotechnology analogue of computer viruses and immunizing software.  Perhaps the prospect that the biotech equivalent of hacking tools will soon appear keeps the JASONs awake at night.  DARPA is preparing to ride the biotechnology tiger.  Which one?

Which Tiger                

  (1) Defense Advanced Research Projects Agency.   Building the Safe Genes Toolkit.  https://www.darpa.mil/news-events/2017-07-19

(2) Kristen V. Brown.   Why DARPA is Investing Big in Gene Drives.  Gizmodo, 5 December 2017.  https://gizmodo.com/why-darpa-is-investing-big-in-gene-drives-1821028638

(3) Friends of the Earth, 6 December 2017. https://foe.org/news/military-revealed-top-funder-gene-drives-gates-foundation-paid-1-6-million-influence-un-gene-drives/

(4) Ewen Callaway.   U.S. Defence Agencies Grapple With Gene Drives.  Nature, 21 July 2017. https://www.nature.com/news/us-defence-agencies-grapple-with-gene-drives-1.22345

(5) Michael Reilly.   In Africa, Scientists are Preparing to Use Gene Drives to End Malaria.  MIT Technology Review, 14 March 2017.   https://www.technologyreview.com/s/603858/in-africa-scientists-are-preparing-to-use-gene-drives-to-end-malaria/

(6) Carl Zimmer. ‘Gene Drives’ Are Too Risky for Field Trials, Scientists Say.  The New York Times, 16 November 2017.  nyti.ms/2jvLMKN

(7) The Editorial Board.   Gene-Drive Technology Needs Thorough Scrutiny.  Nature, 5 December 2017.  https://www.nature.com/articles/d41586-017-08214-4

(8) Ewen Callaway.   ‘Gene Drive’ Moratorium Shot Down at U.N. Biodiversity Meeting.  Nature, 21 December 2017.  https://www.nature.com/news/gene-drive-moratorium-shot-down-at-un-biodiversity-meeting-1.21216

(9) David Baltimore et al.   A Prudent Path Forward for Genomic Engineering and Germline Gene Modification.  Science, 19 March 2015. http://science.sciencemag.org/content/early/2015/03/18/science.aab1028.full

(10) Heidi Ledford.   CRISPR, the Disruptor.  Nature, 3 June 2015.  http://www.nature.com/news/crispr-the-disruptor-1.17673

(11) Michelle Rozo and Gigi Kwik Gronvall. The Reemergent 1977 H1N1 Strain and the Gain-of-Function Debate.  mBio, 18 August 2015. http://mbio.asm.org/content/6/4/e01013-15.full

(12) Julie Steenhuysen. Exclusive: U.S. Needs to Improve Oversight of Labs Handling Dangerous Pathogens.  Reuters, 30 October 2017. www.reuters.com/article/us-usa-laboratories/exclusive-u-s-needs-to-improve-oversight-of-labs-handling-dangerous-pathogens-report-idUSKBN1D00CM

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Thinking About the Brainternet

 

Articles pondering connecting humans to the internet have been popping up frequently (1-5).  Is the next phase of our evolution “ultra high bandwidth brain-machine interfaces to connect humans and computers” (1)?  A company known as Neuralink, owned by Elon Musk, is working toward creating what they term the whole brain interface (1). 

What Might Happen?

Evocative terms like “neural lace” (4) and the “Brainternet” (5) are being coined to describe future technologies intended to enhance human brain power through direct computer connections.  The possibility the collective knowledge of the Web could be a virtual part of our brains (3) has led some to label the new powers to be conferred as ‘God-like’ (2).  How far Neuralink will be able to conjoin brains and computers remains to be seen, but as Christopher Markou points out (1) it is important “that we ask good questions early and often.  If we don’t, they’ll be answered for us.”  Dr. Markou examines the Neuralink concept and its many profound implications skeptically (1).  He reminds us that security, privacy and the prospect other concerns may arise such as intrusive public mandates need to be examined proactively. 

Brainternet

 

All Brainternet-izens Will Not Be Equivalent 

Dr. Daniel Willingham suggests that while most Americans can read, some struggle to comprehend written content because they lack sufficient background factual knowledge (6).  Is it possible that simply having access to ‘all knowledge’ will make us omniscient geniuses?  Just as reading words is different than comprehension, a broad education and solid critical thinking skills may be a huge advantage.  Smartphones have not turned everyone into an Einstein and some of us will probably be a lot better at profiting from the integrated mind than others.          

Could We End Up Enslaved by Another Invisible Algorithm?

In one sense the idea of having all the knowledge of the world available for us is a no-brainer.  But, what exactly will that mean in practice?  Probably many or most of us feel they know it [knowledge, factual information] when they see it, but how will the Brainternet enable us to parse a massive cacophony of competing, sometimes contradictory, content in ways that will make us smarter?  It’s wonderful to imagine we could all have the complete thoughts of Aristotle at our instant beck and call.  But how will the products of great minds be balanced against the outbursts of an Alex Jones?  Will information be rated by number of links?  What happens when scientific knowledge is politicized (7)?  Or will new algorithms serving commercial interests track the information each subscribing brain seems to prefer, fake news or not, and serve up more of the same?  Self-education through the ‘University of Google’ certainly has its merits, but there are also known pitfalls which means creating super brains demands a great deal more than implants hooking us up to the internet.  Somebody we can trust has got to organize and run this show.                

Complexities of Ever-changing Information

The problem with science is that although many of the questions remain the same, our answers may evolve with time.  A quote of uncertain origin that is often attributed to Mark Twain seems appropriate –  

It ain’t so much the things we don’t know that get us into trouble, it’s the things we do know that just ain’t so.” 

Scientific research by its nature is not always definitive because answers are provisional and subject to challenge.  This self-correcting aspect may produce errors and interesting quandaries; how fast should one accept the latest scientific advance as definitive enough to take action based on it?   Let’s say you accessed the Brainternet on Monday and got the latest information on a potentially promising, although controversial, treatment for multiple sclerosis (MS).  But, if you come back on Tuesday with the same query, a newly posted article by Helen Branswell and its links might lead you to a totally different conclusion (8).  On Monday, you may have felt a certain therapy had enough merit to try it.  But, if you had just waited until Tuesday, assuming the article was indexed in the databases your super brain scans, maybe you would have been more hesitant.  Or maybe you would have labeled the new information fake news and charged ahead anyway.  If future information assessment techniques are scrupulously fair and balanced, perhaps many of us will end up literally paralyzed by information overload, unable to decide what to do, waiting for the latest news and certainty that never comes.  Then again maybe we and all our social media friends will die after chugging down a miracle immortality elixir that turns out to be a toxic hoax.      

The Brainternet will only be as strong as its weakest link, your brain. 

Alien hand tool   

 

(1) Christopher Markou.   Neuralink Wants to Wire Your Brain to the Internet – What Could Possibly Go Wrong?  The Conversation, 2 May 2017.  https://theconversation.com/neuralink-wants-to-wire-your-brain-to-the-internet-what-could-possibly-go-wrong-76180

(2) Richard Gray.   Dawn of Human 2.0?  Nanobot Implants Could Soon Connect Our Brains to the Internet and Give US ‘God-like’ Superintelligence, Scientist Claims.  Daily Mail, 2 October 2015.    http://www.dailymail.co.uk/sciencetech/article-3257517/Human-2-0-Nanobot-implants-soon-connect-brains-internet-make-super-intelligent-scientist-claims.html

(3) Maria Konnikova.   Hacking the Brain.  How We Might Make Ourselves Smarter in the Future.  The Atlantic, June 2015.  https://www.theatlantic.com/magazine/archive/2015/06/brain-hacking/392084/

(4) April Glaser.   Elon Musk Wants to Connect Computers to Your Brain So We Can Keep Up with Robots.  Recode, 27 March 2017.  https://www.recode.net/2017/3/27/15079226/elon-musk-computers-technology-brain-ai-artificial-intelligence-neural-lace

(5) David DiSalva.   Are You Ready to Have Your Brain Connected to the Internet?  Forbes, 24 September 2017.  https://www.forbes.com/sites/daviddisalvo/2017/09/24/are-you-ready-to-have-your-brain-connected-to-the-internet/#61d6815e370a

(6) Daniel T. Willingham.   How to Get Your Mind to Read.  The New York Times, 25 November 2017.  https://nyti.ms/2i6t4cm

(7) Jeff Tollefson and Amy Maxmen.   US Energy Agency Asked Scientists to Scrub References to Climate Change.  Nature, 25 August 2017.  https://www.nature.com/news/us-energy-agency-asked-scientists-to-scrub-references-to-climate-change-1.22513

(8) Helen Branswell.   Scientist Concedes His Controversial MS Therapy, Once a Source of Great Hope, is ‘Largely Ineffective.’  STAT, 28 November 2017. https://www.statnews.com/2017/11/28/multiple-sclerosis-paolo-zamboni/

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CRISPR Genetic Editing – Who’s Driving the Bus?

CRISPR gene manipulation technologies seem almost certain to offer both enormous benefits and some substantial risks.  Scientists, including some of the key developers of CRISPR tools, have worked diligently to educate both their colleagues and the public about the staggering opportunities and complex issues the new capabilities will create (1).  Guidelines and recommendations for the use of CRISPR technology in research have been produced, but fast moving developments worldwide in academic and corporate research laboratories are challenging the traditional ways of governance.  Responding to emerging advances, an eminent group of scientific community opinion leaders suggested researchers avoid CRISPR editing of the human germline (1).  While noting that human germline genetic manipulations may be permissible in the future, the National Academy of Science and National Academy of Medicine recommendations affirmed this conservative stance (2).

What Do Human Germline Editing and Gene Drive Eradication Conservation Have in Common?

An already tricky discussion has become more complicated (3, 4, 5).  Dr. George Church is arguing that U. S. constraints on human germline editing research will have damaging consequences (3).  At the same time Dr. Kevin Esvelt, the leading developer of gene drives, a CRISPR-based technology that may enable autonomous genetic re-configuration of entire species, expressed concerns using the types currently in hand to eradicate invasive species might be destructive (4, 5).  Human germline editing measures and gene drives serve vastly different purposes, but the unfolding discussions (1, 3, 4) illustrate opinions as to how best to use them and current comprehension regarding the ultimate implications of their use are fluid and contentious.

Modifying the human germline and unleashing gene drives pose difficult ethical dilemmas because the decisions will have far-reaching ramifications, potentially involving generations yet to come.  Eliminating a dread genetic disease might be good, but what if editing produces currently unforeseeable trade-offs such as increased sensitivity to an infectious disease?   The possibility gene drives might spread out of control has implications for other efforts such as eliminating malaria.  Freed gene drives are unlikely to respect international borders which will make regional discussions and negotiations essential.  A gene drive to reduce malaria vector mosquito populations seems ready, but getting public acceptance for release may be complicated (6).  Some of the projected study areas are widely separated geographically – will neighboring countries agree or resist gene drive release?  Perhaps people will prefer to see how impending malaria vaccine trials (7) fare or employ available alternative disease control measures before trying gene drives.  How will the wishes of the public be assessed? 

Where Do We Stand?

Scientists have called for public discussions regarding the use and implications of CRISPR (1).  Many of those involved directly in creating CRISPR gene manipulation technologies have been extraordinarily proactive in their outreach to inform citizens of the tremendous potentials and vexing problems ahead.  Now comes the hard part.  Scientists have a tenuous research strategy, but sharply differing opinions as to how and how fast to go forward now being expressed.  Plus some of their ideas are changing substantially as new facts are revealed.  Add to the mix the fact that private corporations are rushing to exploit all aspects of CRISPR technology and we seem headed inexorably toward a great deal of confusion. 

Strange

Shifting Situations

Scientific and biomedical breakthroughs have sometimes shocked us, but the calls for discussions by researchers were probably more obligatory platitudes than a real desire to communicate.  Often concerns could be soothed by noting that any real problems still lay far ahead in the future.  With CRISPR and gene drives much of the future has already arrived – these tools exist today and some are anxious to use them.  Are most scientists prepared to respect an extended moratorium on human germline editing or not?  If a group has gone to the effort and expense to create an anti-malaria gene drive, will they remain silent if theoretical concerns stemming from computer modelling threaten to thwart their hard work?  Could they declare conclusions they dislike to be erroneous (scientific ‘fake news’) and ignore them?  How inclusive will corporate funders be when it comes to obtaining region-wide public approval for projects that could have permanent region-wide ecological impacts?  Who ensures the research subject autonomy of an entire geographic region is respected adequately? The situation is novel, fluid and ideas held forth with confidence today may be discovered to be untenable tomorrow.  How will the public decide which risks they will accept or reject if experts contradict each other?      

Who’s Driving This Bus?

CRISPR technology emerged so quickly that even the scientific community has been forced to catch up to events.  The public has seen a range of CRISPR-inspired ideas from resurrection cloning fantasies to serious proposals for disease control and ecosystem health management.  However, the scientific community is diverse and viewpoints are subject to revision based on continuously incoming data.  That suggests achieving a broad public agreement as to what is and is not permissible is liable to be difficult and confusing.  Despite the urgency, some of the plans to employ CRISPR technologies would clearly have scant margin to avoid committing irreversible errors of sweeping scope.  Judicious, evidence-based decision making is not remotely the same as paralysis induced by fear of unknown risks.  If we are not able to recognize, and restrain as necessary, the forces propelling us, the road ahead could get bumpy.

Bus5

 

(1) David Baltimore et al.   A Prudent Path Forward for Genomic Engineering and Germline Gene Modification.  Science, 19 March 2015. http://science.sciencemag.org/content/early/2015/03/18/science.aab1028.full

(2) http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=24623

(3) George Church.   Compelling Reasons for Repairing the Human Germline.  The New England Journal of Medicine, 16 November 2017, 377:1909-1911.  nejm.org/doi/full/10.10…

(4) Carl Zimmer. ‘Gene Drives’ Are Too Risky for Field Trials, Scientists Say.  The New York Times, 16 November 2017.  nyti.ms/2jvLMKN

(5) Kevin Esvelt and Neil J. Gemmell.   Conservation Demands Safe Gene Drive.  PLoS Biology, 16 November 2017.   http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.2003850

(6) Michael Reilly.   In Africa, Scientists are Preparing to Use Gene Drives to End Malaria.  MIT Technology Review, 14 March 2017.   https://www.technologyreview.com/s/603858/in-africa-scientists-are-preparing-to-use-gene-drives-to-end-malaria/

(7) Jen Christensen.   First Malaria Vaccine to be Widely Tested in Africa Next Year.  CNN, 24 April 2017.  http://www.cnn.com/2017/04/24/health/malaria-vaccine-trial-who/index.html

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