Potentially Pandemic Pathogen Research – Too Much Information?

The resumption of experiments to enhance the transmission capabilities of H5N1 bird flu (influenza) viruses has renewed controversy within the scientific community over this research area (1).  Critics have called into question both the fundamental scientific merits of the work as well as raising concerns the artificially augmented viruses might escape the laboratory and create a pandemic.  Explaining it contains “proprietary and grant competition information” (1) a risk-benefit review of the situation conducted by the government will not be made public, irritating some of those questioning the value and advisability of this research.  Notwithstanding concerns about divulging confidential information and given that some methods and results have already been published in the open literature, it is hard to believe a suitably redacted account of the testimony, evidence and discussions leading to the final go-ahead decision cannot be assembled.  This leaves the public with no visibility into an important decision-making process allegedly made in the greater public interest.            

Chance and Necessity

It is sometimes necessary to work with exceptionally dangerous pathogenic agents.  Well-trained personnel in appropriately constructed facilities adhering to carefully designed operational protocols can perform such efforts with a high degree of safety.  However, when it comes to conducting experiments designed to increase the transmission risk of a potentially pandemic pathogen (PPP) like avian influenza H5N1 where the consequences of error could be catastrophic, will high-containment facilities operated under the most stringent rules ensure safe containment? 

Shortly after a research moratorium had been lifted (1), heightened concerns following publicized accidents at high bio-containment labs forced another general suspension of gain-of-function experiments with avian influenza and other dangerous viruses.  Pathogen escapes from laboratory control that produced disease outbreaks are documented in the public record (2) and safety lapses at high-containment facilities continue to be reported (3).  Attempts have been made to quantify the public health risk posed by research with PPPs such as H5N1 bird flu viruses (4).  Noting the expanding number of laboratories now attempting to create airborne route-transmissible highly pathogenic avian influenza viruses, one author concludes the current risk of an accidental pandemic is now about equally likely as a natural event (4).  It is impossible to gauge whether a human pandemic caused by an escaped engineered bird flu virus would produce an elevated death rate (4), but the realization such a tragic event could be so likely to occur is shocking.                 

Half a Job?

Making certain all laboratories performing PPP research have adequate resources, proactive plans in place to mitigate mishaps and well-trained staff are essential, but may be addressing only the most tractable part of a far larger, more problematic and steadily expanding biosecurity problem.  In addition to rigorous oversight of trained professional scientists and their facilities, it is essential to account for the possibility a PPP such as H5N1 bird flu artificially selected to be airborne transmissible between humans may be deliberately released (5).  Unfortunately, the diverse roster of actors who conceivably might hatch such plots ranges from a single, demented person to entire nation-states.  Along with the limited factual information available on such actors, risk estimates of the threats posed by nefarious actions more precise than assertions ‘it could happen’ are guesswork (5). 

The authorities are divided over the interpretations of objective evidence for prior deliberate releases of pathogenic agents.  There is no question that the Amerithrax event of 2001 was an attack with a biological agent, but even with an intense forensic effort and solid corroborating physical evidence, figuring out who launched it was mired in egregious error and controversy (6). 

Based on genetic sequence analyses, a consensus has been reached the 1977 Russian influenza pandemic was not a natural event (7).  This strange situation has figured prominently in the debate over whether or not to permit experiments to create H5N1 bird flu viruses that might be capable of efficient airborne transmission between humans.  Noting that the 1977 H1N1 influenza pandemic was more likely to have come about due to vaccine development or vaccine trials than a laboratory error, some scientists argue this possibility should temper concerns over accidental release of augmented influenza viruses from a secure research facility (7).  As no objective evidence exists either way, how reassuring that line of reasoning is depends on what one wishes to believe constitutes the true account of events explaining the sudden 1977 Russian flu virus emergence.  However, the vaccine hypothesis leaves a few more open questions to explore.

Why That Vaccine?

Influenza vaccine production and testing procedures do seem intrinsically more likely to cause an accidental release of virus than research lab work.  However, it is important to keep in mind a vaccine production mishap scenario still fits well with the deliberate use concerns posed by Inglesby and Relman (5).  The release during production/testing operations hypothesis leads to questions about exactly who, and for what purpose, was going to the trouble and expense to manufacture vaccine for a flu virus that had not circulated for over 20 years and therefore had no conceivable clinical utility.  Whatever their true purpose and origins, the events of 1977-78 demonstrate it is possible to launch an influenza pandemic that would be highly effective against a select immunologically naïve population such as persons of prime military service age. 

Too Much Information

Inglesby and Relman (5) point out that technology widely available today makes publishing complete genetic sequences of agents like lab-created influenza almost equivalent to distributing the virus itself.  Researchers would not provide such potentially dangerous viruses to persons without an appropriate need to acquire them and a demonstrated capacity to work with them safely.  Unfortunately, refusing sample requests may no longer present an insurmountable barrier for persons denied access by professional scientists.   Some experiments creating H5N1 influenza viruses with possible person-to-person airborne transmission capability have been published in full (4).  That means persons who would like to have such a virus and finding themselves stymied by professional scientists could make use of the published genetic sequence blueprints to build their own. 

Smallpox is extinct and the virus responsible for the original SARS outbreak seems to be as well.  However, PPP viruses like influenza H5N1 are still in circulation in some parts of the world which elevates the potential threat for possible illegitimate acquisition and malevolent use.  Persons without a technical capacity to synthesize a virus genome in vitro might be able to acquire samples and emulate published methods to gin up viruses that have potential for airborne spread between humans or create other types of mayhem.  Knowing with certainty that others before them have succeeded could be a vital bit of information – and motivation – to press forward with their own plans.     

            

Decisions regarding the information about influenza research appropriate for release have led us to astonishing contradictions and an alarming predicament.  When it comes to the possible risks posed by PPP research, the authorities have dutifully restricted information that would enable the public to make informed decisions about the research priorities of professional scientists.  At the same time, they have allowed the essential knowledge required to create and re-create potentially deadly pandemic forms of influenza viruses to be actively disseminated to the entire world through open publication in the scientific literature. There is no telling who might end up making use of that information.     

 

(1) Jocelyn Kaiser.   EXCLUSIVE: Controversial Experiments That Could Make Bird Flu More Risky Poised to Resume.  Science, 8 February 2019.  https://www.sciencemag.org/news/2019/02/exclusive-controversial-experiments-make-bird-flu-more-risky-poised-resume

(2) Martin Furmanski.   Laboratory Escapes and Self-Fulfilling Prophecy Epidemics.  Center for Arms Control and Nonproliferation.  https://armscontrolcenter.org/wp-content/uploads/2016/02/Escaped-Viruses-final-2-17-14-copy.pdf

(3) Denise Grady.   Deadly Germ Research is Shut Down at Army Lab Over Safety Concerns.  The New York Times, 5 August 2019.  https://www.nytimes.com/2019/08/05/health/germs-fort-detrick-biohazard.html

(4) Lynn C. Klotz.   Is There a Role for the Biological Weapons Convention in Oversight of Lab-Created Potential Pandemic Pathogens?  Bulletin of the Atomic Scientists, 27 August 2019.  bit.ly/327nis6

(5) Thomas V. Inglesby and David A. Relman.   How Likely is it that Biological Agents Will Be Used Deliberately to Cause Widespread Harm?  EMBO Reports 17(2):127-130.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5290809/

(6) Scott Shane.   F.B.I., Laying Out Evidence, Closes Anthrax Case.  The New York Times, 19 February 2010.  https://www.nytimes.com/2010/02/20/us/20anthrax.html

(7) Michelle Rozo and Gigi K. Gronvall.   The Reemergent 1977 H1N1 Strain and the Gain-of-Function Debate.  mBio 6(4): e01013-15.    https://mbio.asm.org/content/mbio/6/4/e01013-15.full.pdf

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Will A New Law Prevent CRISPR Mishaps? Gut Check

The great state of California has enacted a consumer protection law requiring DIY CRISPR kits to have labels declaring they are not intended for self-administration (1, 2).  Although the U.S. Food and Drug Administration (FDA) oversees gene therapy products and has flatly stated selling “do it yourself” kits is illegal (3), the California law is the first which addresses CRISPR technology directly according to bill author Senator Ling Ling Chang (4).

Concerns About Safety

Publicity stunts have raised the DIY biohacking community profile and increased worries about the safety of persons trying to modify their own DNA (5).  The notion that the proliferation of increasingly easier-to-use DNA alteration technologies outside the controlled domain of professional laboratories might result in catastrophe has troubled the scientific community (6).  A world renowned researcher in the area apparently taking note of at least one instance of biohacker theatrics was disturbed enough by the implications to call for surveillance and licensing (6).

California Dreaming

The new law (2) is a brief and interesting read.  Citing the anticipated enormous health and economic benefits of CRISPR technologies, supportive of the educational utility of CRISPR kits, the Legislature seeks to “ensure the safety of the consumer and the public without stifling innovation.”  Part of the biohacking dream is that the diversity of new minds working on problems in unconventional ways might yield important insights or an amazing product (4). 

Reacting to real world developments, the California legislature is ahead of the curve; no one currently manufactures the sort of gene therapy kits the new law is requiring to carry warning notices (4).  However, few things advance faster than biotechnology and that, as well as the consequential challenges they bring, may change everything tomorrow.  Perhaps we are already well on the way to the next issue.                         

A Little Mouse Told Me

Aware of the potential risks of self-experimentation, one kit manufacturer is encouraging his customers to experiment with CRISPR using animals such as frogs (6).  Clearly safer than personal experiments, what could possibly go wrong?  With the currently available kits probably not much, although concerns have been raised about pathogenic potential of bacteria used in one of them (7). 

The microbiome – the living, active microbial communities residing in and on animals – is recognized to play critical roles in our health and physiological functions.  We have also long understood these systems are dynamic and sensitive to external forces.  For example, disturbing the normal gut microbial flora composition by antibiotic treatments may lead to the emergence of a serious, sometimes fatal, disease such as pseudomembranous colitis.  Imagine a budding entrepreneur following some exciting reports of microbiome experiments conducted in mice who gets interested in exploring the role of the gut bacterial flora on weight gain.  All things being equal, could the presence of one key species of bacterium help keep a mouse strain at normal body mass, while another is associated with development of obesity?  One means to test the idea would be to selectively eliminate microbe species and see what happens.  CRISPR technology makes such precision elimination experiments feasible (8-10).

Making the generous assumption the investigations reveal eliminating one species of bacterium keeps mice lean, it might be tempting to think about extrapolating this knowledge to the human condition.  Maybe a simple gut hack achieved by slugging down some broad spectrum antibiotics (11) followed by reconstitution with a starter culture from a lean friend would succeed.  However, unleashing a CRISPR system programmed to attack only the species convicted by well-controlled experiment of weight gain promotion without otherwise disturbing gut flora function would be a true breakthrough method.  Unlike prior publicity stunts in which self-injected CRISPR gene editing molecules had no chance of yielding a meaningful impact (4), with the right approach a bacterium-targeted CRISPR system might perturb the gut composition of the target.  Hopefully, before trying it out in people, the audacious investigator will have thought long and hard about how to assess the success or failure of their protocols as well as what to do if something goes wrong. 

 

 

Sneaky Exchanges

In a perfect world, all persons involved in testing these selective gut flora elimination strategies will be volunteers.  We live in a complex world.  Many gut bacteria are well adapted for efficient person-to-person transmission.  We exchange bacteria as a consequence of the normal activities of daily living, sometimes becoming aware of the process when we pick up pathogens like those causing traveler’s diarrhea.  It is conceivable that amateur scientists working with bacteria at home, but perhaps a little vague on essential laboratory practices such as aseptic technique, inactivation/disposal methods and proper storage procedures might unwittingly transmit engineered bugs to themselves, their families, friends and communities.  An unfortunate sequence of events might lead to everyone nearby being in on the experiments, like it or not.

To manage (hypothetical) risks of amateur experimentation with bacteria, legislative authorities may need to broaden their purview beyond simply discouraging self-experimentation.  Perhaps CRISPR kit producers will be mandated to use debilitated bacterial strains unable (or unlikely) to persist in the normal human gut.  Cautioning persons with immune system disorders, undergoing steroid or other immune system suppression therapies about the use of the kits might be in order.               

Legislate or Live With It?

At the moment no home kits to use CRISPR to selectively eliminate gut flora bacteria are being sold and perhaps they never will be.  Maybe an ambitious biohacker will study the field, adapt the available tools and devise one of their own.  Drawing inspiration from a number of sources perhaps this person will insert both CRISPR target recognition and cleavage genes into a transfer-competent, broad-host-range plasmid to yield a bacterial analog of autonomous, self-propagating gene drives (12).  Should such constructs escape control, how widely might they wander the microbial world?

CRISPR genetic editing technology and the equally powerful self-governing invention based on it, gene drives, present us with fantastic opportunities and possible dangers.  Everyone who works with or builds on these new innovations will have to be careful because once released, through design or accident, some of these genetic tools may be impossible to eradicate.  Like it or not, all of us may end up having to live with their benefits and environmental legacies.     

Will enacting laws protect us from CRISPR experiments gone awry?  Biohackers are one area of concern, but legislators are well advised to keep a wary eye on the professionals as well.  The increasingly complicated situations to come will test both the resolve and imagination of our leaders.  

(1) Senator Ling Ling Chang.   Governor Signs Senator Chang’s Bill to Address Human Biohacking.  https://chang.cssrc.us/content/governor-signs-senator-chang-s-bill-address-human-biohacking

(2) California Legislative Information. Senate Bill 180.  July 30, 2019.  https://leginfo.legislature.ca.gov/faces/billNavClient.xhtml?bill_id=201920200SB180

(3) U. S. Food and Drug Administration. Information About Self-Administration of Gene Therapy.  https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/information-about-self-administration-gene-therapy

(4) Antonio Regalado.   Don’t Change Your DNA at Home, Says America’s First CRISPR Law.  MIT Technology Review, 9 August 2019.  bit.ly/2KBmtAH

(5) Sarah Zhang.   A Biohacker Regrets Publicly Injecting Himself with CRISPR.  The Atlantic, 20 February 2018. https://www.theatlantic.com/science/archive/2018/02/biohacking-stunts-crispr/553511/

(6) Emily Baumgaertner.   As D.I.Y. Gene Editing Gains Popularity, ‘Someone is Going to Get Hurt.’  The New York Times, 14 May 2018.  https://www.nytimes.com/2018/05/14/science/biohackers-gene-editing-virus.html

(7) Annie Sneed.   Mail-Order CRISPR Kits Allow Absolutely Anyone to Hack DNA.  Scientific American, 2 November 2017.  https://www.scientificamerican.com/article/mail-order-crispr-kits-allow-absolutely-anyone-to-hack-dna/

(8) Ahmed A. Gomaa et al.   Programmable Removal of Bacterial Strains by Use of Genome-Targeting CRISPR-Cas Systems.  MBio 2014 Jan-Feb 5(1): e00928-13.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3903277/

(9) Laurel Hamers.   Smuggling a CRISPR Gene Editor into Staph Bacteria Can Kill the Pathogen.  Science News, 1 October 2018.  https://www.sciencenews.org/article/smuggling-crispr-gene-editor-staph-bacteria-can-kill-pathogen

(10) Muhammad Abu Bakr Shabbir et al.    CRISPR-Cas System: Biological Function in Microbes and its Use to Treat Antimicrobial Resistant Pathogens.  Annals of Clinical Microbiology and Antimicrobials 18:21-30.  https://ann-clinmicrob.biomedcentral.com/articles/10.1186/s12941-019-0317-x

(11) Kate McLean and Mario Furloni.   Gut Hack.  The Atlantic, 21 February 2018. https://www.theatlantic.com/video/index/553796/gut-hack-biohacking/

(12) Gene Drives Explained: How to Solve Problems with CRISPR https://www.synthego.com/blog/gene-drive-crispr

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The Perseids Once and Again

This morning (12 August 2019) I got up before dawn to catch a bit of the annual Perseid meteor shower.  Conditions were not optimal; I live in a large city and had to wait out our interfering Moon and some clouds, but I still managed to see a few streak across the sky.  Under dark skies and optimal conditions the Perseid shower is anticipated to reliably produce around 60 meteors per hour at its peak.       

A Northern summer event familiar to sky watchers long before its nature and origin were understood, the meteors are debris from Comet Swift-Tuttle that seem to rain down on us from the constellation of Perseus.  Although Perseid meteors vary in brightness, the most dazzling ones outshine all the competing stars, are often a striking yellow in color (to my eye) and feature short duration trails.  Because they zip through the sky so quickly, the briefest glance away can mean missing one completely and to know of its passage only by the remarks of fellow observers.

 

My friend, Mark Thorson, and I became regular observers of the Perseids and other meteor showers in 1968.  This event came to mark the impending end of our summer vacations and return to school, something to look forward to and dread at the same moment.  I recall how those times were turbulent, but sky watching and waiting for meteors while debating whether the constellation Cassiopea actually traced out the letter “M” for Mark got us away from the turmoil.  A few years later, facing getting caught up in the draft, Mark enlisted in the Army.  He was able to avoid being sent to Vietnam, but in my opinion, military service contributed directly to his early death.     

The vast majority of Perseid meteors end their existence in an incandescent flash across our sky.  The shower will return next year, but for the bits of comet dust putting on the show, the performance is always a fleeting one-and-done.  That means while each Perseid meteor shower is similar to those of the past, every show is absolutely unique.  It is hard to believe that over 50 years have passed since Mark and I stood in my backyard and watched these spectacular displays put on just once in the entire history of the Universe and seen by no one but us in quite the same way.  Appreciative of the opportunity granted me, this morning I was privileged to experience the Perseid meteor shower once and again.

Rest in peace, Mark W. Thorson.

Saint Anthony Guide (S.A.G.)

My college calculus class started with something unusual.  The school was small, but I still knew only a small fraction of the students in my classes.  Our instructor, an enthusiastic young mathematics dynamo named Tom Trevathan, insisted we begin by standing up, giving our names and majors and offering a few words to explain why we signed up for this class.  Then we got straight to work on rates of change and derivatives.

Today’s Lesson – The Outlier 

The second day featured something even more out of the norm.  Another student had joined this class and our instructor, perhaps wanting to help him feel like part of the group, immediately took a few moments to introduce him, butchering the pronunciation of his last name in the process.  He was Francis Babue and his story was decidedly different from the average student.  Retired and returning to school after an absence of well over 50 years he was as old, or older, than most of our grandparents.

We were accustomed to seeing ‘older’ students in our classes because this was an era when many young men honored a military service obligation and returned to civilian life a few years later.  Located in a city, this school had a sizeable a commuter population which included quite a few veterans using their G.I. Bill education benefits.  Most returning veterans were probably 5 years or so older than the typical student like me.          

Why?

You can probably imagine how it went that semester.  I think I may have been the only student to ever speak to Francis (a.k.a., Frank).  However, if he felt out of place, his outward behavior never betrayed it.  Although at that moment in time no one would have referred to it in this way, Francis was too busy checking off items on his bucket list to worry about such matters.

The class met 4 days a week, so we had a good number of conversations as we killed time waiting in the hallways before our instructor showed up.  When I asked why he decided to take this class, Francis had two answers.  One was that he had worked for a construction company that built towers for high-tension electric power lines.  He wanted to understand the full mathematical basis underlying why these things were built the way they were and to do that he needed calculus and more.  We got into some of that basic information when the class covered the hyperbolic functions that describe how cables supported at both ends fall along a curve known as a catenary.  I have a feeling our instructor covered that specifically for Francis.

The other goal was more wide-ranging; he hoped to be able to help someone in the future.  He never said this, but I suspect Francis intended to be the person he wished had been around when he had math questions, but could find no one to answer them.  A physically demanding outdoor job, the ordinary necessities of making a living and college class schedules meant that his answers would be long delayed.  The good news was he was finally acquiring the knowledge he had long sought.

Foreseeing the Future?                               

Francis knew I would be unable to complete all the math courses I was interested in before I departed college for the military.  I suspect he knew from experience what was likely to happen to me as I ventured through the world.  He gave me a small book – one he had carried for a while and thought I might find useful – a first edition (1928) copy of Calculus for the Practical Man by Claude Irwin Palmer.  I have come to believe he gave me the book he had carried for so long to serve as a reminder I needed to stay curious about such things and to come back to them when I had the chance.  Over 40 years later I still have that book with his name and the Saint Anthony Guide (S.A.G) stamp he placed in it.   I am currently working through a linear algebra course.

 

Francis lived to the fullness of his years and I do not know how many other persons he helped, but he certainly gave me a gift that carried forward far into the future.  Maybe such actions come naturally to mathematicians and builders of power lines who know their works reach out to distant ends they cannot see, but still perceive.  Now that it is my turn, I hope I measure up to his example.  S.A.G.

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What Has The Thirty Meter Telescope Already Shown Us?

JayVay

What Has The Thirty Meter Telescope Already Shown Us?

by Guest Blogger,
Tyler Kokjohn, Ph.D.

The Thirty Meter Telescope (TMT), a 2 billion-dollar behemoth, will not see first light for years (1), but the effort to build it might have already illuminated something important.  It seems nothing for the proposal to locate the TMT on the summit of Hawaii’s Mauna Kea has come without controversy and while the state supreme court recently settled the legal issues, the situation on the mountain is now clearly deteriorating (2).

This forthcoming technological marvel will assure continued U.S. national leadership in astronomy research and be a job-creating boon for the local economy (3).  Locating this advanced concept telescope at the premier observing site of Mauna Kea will enable researchers to study fainter and more distant astronomical objects than has been possible previously (3).  However, Mauna Kea is a sacred site to…

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Could Rogue Scientists Be the Canaries in the CRISPR Coal Mine?

CRISPR genetic technology has developed at such a frenetic pace even the scientific community seems challenged to keep pace with fast-emerging accomplishments.  Aware an announcement the first human embryos had been genetically modified was imminent, a group of leading scientists published a consensus opinion as to how CRISPR research and development might reasonably proceed (1).  If these distinguished scientists were worried the time to get ahead of events was short, subsequent developments proved that concern was justified.  A few weeks after their call to action the initial report of human embryo genetic editing using CRISPR methods was published in a scientific journal (2).

Noting the potential enormous benefits this new technology could bring, the expert group recommended adopting a notably conservative approach toward modifying the human germline.  Endorsing basic CRISPR research, they asserted a great deal more groundwork work must be done before attempts to modify the human germline could be considered.  Although the word moratorium was not used in their statement, for the time being researchers were being asked to refrain from taking actions that would lead to the permanent and heritable modification of the human germline.

The scientific community has created explicit guidelines and recommendations for the conduct of genetic editing research.  This was a critical action, but CRISPR technology has already escaped the confines – and jurisdiction – of academic laboratories.  Will private, profit-seeking corporations conform to operational limits delineated by the national academies?  Turns out it might have been reasonable to inquire whether the scientists themselves would all follow the new guidelines and long-established norms for research involving human subjects.

Our Fast-Arriving Future 

Taking note of the precarious oversight situation, Stephen Buryani wrote (3);          

“There has been a failure over the last decade of any center of power within the scientific community to develop a coherent moral and logistical framework for the future regulation of the technology.  This situation practically guarantees that research will creep ever closer to the red line of human genome editing until inertia finally carries it over.”

The situation was so fluid that by the time this article was published, the prediction of a red line transgression – human germline editing – had already come true.  Twice (4).  But, equally stunning; it was no incremental inching forward that ultimately carried us over a clear taboo.  A well-trained and well-connected scientist deliberately violated that limit in order to achieve a personal goal of creating the world’s first CRISPR-edited babies, drawing widespread condemnation for his unethical and premature action (4).  Now another researcher clamoring for permission to embark on a similar quest to produce his own version of the CRISPR babies is stoking more controversy (5).  

No Stopping It?

One scientist’s claim that CRISPR editing of the germline cannot be stopped might seem like purely self-serving bluster (6), but rules governing acceptable uses of such technologies vary between nations (5).  It is easy to envision there may be a person untroubled by ethical constraints and able to find just the place to do what he or she wants to do.

In their book Regenesis, George Church and Ed Regis suggest that when it comes to public acceptance of controversial new technologies, eventual success will overcome objections (7).  Citing the example of in vitro fertilization, they maintain that as techniques are perfected and people realize such methods might work for them, opposition will predictably fade.  It is a compelling hypothesis.

Rogue Scientists – Danger

Will that model hold for CRISPR gene editing?  I imagine that when Drs. Church and Regis wrote their march of progress example they extrapolated direct, personal experience into unstated assumptions.  Not with the lab work, but the investigators, whom they seem to have envisioned as competent and ethical professionals.  How might things progress if CRISPR editing of human embryos is forced ahead by unethical rogues? 

We have definite indications that the editing of the human germline may not unfold according to the vision sanctioned by the national academies.  Maybe the rogues will get lucky and advance the field through their callous choices to treat innocent subjects in an instrumental fashion (6).  No matter the final outcome, a substantial number of scientists remaining silent about clearly premature and unnecessary experiments going forward anywhere will set several extremely poor precedents (4).  Scientists often complain the public is ignorant of their work and loudly proclaim the urgent need for dialogue regarding new advances.  As pointed out explicitly (4), the time has come for them to actively express support for long espoused scientific community research principles.                          

Rogue Scientists – Opportunity

Reacting to the birth of two babies that had been genetically edited using CRISPR technology, United States Senate members Dianne Feinstein, Marco Rubio and Jack Reed introduced a bipartisan resolution calling for international ethical standards for gene editing research (8).  Cognizant of the potential, but concerned about possible misuse, the Senators urge immediate action to prevent ambitious, but unethical, researchers from conducting work in nations with the fewest regulatory restrictions.  Accordingly, the resolution encourages the Secretary of State to work with international organizations to create a consensus governing the limits of ethical clinical use of genome-edited human embryos (8).

Notwithstanding the creation of CRISPR genome editing research guidelines by the national academies, scientific organizations have no authority to compel anyone to comply with them or conduct work in an ethical manner.  The world is a diverse mix of jurisdictions, opinions and regulatory rules.  While scientists would probably wish to keep politicians out of their research, perhaps the creation of international standards for this powerful new technology has now become a practical necessity.  Like it or not, opinion leaders and the scientific community rank and file might wish to energetically support the Senate resolution and take proactive actions to ensure it culminates in productive measures.         

The unethical actions and unreasonable demands of rogue scientists have brought issues of CRISPR genomic engineering before the public with force and clarity.  Perhaps these norm breakers will serve as canaries in the coal mine and alert the world to the urgent need to devise a practical working plan for this promising and powerful technology.   

(1) David Baltimore, et al.   A Prudent Path Forward for Genomic Engineering and Germline Gene Modification.  Science 348(6230):36-38, 19 March 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4394183/

(2) David Cyranoski and Sara Reardon.   Chinese Scientists Genetically Modify Human Embryos.  Nature, 22 April 2015.   https://www.nature.com/news/chinese-scientists-genetically-modify-human-embryos-1.17378

 (3) Stephen Buranyi.   What is the World to Do About Gene Editing?  The New York Review of Books, 21 March 2019.  https://www.nybooks.com/daily/2019/03/21/what-is-the-world-to-do-about-gene-editing/

(4) David Cyranoski.   The CRISPR-Baby Scandal: What’s Next for Human Gene-Editing?  Nature, 26 February 2019.  https://www.nature.com/articles/d41586-019-00673-1

 (5) Genna Buck. ‘It’s Totally Irresponsible’: Canadian Ethicist Slams Rogue Russian’s Plan to Edit Human Embryos.  National Post, 8 July 2019. https://t.co/G7jE5R7Zfw

(6) Jon Cohen.   Russian Geneticist Answers Challenges to His Plan to Make Gene-Edited Babies.  Science, 13 June 2019.  https://www.sciencemag.org/news/2019/06/russian-geneticist-answers-challenges-his-plan-make-gene-edited-babies

(7) George Church and Ed Regis.   Regenesis.  How Synthetic Biology Will Reinvent Nature and Ourselves.  Basic Books.

(8) Press Release, 15 July 2019. Senators Call for Ethical Standards for Gene-Editing Research.  https://www.feinstein.senate.gov/public/index.cfm/press-releases?id=A019C1BC-304E-4394-8FA8-F0F799C8537D

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Polio Evades Eradication – Unfortunate Legacy of a CIA Operation?

Public health authorities once hoped to have eradicated poliomyelitis completely decades ago.  Enormous progress has been made, but one form of the wildtype virus along with mutant oral vaccine strains continue to produce disease (1).  Last year these viruses paralyzed around 130 persons worldwide, a tiny number compared to the era before vaccines were available.  However, polioviruses usually do not produce clinically-apparent disease and the most feared manifestation of poliomyelitis – permanent, flaccid paralysis of voluntary muscles – is actually the rarest outcome of infection.  For every paralysis case which appears, hundreds more persons almost certainly harbored and transmitted the viruses silently, thwarting efforts to eliminate this disease in some locations (1).

Going Backwards

Despite expending billions of dollars to acquire and distribute vaccines, the number of polio cases is increasing (1).  In Afghanistan and Pakistan, political turmoil, deadly attacks on vaccinators and armed conflict have made mass vaccination campaigns impossible or eroded their effectiveness.  In parts of Africa where rates of polio immunity are low, outbreaks have been sparked when viruses used in oral vaccines have mutated to paralysis-causing states and spread.  WHO-mandated changes in composition originally intended to decrease risks posed by oral vaccines are now creating new concerns Africa could be poised to suffer a major polio outbreak (1).

A Confluence of Negative Trends

It is clear that several factors are now frustrating the longstanding effort to drive polioviruses to total extinction.  Perhaps one of them is an unintended consequence of the search for Osama bin Laden (2).  The CIA arranged for a hepatitis B vaccination program to be conducted in the community where they believed he had taken refuge.  However, the real goal of the sham vaccination effort was to collect DNA samples from members of one household to determine if any bin Laden children resided at this location.  Health workers providing polio vaccines had been allowed to enter the surveilled compound previously suggesting a group offering hepatitis B vaccines might be allowed in as well.  Full details of the operation have not been revealed, but if granted access, stealthy collection of small DNA samples would have been possible.  DNA evidence of his children would have increased confidence Osama bin Laden was also at that location before a dangerous kill or capture mission was launched (2).

The Final Legacy?

It is not known whether the covert sampling operation actually succeeded in getting confirmatory DNA information for agency analysts (2).  However, the secret effort was exposed quickly and provoked some severe reactions against polio vaccination teams (2, 3).  Militant group bans on vaccination team activities predicated on charges of espionage and sporadic deadly attacks on those who did not heed the orders have persisted for over 8 years.  It is not possible for polio vaccination efforts to proceed effectively in some areas of Pakistan and Afghanistan (1), the last places on the planet where wildtype poliovirus still circulates. Almost within sight of one critical end stage milestone, the longstanding and worldwide effort to exterminate polio is stalled.  The costly and perhaps ultimately tragic public health legacy of a clandestine CIA operation.  

(1) Leslie Roberts.   Surging Cases Have Dashed All Hope that Polio Might Be Eradicated in 2019.  Science, 10 July 2019.  https://www.sciencemag.org/news/2019/07/surging-cases-have-dashed-all-hope-polio-might-be-eradicated-2019

(2) Saeed Shah.   CIA Organized Fake Vaccination Drive to Get Osama bin Laden’s Family DNA.  The Guardian, 11 July 2011.  https://www.theguardian.com/world/2011/jul/11/cia-fake-vaccinations-osama-bin-ladens-dna

(3) Donald G. McNeil, Jr. 2012. I.A. Vaccine Ruse May Have Harmed the War on Polio.  The New York Times, 9 July 2012.    https://www.nytimes.com/2012/07/10/health/cia-vaccine-ruse-in-pakistan-may-have-harmed-polio-fight.html

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Remember Frankenstein

The birth of the first babies engineered using CRISPR technology produced enormous turmoil within and far beyond the scientific community (1).  This premature and patently unethical effort resulted in the imposition of immediate sanctions, the swift drafting of new regulations and broad condemnation.  However, disapproval was not universal (2, 3).

Behold, the Slippery Slope

Another researcher has attracted worldwide attention by proposing to conduct virtually identical CRISPR gene editing experiments on human beings (4).  Targeting the same gene as his reprimanded colleague, pending government approval, he projects implanting edited embryos as soon as this year (4).  As was the case for the first CRISPR babies, the edits are intended to make the subjects resistant to HIV infection.  The objections to undertaking such experiments range from technical concerns over editing accuracy and efficiency to uncertainties over the ultimate impacts on long term health (5).  Reservations over the medical urgency and attendant risks were glossed over or left unaddressed by the researcher (6).    

It is clear that the number of persons who conceivably might benefit as a result of these editing experiments is vanishingly small (5).  If the goal is to enable HIV-infected women to become pregnant and there are better conventional ways to accomplish that, why is this genetic editing experiment necessary?  It is very hard to escape the suspicion that this research proposal has little to do with the needs and desires of the future mother and/or her unborn child.  The statements of the researcher make it clear this is a simple proof-of-concept exercise (5) and he appears to be fishing for a situation – any situation – that will enable him to burnish his professional stature.  Perhaps he views paralleling an already used approach that (as yet) has not produced dangerous off-target consequences as the fast track to reaching his personal goals.                       

Anxious to embark on his personal quest, this ambitious scientist is unwilling to wait until the essential preliminary work is done to assess and perfect CRISPR technology before it is used to alter the human germline.  His derivative project will open no new scientific territory while exposing human subjects to unknown levels of risk.  At this stage of development, forging ahead to edit embryos reveals a remarkable and callous indifference to the facts. 

 You Can’t Stop It?

Asked how he imagined the researcher who created the first CRISPR babies will be regarded in the future, the person hoping to emulate him answered by invoking a Russian proverb; “…if you have success, you are right.”  So, if he’s lucky and the babies are OK, he is destined to be considered to be a good researcher (6).  Here is an alternate view – this scientist willfully rolled the dice with innocent human lives to conduct an unnecessary and reckless experiment.  Lucky outcome or not, he exposed himself as an investigator who viewed human subjects as strictly instrumental to his goals.      

Stop me if you’ve heard this one before; driven scientists create something far bigger and more powerful than themselves which escapes control.  This time it is CRISPR genome editing technology taking on a metaphorical life of its own.  It is true that scientific society advisory committees lack legal authority to halt work which violates their guidelines and prohibitions (4).  However, it is also clear that in some localities a combination of professional and governmental oversight is able to channel research programs to conform to the broader consensus.  Despite self-serving assertions that human germline editing cannot be stopped (6), the current situation is not a free-for-all and whether this researcher will ever receive formal governmental approval to proceed remains unknown.  A glory-seeking researcher may have forgotten the Frankenstein story, but hopefully some in authority still remember its most important lessons today.   

 

(1) Anonymous.  China Set to Introduce Gene-Editing Regulation Following CRISPR-Baby Furor.  Nature, 20 May 2019.  https://www.nature.com/articles/d41586-019-01580-1

(2) Sharon Begley.   Fertility Clinics Around the World Asked ‘CRISPR Babies’ Scientist for How-To Help.  STAT, 28 May 2019.  https://www.statnews.com/2019/05/28/fertility-clinics-asked-crispr-babies-scientist-for-how-to-help/

(3) Anonymous.  How to Turn Science Fiction into Science Fact.  Neo.Life, 28 June 2019.  https://t.co/V5oSmxfd6h

(4) Rick Berke.   Alarmed by New ‘CRISPR Babies’ Plan, Top Science Figures Say They’re Powerless to Stop It.  STAT, 24 June 2019.  https://www.statnews.com/2019/06/24/outraged-by-new-crispr-babies-plan-top-science-figures-say-theyre-powerless-to-stop-it/

(5) Pete Shanks.   The Russian Threat to Perform Human Germline Editing.  Center for Genetics and Society, 25 June 2019.  https://www.geneticsandsociety.org/biopolitical-times/russian-threat-perform-human-germline-editing

(6) Jon Cohen.   Russian Geneticist Answers Challenges to His Plan to Make Gene-Edited Babies.  Science, 13 June 2019.  https://www.sciencemag.org/news/2019/06/russian-geneticist-answers-challenges-his-plan-make-gene-edited-babies

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CRISPR – When the Facts Don’t Matter

Notwithstanding negative reactions to the announcement the first CRISPR babies had been born (1), a new article published in the South China Morning Post suggests fast-arriving improvements to the methodology could lead to its legally approved employment in a year or two (2).  Likening the possible threats posed by gene-editing technology to thermonuclear weapons and noting the U.S. and China are in a heated race to perfect the techniques, it seems more regulations are going to be needed to stave off disaster (2).     

Scary Theory Collides With Harsh Realities

A two-year time frame to perfect the CRISPR editing technology and gain legal approval for its use to edit babies (2) seems overly optimistic given that scientists currently have no idea what adverse consequences might follow genomic modifications (3).  The birth of the first CRISPR babies has left us deeply concerned over their future health and these knowledge gaps will not be filled anytime soon, which suggest ethical considerations alone would preclude similar efforts in human beings.

What of the specter of weapons of mass destruction and immoral uses such as “creation of a super-baby” (2)?  It is not clear exactly what the author (2) meant by “super-baby,” but perhaps we were to envision armies of enhanced soldiers launching Armageddon.  Again, much of the genetic underpinnings of complex traits like intelligence is not understood well enough to enable scientists to engineer it on demand. 

For the time being the prospect of super babies seems remote, but mindful of fast-emerging technology, the need for regulations and standards remains acute (2).  The scientific community has consistently failed to keep pace with concrete developments, often left reacting after the fact to research that inched up to and then crossed informal red lines (4).  This is passively fostering a situation where future human germline editing is all but a self-fulfilling prophecy (4), one that could become a reality without sufficient public input and due consideration.          

Could the Scientific Community Find Itself Marginalized?

CRISPR technology has been disseminated across the world.  Its rapid commercialization and comparative ease of use may leave regulations and edicts issued by the scientific community a feeble means to channel and control it.  A recent news story (5) crystallized the issues; despite the overwhelming public disapproval of his actions, the scientist who created the first CRISPR babies was immediately sought out by a fertility clinic to show their technicians how to do such things.  Scientific community consensus and possible censure clearly meant nothing to that organization.  The tools are out there, this revolution may take place beyond the jurisdiction of national academies and traditional research funding agencies.  The world is a hodgepodge of laws and regulations governing human genome editing and we have already seen these gaps exploited (6).  The ‘life finds a way’ quip from the movie Jurassic Park could become ‘genetic engineers find a place.’

When Facts Don’t Matter        

There is something more chilling to ponder that has taken place not in some far-flung secret location, but right before our eyes.  If the stem cell technology miracle cure free-for-all (7) is any predictor, the new genetic editing services to come may not have to work or be proven safe to attract professional practitioners and paying customers.  With profits to be made, both facts and ethics can easily get lost in the frenzy. 

We may not face super-babies soon, but genome editing technology poses formidable problems that must be addressed.  Rushed into the commercial sector by creators bent on seizing patents and profits, these goal-driven scientists may not have served the best interests of the public.  Far different from the situation with nuclear weapons, CRISPR technology was almost instantly proliferated worldwide and its future applications may not be easily regulated by traditional mechanisms.  It is conceivable that both ordinary citizens and scientific community elites will end up as mere spectators to unfolding events.          

 

(1) David Cyranoski.   China Set to Introduce Gene-Editing Regulation Following CRISPR-Baby Furor.  Nature, 20 May 2019.  https://www.nature.com/articles/d41586-019-01580-1

(2) Stephen Chen.   Gene-Editing Breakthrough in China Comes with Urgent Call for Global Rules.  South China Morning Post, 1 June 2019.  https://t.co/TTwJXuLT9K

(3) Antonio Regalado.   China’s CRISPR Babies Could Face Earlier Death.  MIT Technology Review, 3 June 2019.  https://t.co/EF01cqnxvZ

(4) Stephen Buranyi.   What Is the World to Do About Gene-Editing?  The New York Review of Books, 21 March 2019.  https://www.nybooks.com/daily/2019/03/21/what-is-the-world-to-do-about-gene-editing/

(5) Sharon Begley.   Fertility Clinics Around the World Asked ‘CRISPR Babies’ Scientist for How-To Help.  STAT, 28 May 2019.  https://www.statnews.com/2019/05/28/fertility-clinics-asked-crispr-babies-scientist-for-how-to-help/

(6) Michael Reilly.   A Three-Parent Child Was Conceived in Mexico, Because the U.S. Won’t Allow It.  MIT Technology Review, 28 September 2016.  https://www.technologyreview.com/s/602499/a-three-parent-child-was-conceived-in-mexico-because-the-us-wont-allow-it/

(7) U.S. Food and Drug Administration. 2017.  FDA Warns About Stem Cell Therapies.  https://www.fda.gov/consumers/consumer-updates/fda-warns-about-stem-cell-therapies

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