A quick post today, inspired by a fabulous essay by the redoubtable science communicator duo, Tara Haelle and Dr. Emily Willingham, on the possibilities and pitfalls of genetic testing and personal genomics in the Undark Magazine. It spawned a few, relatively random musings on this topic, admittedly a topic I have not hithertofore explored much. I wrote my thoughts as a comment after the magazine essay, but I don’t know if or when it would appear. So here they are, as a blog post.
Last month, PLOS One published a study which held significant interest for me; as a long time sufferer from acid reflux (which is currently reasonably controlled by regular use of a PPI – Proton-pump inhibitor – class of prescription antacid), I was curious to dive into this Randomized Controlled Trial (RCT) study from Beth Israel Deaconess in Boston, in which the investigators observed that Patient-Provider Interactions Affect Symptoms in Gastroesophageal Reflux Disease (GERD) as well as dyspepsia and other acid-reflux related issues, which affect 2-4 out of every 10 people in Western world (similar statistics were observed in the Northern part of India). The name of the study medication, Acidil, wasn’t immediately familiar to me, but it turned out to be a ‘homeopathic preparation’, which – along with the placebo-controlled designed – piqued my interest further. Although the severity of GERD symptoms may fluctuate due to different reasons, it is usually not one of those self-correcting conditions in which homeopaths often claim beneficial effect. So, sufficiently interested, I delved deeper.
Not apropos of anything, an ethics question flitted through my mind as I was reviewing a rather interesting paper for a journal, which shall remain nameless. As for all questions of such deep significance and importance, I would love to turn to my most valuable resource, the scientists and/or blogger tweeps with whom I communicate and/or interact and/or whom I follow on Twitter. I do see the social medium of Twitter to be a valuable tool for collaboration, and I hope there’d be someone there, who can answer my question – either in 140 characters on Twitter, or more at length, here in the comments.
The things that I learn from Twitter! This is rather interesting: a bright teenager from West Yorkshire, UK, got tired of hearing that his ginger haired brother wasn’t his biological sibling. So, he did what teen-aged school students would normally do – kidding! – he built a PCR machine, by hand, utilizing electronic components scavenged from an old VCR (who knew those were still around!). He used that home-spun PCR (Polymerase Chain Reaction) machine to amplify cheek cell DNA from his brother, and sent off the amplified specimen to a laboratory to be analyzed; the results, as he expected, showed his brother to indeed have a specific mutation in the gene for melanocortin 1 receptor (MC1R), which renders his hair color ginger.
As perhaps characteristic of ‘science by press release’, the Sun UK article which mentioned this was quite light in terms of scientific information. For example, I have no clue how he extracted the DNA from the cheek swab, what enzymes/primers he used for the amplification reaction, or whether the lab tested the DNA for only the mutation or if it was also a full sibling test. Nevertheless, the feat was quite impressive, and most certainly, massive plaudits to the youngster for his engineering skills and good understanding of biology.
However, there are three germane questions that concern me a bit. I want the best for this bright and industrious student, and therefore, these questions are best considered right at the outset, so that there is no adverse situation later, that hampers his education and training. The questions have to do with:
- Privacy: The student used his brother’s DNA to extract a medical information (about the presence or absence of the mutation). I don’t know about the UK, but in the US such a use would generally be covered under HIPAA (Health Insurance Portability and Accountability Act of 1996), as well as possibly other Federal regulations. Of course, HIPAA doesn’t apply to individuals, but it would presumably apply to the laboratory which analyzed the DNA for the mutation. Now, under the provisions of HIPAA, the protected health information (PHI) may be disclosed to the individual to whom the information directly pertains (in this case, the brother); it also may be disclosed for the purpose of research (which this use seems to qualify as), but only in a manner approved by an institutional review board or privacy board. These rules may not apply to the young folks, but I wonder if the Sun UK, which publicly disclosed the presence of the MC1R mutation in the brother, has obtained the required permissions. (Once again, I confess to my ignorance of the privacy process in the UK.)
- Ethics: I wonder if there exists a mechanism for handling genetic information of this kind, in this kind of a situation. What if one of the aspects of the test results indeed showed that the brothers were not biological siblings – in that event, who would handle the ethical quandaries arising out of such information? To me, a worse ethical dilemma would arise out of the fact that individuals carrying MR1C polymorphisms may be at a higher risk for melanomas; now that this information is public for the brother, what if he is refused healthcare coverage for being high-risk for certain cancers?
- Intellectual Property: For better or for worse, the PCR was patented, and by March 2006, these foundational (a.k.a. early process) patents expired for both the US and Europe. However, patent battles associated with components of the in vitro PCR process (as well as modifications of the basic process, such as Real Time PCR) continue intermittently. Moreover, there appear to be some currently valid patents for various components of the PCR machine (US Patent Office links here and here). There are now guidances available on the internet for building Open Source PCR machines. In addition, a 2006 study on the impact of patent protections on PCR found that one of the reasons why PCR was such a celebrated and widely used tools despite heavy protections was a policy of “rational forbearance” from suing researchers for patent infringement by the companies which held those patents; there is no reason to consider/fear that the said magnanimity on part of these companies would wane. Nevertheless, it is always a good practice to familiarize oneself with these intellectual property matters.
In the final synthesis, my raising these questions is not intended to dampen the spirit of this remarkable youth, or diminish his significant achievement in any way. However, in an increasingly complex world, it is also important to be trained in recognizing the possible consequences of one’s actions, and acting accordingly. I wish this student all the very best; he is truly an inspiration to many of his age and beyond.
A recent edition of Nature News brought some terribly worrisome news: People for the Ethical Treatment of Animals (PETA), the anti-science, anti-knowledge, anti-animal experimentation pressure campaign group based in Norfolk, Virginia, has apparently secured –
… written assurances from the world’s two largest air-cargo carriers, FedEx and UPS, that they will not transport mammals for laboratory use. UPS says that it is also planning to further “restrict” an exemption that allows the transport of amphibians, fish, insects and other non-mammals (Nature, 489: 344–5, 20 September 2012).
As this Nature News report, as well as the Editorial highlighting this issue (Nature, 489: 336, 20 September 2012), indicates, this particular move is not likely to have too serious an impact on the availability of animals for laboratory research, because FedEx and UPS are ordinarily not involved in the movement of too many animals in any case. However, the significance of this incident is in that it portends a rather disturbing trend.
A Nature News report from March this year (Nature, 483: 381–2, 22 March 2012) indicated how various major airlines across North America and Europe have been succumbing to the pressure tactics from PETA and refusing to transport non-human primates; how transportation of research animals — including sophisticated mouse models of various diseases — into the UK has been discontinued by ferry companies who capitulated to campaigns orchestrated by PETA. And this trend, which shows no evidence of bucking, has biomedical researchers deeply worried all over the world. As the Nature Editorial cautions, “the bid to halt air transport of lab animals poses an imminent threat to biomedical research.“
It’s not just the mammalian models of biological systems that are at risk. If UPS does indeed restrict the transport of non-mammals and lower species (including amphibians, insects, crustaceans, molluscs and fish), pressure from groups like PETA may well wean FedEx and other carriers off this particular business segment. And the devastating impact would be keenly felt by the researchers who study these organisms. The Nature News report quotes neurobiologist and behavioral researcher Darcy Kelley, who expressed her grave concern that a restriction on the shipping of the frog, Xenopus, would be a tremendous setback for her research work – particularly since “… It takes Xenopus females two years to get to sexual maturity…”, making it challenging for a research laboratory to initiate a colony and maintain a study supply of the amphibians for research use. Kelly further states, “… maintaining an animal colony is a very expensive proposition” – something that most animal researchers know first-hand – not to mention, a proposition that is not entirely free of PETA’s ire and interference, as history has shown.)
Kelly examines sensory, neural and muscular systems involved in vocal communication in Xenopus to understand how one brain communicates with another; for her work, she utilizes three supply companies in three states, all of whom send the amphibians via UPS by Air for next-day delivery.
And not just Xenopus research. A significant part of Drosophila (fruitfly) research in the United States depends on FedEx which currently ships the fruitflies from suppliers such as the Drosophila Species Stock Center at the University of California, San Diego, and the Bloomington Drosophila Stock Center at Indiana University; Carolina Biological Supply in Burlington, North Carolina, ships via FedEx Drosophila, crayfish, mussels, and many other non-mammals, to science teachers.
What is the most troublesome aspect of this? It’s not PETA’s mindless, ignorant, unthinking, extreme activism. Rather, these events are a testament to the fact that advocates of animal research – including scientists, researchers, administrators, communicators, a wide community that includes me – are failing miserably to make the case to the general public for the legitimate and compassionate use of lab animals in scientific research, leaving the public vulnerable to the lies, misinformations and misrepresentations that groups like PETA use to further their agenda. It means we, as a community, are failing to educate our fellow members of the society about what we do and why. This bothers me a lot.
As a conscientious researcher who works with rodent models, I am aware of my responsibilities as a scientist. When devising my experiments, I firmly adhere to the principle of 3Rs – Replacement, Refinement and Reduction wherever possible – a widely accepted ethical and rational framework for humanely conducting scientific experiments using laboratory animals (See a nice essay expanding on this at the “Speaking Of Research” blog). All research involving animals are regulated strictly via federal mandates and guidelines (in the United States, as well as in most industrialized nations) to which my institution and I adhere inflexibly. But I am by no means unique in this respect. All scientists/researchers at reputable institutions, who work with animals on biomedical projects, subscribe conscientiously to the same framework, not only because of ethical considerations, but because of scientific imperatives as well. But while we, as researchers, understand this, it patently appears that we are doing a shoddy job of impressing this upon the general public.
Let me elaborate on the concept of Replacement, because it is central to the understanding of the objections against animal experimentation. Wherever possible, animal models must be replaced either absolutely (i.e. by using techniques which do not involve animals, such as computer modelling, in vitro techniques such as biomodeling and tissue engineering, or even human volunteers), or relatively (i.e by using in vitro or ex vivo technologies, such as animal cell lines (usually derived from cancers), organs and tissues harvested from relatively few animals, and so forth). For example, technology now exists to allow a few cells of the trachea (‘windpipe’) from one or two mice to grow onto an artificial support at the interface of air and liquid medium; in this way, these cells are able to mimic somewhat what happens in the trachea when airborne pathogens, bacteria, fungi or viruses, come in – allowing the researchers to study them in real time. Studying the same events earlier would require many mice. However, it is important to emphasize that not everything in the body, in health and in disease, can be studied in this piecemeal fashion.
Two significant examples jump to the mind straight away: infectious disease/immunology research, and research in metabolic diseases. It is not possible to study these two in an isolated manner without the use of a host. Both these phenomena involve cells that run inside the whole body, and chemical messages that carry internal signals from one part to the other and may act differently depending upon the situation or destination; both these involve responses that occur throughout the whole body of the host. Not all the intermediate components of these processes are even known (which is why ex vivo work or in silico modeling doesn’t provide the complete picture).
Last month, PETA had announced with great fanfare how a grant from the group helped Egypt ‘completely end’ the use of animals in its leading trauma training program, and use instead a state-of-the-art human-patient simulator. This is GREAT news, a great example of replacement and refinement. Use of a human patient simulator is a great training tool, already in use in many teaching hospitals in the US, such University of Texas and the Virginia Commonwealth University, but it cannot provide any information about the actual pathogenesis or dissemination of the disease, nor the intricate details of the body’s response to the disease conditions.
Another area where animal experimentation is absolutely necessary is basic biological sciences. Nature’s infinite beauty is manifest – to those that can see it – in the intricacies of the body’s biological processes. Why is it important to study them? The same processes are active in both health and disease, and without knowing more about them in health, it is impossible to decide what to do in disease. Any knowledge that is gained helps, as a matter of course, both humans and animals. Imagine Professor Kelly’s work on Xenopus that can yield important clues about the neurology of social communications; or, Drosophila work that identified the Toll Receptors, pattern recognition receptors that help fight pathogens, in a manner remarkably similar to the action of the Toll-like receptors in mammals; or, the animal experimentations that have given rise to vaccines, or medicines for bacterial infections, or furthered the understanding of what happens in Alzheimers or Parkinson’s. Knowledge derived out of animal experimentation progresses our understanding of the interaction of biological beings – humans and animals – with the environment, and saves lives, both human and animal.
PETA folks, whose objections to animal experimentations are absolute (and rather simplistic), are nothing more than right wing evangelicals who channel their energy into what they perceive as ‘animal rights’. Despite their general odiousness and intellectual myopia, I have always believed that they, too, serve a useful role – well, mostly – as an equivalent of the ‘checks-and-balances’ model; they remind us of our obligations as scientists towards conduct of responsible research. But, as these recent events indicate to me, PETA is gaining valuable ground, aided by their relentless campaigns, however lacking in truth and substance. For example, a concerted thrust undertaken by PETA-India recently got the Indian national airline, Air India, to agree to cease transporting research animals within the country from government suppliers such as the National Institute of Nutrition in Hyderabad, to the detriment of research efforts. Such success of their campaigns can only embolden PETA and their ilk; to my mind, this should galvanize the scientists into becoming better educators, as well as vocal and passionate commentators, on the issue of animal research. Otherwise, the danger to biomedical research is imminent. The Nature Editorial agrees with me. I quote:
“If this is not enough to make scientists sit up and take notice, they might consider the use of lab rodents, now under threat in India from a PETA campaign… As PETA undertakes a systematic push to target all major cargo carriers, scientists in any country who rely on air freight to deliver rodents should be on notice that their turn may be next. Of course, in the increasingly global world of science it is already, in many senses, everyone’s turn…
… Biomedical researchers in many different countries, through reticence and passivity, are losing the battle for the hearts and minds of the public when it comes to the need for, and legitimacy of, animal research. Why else would high-profile companies be willing to indicate, however implicitly, that they want no part in a transportation infrastructure that is crucial to global biomedical science?
… If individual scientists wait until they are personally affected… it will be long past too late to mount the vigorous, public campaign in defence of animal research that is so sorely called for at this moment…
… As researchers join this battle — and join it, they must — they should, as a first step, work through their institutions, academic societies and umbrella groups to make an urgent, articulate, unified case to UPS and FedEx that the shipping of animals, mammalian and otherwise, is essential for both biomedical research and scientific education.”
Truer words have never been said. It is high time scientists and science communicators asked loudly and in unison, all this opposition to animal research, who benefits, really?
I am really in two minds as I write this.
This post was prompted by a news item on Teh Grauniad this morning, brought to my attention by that esteemed daily’s twitterfeed. The title and the byline goes as:
Girl, nine, benefits from UK’s first IVF ‘saviour sibling’ therapy
Doctors treat girl with rare blood disorder by transfusing healthy bone marrow from baby brother created at IVF clinic
Intrigued, I read through the report.
The story, reporting a first-of-its-kind-in-UK procedure, is of a nine-year old girl with congenital Fanconi’s anemia, an autosomal recessive (or X-linked recessive in ~2% cases) disorder that can result in bone marrow failure; younger patients eventually develop acute myelogenous leukemia (AML), various other hematological abnormalities, kidney problems, and developmental issues, while older patients often develop carcinoma of head and neck, GI, or genito-urinary tract.
The 13 genes involved in Fanconi’s anemia (including 1 that is identical to the well-known breast-cancer-susceptibility gene, BRCA2) encode proteins that assist the recognition and repair of damaged DNA; one or more of these genes are inactivated in Fanconi’s anemia, a relatively rare disease, with a prevalence of 1-5 cases per 1 million persons (N Engl J Med 2010; 362:1909-1919). In this girl’s case, the poor parents were possibly unwitting hapless carriers (a copy each) of the inactivated gene(s), so that the girl received no active copy at all.
Therapy with androgens and hematopoietic growth factors may be effective for treating bone marrow failure in Fanconi’s anemia; however, the disease often becomes refractory to these treatments. For such patients, hematopoietic stem-cell (bone-marrow) transplantation is the only viable option, if a matched donor is available. Preimplantation genetic diagnosis is a new approach for identifying potential sibling donors for patients with Fanconi’s anemia (See the NEJM Paper above). However, the older brother of this girl was found to be an unsuitable donor, and a worldwide search also failed to find a suitable tissue donor match.
The young parents, in their 30s, chose to have an baby by in vitro fertilization (IVF), in which doctors implanted two out of 6 embryos created by IVF. Several tests showed that the implanted embryo was free of the genetic defect. One year after the boy was born and found to be a good tissue match for this sister, the doctors at the Bristol Royal Hospital treated the girl by transfusing healthy bone marrow from him. She has been monitored carefully for six-months, and is now well enough to consider returning to school.
This is a life-affirming story, as well as one of the wonders of modern medicine and applied biology. I am genuinely happy for the little girl, who got better, as well as a baby brother as a bonus out of it.
Yet, I am ashamed to admit, I cannot shake off a nagging feeling.
I have grown up on a staple of Bollywood (Hindi) movies, where sisters, brothers, parents, children were all ready to sacrifice themselves for the good of their [insert appropriate] family members. ‘Self-abnegation’ and ‘renunciation for the good of humanity’ and so forth are concepts that my parents, followers of Hindu philosophy and spiritual beliefs, drilled into me through endless mythological stories and parables and fables. So I should be comfortable with this situation where the younger brother saves the elder sister’s life, right?
And yet, I can come to no easy terms with the ideas that:
- This child, the youngest son, was not borne out of love, but merely as a tool to be utilized, even if the cause was noble.
- The bone-marrow was drawn from the child (a painful procedure per se) when he was just one-year old, much below an age where he was capable of giving consent. The boy was simply not in a position to agree or disagree to the procedure, a fact that is unaltered by the parents being empowered by law to provide proxy consent on his behalf. So, even though the son may have happily donated all his organs or even his life for his sister (à la my Hindi films), what if he refused, what if he could refuse? We will never know, will we?
Those who know me well know that I am not, I repeat, not, anti-abortion (those of you who are aware of the US scenario will appreciate the full force of that statement). I don’t consider a ball of cells (morula, gastrula, blastula) to be a living individual. I do draw a line at the fully-formed fetus, with neurological and cardiac activity, but to me, pre-partum, the mother’s health, well-being and wishes are paramount. But this is not one of those situations.
Here is a child who was created with the specific purpose of saving his sister’s life (hence the somewhat awful news-media moniker, ‘saviour sibling’). The fact that he had no say in being used thusly gives me a pause. How ethical was it to do that? Does the successful end (remission of his sister’s disease) justify the means? Will his life be just like anyone else’s? Will his parents love and cherish him like his elder siblings? Will his parents and sister be eternally grateful to him, thereby spoiling him silly and making a brat out of him? I don’t have any answer to these questions. Perhaps only time can tell.
How did you react to this news? Did any of you face the same ethical dilemma as I did? Or, am I just over-reacting or confused? Please let me know in the comments.