Wir wussten nicht

By Mark McQuain

It has been said that “the only thing necessary for the triumph of evil is that good men do nothing.” Implied in this statement is that, first and foremost, the good men and women must be aware of the evil before they could be held morally obligated to act against that evil. There are subsequent issues associated with that obligation, such as does one even have the ability to act and, if so, how much personal harm or risk must one endure before being morally absolved of the responsibility to act. Regardless, knowledge of the evil is a requirement before moral culpability to act against that evil can be expected or assigned.

Therefore, a claim of “we did not know” would certainly absolve people of any moral responsibility from failing to act. But only if that denial is true. Challenging the validity of such a denial is reasonable because the denial is the easiest way to escape moral culpability. Consider the following two examples where claims of “not knowing” were possibly used to avoid moral responsibility.

When the Dachau concentration camp was liberated by the U.S. Seventh Army at the end of World War II, it was reported that the local German townspeople denied that they knew what was going on at the camp, claiming “Wir wussten nicht” – “We did not know”. General Walton Walker started the practice of bringing local townspeople to view such camps by ordering the Mayor of the town of Ohrdruf and his wife to visit the Ohrdruf labor camp. After the visit, it was reported the Mayor and his wife returned home and killed themselves.

Did they really not know?

Recently, the movie “Gosnell: The Trial of America’s Biggest Serial Killer” was released with minimal coverage by Hollywood or mass media. Reportedly, the producers had to resort to crowdfunding to initially get the project off the ground. Kermit Gosnell was a physician in Philadelphia who operated the Women’s Medical Society Clinic where he performed late term abortions. He and his clinic had multiple complaints and legal actions related to unsafe office practices as well as several procedure-related deaths prior to eventually being raided on unrelated drug dispensing charges. What the investigating officials found upon raiding the facility would fairly be described as a “House of Horror” for the unsanitary conditions, use of untrained staff, expired medications and multiple fetal remains randomly strewn around the clinic. Dr. Gosnell was convicted of first degree murder in the deaths of three infants, involuntary manslaughter on one female patient and 21 felony counts of performing illegal late-term abortions. During the trial, state and city regulators were repeatedly called out for their failure to act sooner, given the high volume of prior allegations and complaints.

Did they really not know?

Wir wissen nicht. (We do not know.) And, perhaps, we will never know.

Abortion by mail

By Steve Phillips

A recent article on the CNN website reports on a European organization called Aid Access which has recently made the medicines used for medical abortion available to women in the US by mail. The organization utilizes telemedicine in the form of online consultations to prescribe the abortion drugs from a pharmacy in India to be mailed to the woman desiring an abortion in the US. It is clear that this violates FDA regulations. To ensure the safe use of mifepristone the FDA currently requires that the drug, which has no medical indication other than induction of abortion, is only available to be dispensed in clinics, medical offices and hospitals, by or under the supervision of a certified prescriber. At issue is whether those restrictions should be lifted to allow more open prescribing of mifepristone.

The appropriate reason for the FDA to have additional restrictions on certain drugs is safety. Those who advocate lifting the restrictions on mifepristone argue that the safety of this drug has been established and cite FDA statistics that the risk of death from using the drug to induce medical abortion is only one in 155,000. This makes its use much safer than either surgical abortion or continuing a pregnancy to term. Those who oppose lifting the restrictions counter with concerns that the unsupervised use of the drug may also lead to failure to diagnose ectopic pregnancy and can result in situations that require surgical intervention, which may have increased risk in an unsupervised patient.

While there are risks to the use of mifepristone, it is hard to make the case that the risk of harm to the mother is high enough to warrant the additional restrictions that currently are required for this drug. That makes it hard to justify limiting access due to true concern about the risk to the woman whom uses it. This is not the case for another regulation regarding abortion. Laws that require abortion clinics to meet the same standards as outpatient surgery centers have a clear justification. Surgical abortion has similar risks to other outpatient surgeries, so it is reasonable to require the same safety measures for an abortion clinic and an outpatient surgery center.

There is one risk related to the use of mifepristone, which is not usually discussed, which does support the additional restrictions on its distribution, but in a somewhat perverse way. That will be the focus of my next post.

Where do I Store the Name of your Dog?

Following a long office day of wrestling with my current nemesis, our office electronic medical record (EMR), I was pleased to read a lovely article by Dr. Taimur Safder in the current NEJM entitled “The Name of the Dog”. I’ll not summarize it as the link is free and the article is short and makes the point of today’s blog wonderfully.

I realize the EMR is not actually alive and, lacking agency, is unable to act as my archenemy and cause my downfall, or that of my patients. Further, I have a degree in electrical engineering so the technology of the EMR is not the issue either. I will grant that current and future data mining of the EMR may benefit untold numbers of patients. I will also concede that EMRs will (eventually) be bolstered with AI tools that will improve diagnostic accuracy and reduce or eliminate costly unnecessary testing.

My concern is that the EMR causes me to focus so much on the data collection that I spend less time getting to know my data source (my patient) as more than the sum total of discrete data points. There really isn’t any good place in the EMR to put the name of my patient’s dog. If I am going to treat my patient as more than a something, perhaps as a someone, then more than just reductionistic data acquisition and processing will have to take place.

With that in mind, please take a moment to view one of my favorite paintings by Sir Luke Fildes at the Tate Gallery called “The Doctor”. The painting depicts a country doctor sitting at the bedside of a young patient, with the child’s parents in the background. One can imagine the concern of the child’s father and almost feel the anguished prayers of the child’s mother, but both are interestingly relegated to background positions in the painting. The focus of the painting is the focus of the lamp in the painting – the country doctor and his patient.

Medicine in the 19th Century was limited in terms of meaningful data collection and limited further by actual effective treatments. In other words, the EMR of the 19th Century could have been completed in mere minutes and the diagnosis and treatment, such as it was, rendered in a few minutes more.

Given those limitations, perhaps not surprisingly, one gets the sense that the depicted outcome was far from certain and also that the country doctor had been in the home a while – there was at least time for tea at the table. What on earth was he still doing there? Maybe in absence of a definitive diagnosis and immediate cure, what the doctor could provide was his time, his empathy and his focused, loving concern. One gets the sense he would likely remain with his patient and the family as long as he was needed to offer what help and hope he could.

That seems like a reasonable example of how one imago Dei might care for another.

Would that I could consistently convey that level of steadfastness, that empathy and that loving concern to all of my patients without frantically looking for that special place in my EMR to store the name of your dog.

Is More “Ruining” of Medicine on the Way?

By Mark McQuain

Ask older medical doctors their opinion on the current state of the practice of medicine and I suspect the majority will give you an earful, generally along the lines of “How [blank] has ruined the practice of medicine”, filing in [blank] with any number of things, including the government, insurance companies, pharmaceutical companies or doctors themselves. “Ruined” is a strong claim and even if true, I certainly don’t know how to assign blame as there is probably plenty to go around. Regardless, new initiatives by any one of these groups warrants watching. So, a recent September 20 NEJM editorial about a proposed change in reimbursement by the Centers for Medicare and Medicaid Services (CMS) made me wonder if more “ruining” is on the way.

The NEJM article nicely summarizes the current state of affairs (additional summary for those without subscription below):

“Medicare pays for office visits using five levels of codes based on clinical complexity, medical decision-making complexity, and time. For visits with established patients, physicians are currently paid $22, $45, $74, $109, and $148 for levels 1, 2, 3, 4, and 5 visits, respectively; for new patients, they receive $45, $76, $110, $167, and $172. This pricing structure in the Medicare Physician Fee Schedule, established by Congress in 1989, is the basis for physician payment by both public and private payers.”

CMS is proposing to collapse levels 2-5 reimbursements into a single payment of $93 for established patients and $135 for new patients. Documentation requirements would also be reduced to level 2 requirements thus arguably reducing some of administrative bureaucracy physicians say interferes with patient care, allowing them to spend more of this freed-up-time with patients. As an “older medical doctor”, I am certainly happy to reduce my administrative burdens so this sounds good. What could possibly go wrong with: “CMS is from the government and they are here to help”?

The authors of the NEJM article applaud CMS for their efforts to reduce administrative burden but then go on to list some potential unintended consequences. The biggest is that physicians lose the financial incentive to care for more complex patients. They hypothesize that this could result in some physicians reducing office visit times and bringing patients back more frequently, thus fragmenting the care of more complex problems and patients. They also worry that this payment policy will further maintain disparities between physicians who spend practice time on so-called cognitive evaluation and management issues versus time on the portions of their practice that receive reimbursement from procedures, imaging or laboratory fees. Lastly, if private payers don’t follow suit, the authors point out that physicians may shift further away from providing care for Medicare and Medicaid patients in favor of private insurance that does reimburse better for the complex problems.

Reimbursement is only one factor affecting today’s practice of medicine though certainly one that cannot be ignored. Many Christian physicians consider their practice of medicine as more of a calling than simply their occupation. I pray that external factors be kept from “ruining” that calling.

Noninvasive prenatal testing and sex-selection abortion

By Steve Phillips

The National Health Service in Great Britain has decided to implement the use of noninvasive prenatal testing (NIPT) and that has raised some concerns. It would seem natural for there to be concern about this test used to detect prenatal genetic conditions such as Down syndrome, which commonly leads to the choice to abort the fetuses with those conditions. However, according to a recent article in The Conversation by Jeremy Williams one of the major concerns is the use of this technique to facilitate sex-selection abortion. Williams states that one of the major political parties has proposed a policy of banning the use of NIPT for sex determination and has described sex-selective abortion as “incredibly unethical”.

Williams concedes that the idea that sex-selection abortion is morally wrong and ought to be prevented is widely held even by those who otherwise have no moral objection to abortion but suggests that taking that position is problematic for those who believe that a woman has a right to choose to have an abortion. Williams lists several reason that people give for why the sex-selection abortion is wrong. These include idea that sex selection abortions are done due to a trivial preference, concern that sex selection abortion constitutes unjust discrimination against female fetuses, concern about women being coerced into this type of abortion, and that it teaches that the lives of girls are not as important as boys. He is concerned that if these reasons are accepted they would apply more broadly than to just this one type of abortion, and he is right. Many abortions are done for reasons that seem trivial compared to the value of the life of the fetus. Any abortion that is done because of the characteristics of the fetus, including having a genetic disorder such as Down syndrome, are both unjust discrimination against those who have such a disorder and express a message that people who have such a disorder do not have the same value as those who do not. Many women are pressured into having abortions, and do not actually freely choose them.

The problem with what Williams has written is that sex-selection abortion is just clearly wrong. It is wrong to kill a fetus because that fetus is female and end the life of the girl and woman who that fetus would have become just because she is female. That is a clear violation of women’s rights. The fact that this helps us see that abortions in other situations are also clear violations of more universal human rights should make people question whether those abortions are also wrong. It does not mean that sex selection abortion is permissible.

Getting the Best Possible Organs for the Rest of Us

By Mark McQuain

A recent September 6th Perspective in the NEJM entitled “Voluntary Euthanasia – Implications for Organ Donation” teases with the following lead-in:“Canada now permits physicians to hasten the death of a patient by means of physician-assisted suicide or voluntary euthanasia. This development creates a new pathway for organ donation – and with it, some challenges.” Kudos to the NEJM marketing department for luring me into finally buying a full subscription. I’ll summarize some key points for those without a subscription.

The article begins by summarizing some differences between the comatose patient receiving end-of-life care in a standard ICU environment and the situation of individual intending voluntary euthanasia in a hospital. Healthcare teams may rely on surrogate decision making in the first instance but require first person consent in the euthanasia instance. Also, use of sedatives and analgesics in traditional end of life care are guided by the doctrine of double effect (intending comfort but not death) whereas physicians are not legally required to titrate those same medications in the instance of voluntary euthanasia (where euthanasia is legal). These issues are effectively the non-controversial portion of the article.

The heart of the article dealt with what one ought to do in the situation of a patient who wants to donate his or her organs “in the best condition possible” while receiving voluntary euthanasia. This would involve “procuring the patient’s organs in the same way that organs are procured from brain-dead patients (with the use of general anesthesia to ensure the patient’s comfort).”

The problem is that these patients aren’t brain dead yet. The authors are frustrated that awaiting brain death, even in voluntary euthanasia, results in sub-optimal quality of the donor organs. Harvesting organs from voluntarily euthanized patients before they are brain-dead “would require an amendment to the Criminal Code of Canada, which defines medical assistance in dying as the administration of a ‘substance’ by a qualified provider. By this definition, organ retrieval is not an accepted cause of death.” (N.B.- Though it most certainly is the cause of death!)

For those unable to retrieve the NEJM article, I offer a similar article by Dominic Wilkinson and Julian Savulescu supporting the same ethical argument (that it is OK to cause the death of an individual by harvesting their organs if they wished voluntary euthanasia). They summarize Dr. Robert Truog’s bioethical position (one of the authors of the present NEJM article) in footnote 66 as follows:

“Truog’s justification for ODE [Organ Donation Euthanasia] is different from that presented here [in our paper]. He argues that current concepts of brain death and the dead-donor rule are incoherent, and he proposes an alternative based upon the principles of autonomy and non-maleficence. We find Truog’s arguments compelling. Our paper can be seen as providing a complementary argument in favour of ODE. Truog favours a narrow definition for the group of patients who may consent to this procedure: only those who will die within minutes of withdrawal of life support, or who are permanently unconscious. Our definition of LSW [Life Support Withdrawal] donors overlaps with Truog’s, but includes the larger group of patients from whom it is permissible to withdraw life support in intensive care, and whose death is highly likely to ensue (though not necessarily instantly).”

To be blunt, what both groups are arguing is that it should be OK to surgically remove organs from an individual who is not brain dead though has already consented to voluntary euthanasia, knowing that the surgical removal of the organs will cause the immediate death of the individual. The priority of marrying euthanasia and organ donation is obtaining the best possible organs for the rest of us.

As a counter argument, I again turn to Wesley Smith for his thoughts in a recent National Review article similarly entitled “Canada Conjoining Euthanasia/Organ Donation”. It is short and to the point.

I must concur with Wesley Smith: The slippery slope of euthanasia is getting more slippery. How long before we grease those skids further by paying for the organs so harvested?

Reducing Abortion Regardless of Roe v. Wade

By Mark McQuain

The selection of the next Supreme Court Justice has perhaps naturally unleashed a flurry of op-eds describing the post-apocalyptic world that will result from any partial or complete reversal of Roe v. Wade. In the July 18th, 2018 Perspective in the NEJM, Dr. Julie Ingelfinger offers the tragic case of a foreign nursing student she befriended while both were training in New York in the late 1960s. The student was finishing her final nursing year and was engaged to be married when she became pregnant despite the use of contraceptives. Per Dr. Ingelfinger, neither the student nor fiancé had “the means to provide for a baby, so they reluctantly decided that terminating the pregnancy was the only choice.” The only abortion option available at that time, pre-Roe v. Wade, was a “back-alley abortion.” After the abortion, the student developed sepsis, resulting in a hysterectomy and kidney failure. Dr. Ingelfinger oversaw the dialysis and despite appropriate medical care, the student died suddenly from complications of the dialysis. Dr. Ingelfinger’s reason for sharing this story now is to remind us that back-alley abortions resulted in similar complications in many other young women pre-Roe v. Wade and warn that if Roe v. Wade is overturned in the future, young women seeking abortion will again suffer the same fate as her nursing student friend.

In a similar vein to Dr. Ingelfinger’s editorial, there is a second op-ed on CNN website on May 5, 2018 by Danielle Campoamor entitled “Why Supporting Abortion is a Pro-Life Position”. She fears any future restrictions in Roe v. Wade will result in the suffering or death of young women seeking an abortion and wants everyone to have the “safe, affordable and relatively easy abortion” that she experienced:

“I wasn’t subjected to mandatory waiting periods, forced counseling or an abortion provider required to regurgitate state-mandated, inaccurate information. I didn’t have to travel long distances, worry I was getting there too late in the pregnancy, find money to pay for child care or walk past angry or intrusive protesters. Instead, I went in pregnant and, a few hours later, came out with my future back in my control.”

In both articles, the focus is unilaterally on the health and life of the mother. Ms. Campoamor’s position is easily challenged, if not decimated, by including the health and life of the baby in her calculus. Dr. Ingelfinger’s premise requires more unpacking.

Her position appears to be that all future unwanted pregnancies in an overturned-Roe v. Wade world would require a pre-Roe v. Wade “back-alley” surgical abortion. Many Latin American countries have never legalized abortion yet their illegal abortion fatalities have dropped as medical abortifacients (morning after pills) have replaced surgical abortion methods. Interestingly, both the author of the previously linked article on the Latin American experience and Dr. Ingelfinger cited economics (and not legality) as a main reason for choosing abortion. Analysis of the statistics on why women in the US choose to abort challenges this assertion. A clear understanding of these statistics might help identify strategies that lead to a voluntary reduction in the number of abortions, absent changes in the legal status of abortion.

There is a nearly 15-fold increased risk to carry a baby to full-term than it is to have an elective abortion. We have “successfully” divorced sexual activity from the risk and responsibility of bearing and rearing a child, as long as we are willing to use abortion as the definitive stop gap in maintaining our birth control. From my standpoint, this success and this control has come at a terrible price, namely the deaths of over 60 million babies in the US alone. Sadly, I pessimistically do not believe that there will be a meaningful change in the Federal law regarding abortion, regardless of who becomes our next Supreme Court Justice (link requires subscription). There are simply too many women and men who have come to rely upon the type of control of their future activities that abortion provides. Therefore, I ask Dr. Ingelfinger, Ms. Campoamor and all of those on the other side of the abortion divide: must all unwanted pregnancies end in abortion (medical or surgical), regardless of the status of Roe v. Wade?

Mumbling orphans—a bit more

Mark McQuain has raised the persistent, vexing issue of the pricing of drugs for rare diseases—in the case at hand, Sarepta’s eteplirsen (Exondys 51) for Duchenne Muscular Dystrophy, the disease over which the late comedian Jerry Lewis lost sleep every Labor Day weekend for years.

Mark provided an excellent summary (he calls it “crude,” but it’s anything but that).  In this case, the concern is not just price for a truly rare disease, but whether the drug showed sufficient evidence that it worked for FDA to approve it.  In the absence of alternative treatments, that was the truly tempestuous issue for Sarepta.  (Recall that under the 1962 Kefauver-Harris amendments to the Federal Food, Drug, and Cosmetic act, drug manufacturers in the U.S. may not sell a drug unless the FDA finds it not only safe, but effective—a standard that generally applies worldwide.)  It’s one thing for a drug to have a high price, but rather another if it doesn’t work, or doesn’t work very well.  (I decline to comment publicly about the Sarepta data; outside my expertise.  Those seeking a case in point may wish to consider Avastin for breast cancer.)

And to be sure the high price concern dogs other treatments that appear to work quite well—such as high-profile ones for cystic fibrosis or for cancer.  A case can be made that such drugs are worth the price, that too much government heavy-handedness risks stifling innovation, and that a search for the “just price” is misguided, but also, for sure, that society should share the costs of some of these drugs, that measures should be taken to limit out-of-pocket costs to disease sufferers, and that reimbursement approaches are ripe for overhaul.  In that last bucket: if drugs work only some of the time, only pay for the cases in which they do work; foster true competition (rather than having the costs of all drugs in a class go up when a new one is introduced, as if drugs were houses); eliminate the middle man (i.e., pharmacy-benefit managers that take a cut—that appears on the horizon); and the “biggie,” having government payers push back harder on prices.  At least some of these measures seem likely, and at least some seem warranted.

But overall, high costs for truly innovative treatments are justifiable, where no alternatives existed previously and especially when other, more expensive and quite possibly less effective medical treatments may be obviated (see: drug treatment for hepatitis C vs liver transplantation).  This is not to endorse price gouging for existent, cheap drugs that fall into an incidental monopoly (in which case, BTW, elimination of said monopoly, through regulatory facilitation of alternative sources, is warranted).

The Cost of Getting RNA to Mumble

By Mark McQuain

In my previous blog entry, I crudely summarized the genetic basis for Duchenne Muscular Dystrophy (DMD) and one pharmaceutical company’s (Sarepta) current effort to research, manufacture and finance a genetic treatment that increases the production of a muscle protein missing in patients with DMD called dystrophin. Please see my previous blog entry for that summary or this article for a more detailed thorough overview of the science and investigational process to date. For this blog entry, I want to consider the bioethics of the cost of Sarepta’s treatment eteplirsen (Exondys 51), currently estimated on average to be around $300,000 per year.

DMD is a devastating disease that generally causes the patient’s death by his mid-twenties but it only affects a very small number of boys and young men worldwide, estimated to be around 400-600 newborn males in the US each year. This small number of patients places medications for DMD in a category called Orphan Drugs, those that benefit fewer than 200,00 people per year. Eteplirsen is only beneficial in the 15% of DMD patients that have the specific RNA defect in dystophin protein production that eteplirsen corrects. Back-of-the napkin calculations mean that if 15% of all 600 boys born in the US every year with DMD (90 boys per year) used Sarepta’s $300,000-per-year drug, that is a $27 million increase in revenue (not profit) to Sarepta each year. While that sounds huge, it ignores the massive expensive cost barriers to bringing such a drug to market, including research, investigational studies to gain FDA approval and legal financial risk with future adverse effects yet unknown. Inability to gain FDA approval prohibits access to capital markets necessary to fund such a process. Were it not for grants available for orphan drugs, it is unlikely that eteplirsen would exist. Better for drug makers to target their R&D to a bigger disease market for the chance of a bigger reward (consider Bayer aspirin and their $3.3 BILLION profit in 2011 alone).

There are calls for Sarepta to “give back” some of their potential future income, calls from the very organizations that were their staunchest supporters in their FDA approval process. Strong ethical arguments are made that the company did benefit early on by using federal grants and this alone should require the company to reduce a portion of their future income by lowing the cost to patients. Calls for the FDA to federalize Sarepta’s patents and take government ownership will most certainly go unheeded as that would cause every other orphan drug manufacturer to immediately discontinue any further financial risk for fear of similar confiscation.

There are, however, opportunity costs beyond the financial. Some would say that the FDA approved eteplirsen with extremely flimsy data, as less than 10 boys showed borderline promising results when the drug was approved in November 2016. That FDA approval allowed Sarepta to survive as a company. Per the editorial board at the Wall Street Journal(subscription needed):

“But if FDA had cashiered that therapy, Sarepta would have lacked the resources to continue its research and testing to treat Duchenne and develop what may be an even better drug. If eteplirsen had failed to get approval, dollars and brain power would inevitably have flowed toward treating other diseases with more promise of success. FDA has tremendous influence over private investment.”

Indeed Sarepta has new genetic treatments in the pipeline which reportedly do provide increased levels of dystrophin, even for RNA patterns beyond what eteplirsen can presently correct. Have the ends justified the means? Presently, for DMD patients, despite the $300K yearly price tag for eteplirsen, that answer may be – yes. Sadly, there are no other currently functional treatment options for DMD – yet.

From a public health standpoint (and a public funding standpoint), orphan drugs for treatment of small population diseases like DMD are non-starters. Is the only answer to provide the opportunity for great financial reward to encourage individuals to assume all of the private risk?

Forcing RNA to, at least, Mumble…

BY MARK MCQUAIN

We are at a turning point in medicine where instead of supplementing patients with proteins or enzymes that their bodies fail to manufacture due to genetic abnormalities, we soon may be able to re-engineer the abnormal DNA, restoring the DNA’s ability to instruct the body to make those same proteins or enzymes. On our way to full-fledged genetic engineering, we have learned that DNA makes something called RNA, which can be thought of as specific instructions for assembling these vital proteins, telling cells exactly how to assemble protein building blocks, called amino acids, in their proper sequence. Even a very minor disorder in a very long amino acid sequence of a protein can cause that protein to function poorly or not at all. When bad DNA makes bad RNA, or when good RNA gets subsequently damaged or misread, the protein either gets assembled in a garbled fashion, or not at all. Think of RNA as the boss of protein production who can speak clearly, mumble or say nothing at all. Recently, there is one well-known disease where it looks like it is possible to force bad RNA that presently says nothing at all to, at least, mumble.

The disease is Muscular Dystophy (MD) and the missing necessary protein is called dystrophin. Dystrophin is responsible for the structural integrity of muscle. Poorly formed or garbled dystrophin results in a mild form of MD, such as one called Becker Muscular Dystrophy (BMD) where patients can live well into their 40s or 50s. If no dystrophin is produced at all, a severe form of the disease called Duchenne MD (DMD) results, in which muscles simply fall apart over a shorter period of time, causing patients to stop walking in their teens, usually dying in their twenties from cardiac or respiratory muscle failure. While it would be great to restore normal production of dystrophin in patients with DMD, one company called Sarepta, appears to be able to cause patients with DMD, who normally do not make any dystrophin, to produce a garbled dystrophin, giving them a milder BMD-like disease.

Consider the following sentence: “The big red fat cat bit the sly fox and ate the shy jay”. The individual letters represent the RNA sequence and the three letter words represent unique amino acid protein building blocks, resulting in a meaningful protein sentence – think of this as the normal dystrophin protein in a healthy person. If the RNA was missing the 22nd through 24th letters (the 8th word “sly”), the sentence becomes: “The big red fat cat bit the fox and ate the shy jay”. It is a minimally garbled version of the first sentence but still meaningful – think of this as the dysfunctional dystrophin in milder BMD. If the original RNA sequence was missing only the 7th and 8th letters, the sentence becomes: “The big dfa tca tbi tth esl yfo xan dat eth esh yja y”. This sentence has no meaning beyond “The big” – think of this as no dystrophin in severe DMD. If we could get the RNA reader to ignore the first letter “d” in the last RNA sequence, the sentence becomes: “The big fat cat bit the sly fox and ate the shy jay”. We are back to a minimally garbled version of the first sentence but still meaningful – think of this as another dysfunctional protein in a milder “Becker-like” MD. This is how scientists at Sarepta appear to have taken an RNA sequence that originally said nothing and forced it to mumble, producing a new garbled form of dystrophin, which works better than no dystrophin at all.

I realize this has been a long walk in the weeds for some of our regular readers but hopefully it has provided some helpful background into the current treatment of MD and a sense of how much further we have yet to go. I will use this blog entry as background for my next blog entry to discuss some of the bioethics around the cost of getting RNA to mumble.

For now and for me, advancing medical knowledge like this convinces me of how fearfully and wonderfully we are made. (Psalm 139:14)