Much like the reflected glory of working in an institution with Nobel prize-winners, I am basking in the reflected glory of working at an institution that has more or less successfully applied gene therapy to alleviate the suffering of children with incurable genetic diseases. And they’re fighting the good fight, because sometimes, they win.

Luigi Naldini wrote, in his Perspective:

[This study is] the successful first clinical testing of an HIV-derived vector in hematopoietic stem cell (HSC)–based gene therapy. The procedure was used to treat a severe neurodegenerative disease, X-linked adrenoleukodystrophy (ALD), and the results indicate stable expression of a therapeutic gene in a substantial fraction of patients’ hematopoietic cells, as well as clinical benefits.

Why was it so necessary to use gene therapy as opposed to other cutting edge tools? First, the setting. In the words of the authors:

The ALD protein participates in the peroxisomal degradation of very-long-chain fatty acids (VLCFAs) in oligodendrocytes and microglia, and deficiency of this protein disrupts myelin maintenance by these cells. Affected boys enter a phase of active multifocal brain demyelination when they are 6 to 8 years old. Most die before reaching adolescence.

It makes one quail. Your little boy starts school, is perfectly normal, and then the nightmare begins… “In untreated ALD patients, the decline of performance and verbal functions is inevitably continuous and devastating during the first 2 years after the onset of inflammatory demyelinating lesions.”

Second, the only other possible treatment is to find an allogenic bone marrow donor. We all know how difficult and random that can be. After that, and if the lesions are not too advanced, the child has to survive the graft and it has to take, none of which are givens. Thus, successfully validated gene therapy is true hope for a previously hopeless situation.

The authors were very careful to not publish their results immediately but have been following their treated patients for the last two years. They have applied a technique to make sure that the treated cells of the immune system, which then infiltrate brain tissue and act as portable garbage removers of the VLCFAs, remain stable and display no warning signs that they could become cancerous. One of those signs could be that only one or a few engineered cells survive and multiply unduly.

They used a delightfully modern technique of high-throughput sequencing to make sure that there were lots of different sites of insertion of the therapeutic vector present in the circulating blood cells, and that that diversity did not diminish over time.

The treatment is at least as good as bone marrow transplantation in preventing additional degradation. In part of the brain of one of the patients, there was actually reversal, “a process that does not occur spontaneously in ALD.”

Two seven-year-old boys clearly benefited from this new technique. May there be many more.

Finally, the discussion concludes, rightly:

HSC gene therapy might also be considered as a therapeutic option for adult ALD patients who develop cerebral demyelination, for whom the mortality risk of allogeneic HCT is ~40%.

Hooray for Marina, Alain, Patrick and all their collaborators! Hooray for these two little boys and their families!
-
Cartier, N., Hacein-Bey-Abina, S., Bartholomae, C., Veres, G., Schmidt, M., Kutschera, I., Vidaud, M., Abel, U., Dal-Cortivo, L., Caccavelli, L., Mahlaoui, N., Kiermer, V., Mittelstaedt, D., Bellesme, C., Lahlou, N., Lefrere, F., Blanche, S., Audit, M., Payen, E., Leboulch, P., l’Homme, B., Bougneres, P., Von Kalle, C., Fischer, A., Cavazzana-Calvo, M., & Aubourg, P. (2009). Hematopoietic Stem Cell Gene Therapy with a Lentiviral Vector in X-Linked Adrenoleukodystrophy Science, 326 (5954), 818-823 DOI: 10.1126/science.1171242

Back in Paris from a brief stint in Marseille:

Funny, the difference 800 km makes. Everything is so much dimmer up north and continental.

The once-homeless and still clearly jobless fellow who sits at the corner of the escalator coming up into Montparnasse train station, has a bright smile and a handshake ready every day, at nearly any hour I head into the laboratory. I think he is Eastern European in origin, given his accent. The top of his pate shines from the top of the stairs that I take down to pass him and head to work. I wonder if he has ever taken the TGV*.

*(train a grande vitesse = high-speed trains leaving from all the major Paris stations)

The passage Vaugirard brings one efficiently through a city block and comes out facing a street that leads right into the ambulance emergency entrance to the Necker Children’s Hospital. I head in after lunch, after the flight back to Paris with my children. I missed the man who daily, mops the tiles of this semi-outdoor passageway, but it’s only normal as he has a schedule to follow. He’s an equally cheerful sort to the gentleman I described above, seemingly from the Caribbean but with a pure metropolitan French accent, also always ready with a handshake. Or a clasp, to be more precise. This is the working man’s clasp, a break from the mop. Vacation coming up? Had a good weekend? Bon courage!

When pigeons strut across my path along down there, as they are fat and happy from the crumbs scattered by people breaking off the ends of the baguettes they purchased at the chain bakery at the top of the stairs, I divert my path around theirs. I dislike making pigeons or sparrows expend extra energy, or adrenalin, or otherwise cause stress in their little birdbrains. Perhaps they will not sully my hand-clasping friend’s handiwork quite so quickly, if I don’t make them shit in fear? But the toddlers on their way to the creche along there are quite happy to make up for lost occasions.

No point to any of this musing, just noticing.

About two weeks ago, I started to be plagued with an inflammation of the membrane that encases the knee joint, called bursitis. The membrane secretes extra synovial fluid, and the pressure was indeed painful. I was struck by the amount of sympathy that this particular affliction elicited from my family and friends. (Thanks!). Since it keeps flaring up, an infiltration of cortisone into the joint this afternoon may calm things down for up to a month.

However, my expressions of pain in form of complaint are not really proportional to the pain itself. My complaints are verbal outlets to reduce the mental pressure that results from the frustration engendered by the pain. But the best way to describe pain itself is to elicit an empathetic reaction in the listener, by which they draw parallels with their own painful experiences and use their imagination to extrapolate.

Having tried a number of hands-on methods to learn about pain, all I can say is that the kind of pain induced really differs, but not how. It’s strange not to have the words to describe the the quality of feeling between them, but I can class them in order of least to most disagreeable ¹. When I look at the list, factors in the pain felt seem to be:

• Actual damage caused

• Novelty

• Chronicity

The British Pain Society among others has published a series of standard language translations of pain measurement scales for cognitively unimpaired adults.

The criteria being assessed are:

• Intensity (over time or not)

• Distress

• Relief upon treatment

A variety of other methods for assessing the same criteria in people who have problems using language are presented on a consecrated website called pain.com by Dr. Feldt.

As she points out, “Persons with dementia may not initiate conversations about pain or seek relief for pain because they have forgotten where they are, whom they should tell, or what event initially caused the pain.”

But they feel pain, and can be relieved from it with treatment. So verbal representation of pain and the attendant surprise or shock, is already distinct from the state itself.

A Checklist of Nonverbal Pain Behaviors (CNPI) is available here, and Dr. Feldt’s article from which it is derived is here

I wonder if, like for children, elderly people with dementia would actually find pain more distressing, and therefore more painful, when they can not draw on their memories of previous experiences of that particular kind of pain (eg. damage to the skin, or visceral pains of different sorts)? In addition, since they can express their feelings less well, they clearly don’t always get the reassurance and treatment they need.

A paper from the appropriately named journal, Pain, cites and presents additional evidence that the experience of pain can be somewhat analgesic for new encounters with pain: “Evaluation of pain severity depends on the context in which pain occurs.” One of the authors, Dan Ariely, has also written a very personal pamphlet describing his experience with burn pain and his subsequent step(s) back and analysis of its perception.

Ariely notes a number of interesting observations.

First, the altered perception of time, like for the pain itself, has to do with the level of shock – it’s a coping mechanism. Good for getting away from whatever caused the pain, but bad for the perception of how painful it was. What I called novelty, above.

Second, “pain that worsens over time is perceived to be more painful than pain that improves, or one that remains at the same level.” (cf citations therein). Related to what I called chronicity, and what the BPS termed “relief upon treatment”. Again, if the overall memory of the pain is something that gets progressively worse over time until the last experience of it, then one’s tolerance is reduced, the next time it happens. This makes me think somewhat of childbirth ². The fear of the pain is certainly part of the pain, and I came to that conclusion before I read any of Dr. Grantly Dick-Read ’s work. My first birth experience was already not horrific (although a touch of morphine when the forceps went in was welcome),so I was not dissuaged by the pain for a second delivery with really no painkillers. As it went better and faster than the first, I’d face another with even less anxiety (this does not suggest it’s underway, nor that I am dogmatic about avoiding painkillers for childbirth!). This willingness to face another delivery is contrary to some, but luckily, not most.

For the memory-impaired elderly person, perhaps the lost analgesic effect from not being able to draw on earlier painful experiences ³, is somewhat offset by not remembering that a chronic pain is objectively worse than a day earlier, or a month earlier? Or is there really such a thing as objective pain? Probably not. I’d have to experience renal colic to know if it is more or less painful than peritonitis. Pain is relative, and it’s really in the mind.

For children, I can attest from personal experience that their memory of an earlier painful event that did not improve, conditions their anxiety and therefore their perception of the next. My daughter had a number of skin reconstruction surgeries, and it was bandage-changing in the first couple weeks after each that was the most stressful and, presumably, painful. Like Ariely, she had to have iodine bath/shower sessions to unstick the first bandages, wash away the accumulated necrotic crud, and apply new ones. In later weeks, the glue from the bandages usually took off a superficial layer of the surrounding epidermis, to add injury to injury.

Nearly a decade later, when I came across one of the nurses who had participated in these sessions, she clearly remembered my daughter, her reactions, and my earnest efforts to make the bandage-changing as anxiety-free as possible. Also like Ariely, there were the nurses who allowed my daughter and myself “to have breaks and even, from time to time, remove some of (her) own bandages” and, especially early on, the ones who “gave [us] no control over the treatment process”. For the operations in the first year, letting her remove her own bandages was clearly not ideal. But quickly, I stepped in, realizing that if I could communicate any sense of control and expectation to my daughter, it was a comfort to both of us.

I should also add that my son is quite frightened of the pain of needles, to the point of tensing up so much that he’ll squeeze out blood upon an intramuscular injection ⁴.

Working at a children’s hospital, and frequenting collaborators at another specialized in cancer treatments, has shown me many examples of children who bear what seem to be excruciating conditions with a phenomenal amount of forebearance, because they are reassured. In this respect, not having a past reference point can be a boon.

So, to sum up all this, anxiety and the relationship of the ongoing experience to previous ones (based on memory), seem to be major factors in pain perception.

Footnotes

¹ Here are the owies that come to mind. There are probably a couple other minor ones.
- Epilation
- Superficial cuts and skin fissures
- Sunburn (I never let it get bad)
- Breast compression in mammograms
- Muscular fatigue from exercise
- Over-stretching
- Muscle aches from fever or lack of sleep
- Perineural fibrosis aka Morton’s neuroma
- Violent contusion (eg. falling, bike accident)
- Slamming a nailbed in a heavy metal frame of some sort or another
- Abscesses such as in the jaw, skin or breast
- Migraine
- Sciatica
- Burn (second degree)
- Sprains or cartilage issues (ripped meniscus or intervertebral disk issues, arthritis)
- Visceral pain such as childbirth, kidney infection, appendicitis
- Peritonitis (a whole other category despite being visceral)

² Childbirth, with its attendant possibilities of medical problems, is often brandished as an example of severe pain.

³ Older patients with visceral disease are more likely to present without pain

⁴ More recently, we’ve used topical analgesic like 1% lidocaine an hour ahead, under an occluding bandage, to great effect. A hint to other parents who find that the massively proven benefits of vaccinating their children outweigh the unsubstantiated inconvenients. But apparently, getting rid of the anxiety may be even better in eradicating pain than getting rid of the nerve transmission, though the assurance that the latter is effective may also reduce anxiety in a kind of positive feedback loop. A little harder to get rid of other kinds of anxiety.

This week’s Nature featured a Letter ¹ by Vecsey and colleagues entitled, Sleep deprivation impairs cAMP signalling in the hippocampus.

As an aside, a good title for the Good Paper Journal Club, were it not moribund from lack of time for people to keep it alive. And I see why this subject appealed to the editors, since it can appeal to all of us. Who among my readers is not sleep-deprived at some point or another?

I am another researcher experimenting on herself (how the sleep deprivation is acquired is another story, we’ll put it in Supplemental Methods, shall we?). How much short-term memory non-consolidation will I be able to tolerate until I actually forget to get up and pour more coffee? (Or: will I forget where I placed the mug?)

Caffeine is a non-specific phosphodiesterase (PDE) inhibitor. By inhibiting PDEs, caffeine prevents the PDE enzymes from being so quick about converting cyclic adenosine monophosphate back into its non-cyclic form.

In the other direction, epinephrine (of the famous epi pen) will activate other enzymes that push in the other direction, converting other derivatives back into cAMP.

In adrenalin rushes and caffeine highs, you are alert, and can have side effects such as heart palpitations. Having more cAMP around is a good way to rapidly relax bronchial (and uterine?) smooth muscle – hence, good for rapid relief for asthmatics, and curiously, as a vasoconstrictor, relieving Quincke’s edema or migraine, respectively.

Well, the article in question showed why brief sleep deprivation in a mouse model leads to difficulty in some memory tasks stored in the hippocampus. The lack of cAMP means the synapses, the major communication connections between neurons, don’t change in response to use, they way they should. In particular, it’s because there is too much of one of the PDEs around – it seems to be synthesized in response to the sleep deprivation – specifically, the PDE4A5 isoform of the PDE4 enzyme.

Treatment of mice with [broad, but also more specific] phosphodiesterase inhibitors rescued the sleep-deprivation-induced deficits in cAMP signalling, synaptic plasticity and hippocampus-dependent memory.

While the most specific PDE4A5 inhibitors are being developed to rescue synaptic plasticity and memory deficits produced by a brief period of sleep deprivation and enable the consolidation and persistence of memory, would you please brew me another strong, black cup of java?

Maybe that third cup will help me remember to save all my changes in both open spreadsheets when I close the program, and also to remember that the dialogue “Save changes?” is not the same as “Close the program?” when my itchy trigger finger on the mouse hovers over the “No” response.

If only I had a counter to see how many times I had to change windows, and go back and double-check, when flipping between the article, PubMed, and this post. I had better go try to terminate my test of the relevance of the sleep-deprivation mouse model to memory behavior of a scientific peer, this weekend.
—

¹ Nature 461, 1122-1125 (22 October 2009) doi:10.1038/nature08488

After the serious Lab Waste video by a local blogger whom we all know and love, here is The Safety Song:

Starring the world-famous Bokor Monster.

Courtesy of The Sounds of Science, from creative members of my alma mater.

A major plus for an American living in Western Europe is the proliferation of small, farmers’ style markets. While there are a few communities with such markets on the Western edge of the Atlantic, it’s not standard.

In France, the covered market has also become less standard over time, with the convenience of parking and packaging in what are known as “hypermarkets”. For the working scientist in the city, it can be very attractive to order all heavy things online to be delivered during a programmed two-hour window directly to your door.

However, nothing beats the local Market.

It’s possible to spend one’s Sunday morning revising a manuscript, look up at noon and realize you have nothing to feed your family at lunch, and dash down the street to the covered market.

The next time this happens to me, I will bring my own camera. It’s pittoresque à souhait – the seventeenth-century footpaths one can take perpendicular to the market road, the early twentieth-century meulières along the way, none of which are alas mine, and hedges and roadworks galore.

I was able to score the last one of these (resisting the particularly well-done, crunchy fried potatoes):

in favor of a couple of these:

and enough of these:

followed by decidedly non-pasteurized:

(only the one on the right, Abondance)

and, thanks to the wine-making family connections of my former student, some of this (actually it was from Domaine Maurice Gavignet, which I’d recommend):

And these to finish ¹.

I was going to actually wax poetic about the perfectly gorgeous and abundant orb-weaving spiders I met on the road, and their marvelous works of industry, and how they each seem to have a favorite leg to hook each segment of their web onto the support threads. But I’m afraid if I put up photos, that will put you off your appetite.

The French would never forgive me.

¹ Thanks to all the photographers for making their photos available with the CC license.

My first Ph.D. student successfully defended her thesis yesterday afternoon, completing the journey during which we took the above photo, years ago.

She did a great job.

I have all sorts of interesting feelings about this process that I’m not quite sure how to put into words, but pride is up there high on the list.

She’ll be back in November, hired by our cardiology colleagues to continue stocking DNA for a prospective research cohort into certain heart defects, and then will spread her wings and fly to a great lab in the U.S. for her postdoc.

I need to take stock, but perhaps the weekend will help with that.

Any other advisors feel a bit of “empty nest” syndrome? And relief?

How is it possible to concentrate on football scores, or even Nobel results, in the face of small or large tragedies?

It all has to do with what you pay attention to.

This blog post discusses papers that did research into attention and distraction, describing the balance between

top-down, controlled attention towards current goals and goal-relevant stimuli [and a differently wired network that] interrupts or “circuit-breaks” [the former].

In other terms, it’s what happens when you return home from a choir rehearsal, intending to revise your student’s paper, and you sit down and make the grave mistake of picking up the TV remote.

Current goal: Finish revision.
Circuit breaker: Hugh Laurie.

So when I pick up the free newspaper left on a train seat, and I dawdle over the last-ditch efforts to find Indonesian survivors, is this attention or distraction? Is this morbid curiosity and sensation-seeking, or guilt and gratitude that I’m not there (and not even helping, except for periodic donations to some non-governmental organizations that step in regularly under such circumstances)?

Of course, I’d rather think the latter, but we’re all aware that is a great example of bias.

My favorite way of having the ventral attentional network step in, is when a colleague brings up a new problem based on an interesting patient. This happened earlier this week. A novel stimulus from an unexpected angle – then my brain gets to work on, what experimental approach in developmental biology would allow my geneticist friends to get an extra handle on this problem?

Much more fun than revising articles and figures. Much.

I received a polite complaint from an attendee, followed by an equally polite request from one of the conference organizers, to remove my notes concerning their, or all, talks respectively. But I had cleared it with another organizer on site, though I don’t want to get them in hot water, either. So I just sent the following:

Dear participants in the NTD meeting,

It was a true pleasure meeting you in Vermont. Thank you for all the many interesting conversations and lines of inquiry we pursued together.

I’m writing because I wanted to alert you all to the fact that I make my conference notes available to my laboratory, and thereby to the world at large, on our lab wiki. The notes I took during the four days in Vermont, warts and all, have been posted since those days, at these links:

(The same ones I provided earlier).

I had made my live conference notes known early on to only one of the organizers, and that was a mistake. Coincidentally, Nature recently wrote an editorial about how difficult it is for conference organizers to take a hard-and-fast line, but I’d add that it is a little difficult for attendees to know what line to take as well:

http://www.nature.com/nature/journal/v460/n7252/full/460152a.html

There is also a Nature-run forum discussing this issue here, to which you certainly would be welcome to contribute if you have an opinion on the question (rather than writing back to this mailing list):

http://network.nature.com/groups/naturenewsandopinion/forum/topics/4044

My take is that a communication at a conference is already a type of publication. However, I recognize that it is not a universally held position.

Please have a look at the links I provide above, and if you are at all uncomfortable with my personal take on your presentation, I invite you to send me an e-mail and I will remove my notes about it. Unfortunately, I can’t do much about Google’s cache, but I think it unlikely that anyone would track things that far.

My sincere apologies to anyone who may be unhappy with learning about this retroactively rather than proactively. (Also, sorry if I didn’t take notes and that bothers you! It just meant that the abstracts sufficed for me, or I had stopped live notes by that point.)

Have a great weekend and please excuse me for any offense ¹ I may have caused.

Sincerely yours,
Heather

¹ Link not in the e-mail.

And then I wrote the organizer who brought up the issue, saying I’d be willing to remove all my notes if they consider it necessary. I suspect that I’ll have to just keep the notes on my computer, like for some sensitive group meeting discussions. For the latter, at least I know what I need to elide. But for a conference?

The voiced concern was, for unpublished data, that confidentiality is not observed (though the confidential nature of conference communications was not made explicit, I thought) and that later publication of the material might be jeopardized.

While I admit the former, is the latter at all true? I thought we had sort of settled that question already.

Update:

The other major organizer wrote me and asked me to remove all notes. So I did. And I replied: (because I was sorry to do it)

I’ve often posted my notes from conferences to my lab wiki. I did ask you if I could, and you told me on site that it was alright. Perhaps I wasn’t clear about it, or perhaps you thought it was restricted to my lab only.

I’ve complied with your and (…)‘s request just now, but I was not the only one sending live impressions from the meeting to co-workers in ways that leave traces on the Internet. Therefore, in the future, it might be safer to make the conference policy fully explicit relative to divulgation of notes to each attendee’s laboratory, Ph.D. program institution or the world at large.

Even then, as the links I provided make clear, explicit policy is no guarantee of full confidentiality. This is the risk people take when they attend conferences, and it will become ever more present, as the density of Blackberries, laptops and iPhones in the room attested.

Doesn’t this sound like a bad joke?

You don’t get in often enough to clean your mouse cages. The tech in charge of the animal facility gets huffy about it. You run up against him when you pop into lab fairly late at night, probably to get things tidied up before you get married that weekend.

You get murdered. The tech gets accused and locked up unless he raises millions of dollars in bail.

Some variant on this scenario actually happened. Ms. Le went missing while I was at the conference in Vermont; CNN spent hours speculating about it, showing photos of the security cameras over the modern lab building where she worked, the badges one needs to swipe to get into it to start. The attendees murmured about it. Anyone who has been into lab late at night to take care of experiments or animals thought about it.

Lauren is a postdoc at Yale, and perhaps can report on what her institution proposes to reassure its employees about their safety in the workplace – from humans. I’m afraid there are no right answers, only wrong ones, and hindsight is always the clearest.

I also extend my heartfelt sympathy to the families of Annie Le and Jonathan Widawsky. Now I think of it, to the family of Raymond Clark III, as well. I’m sure they could all benefit from sympathy right now.