Engineering lungs

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This past weekend, I attended my 35th high school reunion. It’s a strange phenomenon to be meeting people you haven’t seen since you were 18, and further weirdness ensues when we discover that most of them are already grandparents. There have been a lot of life changes in 35 years. Saddest of all, though, is the ritual listing of the deceased…and I learned that one of my former classmates died in her late 40s of emphysema, a progressive and irreversible lung disease that leads to the near complete loss of lung function. The only cure right now is a lung transplant, and patients who’ve been suffering with emphysema for long typically have so many other problems that they’re poor candidates for surgery, not to mention that the waiting list for organs is long, and a transplant means a life-long commitment to anti-rejection drug treatments.

There will come a day, though, when new lungs can be built and replacement surgeries more common. That day is definitely not yet here, though, but there are promising signs on the horizon. One such sign is recent work in tissue engineering to grow lungs in a dish.

We can grow functional rat lungs in a tissue culture chamber now, which show some limited ability to support respiration when transplanted back into another rat. Here’s an overview of the procedure; I’ll go through it step by step.

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Schema for lung tissue engineering. (A) Native adult rat lung is cannulated in the pulmonary artery and trachea for infusion of decellularization solutions. (B) Acellular lung matrix is devoid of cells after 2 to 3 hours of treatment. (C) Acellular matrix is mounted inside a biomimetic bioreactor that allows seeding of vascular endothelium into the pulmonary artery and pulmonary epithelium into the trachea. (D) After 4 to 8 days of culture, the engineered lung is removed from the bioreactor and is suitable for implantation into (E) the syngeneic rat recipient.

The first step is to collect a donor rat lung. The organ is cut out of a living rat, who will quickly become a dead rat; this part of the procedure probably can’t be scaled up to human transplantations, for obvious reasons. However, lungs from dead people or perhaps even lungs from appropriately sized animals will be adequate.

This donor lung is then stripped of all of its living cells. This is done by perfusing it with a detergent solution. Membranes dissolve and rupture in the presence of detergent, so all of the cells in the lung are basically destroyed, their contents, including cytoplasm, nucleus and DNA, and membranes and organelles are washed away.

What’s left then? Connective tissue and extracellular proteins. All that’s left is a frothy, fragile matrix of fibers like collagen and elastin, and imbedded signaling proteins that will be useful in supporting the growth of new cells. It leaves behind a kind of porous, pale ghost lung, a collection of microscopic struts that just needs to be draped with new cells.

This is the key step. Lungs are complicated, delicate membranous structures, and it would be hard to regrow it entirely from scratch. Starting with an acellular scaffold, though, a kind of skeleton of a lung that sketches out the arrangement of alveoli and blood vessels gives the tissue engineering a head start. It really is amazing how much of the organization of the lung is still left when all of the cells are removed: the photos below show the air spaces left behind (on the left) and the major blood vessels (on the right). There are no cells here! This is just an outline of the structure left by the still extant connective tissue!

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What’s promising about this so far is that almost all of the antigenic components of the lung are removed; if this lacework of proteins were transplanted into another animal, it probably wouldn’t provoke an immune response. Of course, it also wouldn’t work as a lung, because there are no gas exchange surfaces present, and everything is leaky. It’s only a skeleton of a lung, remember…so let’s fix that.

The next step is to suspend the lung framework in a chamber, with tubes attached to the airways and to the blood vessels. Living, isolated lung epithelial cells are then introduced into the airways, and lung endothelial cells (the cells that line blood vessels) are introduced into the pulmonary arteries and veins. These cells stick to the scaffolds and grow. They actually grow better in the lung matrix than they do in a petri dish, probably because of the presence of growth factor proteins lurking in the acellular scaffold.

The new cells use the matrix as a guide and repopulate and rebuild the cellular structure of the lung. During this whole process, the tissue culture medium is pumped through the arteries to mimic the effects of blood pressure, and air is pumped into the airways. It works beautifully. New columnar epithelial cells grow to line alveoli, and endothelial cells line the blood vessels appropriately, and the cells produce the right secreted proteins, like surfactants that reduce surface tension and are important for allow lungs to inflate. It takes about a week for the new lung tissues to form, and they are robust, producing sheets of cells that can tolerate the same pressures as intact, normal lungs.

Now for the real test. The regrown lungs were transplanted into living rats for 45 minutes to two hours. They worked! Everything stitched together nicely, and the engineered tissues pinked up nicely as blood flowed into them. Blood was visibly oxygenated as it passed through the new lung, and measurements of the partial pressure of oxygen and carbon dioxide in the blood showed that the former went up and the latter went down, exactly as it is supposed to do.

This is all very promising, but the transplantation times were very short, and you might be wondering why. These lungs aren’t perfect. There was bleeding from the blood vessels into the airways, and also some blood clotting — for this to work, the barrier membranes have to be essentially perfect, and they aren’t, yet. The poor rats’ lungs would have spluttered and fallen apart with prolonged use, and the blood clots would have led to thrombosis eventually.

Another problem, and one that has to be solved eventually if this is ever to work for human transplantations, is the source of the cellular components. The connective tissue stuff is only weakly antigenic, so isn’t going to provoke a strong immune response, but repopulating it with foreign cells brings the rejection problem roaring right back. What we need next for long term success is to find a source of lung adult stem cells, or a way to induce pluripotent stem cells to make the cell types needed.

That’s right, we need more human stem cell research. If you need a new lung, and we’re going to have to reengineer one for you in a dish, we’ll need a population of autologous cells — cells from you — to reseed an acellular matrix taken from a cadaver or a pig with lung tissue that won’t trigger an immune response.

This is a long way from being useful for humans, with two big problems still facing us, refinement of the tissue-engineering technique to produce more reliable and complete membranes, and the all-important stem cell research to allow us to create sources of immunologically-compatible cells, but the cool thing is that the questions that need to be answered are in crystal-clear focus, and there are strategies to get us the answers. Time and money and a less restrictive regulatory environment for stem cell work is all that is needed.

Petersen TH, Calle EA, Zhao L, Lee EJ, Gui L, Raredon MB, Gavrilov K, Yi T, Zhuang ZW, Breuer C, Herzog E, Niklason LE (2010) Tissue-engineered lungs for in vivo implantation. Science 329(5991):538-41.

The Problem With Science Is Dumb Non-Scientists

Man, that Heffernan article is turning out to be such an excellent marker for stupid. Now some Catholic wanker is citing it as supporting his claim that scientists are all nasty people, claiming that the problem with science is scientists. Being Catholic, you know exactly who he is going to complain about.

Heffernan writes about the meltdown over at Science Blogs. “Science Blogs”, as you may well remember is the home of blogger PZ Myers who is famous for advancing science by desecrating the Eucharist. While Myers is the most read of the misogamists at Science Blogs, his penchant for the unpleasant is rather standard fare.

“Science Blogs” has recently seen many of its bloggers leave in protest over the addition of a new nutrition blog called Food Frontiers. Science Blogs’ sin that PepsiCo sponsors the site. It is indubitable that nobody does righteous indignation quite like the ungodly.

Wow. Every sentence is wrong.

  1. There is no meltdown. There was risk of one, but Seed got their act together, and we’re all working away productively now.

  2. Cracker abuse is so 2008. Get over it. And no, that wasn’t science, nor did I claim it was: it was a protest against the inanity of reactionary Catholics.

  3. Misogamist? Moi? I’ve been happily married for over 30 years!

  4. Nobody quit over the addition of Food Frontiers.

  5. It was not a sin that Pepsi sponsored the site. The problem was that it was not labeled as an advertisement, and blurred a boundary between advertisement and content. That’s what got people upset, as well as a pattern of infrastructure neglect.

  6. Funny about that ungodly business. I’m definitely ungodly; I’m still here. So is Greg Laden. ERV thought it was all a tempest in a teacup. Jason Rosenhouse didn’t even seem to notice. The biggest ungodliest bloggers here seem to have had a range of reactions; and several of the people who decamped were theists.

Like I said, everyone who cites the Heffernan noise positively seems to be factually incompetent, including Heffernan herself.

The rest of that wanker’s article is just as bad. To defend his claim that scientists are all rotten people, he cites two examples. Galileo: not as nice as you’d think! After all, the Catholic church didn’t behead him, but only sentenced him to a life of confinement, and he had been very rude in mocking the Pope by putting his words into the mouth of a character called Simplicio in his dialogue.

His second case is Alfred Wegener, who he claims was persecuted by a scientific inquisition (every bit as bad as the Catholic inquisition, apparently — despite the fact that we don’t use thumbscrews). Here’s what scientists did to the discoverer of continental drift:

For his insight, Wegener was mocked and criticized and ultimately ostracized by the mainstream scientific establishment. Ultimately he died virtually unknown on an expedition trying to prove his theory.

Well, no. He was a well-respected meteorologist who died on an expedition to Greenland to study Arctic weather. He wasn’t ostracized at all, but was a working scientist right up until his death. His theory of continental drift was criticized and rejected in his lifetime, because he had no mechanism and because his evidence was all circumstantial. That’s what scientists are supposed to do — demand solid evidence. And when that evidence came in after Wegener’s death, the theory was accepted.

I’m kind of impressed. That Heffernan article is smoking out a lot of nobodies who are proudly standing up to demonstrate how stupid they are.

Two checklists for feminists

That implicit consent thread has just broken a thousand comments, so I’m closing it and inviting everyone to move here.

Just to keep it interesting, I found (via Jen) a couple of lists. The one on the left is from one of those liberal progressive sites, and clarifies the whole issue of male privilege, which many of the commenters still fail to comprehend. The one on the right is from a batty wingnut site, where each point is greatly expanded into an exercise in blaming women.

Here’s your opportunity to find some common ground, I hope. There probably aren’t many commenters here who find the list on the right in any way convincing or based on reasoning and evidence (at least, I don’t think Lubos Motl is a commenter here.)

The Male Privilege Checklist

1. My odds of being hired for a job, when competing against female applicants, are probably skewed in my favor. The more prestigious the job, the larger the odds are skewed.

2. I can be confident that my co-workers won’t think I got my job because of my sex – even though that might be true. (More).

3. If I am never promoted, it’s not because of my sex.

4. If I fail in my job or career, I can feel sure this won’t be seen as a black mark against my entire sex’s capabilities.

5. I am far less likely to face sexual harassment at work than my female co-workers are. (More).

6. If I do the same task as a woman, and if the measurement is at all subjective, chances are people will think I did a better job.

7. If I’m a teen or adult, and if I can stay out of prison, my odds of being raped are relatively low. (More).

8. On average, I am taught to fear walking alone after dark in average public spaces much less than my female counterparts are.

9. If I choose not to have children, my masculinity will not be called into question.

10. If I have children but do not provide primary care for them, my masculinity will not be called into question.

11. If I have children and provide primary care for them, I’ll be praised for extraordinary parenting if I’m even marginally competent. (More).

12. If I have children and a career, no one will think I’m selfish for not staying at home.

13. If I seek political office, my relationship with my children, or who I hire to take care of them, will probably not be scrutinized by the press.

14. My elected representatives are mostly people of my own sex. The more prestigious and powerful the elected position, the more this is true.

15. When I ask to see “the person in charge,” odds are I will face a person of my own sex. The higher-up in the organization the person is, the surer I can be.

16. As a child, chances are I was encouraged to be more active and outgoing than my sisters. (More).

17. As a child, I could choose from an almost infinite variety of children’s media featuring positive, active, non-stereotyped heroes of my own sex. I never had to look for it; male protagonists were (and are) the default.

18. As a child, chances are I got more teacher attention than girls who raised their hands just as often. (More).

19. If my day, week or year is going badly, I need not ask of each negative episode or situation whether or not it has sexist overtones.

20. I can turn on the television or glance at the front page of the newspaper and see people of my own sex widely represented.

21. If I’m careless with my financial affairs it won’t be attributed to my sex.

22. If I’m careless with my driving it won’t be attributed to my sex.

23. I can speak in public to a large group without putting my sex on trial.

24. Even if I sleep with a lot of women, there is no chance that I will be seriously labeled a “slut,” nor is there any male counterpart to “slut-bashing.” (More).

25. I do not have to worry about the message my wardrobe sends about my sexual availability. (More).

26. My clothing is typically less expensive and better-constructed than women’s clothing for the same social status. While I have fewer options, my clothes will probably fit better than a woman’s without tailoring. (More).

27. The grooming regimen expected of me is relatively cheap and consumes little time. (More).

28. If I buy a new car, chances are I’ll be offered a better price than a woman buying the same car. (More).

29. If I’m not conventionally attractive, the disadvantages are relatively small and easy to ignore.

30. I can be loud with no fear of being called a shrew. I can be aggressive with no fear of being called a bitch.

31. I can ask for legal protection from violence that happens mostly to men without being seen as a selfish special interest, since that kind of violence is called “crime” and is a general social concern. (Violence that happens mostly to women is usually called “domestic violence” or “acquaintance rape,” and is seen as a special interest issue.)

32. I can be confident that the ordinary language of day-to-day existence will always include my sex. “All men are created equal,” mailman, chairman, freshman, he.

33. My ability to make important decisions and my capability in general will never be questioned depending on what time of the month it is.

34. I will never be expected to change my name upon marriage or questioned if I don’t change my name.

35. The decision to hire me will not be based on assumptions about whether or not I might choose to have a family sometime soon.

36. Every major religion in the world is led primarily by people of my own sex. Even God, in most major religions, is pictured as male.

37. Most major religions argue that I should be the head of my household, while my wife and children should be subservient to me.

38. If I have a wife or live-in girlfriend, chances are we’ll divide up household chores so that she does most of the labor, and in particular the most repetitive and unrewarding tasks. (More).

39. If I have children with my girlfriend or wife, I can expect her to do most of the basic childcare such as changing diapers and feeding.

40. If I have children with my wife or girlfriend, and it turns out that one of us needs to make career sacrifices to raise the kids, chances are we’ll both assume the career sacrificed should be hers.

41. Assuming I am heterosexual, magazines, billboards, television, movies, pornography, and virtually all of media is filled with images of scantily-clad women intended to appeal to me sexually. Such images of men exist, but are rarer.

42. In general, I am under much less pressure to be thin than my female counterparts are. (More). If I am fat, I probably suffer fewer social and economic consequences for being fat than fat women do. (More).

43. If I am heterosexual, it’s incredibly unlikely that I’ll ever be beaten up by a spouse or lover. (More).

44. Complete strangers generally do not walk up to me on the street and tell me to “smile.” (More: 1 2).

45. Sexual harassment on the street virtually never happens to me. I do not need to plot my movements through public space in order to avoid being sexually harassed, or to mitigate sexual harassment. (More.)

45. On average, I am not interrupted by women as often as women are interrupted by men.

46. I have the privilege of being unaware of my male privilege.

8 Ways Fascist Feminists Are Ruining America’s Women

8. Encouraging Promiscuity

7. Sanctioning Victimhood

6. Dabbling In Misandry

5. Destroying Chivalry

4. Attacking Motherhood

3. Requiring A Feminist Litmus Test

2. Promoting Lies and Manipulation

1. Glorifying Abortion

In the list on the left, it’s true for me on 45 out of 46; the only exception is #15, just because of the quirks of being at this particular small liberal arts university.

Wherein ‘jerk’ is defined as anyone who vigorously opposes creationism

Virginia Heffernan did us all a favor: it’s easy now to tell who the ignoramuses are by looking for favorable reactions to her ill-informed screed. And of course, if you want to find a real ignoramus, we wouldn’t even need that much: we could just look to Rod Dreher, apologist and apparatchik of the Templeton Foundation. He thinks Heffernan is onto something, by which I think he means she reiterates his same clueless biases.

Heffernan is onto something here, and not just with ScienceBlogs. A few years ago, I was in an editorial board meeting with some pro-science academics and others, who had come in to speak to us about some issue, I forget precisely what, having to do with science education in Texas. We entered that meeting entirely on their side, but by the time it was over, we were, as I recall, still on their side on the merits of the argument, but we had a distinctly nasty taste in our mouth. The advocates were simply dripping with contempt for their opponents, and carried themselves with an aristocratic hauteur, as if they considered it beneath them to be questioned by others about this stuff. I never quite got a handle on why they acted that way, but reading Heffernan, it’s more clear: I thought these people had come to argue about science and science education, but whether they realized it or not, they were class warriors. They acted the same way you would expect 19th century colonial English vicars to behave if asked to give a serious thought to the protestations of the dark and inscrutable Hindoos of the Raj.

What is it with science-oriented advocates who consider contempt a virtue? Who, exactly, do they think they are going to persuade? (You could say the same thing about sneering political bloggers, sneering religious bloggers, and, well, sneerers in all forms of public discourse, inasmuch as sneering seems to be a popular pose these days.) Most of us are tempted to sneer every now and then (I certainly am guilty of this), but some of these people adopt sneering as a basic intellectual stance to the world. It works for drag queens and comedians, who have it down to an art, but for the rest of us, it’s just ugly and, ultimately, boring. In the case I mention, the self-righteousness the pro-science folks could barely contain actually undermined their authority and effectiveness before a sympathetic audience. Nobody likes jerks, except other jerks.

He forgets precisely what, but it had something to do with science education in Texas. Hmm. What could have pro-science educators and academics “dripping with contempt” on that subject? Has he considered the possibility that just maybe the agents provocateur of the creationist side in the culture war in Texas deserve some contempt? It’s hard not to look at someone like Don McLeroy, professional science-denier and flaming creationist asshole, and not feel considerable disgust that that man was in charge of destroying the public school curriculum in the state.

But I forget: Dreher is part of an organization whose goal is to make those poisoners of the minds of children comfortable.

Does Mr Dreher think he’s going to persuade a Don McLeroy, for example, to somehow stop trying to inject lies about the age of the earth or the inadequacy of evolutionary theory into textbooks? I’d like to know how. I’d especially like to see it done. I might just have to back off on my ‘sneering’ at the liars for Jesus if one of these namby-pamby wimps for theistic evolution managed to convince a few of these stark raving mad creationist opponents of science to change their tunes; if they were actually successful in persuading leading creationists, I’d have to admit they have a good strategy.

But of course they don’t. They only work to hush the critics of creationists. I, for one, admit that I have no hope in hell of ever persuading the likes of McLeroy or Ham or Hovind or Comfort of ever recognizing good science, and I don’t think anyone else can, either. So I content myself with being intellectually honest and not pretending that they’re part of a community of reason, and will continue to point and laugh and encourage everyone else to treat these clowns appropriately.

Say hello to Scientopia

Many of the Scienceblog expatriates plus a few others have formed a new collective, Scientopia. It looks like a good bunch of people and a new and maybe better bottom-up approach to organizing a blog network — I’ll be reading them and looking forward to their growth.

Although, I do have to say that I’m not a fan of their published code. It throws around the word “respect” way too much, which happens to be one of those words that annoys me, because it is too easily assumed when it should be earned. I don’t respect everyone who blogs on science, and not everyone respects me (nor should they)…but it does put me on edge when a group announces a demand for mutual respect and also lays out a protocol for eviction, when I know that several of the people in the collective had little respect for some others on the Sb network. I have no respect for the pretense of respect.

But let’s all hope for the best and much success to Scientopia.