blog.bioethics.net

German Scientists Remove HIV-1 From Human Cells

2007-06-29T06:06:00.000-04:00

Today's issue of Science includes a publication by researchers at the Heinrich Pette Institute for Experimental Virology and Immunology in Hamburg and their partners at the Max Planck Institute for Molecular Cell Biology and Genetics, discussing the results of their attempt to use enzymes to remove a specific, rarely mutating sequence of HIV-1: successful results.

The treatment would involve removing blood from a patient, isolating their stem cells from that blood, treating with the enzymes, then returning the treated cells to the body to "boost" the immune system. Of course, there will first be several years of mouse trials before human trials, but they are cautiously optimistic that there will be a cure for HIV infection within a decade.

While it is of course important to note that this is high-tech medicine that would at least initially only be available to the wealthy (or at least well-insured) in industrialized nations, it is equally hard to not be excited by the potential within this research.

-Kelly Hills

Two Studies of SSRI Antidepressant Use During Pregnancy Are Reassuring

2007-06-28T14:57:00.000-04:00

Two new studies (CDC and Slone), published in the June 28, 2007 issue of the New England Journal of Medicine, examine whether or not SSRI antidepressants contribute to birth defects if taken during pregnancy. The results are very reassuring. In an accompanying editorial by Michael F. Greene, MD, he writes:

...neither SSRIs as a group not individual SSRIs are major teratogens on the order of thalidomide or isotretinoin. Patients and physicians alike would prefer it if there were clear lines separating "risk" and "no risk" and if all studies gave consistent results pointing in the same direction. Unfortunately, this is often not the case, and the data to inform potential risks of SSRIs are no exception. The two reports in this issue of the Journal, together with other available information, do suggest that any increased risks of these malformations in association with the use of SSRIs are likely to be small in terms of the absolute risks.

I've listened to and read some of the media reports on these studies and want to commend the authors and journalists for presenting a balanced picture of the risks. The researchers are quick to point out that these studies do not compare the very small increase in absolute risks that they found for some very rare birth defects to the risks of not treating depression during pregnancy. Inadequate treatment of depression during pregnancy has been linked to self-neglect, poor nutrition, tobacco and alcohol use, lower utilization of prenatal care, exacerbation of postpartum depression, and maternal suicide. Maternal depression increases stress hormones that may also affect placental function and fetal development, disrupt mother-infant bonding, contribute to low birth weight and prematurity, and result in long-term physical and behavioral complications. The Committee of Research on Psychiatric Treatments of the American Psychiatric Association identified treatment of major depression during pregnancy as a priority area for improvement in clinical management.

Studies indicate that between 10-20% of pregnant women experience depression. Women with a history of depression have a 70% chance of a recurrent depressive episode in the first trimester when antidepressant drugs are discontinued prior to or at the point of conception.

Based on the findings from these two studies and what we already know about depression during pregnancy, health-care providers and members of the media are being responsible when they caution pregnant women about stopping the use of SSRIs simply because they are pregnant. The decision about whether to continue or discontinue taking an antidepressant during pregnancy is one that women need to make with all the facts and with the assistance of an informed health-care provider.

Andrea Kalfoglou
Cross-posted to the Women's Bioethics Blog.

Recognizing blogging talent when they see it, the Women's Bioethics Blog has recently asked Andrea to become a part of their writing team. She joins their fabulous staff of writers, who include our regular blog contributers Kelly Hills and Sean Philpott (who is also responsible for the bioethics newsfeed), as well as AMBI faculty Alicia Ouellette and Linda MacDonald Glenn. Congratulations, Andrea!

The Locus and the Aphis - Moving Towards Herland

2007-06-28T11:30:00.000-04:00

"What strikes you as the oddest feature of your experience, so far?"
I considered. "There's so much—"
"Might it not be that you have not seen a single man?" she suggested.
I thought back. I remembered the wondering tone of one of the Mothers asking: "What is a man?"
"That's certainly one of them," I agreed. "Where are they?"
She shook her head, watching me steadily.
"There aren't any, my dear. Not any more. None at all."
-Consider Her Ways, John Wyndham

As news comes that scientists have created human embyronic stem cells from unfertilized eggs, the perennial dystopic fear of a world without men is once again racing through the media. Coupled with recent advances in creating sperm from bone marrow, and the assumption that it will be possible to use female bone marrow to make sperm, and we're on our way to Herland.

But the idea of a single-gendered society isn't new; in fact, it's a common science fiction trope that’s hauled out whenever reproductive advances (or discoveries, if you’re not so sure it’s an advance) are announced. And whether or not that fiction is dystopic or utopic probably depends on your point of view - or at least your gender.

Like most dystopic fiction, the single-gender society stories are warning stories about what’s going on in contemporary (for the time they were written) culture. Some, such as Herland, are making exaggerated arguments that woman can be equals to men, while others reflect the thinking behind separatist feminism. It’s actually in Wyndham’s short story, published in the 1950s, that I think we can see what the actual issue is behind these ideas of new reproductive methods.

So when the crisis came it turned out that scarcely any of them knew how to do any of the important things because they had nearly all been owned by men, and had to lead their lives as pets and parasites.
-Consider Her Ways, John Wyndham

I am not actually convinced that the issues behind any of the articles questioning the ethics of the research into “eliminating men” are actually ethical issues of medicine. I’m inclined to believe that they are ethical issues about society, reflecting anxiety about the social role of men, women, and the family unit. As we’ve talked about, the very basic notion of what a family is, is in flux - one mom, two dads, no dads? And with that flux, comes fear - fear of the unknown, fear of what technological potential is out there, and just maybe, the fear of not being needed at all.

In my previous musings on family, I said that what matters is not the genetic code tying us together, but the social construct that allows us to feel tied together. The logic seems to go, if women can do everything men can, without men, including creating a child, then what do we need men for? In other words, what happens if the social construct changes?

It’s a good question, and excellent fodder for science fiction stories. But personally, I don’t see it moving beyond a good story – not in any mass scale way that’s going to shake the very fabric of society. Certainly reproduction is being detached from sex, it has been and is becoming moreso as new ways of reproducing and assisting reproduction are being discovered. That doesn’t make sex any less fun, though – it just makes it not intimately tied to reproduction. And as technology continues to progress, we’ll need to continue redefining what it means to have children, and to be a family.

But short of a mass plague that wipes out most, or all of a gender, I simply have a hard time believing that we’re going to render man, or woman, extinct. Not necessary to reproduce, probable – but not necessary at all seems only the realm of fiction.

-Kelly Hills

ACT creates embryonic stem cell line; keeps embryos alive

2007-06-27T14:52:00.000-04:00

Advanced Cell Technology (ACT) announced in Nature Magazine in August of 2006 that they were creating embryonic stem cell lines from biopsied embyros. The headlines were a bit misleading, suggesting that this method did not result in the destruction of the embryos, when it did. Today, ACT announced at the fifth annual meeting of the International Society for Stem Cell Research (ISSCR) in Cairns, Australia that they had created three separate embryonic stem-cell lines without actually destroying the biopsied embryos. These three embryos are still alive in a freezer. ACT is now calling upon NIH to fund research using these three stem-cell lines because their creation is compatible with President Bush's statement he made following his veto of a bill from Congress that would have expanded federal funding for embryonic stem-cell research. While I applaud ACT's creativity in trying to work within the current US regulatory limits on embryonic stem-cell research, I'm curious what ACT plans to do with these frozen embryos. Will they ever be gestated, or will they just remain "undestroyed" for the next few decades? Another question that bugs me: who actually "owns" these embryos? If they are gestated and born, will they have "registered trademarked" stamped on their foreheads?

-Andrea Kalfoglou

Primate Cloned Stem Cells? Maybe.

2007-06-21T14:38:00.000-04:00

China Central Television (CCTV) is reporting that US researchers (Shoukhrat Mitalipov of the Oregon National Primate Research Center) in the US have produced the first embryonic stem-cell line using SCNT (cloning) from rhesus monkeys -- and that they were able to get these cells to differentiate. The researchers reported their findings at stem cell research conference in Cairns, Australia, this week. From the report, it sounds like Dr. Mitalipov has the data to prove his claim, but after the Korean human stem-cell scandal, we should all be skeptical until the peer-reviewed publication is out.

In other stem-cell news, scientists in Belgium report that they were able to create 13 "embryos" using in vitro matured oocytes and SCNT. 13 cleaved to the 2 cell stage; 10 went beyond the 2 cell stage; and two cleaved multiple times creating morulae. This is exciting news because it means that cloned human stem cells might be possible to produce using ovarian tissue rather than requiring women to go through an oocyte donation process to procure in vivo matured oocytes. The research also shows that oocytes, harvested for reproductive purposes, that fail to fertilize, also are unsuccessful candidates for SCNT.

-Andrea Kalfoglou

Bush Vetoes Stem Cell Research Act

2007-06-21T11:32:00.000-04:00

Well, as expected, Bush has vetoed the recently passed measure lifting the restrictions on human embyronic stem cell research.

As the New York Times notes, this veto

puts him at odds not only with the majority of voters, according to polls, but also with many members of his own political party. Republicans sent him a similar measure last year when they controlled Congress. But even with considerable support from the Republican minority this year, Democrats concede they do not have enough votes for a veto override.

The veto also guarantees that debate about hESC research will be at the forefront of the 2008 presidential elections. Regardless of the candidates position, they're going to have to talk about the ethics and science of the research and attempt to sway the voters to their particular views - anyone know how many candidates have bioethicsts on staff this time around?

Given how many states have started to fund stem cell research on their own, it will be interesting to see if any candidate believes that advocating a Bush-like ban on hESC is a viable campaign platform, and if so, how they will justify being so out of touch with voter prferences.

-Kelly Hills

Edited at 2:35pm EST:
This segment of NPR's Morning Edition contains an interview with Alta Charo, discussing how the restrictions affect scientists, and Andrea Kalfoglou writes in with the suggestion that people interested in a comprehensive read on the stem cell measure and veto check out this link. Thanks, Andrea!

Art Caplan on MSNC: Media’s Cooing Over Sextuplets is a Disservice

2007-06-21T11:03:00.000-04:00

Over on MSNBC, Art Caplan writes about news outlets going gaga over megamultiples, and forgetting to report the downsides:

One of the biggest problems arising when megamultiples — more than three babies born all at one time — arrive is the gushing media coverage of the births. First, there's the dash to get a camera into the nursery for baby pictures. Exhausted moms are interviewed right after birth, dazed but thrilled about their little miracles. Dads are shown looking exhausted and overwhelmed as they meet their basketball or hockey team to be.

Why quintuplets, sextuplets and septuplets happen and what the real price is in the long run for megamultiple births are subjects that, while crucial for understanding the reproductive revolution and its benefits and costs, remain almost unexamined in newspaper, television and magazine accounts. And that is unfortunate, because these costs aren’t limited to just health and financial challenges faced by the family welcoming the new additions, but to society as well.

Earlier this month, two sets of sextuplets were born after their parents used assisted reproductive technologies, and their births generated a lot of media attention. Brianna and Ryan Morrison had four boys and two girls at Abbott Northwestern Hospital in Minneapolis on June 10. Ten hours later, Bryan and Jenny Masche welcomed three boys and three girls at Banner Good Samaritan Medical Center in Phoenix.

The “TODAY” show spent a considerable time cooing about the births of two sets of sextuplets in such a short period of time. The show jumped right into the lives of the Phoenix family. Thirty seconds did not elapse during story promos or actual coverage without the word “miracle” being invoked. The NBC program was hardly alone in going weak-kneed over the births of so many of babies.

CNN chimed in with “good news” reports on its “American Morning” program. The newscaster noted gleefully how “tiny” the babies were.

TV coverage in Phoenix described the births as “gifts” and “bundles of joy,” among other gushing terms. Stations pitched in to help the family raise money and collect baby diapers and clothes. The Minnesota media did not miss a chance to refer to their local sextuplets as “blessings.”

The Boston Globe, Newark Star Ledger and many other papers ran short stories that heavily emphasized the good news about the sextuplet births and noting how pleased and happy the parents were.

Going gaga
There is plenty to celebrate when babies are born. I am not arguing that joy and delight have no place in media coverage of these events. But the media owe us more than just cheering, gushing and cooing when reproductive technologies create babies in numbers that do not occur naturally and, more seriously, that carry tremendous risks.

In the case of the Masches, the mother went into life-threatening heart failure right after the births. Too much blood was in her body from supporting all the fetuses and she nearly died. News reports noted this problem but passed over it to get back to the positive side of megamultiples. The Minnesota babies were born extremely premature at 22 weeks. Sadly, three have already died.

But the downside of megamultiples, in terms of risk to the fetuses or the moms, got little media play in the initial stories about the two sets of sextuplets.

When megamultiple pregnancies occur due to fertility treatments, it spells potential trouble for both the mother and the fetuses. Gestational diabetes, strokes and preeclampsia — a potentially lethal form of hard-to-control high blood pressure — are huge risks for moms having more than twins. And moms expecting triplets or more are almost guaranteed to have Caesarean sections.

The babies themselves are put at grave risk when there are more than two. Having megamultiples means the babies face less room to grow in the womb, prematurity and low birth weights. All of these translate into high risk for mental retardation, learning disabilities, cerebral palsy and vision and hearing loss for the babies. They are also 20 times more likely to die in the first month of their lives than singletons.

Infants born in big numbers also need to spend a lot of time in neonatal intensive care units to allow vital organs to develop, which means they require expensive, high quality medical care. Those costs are almost always borne by either insurance plans or state Medicaid funds, meaning you and I pay their bills. And obviously, if there are complications that affect the children as they grow, helping the kids — and the parents — with their health problems through special education, multiple surgeries and rehabilitative care can run into the millions of dollars.

No accident
Multiple births are not, as the media coverage would have you believe, unadulterated, wondrous miracles with no downside, nor are they generally the result of accidents, divine will or luck.

Fertility clinics sometimes transplant more than three embryos at a time into women, knowing that megamultiples could result. But a clinic can look good in comparison to its competitors by saying it can succeed in delivering babies to infertile couples. So some, incredibly, continue the practice, understanding it may be at the cost of the mom and babies’ health.

Some infertility programs also give women drugs to make them ovulate more, but then don’t monitor the patients carefully to ensure that the couple doesn’t have unprotected sex if the drugs are a little too successful and produce too many eggs.

And some clinics do not explain clearly what the real dangers are of having megamultiples. Nor do they fully encourage the option of eliminating one or more of the fetuses in utero — a procedure called selective reduction — to preserve the health of the more viable babies if there are complications or problems in the pregnancy.

Megamultiple births are not the miracles the media makes them out to be. In fact it could be argued that we should be doing more as a matter of public policy to discourage megamultiple births by getting infertility programs to do more to minimize the risk of creating them. But, given the kind of “check your critical senses at the door” media coverage that always seem to accompany these births, these are not ideas you are likely to be asked to consider in thinking about the realities about megamultiple births.

What about all those frozen embryos?

2007-06-20T16:03:00.000-04:00

An interesting paper looking at the potential fate of the nation's hundreds of thousands of frozen embryos will show up Thursday on the Science site (It's there now -- see also two related press releases from Duke and JHU). Ann Drapkin Lyerly (Duke Med Center) and Ruth Faden (JHU's Berman Institute of Bioethics) surveyed more two thousand infertility patients from across the country (response rate: 60%) about their preferences for the disposition of their leftover embryos. The authors report that among survey respondents who still had embryos in the freezer, 49% indicated that they were "somewhat" or "very likely" to donate their embryos for research purposes. This group expands to 60% if the question narrows the possible uses to stem cell research.

After making a few assumptions and taking the survey responses into account, the authors conclude that infertility clinic freezers currently hold somewhere between two thousand and three thousand potentially available and viable stem cell lines.

One other interesting finding from the survey: the number of respondents who reported being somewhat or very likely to donate their embryos for cloning research was larger than that of those who would donate their embryos to another couple hoping to have a baby.

-Greg Dahlmann

Why Can't You Use Sex to Sell Condoms?

2007-06-18T12:41:00.000-04:00

The NYTimes reports that the makers of Trojan condoms have developed a new marketing campaign called "Evolve." The message is all about thinking about your own health and that of your partners everytime -- a great public health message. However, CBS and the FOX networks are refusing to air these new TV commercials even during late night programming. This ad seems tame compared to some that are used to sell Viagra, shampoo (remember the "Organic" experience), and even dishwashers. Hurray to ABC, NBC, MTV, Comedy Central and Adult Swim who will air the commercials, and a great big wimp award to CBS and FOX.

-Andrea Kalfoglou

On Human Genomes and “Rewriting the Textbooks”

2007-06-18T12:36:00.000-04:00

I hate when the media proclaims, “They’ll have to rewrite the textbooks.” It’s easy for them to say. They don’t do it.

I do.

That phrase will likely be bandied about this week with the multiple publications from the ENCODE project. That stands for the Encyclopedia of DNA Elements Project, a mega-effort from 35 research groups around the globe to dissect a representative 1 percent of the human genome (The ENCODE Project Consortium, Genome Research).

True, the media/public may have gotten their fill of geno-news of late, what with the grandstanding PR event of James Watson having his 3 billion DNA bases exposed, so to speak, and the turning on of stemness genes in mice, apparently circumventing the embryonic route. And if Paris Hilton tries a jailbreak, all news of import will vanish.

I’m the author of a college-level human genetics textbook, currently working on the 8th edition – I now measure my lifespan in editions (Lewis, forever). It’s not written by a nameless committee with a lone EdD slapped on the cover, nor a computer, nor am I just an assistant to a “real” scientist. Forgive the defensiveness, but I get these comments often. People write textbooks, and people who write science textbooks are generally scientists.

Whether or not to make a radical change in a textbook is a judgment call based on knowledge of the field, and of science in general. Basically, a finding has to be repeated sufficiently to stand the test of time. It doesn’t necessarily have to make sense or go with the prevailing wisdom. This is the case with the ENCODE findings. Among a deluge of data, what has emerged is that much of the DNA sequence that evolution has apparently conserved in diverse genomes (I’m not talking an Italian compared to Nigerian, but, say, a wombat to an ape) needn’t have the same or even any apparent function. Yet disturbingly many DNA sequences that are diverse and unique and therefore not thought to be constrained by evolution can nonetheless have important functions. This will turn the idea that “if it’s important, evolution would have kept it much the same across species” on its head.

An equally important finding makes me want to get up and cheer. “Junk” DNA isn’t junk after all. I can hear a collective “duh” from the genetics community. The unfortunate term “junk DNA”, while possibly first uttered by geneticists back in the 1970s in the wake of the discovery of introns (Gilbert, 1977), quickly became a media term that has gained momentum, even as geneticists have indeed discovered what much of the DNA sequence that doesn’t encode protein actually does. (I distanced my book from the term early on: “Said one speaker at a genomics conference, ‘Anyone who still thinks that introns have no function, please volunteer to have them removed, so we can see what they do.’ He had no takers.”) I’ve never, ever heard a scientist call any DNA junk. Only those with mutations in the arrogance gene would term something garbage just because we can’t figure out what the heck it does.

Of course I’ve made mistakes too. Paramount among them was the mention of the adeptness of a certain Korean researcher in manipulating human embryos to obtain stem cells. I yanked that out fast when his adeptness at faking data was revealed. And I’d already mentioned ENCODE in the edition that is now gestating. But I’m spending this glorious Father’s Day, well, rewriting the textbook to knit these new results into the appropriate chapters. I suspect further changes lie ahead. ENCODE chose it’s representative 1% from 44 well-studied regions of the genome. But imagine describing a large lecture class from a specifically-chosen 1% of the students. Or the planet. Or anything. (Note to media: “well-studied”. Scientific advances are not overnight breakthroughs.)

The media will undoubtedly jump on the unexpectedness of the results too, playing it as a fault, of scientists flip-flopping, when in actuality, changing hypotheses to fit new data is the very essence of science. There is, after all, no such thing as “scientific proof”, despite the pervasiveness of the term. There’s only scientific evidence, and the more the better -- even if it turns long-accepted ideas upside down – like now.

I can’t wait for the next chapter.

-Contributing editor Ricki Lewis

The ENCODE Project Consortium, 2007. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447:799-816

Genome Research, 17(6), the entire June 2007 issue. http://www.genome.org/current.shtml

Gilbert, A. 1978. Why genes in pieces? Nature 271:501.

Lewis, R. Human Genetics: Concepts and Applications, McGraw-Hill Higher Education, 2007.

Overstating the Case of Genetic Selection

2007-06-16T00:53:00.000-04:00

In his latest op-ed column (below), conservative David Brooks overstates the case that everyone is looking to upgrade their future off-spring by using donor gametes. He's worried that people like him (under 5'9 and not blond) will become a dying breed. The truth is that most folks would really prefer to procreate with their spouse the old fashioned way. They only turn to gamete donation as an alternative when there's a breakdown in the system. While one percent of all US births are the result of IVF, less than 10% of those births involve and egg donor. Since no one keeps track, there's no way of knowing how many kids are born each year as the result of sperm donation; however, I really doubt there are enough where we will all eventually resemble Pamela Anderson or Arnold. Still, there are some pretty funny quotes.

- Andrea Kalfoglou

June 15, 2007
OP-ED COLUMNIST
The National Pastime

By DAVID BROOKS
At this very moment thousands of people are surfing the Web looking for genetic material so their children will be nothing like me. They are looking through files at sperm bank sites with Jetson-like names such as Xytex, which have become the new eBays for offspring.

These sites take sex and turn it into shopping. They allow you to browse through page after page of donor profiles, comparing weight, noses, personality and what one site calls “tannability.”

Shoppers can use these sites and select much better genetic material than would be possessed by someone they could realistically lure into bed. And they can more efficiently engage in the national pastime — rigging our childrens’ lives so they’ll be turbocharged for success.

When given this kind of freedom of choice, people seem to want to produce athletic Aryans with a passion for housekeeping. There is tremendous market demand for DNA from blue-eyed, blond-haired, 6-foot-2 finely sculpted hunks who roast their own coffee. These are the kind of guys you see jogging in the park and nothing moves. They’ve got a stomach, a chest and flanks, but as they bounce along nothing jiggles, not even their hair. They’re like Arnold Schwarzenegger in his prime from the shoulders down, and Trent Lott from the scalp up.

Nor is brainpower neglected. In a bow to all that is sacred in our culture, one sperm bank has one branch located between Harvard and M.I.T. and the other next to Stanford. An ad in The Harvard Crimson offered $50,000 for an egg from a Harvard woman. A recent ad in the Chicago Maroon at the University of Chicago offered $35,000 for a Chicago egg and stipulated, “You must be very healthy, very intelligent and very attractive, and most of all, very happy. Liberal political views and athletic ability are pluses.”

(Is liberalism genetic? I thought it was the product of some environmental deprivation.)

In any case, a Harris poll suggested that more than 40 percent of Americans would use genetic engineering to upgrade their children mentally and physically. If you get social acceptance at that level, then everybody has to do it or their kids will be left behind.

Which means that sooner or later reproduction becomes a casting call for “Baywatch” and people like me become an evolutionary dead end. For centuries my ancestors have been hewing peat in Wales and skipping school in Ukraine, but those of us in the low-center-of-gravity community will be left on evolution’s cutting-room floor. People under 5-foot-9 can’t even donate sperm to these banks, so my co-equals are doomed, let alone future Napoleons.

The people who do this will pay no heed to the fact that mediocre looks have always been a great spur to creative achievement and ugliness is the mother of genius.

In a world in which Brad Pitt is average, say farewell to loneliness, sublimation and nerds’ witty bids for attention. In a world in which everyone is smart, good-looking and pleasant, everyone will be fit to perform in hit movies, but no one will be fit to review them.

I’m not under the illusion that any of this can be stopped. Conservatives like me think that if you want your kids to have Harvard genes you should have to endure living with a Harvard spouse. But the rest of the country is not with us. There’s no way people are going to foreswear the joys of creative genetics. “I would probably choose somebody with a darker skin color so I don’t have to slather sunblock on my kid all the time,” one potential mother told Jennifer Egan of The Times Magazine last year.

So as my kind heads off to obsolescence, I wonder about the unintended consequences. What if it’s true, as some believe, that genes are dominant and home environment has little effect on children? You could have two lesbian bikers giving birth to Mitt Romney.

What if parents are perpetually buying genes on the downward slope? After all, for maximum success, you don’t want President Kennedy’s genes. You want Joseph Kennedy’s genes. You don’t want Bill Clinton’s genes. You want his father’s. What if we get the national equivalent of the 38th generation of the House of Windsor?

Or, on the other hand, what if nurture still trumps nature? After all, if you look at world-historical figures you’re struck by how many had their parents die when they were about 12. How many superconcerned moms and dads are going to put that in their datebook?

Stem Cell Research - State Moving, Feds Not

2007-06-15T13:34:00.000-04:00

David Jensen notes in California Stem Cell Reports that the California Institute for Regenerative Medicine (CIRM), the agency which manages the state’s stem cell research program, has just awarded over $50 million in laboratory and training grants for human embryonic stem cell (hESC) research. These grants are intended to support research on stem cell lines which fall outside current federal funding guidelines. BY CIRM’s arithmetic, this brings California’s total hESC funding awards to over $200 million, or more than five times the $37 million NIH is expected to spend on hESC research this fiscal year. The CIRM press release with the details can be found here.

CIRM’s been active on other fronts as well. As David Magnus reported last week, the California Supreme Court refused to accept an appeal of a lower court decision that upheld CIRM’s constitutional status, which appears to clear the way for the state to issue the $3 billion in general obligation bonds authorized by Proposition 71. CIRM’s even going international. As reported here, the state of California and the Canadian province of Ontario have just announced a joint stem cell research program to which Ontario will contribute $30 million over 5 years.

California’s far from the only state that’s been active on the stem cell front this year. New York has more or less firm plans to spend some $600 million on stem cell research, and gossip has it that Governor Eliot Spitzer may introduce a proposal for a bond issue to support this research on a larger scale. Maryland has just awarded some $20 million in stem cell research grants, and the state legislature has just approved an FY2008 budget that appropriates some $23 million in research support. Connecticut is spending some $10 million per year on stem cell research. Massachusetts governor Deval Patrick has just unveiled a major package of stem cell initiatives that would spend some $1.25 billion in state and private funds, outlined here.

Meanwhile, things are moving slowly, if you want to call it moving, inside the Beltway. Congress is expected to take final action shortly on a bill which would expand the number of stem cell lines eligible for federal funding support, but the President has announced he’ll veto it just like he did last year, and there don’t appear to be enough votes to override a veto. Nothing’s going to happen until this administration leaves office, and not much may happen even then. Focusing on the feds is gonna be pretty boring for the foreseeable future — somebody want to organize a paint-drying contest to provide a little excitement?

-Jim Fossett
RIG/AMBI
Federalism and Bioethics Initiative

Nature Retracts Figure in Highly Cited MAPCs Study

2007-06-14T18:12:00.000-04:00

As is being reported, well, everywhere, Nature has made the decision, after review, to retract a figure used in a highly cited 2002 study on adult stem cells in (mouse) bone marrow. In this study, the researchers seemed able to coax those multipotent adult progenitor cells to form other tissues in the body. At the time, this was hailed as a major break through in adult stem cell research, and seemed promising for stem cell therapy, but the results have been difficult to replicate. And while the figure has been retracted, the paper has not.

Meanwhile, Catherine Verfaillie and her coauthors are now having other papers investigated by the New Scientist, who raised the initial concerns over the first image. Full details can be read here.

-Kelly Hills

Feminist Approaches to Bioethics (FAB) Takes Two Leaps Forward

2007-06-13T14:45:00.000-04:00

Our friend Andrea Kalfoglou writes:

Feminist Approaches to Bioethics (FAB), was founded in 1992 at the Inaugral Congress of the International Association of Bioethics, but it has recently taken steps to be a much stronger presence in the international bioethics arena. First, FAB has revamped its website. Second, FAB has founded a new international journal. There are descriptions of the first three planned issues with a call for papers listed on the website. FAB members always get together at the annual American Society for Bioethics and Humanities meeting, so if you plan to attend ASBH this October in Washington, DC, don't forget to attend. Membership for FAB will be changing next year. The modest dues, based on income level, will include a subscription to the new international journal. Consider joining FAB and helping it grow as an international presence in bioethics. Congratulations FAB!

House Passes Stem Cell Research Enhancement Act of 2007

2007-06-07T22:50:00.000-04:00

With a vote of 247/176/10, the House has voted to pass the Stem Cell Research Enhancement Act of 2007. The breakdown is about as you would expect, with the majority of the yes vote being Democratic (210), joined by 37 Republicans. The 160 Republicans voting no were joined by 16 Democrats, while 6 Democrats and 4 Republicans didn't vote.

Unfortunately, it will probably be a short-lived victory, as Democratic leaders have acknowledged that they do not have votes necessary to override Bush. For his part, Bush has said that recent stem cell news has reinforced his conviction that stem cell science can progress in ethical ways without using embryonic stem cells, and that he will veto the bill when it hits his desk.

-Kelly Hills

Art Caplan on MSNBC: Does Stem Cell Advance Provide an Ethical Out?

2007-06-06T17:10:00.001-04:00

The big science news of the day -- and maybe the year -- is that researchers have, in mice, managed to transform skin cells into what seem to look and act like pluripotent stem cells. (There's coverage everywhere, including: NYT, WP and Nature.) This development opens the possibility that maybe we can bypass many of the ethical questions that have surrounded research into human embryonic stem cells.

While this is exciting news, there's one phrase we shouldn't overlook: in mice. As Marius Wernig, one of the researchers from the Whitehead Institute involved with this research, was quoted in a press release today, "We are optimistic that this can one day work in human cells. We just need to find new strategies to reach that goal. For now, it would simply be premature and irresponsible to claim that we no longer need eggs for embryonic stem cell research."

On top of things as usual, Art Caplan notes over at MSNBC that doctors and funders shouldn't put all their embryos in one basket:

Just as Congress is about to vote on a bill that would require federal funding for embryonic stem cell research, something has me tempted to join the ranks of those loony tunes who see conspiracies lurking around every corner. The bill, the Stem Cell Research Enhancement Act of 2007, passed the Senate by a big margin in April. But just as the House prepares to vote later this week, news breaks that scientists have made progress in finding alternative ways to generate cells from other types of cells that can mimic the special powers of embryonic stem cells.

Convenient timing for those who oppose embryonic stem cell research, isn't it? It's certainly not the first time a scientific "breakthrough" has promised an alternative to embryonic stem cells just as funding issues were under debate. It has happened so often that even the wolf is no longer listening to the boy crying out, "there are alternatives!" Except this time, there is a big difference. There really has been a breakthrough.

Today's news about other ways to create embryonic-like stem cells, published in the journals Nature and Stem Cell, comes from mainstream, cutting-edge, world-class scientists. This is news worth listening to.

Rudi Jaenisch, a leading expert on cloning, and teams of scientists at the Whitehead Institute for Biomedical Research and the Massachusetts Institute of Technology were able to do some elegant engineering in which they genetically tweaked skin cells in mice to reprogram themselves and act like embryonic cells. They used artificial viruses to carry genetic information into a large batch of mice skin cells to turn on certain regulatory genes in the cells that normally only work in embryos. By injecting the reprogrammed cells with markers into early-stage mouse embryos, researchers were able to show that these reprogrammed cells turned into all manner of cells in the adult mice that grew from the embryos.

That is exactly what stem cell researchers are seeking - cells that could be manipulated to turn into other types of cells to repair diseased ones in our bodies.

This is very big news indeed. So why bother with a vote in Congress on funding human embryonic stem cell research? Shouldn't we simply put all of our federal funds into this type of reprogramming research?

End to ethical quandary? That would make President Bush and others who oppose the destruction of human embryos happy. And those who want to see progress made in trying to cure conditions such as diabetes, spinal cord injuries and Parkinson's disease should be pleased as well. Ethical dilemma solved!

Well, not so fast. I'm afraid that ditching embryos and jumping to fund alternatives is not the right response to this fascinating news about mouse cells.

This research is promising, but it's in mice. Many technical hurdles remain for translating this work to human cells. Some of the techniques used by the MIT scientists to isolate embryonic mouse cells are known not to work in human cells. Also, using cells that have been changed by means of viral vectors can pose health risks. This form of gene therapy has proven very difficult to do safely in human beings.

It is certainly true that the reprogramming option in both animal and human cells deserves funding, but so does human embryonic stem cell research. As much as critics of this field of research would like to have you believe that human embryos in dishes are people, that moral argument is not compelling.

Human embryos in dishes are not people or even potential people. They are, at best,possible potential people. Frozen embryos in infertility clinics face a fate of certain destruction anyway. The moral case against using them, or cloned embryos, which have almost zero chance of becoming people, is no less compelling because progress has been made in another area of research.

The existence of a new way to perhaps make embryonic-like stem cells is not enough to make frozen embryos and cloned embryos off-limits for American scientists or for research relying on federal funds.

Those in favor of human embryonic stem cell research, and that is the majority of Americans according most polls, including one done by CNN just last month, do not have to change their minds about the morality of such research even when another avenue for creating embryonic-like cells is found in mice.

Explore all possible avenues If you are an Iraq War veteran stuck in a wheelchair, if you are taking care of your father who is losing his ability to walk due to Parkinson's, if your child suffers from juvenile diabetes or if you need new skin as a result of terrible burns, you want scientists to pursue all the ethical options available for stem cell research. No one knows for sure whether any of them will work. But it is certain that if they are not all aggressively pursued with generous federal support, then the chance of any line of research ever turning into a therapy is greatly reduced.

The House should pass the Stem Cell Research Enhancement Act of 2007. President Bush will surely veto it, undoubtedly invoking this latest work on reprogramming adult cells as one of his reasons. Congress should then override that veto.

On the frontiers of science, good news about one promising route should not cause anyone to abandon other possible roads until someone actually gets to where they are trying to go - in this case, the goal is new cures for the sick, the dying and the severely disabled. Too many lives are riding on this to be fooled into taking the wrong detour.

mouse photo: Sam Ogden and Whitehead Institute

blather before the good stuff: Greg Dahlmann

The Blind May See With the Help of Embryonic Stem Cells

2007-06-06T17:07:00.000-04:00

A wealthy US donor has given British scientists $8 million to further research on using embryonic stem cells to treat macular degeneration reports Reuters. The motivation, according to the report, was frustration with the barriers to research in the U.S. This is probably a great strategy. If researchers are successful in helping the blind to see within 5 years (as they predict) and are able to make this a routine therapy within 10 years, it's going to be very difficult for the American public to resist. Having watched my grandfather live blind because of macular degeration for many many years, I wish the British researchers overwhelming success. I'm curious what conservative leaders are going to say to those who are blind about whether or not it's ethical to use the therapy once it's available. It's time to start addressing this question. I'm personally working with the Greek Orthodox Archdiocese to struggle with these questions. Are you other bioethicists out there doing your part?

-Andrea Kalfoglou

XDR-TB Blues

2007-06-04T16:10:00.000-04:00

Tuberculosis has a strange history. It is an ancient disease: Hippocrates long ago identified phthisis, the Greek term for tuberculosis, as the most widespread disease of his day, and over the centuries the disease has killed millions. But it is also curable. Albert Schatz, a graduate student at Rutgers, isolated the antibiotic Streptomycin in 1943, which has proved effective against tuberculosis in treatment programs around the world. Ideally, that should have been the end of TB's story as a major source of mortality. It has not turned out that way.

Effective treatment of TB requires taking the current drugs of choice (Rifampicin and Isoniazid) for a number of months, which patients are not always able to do, particularly in resource-poor countries, where drug supply chains, availability of health workers, funding of tuberculosis programs, and even the drugs themselves may be unreliable. Treatment interruption is largely responsible for the worldwide rise of multidrug resistant or MDR-TB, and of extensively drug resistant or XDR-TB. The upsurge of drug resistance is obviously a step backwards: it evokes the pre-1943 days, the days before drug treatment, the days of sending patients to sanatoria for fresh air, and in the last resort, submitting them to ghastly surgical interventions.

The newspapers, television and blogs have been filled this week with the story of Andrew Speaker, the lawyer from Georgia who took an international flight from Prague to Montreal after having learned from the Centers for Disease Control and Prevention that he is suffering from XDR-TB. Despite his apparent low infectiousness (having tested negative on skin tests, not being symptomatic), despite the lack of one known case of contracted active TB within an aircraft, and despite physicians not expressly forbidding him to fly, Mr. Speaker is largely being treated as a kind of bioterrorist, a fugitive, or a 'rascal', as this talking head (Dr. William Schaffner) on CNN video refers to him. On another CNN fear-inducing clip, one of Speaker's fellow passengers talks about her concerns about getting TB and possibly tranmitting it to family members by 'eating and drinking with them.' The CNN anchor does nothing to correct the misconception. Meanwhile, every expert and his dog is lining up to justify strict quarantine. On a brighter note, NPR gives a nuanced view of the case and MSNBC provides useful factoids to help prevent further stigmatization of TB patients.

Let's see how the other half -- in the southern hemisphere of our planet -- lives with XDR-TB. While Speaker was flown to a high-tech TB facility in Denver on private CDC jet, things look a bit different down in Brooklyn Chest Hospital in Cape Town, South Africa. There, XDR-TB patients can only get a hospital bed after many months, if at all, and MDR-TB patients fare no better. This means that there are many identified (and who knows how many unidentified) MDR and XDR-TB patients out and about in the Cape Town community. Whereas in America this would probably lead to mass hysteria, local health providers in South Africa take a pragmatic approach: since isolation is not feasible, these patients may have to be treated within community settings, and ways will have be devised to prevent them passing on infection to others.

"We need to now as a department and as a society come up with the best and most humane manner to care for untreatable infectious patients. Maybe put infection control measures in place at community level and do lots of health education so that patients can be with their families and loved ones," says Dr Marlene Poolman, Deputy Director for TB Control in the province.

Watching Andrew Speaker on Good Morning America is about as close as the vast majority of Americans are ever likely to get to an XDR-TB patient. Other countries can't radically separate healthy citizens from such 'rascals', because they don't have the resources. Still, Speaker is a victim just like any patient with drug-resistant TB: a victim of poorly funded and implemented primary TB programs around the world, the rich spawning ground of drug-resistant strains. Perhaps now that an affluent citizen of the North has been struck by a disease far more prevalent in the impoverished South, more attention will be paid to global TB control. Or maybe we will just speculate and sermonize about his rascally behavior.
-Stuart Rennie

Florida May Require and Ban Stem Cell Funding

2007-06-04T15:49:00.000-04:00

Yet another state getting into stem cells! Two mutually exclusive constitutional amendments, both of which might pass...

The Florida Supreme Court ruled that competing proposals to change the constitution to deal with the issue can go before the electorate in 2008 if the groups pushing the proposals get enough signatures to get them on the ballot. The court said unanimously that the proposed ballot language that voters would be asked to decide on in both cases is clear enough, and only deals with one subject, as required by law. In both cases, the justices said the ballot proposals are clear enough to allow voters to understand the likely consequences of what they're voting on.

One amendment, sponsored by Floridians for Stem Cell Research and Cures, Inc., would require the state Legislature to appropriate $20 million a year for 10 years on grants for embryonic stem cell research. There would be a prohibition on using the embryos for reproductive cloning, that is, to make a baby. And they could only be used if the donors had consented and hadn't been paid to provide the embryos, other than to compensate them for what it costs to actually donate the cells, under the proposal.

The grants would have to go to nonprofit academic and other research institutions in Florida and the winners of the grant money would be chosen based on a peer review process. All of that is included in the proposed amendment.

The amendment to ban state spending on embryonic stem cell research, sponsored by Citizens for Science and Ethics, Inc., is so simple and short that no one argued against it when the Supreme Court held arguments on whether the ballot language was fair. The proposed change simply reads: "No revenue of the state shall be spent on experimentation that involves the destruction of a live human embryo."

Although it's unlikely, there is the possibility that voters could somehow pass both, thus requiring the state to spend money on the studies while simultaneously preventing it from spending money on such studies.

Nothing in the constitution or the law addresses what would happen in such a case, meaning it would have to be decided in the courts. "There is no rule in the constitution with respect to that scenario," said Mark Herron, who practices elections law in Florida.

Ya gotta love it..
-Jim Fossett

The Devil on the Doctor's Shoulder

2007-06-04T15:31:00.000-04:00

We have written before about Stanford banning even small gifts from pharma reps, the influence gifts have, and the JAMA article and recommendations on inappropriate gifts.

Now the LA Times has a piece by a family physician in Seattle talking about accepting the lunches and baseball tickets and other gifts from the drug reps. Interestingly, it's not necessarily a flattering piece, and highlights many of the issues that have been raised about the bias that these gifts create. But it also offers if not a sympathetic explanation of why a doctor would accept the gifts, an explanation that I'm sure many of us can relate to, even if we don't approve.
-Kelly Hills [hat tip to Birgitta Sujdak-Mackiewicz!]

Dutch Kidney Donor Reality Show a Hoax

2007-06-01T17:15:00.000-04:00

April 1st seems to be few months late this year; the Dutch reality television show that some of us got opinionated on, The Big Donor, aired today, and in the last moments of the telecast, was revealed to be a hoax. Straight from MSNBC:

In the last minutes of the program, [“Lisa,” the 37-year-old woman who had been said to have been suffering from a brain tumor] was revealed as a healthy actress and program makers stunned viewers by saying ”The Big Donorshow” was a hoax.

The contestants were also part of the deception, although all three are genuine kidney patients.

“Their life is bitter reality,” the presenter said after revealing the deception, just at the moment at which Lisa was to have made her choice.

So now, of course, BNN is getting heaps of praise for drawing attention to the plight of those waiting for transplants, and the shortage of organs that exist. The Dutch education minister has said it was a fantastic stunt, and an excellent way to draw attention to the shortage in donated organs.

Er - really? I'm not sure heated water cooler debate over whether or not something is tasteless and going too far is really the best way to draw attention to an issue that needs addressing. Taking the example of The Big Donor, which apparently ran appeals for viewers to donate organs through-out its broadcast: does creating an emotional or gut-wrenching scenario, then revealing it to be a hoax at the end, really result in people saying "oh, well, I'll still donate", or do you end up with a more negative association? Feeling bad, feeling generous, and then feeling taken.

I don't know. The makers of the program say they hope that people's outrage over the show, and the hoax, will turn into outrage at the shortage of organs. Whether or not it will simply remains to be see. But they were right on one count - the show has certainly got people talking.
-Kelly Hills

Assisted Suicide Debate Has Passed Dr. Death By

2007-06-01T13:21:00.000-04:00

Art Caplan writes at MSNBC:

The last time I saw Jack Kevorkian was April 23, 1994, in a courtroom in Pontiac, Michigan.

Oakland County prosecutors had charged him in the death of 54-year-old Janet Adkins of Portland, Ore. The charges were assisting in a suicide, murder and delivering a controlled substance for administering drugs without a license. I was there to testify that what he had done to Adkins - providing her with his "suicide machine," which she used in the back of his 1968 VW van parked in a dark campsite to end her life - was both immoral and a gross violation of medical ethics.

Kevorkian, who became known in the press as "Dr. Death," was found not guilty. A few years later he was asked by Thomas Youk, a 52-year-old who had trouble breathing and swallowing due to advancing Lou Gehrig's disease, for help in dying. Kevorkian injected him with a lethal dose of potassium chloride while videotaping the ghastly proceedings. He sent the tape to "60 Minutes," which aired it. This gave prosecutors incontrovertible evidence that Jack had gone from assisting in suicides to personally killing people. He was sentenced to 10 to 25 years for murder. After serving just over eight years, Jack is back.

I believed Kevorkian was a very dangerous killer then, and I still believe it now. He helped dozens of depressed and disabled people die without trying very hard to convince them to live.

That day in the Pontiac courtroom, he stared and scowled as I said that it was unethical for a doctor to help kill someone they barely knew, who was not terminally ill and who was still enjoying a good quality of life. Adkins had been told she had Alzheimer's but it was not clear how many months or years of quality life she had left when she used Jack's jury-rigged death machine to infuse a lethal dose of drugs into her bloodstream.

All this matters because now that Kevorkian is out of jail, he has said he plans to reinsert himself as a vocal participant in the ongoing debate in America over assisted suicide.

No doubt he will get an audience. There are plenty of Americans who still, incredibly, view him as a hero. And the media loves him, too, knowing the audience-grabbing power of an unrepentant killer.

To be fair, there are those who admire Kevorkian as the lightening rod who changed how Americans view both the care of the dying and assisted suicide. After all, didn't he bring these issues center stage in courtrooms, state legislatures and the media? No one else did more than he did to promote assisted suicide.

Fanatic, not leader
But I do not see him this way. He was more of a fanatic than the founder of a movement. A zealot who could rally public opinion but could not shape it. You see, Kevorkian believes in suicide on demand. He thinks that doctors have an obligation to help anyone who decides that their life is not worth living, whatever their reason. Some of the 130 people he helped die had no terminal illnesses. Some were clearly depressed. Others had histories of mental illness. Only a few got any counseling. Kevorkian helped them all to die.

Kevorkian's problem was and is that he likes death way too much. The enthusiasm he brought to his cause was always deeply troubling. No doubts, no ambivalence, ever seemed to cross his mind as he dispatched his victims. The fact that he helped some to die within hours of meeting them, the fact that he would turn a disabled man's death into a national spectacle by giving a tape of his murder to "60 Minutes" - never mind that they used it! - and the fact that he never seemed to try particularly hard to talk those who came to him out of their decision to die made him morally suspect then and hardly worth hearing from now.

There are other reasons besides his fanaticism and moral obtuseness that we don't we need to hear anymore from Jack Kevorkian.

When Kevorkian went to jail, polls showed Americans were not sure what to think about legalizing assisted suicide. They still are not. According to an Associated Press poll out this week, 48 percent of people said assisted suicide should be legal; 44 percent said it should be illegal.

Debate has passed him by
But the debate has grown more sophisticated than it was when Kevorkian was offing people on TV.

The citizens of Oregon legalized a form of physician-assisted suicide in 1997. Proponents said the biggest obstacle they faced was Kevorkian and what he had done. They convinced people to vote for legalization despite Kevorkian, not because of him.

Critics who knew of Kevorkian's seeming disinterest in those he helped to die worried about abuse of the vulnerable and dying in Oregon. However, the passage of the carefully crafted Oregon law seems to have accomplished the goal of giving the terminally ill the option of controlling their death without encouraging them to die.

What is so interesting is that almost no one who asks for a lethal dose of medication actually does end their life. The Oregon law requires a determination of terminal illness by two doctors, counseling and a waiting period before a doctor can assist in dying.

It was the Oregon law, not the actions of Jack Kevorkian, that shook the complacency of the medical and nursing professions in that state and across the country. And it was the rise of palliative care and hospice as an alternative to rather than as a result of Kevorkian that has made dying a less horrifying prospect all over the United States.

We are far from ensuring a dignified and pain-free death for every American. The Terri Schiavo case was a stark reminder that your right to control how and where you die is not beyond the meddlesome grasp of pandering politicians and religious harpies. But we know now what we did not know when Kevorkian went on his assisted-suicide rampage - that we have a duty to make dying bearable and to ensure that each person gets the support, technology and pain control they wish.

The fact that Jack is back is no cause for celebration. The world of death and dying has, thankfully, passed him by. There is still more to talk about but not much useful that Jack Kevorkian can possibly say.

Sperm Donors Undervalued

2007-06-01T13:05:00.000-04:00

Be on the look out for an upcoming article in the June issue of the American Sociological Review by US Sociologist Rene Almeling. Her comparative study between egg donors and sperm donors reveals that sperm donors are undervalued fiscally, and are also treated with less appreciation, and are less prepared for the emotional consequences of being genetic donors. Almeling speculates that these inequalitites are perpetuated by gender-stereotyped social attitudes towards motherhood and fatherhood. Egg donors are made to feel like they are doing something very special for the recipient couple, while sperm donors are treated as though they are getting paid for something they would do anyway. Hopefully Almeling's research will lead to better informed consent for sperm donors to help them consider the long-term implications of participating in a collaborative reproductive process.

-Andrea Kalfoglou

Another State Joins the Stem Cell Business

2007-05-31T21:47:00.001-04:00

Jim Fossett brought to my attention that yet another state, Maryland, is getting into the stem cell business.

The Bioethics Quilt Project

2007-05-31T20:26:00.000-04:00

Karama Neal sent along some great links about the Bioethics Quilt Project by Muhjah Shakir, assistant professor of occupational therapy and senior scholar at the National Center for Bioethics in Research and Health Care at Tuskegee University. Professor Shakir has been working with the female partners of the men in the U.S. Public Health Service Syphilis Study (Tuskegee) to create a quilt and find out the impact the study had on contemporary women in Tuskegee and Macon County, Alabama.

“I had long since wanted to use quilting as a method to engage a group around,” she said. “The community had a long history of quilting, so the quilt project was a great way to engage the community and learn of the impact of the syphilis study.”

This project involves women between the ages of 55 and 96 meeting twice a week to tell their life stories, create a quilt and journal. Each creates a square to depict how they are feeling. This is designed to develop a capacity for reflection in the women.

Shakir said the squares vary in their symbolism and meaning. “Each square tells a particular story from the woman’s own perspective,” she said. “The quilting has become a community narrative of Tuskegee.”

You can also hear both Professor Shakir and Harriet Washington, the author of Medical Apartheid: The Dark History of Medical Experimentation on Black Americans from Colonial Times to the Present discuss the history of experimentation on black Americans, as well as how the quilt project heals old wounds via art.
-Kelly Hills [with many thanks to Karama]