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Henrietta Lacks parallels

Laura’s recent post about Rebecca Skloot’s visit to Emory on March 29 made me realize how long it’s been since I’ve posted anything here.

Skloot’s book on Henrietta Lacks, the woman whose cervical cancer became immortalized as Hela cells, has been well-reviewed. In recent interviews, Skloot describes how she had to earn Lacks’ daughter’s trust, which was difficult given the family’s past experience with scientists _and_ journalists.

This reminded me of two other situations I’ve read about recently.

The first was James Agee’s book Let Us Now Praise Famous Men. Christina Davidson talks about Agee’s and photographer Walker Evans’ relationship with the Alabama farming family they described in the book. Family members reportedly felt mistreated by Agee, Evans and their successors. It seems like Davidson had to walk a path resembling Skloot’s.

A similar theme emerges from Dorothea Lange’s iconic Migrant Mother photos. The children of Florence Owens Thompson, the Cherokee woman in the photos, resented becoming poster children for Depression-era poverty.

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Them’s fighting words

Rob Davis at Voice of San Diego cracks me up.

Recently he was in a protracted struggle with Mayor Sanders’ office over a CPRA (California Public Records Act) request. He had requested internal mayoral office e-mails dealing with plans for water cuts, and for whatever reason, Sanders’ people didn’t want to release them. So Rob bombards his readers with stories like “Pudgil Watch, Update 11” (Darren Pudgil is the mayor’s spokesman) and eventually threatens to sue.

I can’t discern whether Rob got anything useful at the end of all this process.

My experience with CPRA/FOIA requests is slim. A few years ago, I got great results from asking the San Diego County DPLU office for emails about Rancho Guejito. But subsequent requests to Supervisor Bill Horn’s office, eh, not much came back. Don’t know if they excluded interesting emails or simply never email about anything interesting.

Anyway, this time Rob has records describing the San Diego Airport Authority’s officials living well at the public’s expense. And he apparently has a sharp exchange with chairman Bob Watkins:

He suggested that a voiceofsandiego.org reporter couldn’t relate to business class travelers because the reporter didn’t make enough money. Watkins compared voiceofsandiego.org‘s examination of authority expenses to a “person who works for the Internal Revenue Service who’s making $40,000 a year and goes in and audits someone who lives in a $1 million home or $2 million home. They’re going to be skewed in terms of, ‘Wow, I don’t have that.'”

Them’s fighting words! I can imagine an offended reporter thinking “I could have been a rich slimeball like you, but I chose to serve the public honorably!”

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Watson out of touch

James Watson has a curious status in biology today. It would be impossible to find a scientist who would fail to acknowledge his accomplishments. At the same time, he is well known for making comments that would crush the reputation of other men.

This sentence in his recent NYT op-ed stuck out at me:

Hardly anyone I know works on Sunday or even much on Saturday, as almost no one believes that his or her current work will soon lead to a big cure.

Please! This sentence indicates that Watson hardly knows anyone who does the real physical work in the lab. Even though I don’t pipet all weekend anymore these days, I’m sure that plenty of graduate students and postdocs across the United States will be doing just that this weekend. All the evidence I get is that biomedical research is even more grueling and competitive now compared with a decade ago.

Let us keep in mind that Watson’s notorious book Double Helix describes science as a “clawing climb up a slippery slope, impeded by the authority of fools, to be made with cadged data…,with malice toward most and charity toward none.”

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Memory T cells

Alert to journal editors, especially in immunology/signal transduction:

There have been three high-profile papers on signal transduction pathways affecting memory T cells recently.

We have the metformin paper in Nature from Choi’s group at Penn. The mTOR rapamycin paper from Ahmed + Larsen at Emory. And the Wnt paper in Nature Medicine from NIH.

And how about sphingosine-1-phosphate?

Aren’t these all different facets of the same thing?

Amazingly, there was just a piece in Nature Reviews Immunology on “Immunoregulatory functions of mTOR inhibition” that only says this at the end: “Insight is also needed into the role of mTOR in memory.”

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Lampreys

A recent paper from Max Cooper’s lab at Emory has provided an example of an alternative path for evolution, one that disturbs and complicates our picture of how the immune system might have evolved.

Like discovering a place where everyone drives steam turbine-driven cars. Makes me think about Stephen Jay Gould and how evolution doesn’t always have a defined direction leading up to humans.

A review: the cut-and-error-prone-paste process of V(D)J recombination, which assembles antibody genes, seems to have jumped into the early vertebrate genome hundreds of millions of years ago.

When and how did this happen? John Travis’ essay makes the point that recently this process is looking less like a “big bang” and more gradual. But then came the lampreys.

T cells and B cells are two arms of the immune system that resemble each other. One responds to peptides displayed by MHC, a useful tool for fighting viruses inside our cells. The other makes antibodies that bind to antigens and can secrete the antibodies, which are great for clearing nasty pathogens from the blood.

Both have receptors on their surfaces that get rearranged by V(D)J, and the genes look similar. One possible order of events is this: there was a primordial “antigen receptor” bearing cell. V(D)J invades the genome, then this primordial cells splits off into T and B.

But no! Lampreys have cells that look like T and B, without V(D)J or the genes that make it possible, RAG1 and RAG2. One set of cells make secreted “variable lymphocyte receptors” and the other doesn’t. One looks like T and the other looks like B, judging from the genes they express.

Lampreys use another genetic shuffling tool to assemble their VLR genes – looks like gene conversion.

It’s worth pointing out that mice and people get most of their immunological diversity from V(D)J but rabbits and chickens don’t, using gene conversion/hypermutation (a process that may have predated V(D)J).

So it looks like the distinction between T and B may have existed first, before V(D)J complicated matters.

Still puzzling is the apparent absence of MHC and a thymus in lampreys, so what T cells respond to and where they develop in lampreys is unclear.

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Evolution of VDJ

Our immune systems have the impressive ability to handle a wide variety of nasty bugs, but when you look “under the hood” at the genes involved, it can look like a Rube Goldberg machine.
Antibody genes get taken apart and put back together in a semi-random way that generates a vast armory of tools, all varying slightly from each other. This process, known as V(D)J recombination, generates the diversity (many genetically different cells within one person!) necessary to respond to what nature throws at us.
It’s hard to believe that a process like this could emerge bit by bit through evolution, but the immune system was actually a centerpiece of the 2005 Kitzmiller v. Dover trial, where a Pennsylviania school district’s requirement to teach “intelligent design” was successfully challenged.
John Travis, as part of a series of essays celebrating Charles Darwin’s life and work in Science, describes this in greater detail. He lays out how scientists have gradually built their understanding of how V(D)J recombination may have been at first “planted” in animals’ immune systems and blossomed later on.

By the way, one of the papers that emerged from my time in David Schatz‘s lab is on the evidence list for the trial! I was thrilled to discover this even several years later. My fellow graduate student Alka Agrawal was first author of the paper. She went on to win a prize for an essay explaining the significance of our work.

RAG-mediated transposition and a model for the origins of split antigen receptor genes. (A) Possible structure of the original transposable element that integrated into the germ line of an ancestral vertebrate. Dashed arrows indicate the direction of transcription of the RAG1 and RAG2 genes. (B) The current "split" nature of immunoglobulin and T cell receptor genes is proposed to have arisen from RAG-mediated transposition of one or two excised elements into a primordial receptor gene exon (dark green), thereby dividing the exon into two or three gene segments, each flanked by one or two recombination signals (black and white triangles). These gene segments would represent the evolutionary precursors of current V, D, and J gene segments. Different patterns of gene duplication (right) would result in the "mammalian" or "cluster" configurations of gene segments characteristic of the heavy-chain locus of mammals or cartilaginous fishes, respectively. The constant region exons (C) are represented as a single gray rectangle.

RAG-mediated transposition and a model for the origins of split antigen receptor genes. (A) Possible structure of the original transposable element that integrated into the germ line of an ancestral vertebrate. Dashed arrows indicate the direction of transcription of the RAG1 and RAG2 genes. (B) The current "split" nature of immunoglobulin and T cell receptor genes is proposed to have arisen from RAG-mediated transposition of one or two excised elements into a primordial receptor gene exon (dark green), thereby dividing the exon into two or three gene segments, each flanked by one or two recombination signals (black and white triangles). These gene segments would represent the evolutionary precursors of current V, D, and J gene segments. Different patterns of gene duplication (right) would result in the "mammalian" or "cluster" configurations of gene segments characteristic of the heavy-chain locus of mammals or cartilaginous fishes, respectively. The constant region exons (C) are represented as a single gray rectangle.

Travis points out that more recently, scientists have found that enzymes resembling RAG1 and RAG2, the “scissors” that cut the DNA to initiate V(D)J, have been found in sea urchins (ie before vertebrates emerged), and it’s not clear what they do there.

Travis writes:

Their existence in the urchin suggests that the transposon [jumping DNA] with these enzymes invaded animals far earlier than had been thought but was lost in most lineages except for jawed vertebrates, which adapted them to perform VDJ recombination. That’s an easier version of the story for some immunologists to swallow, as it allows more time for mutations to deactivate the jumping ability of a transposon and convert its DNA to a new job.

Clearly, our picture of how VDJ evolved will continue to change as more genomic/wet biological information becomes available for species close to the vertebrate/invertebrate line, like lampreys. That leads me to my next post…

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Stem cell discussion at BIO convention

The public’s expectations for advances and cures in the stem cell field are ahead of reality, biotechnology executives and venture capitalists said Monday.

I attended a discussion at the BIO convention now underway in Atlanta on stem cell technology. It was worthwhile to get an idea what top industry people are saying, even if there wasn’t a ton of breaking news.

Scientists are forging ahead, most obviously with the recent discovery that it is possible to convert differentiated cells back into stem cells without introducing new DNA. Still, regulatory, patent and financial issues will probably slow the clinical development of stem cell technology over the next decade, said venture capitalist Steve Burrill, part of a four-member panel at BIO Monday.

Every company smaller than $1 billion, and that includes much of the field, the capital markets will neglect, Burrill said.

“These are some of the most complex biologics anyone has worked with. Cells are just going to be harder,” said Richard Gregory of Genzyme.

Other panelists: Paul Grayson of Fate Therapeutics, Ian Ratcliffe of StemGent

Outside the United States, desperate patients are being offered unproven stem cell “treatments” as a way to treat several neurological diseases. Someone on the panel (Gregory?) said he’d been to Beijing and was apprehensive about possible outcomes. But at the same time, some US companies may look to more flexible regulatory regimes as a way around a conservative FDA.

Some suggested that a field emphasizing transdifferentiation, directly converting one type of donated differentiated cells from patients into another that can be used for therapy, may grow out of the stem cell field. (Harvard’s Doug Melton was mentioned reverently.) This would have the advantages of avoiding early-stage embryos and probably reduce the ability of introduced cells to cause tumors.

Moderator Aaron Rowe, a writer with Wired, at one point asked the panel “How would you reform the FDA,” since the regulatory environment was so uncertain.

Panelists discussed the wisdom of allowing patients to take on considerable risks of volunteering for stem cell trials. Although I did not mention it during the discussion, I worry about a potential Jesse Gelsinger scenario. If a patient dies, everyone will ratchet back risk, even if he/she could grasp what he was getting into.

James Wilson makes this point in an essay in Science. Well worth reading.

(Commentary on Wilson)

Burrill had a elegant summary, saying that AIDS activists had changed the risk vs reward profile of clinical research, allowing patients in urgent need to take on more risk. Then Vioxx came along and made the FDA and industry more conservative, swinging the pendulum back.

Rowe tried to get panelists to come up with a two-word catchy phrase describing small molecules that can guide stem cell differentiation. He conjured up an image of postdocs poring over heat maps, playing the appropriate signaling pathways like violinists, but the panel rejected this picture as too ambitious.

Some of the products the panelists discussed:

Genzyme’s Mozobil, a stem cell mobilizer

Fate Therapeutics is planning a phase Ib trial for a small molecule that could aid homing by stem cells in bone marrow transplants.

Technology challenges discussed:

Growing pluripotent cells in suspension culture (without feeder cells) – I don’t know if this is really possible, because stem-ish cells will always need various ligands, properly arranged, to make them happy. Maybe some kind of artificial matrix.

I would add: quality control assays to ensure that a batch of cells is not tumorigenic, isn’t missing chromosomes, stuff like that.

The San Diego Biotechnology Network’s blog also has a post about the same session from Mary Canady, emphasizing Fate Therapeutics more.

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