Stem Cells from Fat

Bio.com is reporting -- okay, more like carrying a press release -- that Healtheuniverse, Inc., is preparing for clinical trials of stem cells recovered from human fat tissue.  Quoting from the document in question:

Scientific protocols are being prepared for the first human clinical trials using the company's proprietary stem cell technology. This technology uses adipose tissue, or fat which can be used as an abundant source of stem cells for tissue engineering and regenerative medicine. The Company intends to sell this proprietary technology to physicians, clinicians and medical organizations through a packaged product line and licensing agreements within the worldwide regenerative medicine market which is estimated to grow to $500 billion by 2010.

First, clinical trials for regenerative medicine are just getting underway, which means that in only 4 years we are very unlikely to see a $500 billion market.  Second, Healtheuniverse?  HEALTHeUNIVERSE (Ticker: HLUN.PK), according to the website.  A stylism that bears an uncomfortable similarity to www.healthEuniverse.com, and looks like it was suggested by the namebots at Network Solutions.  Brings back nightmares from, say, circa 1999.  But then they are in Biopolis, Singapore, so perhaps I should forgive the name.

All fun derived from the name aside, the technology in general shows great promise.  Zuk, et al., published a paper in Molecular Biology of the Cell in 2002 (full text at PubMed) showing that, "Human adipose tissue is a source of multipotent stem cells."  This may be a way to generate therapeutic patient specific stem cells from adult tissue without cloning.  For example, Timper, et al,. published just last month (PubMed) an article demonstrating, "Human adipose tissue-derived mesenchymal stem cells differentiate into insulin, somatostatin, and glucagon expressing cells."

So, promising, and still off in the future.  But I don't think a company trading on the Pink Sheets will be my first stop for stem cell therapy.

Beyond Genetic Modification in Biological Technologies

Jamais Cascio over at WorldChanging points to a short report on Non-GM Biotech for the Developing World.  Focusing mostly on breeding techniques and molecular diagnositics, the brief suggests policy makers should be thinking more clearly about the benefits of technology beyond genetic manipulation.  I definitely agree, and the topic deserves considerably more attention than it is presently getting.  One could, say, write a whole book about the full range of biological technologies and their potential.  I suppose I should get a move on.

On Hwang Woo Suk and the Stem Cell Debacle

I've resisted writing about Hwang Woo Suk's fraudulent paper in Science about producing patient specific stem cells.  It just isn't really that big a deal.  A guy who claimed proficiency with chopsticks was directly correlated with producing cutting edge science -- surprise! -- turned out to be not so credible.  He was found out.  Science wins.  Science will always win, eventually.

Yet the affair provides an interesting context for thinking about the tenuous standing of cutting edge science.  Uncovering the fraud is frustrating to those waiting for cures for disease or injury, annoying to those waiting for life extension technologies, and disappointing to almost everyone for whom scientific inquiry is the closest approximation to a pursuit of truth; all true.  But guess what?  Science is a human institution, practiced by humans with all of their faults.  It is simply inevitable that those faults affect scientific results and publications.

But what distinguishes science from other human institutions, notably politics, religion, and business, which have all experienced extraordinary fraud and malfeasance recently in the U.S., is that fundamentally science finds its foundations in the physical world.  The progress of science, and its authority, are tied to what is measurable.  Moreover, those measurements must be repeatable.  That is, a result must be testable and verifiable by others to become accepted.  True, uncovering the Hwang fraud took almost two years, but Hwang's fall was inevitable because the requirement for repeatability means that science is self-correcting.  It happens that the holes in the original Science paper appeared not because of questions emerging from labs trying to repeat the work, but rather from suspicious aspects of the paper itself, such different figures of supposedly different cell lines containing similar images.

The scrutiny of these images and other details of the paper applied by scientists within South Korea, fed by suspicion of the great height to which Hwang aspired, only strengthens the process of science.  We didn't actually have to wait for the results of long and laborious experiments, nor did we have to spend money to repeat Hwang's work.  The fraud fell apart under its own weight.  This is a success.

I, like every other practicing scientist, have to wonder how this episode will affect the public perception of science.  I come to the conclusion that the airing of dirty laundry will only improve the position of science in the long run.  There is no other human institution so ruthless in chopping out the dead wood.  After all, if you are lying or pulling a fast one, the very last thing you want to do is get a bunch of really smart people trying to catch you out, all of whose professional standing improves if they do.

The public perception of all this is complicated slightly by the fact that there is a difference between the science you read in textbooks, and the science reported in journals or on the front page of newspapers and news magazines.  In today's New York Times, Nicholas Wade has a very nice article exploring this issue, prompted by the stem cell fraud:

The contrast between the fallibility of Dr. Hwang's claims and the general solidity of scientific knowledge arises from the existence of two kinds of science - a distinction that is often blurred when new advances are reported first by scientific journals and then by the news media. There is textbook science and frontier science, and the two types carry quite different expiration dates.

Textbook science is material that has stood the test of time and can be largely relied upon. It may include findings made just a few years ago, but which have been reasonably well confirmed by other laboratories.

Science from the frontiers of knowledge, on the other hand, is wild, untamed and often either wrong or irrelevant to future research. A few years after they are published, most scientific papers are never cited again.

I find this latter point the most problematic of the scientific enterprise.  Of the papers with short lifetimes, some are not read or cited because they aren't very good or very interesting, some are only minor improvements on previous work, and some fall by the wayside because they describe dead ends.  In all cases, very little science that gets done, and even less that is finally reported in journals, actually affects the world in a meaningful way.   How can you not feel a bit ambivalent about this?  Isn't this emblematic of some sort of waste, inefficiency, or a Proxmire-attracting, willful misappropriation of funds?  Emphatically not!  This is a cost we must bear as part of the never-ending effort to banish our ignorance and improve the human condition.  At both the institutional and the personal level this cost is intrinsic to science.  Every scientist, and every technologist and inventor, for that matter, has plentiful experience with choosing the wrong path.  Alas, the dominant social structures governing funding decisions and career advancement are based predominantly on the number of papers published, rather than upon their content, which means that often the wrong path, the marginal improvement, and the simply boring result in the lab are gussied up for publication to look far more significant that they really are.

The only real defense against this profusion of craptastic papers is the choice of individuals not to write and publish them.  So I have little hope of progress there.  Enough said about that.

A weaker, but necessary, defense lies in peer review.  In lieu of the sudden popularity of all scientists becoming harsh and discerning critics of our own efforts, we must all keep watch on science as a whole, trying to catch mistakes and fraud before publication.  Yet this process, too, is far from perfect.  Too many anonymous reviewers have political reasons for rejecting papers, and many more just don't do a good job of reading the paper they are judging.  I don't really have a solution to this problem, but I have to wonder if removing anonymity from the review process would clean things up.  Yes, you would have the problem that younger scientists reviewing the work of their elders would be exposed to wrath from above.  But what we have now definitely needs improvement.  Witness the Hwang paper.

Mr. Wade explores the notion of improving the quality of papers through requiring authors to state their contributions to a paper, and by requiring all authors to state their explicit agreement with all conclusions in a paper.  I don't have any problems with the latter, but I can say from personal experience that writing an author contribution statement can be extraordinarily painful, a struggle to carve out sufficient acknowledgments of your own efforts and give perspective on another's efforts, particularly when control of the text lies with someone else.  Still, it's worth a try.  And I support the inclusion of author's contributions for the time being.

Alas, this doesn't help with the review process itself, because it doesn't do anything about biases or laziness of reviewers.  Mr. Wade thus incorrectly suggests that clarifying the author's roles in research has anything to do with the decision-making process during review at a journal.  Nonetheless, save conflation of the review process with writing and attribution, his conclusion is right on the money:

Tightening up the reviewing system may remove some faults but will not erase the inescapable gap between textbook science and frontier science. A more effective protection against being surprised by the likes of Dr. Hwang might be for journalists to recognize that journals like Science and Nature do not, and cannot, publish scientific truths. They publish roughly screened scientific claims, which may or may not turn out to be true.

And thus we must labor on, and through those labors attempt to keep science honest and thereby produce a better world.  Science will always win, eventually.

"Playing God in Running Shoes"

Here is Carolyn Abraham's article about Synthetic Biology from the Toronto Globe and Mail, "Playing God in Running Shoes (subscription required to get past the first page)."  Full text here, no subscription required.  Note: I'm not a professor at the UW, as suggested in the article, but rather a senior scientist in the Electrical Engineering Department.  Otherwise, a fine article that goes into not just the technical difficulty inherent in building new organisms but also explores ethical implications of the whole endeavor.  I'm not so sure, though, how Drew Endy is going to feel about being described in the story title that way...

Direct Biological Production of Diesel

Based on the number of Google searches that lead to my post Algae into Biodiesel, there seems to be significant interest in direct biological production of diesel.  National Geographic, c|net, and Technology Review all have carried stories recently about new approaches for generating biofuels and new catalysts for reducing costs and improving yield.

Perhaps this research will finally help land a turbo diesel roadster on my doorstep.

Wired Magazine's version of the Global DNA Foundry Map

Wired 13.12 (December 2005) contains the magazine's version ("A Genome Shop Near You") of the Global Distribution of Commercial DNA Foundries map I helped make this past summer.  Not all of the foundries on my map are on Wired's version, and they found a few more, but the gist is the same.  Jerry Epstein and Anne Yu at the Center for Stratetic and International Studies contributed to making the original map.

The Rise of Chinese Biotech

On the theme of increased participation of developing countries in biological technology, Rik Wehbring pointed me to a Reuters story, "Low Cost Spearheads China Drive Into Biotech".  As I have written previously here, in addition to investment by Western companies China is putting considerable effort into developing both domestic R&D and domestic clinical expertise.

The Reuters story notes that

China already boasts more than 20 biotech parks dotted around the country and 500 biotech enterprises.  Some 300 of these companies are focused on medicine, with the balance mainly targeting agriculture.  The Chinese government and local governments have both been active in supporting the sector, with total state funding last year reaching the equivalent of 270 million euros ($325 million).

Because "the cost of biomedical research in China is only about 20 percent of the cost in Western countries", that $325 million goes quite a long ways.

We can expect drug development and biomedical research to take off in India as well.  A friend of mine with investments in the U.S., Europe, and in India cites cost figures for India identical to those for China.

So I ask you, without considerably greater investment in education and domestic R&D, how are either the U.S. or Europe going to compete?  What is it going to take for policy (politicians) to catch up to reality?

Progress on Cell-Based Therapies

Spinal cord injury and HIV are the targets of two innovative cell-based therapies, with the planned HIV treatment relying on gene-therapy to produce in vivo RNA interference (RNAi).  In a very short news piece in Nature (subscription required), "Pioneering HIV treatment would use interference and gene therapy", Erika Check writes that;

If the FDA says yes, [John Rossi and his team at  at City of Hope's Beckman Research Institute] will test the therapy on five HIV patients who have a blood cancer called lymphoma. They will treat the patients' lymphoma with aggressive chemotherapy and a bone-marrow transplant — a normal procedure. But before the transplant, they will use gene therapy to add stretches of DNA to stem cells in the bone marrow. It is hoped that molecules encoded by the added genes will trigger the cells' RNAi defences against HIV.

The trial is different from the RNAi trials already under way, because the molecules used in those studies remain in the body for only a short time. The City of Hope researchers will deliver DNA packaged into a gene-therapy vector that could persist in patients for months or even years.

The Recombinant DNA Advisory Committee is having Rossi perform additional safety tests before giving the OK for the trial.  If this works out, it will demonstrate a remarkably powerful way to alter human physiology through the permanent (?) addition of a new RNAi pathway.  The strategy pursued by Rossi, et al., would provide a pool of stem cells that produce lymphocytes immune to HIV.  Since HIV shows some tropism for neural and other tissues, the treatment may not completely rid patients of the virus, but as lymphocytes carrying HIV die out at least the patient would have a source of healthy immune cells.  As this research goes forward, we can expect significant press coverage because the technique will probably find immediate use in treating many other chronic diseases.

The work on repairing spinal cord injury through cord blood cell transplantation has received surprisingly little press.  In an article in Cytotherapy, K-S Kang et al., demonstrate that multipotent stem cells (MSC) derived from umbilical cord blood colonized the site of a spinal cord injury in a 37-year old women who had been a paraplegic for almost 20 years.  The MSCs were amplified in vitro and then surgically transplanted to the site of the injury.

Prior to treatment, the patient showed no somatosensory or motor activity in her lower body, and nerve conduction studies confirmed the extent of the damage.  After transplantation, the patient regained significant sensation within 2 weeks and could maintain an upright posture.  She was able to move her lower legs shortly thereafter.  Nerve conduction studies were used to confirm the extent of recovered electrical activity.  CT and MRI demonstrated regeneration of the spinal cord.

My neurophysiology is more than a tad rusty, which means the import of some specific things reported in the paper isn't immediately clear to me, but the overall results are enough to make anyone take notice; a previously paralyzed patient is now able to at least feel stimulation in her lower limbs, maintain an upright posture unassisted, and has regained some motion in her lower legs.

The specific mechanisms behind the recovery must now be determined, including how the MSCs produce such dramatic improvement.  The authors also note that they cannot rule out the surgery as effecting some recovery.  But the demonstrated increase in electrical activity and motion is extraordinary.  And you have to imagine that the ability to maintain an upright position unassisted for the first time in 20 years is by itself an enormous gift.

This is just one patient, and just one paper, so lots of work is required before anything like this becomes standard treatment.  It is also unclear what the long term effects of the procedure and the new cells will be.  Then there is the little problem that in the U.S. working with stem cells is a tad problematic, regardless of their source.  This study notably, took place in Korea.

Nonetheless, what fantastic news.