Wednesday, February 26, 2014

Mitochondrial replacement / 3-parent babies: opening the door to human enhancement

This week the NY Times had an interesting opinion column on mitochondrial replacement, a procedure currently under review by the FDA. The idea is that there is a cohort of inheritable diseases based on defects in the mitochondrial genome. In the embryo the mitochondria are all derived from the fertilized egg so the defects are passed from the female partner. Thus the approach for potential parents where the woman has a mitochondrial defect would be for in vitro fertilization followed by transfer of the fertilized nucleus to an enucleated egg from a healthy donor. Thus the embryo would have three parents, the male and female who contribute the nuclear genome and the female who contributes the mitochondrial genome. 

It is hard to argue with the use of mitochondrial replacement to prevent the passing of defective mitochondrial genomes to children. In the current situation women who know they posses such defects must choose between refraining from having children or passing their defects to their offspring. However, if this approach is to be approved by the FDA it is important to go forward with the understanding that it will open the door to widespread use in other contexts. Mitochondrial transfer will become yet another tool in the growing armamentarium of human enhancement technologies, where advances made in the name of disease treatment are subsequently applied to enhance the physical or cognitive abilities of healthy individuals. A possible additional use is improving success rates for older women during in vitro fertility treatments. Beyond that application looms a whole range of other possibilities. The most obvious, given the connection between mitochondrial energy generation and muscle function, is to seek to enhance the athletic prowess of offspring. Sequencing mitochondrial genomes is trivial with current ‘deep sequencing’ machines and it would be quite easy to sort through the mitochondrial genomes of thousands of individuals seeking genetic patterns associated with outstanding athletic capabilities. The ethical and societal implications of such efforts are very hazy, but what is clear is that it will happen if given the chance. 

Thursday, February 20, 2014

NIH Study Sections: Are They Giving Money to the Right People?

A column in last week’s SCIENCE described a study by Michael Lauer of the NIH who compared NIH peer review of the merits of grant proposals to the publication record and impact factors of the investigators who submitted those proposals. He found essentially no correlation between high evaluation by the NIH study section and future publication productivity. This result has apparently triggered some hand wringing at the NIH and calls to alter the way in which study sections work. However, this concern may be misplaced.

Every scientist who is worth his/her salt can recount experiences where an NIH study section trashed a grant on a topic that later turned out to be quite important. It has been pointed out many times that NIH study sections are inherently conservative and tend to reflect the existing consensus in a field. Major breakthroughs, however, come from science that disrupts consensus. This has been understood ever since Thomas Kuhn and The Structure of Scientific Revolutions. The issue is how to identify breakthrough science and differentiate it from misguided error. To give the NIH some credit, in recent years it has implemented a number of granting programs that try to stress innovation (e.g. the Pioneer awards) as well as funding for beginning investigators who may have some new ideas.

Almost the converse situation prevails in publication where the ilk of Nature, CELL and other high profile journals try to focus exclusively on ‘hot’ topics.  Over time some of the designated hot areas prove to be not so hot and dwindle away, but nonetheless the ‘hot’ articles will have generated high impact factors. No wonder there is a discrepancy between NIH funding and publication impact!

Although there is no need to obsess about the grant/publication disparity, it is clear that the NIH peer review system could use some renovation (as well as more money to dispense). The titles and functions of study sections still primarily reflect a disease/organ system specific orientation. However, current biomedical science is developing information and insights that cut across traditional boundaries. If the study section system were more reflective of the thrust of current research there would probably be fewer misfires on grant funding. 

Wednesday, February 12, 2014

Accelerating Medicines Partnership. NIH opts for Big Projects with Big Pharma- but at what cost?

A recent piece in SCIENCE described the enthusiasm of NIH Director Francis Collins for the Accelerating Medicines Partnership (AMP). The goal is to cut down on the more than 95% failure rate for drug candidates by linking between NIH funded research and industry. At first glance one is cheered to learn that the NIH will devote resources to a partnership with drug companies to seek new treatments for Alzheimer’s and other chronic diseases. But where will the money come from?  There is essentially no new money in the NIH budget, so these efforts will divert funds from traditional NIH individual investigator grants (R01s) to these larger projects. There are two problems with this. The first is that it is unclear whether such top-down, large-scale research efforts really pay off in terms of fundamental advances. The second is that small laboratories, particularly young investigators just getting started, will not be able to compete effectively for these large projects. The multi-year drought in R01 funding that began with the onset of the great recession is already beginning to winnow talented young people from careers in biomedical research. Is it wise to make their lives more difficult by further constraining R01 funding?  My guess is that greater advances in understanding chronic diseases would result from keeping a few more bright young investigators in the game, rather than putting money into mega-projects.  Converting advances in basic research into therapies is really the responsibility of the pharmaceutical and biotech industries, not the NIH. If industry isn’t doing its job maybe it needs some carrots (or sticks) to push it in that direction.

Sunday, February 2, 2014

Cooking Up Stem Cells: Implications for Human Enhancement and Ageing

Every once in the while a research paper is published that really astounds you. Such is the recent pair of NATURE papers from Obokata et al (1).  What is described is an extremely simple way to convert mature differentiated cells to stem cells by exposure to stresses such as low pH. This process is called Stimulus-Triggered Acquisition of Pluripotency (STAP). The STAP cells seem to be able to contribute to all tissues in chimeric mice and to be passed through the germ line, the hallmark of truly pluripotent stem cells. Interestingly, the STAP cells can contribute to both embryonic and placental tissue. This is unlike iPS cells, whose pluripotency is induced by expression of a small set of transcription factors, and which can only contribute to embryonic tissue.

Assuming that it can be extended to human cells, this amazing result has numerous potential implications.  First of all it calls into question the much-touted concept of cancer stem cells. Perhaps these are simply cells that have been converted to stemness by the harsh tumor environment (low pH, low O2). Second, by making stem cell production far easier the STAP approach will hasten implementation of stem cell based therapies in various diseases. But perhaps most interesting consequence may be in the nascent field of human enhancement. By virtue of being able to generate large numbers of stem cells from an individual’s own cells it may be possible to retard the accumulation of senescent cells that have been implicated as a key factor in the tissue degeneration that accompanies increasing age (2).  So are STAP cells the fountain of youth? We shall see. 

(2) Baker, D.J., Wijshake, T., Tchkonia, T., LeBrasseur, N.K., Childs, B.G., van de Sluis, B., Kirkland, J.L. and van Deursen, J.M. (2011) Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 479, 232-236