Thursday, June 12, 2014

Antisense and siRNA: Parochialism in Research

I enjoyed reading an excellent review in Science Translational Medicine on problems and possibilities concerning therapeutic utilization of siRNA. The authors, from MD Anderson Cancer Center, covered all the key issues including target selection, delivery, toxicity and pharmaceutical feasibility. An interesting sidelight for me, however, was that the article focused solely on siRNA and completely ignored single stranded oligonucleotides such as ‘classic’ antisense or splice switching oligonucleotides although these molecules share exactly the same prospects and problems as siRNA. This reflects a schism of interests in the oligonucleotide therapeutics field with one group of investigators (and companies) promoting the virtues of siRNA while another cohort focuses on single stranded oligos. Fortunately there are venues where the two groups can communicate- one being the annual meeting of the Oligonucleotide Therapeutics Society where all forms of nucleic acid therapy are considered. It’s an interesting commentary on science, however, that even in a relatively small field a considerable amount of parochialism can come into play.

Friday, May 23, 2014

Senescence and Ageing

An impressive review in thus week's NATURE surveys the complexities of the causes and mechanisms of cellular senescence. Of particular interest is the increasing evidence for  a critical role of senescent cells in the aging of tissues and organs. This can come about in many ways including loss of stem cell capabilities. However, one key aspect is the ability of senescent cells to produce inflammatory factors that then lead to tissue degeneration.  The growing information on the link between cell senescence and aging opens the door to  possible therapeutic approaches that might slow down the decline of functions with age. 

Friday, May 16, 2014

NIH Bows to Political Correctness

The NIH has long sought to ensure that the diagnostic and therapeutic research it supports will be of value to both men and women.  For that reason it has emphasized steps such as full inclusion of females in clinical trials. Now however, new policies are broadening that mandate to an unreasonable degree.  Not only will scientists be asked to include females in clinical trials and in more basic studies using animal models of disease, but they will also be asked to use cell lines derived from both males and females (1).

NIH policies to encourage full representation of females in clinical trials and use of female animals in basic research are sensible and laudable. But extending that policy to cell lines- ridiculous! Most cell lines used in basic research laboratories have been in culture for decades. They are so far removed from the original tissue cells that their responses to drugs or other stimuli are vastly different—this being a major problem for drug development. Insisting on equal representation of male and female cells in basic research is political correctness run amok!!


Thursday, May 8, 2014

Young Blood for Ageing Organs

There has been a great deal of interest in the idea of using stem cells to reverse age-associated declines in organ function. However, recent studies have shown that ageing tissues often have plenty of stem cells; nonetheless, the stem cells lose their ability to differentiate and to repopulate tissues with healthy cells. Now, in recent issues of SCIENCE (1) and NATURE MEDICINE (2), several research reports have shown that factors in the blood of young mice can reverse age-related declines in stem cell and tissue function. Some of these studies used parabiosis, that is joining the circulatory systems of old and young animals. Another study focused on GDF11, a TGF-beta type growth factor whose expression declines in older animals. Injections of this protein improved both muscle function and (in another report) growth of brain blood vessels and olfactory neurons. Perhaps the most exciting study (2) demonstrated that blood from young mice could reverse age-related declines in hippocampal cells and associated cognitive impairments.

There has always been tremendous interest in seeking means to slow the declines associated with ageing. However, the work discussed here, as well as other recent studies, suggest that an actual reversal (at least in part) of the ageing process may be possible. While this is all still far away from use in humans, it offers a tantalizing prospect that could have enormous implications both medically and in terms of impacts on society. 



Friday, May 2, 2014

Finally, some sound thoughts about PhD training from the big shots!

PNAS recently published an opinion article from four very prominent individuals about the current malaise in biomedical research and training.  The authors were Bruce Alberts (former editor of SCIENCE), Marc Kirschner (a Dept Chair at Harvard), Shirley Tilghman (former President of Princeton) and Harold Varmus (nobelist, and Director of the National Cancer Institute). This is about as high powered as you can get in science!

The article analyzed several problematic aspects of the current biomedical research system but prominently featured the depressing scenario regarding PhD training. Based on various perverse incentives, both senior faculty and university administrators have continued to expand the PhD trainee population during a period when employment prospects for biomedical PhDs have drastically diminished. Academia is at saturation, the pharmaceutical industry is eviscerating its research programs, and the growth of smaller biotech companies is just not enough to provide adequate jobs. In my experience more and more PhDs are going into jobs such as clinical trials management, market research, and other administrative functions for which intensive training in laboratory research is not essential. What a waste!

The abovementioned gurus make some valuable suggestions such as:
(1)   Removing support for graduate stipends from research grants and placing them in competitive training grants; this would give NIH more direct control over trainee numbers.
(2)   Placing renewed emphasis on Master’s degrees. In many cases this would provide sufficient science training for some of the jobs mentioned above, while consuming far less time for the trainee.
(3)   Developing stable career paths for staff scientists (as opposed to faculty/principle investigators) in universities and other research institutions. There are lots of talented people who would like to do science but do not want the pressure of constantly seeking grant funding. There should be ways of supporting these individuals.

None of these ideas are new. Many people, including me, have been advocating similar changes for years. However, it is nice to see some very influential people espouse the same ideas. Maybe something will get done about the problem. But don’t hold your breath!

Wednesday, April 16, 2014

The Biomedical Research Brain Drain Continues

Although the NIH budget will go up slightly this year, inflation plus years of stagnant funding is culling more and more good scientists. Funding percentiles remain in the 10% range and the total number of investigator-initiated grants is going down and down (1). The NIH and the academic institutions it supports need to face up to what is clearly a permanently altered funding landscape and go into a salvage mode. In order to maintain the viability of US biomedical science two things need to be given priority.

First, truly talented young scientists must be given every advantage. The NIH currently does provide a small ‘edge’ for first time awardees. However, this does not persist after the first funded grant and thus the duration is really not long enough for a young investigator to get a career going.

Second, highly skilled mature investigators need some stability so that one failed grant application does not imperil their careers.

The US (particularly the NIH) is unique in the world in that science funding is judged and awarded almost purely on the content of individual grants with only limited consideration of the career development path of the applicant. In these days of sub 10% funding, a single reviewer who has a minor technical quibble about a proposal can torpedo the grant and possibly also the applicant’s career.  In many other countries more weight is given to the long-term accomplishments of senior investigators and to the promise of junior investigators. Incorporating considerations of career development in grant review would work toward preservation of human potential in science. Clearly there is a danger of elitism here, but high quality science is inherently an elite activity and surely an appropriate degree of fairness can be built into the process.

Another needed change is that US academic institutions must get their hands out of the cookie jar of indirect costs returns. Sure it costs money to provide facilities for researchers, but universities have charged and over charged for those facilities and have diverted massive amounts of indirect costs from grants to totally inappropriate expenses including university golf courses, parking decks, bus systems and fancy digs for administrators. That money needs to be used to directly support science!

Finally, universities need to exhibit restraint both in the hiring of new science faculty and in the training of students. We are producing far more science PhDs than can possibly find productive careers in this time of diminished funding in academia and the wholesale evisceration of basic research in the pharmaceutical industry. 

Thursday, April 3, 2014

A Tour de Force for Synthetic Biology

A recent report in SCIENCE describes the synthesis and function of an artificial yeast chromosome. Starting with oligonucleotide building blocks the investigators assembled a 272,871 base synthetic version of the 316,667 base natural chromosome III. The artificial chromosome contained a number of modifications including loxP sites to facilitate gene deletions and alterations as as well as changes in stop codons and various sequence tags. The synthetic chromosome seems to work well and to support all essential functions in living yeast.

This molecular biology tour de force has major implications for both basic science and technology. For example, on the basic science side it will allow simultaneous manipulation of multiple genes thus facilitating the investigation of patterns of gene-gene interaction. On the technology side it could allow manipulation of whole suites of genes to produce drugs or other useful molecules that are difficult to synthesize by conventional means. Overall this should be a major step forward for synthetic biology.