Wednesday, January 23, 2013

Academic Drug Discovery Revisited

A thoughtful opinion piece on academic drug discovery in ACS Med Chem Letters by D.M. Huryn makes interesting reading [1]. Much has been written about universities seemingly seeking to duplicate commercial drug discovery efforts or entering into very focused partnerships with ‘Big Pharma’. The author advocates a different approach stating “rather than asking how a university can mimic a drug discovery company, perhaps a better question is what unique features inherent in an academic setting can be taken advantage of, embellished, and fostered to promote drug discovery and encourage success?“ She goes on to emphasize some of the positive characteristics of universities, including strong fundamental biological research and the willingness to take risks.

Indeed, this is exactly what has been happening in many academic drug discovery units, as revealed in a recent survey [2]. Rather than focusing on validated compounds for chronic diseases of rich countries, as is the practice of Big Pharma, academic drug discovery units tend to build on local basic research and to place major emphasis on drugs for orphan diseases or diseases of less developed countries. Moreover, while success for a drug company can only mean a marketed drug, success in academic drug discovery can include the develop of powerful chemical probes for basic biology.

There have been many discussions of the appropriateness of team-based drug discovery in an academic environment that emphasizes individual accomplishment. Certainly there have been some strains in some institutions in this regard. However, as a faculty member at a university with a strong academic drug discovery unit I have mainly witnessed a smooth integration of academic basic science with the screening and discovery process. Likewise, many students and postdocs who have had some exposure to the collaborative discovery process come away the better for it, without compromise of their individual research thrusts. Thus, overall it seems that academic drug discovery is here to stay, that it will not supplant commercial drug discovery, but rather provide an exciting and important complement.

[2] Frye, S. F.; Crosby, M.; Edwards, R.; Juliano, R. US Academic Drug Discovery. Nature Rev. Drug Discovery 2011, 10, 409−410

Friday, January 18, 2013

Human enhancement- changing the trajectory of senescence.

A few recent articles have interesting implications for modulating the processes of cellular senescence and cell death that seem to underlie much of the aging phenomenon [1]. In a recent article in CELL, Sharpless and colleagues described a way to visualize senescent cells and tissues in vivo (mice) using luminescence imaging; interestingly tumors were ‘hot spots’ of cell senescence [2]. However, somewhat in contrast to the studies in [1], the CELL paper did not find a tight correlation between degree of senescence and death of the animals (at least from cancer). Thus there may be senescence-related and unrelated causes of death. In the long term better understanding of the kinetics of senescence will ultimately lead to better approaches for influencing the process.

On a different but related theme, a commentary in Nature Reviews Drug Discovery [3] described recent progress in Alzheimer’s disease therapeutics. Although there have been some recent major disappointments, the quest goes on.  A major change in emphasis is to begin to interdict the process of beta-amyloid formation at earlier stages, essentially when no clinical symptoms are present. This seems another example of the blurring line between therapeutics and enhancement of the functions of healthy individuals. No doubt we will see much more of this as our biomedical technology gets increasingly sophisticated.


Friday, January 11, 2013

NIH’s Feeble Response to Problems in Biomedical PhD Training.

In June 2012 a distinguished committee headed by Princeton President Shirley Tilghman reported to the NIH Director regarding issues in biomedical workforce training. The report indicated that conventional modes of graduate training were not adequately preparing students for the realities of the current job marketplace and suggested a number of approaches to improve the situation [1]. The report advocated increasing the proportion of graduate stipends based on competitive training grants versus those supported by research grants, but did not advocate reducing the total number of students.

While there are many good things about the Tilghman report, to this observer it failed to confront the most basic issue- that we are training far too many biomedical PhDs! The need for biomedical ‘birth control’ is implicit in some of the verbiage in the report’s Executive Summary. “Although the vast majority of people holding biomedical PhDs are employed (i.e. unemployment is very low), the proportion of PhDs that move into tenured or tenure-track faculty positions has declined from ~34 percent in 1993 to ~26 percent today. In contrast the proportion of non-tenured faculty has stayed relatively constant during the same period, while increasing in absolute numbers. The percentages of biomedical Ph.D.s in industry and government have remained relatively constant. The categories that have seen growth are science- related occupations that do not involve the conduct of research and occupations that do not require graduate training in science.“ Thus the data in the report show that approximately 30% of PhD graduates are in positions that do not involve research. Therefore they have no need for the years of intensive research training involved in a PhD. What a waste of the time and energy of those people!

About 43% of PhD graduates are in academia; however, an increasingly large proportion of those are in unstable, largely grant-funded, non-tenure track positions. The research associates, research track faculty and postdoctoral fellows in these unstable positions play a vital role in contemporary biomedical research. Yet no university has found an effective mechanism to introduce some stability and clarity into their career paths.

If one counts tenure track academics (26%) and government and industrial scientist (24%) as individuals who have launched successful careers based on their PhD training, then 50% of trainees have not. This seems a dismal failure of the training system.

The traditional system of graduate training in the US is based not on the needs of the students, but rather on the need of professors for inexpensive, relatively skilled labor to keep their research programs running. It is really farcical to call this graduate education; rather it is better styled as graduate exploitation. The current economic malaise further compounds the situation. The lack of jobs for people with bachelor level credentials pushes more young people into graduate school. However, on the other end of the process the same economic problems have reduced the number of opportunities for PhDs.

Despite all this gloom there are some relatively straightforward ways to improve the situation.

1. All graduate stipends should be based on competitive institutional or individual training grants. This would improve the quality and reduce the numbers in the PhD training pool.

2. To replace graduate labor more emphasis should be placed on postdoctoral fellows and PhD level research staff. Complementary to this, universities need to (or be forced to) set up mechanisms so that some grant funds are sequestered to provide stabilization of non-tenure track research positions. This is not to suggest some form of tenure for these positions, but rather to make sure the career of a staff scientist is not totally dependent on the renewal of a single grant (as is so often the case now).

3. To provide a cohort of scientifically sophisticated, but not research intensive, personnel for various tasks in industry, there should be increased emphasis on Master’s degree programs (as suggested in the Tilghman report).

Unfortunately, the NIH’s implementation of even the limited recommendations of the Tilghman report are feeble at best, as revealed in a recent article in SCIENCE [2].  For example, even such non-controversial items as having students and their mentors prepare ‘Individual Development Plans’, having universities to track careers of graduates, or asking universities to develop new curricula more suited to industry needs are to be done on a voluntary basis. Thus the new policies lack teeth.

Another sad episode in the history of biomedical graduate training- when will we learn!

[2] J. Kaiser. NIH Offers to Help Universities Improve Training, Boost Diversity. SCIENCE 338: 1405 (2012).