More on postdoc problems

An opinion piece in SCIENCE discusses ways to make research careers more stable, in part by limiting PhD production  (1). I agree with their analysis. Steps to limit PhD production and to introduce stable research career pathways for ‘non-PI’ scientists are clearly needed. But we have known this for some time. The problem is that both senior faculty members and their institutions have a strong self interest in maintaining the current situation. An ample supply of cheap and expendable labor is just too good to pass up.  We have commented on this several times in this blog.

(1) http://www.sciencemag.org/content/346/6215/1422.full

 

http://scienceforthefuture.blogspot.com/2010/02/why-are-there-still-too-many-graduate_10.html

http://scienceforthefuture.blogspot.com/2014/05/finally-some-sound-thoughts-about-phd.html

Poor Prospects for Postdocs

This week's Nature (1) highlights two reports, one from the UK and one from the US, that describe the parlous state of the postdoctoral experience for biomedical PhDs. Reduced government support for research, the implosion of the pharmaceutical industry's in-house research, and in the US, cutbacks at state universities, have all limited job prospects. Nonetheless major universities continue to crank out biomedical PhDs.

This is nothing new. See previous posts on this blog elaborating the situation in more detail (2,3).


(1) http://www.nature.com/news/harsh-reality-1.16465

(2) http://scienceforthefuture.blogspot.com/2010/02/why-are-there-still-too-many-graduate_10.html

(3) http://scienceforthefuture.blogspot.com/2014/05/finally-some-sound-thoughts-about-phd.html 

The Migration Dilemma: No we don’t want to hurt families-but-just how many people do we want in the USA?

Today President Obama announced his new immigration policy (1) largely designed to prevent deportations of illegal immigrants from breaking up families. Certainly our nation should not be too harsh on hard-working people who have come here for economic opportunity and who have had children born in the US. However, I can’t help but wonder if this policy will re-activate the floodtide of illegal immigration that has taken place over the last two decades but that has recently shown signs of subsiding.

We are often described as a nation of immigrants and as a descendant of immigrants it is uncomfortable for me to argue that the US should cease to provide opportunities for deserving people. However the great surge of immigration in the 19^th and early 20^th centuries occurred in a very different setting than today. In 1900 the US population was 76 million. Today it is 320 million and is rapidly climbing toward 500 million by mid-century primarily because of immigration and the higher fertility rate of immigrants (2).

This raises the question of how many people do we want in our nation? Do we really want 500 million, how about a billion?  Business interests always favor population growth–more people, more sales more profits. But what about the life-styles of average people? Do we really want to live in the sort of ultra-crowded, polluted, degraded environment that is typical of China and India today?

Another issue is jobs. The combination of competition from abroad in manufacturing and the increased use of automation and computers at all levels of economic activity is limiting employment prospects for Americans. Whether it’s a highly trained software engineer from Bangalore or a carpenter from Guatemala City, the net effect of immigration is to further reduce opportunities for Americans. For the first time in our history even college graduates are having a difficult time finding jobs. Slowing immigration wont solve the problems caused by globalization and automation, but it will mute the effects somewhat.  

The US can’t address global poverty by having the world’s poor move here. Indeed much poverty around the globe is due to over-population. To this observer the intelligent approach for our nation is a combination of stringent limits on immigration coupled with strong support for population control and economic development in the poorer nations of the world.  

(1) http://www.nytimes.com/interactive/2014/11/20/us/2014-11-20-immigration.html?hp&action=click&pgtype=Homepage&module=first-column-region&region=top-news&WT.nav=top-news

(2) http://www.usatoday.com/story/news/nation/2014/04/29/us-born-hispanics-overtake-immigrants/8456933/

  

Prepare to feed the masses? Or push the population curve?

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A recent report (1) from the Earth Institute at Columbia University discusses improved prospects for food production in Africa, indicating that the continent may be able to feed itself despite a projected population increase to 2 billion by 2050.  While improved food production is certainly good news, the report simply accepts the idea that there must be a huge increase in population over the next few decades. Even if hundreds of millions of additional people can be fed, their existence will wreak havoc on the planet. Presumably the additional billion Africans, along with similarly surging populations in south Asia and elsewhere, will aspire to American style (or at least Chinese style) affluence with the attendant disastrous impacts on resource use, pollution, species extinction and global warming. In Africa and around the developing world, investments in agriculture and industrialization dwarf investments in population control. Maybe priorities should be reversed.  

(1) http://blogs.ei.columbia.edu/2014/11/06/will-africa-finally-achieve-a-green-revolution/
 

Population Growth and the Ebola Epidemic

The tragic spread of Ebola virus in Africa has been discussed at length as a failure of public health systems resulting from inept governance and from poverty. However, a root cause of the epidemic lies in the rapid and unchecked population growth in Africa.  Unlike developing countries in other parts of the world, African nations currently do not seem to be undergoing the ‘demographic transition’ that associates rising GDPs with falling fertility (1). The rapid increase in population sets the stage for transmission of diseases such as Ebola in two ways. First, by migration of people from overcrowded agricultural land to forest areas where more contact with animal disease vectors is possible. Second, by the ever-increasing populations in congested urban slum area where disease transmission is facilitated. Effective control of infectious disease epidemics in Africa (and elsewhere) must including more aggressive family planning services.

(1)  Dyer, G. (2013) http://www.straight.com/news/394516/gwynne-dyer-world-population-growth-and-african-exception.

New Hope for Age-Related Eye Diseases

The announcement of a clinical trial of induced pluripotent stem cells (iPS cells) in Japan (1) has somewhat of a personal aspect for me.  I have recently been having some retinal problems consequent to a mishandled cataract operation.  This has made me very aware both of how important and how delicate our visual systems are. The Japanese trial will use iPS cells in patients suffering from age related macular degeneration, a common but difficult to treat eye disease. Since the retinal cells to be implanted will derive from the patient's own cells via the iPS approach, hopefully there will be no immune rejection.

As an older person I cheer the push toward stem cell therapies. It will probably come too late for my generation, but  hopefully a combination of stem cell and genetic technologies will eventually be able to attenuate many debilities that accrue with age.

(1)  http://www.nature.com/news/japan-stem-cell-trial-stirs-envy-1.15935

GDF11- the Elixir of Youth??

A feature article in SCIENCE this week (1) summarized some very impressive work from Amy Wagers (Harvard) and other researchers on blood factors that seem able to partially reverse age-related tissue degeneration. Several groups have used a technique termed parabiosis to establish a shared circulation between old and young mice.  This resulted in improved function in muscles, heart, and nerves of the older mice. One possibility is that blood factors from young mice restore the ability of stem cells in older animals to repopulate damaged tissues. In an exciting new development Wagers and colleagues have identified a protein termed GDF11 as the rejuvenating blood factor. GDF11 is a member of the TGB-beta family of growth factors that regulate many aspects of tissue differentiation and growth.

These results would seem to open up new opportunities for clinical approaches that address ageing per se rather than individual diseases associated with ageing. Some strong arguments have been made that this approach would make a much greater contribution to human health and longevity than disease specific therapies (2).

(1)  http://www.sciencemag.org/content/345/6202/1234.full

(2)  Goldman, D. P., et al. (2013), 'Substantial health and economic returns from delayed aging may warrant a new focus for medical research', Health Aff (Millwood), 32 (10), 1698-705.

Re-branding the PhD

This week’s NATURE has a rather bizarre editorial regarding careers for PhDs (1). The editors acknowledge that currently many individuals with PhDs do not find academic positions, or even positions actually doing research, but rather wind up in a variety jobs that really do not require intensive research training, ranging from high school teaching to investment banking. However, rather than viewing this as a problem in PhD supply-demand economics, the editors chose to put a cheerful spin on the situation and brand all of the ‘alternative careers’ as a good thing.

To my mind the American Society for Cell Biology (2) has a more realistic perspective when it states that in the current context, where less than 10% of enrolled biomedical PhD students will become tenure track faculty, “A faculty job is an ‘alternative’ career”. To be sure NATURE has previously discussed the PhD glut from a more balanced perspective (3). However, the current attempt to view a bad situation through rose-colored glasses is not helpful.

As discussed several times on this blog (4,5) the PhD oversupply is the result of self-interested actions on the part of faculty and university administrators. Cheap labor is needed to keep the grants and publications coming.

(1)  http://www.nature.com/news/there-is-life-after-academia-1.15808

(2) go.nature.com/vh1ewm

(3)  nature.com/phdfuture

(4) http://scienceforthefuture.blogspot.com/2010/02/why-are-there-still-too-many-graduate_10.html

(5) http://scienceforthefuture.blogspot.com/2013/03/more-money-fewer-phds.html

Pharmaceutical Failures and Near Misses: More Examples of Why Finding New Drugs is Too Important to be Driven Solely by the Profit Motive.

Recent stories arising from medical areas as diverse as breast cancer and Ebola illustrate the failures and near-failures of drug discovery by for-profit pharmaceutical companies.

An article in SCIENCE (1) recounts the twists and turns of the highly promising anti-cancer drug palbociclib. This agent selectively inhibits CDK4, a kinase that is involved in cell cycle control and that is crucial to the growth of certain cancers. The history of this drug goes back to the 1990s when it was developed by researchers at Parke-Davis Co. When the giant pharmaceutical company Pfizer acquired Parke-Davis in 2000 palbociclib was almost dropped and its development was delayed for years during the various twists and turns of Pfizer’s recent corporate history. Its re-emergence as a promising drug for breast cancer is primarily due to several independent clinical researchers who championed its use. This type of on-again off-again drug research is all too common in ‘Big Pharma’ where science is often subverted by marketing and corporate strategy issues.

The recent explosion of concern regarding anti-Ebola drugs reflects another aspect of the failure of for-profit major drug companies to deal with problems of great public health concern. As stated nicely in a recent blog post (2) from the CSPO at Arizona State “when we rely on a market-based system to drive medical research that may not be profitable in the short term or even medium term, that system is unlikely to respond to potential future threats — no matter how high the potential cost — if there is not a reasonable promise of economic return in the end“. This of course exactly describes the situation with Ebola as well as with many other diseases that primarily affect less-developed countries and that thus do not provide the prospect of lucrative profits.

The BBC website has summarized recent efforts on Ebola drug development (3). Although several companies are involved in this process, it is important to note that much of the early-phase research on drugs for exotic diseases has been sponsored by governments. For example, promising drugs for Marburg and Ebola viruses being developed by Sarepta Therapeutics and Tekmira Pharmaceuticals, two small biotech companies, have been sponsored by the US Dept. of Defense.

The role of governments in developing innovative technology is often under-appreciated (4); in contrast private companies (particularly pharmaceutical companies) use highly developed public relations tools to claim a leading role in innovation. The emergence of pandemics such as the current Ebola outbreak should be readily anticipated based on the phenomenal increases in both population and mobility occurring in Africa in recent years (5). However, it has been governments and non-profits rather than Big Pharma that have led the way in preparing for such public health emergencies. All of this inevitably leads to the conclusion that drug discovery and development is too important to be driven solely by the quest for corporate profits.

(1)           http://www.sciencemag.org/content/345/6199/865.full

(2)       http://aswenowthink.wordpress.com/2014/08/12/the-real-ebola-dilemma/

(3)      http://www.bbc.com/news/health-28663217

(4)    http://www.sciencemag.org/content/345/6199/883.1.full

(5)   http://www.economist.com/news/middle-east-and-africa/21613349-end-century-almost-half-worlds-children-may-be-african-can-it

Incomprehensible Drug Prices? Yes They Are!

This week in his blog about the Pharma industry ‘In the Pipeline’ Derek Lowe discusses the trend toward increasingly high drug prices especially with regard to new drugs for cancer.  Refuting a post in Forbes by Peter Bach, “Cancer: Unpronounceable Drugs, Incomprehensible Prices” Lowe trots out the old arguments about research costs and patent lifetimes being the root of extreme drug prices. Bach says that drug companies charge what they think they can get away with. Lowe says, so what, so do all other corporations.

Usually I think that Lowe’s blog is excellent and often right on target about important issues in Pharma. However, here I think that he really misses the point. Drugs are not like potato chips. There really isn’t a free market of informed sellers and buyers. Drug prices need to conform to societal goals (better heath) rather than exclusively profit considerations.

The bottom line really is that drug development is too important to be left solely to an industry that is exclusively driven by greed.  We need to start looking at new modes of drug discovery and development that are driven by health needs and not by the need to boost stock prices and CEO bonuses.

http://pipeline.corante.com/archives/2014/08/15/incomprehensible_drug_prices_think_again.php 

Also see:

Pharmaceutical Innovation and Public Policy (ASIN: B00B79ULRK) Kindle ebooks

  

The Robo-Chemist: Another Step Backward for Human Creativity

An unsettling report in NATURE this week describes efforts to develop a robotic chemist. While simple robots are widely used in chemistry labs these days, the ‘robo-chemist’ goes far beyond that. The idea is to develop a machine that will be able to analyze the vast array of information on molecular structures and chemical reactions that is available in public data-bases and use that information to design synthetic routes to new chemicals. The robo-chemist would then follow its own plan and actually synthesize the new entity. Thus massive data crunching would replace the creative intuition that experienced chemists currently use to design and synthesize new chemicals.

The chemical and pharmaceutical industries would love this of course. It would allow them to lay off thousands of experienced chemists and increase their profit margins. Not so great for the chemists though!

The robo-chemist is really a wake up call for educated people who may think that their occupation is safe from the inroads of artificial intelligence and robotics. If Ph.D. chemists can be replaced who is next?

The explosive penetration of computer technology into all areas of the economy comes at a time when rapid increases in total population and in longevity are occurring in the USA. How will our society provide continuous employment for all these long-lived healthy people while machines do more and more of the work?

http://www.nature.com/news/organic-synthesis-the-robo-chemist-1.15661 

Treat Ageing not Disease

An interesting commentary in NATURE provides an overview of the concept that modern medicine should be seeking to increase the ‘healthspan’ rather than addressing individual diseases one by one. Since many diseases are linked to the gradual debilitation associated with old age, the thought is that by blocking those degenerative changes overall health, and perhaps even lifespan, will be enhanced.

Certainly studies in animals have begun to reveal the molecular underpinnings of degeneration during ageing. Thus the mTOR signaling system, telomerase, and damage mediated by free radical triggered inflammation are all clearly important. Drugs such as rapamycin that affect the mTOR system have been shown to extend lifetimes and ‘healthspans’ in animals. Despite this progress at the laboratory level there are many obstacles to implementing these concepts and approaches in clinical practice.

One is funding. Research on ageing per se receives a tiny fraction of that received by cancer or cardiovascular disease research. Another is the lack of good tools and models that would allow study of ageing processes in animals in a manner parallel to the approaches used to evaluate ageing in humans. Since ageing studies can obviously be of very long duration, good surrogate markers would also be important. Finally our entire health care system is set up to be disease and procedure oriented rather than focusing on promoting the overall health of the individual.

It seems to this observer that pursuing the ‘healthspan’ concept will be vital in addressing the health needs of our rapidly ageing population. Some of the exciting findings on life- and health-extension in animals need to be carefully validated and then gradually extended into clinical trials in humans. I am sure that many otherwise healthy older people would be interested in participating in tests of drugs or other approaches that might provide a measure of rejuvenation. I know I would.    

http://www.nature.com/news/medical-research-treat-ageing-1.15585    

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. 

http://stm.sciencemag.org/content/6/240/240ps7.full 

http://www.oligotherapeutics.org/

 

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. 

http://www.nature.com/nature/journal/v509/n7501/full/nature13193.html 

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!!

(1) http://www.nature.com/news/policy-nih-to-balance-sex-in-cell-and-animal-studies-1.15195 

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. 

(1)

http://www.sciencemag.org/content/344/6184/570.full 

(2) 

http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.3569.html

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!

http://www.pnas.org/content/111/16/5773.long 

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. 

http://news.sciencemag.org/funding/2014/03/1000-nih-investigators-dropped-out-last-year