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. 

Friday, March 28, 2014

Increased Diagnosis of ADHD and Autism: Is This a Medical Issue or a Cultural One?

There are many issues regarding volitional use of cognition enhancing drugs but perhaps the most troubling is the epidemic of prescription drug abuse in ADHD. The treatment of ADHD has become a very controversial topic. Over the last few years there has been a rapid increase the number of ADHD diagnoses, particularly among young boys. Historically 3-7% of children have been diagnosed with ADHD, but recently over 20% of young males have received this diagnosis. It is hard to credit that there have been physiological changes in the population that would result in a trebling of the incidence of this disease. Rather it is likely that social and economic factors are impacting the situation. First, this is a very lucrative market and thus pharmaceutical firms have actively pushed their various drugs. Second, in a time of increasing economic stress it is natural for parents to want their children to do well in school, but at the same time parents may have less and less time to spend with their children. Thus a stimulant becomes a substitute for parental involvement in a child’s education. Third, the diagnosis of ADHD, which is diffuse and subjective to begin with, has been loosened in recent years, thus allowing physicians and parents more latitude in placing their children on medication. Finally, one wonders if the changing roles of males and females in our society may have something to do with the fact that boys receive the preponderance of ADHD diagnoses. What historically would be considered normal behavior for a young male, including a great deal of motor activity, restlessness, and some degree of aggressiveness, is now interpreted as pathological in a society increasingly influenced by female norms of behavior. This may be particularly relevant in the context of diagnosis of ADHD in elementary school children, where women continue to be the great majority of teachers. While some physicians have characterized ADHD drugs a ‘safer than aspirin’ there clearly are hazards in chronic use of powerful brain stimulants such as Ritalin®. Thus, as a society, we seem to be conducting an experiment of questionable value on our children.

Something similar may be happening with diagnosis of autism. A recent report (1) suggests a 30% increase in the frequency of autism in young males. While children with clear autistic characteristics obviously need to be identified and helped promptly, there seems to have been a loosening of diagnostic criteria so that more and more children are being caught in the net of  ‘autism spectrum disorder’. Once again it is unlikely that there is a physiological basis for the apparent increased frequency. More likely, behavioral characteristics that a generation ago would have been deemed just slightly unusual are now being defined as a disease. The driving forces for this are less clear since pharmaceutical companies are not making money from autism.

The long-term consequences of over-diagnosis (and in the case of ADHD over-medication) are very unclear. Some children may be helped by medication or treatment. However, what is the impact of being labeled abnormal to a child’s self-esteem? What are the consequences of chronic use of stimulants such as methylphenidate (Ritalin ®) or atomoxetine (Strattera ®). As a scientist I know that all drugs have side effects but in some cases those effects do not show up for many years. This is a difficult quandary for parents of affected children. 

Sunday, March 16, 2014

Billionaires Bankroll the Lab-Bench

The NY Times (March 15) had an interesting article on the increasing degree to which the ultra-rich have been contributing to the funding of science even as federal support for research has been stagnant. If one accepts the premise (which I don’t) that it is OK for society to allow a few individuals to become so egregiously wealthy that they can give away hundreds of millions, then it is probably a good thing that the money is being used to support science rather than being expended on yachts and fancy homes. However, there are several downsides to this trend.

First of all, when billionaires fund science the inevitable result is extreme elitism. Most of the money goes to the Harvards and Stanfords of the world. However, while there is clearly outstanding science done at these elite institutions there is also great science at mid-level public and private universities. When I think of recent major advances my own field of biomedical research what jumps to mind is RNA interference (from U. Massachusetts and the Carnegie Institution), homologous recombination (to make genetically altered mice)(from U. Wisconsin and U. Utah), and human stem cell technology (U. Wisconsin). All of these incredibly important breakthroughs came from publically funded research at excellent but not ultra-prestigious institutions. While welcoming private contributions to science we need to understand that they can never replace the broad and diverse science funding that comes from federal sources. A scary thought is that some of our ultra-conservative political nitwits are going to use this trend an excuse to attack federal funding of science. Having been around for a while, this reminds me of Reagan’s comments early in his Presidency about wanting to replace the NIH with private funding from drug companies. Considering that the pharmaceutical industry has now almost completely eviscerated its basic research programs we would now be in quite a pickle if Reagan had followed through.

Second, the process by which some investigators have been able to tap into this largess really gives me the creeps. The idea of a 30 second “elevator pitch” to spark a busy donor’s interest with Tweet-like brevity just contradicts the whole concept of evaluating the quality of science on a considered and rational basis.

Third, the sponsored science will inevitably reflect the donor’s interests and perhaps political orientation. Do we really want the Koch brothers funding climate science? At a less extreme level many of the projects mentioned in the Times article barely qualify as science. Private space flights or deep-sea dives are fun ideas and do spark public interest in technology. However, they are trivial in terms of real scientific advances. To be fair private funds have supported many worthwhile developments in science. For example, while it has some critics, the Gates Foundation has revolutionized R&D in the tropical medicine field. The Howard Hughes operation (interestingly not mentioned in the Times article) has supported high quality basic biomedical research for many years. Ultimately, however, the science being done will reflect the interests of the donor and not necessarily the most urgent needs of the field of research. 

Friday, March 14, 2014

More on Designer Babies

This weeks SCIENCE has an excellent opinion article from Thomas Murray, the former head of the Hastings Center, on the topic of ‘Designer Babies’. It deals with the current issue of the FDA’s consideration of ‘3-parent babies’ to prevent the transmission of mitochondrial defects (discussed in a previous blog post here). It also goes on to discuss the approach of the personal genomics company 23andMe that can provide genetic information that can potentially enhance the choice of sperm (or egg) donors so as to avoid genetic disease or possibly to accrue desirable traits. Murray points out the many ethical and regulatory complexities inherent in the whole concept of designer babies. Overall a worthwhile read for anyone interest in understanding the intricacies involved in  approaches to human enhancement.

Friday, March 7, 2014

Human Enhancement in Slate

A recent article in Slate provides a non-technical update on some recent advances in human enhancement technology.  It mentions ‘nootropics’, drugs like modafinil that were originally developed for treatment of CNS disease but are now widely used by healthy individuals to boost mental function. It also mentions some of the amazing brain hardware technologies that have allowed people with spinal cord injuries to control robotic devices with their thoughts.

Unfortunately, like most articles on this subject, it stresses the ‘wow’ factor of individual new technologies without seeing how these technologies are linked to the overall thrust of human enhancement research.  It also fails to address the enormous societal impact that would result from widespread use of enhancement technologies.

This is an area that this blog will be focusing on over the next few months. We will try to engage with the issue of how this emerging suite of technologies will impact not only individuals, but the economy and the overall organization of society.  

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.