(via Scintilla)

The article on "Probiotics modulation of mammalian metabolism" published this week in Molecular Systems Biology by Jeremy Nicholson and colleagues (Martin at al, 2008) has attracted some attention (read the nice summary in Science News) in some (very) popular media (here, here, here and here).

In this follow-up study of the paper published last year (Martin et al, 2007), the team lead by Jeremy Nicholson, in collaboration with Nestlé, demonstrates clear physiological effects of oral probiotics administration on mice harbouring a humanized microbiome. The effects are intricate: both the host flora and metabolism are altered. By analyzing metabolite pools in several compartments (liver, blood, urine, feces, gut), and following in parallel the host microbiota, patterns of correlations between microbial species and metabolites start to be visible and reveal the probiotics-induced modulation of the microbial-mammalian interactions. But the actual paper is really just next door (synopsis), so have a look...

How will these results translate to humans? What will be the best way to influence our microbiome? Drugs or yoghurt? These are fascinating questions and the understanding of how our physiology depends on the microbial flora could have profound consequences, particularly in these times when we seem to be in a "rush to gene-based solutions to all our problems" (Wilson, 2007). Will personal genomics have to ultimately develop into personal metagenomics to include our "extended" microbial genome?

Even if I usually prefer to resist the temptation of a self-promoting section in this blog, I find the attention of the media for this topic interesting (despite the usual variable accuracy of newspaper reports) because it points to an area where systems biology provides insights into topics of immediate interest to the general public.

The NIH has recently started its Human Microbiome Project. In this context, this study also underscores the importance of developing model systems and tools to manipulate the microbiome and to analyze the incredibly dense and intricate interactions that connect host and microbial species. A field where top-down systems biology seems indeed a very pragmatic and promising approach.

Here is the answer provided by Kevin Struhl in an interesting interview published a few days ago in Current Biology (Current Biology 2008 18:R7):

"I think it is flawed at several levels. Anonymous reviews assume that reviewers are unbiased, objective and without personal or scientific conflicts of interest; this is not always true, especially in competitive situations, and there is no mechanism to detect such problems. Aside from the potential for abuse, anonymous reviews create an inequality between authors and reviewers that is unfair and scientifically unjustified. At many journals, particularly those run by commercial companies as opposed to scientific societies, disagreements between authors and reviewers are often adjudicated by editors with modest scientific accomplishments and experience. I favor a process in which editorial decisions are made by practising scientific experts, reviewers are identified by name, and the signed reviews and author responses published online along with the paper. Lastly, it is unfortunate that the biology community has permitted commercial companies to control most of the journals. Competition among journals and business-related decisions about scientific publishing has seriously distorted the literature, and it has created an artificial rating system that is used to judge decisions about funding and career advancement."

The Royal Society seeks your views on the emerging area of synthetic biology. This is your opportunity to shape the focus of the Royal Society's policy future work in this important area. We welcome views from individuals or organisations by 27 August 2007.

• Potential developments and applications
• Current research capacity and geographical distribution
• Societal implications
• Ethical concerns
• Biosecurity risks
• Implications for the environment
• Research support and funding
• Implications for human health
• Legal issues and implications for regulation (national and international)
• Ownership, sharing and innovation frameworks (including intellectual property)
• Biosafety concerns
• Education and training
• Governance and oversight of research
• Economic considerations for developed and developing countries

Observations suggest that current climatic models may underestimate how quickly the climate system is changing (in particular for sea level), according to a report in Science a few weeks ago (Rahmstorf et al, 2007). Another Science paper published last week shows that the capacity of the Southern Ocean CO₂ sink is weakening, which may result in increased atmospheric CO₂ levels in the long run (Le Quere et al, 2007).

I remember Hiroaki Kitano calling the systems biology community, in his talk at the ICSB meeting last October in Yokohama, for ideas on how system-level approaches could contribute to address the challenge of global warming. In response to the studies above, a similar call is now sent to the microbiology community by Jonathan Eisen on his blog. Research topics suggested in his post include:

Marine Microbiology

Carbon fixation processes

Hydrogen production

Carbon sequestration

Methane capture

Microbial fuel cells

A similar list of priorities related to energy challenges, environmental remediation and carbon cycling and sequestration can be found on the site of the Genomics:GTL research program from the US Department of Energy.

For all the topics listed above, systems biology and synthetic biology approaches are likely to be crucial not only to accumulate the necessary fundamental knowledge but also to find ways to translate it into technological applications. Proposals, insights and visionary suggestions are more than welcome...

some additional links:
Special issue on Energy and Sustainability
ASM Report on Microbial Energy Conversion
Microbial ecology meets electrochemistry: electricity-driven and driving communities. Rabaey et al, 2007, The ISME Journal 1:9

(via Kaiser-J 2007, Science 316:529 and discuss [AT] syntheticbiology.org)

The National Science Advisory Board for Biosecurity (NSABB) has released a Draft Report (available as pdf) providing recommendations on how to minimize misuse of biological research. This report was discussed publicly on April 19, 2007 (see webcast).

The 50-page draft makes it clear that there is a difficult dialectic between imposing restrictions on research that can be misused for harmful purposes on one hand, and, on the other hand, the necessity of facilitating open and rapid information exchange to accelerate scientific progress, for the benefit of society in general, but also to precisely counteract potential threats. The report insists on the prime importance of openness in scientific research and clearly states that unrestricted progress and communication should be the "default position".

One major recommendation of the draft report is that Principal Investigators should carry the responsibility for the initial evaluation of the potential for misuse of their own research. Concrete implementations could be inclusion of check boxes in grant proposal forms and annual reports to the researchers institution to formally certify that risk assessment has been performed.

Dual Use Research of Concern is defined as follows:

Research that, based on current understanding, can be reasonably anticipated to provide knowledge, products, or technologies that could be directly misapplied by others to pose a threat to public health and safety, agriculture, plants, animals, the environment, or material.

To aid identification of research that might be qualified as "dual use research of concern", seven categories are listed (inspired from the National Research Council "experiments of concerns", in Biotechnology Research in an Age of Terrorism):

1. Enhance the harmful consequences of a biological agent or toxin.
2. Disrupt immunity or the effectiveness of an immunization without clinical and/or agricultural justification
3. Confer to a biological agent or toxin, resistance to clinically and/or agriculturally useful prophylactic or therapeutic interventions against that agent or toxin, or facilitate their ability to evade detection methodologies.
4. Increase the stability , transmissibility, or the ability to disseminate a biological agent or toxin.
5. Alter the host range or tropism of a biological agent or toxin.
6. Enhance the susceptibility of a host population.
7. Generate a novel pathogenic agent or toxin, or reconstitute an eradicated or extinct biological agent.

The philosophy of self-regulation by researchers appears to be in line with the stated purposes of raising awareness on dual use research issues and promoting a culture of responsibility within the scientific community. The report recognizes however major difficulties in defining a threshold at which dual use research would be clearly "of concern", which makes it difficult to come up with clearcut and concrete recommendations. In the report, NSABB provides "tools" to assist the formulation of an appropriately balanced response via a risk/benefit assessment in research management and communication. The final decision will influence content, timing and distribution of publications reporting "dual use" research. As such, scientific journals will play an important role in developing a "Code of Conduct for Dual Use Research in the Life Sciences":

Those who play decision-making roles in the process of communicating scientific information have an ethical responsibility to consider whether the information being considered for publication could be used to endanger public health, agriculture, plants, animals, the environment, or materiel. Depending on their analysis of the risks and benefits of communications regarding information or technology that meet criteria for dual use research of concern, they may choose to proceed in a way that mitigates or manages the risks associated with communication – for example, by adding contextual information not found in the original article, or delaying communication until a time at which the risks would be reduced.

1. What entity should be in charge of reviewing research identified by PIs as dual use of concern?
2. Is the definition of dual use research of concern appropriate in terms of its "specificity" and "sensitivity"?
3. Are the listed seven categories of potentially dual use research appropriate?
4. Should the PI be the sole and prime responsible to identify his own research as dual use of concern?
5. What additional guidance is required?
6. What burden does these recommendations (eg necessity to review research identified as dual use of concern) represent for your institution?

see also:
Statement on the consideration of biodefence and biosecurity (2003) Nature 421:771
Nature journals' policy on biosecurity
BIODEFENSE: Proposed Biosecurity Review Plan Endorses Self-Regulation. Kaiser-J (2007), Science 316:529
Will Bioterror Fears Spawn Science Censorship? Granick-J (2007) Wired

(via Jonathan A. Eisen, The Tree of Life)
What are the areas that will deeply transform biomedical research over the next decade? One of the possible areas identified for inclusion in the NIH Roadmap is research on the Microbiome (the entire set of microbial species living in the human body). A string of recent studies have revealed a profound impact of the enormously complex mammalian microbiome (Gill et al, 2006) on the metabolism and immune status of the host (for a few examples: Backhed et al, 2004, Dumas et al, 2006, Turnbaugh et al, 2006, Kitano & Oda, 2006, Nicholson et al, 2005). In his blog, J Eisen reports on some of the discussions held at an NIH sponsored workshop on the necessity of a Human Microbiome Project and lists possible research avenues for such a program. From his post:

1. Sequence many "reference genomes." By reference genomes here I mean genomes of cultured isolates that are closely related to organisms known in various human locations.
2. Do metagenomic sequencing of a variety of human mirobiome samples.
3. Conduct large scale human microbiome diversity studies. This could involve rRNA PCR surveys as well as some amount of genome sequencing.
4. Develop the computational tools needed to analyze the massive amounts of data that will come out.
5. Encourage the development of new methods to aid in studies of the microbiome.

A friend of mine asked me recently what field might strike the popular consciousness in the coming years. Could it be that it will be the realization that we are all "superorganisms" (Lederberg, 2000) and that our health does not only depend on our personal genome (Church 2005) and our environment, but also on the extended genome provided by our very private microbiome?