The talk was introduced by Illahee’s Director, Peter Schoonmaker.   In his  blog post, Peter described his summary of my presentation.

I used the occasion to wax lyrical about the congruence of the hologenome theory of evolution with our work on creating an open and transparent innovation cartography tool.

I tried to find a common thread of ‘biological innovation’ that can guide not only the practical realities of improving health, agriculture, environment and energy, but also the formation of productive and equitable economic and social structures and tools.

The full video of this presentation is available on Vimeo:   Enabling Innovation

 

 

 

 

 

The Unknown

“As we know,
There are known knowns.
There are things we know we know.
We also know
There are known unknowns.
That is to say
We know there are some things
We do not know.
But there are also unknown unknowns,
The ones we don’t know

We don’t know.”

 

 

—Feb. 12, 2002, Department of Defense news briefing, Donald Rumsfeld

 

 

 

These now immortal words of the neo-bard Donald Rumsfeld, though often lampooned, actually provide a helpful insight into the nature of innovation and landscapes on which it occurs.

 

Innovation, like navigating the high seas, is as much a matter of not steering a wrong course as it is steering the right one.   This is particularly so for those whose resources are limited, and where the risk of failure courts disaster.In innovation thinking – itself almost an oxymoron – talking about how to make right choices and fostering sparks of creativity seems the dominant discourse.

But the realities of innovation are that most of the innovation process is grueling hard work, and the hard yakka is in avoiding stuff ups: endeavouring mightily not to ‘run aground, or crash into continents’.

So what are these continents, the reefs, the shoals and the currents that could take our ship of creative product and service delivery down to Davy Jones?

In those sectors driven by science-and technology-enabled innovation (SEI),  much of the uncertainty, the obscurity, the buried bommies are in the world of intellectual property, and most of this in the patent literature.

Curiously however – much of the excitement and opportunity of future and futuristic problem solving also lies in this same byzantine, obscure, clergy-ridden literature.

So what is it and how do we navigate it?

Patents are teachings.

They are – according to the letter of the law – fully open documents that exist to enable innovation.   Their very purpose – historically – is to disclose to the entire world exactly how to create a particular new, non-obvious and useful invention.

And in exchange for a full disclosure of how to make this invention, if the invention is described accurately and the patent office agrees that is meets its standards, the owner of the patent acquires a right to exclude others from precisely this invention for a limited time, and in a particular jurisdiction.  The standards of these patent granting agencies however can exist on the continuum from mediocre to execrable and from incomprehensible to inconsistent.   Making the whole enterprise extremely contentious, litigious, expensive and fraught.

So there’s good and bad.  The good is that the patent (and the aggregated millions of such patents) are indeed recipes for enterprise.  The bad is that there’s a dog in the manger.   Each patent grant gives the owner only a right to stop others from actually practicing the patent and does not accord the owner any right to practice her own invention!  This counter-intuitive observation is key to understanding the system and moving forward.

Patents are not innovations, they are inventions.  Modern innovations that hinge on science- and technology, for instance new communications technologies, materials, new energy technologies, new medical devices or vaccines, or new crops, typically don’t hinge on one invention and one technology. They require hundreds of pieces of science and technology to assemble the real innovation – the impact on the marketplace.   And yet each piece of the puzzle, each feature of the landscape, can be represented by a single (or even multiple) patents in many jurisdictions.

There is a metaphor worth exploring.

Patents can be thought of as features on a map.    If we use the maritime charts as thought canvas, each patent could be a submerged rock, a feature on a coastline, a deep channel, a current, a continent!, a reef, a shoal, a distance of blue water; the owners of these patents could be those with control of a port, influence over trading partners, layers of mines or of marker buoys, or indeed fellow sailors and explorers.

But knowing of one or even a few of such features doesn’t really help navigation and doesn’t help one chose a course for effective sailing and trade.

It is knowing how the pieces fit together, how the features learned about through painstaking exploration meld into a map: a navigation chart, that allows choices to be made that limit risk.

Countries whose success depends on guarding and blocking access to seaways ultimately senesce and implode in economic stagnation, while those which navigate and trade on these waters succeed through economic vigor and growth.

The greatest value in maps is not choosing one particular path. Rather it lies in making it possible of choosing any of countless paths, informed by not making hundreds of  counterproductive or even catastrophic courses.   We simply can’t know what opportunities like ahead, but we should be able to avoid clear and present danger.

These are Rumsfeld’s ‘Known Unknowns’.  The things we could know about that we should know about.

Now to innovation:

Knowing of (or even owning) one or several patents is at best one tiny step in choosing or creating an effective innovation trajectory.

Most importantly we need to understand the landscape, the inventions, components, partners, capital we need to pull together to create an economically viable chance.

We can’t guarantee – by its very nature – that an innovation will succeed.

But we can with great confidence find many points that will guarantee its failure.  If we don’t know of the hundred pieces of the puzzle we require to make our innovation work, if we don’t know what they are, who owns them, how long the control is for, what their motivations might be, how we could choose alternative components, we simply cannot move forward with any confidence or energy.

The patent system as it exists now has swollen to an almost unimaginable complexity and opacity.  There are tens of millions of patents issued, with millions in force in over a hundred countries, and all variable in quality, reach and implications.  Each new technology field spawns regulatory and standards information that is implicit in these disclosures, but not explicit.  Patterns of influence and control, of ownership and permission shift like sands.    But these are critical features to understand if we are to conduct and invest in innovative business practice – especially that informed by the excitement of new science.

This is point of great opportunity.  Exposing the Known Unknowns.

And it is the single greatest enabler of innovation.  To help create open public charts – navigation tools – of the world of innovation intelligence.   Combining unprecedented transparency in patent systems with integration of science, technical, regulatory, legal and business information to create a global resource for all innovation enterprise – in public and in private sector – to actually SEE the hidden shoals, the cryptic opportunities.

We need a facility to make decisions based on clarity and confidence, to reduce the ‘Known Unknown’ to avoidable problems and graspable opportunities.

We need to celebrate the excitement of the right kind of unknowns and let this dominate our innovation culture.

Innovation is a balance between creative and generative processes on one hand, and exposure to the sometimes cryptic logic of a market on the other.    Between these poles are reefs and current that we must map to create a more effective system.

Doing this – creating an open, global cartography for science- and technology-driven problem solving and providing a worldwide resource to support informed decisions,  will truly be Enabling Innovation.

In future blogs and presentations, I’ll go into much more detail on what the state of play is in patent and innovation information, and how this can be changed and democratized.

I’ll also explore the exciting parallels between innovation in economics and society, and evolution in biological systems.   I’ll talk about how radical and riveting new understanding of biological systems evolve can inform and guide breakthroughs in innovation system design.

This blog post is derived from an ex tempore presentation I made on a panel in May in Doha, Qatar at the World Economic Forum’s Global Redesign Summit, and again for ‘enable brisbane’ website.

// //

I’d like to share an email exchange I had some months ago with Eugene Rosenberg, one of the authors of some extremely interesting papers outlining the hologenome theory of evolution.   He and his wife, Ilana Zilber-Rosenberg apparently completely independently from me articulated the hologenome theory from their experiences in microbiology and nutrition, and coral microbiology in particular.

Rosenberg E, Koren O, Reshef L, Efrony R, Zilber-Rosenberg I.

Nat Rev Microbiol. 2007 May;5(5):355-62. Epub 2007 Mar 26. Review.PMID: 17384666 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed

Email thread:

from: Eugene Rosenberg <eros@post.tau.ac.il>

to: Richard Jefferson <raj@cambia.org>

date: Wed, Mar 10, 2010 at 7:25 PM

subject: Re: Hologenome theory, microbiome / holobiont

Dear Richard,

Wow. What a joy to read your e-mail and blog. Before commenting, let me inform you that I am a young 75 year old general microbiologist that has published 250 scientific articles, almost exclusively on experimental studies on myxobacteria, hydrocarbon degradation by bacteria and more recently bacterial diseases of corals. My wife, Ilana, is the best nutritionist in Israel, with a strong background in biochemistry and microbiology. We came to the concept of the hologenome (I now include you in the “we”) from am attempt to explain how a particular coral became resistant to bacterial bleaching. Clearly, we share your view of the holobiont as a unit of selection in evolution of animals and plants.

Where do we go from here? Your clear discription of the glucuronide conjugate system is a fine example of how the microbes are an integral part of host metabolism. Furthermore you speculate that these reactions can lead to mating selection. Now to blow your mind- We have been working on the role of bacteria in mating selection for the last two years. It started when my wife found a paper in Evolution, published 20 years ago by Diane Dodd. She took a population of Drosophila from Bruce Canyon and raised half of them on a starch diet and the other half on maltose. After a year, she mixed them, and found the “starch flies” perfered to mate with ”starch flies” and “maltose flies” perfered to mate with “maltose flies.” Although they offered no explaination for this mating selection, my wife and I immediately thought bacteria. So, I put a graduate student, Gil Sharon, on the problem. He first repeated Dodd’s experiment using the standard laboratory strain of D. malanogaster and sucrose instead of maltose. Mating selection occurred after two generations and was maintained for 30 generations. When we added antibiotics, mating selection was abolished, indicating bacteria were responsible. Furthermore, we infected the antibiotic-treated flies with their homologous bacteria (isolated prior to antibiotic treatment) and mating selection was reestablished. We sent a manuscript to Nature and they rejected it, saying they would reconsider if we identified the specific bacterium responsible for the mating selection. This has not been an easy task, but we are still working on it.

Regardless of the particular bacterium, what is the mechanism? We have been extracting flies with pentane and doing GC-MS. There are differences between the “starch flies” and the “sucrose flies”.

Maybe the glucuronide system is involved.

It was a pleasure to hear from you. Let’s keep in contact.

Shalom

Eugene

Eugene Rosenberg, Professor Emeritus
Dept. of Molecular Microbiology and Biotechnology
Tel Aviv University
eros@post.tau.ac.il
+972-3-6409838

—– Original Message —–

From: Richard Jefferson

To: eros@post.tau.ac.il

Sent: Wednesday, March 10, 2010 8:27 AM

Subject: Hologenome theory, microbiome / holobiont relationships etc

Dear Professor Rosenberg,

I am writing firstly to compliment you and Professor Zilber-Rosenberg on your clear, lucid and compelling writing in the last years on the hologenome theory.

I have read these with great interest and pleasure.  I particularly commend you for the fine exposition in the FEMS and the Environmental Microbiology review and opinion piece, respectively.

I am a molecular biologist, and now as well innovation system strategist, currently with funding from the Gates Foundation.    I started work in molecular biology in 1974, and in the late 70′s and subsequently I began working with the glucuronide metabolism pathways of commensal vertebrate microbes, including E. coli.   It became very clear to me fairly early that the suite of capabilities to import, metabolize and ‘share’ the products of xenobiotic and endobiotic metabolism by gut microbes was central to the selective performance of the host and microbiome – the holobiont.

As I became involved in the earliest days of agricultural biotechnology, my focus on systems-level understanding and intervention continued to be informed by this awareness.   I was convinced that the model system approaches which were and are so joyously productive, may not have been as joyously instructive as to the workings and logic of natural systems as embedded through natural (or in agriculture, human) selection.

I’ve written about this approach a little, but I’m not very prolific as a writer (I would make a terrible academic, alas).  I have however been speaking and promoting this work for many years as part of my work as founder of Cambia – an international non-profit institution.

I attach to this a link to my blog (rarely visited, rarely updated) in which I wrote down some of my thoughts.  ( http://blogs.cambia.org/raj/index.php/2007/09/06/the-hologenome-hologenomics/ ).  I also have in my blog (the top of the blog) links to videos of lectures I”ve given at Cold Spring Harbor in 1994 on the hologenome, and its implications; and presentations in South Africa in 1997 (I’d love to share with you my old powerpoint if you’re interested) in which I refer to our molecular work on glucuronide metabolism and the logic of applying eco-therapeutics and the understanding and adjustment of the hologenome to health challenges.     Term ‘hologenome’ and ‘holobiont’ and its critical role in evolution were proposed by me at that CSH lecture and since, and I was overjoyed to read your parallel and independent articulation of their importance, especially with regard to the critical horizontal inheritance opportunities for the fitness of the selected holobiont in a complex environment.

This has continued to be my intellectual focus for much of the last 30 years, but most of my work has been focused on democratizing science-enabled innovation through ‘open source’ type approaches, and through increasing the transparency and fairness of intellectual property systems.

I would be thrilled to be in correspondence with you about these ideas – they shape my thinking in many fields, and I’m musing very hard about setting up experimental systems to test the hologenome theory, which to me is compelling.  My laboratory has been in storage now for over a year since our institute moved from Canberra to Brisbane, but within a year I expect I may be back to full steam.  I’ll likely be doing a ‘sabbatic’ of sorts at Berkeley  from July – December and look forward to getting back into the game, as our Initiative for Open Innovation goes to scale and can be taken over by other champions.

Again, my warmest wishes and congratulations for some of the best science writing I’ve read in a long time.  That we have arrived at virtually identical conclusions from such different perspectives is itself most gratifying.

Best wishes

Richard

Richard A. Jefferson PhD
Chief Executive Officer, Cambia
Director, Initiative for Open Innovation (IOI)
Professor of Science, Technology & Law
Queensland University of Technology (QUT)
G301, 2 George St, Brisbane 4000, QLD Australia
+61 419 499 753 (mobile)  +61 7 3138 4419 (work) +61 7 3138 4405 (fax)
www.bios.net |  www.cambia.org |  www.patentlens.net  | www.openinnovation.org
e: r.jefferson@cambia.org

Cambia\’s Youtube Channel, including Cold Spring Harbor presentation

At that time (September, 1994)  I was trying to set the scene for why studying, understanding and manipulating complex systems with tools and approaches of reductionism would not be enough.

I started in part one with the concept of getting ‘Beyond the Model System’, and used real-world agriculture and environment as the entry point for that discussion.

I then went on in parts II & III to discuss the complexities of crops that were really not ‘model systems’ by any measure, sugarcane and cassava being exemplars. For this I referred to the excellent work of my friend and colleague Bruno Sobral, then at the California Institute of Biological Research and affiliated with Cambia.

Next I outlined the Hologenome concept and the idea that the microbial constitution of the entire ‘selected unit’ was the Great Unknown but perhaps – I argued – the biggest opportunity to create sustainable and robust interventions that were congruent with the logic of natural selection and evolution.

Finally in part V I discussed our thoughts on forming an international activity to create the technologies and thought framework for understanding genetic and organismal diversity. I called this the GRIT initiative at the time, but alas, for all the promotion and exhortation we were unable to secure the momentum necessary to make it happen.

Perhaps we were way before our time? Shortly after this, huge sums of money were spent on DNA sequencing and genome analysis facilities. Probably money well spent in that now we have solid data that supports the contention that the majority of the biosphere is the microbiome, and that most of the ‘visible’ biosphere is itself comprehensively populated with such a microbiome.

Maybe now we can start asking how to go from this observation and from the ability to sequence and describe the numbers and diversity of these microbes to a new ability to grok their role in biological system performance and robustness.

“……..
Of course the only entity that can speak for Monsanto is Monsanto, so commentary by any of us about why or whether they’ll participate is only conjecture.

However, I would comment that ‘financial savvy’ is a great reason for them to participate on several fronts. By thinking of the different ‘levels’ at which technologies act, one can imagine different treatments of these technologies with regard to sharing or hoarding.

This is similar to considerations of the ‘stack’ in software, where such components as operating systems, programming languages, interoperability standards, middleware are generally shared tools required to move the sector forward. Then applications or suites of capabilities represent commercially viable products and services.

The same distinction works in biotechnology.

Core technologies we call ‘enabling technologies’ are required by all players in the game – whether ‘mom and pop’ plant biotech or Monsanto. And these tools require constant improvements, tunings, expansions and revisions. Such tools would be, for instance, the basic ability to transfer genes to plants, the ability to visualize or select these genes when they are transfered, the ability to modulate, enhance or repress endogenous genes, the ability to map and monitor the genetic segregation and location of genes and so on. These tools are not typically specific to any one crop, or even a particular commercial challenge, but are required for almost any plant biotechnology intervention.

Because these tools are complex and are constantly being revised and extended, there exists a very cumbersome thicket of rights and an unfortunate ‘silo-ing’ of activity on their enhancement and replacement.

This basically means that each improvement often yields yet more patents, or more closed and innefficient nnovation systems, and a fragile innovation ecology.   And research to invent truly creative solutions to such core enabling technology challenges is not sufficiently incented because it is virtually certain not to be able to provide a complete solution to the technical challenge – at least in its first iteration.

A typical technology may require dozens of ‘rights’ to be navigated to ensure commercial use without legal vulnerability. There are hundreds of patents associated with the first act of plant gene transfer – the ‘transformation of plants’ by Agrobacterium. And other steps in the complex pathways are similarly complex. One key right withheld is sufficient to stop a commercial project from proceeding, or at least exposing the commercial entity to serious vulnerability. This vulnerability is typically experienced by any entity – small or large – that is embarking on commercial activity (a single farmer is ‘commercial’, so don’t get tied up thinking it only means multinationals).

However, larger corporations have both more exposure (more assets to lose if litigated successfully or subject to brand-associated market losses) and more financial and business means to bring to a solution to this problem; albeit a short-sighted solution.

Academic use is irrelevant and almost always misleading. In the US and elsewhere academics routinely use countless patented inventions with no licenses, and thus their work is not ‘permissive’ in that it cannot routinely be converted to commercial products without much additional ‘freedom to operate’ analysis and R&D.

And yet here is a point at which the economics comes very much to the rescue.

If all entities need these core tecnologies to advance real applications in the sector (agriculture and food – although exactly the same arguments apply to public health and medicine), then there is massive waste of resources by duplication of efforts, and in cross-licensing, non-licensing, re-invention of the tools and work-arounds that effect no substantial commercial advantage.   They simply allow companies to get to the starting gate of product development.  There is also a huge opportunity to harness and galvanise new technology development by collaborative and shared approaches that has been untapped.

There are however Balrogs in the Woodpile (problems) with this vision that are being opportunistically leveraged by ‘middlemen’. Companies that are own rights to key tools – or companies that are spun off to develop these tools – are generally looking to maximize their financial returns, and this strategy, while of questionable value in wealth creation in a sector or society, is being actively pursued as a wealth accumulation tool by these companies (and indeed some universities who use this ‘ransom’ or ‘last brick’ tool in negotiations).

There are companies that build ‘portfolios’ of patents and rights that make use of particular tools either expensive or impossible (remember many of these companies are not obligated to grant licenses!).

I frankly don’t see much added value in these holders of rights to low-level enabling technology, especially for society or for the sectoral advancement. If Monsanto and others do their sums, they may come to the conclusion that the expense of protecting, licensing and acquisition of enabling technology has added almost nothing to their (black ink) bottom line, but rather has cost them very substantial sums of money – and perhaps as importantly – public respect and goodwill that could be associated with greater communication, and more attention to product and service provision.

If on the other hand, a substantial decentralized open source initiative on key enabling technologies is pursued, with a guarantee that all parties may use the technologies at no cost (other than the summed, sunk costs of their actual development), then the transactions would be almost eliminated (a huge cost in itself), the quality of the technology could rapidly be increased, tested, expanded and adapted, regulatory compliance and standards could be harmonized, and the burdens on acquisition of rights and stacking of royalties would be greatly reduced or eliminated.

Take an example that is very important in biotechnology whether agricultural or medical. Homologous recombination technologies. This suite of technologies – which is not yet practically available – will allow subtle, nuanced changes in genomes that are informed and inspired by the now-routine sequencing of genomes and their variants. Done correctly, there is no reason these should trigger expensive regulatory burdens, and so could be a three-fold boon to agriculture; making immediate value of the massive sequence data greatly increasing the robustness of gene expression by modulating it in situ (where it has evolved to be) and by (potentially) dropping regulatory burdens back to levels associated with any conventional agricultural innovation.

There are many extraordinary publicly funded laboratories who have developed – with taxpayer’s money – components of this suite of technologies which I call collectively ‘HARTs’. These university scientists have often filed patents, and these patents are in some cases then exclusively licensed to a very aggressive company that is in fact not a serious player in the actual ‘sectors’ that stand to benefit. Rather this company is a middleman, potentially extracting massive rents (fees) and otherwise slowing the adoption (and as importantly the critical improvements and evolutions) of the technologies.

This is shameful and a huge loss to the worldwide community, and is typical of why the whole open source biology movement is so important. Whle one can argue facilely (and they do) that these ‘tool companies’ make money for themselves – they do – one cannot so easily see that they participate in social wealth creation.

In the IT industry, these types of entities are called ‘trolls’ or ‘patent terrorists’ or worse. Frankly, they are an aberration in my view. With such fine science in the public interest, with proper coordination and a new, low-transaction cost mechanism (BiOS and BioForge), these investigators are at least and in my view more creative and innovative than the trolls. And should thus contribute to society through provision of their tools to the sectors at no additional cost, allowing private and public resources to be focused on development and performance of new products in real markets, or the accommodation of the needs of small or neglected markets – a critical role of public sector that has been apparently lost in the ozone.

But this cannot happen in a ‘back to the future’ mode of publish and make it in the public domain, much as I would love to see this happen. We need leverage tools to ensure that the information and capabilities are coordinated, pooled and their availability is ensured. This is the power of open source. Not the ‘free’ of cost. But the ability to leverage creative improvements of core technology, and to ensure availability for use by those seeking advancement of society through ethical but sound business practices.

So, in summary, I think Monsanto should participate; I think Dupont and Syngenta and Bayer and Dow and others should participate. But they must not drive the agenda by any means. BASF and many smaller companies are participating in fact. As of 2008, we have over 150 licensees of these technologies

However, these companies – and their counterparts in the pharmaceutical and other life-science fields – are like large political entities – countries – that have embarked in a Mutually Assured Destruction scenario. Who will have the courage to blink? And more importantly, how long will the short sightedness that makes cooperation and open collaboration untenable – persist? Think of the arms race.

Who will say – this is foolish, unimaginative and wasteful?

Its a very hard question. I’m in negotiations with many of these companies, and while privately their senior executives and scientists may agree (and their accountants certainly will), they are – like political entities- themselves subject to huge inertial forces.

Imagine their share values when their courageous CEO gets up and says that their business models based on mergers, acquisitions, agressive litigations etc regarding core technologys, are flawed. Imagine his (or rarely her) rapid departure for ‘more time with their family’. They are strangely boxed into a very difficult situation.

So I don’t see an immediate sea-change unless we are successful (which I think we will be) on going towards new ground and new technologies which they can agree to treat differently than the old ones. I doubt that many of the multinationals will suddenly begin freeing up their existing patent portfolios. But I imagine the smarter of them will see the opportunities to redraw the terms of engagement for future technologies and the powerful economics of shared innovation. In spite of their well deserved reputation for hard-nosed, hard-assed business practice, I find there are still some very thoughtful people in Monsanto who may not see the world in a completely oppressive way, and who may be able to engage in this open source revolution.

But frankly, if they don’t, I’m not losing any sleep. There are way too many smart, ethical and committed scientists and citizens to allow science to become a high-cost tool available only to high-capital enterprises. Too much of agriculture, nutrition, natural resource management, energy, public health, and medicine requires new low-margin, localized innovations. And the power of open innovation can help address this.

Some have asked me how we can fight the powerful, carnivorous Tyrannosaurus of the Multinationals. My answer is to look around.

Where are the Terrible Lizards now? Gone. They’ve been out-evolved by mammals.

We just need to out-evolve them. They can adapt or become extinct.

In the last few years our lab has been getting more deeply into Type IV Secretion Systems. We set out some years back to ‘re-invent’ the Agrobacterium tumefaciens plant gene transfer capability in other families and genera of bacteria.

The reasons were twofold. First to invent around a very egregious and complex patent ‘thicket’.

Agrobacterium had been discovered to be capable of transferring genes from itself into higher plants, using a mechanism that is very similar to that used by virtually all bacteria to transfer genes (and proteins) from one bacterial cell to another, and often from one bacterial species to another. This observation was the first prominent inter-kingdom gene transfer described, and was the foundation of plant genetic engineering. So of course, it was patented up and down, backwards and forwards; every improvement, every species of plants…obscene greedfests of patenting. Until no one could actually use Agrobacterium to create crops (not just plants) that were improved. Except of course for a very few multinationals that had acquired strong portfolios and were willing to cross license them narrowly.

Anyway, we found that all the patents referred to this biologically unique (now there’s an oxymoron) capability of Agrobacterium tumefaciens. We reasoned that nothing in biology is unique. (Or as Jeff Goldblum’s darkly prescient character in Jurassic Park opines “Nature finds a way”). So we looked at moving this capacity to diverse bacteria and thus rendering the patents interesting and informative, but not legally restrictive.

It was surprisingly easy! And every one of the bacteria we tried it in worked, and in every plant species combination. Hmmm… so interkingdom gene transfer wasn’t hard? Well….

The other reason we set out to do this work-beyond, which we called Transbacter, was to make the process better. To use bacteria that had evolved a benign and symbiotic relationship with plants (and hence did not induce a pathogenesis response) to do our gene transfer, nicely.

Well, all that is pretty well described. But as we get more into these natural gene transfer capabilities, which are loosely clustered as ‘Type IV secretion systems (T4SS)’ I start to realize that the movement of genes between bacteria and likely, between bacteria and fungi, protists, plants, animals, you name it, is probably hugely more common than previously supposed.

The antibiotic resistance factors that are so promiscuously shared on broad host range plasmids (like the ubiquitous RK2) are moved around with T4SS’s, and of course the first system I cut my teeth on – the E. coli ‘F’ factor (fertility factor) is yet another of these. No self-respecting bacteria seems to lack such a capability.

If our observations about how the Ti-encoded Agrobacterium system can be so effective inother bacteria can be generalized, I think it may mean that a very serious force in metazoan and plant apogenome evolution will be from horizontal gene transfer from microbes. Note I say ‘microbes’ not bacteria, because I bet these types of systems pop up in fungi, protists, archae…etc.

Ok…my fingers are sore from typing this little blog. But there’s the convergent evolution in my scientific thinking – from glucuronide metabolism (and GUS the Wonder Gene) to horizontal gene transfer…now coming full circle.

What fun this period of life sciences could be. I really find 99% of molecular biology boring as bat shit these days. I can’t bear reading journals. But these ideas are much more envigorating, as they seem to smell of a pervasive logic. And as usual, I adore going where the metrics are tough. If you can’t see it and measure it, its not there? No way.

Still, there are new fields that are breathtaking in their implications (to me at least) and which do not lend themselves to being ‘owned’, but – at least at this stage in their development – rather shared.

The single most exciting development in the biological sciences to occur in my lifetime is the idea that microbes are not only ubiquitous but that they may be the most important component that drives the evolution of macro-organisms.

In fact, I’d venture to say that multicellular eukaryotes only exist in nature as complexes of organisms in which microbial genomes are critical, essential contributors to the fitness of the overall ‘individual’ (which itself needs redefining).

Back in September of 1994 I gave an invited presentation at a Symposium at Cold Spring Harbor sponsored by Perkin Elmer Corporation: “A Decade of PCR“.   The symposium was only a couple of days, was a celebration of the impact and future of PCR on life sciences, and featured Jim Watson, Kary Mullis, and a number of other prominent speakers. I was given the task of talking about Agriculture, Environment and the Third World. Rather dauntingly broad marching orders. But I decided that I’d try something fun out on the audience, which was a pretty substantial group of scientists.

While setting the scene with our observations about the complexity of agricultural systems, I wanted mostly to talk about ‘Hologenomics’, a term I coined and defined for that seminar.   As with most of my ideas, I’ve never written it down, but I have spoken about it alot, and thought about it even more. (This comment is a response to a quote from my PhD thesis advisor, who wrote in my letters of recommendation that “Jefferson thinks incredibly quickly, but speaks even faster”….sigh).

For years I’ve been studying the metabolism of glucuronide conjugates by Escherichia coli, and many other microbes associated with vertebrates. Vertebrates, including many humans (!) have a remarkable mode of turning over small molecules from their systems. Most small molecules, including steroid hormones, vitamins, xenobiotics (including most pharmaceuticals and dietary secondary metabolites) are excreted from the body as conjugates of glucuronic acid known as ‘glucuronides’ .

Glucuronic acid is simply glucose in which the 6-carbon is in the form of a carboxylic acid or carboxylate. The conjugates are typically (but not always) beta-1-O-linked glycosides of the aglycone. This conjugation is done in many tissues of the body, including of course the liver, but also epidermis and almost everywhere we look. The conjugates so generated tend to be much more water soluble than the aglycone (for instance, testosterone), and thus can more readily be transported in the aqueous circulatory system, where they can be transfered (recognizing the highly stereospecific glucuronic acid moiety) to an excretion pathway. The conjugates find their way to the kidneys for excretion in urine; the pancreas/bile ducts where they are dumped into the upper intestine; and the axils where they are excreted in apocrine and merocrine excretions (eg. sweat).

Turns out that the majority of steroid hormones are excreted this way, into the bile, where they end up feeding the enormous diversity of bugs in the upper and lower intestine. E. coli is just one of the myriad microbes there, and not even the most prominent one.

But it seems that the excretion of the hormone conjugates (and you can substitute almost any word for ‘hormone’ there, including ‘drug’, ‘toxin’, ‘metabolite’ etc) does not see the story end. Rather, the microbial populations have evolved the ability to transport these compounds selectively (in our own work, through a glucuronide transporter we call glucuronide permease, encoded by gusB locus of E. coli), where the aglycone (the steroid for instance) is cleaved off (by glucuronidase, encoded by gusA) and the sugar (glucuronic acid) metabolized by the microbe. The freed aglyone is then available for re-absorption in the gut.

Thus, thousands of compounds actually cycle through the intestine of vertebrates. Conjugated in the body, transported by circulatory system to a distal site of excretion, imported into microbial systems, cleaved to free the aglycone, which is then reabsorbed into the body. This has been called enterohepatic circulation, back when it was thought that the liver was the only site of glucuronic acid conjugation. I’ve read that as much as 65% of the circulating testosterone, for instance, has already passed through an enterohepatic circulation route.

Glucuronidation, and sulfation to a lesser extent (though this depends on species of molecule and species of macrobiont), are used on most steroids and most drugs to excrete. Hence the cleavage and re-presentation of the aglycone by the microbial populations are critical to controlling the level of these compounds.

Well these compounds include the entire range of steroids that have seminal impacts (excuse the pun) on reproduction, and reproductive fitness, including fertility, fecundity and mate choice. Estrogens, progesterone, testosterone, estradiols, all of them are excreted as glucuronides, and reabsorbed after microbial cleavage. Even the pheromones excreted from the armpits (or legpits…axils…) are generally non-aromatic. Some would say VERY non-aromatic. Perhaps better to say, they are excreted as water soluble, non-volatile compounds. It is the skin microbes that cleave the compounds to release the volatile steroids, such as androstenols, which impact on mate selection and population behaviour of the macrobiont (the big animal we see, for instance the human, mouse, fish, etc)..

Ok, so what is it about hologenomics and evolution? Well any sensible student of evolution will note that the traits that I mentioned, which are hugely impacted by steroid balance, which itself is determined (!) by the turnover of the glucuronide conjugates, are the very core traits that are key to natural selection, namely fertility, fecundity and mate choice.

Holy Cow! The evolutionarily most important traits of a mouse (or human) are encoded by bacteria!

And more importantly, by the balance of extraordinarily complex populations of bacteria in diverse settings. As anyone who has read this far (ie no one) would know, as we get better at looking for microorganisms we get much better at finding them – and it seems that the vast majority of the genomes associated with a human are non-human. Or are they? They are microbial (including eubacteria, but also protists, fungi, archae perhaps) but why are they not ‘human’?

They are causally associated with the behaviour and performance characteristics that have allowed us (or indeed any macrobiont) to persist and flourish under natural selection. So really, that means they are integral to ‘human’. In fact, I would argue they’re as ‘human’ as ‘we’ are. You see, we’re used to seeing our big sloppy nucleus and chromosomes and thinking ‘Yup, that’s the human genome; the book of life’…well, it seems that that’s only the scaffold! The real genome is what I call a hologenome. The apobiont (that would be what looks like me, if I had NO microbes associated with me) is not a holobiont (a complete organism) until the population structure makes it so. So the human genome hasn’t been sequenced, just the parts in a bag that replicates slowly. The little bags that replicate, migrate and reassort rapidly, and which clearly have mission critical functions, are only now being discovered.

And their importance is not yet appreciated. And its not just animal! All macrobionts (big multicellular organisms), including plants, are also a pastiche, an amalgam of many genomes. And so a rice plant is not really a rice plant in the absence of the microbial populations that allow it to perform in the environment.

This concept has big implications for our world view. For science. For medicine and agriculture. It is the tip of a very big iceberg. Its has been said in the last ten years by many scientists that most of the microorganisms in the world are unculturable (some would say that about humans too). Its true that as we begin our exploration of the microbiome we find vast numbers and diversity of microbes that have never been cultivated on media in the laboratory. The likelihood is that they never will. I guess that’s part of why I think they are a part of a hologenome that contributes to the overall natural selective fitness of the holobiont (and perhaps a holosystem?), and can only be thought of in that light.

So if we drop a mouse in a blender, we get (besides a visit from the site bioethics committee) more ‘bacterial’ than ‘mouse’ genomes. By a factor of nearly a hundred! This is the new wisdom. But its wrong. We definitely get more ‘microbiont’ than ‘macrobiont’ genomes. But the mouse is not the macrobiome. The mouse is the sum of these genomes – the holobiont expressing the hologenome – and it is that sum that contributes to the success of the mouse (not of course the blender mouse itself, who would not look at its role as a big success) under evolutionary selection.

And what gets very exciting about this is the following: If I were a macro-genetic-engineer (eg. teleologically speaking) I’d design most of the dull, workaday, scaffold functions to be encoded by slowly evolving, slowly replicating packets – ie nuclear genes. But I’d put the really critical, environmentally responsive functions in packets that could amplify quickly and specifically, could be traded (or not) through well crafted horizontal transfer mechanisms, which could replicate, and hence evolve, very rapidly. In short, I’d put the really cool important stuff in the microbial genomes, and leave the big macrobiont nucleus as a pretty pedestrian framework.

So are we really doing a great job yet at studying human (or mouse, or rouse – isn’t that the singular of rice?) genomics? Nope. Not until we think of the suite of genomes – the apogenomes and their aggregation into a hologenome – as the performance unit of natural selection. A nd therefore of the repository of the logic of life.

It would mean that the logic of ‘eukaryotic’ genomes will be incomplete, maybe even dead wrong, in the absence of the full appreciation of the impact of populations of microbes, which are lynchpins.

So I’m wondering, how do we set up experimental systems to prove this beyond a shadow of a doubt? How do we show that evolution works at that hologenome? Or doesn’t.

I’m rather optimistic that the glucuronide system may afford a model. And the new tools of massive high-throughput environmental sequencing will be a platform. I will be musing on this rather alot.

So let’s keep talking about hologenomics, and even its practical implications.

In a talk in South Africa at the 14th Conference of the South African Society of Biochemistry and Molecular Biology in 1997, in Grahamstown South Africa,  I called this Ecotherapeutics.

The idea that adjusting the balance and constitution of the microbial populations would have huge repercussions on disease and health. Both plant and animal. And that this could constitute the next revolution in life sciences, in which the interventions could be intrinsically ‘un-ownable’, context dependent and robust.

It now seems that the fundamental power of a harmonized patent informatics platform and a facility for supporting open innovation work has become widely appreciated. We’ll be going to scale soon with a sector-agnostic activity we call the Initiative for Open Innovation (IOI) under which the Patent Lens will be a prominent platform.

I’ll write extensively over the next weeks about this, but briefly the idea is to form a worldwide open access capability to integrate, parse, visualize and analyze patent data over all nations and all innovation sectors. We will develop – collaboratively – open source, community participation web apps which will allow creation and curation of ‘landscapes’ of key IP areas, for instance, influenza vaccines, RNAi technologies, cancer diagnostics, agricultural genetic resources and so on.

However, its now becoming clear that this should extend well beyond the life sciences, as indeed virtually all innovation activity is facing the complexities of a patent system in meltdown. Transparency really is critical, but the transparency must provide for high level oversight, not just the piecemeal ability to search for patents. Rather it will be critical that all interested citizens, scientists, business people and policy makers should be able to visualize and appreciate the nature and extent of current and projected patent coverage over areas of particular interest. This will require highly professional curation, annotation and involvement, but it will be greatly facilitated by sophisticated informatics.

Our intention is to work with many nations to digitize and integrate their own patent information so it can be searched in their own languages, and with natural language translation where possible, to open it for inspection to all citizens, everywhere. Of course, APIs provision and mirroring in diverse locations is part of the plan; but the foundation of the platform – the Patent Lens – is anticipated to become an enabling facility for open innovation.

Much more to come in future posts.

Journalists need to engage in this issue fiercely. Why should the public care about science if the science is being privatized and sold to the highest bidder? There is little confidence or indeed evidence that the public sector is striving to ensure that public good emerges in the scrum for patenting and piecemeal rent-seeking from the very institutions they fund.

I’ll update this post as the panel develops, and this theme will recur in the blog.

The entire Biological Open Source movement is based on using the terms under which scientific inventions are shared to leverage greater public benefit. This benefit need not be only in ‘public projects’ but may also come from stimulating more open, competitive and fair private sector development, especially small-to-medium enterprise.

In that discussion we were exploring the parallels between the intense competition to navigate the oceans during the creation of the European mercantile empires of the 1400-1800s, and the ability to navigate the patent world now in the new millennium. In both cases, the proprietary knowledge of the routes, the shoals, the dangers, the currents and the ports was of enormous importance for achieving commercial advantage, and of course economic primacy.

Kenn later went on to write an exceptional piece for Nature Biotechnology about navigating patents in biotechnology, further exploring this metaphor.   In the late 1600’s, the Spanish could risk the Manila Galleon traveling from the far East to Spain via the Pacific Ocean – and many of the annual Galleons sunk – because the reward was so high. The profits on silk, silver and spices were astronomical. Navigation and seamanship would have to be exquisitely well developed to justify smaller profits; simply to drop the risk profile. And indeed over the years, as both cartography and maritime technology improved, so did the volume, quality and reciprocity of trade. And of course it was the tools development that drove the navigational capability: the marine sextant allowed latitude to be calculated, the marine chronometer, the longitude.

It is clear that the ability to see the dangers and opportunities, the detritus and the value within the patent system was going to be critical if science and technology is to achieve a greater social good, especially for small markets or weak market signals – one way to say ‘for the benefit of poor people’.

But the system is of almost awesome complexity. Single patent documents can be hundreds of pages, with arcane language understood by only a few, and rights interpreted and re-interpreted on-the-fly by courts. Thousands of these can exist in a single field of innovation, with many thousands more latent in the system. One or two may be dominant or none. Fundamental biological processes – such as RNAi, have been patented. Most of the important genes of many important organisms – humans, rice, maize, cattle – have been subject to patent applications and sometimes grants, many of them contestable by many separate claimants.

But its actually worse than that. The ownership of the ‘patent’ itself is usually a matter of public record, but the ownership of the rights – the most important feature of a patent – is completely obscured. Nowhere, in most jurisdictions, is there recorded or available the patterns of power; who owns what rights. A University may own hundreds of patents, but for any of the useful ones, the rights have often been sold. But to whom? Not clear.

When a small company licenses a patent, or develops its own patent portfolio, to whom has it licensed and on what terms? The patterns of power and ownership are as important – and in the aggregate perhaps more important – than any other feature of a patent grant. And yet we have no public information whatsoever, except in piecemeal and scattered disclosures. Some jurisdictions, including Brazil, do impose a responsibility on licensees to disclose – at least to the patent office. But most do not. And none make it easy to find this information.

Now, as public agencies and universities come to increasingly dominate filings, the emergence of the trolls from under the bridges makes crossing so much more challenging. Imagine building a cart – or worse, investing in roads – when not only the spokes are proprietary, but the axles, the cart-bed, the yokes and even the oxen. It should be no surprise then that the few innovations from biotechnology to see the light of day and the tests of the market are such lucrative Spanish Galleons as Roundup Ready and Herceptin.

Our maps are still parchment and vellum in an age of informatics.

The Cambia PatentLens aspires to provide an integrated platform on which diverse actors can collaborate to create informatics-empowered and human- enriched environment to reduce the complexity, the opacity and the barriers of the patent system.

We are doing this by collecting, associating and harmonizing the data structures for patents and patent applications for major jurisdictions, combining these with patent status information and making these available at no cost to all.

As with maritime charts, there is a great difference between the resolution required to cross an ocean and that required to navigate safely into anchor at port. We are working towards development of patent landscapes (though in keeping with my maritime metaphor I should perhaps call them seascapes) in key fields of interest where professional knowledge and interpretation is absolutely required to have any sense of the extent of coverage and its meaning. And these will in turn serve as platforms for decision support in biological innovation. If Biological Open Source is to have any traction, it will be through the realization that the delivery of innovations into the market place will be the metric by which we will be judged, not just by collaborative science and information. And this means that the maps to create a clear way forward must be made and followed.