• Quick decision. Even if it is a no, I want to hear it quickly.
• Ready money. If it is yes, please be ready to close very soon.
• No diligence. If a lead investor has already “kicked the tires” on the deal, don’t you do it too. Trust their diligence. Don’t bother our key customers or partners.
• No backtalk. We already have plenty of board members and lots of opinions. Be a board observer. Or, better yet, trust us. Don’t come to the board meetings at all.

       When Managing Partner David Coats and his colleagues founded San Diego-based Correlation Ventures, they had sat on the other side of the table – lead investors looking for co-investors. When they went looking for a fund concept, applicable in both life sciences and high-tech VC, that would both be new and would match the needs of the market, they decided to explore how such a “perfect” co-investor could also make money. They deployed heavy-duty predictive analytics on what they claim is one of the most complete databases of venture capital financings and outcomes, including the fifty thousand deals in their database – ninety per cent of VC deals closed since 1987. This information was scrounged the hard way, according to this recent post on the Nature blog site: Correlation forged relationships with Dow Jones and multiple VC firms to access historical non-public data. That way, they were able to find a mathematical model, described below, that should lead to a strong return while still offering all the advantages listed above.

        Fund-raising went surprisingly well, given the current constrained environment. Correlation Ventures blew past its $150 million target and raised $165 million. This amount will be invested over three to four years in up to fifty companies in chunks as small as $250,000 or as large as $4 million over the lifetime of a company. The list of limited partners (LPs), whose identities were not disclosed, reads like a who’s who: endowments, pension funds, family offices and individuals. I chatted with Coats at Convergence Forum in Chatham, MA, in May, 2011 and again at the JP Morgan conference last week. He said that the fund-raising was so successful in part because of the early and enthusiastic support of thirty top-tier venture fund partners who themselves wrote checks. That sort of endorsement opened doors with limited partners.

       Surprisingly, success in individual deals does not correlate all that well with the “top-tier” nature of the VCs involved. “When you look who the winners are in VC,” Coats explained, “the industry is not nearly as concentrated [at the top tier] as some assume.” Coats is defining winners as investors whose deals generate large cash on cash multiples. In actual fact, he said, “The winners are widely dispersed and the distribution is not random. When you actually look at the data, every year there are hundreds of financings generating large multiples. Most, however, are small deals that are not even led by the top sixty VCs.” And in many of these deals, the lead investor winds up looking for a co-investor to fill out a round. That’s where Correlation comes in.

       It expects to push aside funds that might have contended for the open slot but would not make as quick a decision and that would not in any case have been as cost-effective for LPs. This implies that Correlation takes less carried interest and lower fund fees than “active” funds, but the fund understandably chooses not discuss its fees publicly.

The surprising distribution of success poses a dilemma for limited partners, who tend to invest again and again with those funds that have made them money. This is generally a rational hypothesis, Coats agrees, and a disproportionate number of Correlation’s investments are with top-tier firms. In that regard, Coats admits, Correlation is acting like a limited partner, maximizing relationships. However, Coats and his partners decided to broaden their fund diversity and go after the long tail of investors and deals that are not necessarily in the spotlight.

“The big ‘aha,’” he explained, was realizing that “many big [returns] come from financings that are undersubscribed or take a long time to close.” This is due to a pair of what Coats calls “natural inefficiencies.” One inefficiency arises when funds without long track records find good deals and have trouble finding appropriate co-investors. Another occurs in deal selection by funds that may not be seeing the best opportunities. In a conservative time like the past five years, these inefficiencies would seem to have increased as funds become more conservative about who they follow into deals and as there are fewer and fewer “blue-chip” co-investors to choose from.

The beauty of the Correlation model, according to Coats, is that “the top fifty VC firms could shut down and we believe we would still generate strong returns.” There would be enough deal flow and plenty of winners. It certainly is an alternative approach to an otherwise confounding market in which much of the VC muscle now seems to be concentrated at the top.

Piggybacking to success

Won’t this model, if successful, spawn competitors? And will the inevitable rise of additional “quant” VC funds piggybacking on the success of others distort the market in ways that limit or even destroy the yield? Look at what the Moneyball approach did to major league baseball: the team that applied the statistical analysis of player performance, the Oakland Athletics, had an initial advantage despite having less to invest in superstar players. This worked fine until their approach was cloned by virtually every other major league team, returning the Athletics to mediocrity and the league to its previous imbalance of power.

But will he give me deal flow in the morning?

There will be imitators. In VC, every new fund concept that makes money attracts them. Just look at the proliferation – some would call it an explosion – in royalty-based funds (for example, the new billion-dollar fund raised by Cowen earlier this month). What about the overall impact if copycats generate “clean-room” (reverse-engineered) co-investing models and what if every syndicate starts to have a quant fund as a co-investor? Predictably, Coats had a statistical answer for this. “We have already modeled what we think will happen to the VC industry with our success. Obviously there is greater unpredictability” if and when that happens.

It is too early to say for sure whether the Correlation model – or that of another new fund, Ulu Ventures in Palo Alto, which uses Bayesian analysis to predict the success of internet-enabled consumer and business service companies – will prove successful. After all, plenty of confounding factors not predictable by any model contribute to make investing risky. The risks are especially pronounced when the exit takes several years and the capital needs are as high as they are in life sciences. Holding times for VC-backed healthcare companies are up over five years now, according to this analysis by Silicon Valley Bank.

Some VCs I know see Correlation as a threat, at least to their egos. Others raise the specter of quant-based models such as the notorious Long-Term Capital Management, whose derivatives investing nearly brought down the world financial system in 1998. Please comment, publicly or privately – if there are enough comments, I will post a summary.

To me, their concern seems overblown. The model will work, or it won’t. Either way, Correlation will put more money into the market at a time when it is sorely needed. If the fund succeeds, and I tend to believe that it will, then the impact will be self-limiting. Some VC-backed companies will refuse to take additional money and those that do will not take so much that the market will be warped. One VC summed it up nicely: Correlation’s approach does not have to outperform that top ten or fifteen per cent of VC funds, which will likely keep doing better by actively selecting the best deals. It just has to perform well enough to deliver consistent “bottom of the top quartile” returns to its LPs.

# # #

One secret to both improving consumer health and making money in healthcare IT is the feedback loop: providing a person with her own data as a way to improve compliance and performance. Once she knows, for example, that this meal or that workout leads to success, there is a strong incentive to follow a regimen, make appropriate changes, and then look again. Until recently, feedback loops were clunky. A daily weigh-in. An annual physical. But consumers – dieters, runners, the health-conscious – want much more frequent, high-quality and personalized feedback.

Boston-area newco Segterra is forging new territory with its product www.InsideTracker.com. Segterra is the first to offer healthy consumers a regular glimpse of their own biomarker data coupled with data-driven recommendations for diet and exercise. In exchange for a one-time payment ranging from $169 to $249, InsideTracker provides a blood test (performed at work or home if you are in Massachusetts) and compares the results for key markers with population norms. As Segterra CEO Lee Gartley stated last month in the Boston Globe’s InnoEco blog, “…the online test results ‘show you your levels on a set of biomarkers that we’ve identified as being important for overall health and fitness, like glucose, cholesterol, calcium, and vitamin D… Your levels of creatine kinase, for instance, can tell you whether you have muscle damage from biking too far or bench-pressing a few too many pounds. The report can also suggest foods that can counteract low levels of a particular vitamin or mineral, or ways to vary your exercise regimen for the best results.”

The founders of Segterra learned from the positive examples of successful HIT startups FitBit and RunKeeper. Each of these also depends on consumer’s own data to provide recommendations and create a feedback loop. But unlike these other companies, Segterra collects data that consumers could not measure any other way and then applies its analytics to that data in ways that will yield increasing benefits the more consumers sign up.

Given the growing number of tools available, we expect this trend of self-measurement to surge.

As an advisor to this company, I have a stake in their success. But this in turn provides a special opportunity for my readers. Respond in the comments and include your email address and I will send you a discount code good for $50 off the first test. Don’t worry, I will not publish your email address. I’ll certainly be interested in your experience with InsideTracker. (The service works for those who have access to a clinical lab in the United States – stay tuned for international offers).

# # #

We recently test-drove a new social network for biotech and pharma executives that meets a real need. The new network is called Partnering360. It was launched today by conference organizer EBD Group to coincide with the start of the BioEurope conference in Düsseldorf.

Yet MORE social networks? After Facebook, LinkedIn, Twitter, Foursquare, Quora (for nerds), Mindbloom (for spiritual networking), Xing (for silent Europeans) and Google+ (no one has figured out yet what this one is for), hasn’t that trend peaked? We think it hasn’t and P360 demonstrates why that is the case.

Before detailing what makes this network look like it will be a winner, let’s think about this apparent paradox: an organization that makes its business out of in-person partnering events is joining the headlong rush into online social networking. What are they thinking?

The thinking is actually quite clear. The people who attend partnering events are a self-selected group. They already want to be with each other. They are interested in meeting more people like them in social as well as professional settings. And their organizations often insist that they use the in-person partnering events to broaden their networks in hopes of landing new opportunities. In-person networks get bigger not just through actual partnering meetings but also via social connections – meeting at breakfast, at coffee breaks or at the evening mixers.

But those connections are often fragile. Sometimes they are not immediately work-related. And unless one is a stickler for saving and logging business cards in a contacts database and then following up, the fleeting contacts can easily be lost.

Enter Partnering360. The only participants in this network are people who have attended this group’s events – 14,000 of them at the outset. (Additional industry players may be able to join by invitation later.) Participation is not mandatory but in the early going, Anna Chrisman of EBD Group told me, hardly anyone is opting out. (Good move making the opt-in the default – that makes the platform much more useful). So there is less worry than usual about meeting the “wrong” kinds of contacts e.g. time-wasters. The “right” contacts are all there. And the software, similar to that of LinkedIn, makes it easy to find people and request to connect with them.

The Partnering360 platform, which has been months in the making, grew out of the observation by those at EBD Group that conference participants had flocked to the online partnering platform, called PartneringONE, which had been set up for the group’s frequent events. But the participants had no way to maintain their connections from one event to the next. And PartneringONE’s default was to inform all members of a company’s delegation of each member’s online contacts. That was not a recipe for taking advantage of the serendipity of chance or social meetings.

The rest of the platform is much like LinkedIn, to which some of its content can be linked. It avoids some obvious pitfalls: it costs nothing (charging for this would be a non-starter). It integrates with both LinkedIn and Twitter instead of trying to compete with them. It allows for uploading of a profile photo and other information. If you are on PartneringONE, your profile information will automatically be imported.

Research has shown that one key to benefiting from social networks, online or in-person, is the so-called “weak” connections. As consultant Stuart E. Jackson put it in a mid-October article in Bloomberg Business Week, “The power of weak connections rests on … the assumption: Don’t worry … about having a small number of close friends. Instead, concentrate on making a much larger number of acquaintances—who might be called ‘not-so-close friends.’”  The reason is that this richer and more diverse set of contacts can be a source for all sorts of useful connections. That, of course, is where LinkedIn and social media tools like it come in.Before he started doubting the political import of Facebook and Twitter here, the New Yorker’s Malcolm Gladwell wrote about this power in his prescient 1999 story “Six Degrees of Lois Weisberg” and the point was driven home by social network mavens Nicholas Christakis and James Fowler in their popular book Connected and Christakis’ entertaining TED talk.

Networks that enhance existing professional networks get a +1 (aka a thumbs up) in my book. Here are some areas where this one has room to grow:

• More promotional information. No, I don’t mean ads. Partnering360 is ad-free and it had better stay that way to maintain its value. But just like web sites, information companies want to share is valuable. Chrisman said that there is a plan to add paid video captures of company presentations and I believe this will be welcomed by the community.
• Real discussion groups. In my view, LinkedIn has failed at this. It seems like every group I join is soon swamped by unwanted, often overly promotional posts. Or the group goes silent. Twitter does this well but the discussions die off because they are too public and limited to 140 characters. The exclusive nature of P360 should lend itself to some productive discussions. I hope this functionality is added soon.
• Links to more platforms. I dissed Quora above but in fact it can be useful. Google+ also has promise and shares with Partnering360 some degree of self-selection.

Of course, Partnering360 faces some of the same limitations that any online medium does: this material is legally discoverable. It’s semi-public. It certainly does not enjoy the protection of the high walls of a company’s intranet. Its main challenge is how to get above and stay above the noise. But given how regularly the partnering events occur and how often my readers and I find ourselves attending them, I suspect that this platform is here to stay.

END

Full disclosure: I was a moderator of a social network-related panel (video here) at an EBD event earlier this year and I will moderate another one at BioEurope Spring in Amsterdam in March, 2012.

By Steven Dickman, CEO, CBT Advisors

Can drugs that supposedly “activate” a controversial target – sirtuin proteins – stop or even reverse the aging process? A new report this week said “No.” According to this report, published Wednesday night in Nature, sirtuin activators do not extend lifespan in roundworms and flies and earlier studies that said they did were flawed. Nonetheless, GlaxoSmithKline (GSK) continues to invest hundreds of millions of dollars into developing drugs to hit these targets – more about their findings below – and if the drugs work, for whatever reason, the scientific squabbles will not matter.

I recently had the chance to hear Harvard professor David Sinclair talk publicly about his and GSK’s research into sirtuin activators. Sinclair was the scientific founder of Sirtris and he reported at a forum on longevity in Cambridge, MA, that GSK has high hopes of near-term confirmation in mice that some sirtuin activators do extend lifespan. Based on its continued investment, GSK still believes that the $720 million acquisition of Sirtris in 2008 was a smart one.

To read the rest of today’s post, visit Xconomy here or copy-paste the link:

http://www.xconomy.com/boston/2011/09/23/big-pharma-attempts-to-extend-own-lifespan-by-activating-sirtuins/

What could Google do if it had access to everyone’s health data?

You’re probably already thinking a few things:

1. There’s no way I’m giving Google my personal health data.
2. Didn’t Google already try to do this with Google Health?
3. Won’t this take the “don’t” out of Google’s “don’t be evil” motto?

But bear with us. Imagine a healthcare system 10 years in the future that would make Obama proud.

I go to the doctor and find out that I’m at risk for developing type II diabetes and need to craft an effective set of measures to minimize my risk. I find out that there are multiple recommended approaches, including preventative medicines. We log in to my Google+ health data page and go through the extensive record of my diet, lifestyle and exercise data, as well as my genome. From this, we determine how my response is likely to compare to that of the average person at risk for diabetes.

Even if Obamacare is ultimately upheld, it’s hard to imagine that the government alone is capable of unifying and analyzing all this data through the implementation of electronic health records. A better solution may come from the private sector, where all the necessary tools are already developed. As we know from Wikipedia, the most comprehensive, cost-effective data sets often come from user-generated data.

In comparison to Wikipedia, and Google+, Google Health was never positioned to gain a large enough user base. Google Health also lacked the right social tools to become popular enough to generate anything like “big data.” Google+, by contrast, will likely gain mass adoption because of the Gmail user-base and Google’s recent moves in the smart phone space. Google’s core strengths—aggregate data analytics, Web app and smartphone integration—give it the inside track to become the ultimate user-generated health resource.

But how to proceed? Letting it grow organically might ultimately lead to a flop the way it did with Google Health. Instead, we have a few suggestions to take on and neutralize the privacy issue and grow via a clever acquisition. That way, Google can realize its full potential as a neutral data gatherer and let its users benefit from the analysis.

To read the rest of today’s post, visit Xconomy here or copy-paste the link:

http://www.xconomy.com/national/2011/08/24/how-google-could-transform-healthcare-medicine/

*Rich Whalley is an associate at CBT Advisors, a boutique consulting firm in Cambridge, MA. Rich graduated from MIT in 2010 with a Bachelor of Science in Chemistry.

(Cross-posted to The Health Care Blog on July 20, 2011)

Now that Google has put its ill-fated Google Health project to rest, we are wondering who will make the next big attempt to establish a personal health record (PHR) platform for healthy people. Many have tried and many have failed, and there is still no popular platform for gathering, analyzing and sharing health data.

Adam Bosworth founded Google Health in 2006 to provide an online place for consumers to store their own health data. Bosworth left shortly thereafter and went on to found Keas, a SF-based web startup which takes a more social approach to tracking one’s health via a competitive point system. In a recent interview on TechCrunch, Bosworth spoke about why he thought Google Health had failed, “It’s not social,” and “Google didn’t push to see what they could do that people would want.”

Google Health failed in part because the user interface did not motivate most users to upload their health data. By contrast, one of the fastest-growing health sites on the internet, PatientsLikeMe.com, has built its online health community to an impressive 105,000 subscribers, focused first on patients suffering from chronic diseases like ALS (Lou Gehrig’s disease). The implied reward for this was high given the unmet health need, so it was an easy choice for patients to take the time to enter their valuable data. Healthy people have no such incentive for using PatientsLikeMe, but many seem to want to get in on the action. Armed with smartphones and social network memberships, a new health-savvy generation is looking to catalyze the growth of a new movement.

For every startup entering this field, the million dollar question is “just how easy can we make it for people to enter data and track their health?” It practically has to be automated in order to go viral, a prerequisite for aggregating the “big data” that could lead to marketable conclusions. There is a new line of VC-backed startups tackling this daunting task.

Coming to a Twitter feed near you

Withings, based in France, has produced a Body Mass Index (BMI) weight scale which tracks BMI via iPhone or computer and even sends automatic tweets. Americans can get in-shape, and French people can laugh at the tweets of overweight Americans. With all parties happy, why haven’t we seen more development in this area of diagnostic innovation for healthy people? For one, there’s a large VC question around whether or not these startups can make a large ROI with their one-trick ponies. Won’t they be killed off by apps or hardware add-ons created for next-generation smart phones?

Consider Fitbit, a small, lightweight device that functions as a pedometer that tracks sleep and burnt calories throughout the day. One could argue that a small body clip is much more comfortable to wear than an iPhone 4, but Fitbit is primarily a consumer software play. Its hardware is no more than a tricked-out accelerometer, not unlike the ones found inside Nintendo Wii controllers. Recalling Flip Video, I can’t help but think the VCs at Softtech and True Ventures are losing some precious Fitbit-measured “actual sleep time” over certain prickly questions. Will next-gen smart phones eventually eat up FitBit’s market? Will Fitbit be lucky enough to get an exit before time runs out?

Looking to share data on a universal personalized health platform? Dream on!

Withings, despite being partnered with the late Google Health, seems to have a flop-proof strategy of targeting diagnostic applications that are unlikely to be eaten up by new-fangled mobile devices. They recently released an FDA-approved blood pressure monitor that connects directly to the iPhone, and more impressively, already have two products on the market – with a baby monitor expected to hit the market later this year. While they may not be making big returns just yet, they might be able to become a leader in this space by putting up a solid enough barrier to entry.

What would need to happen for these companies to really take off? It’s probably going to involve a concerted effort from players in social networking to form better integrated health networks – a place for the data to live. Even though Google Health flopped, Adam Bosworth seems pretty confident about his new gig, but Keas is not exactly going viral just yet. So who’s left to take charge of the movement?

Is Google Health really going to waste, or will it be strategically recycled into a 100% post-consumer product?

PatientsLikeMe is currently limited to the chronically ill, and Facebook doesn’t seem to be making strides in this direction anytime soon. One of the most promising new platforms is Google+, termed “the Facebook killer.” If successful, Google has a golden opportunity to use Google+’s platform to provide a framework for people to manage personal healthcare data. For example, Circles allows users to select specific people and groups for sharing personal data of all varieties, including health data. Importantly, the platform can aggregate anonymized data across a very large user base. Will Google+ eventually become the personal health data platform? I would love to see this happen, but so far there is no hint that anyone at Google is working on healthcare apps for Google+. We can’t wait to see some startups tackle this. It’s only a matter of time.

# # #

When I mention to other biologists that I work on exosomes, I am used to getting blank stares. Exosomes, also sometimes called microvesicles, are small lipid vesicles secreted by all cells. Like many dark corners of biology, the exosome field is a province of a few experts and is still largely unknown to the mainstream. But thanks to some exciting early results and a long list of potential medical applications, exosomes are beginning to move out of the shadows and into the light. Exosomes were the subject of two sessions at the annual American Association of Cancer Research (AACR)  meeting earlier this month. In January, the first-ever conference on exosomes brought together more than two hundred researchers from around the world. And now even the popular press is picking up on the applications of exosomes to RNA interference (RNAi) drug delivery and diagnostics in fields ranging from cancer to diabetes.

The concept of cells budding off small particles was actually first mentioned in Charles Darwin’s The Variation of Plants and Animals Under Domestication in 1868 and exosomes were first observed by electron microscopy in the 1980s. For twenty years after that, exosomes were thought by many to be nothing more than “cellular trash bags” that dump proteins deemed to have outlived their “use-by” date. This changed a few years ago, though, when a number of independent studies showed that exosomes actually contain not only protein but also RNA. This discovery opened the possibility of using the RNA in exosomes floating around in bodily fluids to learn all kinds of secrets about the cells that release them.

There first (as usual)

I learned about the diagnostic potential of exosomes in early 2009 when a venture capitalist asked my opinion on a business plan. The company, called Exosome Diagnostics, was being spun out of Massachusetts General Hospital (MGH) to develop new diagnostics based on analyzing the RNA in exosomes isolated from blood and urine. At the time, I was an undergraduate at MIT working on microRNAs. After reading the business plan, the patent filing, and the underlying scientific publication, I called the VC back. “This could be HUGE,” I told him. “We should get in on this,” he replied, and promptly forgot all about it. I did not. After graduation, I opted to learn more about exosomes through a brief stint at the Curie Institute in Paris. I then joined Exosome Diagnostics, which by then was flush with a $20M Series A.

The company’s platform is based on the work done at MGH, which showed that mutant RNA transcripts derived from key genes can be detected in exosomes released by cancer cells. Johan Skog and colleagues had shown that by isolating exosomes from blood and looking at the RNA inside, they could tell whether a patient’s tumor contained mutant EGF Receptor (EGFR) – establishing the proof of principle for exosomes as companion diagnostics. Oncologists could use them to peer into the genetics of tumor and decide whether a patient would be a good candidate for EGFR-inhibiting drugs such as Tarceva® and Iressa®. As pharma companies move increasingly towards targeted cancer therapies coupled to companion diagnostics (think PLX-4032, Plexxikon’s BRAF inhibitor for melanoma, or Crizotinib, Pfizer’s ALK inhibitor for lung cancer), the appeal of a blood or urine test instead of a biopsy to analyze specific mutations is not hard to see. This is particularly advantageous in cancers where obtaining a biopsy is difficult, like brain cancer or lung cancer.

I think that companion diagnostics in cancer are just the tip of the iceberg for exosomes in diagnostics. Several recent studies have shown that different levels of certain RNAs in exosomes and other vesicles isolated from blood correlate with different disease states. In other words, exosomes have RNA “signatures” for different diseases. One recently published study , for example, showed that a specific microRNA in vesicles derived from diabetics’ blood was elevated compared to vesicles taken from non-diabetics. Amazingly, the researchers also showed that this biomarker could potentially be used to identify patients who will get diabetes before any clinical symptoms occur. Although the test in the paper was not yet sensitive enough for the clinic, the results raise the intriguing possibility of using RNA signatures to predict disease, not just diagnose it.

Several reports at the January exosome conference highlighted diagnostic applications of profiling exosomal RNA in different diseases:

1. Signatures of mRNA isolated from exosomes in the blood could be used to classify brain tumors based on aggressiveness.
2. A specific microRNA isolated from exosomes in the cerebrospinal fluid (CSF) was found in brain trauma patients but not in healthy controls.
3. Certain microRNAs isolated from exosomes in the blood of pregnant women could be used to predict premature births.

Although larger studies will be needed to confirm these effects, I imagine that, in the not too distant future, exosomes will join the list of proteins and metabolites currently profiled during routine blood draws. Through methods such as high-throughput sequencing, the RNA inside exosomes (dare I say “exo-transcriptome”?) will be analyzed and will prove spectacularly useful in helping physicians assess and track patient health.

I spy a novel class of biomarkers (Image courtesy Johan Skog and Casey Maguire, Massachusetts General Hospital)

Exciting as the potential of exosomes is in diagnostics, you may be wondering what they actually do. Are the different RNA profiles in exosomes more than a correlation? Do exosomes actually contribute to disease? This was an intense topic of debate at the exosome conference, and, after listening to four days of presentations on the topic, I would venture to say that we still really don’t know. The fact that exosomes contain RNA raises the extremely intriguing possibility that cells throughout the body communicate by sending each other little “packages” of RNA, and the RNA can then perhaps act in the recipient cells – be translated into protein in the case of mRNA or repress the expression of other genes in the case of microRNAs. And, if this is the case, one could imagine hijacking this pathway to deliver therapeutic RNAs and thereby overcome an enormous roadblock.

The main obstacle to realizing the tremendous potential of RNAi therapeutics is the challenge of delivery. Whether or not exosomes are actually used to transfer RNA between cells remains to be proven, but results presented at the exosome conference and recently published by a group at Oxford made the first attempt at this approach. Led by Matthew Wood, the group loaded modified exosomes with an siRNA designed to knock down the BACE1 gene implicated in Alzheimer’s Disease.  Although they used healthy mice as models, the researchers demonstrated proof-of-principle by showing reduced levels of BACE1 in the brain. Of course, it would be reassuring to know what exosomes actually do in the body before injecting them into patients, especially given that exosome-based drugs would be complex biologics composed of several different proteins, not just lipid vesicles. As we learn more about the biology of exosomes, however, I could imagine scientists designing exosome-mimicking particles with the minimum necessary components to carry the RNA therapeutic to its designated site in the body.

As evidenced at the exosome sessions at the AACR meeting, there is increasing interest in exosomes secreted by cancer cells. Cancer exosomes have been found to contain oncogenic mRNA and proteins, and it is thus tempting to speculate that exosomes may have a role in modifying the tumor microenvironment and helping the cancer spread. If true, one could even imagine using therapeutics to specifically target cancer exosomes. Unlike with the use of exosomes for diagnostics, however, the use of exosomes for therapeutics will require scientists to uncover some of the fundamental biology of what exosomes are and how they function. Luckily, as evidenced by the excitement at the exosome conference, there are at least two hundred of them up for the challenge.

# # #

*Dima Ter-Ovanesyan (dimatero@gmail.com) graduated from MIT in 2010 with a Bachelor of Science in Biology. At MIT, he worked on RNAi screens in cancer with Michael Hemann and microRNA targeting with Chris Burge and David Bartel. He was also an associate at CBT Advisors. He currently works at Exosome Diagnostics.

A Boston Biotech Watch Book Review

By Steve Dickman, CEO, CBT Advisors

Marcus Wohlsen’s ahead-of-the-curve new book Biopunk: DIY Scientists Hack the Software of Life, brings us a radical idea: garage biologists are busily “hacking” their own genomes, cooking up a variety of novel and potentially useful wetware inventions. Some of these may look like Rube Goldberg contraptions right now, but they might change the world profoundly, much as mainstream biotechnology already has. Even (especially?) for those of us who live and breathe biotech in Cambridge, Massachusetts, this idea is fresh, even startling.

So much DNA, so little time*

Biopunk chronicles, for one, a young MIT-trained “DIY scientist” who created and ran a DNA test on herself in her Cambridge kitchen for less than $200. The test would cost thousands if ordered from a clinical lab. She used countertop gear to look for – and find – evidence that she had a predisposition for a hereditary and severe disease.

In another chapter, a research team in an undisclosed location crowdsources funds on the Internet to create “the world’s smallest version of the thermal cycler,” an all-important DNA analysis tool that would “wedge open the door … to peer-to-peer biotech.” Combined with “an as-yet hypothetical DNA reading chip” and some samples of pathogen DNA, the team’s invention could give a doctor or nurse working in the field in a developing country “an answer in minutes” about which pathogen had infected a patient.

And more: industrial-strength “DNA photocopiers” known as PCR machines encased not in sheet metal but in wood; an edgy conference called “Outlaw Biology?”; and a pony-tailed bioinformaticist who tinkers after hours in his Mountain View garage with a device that could read DNA electronically, a device that he would give away or sell at cost to developing-world health initiatives or to other biohackers. If it works, it could eventually undermine or augment traditional diagnostic assays based on technologies like ELISA and microarrays.

It is for the developing world, with its cost constraints, lack of up-to-date technology and urgent needs, for which biohacking would seem to hold the greatest promise, as long as it can overcome some daunting obstacles. But for would-be startup founders who need a shortcut to intellectual property, DIY would seem to offer an attractive “quick-and-dirty” alternative. No less a luminary than Freeman Dyson is a full-on advocate for DIY biology. In a 2007 essay entitled “Our Biotech Future” published in the New York Review of Books, he said “I predict that the domestication of biotechnology will dominate our lives during the next fifty years at least as much as the domestication of computers has dominated our lives during the previous fifty years.”

Marcus Wohlsen

Wohlsen, a Bay Area-based science reporter for the Associated Press, plucked the book’s core concept from a brief story he had published. Unfortunately, the moment he has chosen to expand it into a book feels a bit too early. Invisible on Google Trends, “Biopunk” has been mentioned only in a few magazine articles (for example in the New Yorker and Wired), mostly in the context of the promise and threat of mass-producing DNA via “synthetic biology.”

But Wohlsen’s timing does society a favor. Although his choice of topic may not help his book ring the gong of popular science as did, say, James Gleick’s Chaos in the 1980s or Dava Sobel’s Longitude in the 1990s, he has nonetheless caught and illuminated biohacking while it is still a tiny subculture and yet potentially could grow into a powerful force. Could it become a bigger one? Could it – pardon the expression – go viral, with astonishing results? Or will it be tamed and shackled, reduced to a harmless hobby like coin collecting or trainspotting?

Wohlsen is a fine writer with an ear for the absurd. Biopunk is well written, well-organized and has a satisfying amount of fresh material, answering the insistent question “Who ARE these people?” in a way that brings the individuals satisfyingly to life.

But as enjoyable as the book is, it does not describe a “what is” as much as it gives us a glimpse of a “what might be.” Like personal computing before Steve Jobs and the Homebrew Computing Club, DIY DNA is missing both a galvanizing new technology (the personal computer, the internet) and a recognized leader.

Will the next Jobs hack bio?

What’s more, no matter how good it is, a non-fiction book cannot yet capture the world that may yet be created by DNA “hackers.” There are three reasons for this:

• Reason One: DIYers haven’t created enough of it yet. There is no brilliant hack even of the 1988 variety nearly pulled off by Marcus Hess, the KGB Hacker, when he penetrated the network at Lawrence Berkeley Labs and started looking for nuclear secrets (a story I covered for Nature that was later told compellingly by Clifford Stoll in his 1989 book The Cuckoo’s Egg), let alone a hack as subtle and diabolical as that described here (Social Media Tools Used to Target Corporate Secrets: USA Today, March 31, 2011) or even the successful takedown of tens of millions of credit cards by this guy (Kingpin: How One Hacker Took Over the Billion-Dollar Cybercrime Underground by Kevin Poulsen, Crown 2011).

• Reason Two: The possibilities are so massive no one can think of them yet. One could argue that financial or intellectual limitations will prevent the hacking of anything more complex than a bacterium. But that would be so wrong. Wohlsen shows convincingly that the technology of DNA manipulation is available, affordable and already being applied. So what if the “tinkerers,” as they proudly call themselves, have not yet tinkered their way to a gryphon or some other creature we have not even thought of yet? This technology – cloning, sequencing, DNA manipulation and now synthesis – is extremely powerful. Think about that power – to create and fuse entire genomes. Now consider the tools of the moment – of Facebook, Twitter, the internet itself — all tools that foster “distributed intelligence” and group problem-solving. Combine cheap tools to manipulate DNA with the power of networks and you’d better stand back because what happens might rival the power of the nuclear bomb, a comparison Wohlsen aptly draws.

Made to order?

• Reason Three: Before they can create much, the government will stop them. This, it seems to me, is the biggest threat that faces the nascent and promising movement of DNA hacking. As Germans from both East and West Germany used to say just after reunification, the “wall in the head” is much more formidable and hard to dismantle than the actual Berlin Wall was. According to Wohlsen, the troubling arrest and successful prosecution of one apparently non-malicious DNA hacker has already shown that it can chill the field. More systematic government intervention has the potential to freeze it.

If government intervention – through regulation, post-9/11 bioterror laws or “just” by intimidation – were to shut down DNA hacking, this would be both sad and ironic. Sad because it would cut off a potentially limitless source of new discoveries that could benefit humankind. Ironic because forcing DNA hackers back into “societally approved” (read expensive, cumbersome, peer-reviewed) channels or driving them underground would be a denial of the bottom-up, can-do pioneering spirit that is part of the cultural heritage of the United States.

The not so subtle message of Wohlsen’s book is that the very nature of the hacker community – low-budget, decentralized and interested in the pursuit of novel applications for DNA for their own sake – makes it a threat both to public safety as well as to corporate profits.

For the moment, we hasten to add, the threat seems more imagined than real. As Wohlsen puts it, “…bad guys with a semester of community college biology under their belts can get far more destruction for their dollar by whipping up a vat of botulism-causing bacteria in their basements than by trying to splice genes.”

Government meddling may be enough to slow the pace of biohacking. But I hope that does not stop it. Just as free-flowing, non-establishment creativity has helped give us Linux, SETI and the remarkable political power of Twitter and other social networks, DNA hacking may turn out to be a potent source for good.

This will only happen before a couple of those obstacles are overcome. First off, cost is a much bigger factor in home-brewed biology than it has ever been in computing. Second, assuming that some of DIY DNA’s discoveries would ultimately have to be converted into mundane intellectual property (IP) even to be applied effectively in the developing world, let alone in developed countries, the “quick-and-dirty” approach might well be too “dirty” to ever become the underlying IP for a biotech or diagnostics startup. It is no coincidence that a typical biotech company raises $100 million or more before it achieves a viable proof of concept for a new therapeutic. And that is just the beginning.

The best science writing reads like science fiction, introducing people, techniques and discoveries right now that make us feel like the future has arrived and it’s even shinier and newer than we thought it would be. Although neither a critical discovery nor a galvanizing leader has emerged from this potent stew, Biopunk succeeds in thought-provokingly preparing us for the new world that will greet us when they do.

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*Steampunk photo courtesy Curious Expeditions under Creative Commons license

Further reading: DIY DNA in art and science fiction

(Special thanks to EW for these recommendations)

Margaret Atwood’s provocative novels Oryx and Crake and The Year of the Flood explore some possible and frightening futures.

Strange Culture is an indie film chronicling the strange story, also retold in Biopunk, of artist and professor Steve Kurtz who, according to the Netflix plot summary “on the eve of his new exhibit, was shocked by the news that his wife had died of heart failure. The medics on the scene became suspicious of Kurtz’s artistic media, which includes genetically modified foods, and the FBI accused him of bioterrorism.”

Dear Mr. Viehbacher,

In the heat of the discussions regarding an acquisition of Genzyme that now look like they are on track for rapid completion, you may not have had much time to think about exactly what will happen in the aftermath. Sure, you have plans for Genzyme’s products as well as for the teams and facilities involved in producing them. Those products—and their revenue streams—are presumably why you are buying the company.

But don’t forget Genzyme’s excellent R&D….If you downsize Genzyme the severe way that some expect, you might be throwing away enormous potential for future products to benefit human health.

To read the rest of today’s post, visit Xconomy here or copy-paste the link:

http://www.xconomy.com/boston/2011/02/07/how-sanofi-could-start-off-on-the-right-foot-in-cambridge/?single_page=true

A Boston Biotech Watch Book Review

By Steve Dickman, CEO, CBT Advisors

The rise of super-resistant bacteria and the inadequate attempts to combat them: Who but David Shlaes could give us such an entertaining and wide-ranging book, Antibiotics: The Perfect Storm, on such a gloomy topic? Shlaes, a top consultant working on the discovery and development of antibiotics, brings an encyclopedic and wry perspective to a field that, for pharma anyway, has mostly fallen between the cracks.

The broad outlines of the antibiotics tragedy-in-the-making are familiar: overuse and misuse of antibiotics has combined with a slowdown in new drug research to create what Shlaes aptly calls a “perfect storm:” more powerful and versatile bugs are morphing into existence daily, it seems, but the drugs to combat them have ceased to reach the market, felled by irrational regulators and markets not huge enough for Big Pharma. Consequently, we overuse those antibiotics that are still effective, which elicits resistance and then leads to disaster: the spread of multiply resistant superbugs and no way to stop them.

Just two new classes of antibiotics have reached the market in forty-two years, writes Shlaes: linezolid (Zyvox, Pfizer), belonging to the oxazolidinone class, and daptomycin (Cubicin, Cubist), a cyclic lipopeptide. Meantime, the “perfect” bug, equipped with resistance to every known antibiotic, creeps ever closer. In August of last year, reports surfaced about Enterobacteriaceae (gut bacteria) sporting a gene that codes for a penicillin-busting enzyme called NDM-1. The bacteria were found in Pakistan, India and the United States and only a single, old-school, kidney-toxic antibiotic, colistin, showed activity against it.

This sad state of affairs was predicted by Shlaes, who has long been on a crusade to loosen the logjam of unhelpful regulations, especially in the United States. The man is ideally suited to lead the charge. He started out in academia, realized after sixteen years that if he wanted to change the world he had to move into the pharmaceutical industry and then embarked on a successful career as an executive with Wyeth, where he was vice president in charge of infectious disease. From that lofty post, he dove into biotech and worked for Cambridge, MA-based Idenix Pharmaceuticals and joined the board of Novexel in France. He is now a Connecticut-based consultant.

Plenty of industry consultants are on their game; few write books. Shlaes became one of this select group because he is deeply passionate on the dual subjects of improving antibiotics R&D and increasing new drug approvals, and he wants to let his passion move others to action.

The major culprit in Shlaes’ mind – and in the views of some antibiotics-savvy venture capitalists interviewed for this article – is the Food and Drug Administration (FDA). FDA has, according to Shlaes, thoroughly messed up its mandate. Shlaes sees three main issues that have plagued the agency for most of the antibiotics drought of the last two decades:

• FDA has increased clinical trial design stringency to the point where trials become so large that they no longer pay. At the same time, FDA adheres, despite recent progress in some hearings at which Shlaes has presented, to outdated standards for approval. For instance, these include mortality endpoints in community-acquired pneumonia that date from the 1930s and have long since been superseded by other, more up-to-date and realistic measures.

• Because these drugs work so well when they work, there is a double standard for anti-infectives compared to other drug classes. “Tylenol,” Shlaes writes on page 40, “is one of the most widely used drugs in the world … and causes more cases of acute liver failure requiring liver transplant than any other drug. It is still sold without prescription worldwide.” By contrast, antibiotics such as Ketek in sinusitis and bronchitis, which have much lower complication rates, have nonetheless had their marketing approval withdrawn.
• Most troublingly, FDA continues to “move the goal posts” in mandating one set of endpoints early in a new antibiotic’s development and then increasing the requirements as the antibiotic moves closer to approval. Shlaes experienced this firsthand in his years at Wyeth and it has clearly left a bitter taste. One hopes we all benefit from the crusader’s zeal he brings to improving this unhappy state of affairs.

Pharma is a second culprit. Pharma consolidation has gone so far that the revenues from even a top-selling antibiotic barely move the needle. The largest-selling antibiotic in history, Augmentin, peaked at just under $2 billion. By contrast, Shlaes points out, Pfizer and Wyeth had combined 2008 revenues of $71.1 billion. So the economic incentive to try to bring forward new antibiotics is not as strong as Shlaes would like. At the moment, there is a shift occurring in pharma’s thinking, of course, away from blockbusters and toward smaller-market opportunities such as orphan drugs. I imagine that there could be good reason to expect pharma to become more interested in moving back into antibiotics after abandoning them; Shlaes writes that there is no evidence of this.

Shlaes is too heavy-handed in his critique of the biotech response to the antibiotics crisi. It would be nice to have a couple of case studies of biotechs that succeeded (such as Vicuron, acquired in 2005 by Pfizer for $1.9 billion) instead of (1) a blanket statement like “some experts predict that only 10% of biotech companies will succeed” in antibiotics development; and (2) a single case study of one such failure, a Colorado company called Replidyne, that was killed off in large part by FDA moving the goal posts.

A closer look at Achaogen and Tetraphase (in Watertown, Massachusetts), mentioned briefly, would have yielded a rich vein of hope. Both companies have managed to raise large amounts of venture capital money despite all the challenges. Achaogen, based in South San Francisco, has even succeeded at raising as much non-dilutive capital as any private biotech I’ve ever heard of, well over $100 million, from sources such as the U.S. military and the Wellcome Trust. The forces arrayed against successful marketing of new antibiotics can be overcome, these companies’ investors believe, through conducting clever clinical trial strategies (Achaogen) and inventing unique chemistries (Tetraphase). That is a story worth hearing and it would be interesting to hear Shlaes tell it.

In addition to the role of these biotechs, other areas I wish Shlaes had touched on include:

• The epidemic of hand-washing with “anti-bacterial” soaps and its implications for the rise of resistant bacteria
• The role for improved, genomics-based diagnostics in the clinical care of infected persons or those at risk
• The role of genetics-based susceptibility on the part of some of us to certain subsets of the bacteria out there
• Potential contributions by academic consortia in filling the gaps left by the vanished big pharma research and development programs
• A view of antibiotics development through the prism of healthcare costs – stays in sealed intensive care wards can’t be cheap, so it must be in the interests of the healthcare system to have more impactful tools to fight those nasty hospital-acquired infections, especially now that Medicare is slashing reimbursement to hospitals that do not report them …

It is hard to know what to do next when reading such a persuasive argument for societal action. Found a non-profit? Jawbone a regulator? Invest in more biotech companies that pursue anti-infectives? But one thing is for sure: if Big Pharma and FDA manage to pull themselves out of the current morass, it will be due to Shlaes and his allies in industry and academia exerting their maximally persuasive powers to bring about the unending supply of new antibiotics that society desperately needs.

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