This is a post from the 2010 Experimental Biology meeting in Anaheim, part of the SDBN conference reporting channel.

Leroy Hood probably doesn’t need any introduction here, but for those who don’t know, he’s a leader in using a systems biology to address large, complex medical problems. One such problem is prion disease, a disorder caused by a proteinaceous infectious agent which results in neurodegenerative symptoms as the proteins accumulate in the brain. After decreasing in recent years subsequent to the slaughter of 4.4 million potentially prion-bearing cattle in the UK and establishment of new industry practices, deaths due to prion disease are now as high as they were at their height in 2003.

As prion proteins accumulate and physiology is disturbed, there’s a change in gene expression of over 7400 genes. using 8 mouse strains, Dr. Hood used subtractive biology techniques to narrow the list of relevant genes to 333. Of this number, 2/3 were already known to be involved from previous work. An additional 100+ genes discovered were newly implicated. To study the dynamics of accumulation co-occurring with prion accumulation, Hood developed a massive dataset consisting of transcriptme analysis, histopathological studies, and tissue distribution studied, combining these data with known protein interaction data and clinical signs of disease. This massive analysis identified the accumulation networks and revealed the dynamics of the process as it happens over 20 weeks. In the human, prion disease can gestate for 4 years, so 20 weeks is a reasonable time for a mouse model.
One of the neatest things to come out of this work was a a means of predicting the cell type involved, based on the differential expression of the genes. All the novel prion-associated genes were correctly predicted this way. From within this dataset, they further identified 15 proteins found in the blood which track the clinical course of the disease. Instead of a definitive diagnosis only being possible upon autopsy, now the disease state can be monitored via blood markers, resulting in much easier monitoring of at risk populations and a far safer food supply.
Dr. Hood took a few moments to mention that he’s founded a company, Integrated Diagnostics, which is undertaking some fascinating projects. Among these are creation of a human proteome atlas, which will yield a quantitative assay for every known human protein, and a microfluidic chip platform with some impressive stats. He said the chip would be able to assay 50 proteins in 5 minutes using a volume of 300nL of serum (not whole blood, I assume) at attomolar sensitivities. With that level of sensitivity, they’re well within clinically significant ranges for most proteins.
To do this, they invented a novel protein capture technique that used a combination of low-affinity 6mers and click chemistry to create highly stable chips with antibody-like specificity. he cited 5 years until their availability.
In 10 years, he expects genome sequencing to be routinely done as part of medical practice, costing no more than a couple hundred dollars (as the inventer of automated DNA sequencing, I’d believe him). What this would allow, for example, is capturing of an individuals MHC locus during allergy testing and identification of specific auto-antibodies.

Update: The slides for this talk (PDF) are now available, as gave the same presentation at the SAGE Congress.

I’ll be blogging for the next couple days from the 2010 Experimental Biology conference. Today’s session that caught my eye was on measuring the effects of climate change on organisms in their own niches. It turns out that some microenvironments act like lenses, focusing small changes in climate into much larger effects on resident organisms. I also attended a good session on science communication and policy, which will receive a longer and more thoughtful post to come later.

When people hear that the global temperature has increased about 1 degree C in recent years as a result of global warming, it’s understandable that they aren’t really impressed. “One degree? It changes more than that day to day!” Speakers during this session showed how in certain ecological niches, the real difference in terms of physiological effects on an organism are quite larger.
Brian Helmuth from the University of South Carolina kicked off the session with a discussion of tools and models for downscaling the global phenomena to microenvironments. He showed that there’s little correlation between the internal temperature of an animal and the air or water temperature surrounding it. Furthermore, the air or water temperature changes don’t result in the same relative change in temperature for all the organisms in the microenvironment. In other words, a 1 degree rise in air temp tells you pretty much nothing about what effect that has on an organism. Using air temps as a proxy for environmental stress is like trying to guess how what the weather is like outside based on what color shoes people are wearing.

To address this, he developed a sophisticated model for predicting the differential effect of climate change on different organisms, basically an internal “weather forecast” for an organism. They measure a few coefficients such as radiant heat transfer (based on how much insulation the organism has) and evaporative heat loss (from sweating, for example). What this then allows them to do is to properly predict the actual temperature shift as it’s experienced by the individual organism.
It doesn’t take too much imagination to realize that this approach could be extended to look at ocean acidification and other environmental stressors as well. With these new tools, scientists can now predict the effect that microenvironmental changes will have on habitats and start to look at how this interacts with pollution exposure and other challenges facing an organism.

_{Data guys, he mentioned a huge amount of time series temperature data on organisms, stretching back 10 years at a 10 minute resolution. Impressive?}

Drug development is an area that, according to our 2010 poll, you are interested in, and in previous meetings we’ve discussed that San Diego biotech could grow if we would better complement our drug discovery capabilities with drug development. The SDBN was approached by Rondaxe, a drug development services company, with an idea for an event which will highlight companies they work with from outside the San Diego region. The event will be held May 27th, from 9:00 a.m. to 2:15 p.m., and a light breakfast and lunch will be provided. Please join us, the full description and agenda follows, and you can register here.
In coordination with one major consulting firm and one important CRO in the Pharma arena (Rondaxe and TD2), Helsinn Advanced Synthesis is organizing a drug development symposium. Three major companies involved in API Manufacturing, CMC Services/Consulting and Clinical Development will give a short technical and educational presentation related to their expertise.
The symposium will also offer the opportunity to share your ideas with other participants. At the end of this event, the organizers cordially invite you to join them for lunch.

Rondaxe Drug Development Workshop

Synopsis

Helsinn Advanced Synthesis: The choice of the right CMO to avoid pitfalls by successfully transferring your API / HPAI process. Implementing a roadmap to avoid potential problems and extra costs.

TD 2: Integrates world-class preclinical, clinical and regulatory expertise with “-omic” science and provides unique drug development strategies and services aimed at minimizing the risk for clients in the oncology drug development industry.

Rondaxe: De-risking CMC through experience, project and knowledge management; utilizing virtual business development expertise to maximize value realization

Program

9:00 AM	Check-in, Continental Breakfast
10:15 AM	Welcome Speech Pierre Vitaloni, Manager Business Development Helsinn Advanced Synthesis
10:30 AM	Helsinn: Supply chain challenges for the Biotech / Pharma Industry Dr. Waldo Mossi, Senior Director Sandra Moro, Deputy Director Business Development
11:15 AM	TD2: Innovation and Precision – The future of oncology clinical development Linda Vocila, Director of Clinical Operations
12:15 PM	Rondaxe: Improving value realization with de-risked CMC and virtual business development Jeffrey Evans, Rondaxe Managing Member
12:40 PM	Rondaxe: How to stay compliant in the currently changing regulatory environment Karl Hofmann, Rondaxe Quality, President
1:00 PM	Participants’ Discussion & Closing Speech
1:15 PM	Lunch

Event Details

Who: Biotechnology professionals in the greater San Diego area
What: San Diego Biotechnology Network Partner Event May 27th Rondaxe Drug Development Symposium
When: Thursday, May 27th, 9:00-2:15 p.m.
Where: Tango Del Rey, 3567 Del Rey Street, San Diego 92109 (Directions below)
Cost: $20/$15 Academic, +$5 at the door (cash/check only)
Contact: http://sdbn.org/contact
For more information about the event: http://sdbn.org/may

Directions: From the North: South on Interstate 5, Exit Balboa Ave, Straight to 4th Traffic Light then left on Bunker Hill St. Building directly ahead 3 blks. From the South: North on Interstate 5, Exit Grand/ Garnet Ave, Straight to 3rd Traffic Light then right on Bunker Hill St. Building directly ahead 3 blks. Park on the street or in the structure just past Tango del Rey.

Today is the final day of reports from the 2010 meeting of the Society for Biomolecular Science in Phoenix. The meeting organizers have been excellent hosts and I’d like to express my sincerest thanks for their hospitality. After this, I have one last post containing all the interesting little observations and snippets of info that I deserve a mention, but didn’t fit into the larger topical posts. I also had some interesting discussions outside the official event that I’d love to continue online.

This morning’s session was on epigenetics and it probably won’t surprise my academic audience that pharma has, for the most part, passed on debating whether or not there is a histone code and has instead devoted itself to developing tools for writing, reading, and erasing epigenetic modifications. So what are they doing, then?

Histone Acetyltransferases (HATs) are the writers. They’ve developed high-throughput versions of an assay that detects acetylated lysine (the alphascreen assay) to a format which allows them to extend the usable range of the assay into the lower affinity region needed for screening and have found compounds from a compound library called LOPAC1280 which interfere in the assay.

To read the code, bromodomain containing proteins are used. There are 55 proteins that bind to acetylated lysines (sites of epigenetic modification), and because the proteins are actually quite different in their structure, they’re selective about which sites of epigenetic modification they preferentially attach themselves to. So the theory is that the selective binding will reveal the histone code. While it’s possible that up to 55 different patterns of modification can be discriminated by the various bromodomain binding patterns, it’s more likely that there will be significant overlap and the meaning, if any, of the different patterns isn’t yet known. Not to worry, though. Amy Quinn from the NIH Chemical Genomics Center and Tim Wigle from the UNC Integrative Center for Chemical Biology are screening compounds to see if they can disrupt the interaction of just one of these bromodomain proteins, which could then allow targeting of a specific gene with a epigenetic drug. Imagine for a moment, targeting the silenced tumor suppressors in a particular cancer subtype.

If the HATs are the writers of the code, the Histone Deacetylase Complex proteins (HDACs) are the erasers. From a drug discovery standpoint, this is an easier area to work in because you’re just looking for inhibitors of HDAC activity(of which there are already known cancer drugs). Dr. Wigle has done screening of a 100k compound library, finding 600 hits comprising 9 clusters of relevant activity and one cluster they’re not following up on. Looking at the LSD1 demethylase and its substrate the G9a peptide, his team found a class of compounds (UNC0224 and UNC0321) reaching down into the picomolar range in inhibitory strength (Ki). This is a great development, because existing HDAC inhibitors are quite toxic and if you have a compound with a low Ki, you can administer it at a lower dose and get the same level of inhibition with fewer or reduced side effects.

It appears it’s left up to academia to continue to decipher what the code means, but the tools for reading and writing have certainly improved.

At the afternoon session of the Society for Biomolecular Science in Phoenix, it’s all about epigenetics, the study of heritable changes that don’t involve changes in genetic sequence.  Epigenetics explains why identical twins turn out a little different and even clones won’t be exactly identical.

Manfred Jung from Freiberg kicked off the session giving an overview of recent developments in epigenetics and presented what would become the central theme of the afternoon: Here are some diseases which haven’t received the amount of attention they deserve, here are some enzymes and proteins that cause the diseases when there’s something wrong with them, here’s how to target those enzymes. Go get ‘em, boys!

Yes, it is, in fact, Lupus.

So it turns out that when DNA is modified by removal of the suppressive methylation pattern on the CD40L gene, it makes T cells hyperactive. This hyperactivity makes them start to react as if the body’s own native proteins are in fact foreign, leading to the myriad bizarre symptoms of systemic lupus erythematosus, or lupus.  Various things can cause this, everything from too much UV exposure to diet to simple aging.  The good news is that if you’re a guy, you’re 10 times less likely to have a problem, because one of your copies of CD40L will have been X-inactivated.  Actually, there’s good news for everyone.  Richardson showed that there’s a direct correlation between the level of demethylation of the gene and the severity of symptoms, leading to fairly obvious targets for drug discovery.  Other immunoinflammatory diseases – scleroderma and rheumatoid arthritis – also have an epigenetics angle via Fli1.

Smart Mice

Stephen Haggarty, the guy who gave a good stem cell talk earlier, also had something to show on epigenetics.  While it’s clear that some aspects of intelligence can be inherited, the genes involved are not well understood.  Using behavioral testing, Dr. Haggarty was able to show that the memory and mood of mice was affected by agents that altered the methylation status(i.e., the epigenetics) of genes involved in learning and memory.  Interestingly, inhibiting one protein, HDAC2, enhanced memory while inhibiting another enzyme, HDAC1, affected mood.  The problem is that this mechanism of altering gene expression by these epigenetic changes is a general mechanism that works in all cells, so if you administer a drug, you may well affect the level of repression or expression of the gene of interest, but you’re almost certainly going to be affecting a whole host of other processes as well.  Couple that with the poor brain penetration of these relatively large, poorly soluble, hydrophobic molecules and you can see where the challenges lie for drug discovery. Still, Dr. Haggarty did a great job outlining these challenges and since 18 of the 300 genes known to be involved in learning and memory are susceptible to an epigenetic etiology, I would expect pharma interest in this area to remain strong.

One final note: When I was working on GSK3beta inhibitors for modulation of stem cells in bone repair, people always asked me if I had any data on the bones from bipolar patients treated with lithium. It turns out that lithium is also a GSK3beta inhibitor.  I wonder what other effects the inhibitors he worked with have? Also, Dr. Jung has a new book out on epigenetics. Check it out.

I’m blogging this week from the 2010 Society for Biomolecular Science meeting with my colleague Mary Canady.  I’ll be covering the scientific sessions and sharing interesting developments in drug discovery and screening technologies. You can also follow the #SBS10 hashtag on twitter for updates.

On Tuesday, Steve Bryant from NIH gave a report on the increasing utility of the NIH Pubchem database for pharma drug screening programs.  The Pubchem database, named after Pubmed, the go-to resource for life science research abstracts, is an open repository for structure and activity information about molecules which have drug potential. The database is being developed under the Genbank model, wherein researchers are encouraged to upload the results of screening runs so that this information can be linked to in publications and accessible to others.

As a resource, Pubchem has seen strong adoption by researchers in industry and academia.  To give a quick snapshot, the number of contributing organizations have grown 5-fold over the past 5 years. 60000 users submit data daily, with the number unique substances now numbering around 70 million.  For each of these compounds, information on bioactivity is also being collected. Over 90 million activities are associated with these compounds, and the rate of increase of this bioassay data is on the steep part of the exponential growth curve, meaning that number I just wrote is already wrong. While the bioassay information currently requires direct upload, there are plans to derive additional data from published literature.

Following Steve’s report, Josh Bittker gave a brief summary of how the Broad Institute is using Pubchem. They have a reporting mandate as part of a grant and are developing a pipeline for automatically submitting machine readable assay results to Pubchem.  As part of this automatic reporting, there’s an automatic embargo on the data for 1 year.

Simone Graeber then gave an update on an EU effort along the lines of Pubchem.  They go a little further than just a database, developing their own library of 0.5 million compounds, with a 17000 compound subset derived from this covering much of the “activity space” of the larger set and more usable by smaller groups without the resources to screen the whole larger library.  You may be wondering, as someone in the audience did, why they’re developing their own database instead of submitting to Pubchem. Apparently they included some proprietary compounds in their library and there are legal issues complicating the assay result reporting.

I recently gave a talk at BioToasters, the local ‘biotech-focused’ Toastmasters chapter (they’re great by the way). As I started to prepare, I realized that I was going to an organization devoted to public speaking, and that I haven’t had training in ages. I started to think about why I’m so comfortable with public speaking, and realized that a bad situation a long time ago had made me fearless. I started thinking in more general terms, and how learning to be more fearless can benefit us all.

OK, here’s the story. Ten years ago I was a postdoc and gave a talk at an international virology meeting on a college campus. Back then, we used removable slides in carousels (you can now laugh if you’re over 40, and think about the classic Mad Men episode if you’re a fan). The college student that was running the projector dropped, DROPPED, the carousel and put the slides back in random order, without telling anyone. The talk was scheduled for 10 minutes. There was no time to put my slides back in order. I made the best of it, lived to tell about it, and pretty much fearless to this day in front of a ‘live audience’ (I spoke to 400 scientists in Japan once, no sweat!).

In preparing my talk for BioToasters, I began to think of other good things that have come from my bad experiences. Yes, I have sat in the ‘your position has been eliminated’ chair before. More than once… The result? Comprendia. A fantastic network. The SDBN. The OCBN. I was a bit squirmy when watching the movie ‘Up in the Air’ because George Clooney’s job is to terminate employees when a company doesn’t have the stomach to do it themselves. However, his comments in the movie to the recently jobless are spot on: ‘Anybody who ever built an empire, or changed the world, sat where you are now.’

Why does it take an extreme event to make us fearless? I started to think about Randy Pausch, the professor who inspired us all with his ‘Last Lecture‘ which he gave knowing that he had terminal cancer. The lecture is about achieving your wide-eyed childhood goals and dreams (e.g., being an astronaut, working at Disneyland). What’s surprising about Randy’s lecture, however, is that he realized some of his dreams before he knew he had cancer. What may be even more surprising is that he incorporated the attainment of his dreams into his highly technical work in computer science. Do you ever think about your dream job in biotech, and how you could land it and realize some of your dreams?

Yes, this is a lofty, inspirational post. But let me just tell you, that being a small business owner is no picnic, but I have never been as happy as I am now, doing exactly what I feel that I was meant to do. Everything is easier when you’re doing what you love. The things you do mean more to yourself and others.

I don’t suggest quitting your job, but I suggest that you…ask that you…IMPLORE that you to look for an outlet to pursue your dreams. Go for that job in the other department you’ve been eyeing. Start a blog (my answer to everything ;). Connect with other professionals who can help you get something started (and stay tuned for more resources from us to help). Even if you only have time to be the expert on your dream topic, do it. As Louis Pasteur once said, ‘Chance favors only the prepared mind.’ Get out there and prepare yourself, even if you don’t know what it’s for, yet.

If you’d like to see (and hear!) my BioToasters talk, visit http://sdbn.org/shades. You’ll have to sit through the story about the dropped slides again though ;) Oh, and I’m not fearless enough to skydive…sorry if you feel cheated based on the picture…

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When’s the last time you met, had a brief conversation and exchanged cards with 20 professionals in 60 minutes? As a scientist, do you find it difficult to talk your way through a crowd? When it comes to networking, do you have the need for speed? Then maybe speed networking is for you! At last week’s SDBN event our members had the opportunity to meet one potential customer, referral, collaborator, qualified candidate, possible employer after another. Here’s how it worked.

Prior to starting, we gave a brief presentation describing what the next hour was gong to look like. Tables were arranged into a large ‘U’ shape with chairs on each side (members facing each other, see photos on Flickr for more details).  A diagram explained that the people sitting on the outside of the ‘U’ were going to stay in their seats while those on the inside would move one seat to their right upon hearing a cue. The four basic guidelines were…

1. You have 3 minutes total – Why three? Two is too little and five… well that would be too much. We knew that participants would be fried after 60 minutes and we wanted everyone to connect with at least 20 other professionals so… we landed on 3 minutes.
2. Introduce yourself – Allow each person to introduce themselves before starting the conversation.
3. Refine your message – We asked the participants to think about what they wanted to walk away with that night. Was it a contact name at a company they are seeking employment with? A collaborative partner for a project they are working on? Maybe to increase their LinkedIn professional network? Whatever their goal, it needed to be the main message in these brief conversations.
4. Have fun – What’s the point if no one is having a good time!

With participants facing each other, guidelines in place and stopwatch in hand, we were ready to begin. “Your three minutes starts.. NOW!” The room was singing with energy and all 82 participants were engaged. As promised, at the end of the 3-minute cycle we prompted the room to “rotate”… 3 minutes later “rotate” and then again to “roooootate”… you get the picture.

One very short hour later we called the last “rotate” and asked participants to conclude their final conversation. So what ensued after the 60-minute speed networking session… more networking! Could it be that this type of exercise helps you feel more comfortable talking to strangers, communicating a business need and building your social capital? YES!

The post session comments have lead us to believe that this was a very successful event and one that our members would like to participate in again. What are your thoughts? Did you meet anyone that will help you further a professional goal? Did the overall event meet your expectations? How can we improve next time?

Special thanks to Fiona Godsman of Nexxus Scotland for the idea.

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We had a great time in 2008/2009 getting to know San Diego Biotech professionals, and we appreciate the feedback you gave us about 2010 events. Let’s kick off the new year by talking about you! Our January event will be focused on honing your networking and interviewing skills and helping you maximize your career potential in 2010.

The event will include speed networking (described below) along with talks from the experts at PROVEN Scientific Staffing and RxResearch Staffing titled ‘Understanding Behavioral Styles of Interviewers’ (more info) & ‘Outsourcing Trends’ (more info), respectively. These two topics offer valuable insights for any professional looking to further his/her career (we know that’s you!). Aerotek will also be on hand, and we’re going to have as many job listings and hiring managers as possible at the event. Also, check out the SDBN jobs page and subscribe to updates. There are still sponsorship options available, contact us if you’re interested.

SPEED NETWORKING: Here’s how it works – You will meet a handful of local professionals during a number of fast paced sessions. At the end of each session, participants will pair up with their next networking opportunity. In just a few minutes, participants will share business cards, history and offer new contacts with valuable information about their business. For example:

• Who do you know that might need their services?
• What contacts do you have in the area in which I am seeking a job?
• How might we do business together?

Come prepared to have fun and meet some new faces, and be sure to bring lots of business cards! (p.s. Vistaprint is a great source for free ones)

Of course, our venue has a great atmosphere which is always fun and conducive to meeting people, click here to register and we hope to see you there. Also, if you have suggestions for the event, feel free to leave them below, we love feedback.

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Event Details

Who: Biotechnology professionals in the greater San Diego area
What: San Diego Biotechnology Network’s January 19th Maximizing Your Career Potential in 2010
When: Tuesday, January 19th, 5:30-9:00 p.m.
Where: Tango Del Rey, 3567 Del Rey Street, San Diego 92109 (Directions below)
Cost: $20, including appetizers, cash bar ($15 for Academics) +$5 at door, cash/check only
Contact: http://sdbn.org/contact
For more information about the event: http://sdbn.org/january

Directions: From the North: South on Interstate 5, Exit Balboa Ave, Straight to 4th Traffic Light then left on Bunker Hill St. Building directly ahead 3 blks. From the South: North on Interstate 5, Exit Grand/ Garnet Ave, Straight to 3rd Traffic Light then right on Bunker Hill St. Building directly ahead 3 blks. Park on the street or in the structure just past Tango del Rey.

The results are in! We polled you to see what you want with the San Diego Biotechnology Network in 2010. The full results from 68 respondents can be seen here, and here’s a short summary:

1. Drug Discovery, Drug Development, Translational Research, Research Tools, Medical Devices were the top areas of interest. Although Stem Cells and Green/Clean Tech were not highly chosen, companies in these areas were suggested to be featured.
2. Companies you’d like to hear from: Illumina, Celgene, Ambrx, CareFusion, Sapphire Energy, Fate Therapeutics, Life Technologies
3. Charities you’re interested in: Disease areas, community outreach
4. You think the mix of science/networking is good, with a slight bias towards more networking.

To get an overview of the feedback, check out the tag cloud of the essay answers–we think it gives a nice flavor of what you’re looking for and what to expect in 2010. We were encouraged by your feedback and willingness to participate and will start giving you more ways to get involved soon. Leave more feedback below, we can’t get enough of it!

We’re working on the 2010 schedule and finding volunteers, partners and sponsors, now is the time to contact us to get involved!

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