A Note from Laura A. Briggs, Vice President, Research and Discovery

As I look back over the past year it strikes me that, in addition to a year of screening, it has also been a year of incredible change and significant growth and development of people. Although we have been screening since 2004, until 2009 we also had active molecular biology and cell biology groups. We worked on many parallel efforts, in addition to screening, and our screens were much less sophisticated and expensive. With the development of the hTERT RT-PCR screen came the ability to directly evaluate compounds for their ability to induce telomerase; something we, nor anyone else before us, had the ability to do in a high throughput manner. We found the golden tool, and this year we developed the means to reliably and efficiently apply it while dealing with the increased cost of the screening effort and the decreasing utility of our funds. We needed to develop a system that would maximize our output and reorganize our personnel into a drug discovery company.

Sierra Sciences has always been a very dynamic company, bending with the incoming and outgoing tides; not breaking. We recognize and accept that our work is about change. This year, many of us found ourselves in new positions, no longer on the bench as much as we'd like but thrust into new roles with new responsibilities. Our newly appointed project leaders, Penny Burke, Beril Karakas, October Pawlik, Jessica Wheeler and Jim Zhang accepted their roles and performed at top-notch levels with immense professionalism and high standards. Their efforts were directed by Lancer Brown, acting as the program director of the screening. Lancer accepted the role of program director for the entire screening process with professionalism, incredible efficiency and dedication. He has been the brightest star this year and I can honestly say we would not be where we are today without Lancer. No matter what I throw his way, he catches it and carries it to the finish line in ways I barely dreamed possible. Lancer was recently promoted to a Scientist 3 position and, although he is the program director of screening, we have officially given him the title and he is now the Program Director of Screening.

The principal shift we put into action this year was a Structure Activity Relationship (SAR) focused primary screen which lead us to the discovery of 33 distinct chemical families that induce the expression of the human telomerase protein component (hTERT). We accumulated 198,104 datapoints which round out the database used by Federico Gaeta, our medicinal chemist, to direct the SAR efforts. We screened 153,620 compounds without a sophisticated database/software system and tracked 515 compound plates of our 940 total, all tested out of sequence, in accordance with our SAR focused efforts. Hit compounds were then assayed in four additional screens including concentration response curves, toxicity and TRAP. We have conducted many assays and rejected few, while maintaining incredibly high standards.

These efforts lead us to the next phase of discovery, SAR and collaborations with Nanosyn and ChemDiv who supply us with specifically engineered and synthesized compounds. Our first custom SAR plate, tested at two concentrations, resulted in Hit rates of 54% at 33 uM and 27% at 3 uM.

Our efforts have attracted the attention of others as well. We routinely screen compounds sent to us or suggested to us by others, emphasizing our philosophy, we want to see aging cured, even if we are not the ones to do it. We have shared our lead compounds with other companies including Johnson&Johnson, BioTime, and numerous academic institutions, and established collaborative efforts with many. One such collaboration resulted in the submission of the article, An RNAi screen for TERT transcriptional regulators identifies HIF1alphs as critical for telomerase function in murine embryonic stem cells, coauthored with Dr. Richard Allsop, University of Hawaii.

We have grown together as a team. We do not always agree, but we are confident enough to voice our opinions and respect each other enough to listen. Our science is becoming more and more transparent in that we know our role in the effort, and are aware of the project as a whole. We are more focused, and that focus has allowed us to grow together.

We have many new faces this year-people who have made themselves instrumental to the effort. Randy Lee, perhaps the biggest footprint ever seen at Sierra Sciences, is working, with the help of Lancer Brown and Beril Karakas, to build the infrastructure required to organize and track the data. His enthusiasm and passion drive us, he has a huge heart for the work, he makes us think, and think, and think again. Matt Sturdivant, whose aptitude on the Biomek is phenomenal, is involved in robotics, compound management and inventory maintenance. Roxana Khalili, who has learned cell culture technique and experimental design quickly and efficiently, is an excellent worker, intelligent and competent. Our operations department grew as well. Paul Ciotti, Kelly Colby and Kimberly McPherran have added additional levels of organization and competence that have benefited the company.

Old faces continue to play important leadership roles in the company, particularly Mietek Piatyszek, Chris Foster, Hamid Mohammadpour, Jessica Wheeler, Jim Zhang, Terry McAfee, Ernie Vierra, Terry Carter, and Ted Rowe.

We have some old faces in new positions. Penny Burke, originally from the Molecular Biology group has become proficient in all aspects of the company. In addition to her many responsibilities, she is currently working on further optimization in the hTERT RT-PCR assay. Dan Hickman jumped into a new position working with Randy and Ted, and has now finished his first semester of computer training. As a result of Dan's efforts, under Randy's direction, we now have all of our compounds in one searchable file. This is something that has been needed for years, yet until this year we did not the in-house personnel to execute it. Beril Karakas moved off the bench and into data processing where she has demonstrated incredible leadership qualities and taught herself to become an Excel wizard when we really, really needed it. She has pulled more and more out of the spreadsheets, monitored our progress, processed the data and kept compounds moving through the system, often working in the middle of the night so the information is ready for work the next day. October Pawlik stepped into the position of overseeing the robotic efforts, a task she took on before she knew how to run the robot. Her organizational skills are amazing. She developed our checklists, inventory spreadsheets and cost analysis that have benefited us in so many ways. The dynamics between robotics and operations have lead to a seamless supply of product. All of these efforts are coordinated with extreme efficiency, all while maintaining a full load at UNR. We are looking forward to the day she graduates and we can tap into more of her creative fire.

Many of us have learned to run the robot under Jim Zhang's direction: October, Matt, Beril, Penny, Katie, Richard and Lancer. October, Matt, Beril and Lancer have also learned to program and maintain the robot. Many have played critical supportive roles, particularly Katie Quarisa, Richard Cao and Roxana Khalili. Your dedication and positive attitudes are greatly appreciated.

And the science would not carry on without the operations group, headed by Kela Guiles. Thank you Kela, Ernie, Terry, Jon Cornell, Teo and Ted for all the support and hard work. This year has seen a more seamless interface between science and operations. Thank you. Ernie has been a shining star this year. With his help we have systems in place to keep the flow of materials coming. We really appreciate his patience and dedication to his job.

We've grown a lot; we have a ways to go. I don't know exactly what the next year will hold for us but looking back on the past year, our team has much to be proud of. We have come together as an efficient and dedicated team and accomplished much. Federico has never failed, and he doesn't intend to make Sierra Sciences his first. Neither do we.

I'd like to thank Bill Andrews and Richard Offerdahl and Pierluigi Zappacosta for the opportunity they provide for us to be a part of this effort. Without you there wouldn't be a Sierra Sciences. Thank you for your leadership, motivation and support.

I want to finish by sharing an email sent by Dr. Mike West, President and CEO of BioTime, which I think clearly portrays the reason for great pride. This epitomizes my perception of the team here. Mike West writes, "I want to express a very large thank you from the BTIM team for letting us test your compounds on our stem cell lines. We did see some interesting data, but what is most impressive to me is the professionalism and hard-working ethic displayed by your team. We just got some data sent just now, and your group has obviously been in the lab way beyond normal business hours. I rarely see such exacting and assiduous work".

So reflections on 2009 are filled with gratitude and pride for the efforts of everyone at Sierra Sciences. Thank you and cheers to 2010. Keep up the great work!

Laura A. Briggs
Vice President, Research and Discovery, Sierra Sciences LLC

SIERRA SCIENCES NEWS

Horizon is a popular and long-running science program which airs a one-hour TV documentary each week on a scientific topic, and has a viewership of 2.5 to 3 million people each week, occasionally peaking as high as 5 million.

Of the 60-minute program on aging, approximately ten minutes are expected to be devoted to the segment about Dr. Andrews and Sierra Sciences. The program will first air exclusively in the UK, but is expected to be released in the United States later in 2010.

Dr. Andrews will be revisiting New York City next month following his presentations at the Roger Smith Hotel this past fall. If you weren't able to make it to those presentations, now's your chance! As before, Dr. Andrews will be speaking on telomere biology and finding a cure for aging through activation of telomerase.

The Roger Smith Hotel is only about five minutes away from Grand Central Station, at 501 Lexington Avenue, NY 10017. There is still seating available, but slots are limited. If you are interested in attending this talk, please e-mail Gerard McKeon at gerard@blacktiemagazine.com.

Next month, Drs. Andrews and Briggs, along with Lancer Brown, a senior scientist at Sierra Sciences, will attend the Keystone Symposia conference "New Insights into Healthspan and Diseases of Aging: From Molecular to Functional Senescence."

This focus of this conference is on "the molecular and cellular mechanisms by which tissue and organ function deteriorate and homeostasis fails." The conference has booked 48 leading experts on the science of aging and senescence into speaking roles, and is expected to be attended by hundreds of scientists.

Over the last several years, there has been a noticeable upswing in the number of scientific conferences being held to collaborate on approaches to defeat the aging process. Although the goal of curing aging is still sometimes perceived as existing on the fringe of mainstream science, we're encouraged by the existence of these conferences, and excited to be taking part in this one.

ANTI-AGING NEWS

The idea that Alzheimer's disease is a condition of old age may seem like an obvious one. After all, it's a disease that predominantly strikes the elderly. However, the hypothesis that Alzheimer's is caused by old age, rather than merely associated with it, is one that has had little evidentiary support in the past.

This had led us to ask the troubling hypothetical question: when we do succeed in substantially extending human lifespan through intervention into telomere length, will we still have Alzheimer's disease to contend with? Will beta amyloid plaques continue to build up in the brain even if the body isn't aging? Would curing aging have any real meaning if people ended up with dementia despite having fit, youthful bodies?

However, encouraging new research has been published this month suggesting that Alzheimer's may be caused by aging itself. Researchers at the Salk Institute for Biological Studies found that when they modulated genes regulating the IGF-1 signaling pathway in mice, a technique already proven to extend the lifespans of mice by up to 35%, the incidence of Alzheimer's in those mice significantly decreased.

There is still an enormous amount of research that needs to be done on the interplay between aging and the human brain, but these preliminary findings are certainly encouraging.

The paper, "Delaying the aging process against Alzheimer's disease" by Salk Institute was published on December 11, 2009 in ScienceDaily.

More information on this research can be found at: http://www.sciencedaily.com/ releases/2009/12/091210125542.htm.

Sierra Sciences has a Facebook page that we use to keep our supporters up to date on the progress of our company. If you have a Facebook profile, you can receive these updates by "becoming a fan" of the company. Just visit this address and click "Become a Fan".

http://www.facebook.com/home.php?#/pages/Sierra-Sciences/130839216671?ref=nf

Hope to see you there!

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