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Lab News -- October 7, 2011

October 7, 2011

LabNews - October 7, 2011PDF (1.8 Mb)

Anthrax attacks - 10 years later: Bioterror attack on US soil helped accelerate Sandia’s move into biotech and biosecurity arenas

By Renee Deger

The nation was still reeling from the 9/11 attacks when the first of what are called simply the anthrax letters arrived at the offices of two media outlets. The letters were postmarked Sept. 18, 2001; three weeks later, and four days after the first death, two more letters were posted, headed for Senate offices. 

ANTICIPATING THREATS — In this 1999 photo, Sandia researcher Mark Tucker (6632)examines two petri dishes: one with a simulant of anthrax growing in it (left), the other treated with the decontaminating formulation developed at Sandia (right). (Photo by Randy Montoya)

Perhaps because the range of important dates connected to the anthrax letters stretched over a period of weeks and because the first was so soon after the 9/11 attacks, the events are often linked in our collective thinking. And at first, many feared they were. In the first days after Sept. 11, 2001, before US authorities could determine whether the 9/11 attacks were a single assault or a beginning, the fear of a biological attack loomed large. Whether an airborne dispersal of some dangerous pathogen or an assault on facilities that housed them, biological attacks were a big part of the conversation as US authorities tried to anticipate any and all kinds of attacks and were looking to Sandia for guidance.

Almost immediately, Senior Manager Duane Lindner (8120) was asked to investigate how well Sandia’s environmental detection tools, developed in the late 1990s, would operate in a plume of concrete dust should they be needed right away at ground zero. Still another team was examining what it would take to protect federal facilities near the World Trade Center crash site if a biological or chemical release were imminent. And Senior Manager Ren Salerno (6820), who at the time was a technical staff member, flew to Washington the day before the first letters were posted to discuss with US Department of Agriculture officials the security of the government’s infectious disease research labs.

The discovery of the first anthrax letters – so soon after the terrorist attacks – pitched fear into frenzy as worst fears were realized, again in a way that was before unimaginable. Within weeks, Sandia was mobilized on multiple fronts in the biological sphere. Tapping Sandia’s longtime strengths in physical security and technology development, these new programs solidified the foundation for Sandia’s then-nascent biological programs that today are recognized globally and are poised for significant growth. 

 “Suddenly, this was not a theoretical event, it was not a hypothetical, it was not something that would only happen somewhere else,” Duane says. “We had individuals dying from exposure to anthrax. Just the stark reality of this was very much driven home. And it highly motivated everyone involved. “

Foam marks the beginning

In 1995, the Aum Shinrikyo cult in Japan killed 13 people by releasing sarin gas into the Tokyo subways. It was a wake-up call for counterterrorism experts that such nontraditional weapons in the hands of fringe organizations could exact a high toll. US legislation that passed the following year authorized DOE to establish the Chemical and Biological Nonproliferation program, and Sandia was tasked with developing detection and decontamination technologies. One result of this early drive was the MicroChemLab, a handheld detection device for sampling air, water, and surfaces. Another was the now-famous Sandia Decon Foam, which was used to decontaminate a large number of the buildings in Washington that had been contaminated with anthrax. 

“Even as the buildings were being evacuated in Washington, we were asked how quickly we could get people on the ground to oversee the decontamination of contaminated facilities,” Duane says.

Also in the late 1990s, Sandia conducted the Defense of Cities study on behalf of DOE and DoD’s Defense Threat Reduction Agency (DTRA). The study established a framework for evaluating and utilizing detection technologies to protect large urban areas in the event of a biological attack. Based in part on that analysis, the government decided to immediately deploy the BASIS system – a biodetection system under development at Lawrence Livermore and Los Alamos national laboratories – in the Washington, D.C., area. In the following months, national efforts to define and evaluate urban bio warning and response systems intensified. With DTRA funding, Sandia, Lawrence Livermore, and Los Alamos established the Albuquerque Test Bed. Environmental sensors and medical monitoring systems were deployed throughout the city to evaluate operational issues connected to such systems.

At the same time, Sandia was asked by the Executive Office of the President to evaluate other proposed biodetection systems for potential national deployment. That work helped define what has become BioWatch, which is now deployed in more than 30 cities nationwide. Today, Sandia operates the BioWatch Indoor Reachback Center and is charged with responding 24/7 should there be a positive from those parts of the system that are deployed in key facilities around the nation. Sandia also is responsible for defining technical requirements and standards for new generations of the BioWatch equipment and for developing the Concepts of Operations (ConOPs) for responding to a positive detection event.

The emergency use of the Sandia Decon Foam also prompted similar long-term projects that required developing a systems-level solution to decontamination and restoration. “We had a specific technology that was very, very effective. We knew that,” Duane says. “It was when we actually took it into the field, when we took it to Washington to start decontaminating facilities that suddenly we saw the whole system problem.

 “We had to rethink what we needed to do,” Duane says. “You have to know where the contamination is, you have to do an assessment. Then you decontaminate. Following decontamination, you have to go back in and do clearance sampling. You have to ensure the decontamination activity has been effective, that the place is now safe to occupy. So the technology was very important, it was critical, but ultimately it was insufficient.”

The realization of all the factors that decontamination and restoration entails has turned into a number of multiyear, systems-level projects that brought together teams of professionals from a variety of disciplines to develop and demonstrate scenarios. The most recent program to be completed, the Interagency Biological Restoration Demonstration (IBRD), wrapped up in December but is serving as a precursor to other, more expansive projects just getting under way.

Going global

For Ren, the anthrax letters cemented multiple projects, which he had proposed several times over the prior year but failed to get backing. They have since led to Sandia’s global activities in biological threat reduction. Within weeks of the anthrax letters, biologists and physical security experts were tasked to assess and secure all of the USDA’s biosafety level three (BSL3) infectious disease research laboratories by that December.

 “We were road warriors — traveling constantly,” Ren says. Over the following two years, the Sandians then secured another dozen or so US bioscience labs operated by different agencies.

The work stemmed from a conference Sandia staged in 2000 for both Russian and US laboratories on biosecurity. It was a project Ren got under way upon his arrival at Sandia the prior year, when he was tasked to figure out what role Sandia could play in the area of biological threats. It was an interest Ren had developed while working for the United Nations. Seeing Sandia’s long history in physical security, developed around securing nuclear weapons, Ren targeted bioscience laboratory security.

 “I was making the rounds, but didn’t get any attention outside the immediate circle of laboratory specialists,” Ren says. But when the 9/11 attacks occurred and Washington needed an expert, the call went out to Sandia. “Because I had thought about it, we became the experts.”

In the process of securing US laboratories, Ren and his team began developing a methodology for laboratory safeguards and security.  The USDA contracted Sandia to write an early version of what Ren and manager Jennifer Gaudioso (6822) later published as the “Laboratory Biosecurity Handbook,” which has become the industry standard.

 “We had requests to do a lot more laboratories, but instead of securing individual facilities, we focused on creating a methodology that other labs could use,” Ren says. “Once we decided the US was in pretty good shape, we realized the same vigilance and knowledge were lacking internationally and we turned our attention overseas.”

The international contingent of what is now known as Sandia’s Countering Biological Threats programs, the International Biological Threat Reduction program, is now active in more than 40 countries worldwide, securing laboratories, training laboratory and public health professionals, and developing innovative programs to promote the safe and responsible use of dual-use technologies, materials, and expertise.

Biosciences took shape

In the late 1990s, as the work in detection and decontamination got under way, Mim John, at one time the California site VP who is now retired, asked her managers to examine how Sandia could contribute in the area of biological threats. Director Len Napolitano (8900) took that on, leading a small committee that researched the space and developed recommendations for Sandia’s role.

In 1999, Sandia’s executive leadership gave the go-ahead to expand Sandia’s bio programs. To seed the new specialties, areas of biosciences around biodefense were targeted for a succession of Laboratory-Directed Research and Development Grand Challenges that continue today. 

 “This was the first area of fundamental science that did not have a tie back directly to our nuclear mission, but Sandia was transitioning from a nuclear lab to a national security lab,” Len says. “It helped build competencies for other national security problems we should be addressing. This was a new class of threat. We were looking for bigger tanks or faster planes and they were mailing little envelopes.”

In the years that followed, Sandia specialists, tasked by the FBI, determined the form of bacillus anthracis contained in those letters was not a weaponized form. According to a press release Sandia issued in 2008 about the research, which was conducted from 2002-2008, “the possibility of a weaponized form was of great concern to investigators. This information was crucial in ruling out state-sponsored terrorism.” 

Still, the letters, especially coming so soon after the 9/11 attacks, were a flashpoint for researchers and for funding agencies. Sandians began to put together more projects, and were able to secure funding to help solidify the Labs’ foundation in bioscience.

21st century technology

Sandia’s biological-related programs, which are part of the International, Homeland, and Nuclear Security Strategic Management Unit (IHNS SMU), now comprise the international and diagnostic areas but also delve into the fundamental biological and chemical processes of both pathogens and human hosts to identify and develop treatments, forensic frameworks, and other countermeasures, including presymptomatic diagnostic profiles and devices. Sandia also has an extensive biofuels program in the Energy, Climate, and Infrastructure SMU. 

 “If we were to be a broad-based national security lab, able to help the US respond to all sorts of unusual threats, then we needed to consider biology and the anthrax letters served to amplify the need for biological expertise,” says John Vitko, who was then-director of 8100 and is now retired.

John was placed at the helm of Sandia’s fledgling biodefense programs. He then was tapped to help draft the blueprint for the Department of Homeland Security Science and Technology Directorate when that organization was established. He then went on assignment to DHS (under an Interagency Personnel Assignment) to head their Chemical and Biological Defense Directorate. 

 “The 21st century belongs to biology,” John says. “And if you’re going to be a 21st century laboratory, you need to be well-versed in the technologies that drive the issues.” - Renee Deger

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Virus-like particles could combat cancer and bioweapons

By Patti Koning

For nearly 70 years, chemotherapy has been one of the primary methods used to treat cancer and has saved or prolonged countless lives. Anyone who has personal experience with cancer can attest, however, that chemotherapy drugs have many well-known and potentially fatal side effects. Cancer researchers have, therefore, been trying for more than three decades to direct therapeutics to cancer cells to treat the disease without killing normal cells and tissues. Unfortunately, little progress has been made.   

Tiny but powerful — Virus-like particles that deliver therapeutics to cancer cells, developed by Sandia Harry S. Truman Fellow Carlee Ashley in collaboration with the UNM cancer center, could also be a powerful tool to combat a bioweapon attack. (Photo by Randy Montoya)

“Cancer cells are more similar to normal cells than they are different,” says Sandia researcher and Harry S. Truman Fellow Carlee Ashley (8621). “This makes targeted drug delivery really challenging because it’s difficult to identify targeting molecules that will bind to cancer but not to anything else.”

Carlee, in collaboration with Jeff Brinker (1002) and the University of New Mexico (UNM) Cancer Center, may have found the solution in virus-like particles (VLPs), protein nanoparticles derived from naturally occurring viruses or bacteriophages (viruses that infect bacteria). See the April 22, 2011, issue of Sandia Lab News for a related story on this research.

Cell-specific delivery of diverse cargos

In a paper titled, “Cell-specific delivery of diverse cargos by bacteriophage MS2 virus-like particles,” featured on the cover of the July 26 issue of ACS Nano, Carlee and her co-authors reported the use of 30-nm VLPs, derived from MS2 bacteriophage, to selectively deliver chemotherapy drugs as well as new-generation therapeutics like small interfering RNA (siRNA) and protein toxins to human hepatocelullar carcinoma (HCC), a form of liver cancer. In addition, they delivered quantum dots used for imaging and diagnosis of early-stage cancer.

“We observed highly specific delivery of these therapeutic molecules to liver cancer cells as opposed to control cells, like normal liver cells, cells that line the blood vessels, and several types of immune cells,” Carlee says. “The end result was that we only need two or three of these VLPs to be taken up by a cancer cell in order to kill it.”

To create the tiny but powerful VLPs, the researchers remove the bacteriophage RNA that normally allows it to replicate inside bacteria and replace it with chemotherapeutic drugs or anything else they want to deliver to cancer cells. They then modify the VLP shell, which is composed of protein, with peptides that bind to cancer cells and promote uptake of drug-loaded VLPs.

“The main advantage of MS2 VLPs, in comparison with other VLP delivery systems, is that we can encapsulate drugs in the interior volume rather than conjugating them to the exterior surface of the particle,” explains Carlee. “Then we use well-established genetic manipulation techniques to display targeting peptides on the VLP surface. The end result is that we can kill cancer with almost absolute specificity.”

Identifying peptide sequences

Identifying peptide sequences that bind to cancer cells but not to anything else is one of the biggest challenges in the field of targeted drug delivery. The molecules expressed by cancer can vary from patient to patient and as the disease progresses from benign to metastatic states, further complicating the problem.

To address this issue, David Peabody, professor of molecular genetics and microbiology at UNM and corresponding author of the ACS Nano article, has created a library of 10 billion VLPs, each displaying a randomized peptide on its surface. “We don’t need to know the peptide sequence that binds to a specific cancer cell. We can simply expose the library to a cell of interest and see which VLPs bind to it,” Carlee explains. “This method enables easy identification of targeting peptides when there are no known sequences that bind to a particular type of cancer.”

A very versatile system

Once VLPs with high affinity targeting peptides are identified, researchers can then use the exact same particles for drug delivery. “Our particles are the only ones developed to date that can do both,” she says. “This strategy can be used to rapidly identify peptides that target primary and metastatic tumor cells, as well as peptides specific for an individual patient. It’s a very versatile system.”

With Oscar Negrete (8621), Carlee is working on a related project supporting Sandia’s biodefense work that seeks to use VLPs to target cells infected with Nipah virus, a bio-safety level (BSL) 4 select agent with potential for use as a weapon by our adversaries. The idea, she says, is to deliver siRNA to Nipah-infected cells to silence the expression of viral proteins that enable viral replication.

In a parallel project, they are developing VLPs to vaccinate against Nipah and related viruses. “These two projects give us a very comprehensive way to treat viral infections using a single particle. Using VLPs, we can potentially prevent an infection, as well as treat an infection that has already occurred,” she says. 

“The hepatocellular carcinoma and Nipah virus projects provide a very powerful example, demonstrating how advances developed in the fight against cancer can also be applied to Sandia’s important national security effort to counter biological threats,” adds Glenn Kubiak, director of Sandia’s Biological and Materials Sciences Center 8600.

Carlee and the UNM team are now working toward Federal Drug Administration approval of MS2 VLPs as delivery vehicles, which is a very long road. They hope to start the first phase of human clinical trials at the UNM Cancer Center within five years. -- Patti Koning

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White House Business Council Roundtable on Water, meeting at Sandia, advances possible roadmap of water standards and technologies

By Neal Singera>

New Mexicans think of water problems in terms of scarcity and drought.  But a collection of 21 experts convened, at the behest of the White House, at Sandia in late September showed that these problems were only, so to speak, the trunk of the elephant.

Not just scarcity or drought — The White House-sponsored roundtable water meeting at Sandia allowed experts from around the country and a variety of disciplines to discuss elements of a possible roadmap to guide the federal government in creating “smart-water” communities. For more about the conference, see page 5. (Photo by Randy Montoya)

Frank discussions among normally stovepiped  participants — ranging from high-tech and manufacturing industries to water associations, universities, and local and state government water boards — may stimulate preparation of a roadmap that could guide the federal government in supporting sustainable, “smart-water” communities.

Just the term “smart water” drew fire from several participants. Analogizing it to “smart power grid” metering, Lester Snow from the California Water Service Group said, “The energy-water analogy is great when looked at from 50,000 feet [up], but breaks down when you look at the subject more closely.

“Water rights are much more prevalent than energy rights. Water is cheap and it’s private property,” he said. “This leads to the ‘classic tragedy of the commons.’

That is, individuals pump the water, but if something happens, it’s the community’s problem.”

Another participant called the nation’s water supplies “a fragmented system with a thousand variations.”

A water resources engineer said that while many factors played a role, “the gorilla in the room is social/economic issues: Who owns the water, what they can do with it, and how it can be made available to new uses.”

Others mentioned the value that could be added by new technologies, if developed and purchased, in tracking water flow and purity from reservoir to tap. Also of value would be weather forecasting and satellite observations that determine and predict the current and future state of mountain snow banks.

Several participants mentioned the enormous amount of water — perhaps as much as 40 percent — leaked from reservoir to tap in many cities from cracks in huge underground pipes. Laid fifty to seventy-five years ago, some have exceeded their expected lifetimes.  “Mayors have their eyes above ground for votes,” one participant said. “What’s below the ground is easily ignored unless there’s a disaster.”

The roundtable discussion energized Sandia VP 8000 Rick Stulen, who co-hosted the meeting with National Institute of Standards (NIST) Director Pat Gallagher.  

“The place of a national laboratory is to bring people together to work out solutions to national problems,” said Rick after the meeting. “Sandia’s interest is water security, but that resonates with other water problems.”

Expanding the discussion of wastewater treatment and fresh water supply into international terms, Christine Landavazo, a staffer for Senator Jeff Bingaman, said that she had been in discussions with a number of  Israeli companies that have been producing innovations for their water-starved nation for the last 50 years.

“They’re amazed at how much water our systems waste,” she said. Better technologies are out there, she said, but companies need national demand to make marketing them here feasible.

Gallagher spelled out the roles of relevant federal agencies like this: the Environmental Protection Agency regulates water use; DOE is interested in water but only for energy; and NIST could serve as a kind of go-between for government and industry.

Said Gallagher, “The normal way things happen in government is that a bunch of feds get together and say, ‘Wouldn’t it be great if . . . ?’ They dangle some money for proposals and people run around with their hair on fire coming up with ideas. But wouldn’t it be great if people came together and said, on their own, ‘We could catalyze the following things.’ You have the opportunity to be the North Star, to help form the road to travel.

“Regulations are inevitable. If we don’t set our own, international standards will be imposed and we’ll be operating reactively. For NIST to be helpful, we need an organized voice from your community. A roadmap is the result of companies and individuals working together. We have the vehicle to help the group form and support it, but you’re going to need to be the driver.”

A closed blog available to participants and certain meeting observers will enable participants to continue their discussion from afar.

Preparations for the meeting were achieved by a planning committee led by Rob Leland. Helping were Sandhya Rajan, John Merson, Erick Ridley, Bob Hwang, Tara Camacho-Lopez, and others. -- Neal Singer

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