About

Scientific consultant for biomedical enterprises, advising on both technical issues and business development, after retirement from Government service. Specific areas of expertise include infectious disease and biodefense with a focus on novel solutions for detection, treatment and prevention of drug-resistant bacterial infections (e.g., diagnostics, monoclonal antibodies, bacteriophage, antimicrobial peptides). Currently serving on scientific advisory board of CARB-X and supporting commercial development programs in viral diagnostics and therapies (SARS-CoV-2 virus), phage therapy and food sciences.

Experience

• Independent Scientific Consultant

  • • Consultant : ( Jun 2018 – Present [Oct 2021] / 3 yrs 5 mos / Location : Potomac, MD )

      1. • Scientific consultant for biomedical enterprises, advising on both technical issues and business development. Specific areas of expertise include infectious disease and biodefense strategy.

• National Institutes of Health

  • • Senior Scientific Officer ( Mar 2013 – Jun 2018 / 5 yrs 4 mos / Location : Bethesda, MD )

      1. • Concept Acceleration Program with focus on Platform Technologies and Diagnostics, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Disease. Supported efforts to improve preparedness for emerging and re-emerging disease, antibiotic resistance and vector-borne diseases. Member of PHEMCE working groups and Scientific Advisory Board of CARB-X.

• US Department of Defense ( Employment length : 3 yrs 11 mos )

  • • Chief Scientific Officer ( Jul 2012 – Mar 2013 / 9 mos / Location : Fort Belvoir, VA )

      1. • Chief Scientific Officer, Transformational Medical Technologies, Joint Program Executive Office. Advanced development of medical countermeasures for biological threats and emerging diseases (Ebola, high consequence influenza, anthrax and other bacterial threat agents).

    • Chief Medical Sciences Officer ( Mar 2011 – Jun 2012 / 1 yr 4 mos / Location : Fort Belvoir, VA )

      1. • Chief Medical Sciences Officer, Chemical and Biological Directorate, Defense Threat Reduction Agency. Research and development of medical countermeasures for chemical and biological threats.

    • Scientific Director ( May 2009 – Mar 2011 / 1 yr 11 mos / Location : Fort Belvoir, VA )

      1. • Scientific Director, Transformational Medical Technologies Initiative, Defense Threat Reduction Agency. Oversight of major scientific initiatives to detect and counter biological threat agents, including those that are engineered. Served on Scientific Advisory Group of Department of Homeland Security, National Biosurveillance Advisory Subcommittee of the Centers for Disease Control and the Integrated Portfolio Advisory Committee for CBRN Medical Countermeasures.

• Veritas, Inc. (biotechnology)

  • • President and CEO ( Dec 1994 – May 2009 / 14 yrs 6 mos / Location : Rockville, MD )

      1. • Biotechnology research and development company specializing in genomics and protein engineering. Programs in biosensors for biological threat agents and vaccine development.

• Human Genome Sciences

  • • Director, Cell Biology ( Sep 1993 – Dec 1994 / 1 yr 4 mos / Location : Rockville, MD )

      1. • Gene discovery and product development related to human hematopoiesis and regenerative medicine.

• National Institutes of Health ( Total Duration: 16 yrs 2 mos )

  • • Chief, Section on Immunology ( Sep 1987 – Sep 1993 / 6 yrs 1 mo / Location : Rockville, MD )

      1. • Section on Immunology, Laboratory of Physiologic and Pharmacologic Studies, National Institute on Alcohol Abuse and Alcoholism. Research program on intracellular Ca2+ dependent signaling mechanisms that regulate neuronal and immune responses (calcineurin, cyclic nucleotide phosphodiesterases)

    • Research Pharmacologist ( Aug 1977 – Sep 1987 / 10 yrs 2 mos / Location : Bethesda, MD )

      1. • Intramural scientist (tenured), Laboratory of Cellular Metabolism, National Heart, Lung and Blood Institute. Biochemistry and molecular biology of enzymes involved in Ca2+ dependent intracellular signaling events (protein phosphorylation and cyclic nucleotides).

EDUCATION

• Stanford University School of Medicine

  • • Doctor of Philosophy (PhD) / Pharmacology / 1972 – 1977

• Stanford University

  • • Bachelor of Science (BS) / Biological Sciences / 1968 – 1972

    • Activities and Societies: Member, LSJUMB (1968-1972). Stanford in Italy (Firenze), 1970.

You'll find Dr. Randall L. Kincaid, a former National Institutes of Health research chief, in a converted Rockville warehouse toiling away on a scientific frontier called protein expression.

The erudite and affable Dr. Kincaid gave up his well-equipped high-tech laboratory at the federal government's National Institutes of Health in Bethesda -- not to mention the prestige and salary of working at the sprawling life sciences hub -- for these stripped-down quarters in an industrial park.

Why? He wanted to move into private industry and launch his own biotechnology company, Veritas Inc.

Today, the company's employee roster has all of two people -- Dr. Kincaid and another scientist he just hired. And Veritas' lab equipment is of the hand-me-down variety. But the scientist and the entrepreneur in Dr. Kincaid are ever hopeful.

He's not the first, nor likely the last, NIH scientist to start a biotechnology company in Maryland. And many, it turns out, have become success stories.

In fact, some experts say that without NIH's presence in Maryland, the industry, which is trying to unlock nature's secrets to treat and cure diseases, improve crop yields and control environmental contamination, might be a shadow of what it is today in the Free State.

"NIH is the engine that's driving biotechnology in Maryland -- indeed in the country," said Dr. Michael M. Gottesman, the deputy director for research at the NIH campus, who has studied NIH's effect on Maryland's biotechnology industry.

By launching Veritas, Dr. Kincaid joined a list of prestigious NIH scientists and high-level managers who have left the world-class institution to either start their own firm or join forces with others to launch a biotechnology company in Maryland.

And there are even more scientists and managers -- no one's sure how many exactly -- who have been hired from NIH by Maryland biotechnology companies.

Drs. Scott Koenig and Robert Hohman, for example.

Dr. Koenig was lured to Rockville-based MedImmune Inc. and is now director of research at the vaccine and drug developer.

Dr. Hohman, a former NIH scientist, is vice president for research and development at Oncor Inc., a Gaithersburg-based company developing genetic tests.

The experience of working at NIH before launching a biotechnology company can be pivotal, say some who have done so.

"What you learn working at NIH, in the larger sense, is the absolute breadth of possibilities available in the world of biotechnology," said Dr. Kincaid, whose protein expression work could one day draw clients from the bio-pharmaceuticals and biotechnology industries working on gene therapy.

The field of protein expression involves seeding bacteria with DNA so it will produce, or "express," in large amounts the protein for which the DNA is coded. The field is considered promising because it may offer a way to mass produce therapeutic genes.

"If I had worked at an institution that had a narrower view of what's possible, I doubt I would have thought that starting my own company and seeing it become a success was possible," said Dr. Kincaid.

As a result of the ripple effect on Maryland's economy from scientists such as Dr. Kincaid spinning out of NIH, some biotechnology experts believe that the institution has emerged as the single most important "fuel" driving Maryland's growing biotechnology industry, which generates an estimated 13,000 jobs in the state.

By the end of the decade, as more products are approved for marketing, that could rise to 20,000, predict some experts, including Dr. Gottesman.

That would make the industry a larger employer than NIH, the world's largest center for life-science research with 16,000 employees.

No one is certain just how many people have left NIH to start or help launch one of the 176 biotechnology companies in the state, said Dr. Gottesman. But he's documented at least 10 companies.

Marsha Schachtel, director of technology development for the state, said that historically the vehicle that has helped scientists with the entrepreneurial urge leave NIH and start a new venture is what's known as the CRADA -- cooperative research and development agreement. Under that deal, NIH pays a scientists to conduct research projects NIH needs completed.

"If you look at the largest biotech companies in Maryland, most are NIH CRADA babies," said Ms. Schachtel.

These ventures include what many consider the first biotechnology company in Maryland, Bethesda Research Laboratories (BRL), which was founded by NIH scientists in the late 1970s thanks to a research agreement with NIH. The company evolved to become Life Technologies Inc., a $270 million publicly held concern now based in Gaithersburg.

One of the top executives of BRL, M. James Barrett, a former NIH director, helped launch another company, Gaithersburg-based Genetic Therapy Inc. in 1986. Dr. Barrett is now Genetic Therapy's CEO and is often introduced as "the father of biotechnology in Maryland."

His company, which is among a small group of pioneers in the United States trying to develop genetic therapies for diseases such as cystic fibrosis, AIDS and cancer, now employs more than 150. Its field of research is so promising that Swiss pharmaceutical giant Sandoz AG bought the company last year for nearly $300 million.

Human Genome Sciences Inc. of Rockville is another Maryland-based company founded as a result of NIH brain power and now exploring how gene manipulation might be used to treat diseases. It has struck several research alliances with major food and drug developers and has seen its stock price more than triple since last March.

Human Genome was launched in Maryland in 1992 to develop for commercialization the discoveries of Dr. Craig Venter, a former NIH scientist who left the institution to start the Institute for Genomic Research, a Gaithersburg-based nonprofit corporation. It's now funded by Human Genome.

Perhaps the most notable NIH researcher to leave the institution to start a new venture in Maryland to start a new venture in Maryland is Dr. Robert C. Gallo, the former director of the tumor cell biology laboratory at NIH's National Cancer Institute in Bethesda.

Dr. Gallo, who has a worldwide reputation for his work on AIDS, is setting up a new laboratory at the University of Maryland's newly renovated biomedical center in Baltimore, where he will attempt to develop disease treatments that can be commercialized.

William Haseltine, Human Genome's founder and chief executive officer, said that aside from having access to top NIH scientists such as Drs. Gallo and Venter, biotechnology companies can easily find qualified lab technicians and other workers in the region to hire.

A key reason: the rich pool of people working in the life sciences at NIH.

"NIH is the major attraction for a biotechnology company to locate in Maryland," said Dr. Haseltine.

A majority of those companies are located within 30 minutes of NIH, most of them concentrated in Montgomery County's high-tech corridor that runs from Bethesda to Gaithersburg along Interstate 270.

Also, noted Dr. Haseltine, his company has found that its proximity to the NIH's National Library of Medicine and its huge pool of experts is a powerful magnet for landing top scientific talent from across the country.

Dr. Gottesman and other experts venture to say that NIH's influence on the state's biotechnology industry is so powerful that if the federal government were to move NIH out of Maryland, the industry itself might follow.

In other states with high concentrations of biotechnology companies, such as Massachusetts and California, the industry is tied more to high profile universities such as Harvard and Stanford, rather than to a government institution.

To get an idea of just what effect NIH has on the state economy, economists studied the issue last year, though the report did not look at companies started with NIH brainpower. Still, the bottom line: NIH's effect on Maryland is huge.

The 1995 study by the state Department of Business and Economic Development found that the institution, which has an annual budget of more than $11 billion, pumps at least $1.7 billion, or about 17 percent of its total budget, into the Maryland economy.

That $1.7 billion -- 30 times more than what the commercial fishing industry generates in the state -- includes research grants, equipment purchases, construction activities, taxes, and employee salaries.

(Nationwide, the study found that NIH contributes about $45 billion to the U.S economy, or almost as much as the national budget of Austria.)

The bulk of NIH's spending in Maryland is clearly for research and administrative needs at NIH.

But NIH also sent about $550 million to biotechnology researchers at area universities and private companies. Dr. Gottesman estimated that the 1996 figure is probably about $600 million, or about what it costs the state to build 50 elementary schools.

Researchers at Johns Hopkins University and the University of Maryland, which each have strong biotechnology programs and which license out new discoveries for commercialization, are the major recipients of the outside research contracts that NIH struck in Maryland.

In 1994, the year for which the most recent figures are available, those contracts totaled more than $317 million.

But three biotechnology companies -- Westat Inc., ROW Sciences and Advanced Biosciences Laboratories -- together were paid nearly $100 million in 1994 for NIH work.

Dr. Kincaid, who spent more than a decade working at NIH, said he's now seen -- from the inside and the outside -- the institution's powerful effect on the industry.

"NIH's total effect on the biotechnology industry is probably incalculable," he said.

NIH offspring

Maryland biotech companies started by former NIH scientists and directors, with the number of U.S. employees (in parentheses) and the companies' their main businesses.

• Biotech Research Laboratories, Rockville. (50 employees) Cell and molecular biology services

• Cellco, Germantown. (30) Cell culturing products/services

• Genetic Therapy, Gaithersburg. (150) Gene therapies for diseases

• GenVec, Rockville.(20) Gene therapies for diseases

• The Institute for Genomic Research, Rockville. (85) Genetic mapping research

• Kemp Biotechnologies, Frederick. (5) Cell culture products/services

• Life Technologies, Rockville & Frederick. (900) Biotechnology research supplies

• Lofstrand Labs, Gaithersburg. (25) DNA, RNA and protein labeling services

• Peptide Technologies, Gaithersburg. (10) Synthesized and purified peptides for research

• ROW Sciences, Rockville. (550) Contract research/computer analyses

• Veritas, Rockville. (2) Protein expression and enzyme services

These punctuations in the RNA-to-protein translation process have unexpected consequences: They can change the timing by which nascent proteins fold as they elongate and peel away from ribosomes. This means that two stretches of mRNA that differ only in synonymous codons can translate into two proteins that have identical amino acid sequences but different three-dimensional shapes. Such differences can convey important, even grave, biological and medical meanings. It's akin to the way the same hand can fold into an affirming thumbs-up gesture or into a shape involving the middle finger that conveys another sentiment altogether.

"We know that one individual given drug A will have to sleep for three days, but another taking the same drug will suffer no such effect," notes Michael M. Gottesman, chief of the Laboratory of Cell Biology at the National Cancer Institute (NCI) in Bethesda, Md. He now thinks that such individual differences in response to drug treatments and in susceptibility to diseases could correspond to different synonymous codons that lead to differently folded protein products. Most researchers have assumed that this type of genetic variation is too subtle to matter much. In fact, an often-used moniker for the variation is "silent polymorphism." Nonsilent polymorphisms are those variations in a gene's code that do lead to amino acid changes.

Last month, Gottesman and coworkers reported results of their investigation of a silent polymorphism that isn't so silent (Science, DOI: 10.1126/science.1135308). They found it in the gene that codes for P-glycoprotein (P-gp), a protein that takes residence in cell membranes, where it pumps drug molecules out of the cell. By purging the cell of drugs, this protein renders about half of human cancers resistant to a diversity of drugs.

Gottesman's group discovered that a silent polymorphism sometimes found in this gene gives rise to a version of P-gp that is less effective at expelling drugs from cells than the "wild type" of the protein. The researchers conjecture that the altered protein function derives from a synonymous codon's effects on the timing of translation and folding as the P-gp protein is being made and as it insinuates itself into a cell's membrane. In their studies, the researchers expressed the gene with and without the silent polymorphism in cultured human carcinoma cells, an AIDS-related human cell line, and two lines of cells derived from monkey kidney.

"The beauty of the paper is that it is based on natural examples," that is, living cells, comments Anton Komar of Cleveland State University. He was one of the first scientists to suggest, in the late 1980s, that silent polymorphisms in genes might have important biological consequences. Previously, Komar and others had found evidence that synonymous codons might affect protein folding, but those studies were done in cell-free test-tube preparations. "Nobody paid attention," Komar recalls. The consensus view, he points out, has long been that only those polymorphisms that translate into amino acid substitutions in the associated proteins were biologically or medically significant. To Komar, Gottesman's findings ought to change that view.

"Looking closely at silent polymorphisms could become a vast project now," Komar says. "We have the whole genome in hand."

Gottesman was attracted to research into silent polymorphisms three years ago during a discussion with Randall Kincaid, a former immunology lab head at the National Institutes of Health in Bethesda, who now runs Veritas, a biotech company in nearby Rockville. Kincaid mentioned a malaria vaccine project that required him to produce loads of a human protein in a microbial host. The protein, however, kept folding up and aggregating into unusable clumps. Kincaid told Gottesman that to circumvent this protein-folding headache, his team used a genetic engineering technique that involves exchanging some of the codons in the human gene with synonymous codons that are more prevalent in the microbial host used to manufacture the protein in bulk.

During that 2003 discussion, Gottesman says, "a light bulb went off in my head." For Gottesman, Kincaid's protein-folding headache sounded like a potential answer to a mystery he and his colleagues had been encountering in their research on P-gp. Listening to Kincaid, Gottesman wondered if the differences in folding that his team had observed stemmed from the silent polymorphisms found in the gene for P-gp.

Silent polymorphisms are among a more general class known as single-nucleotide polymorphisms, or SNPs (pronounced "snips"). SNPs consist of one nucleotide letter substituting for another. In the mRNA transcribed from a gene, every string of three nucleotides constitutes a codon that corresponds to and is ultimately translated into one of 20 amino acids.

For example, the mRNA codon designated UUU (uracil-uracil-uracil) encodes the amino acid phenylalanine, whereas the codon UUA (uracil-uracil-adenine) encodes leucine. Because a leucine replaces a phenylalanine, the polymorphism is nonsilent in this case, and the codons are nonsynonymous. On the other hand, the mRNA codons GGU, GGC, GGA, and GGG all encode glycine. That makes them synonymous codons, and their protein constructs all have the same amino acid sequence.

Gottesman's group traced one particular silent SNP in the gene for P-gp—in which a GGC codon changes into GGT—to altered protein activity. Both codons correspond to glycine. Using several analytical methods, the researchers concluded that the folding, final shape, and function of P-gp indeed are influenced by silent SNPs.

"These results may not only change our thinking about mechanisms of drug resistance, but may also cause us to reassess our whole understanding of SNPs in general and what role they play in disease," states NCI Director John E. Niederhuber in a press release.

Komar conjectures that synonymous codons might affect protein folding by tweaking the timing of that folding. In cells, he notes, the concentrations of amino acid-toting transfer RNA (tRNA) molecules, each of which corresponds to a specific mRNA codon, roughly mirror the overall frequencies at which the codons appear.

During protein translation, the mRNA codons sequentially specify which tRNA must come into the ribosome complex to deliver the next amino acid to be stitched onto the growing protein. A polymorphism that substitutes an infrequent codon for a relatively common but synonymous codon ought to result in a delay in translation because there is less of the corresponding amino acid-bearing tRNA around, Komar says. Because of the momentary pause, the growing protein could fold in a different way than if the pause were absent.

The details of the altered folding kinetics remain largely unknown, but recent work by Luda Diatchenko of the University of North Carolina and her colleagues has opened up one route of investigation into those matters (Science 2006, 314, 1930). Like Gottesman's group, they found that different synonymous codons in a gene can lead to changes in the production of its protein product. The gene Diatchenko's team studied encodes a neurotransmitter-degrading enzyme called human catechol-O-methyltransferase, or COMT. This enzyme is central to the regulation of pain perception. The COMT gene exists in three common variants, each one consisting of both silent and nonsilent codon changes.

Depending on which variant a person has, he or she is likely to have low, average, or high pain sensitivity. The researchers found that differences in COMT production derive far more from differences in synonymous codons in the COMT gene than in nonsynonymous ones that lead to amino acid changes.

Moreover, Diatchenko and her colleagues were able to relate those codon and clinical differences to the presence or absence of a specific stabilizing loop structure in the mRNA molecules encoding the enzyme. The mRNAs that were more stable yielded COMT activities up to 25 times higher than that associated with the least stable mRNA. The researchers surmise that these stability differences influence either the rate at which the mRNA molecules are degraded or at which they can be translated into protein. Because the more stable mRNAs produce more of the neurotransmitter-degrading enzyme, they ultimately correspond to less pain sensitivity.

"We need to give much more weight to synonymous changes," Diatchenko concludes. "Now that we know that the difference in COMT expression depends on the secondary structure of mRNA, we can think of targeting this mechanism" to alleviate such conditions as persistent pain, she says.

Confirming that the genetic code has built into it "colons or commas" that influence the kinetics of protein synthesis and folding, Komar notes, is a reminder that the code has yet to be fully decrypted. It's a molecular poem whose deconstruction must continue. The question now for Komar and others is whether they've identified a previously hidden stratum of meaning in the genetic code that will significantly help account for the differences that make individuals unique, in illness and in health.

On Tuesday evening, April 28, 2009, [Dr. Darrell Ray Galloway (born 1946)] was alone in his condo in Alexandria, Virginia, watching television and trying to unwind after work. His wife was in southern Utah, where they have a house, and where they hoped to retire soon. Galloway was a senior official at the Pentagon’s Defense Threat Reduction Agency, and for days he had been going to meetings about a new strain of influenza from Mexico that was spreading fast. The strain, which combined genes from humans, swine, and birds, had become known as swine flu. Earlier that month, two children in Southern California had caught it. Then the virus swept through a high school in Queens; more than a hundred students with symptoms were sent home. The Obama Administration had declared a national public-health emergency. That night, Galloway watched news reports from Mexico City about overcrowded hospitals and closed schools; an estimated hundred and fifty people had died. He telephoned his eldest son and urged him not to make a planned trip to Mexico.

[Dr. Darrell Ray Galloway (born 1946)] is sixty-four years old. He is a short, athletic man with a welcoming but serious manner, like that of an amiable high-school baseball coach. The son of an intelligence officer, he was inspired to become a scientist by the launch of Sputnik and the space race that followed. In his spare time, he is an amateur astronomer, and he has built a small observatory in his back yard in Utah. He and a group of friends love to tinker with three old Soviet MIG fighter jets that they keep in a hangar nearby.

A former professor at Ohio State, Galloway is a microbiologist, and knew the grim history of influenza, a virus that often mutates faster than the body’s immune system can respond to it. The pandemic of 1918 infected a third of the world’s population and may have killed as many as fifty million people. In 2003, a strain of avian influenza emerged in Asia that was particularly lethal to humans, and the possibility that it could cause a human pandemic was a source of constant worry. But the virus did not spread between humans and remained confined largely to birds. Swine flu was a new, similarly threatening strain.

The Defense Threat Reduction Agency was created after the Cold War to protect the United States from weapons of mass destruction and to help other countries deal with the dangers of loose nuclear, chemical, and biological weapons. [Dr. Darrell Ray Galloway (born 1946)] was authorized by the military to work on a specific set of threatening diseases that were considered potential weapons in war or in terrorism, including anthrax, smallpox, tularemia, plague, and the Ebola and Marburg hemorrhagic fevers. Influenza, Galloway said, “was outside my lane.” But countering it would test the government’s ability to respond quickly to a biological threat. [NOTE - "when" was Galloway assigned to the DTRA? .. According to Linkedin : 2001 - 2003 Deputy Director, Biodefense Research Directorate, Naval Medical Research Center, Rockville, MD / 2003-2007 DTRA ] That night in April [of 2009], he resolved to do something about the looming pandemic.

The next morning, when [Dr. Darrell Ray Galloway (born 1946)] arrived at work, he summoned his staff and announced that they were to begin work immediately on creating a new antiviral drug to combat the swine flu. “I said, ‘What are we waiting for?’ ” Galloway recalled. “ ‘This is about as real as it is going to get.’ ”

A day later, at a meeting in the Pentagon, Galloway ran into stiff objections. Several officials said that it was a mistake for the military to get involved in the swine-flu outbreak. Galloway felt that the government was reacting too slowly to the spread of the pandemic. “I finally got fed up and blew my stack,” Galloway told me. “I said, ‘I didn’t come here to ask anybody’s permission to do this. I have done it.’ ” He got up and left, and the meeting broke up. Afterward, no one tried to stop him.

The Biological Weapons Convention of 1975 outlawed germ warfare. But in the nineteen-nineties two events unnerved the Pentagon. It was revealed that the Soviet Union had built a vast, illicit germ-warfare program, and that a Japanese cult, Aum Shinrikyo, had experimented with anthrax. The September 11th attacks increased the fear that terrorists could acquire dangerous pathogens; the anthrax letters in the weeks that followed raised the alarm. Former President George W. Bush, in his memoir, writes that, in October of 2001, while he was travelling in China, a White House pathogen detector went off, indicating the presence of deadly botulinum toxin. Vice-President Dick Cheney, his face pale, spoke with Bush in a video conference to inform him, saying, “The chances are we’ve all been exposed.” It turned out to be a false alarm, but, Bush writes, “at the time, the threats were urgent and real.”

Between 2001 and 2010, Congress approved fifty billion dollars to protect against biological threats. In addition, a special reserve fund of $5.6 billion, known as Project BioShield, was created in 2004 to help build a national stockpile. But after several years it became clear that money was not solving the problem. David Franz, the former commander of the United States Army Medical Research Institute of Infectious Diseases, told me, “We can’t afford it. We realize now how much it costs to make one vaccine for one pathogen. It is enormous, especially when you don’t know if you are ever going to need it.”

In 2006, the Pentagon ordered an unusual five-year research initiative to counter germs being used as weapons of war or terror, and assigned [Dr. Darrell Ray Galloway (born 1946)] to launch it. Instead of targeting pathogens one by one, an approach known as “one bug, one drug,” the initiative would seek to invent therapeutic drugs and vaccines that could counter multiple germs. They would also develop new processes that could be used to quickly create drugs and vaccines to fight previously unknown pathogens. Galloway and another official called it the Transformational Medical Technologies Initiative.

T.M.T.I. set extraordinary expectations for itself. An official description said that it would “spark another medical revolution,” similar to the mass production of penicillin in the Second World War, and declared that it might create new drugs and vaccines “within days.” As Galloway envisaged it, T.M.T.I. would start with basic research and go as far as possible toward developing a new drug or vaccine. No other single government agency was trying to do anything quite so ambitious.

[Dr. Darrell Ray Galloway (born 1946)] faced huge obstacles. The Defense Threat Reduction Agency had plenty of nuclear experts on its staff, but there were few people there with experience in microbiology or biotechnology. Critics argued that the program had overstated its capabilities. [Dr. Michael Thomas Osterholm (born 1953)], the director of the Center for Infectious Disease Research and Policy at the University of Minnesota, told me that T.M.T.I.’s plans to create drugs rapidly were the result of “wishful thinking,” and were “like trying a moon shot in ten minutes.” Bringing a new commercial drug or vaccine from laboratory to market in the United States can take ten to fifteen years and cost more than a billion dollars. The process of winning Food and Drug Administration approval, as the Pentagon has pledged to do with any drug or vaccine given to troops, involves preclinical testing in laboratory animals and three phases of clinical trials with human volunteers.

Nonetheless, Galloway pressed ahead. According to Patrick J. Scannon, the founder of a biotech firm called XOMA, who was an adviser to the military on biological issues during the Clinton and George W. Bush Administrations, “The Defense Department was creating a drug company.”

While [Dr. Darrell Ray Galloway (born 1946)] was setting up the program, concern about biological war and terror waned slightly. No weapons of mass destruction were found in Iraq, and although Al Qaeda had attempted to work with anthrax before September 11th, it had not got very far. There hadn’t been a terrorist attack using biological agents. But there were numerous dangerous outbreaks of naturally occurring infectious diseases around the world. Between late 2002 and mid-2003, a virus that causes severe acute respiratory syndrome, or sars, spread from southern China to twenty-eight countries and killed nearly eight hundred people. Then came avian influenza and swine flu, also known as 2009 H1N1.

There are two medical ways to deal with influenza: vaccines, which are given to healthy people before they are infected; and antiviral drugs, which can suppress the virus after infection, and give the body’s immune system time to regroup and recover. Galloway focussed on drugs because the existing antivirals had a limited impact. Tamiflu, one of the leading products, can shorten the duration of flu by only a day or two, and the swine-flu strain was already resistant to two other antivirals, developed in earlier years. It was possible that it would become resistant to Tamiflu as well.

[Dr. Darrell Ray Galloway (born 1946)] had assembled a technical staff for the T.M.T.I. program, and he had an early success with a drug to fight the Ebola and Marburg viruses. He saw swine flu as an opportunity to do more. “I wanted to prove that the program worked,” he told me. He also wanted to accomplish something tangible, if not strictly about war or terrorism. “How would it look if the government had a way to do this and we just sat on our hands?” he said. “If my job is to build a capability to respond to any unknown virus, how about this one?”

Another small team of scientists and medical experts within the Defense Department shared this sense of urgency. They had been trying for several years to modernize the way vaccines are made, and, during the pandemic, they decided to try to build a swine-flu vaccine using an entirely new method. Galloway was focussed on treatment; this group pursued prevention, under a program they called Blue Angel.

Vaccines are potentially the most powerful tool for preventing widespread illness and death from a virus. But they can be very difficult to create. Since the nineteen-fifties, there has been one F.D.A.-approved way to manufacture flu vaccines: inserting weak forms of the virus into chicken eggs. The egg-based vaccine depends on six discrete steps, and takes at least six months, or longer, to produce. The Centers for Disease Control and Prevention started preparations for a new vaccine in April, right after swine flu entered the United States. But a second wave of influenza would likely begin in four months, at the end of the summer.

The White House was concerned that the vaccine wouldn’t be ready in time for a pandemic. President Obama had just taken office, and aides worried about the prospect of a public-health disaster in his first year. Was there an alternative way to get a vaccine? The White House Homeland Security Council and the Office of Science and Technology Policy [ where Rachel Elizabeth Levinson (born 1952) worked until 2005 ... the wife of Dr. Kincaid ] sent out a series of e-mail queries to government scientists in late April. One of them went to [Dr. Michael Vincent Callahan (born 1962)], a physician specializing in infectious diseases and rapid response who works at Massachusetts General Hospital and at the Defense Advanced Research Projects Agency, or darpa.

[Dr. Michael Vincent Callahan (born 1962)], who is forty-eight years old, thrives on practicing medicine under austere conditions in forbidding places. In earlier years, he served as an expedition doctor: climbing mountains and slogging through jungles with teams of explorers. One of his current projects is to help acclimate U.S. soldiers to the mountains of Afghanistan. “My thing is altitude and disasters,” he told me. When we met, he had just finished a night of hospital duty and was running on three hours of sleep. He repeatedly jabbed the button on a coffee machine, gulped down three cups of espresso, and chewed on candy-size tabs of an experimental nutraceutical that is supposed to bolster the immune system.

President Eisenhower established darpa in 1958, to undertake high-risk research in an attempt to find solutions to real problems. [Dr. Michael Vincent Callahan (born 1962)] and others at the agency quickly pulled together Blue Angel from a sheaf of futuristic programs they had been developing. Among them was PHD, an advanced blood test that could detect who would or would not become sick, days before symptoms arrived. Another, known as mimic, could model the human immune response in a test tube, creating a swift way to check the efficacy of vaccines. A third was save, a relatively inexpensive ventilator designed for the battlefield, which was the size of two large paperbacks and could be widely used by civilians in places such as school gyms if hospitals were overcrowded.

But the centerpiece of the program was an effort to modernize and speed up the production of vaccines. Instead of using chicken eggs, Callahan wanted to insert genetic code into specially grown tobacco plants. The code would cause the plants to generate viral proteins, and these could then be made into the active component of a vaccine. Tobacco is fast-growing and easy to manipulate genetically; in theory, once you have inserted the genetic code of the virus, the plants can quickly make pure and safe proteins in huge quantities. No one had yet made a vaccine for the public this way, nor had there been human clinical trials to determine if the vaccine could induce immunity in large numbers of people. But the Obama Administration was looking at all possibilities.

The White House contacted Callahan on April 28th. According to his records, officials requested a timeline with worst-case, medium, and optimistic projections for using the tobacco-plant method to manufacture hundreds of millions of doses of vaccine. Just then, Callahan was planning a “live-fire exercise,” an experiment in which he would use tobacco plants to try to make the active components of an avian-flu vaccine. He quickly substituted swine flu. The experiment was to be carried out by the Center for Molecular Biotechnology, in Newark, Delaware, a nonprofit branch of Fraunhofer U.S.A., a subsidiary of the large German applied-research and technology organization. Callahan sent a fragment of the swine-flu genetic code by e-mail to the executive director of the center. The center, using the tobacco plants, produced a purified protein in twenty-one days. This wasn’t a finished vaccine, but it suggested that the process of making one could be rapidly accelerated.

By contrast, it proved hard to grow the weakened strain of swine flu that could be placed in eggs. When it was finally shipped to the manufacturers, they found that the growth in the eggs wasn’t optimal for large-scale production. The manufacturers tweaked the strain, but not until the end of June were they ready to begin mass production.

On June 11th, the World Health Organization raised the alert level to six, meaning that a full-blown global pandemic had begun.

[Dr. Darrell Ray Galloway (born 1946)] kept an eye on Callahan’s work, but he stayed focussed on building a drug, not a vaccine. The first step was to acquire a full genetic blueprint of the swine-flu virus, and, to do this, he turned to [Dr. Walter Ian Lipkin (born 1952)], one of the leading detectives in the viral and bacterial world. A professor at Columbia University and the director of the Center for Infection and Immunity at the Mailman School of Public Health, Lipkin scrutinizes hundreds of pathogens every week, sifting the genetic codes for clues to their origins, behavior, structure, and identity.

Viruses are barely life forms. They infect a cell, hijack its machinery to replicate themselves, and then escape to infect new cells. The genes of the influenza virus are carried in RNA, or ribonucleic acid. Unlike many other viruses and organisms, the influenza virus does not correct genetic errors when it replicates, so it produces offspring that are not identical. The slightly different versions of the viral genome collectively resemble a swarm. To sequence the virus’s genes, Lipkin needed to scan as many versions as possible. Then he lined up the data to create a “consensus” snapshot of the swarm.

On April 30th, Lipkin and his staff acquired a specimen of the virus taken from the school outbreak in Queens. On May 1st, they began to sequence it. Every hour or so, they telephoned or e-mailed a progress report to [Dr. Paula Marie (Morgan) Imbro (born 1962)], a geneticist at the Tauri Group, in Alexandria, Virginia, who had been providing advice to Galloway’s T.M.T.I. program for more than a year. Lipkin’s staff sent [Dr. Paula Marie (Morgan) Imbro (born 1962)] the swine-flu sequence when it was finished. It looked like a piece of fine embroidery—tiny dots of green, blue, yellow, red, and purple. Lipkin had sequenced the virus in thirty-one hours.

[Dr. Darrell Ray Galloway (born 1946)] had solved the first major problem in developing his drug. To deal with the next, he chose [Dr. Patrick Lynn Iversen (born 1955)], a scientist at AVI BioPharma, a small biotech company in Corvallis, Oregon. They had worked together on the Ebola and Marburg viruses. On May 3rd, the swine-flu sequence arrived in Iversen’s e-mail in-box. The son of a national-park ranger, he is a hefty man, fifty-five years old, with a handlebar mustache and a gentle voice. He earned a Ph.D. in pharmacology at the University of Utah, and later became an assistant professor at the University of Nebraska. From his early days in science, Iversen was fascinated by the possibility that a chemical substance could target a precise location in genetic material, such as that of a virus or a tumor, and change its behavior.

Dr. Patrick Lynn Iversen (born 1955)]’s main research involved a technology known as “antisense,” which was first discovered in the nineteen-eighties. The process involved chemically synthesizing a short strand of DNA or RNA that could precisely interlock with a sequence found in a natural virus, like one Lego block attached to another. The natural strand was known as the sense strand, and the synthetic one as the “antisense” strand. If the antisense strand could attach tightly enough and in the right place, it would become a wrench in the gears of the genetic machinery, and stop the virus from replicating. The strand, in theory, could thus be turned into a powerful antiviral drug.

In the nineteen-eighties and nineties, Dr. Patrick Lynn Iversen (born 1955)] wrestled with the forbidding obstacles in antisense technology. One of the most difficult was to deliver the antisense strand to the right place at the right moment, after the virus had penetrated the cell, but before it had replicated and escaped to infect other cells. To accomplish this, the synthetic strand must be non-toxic, and it must not interfere with other genetic processes in the body. It must be potent enough to be effective and strong enough to resist rapid degradation. It must bind tightly to the invading virus. Each step in the process is complicated. Some of the early hopes for antisense technology were later dashed, and one scientific paper in the late nineties declared, “The technology remains in its infancy.” According to Cy Stein, of the Albert Einstein-Montefiore Cancer Center, in the Bronx, who also began working with antisense in the eighties, “The concept is the best idea since the hole in the toilet seat. But, in making this happen, there is one barrier after another that nature puts up to prevent you from doing what you want to do.”

In 1997, [Dr. Patrick Lynn Iversen (born 1955)] left Nebraska and joined AVI BioPharma, which had pioneered antisense chemistry. In his first years there, he tried to figure out how to use antisense to combat major diseases such as aids and cancer. But after September 11, 2001, he became preoccupied with viruses and terrorism. He had been planning to fly to New Jersey that day, but his flight was cancelled and the drive home from the airport took three hours. Along the way, he thought about the potential use of viruses: “I just thought, you know, flying a plane into a building—for a sort of low cost, you create a very high-cost event. If I were a terrorist, I would do a virus. This came to me as I was driving home, thinking, Things are a lot scarier if you could take a dog with some zoonotic virus and let him go in some neighborhood and the next thing you know people are tying up the whole medical system.”

[Dr. Patrick Lynn Iversen (born 1955)]’s new focus soon led him to obtain a patent on using antisense to target four major virus families. In some virus families, certain parts of genetic code appear the same across several species. These locations are known as “highly conserved regions,” meaning that they do not change from one strain of influenza virus to another. If he could target them, he thought, antisense technology could knock out different strains.

In 2002, the West Nile virus infected two dozen Humboldt penguins at the Milwaukee County Zoo, killing eleven. [Dr. Patrick Lynn Iversen (born 1955)] called Roberta Wallace, the senior staff veterinarian at the zoo, offering to synthesize an antisense compound against West Nile virus if she would give it to the remaining sick penguins. When Wallace agreed, he took the sequence of the virus from a database, designed the compound, and sent it to her in a vial. She injected it into three sick penguins. The birds survived the infection.

The success of the injection provided only anecdotal evidence that antisense could work, and Iversen was eager to find a more difficult challenge. On February 11, 2004, he made a presentation to the U.S. Army Medical Research Institute of Infectious Diseases, at Fort Detrick, Maryland, the Army’s premier laboratory for biodefense research. Hours later, a researcher at Fort Detrick accidentally stuck herself in the thumb with a needle while injecting mice with the Ebola virus. Ebola has gruesome symptoms that often cause the victim to bleed to death; there is no licensed vaccine or therapeutic drug to stop it.

While the terrified researcher was put in isolation, in a complex known as the Slammer, two cinder-block patient rooms that were hermetically sealed and filled with monitoring equipment, laboratory officials called [Dr. Patrick Lynn Iversen (born 1955)]. They wanted to know how rapidly he could synthesize an antisense compound against the Ebola virus. He quickly designed compounds based on the genetic sequence. Chemists worked for two days to synthesize it. In a telephone conference call, the F.D.A. gave emergency approval for use of the untested drug. The president of AVI BioPharma flew to the East Coast, carrying the vial. In the end, the researcher did not come down with Ebola, and she did not need Iversen’s drug. But the rapid response persuaded everyone involved, including Iversen and the Army laboratory, to launch a major new research effort into antisense and viruses.

One of the most enthusiastic participants was the researcher who had had the accident. She joined Iversen, and others in the lab, to create, test, and modify antisense compounds to counter viruses, including Ebola and Marburg. The first generation wasn’t potent enough; the second generation had problems with toxicity. With the third generation, the scientists had something to boast about. In 2006, they published the results of a trial in which seventy-five per cent of the monkeys given an antisense compound survived infection with the Ebola virus.

[Dr. Darrell Ray Galloway (born 1946)]'s programs had funded some of the Ebola and Marburg research, just as T.M.T.I. was getting started. He told me he knew that the antisense technology was working against those exotic viruses, and he felt confident that it would work against others. In the first hour after he launched the swine-flu effort, Galloway instructed his staff to call [Dr. Patrick Lynn Iversen (born 1955)] and invite him to join them. Iversen immediately agreed. On May 5th, the T.M.T.I. program, on Galloway’s orders, rushed a $4.1-million contract to AVI BioPharma. This kind of speed is almost unheard of in defense contracting. An accompanying memo from T.M.T.I. said it was possible that the experimental drug could be designed and found effective “in four to six weeks.” After that, “millions of doses” could be produced in time for the fall wave of swine flu. The memo warned that a pandemic could cripple military deployments, but it said nothing about the time required for testing by the F.D.A.

“This is where I get most of my negative thinking done.”

[Dr. Patrick Lynn Iversen (born 1955)] puzzled over the genetic sequence in the first days after he received it. He could not find the precise site he needed in order to attach the antisense compound. Lipkin had produced a richly detailed genetic blueprint, but the highly conserved region that Iversen needed was cloudy, as if covered with translucent tape.

Within days, [Dr. Paula Marie (Morgan) Imbro (born 1962)], the geneticist, had helped [Dr. Patrick Lynn Iversen (born 1955)] find a trove of swine-flu genetic sequences in a European database. They worked together on the phone—Iversen in Oregon and Imbro in Virginia—scrutinizing more than a thousand sequences each. Finally, Iversen recognized the precise place where he could attach his compound.

With the chemists, he attempted to create a synthetic compound that would latch on to the viral RNA in the right place, and stay there. On May 14th, he phoned the T.M.T.I. program: he and the chemists had succeeded. Afterward, [Dr. Patrick Lynn Iversen (born 1955)] held the substance in a small glass vial. It was fluffy and white. On closer examination, you could see that it was made up of spindly rods that seemed clean and pure.

[Dr. Randall Lawrence Kincaid (born 1951)], a biologist and entrepreneur who that week had become the scientific director of T.M.T.I., described Iversen’s work: “He distilled the background of influenza, the intricacies of the virus itself, and the types and strategies that would likely work or not work. I thought, Man, this is a guy who either has thought about this for a long time or is incredibly smart and in a few days came up with this. Either way, it is great.”

Engineering the compound did not mean that [Dr. Patrick Lynn Iversen (born 1955)] and [Dr. Darrell Ray Galloway (born 1946)] had found a workable drug. The next step was to test the substance in laboratory animals, starting with mice and moving on to ferrets, which are extremely susceptible to influenza infection and develop some of the symptoms seen in humans. After the blistering pace of events in May, the animal tests were delayed, week after week. There weren’t enough ferrets, and reams of paperwork were needed to obtain permissions from special committees, which sometimes meet only once a month.

In July, the influenza project faced a worrisome new crisis. In Argentina, the mortality rate among patients with swine flu began to soar. It was nine times as high as elsewhere. If the virus had mutated into a much more dangerous strain, it would make the egg-based vaccine useless, and it could also force [Dr. Patrick Lynn Iversen (born 1955)] to start over. Most people who had come down with swine flu in the spring had survived; a mutation could mean that the death rate would be much higher when the virus returned in full force in the fall. Several specimens from Argentina were rushed to Lipkin’s laboratory, at Columbia University, and the first analysis was carried out over the July 4th weekend. The researchers, entering the lab for dangerous pathogens, donned heavy protective suits. It turned out, however, that people in Argentina were being infected not only by the swine-flu virus but, at the same time, by streptococcus, a bacteria.

In August, [Dr. Patrick Lynn Iversen (born 1955)] got the laboratory-mice tests under way, but the first weeks were frustrating. The mice were set out in groups of ten and infected with a strain of influenza. Then one group was given the antisense compound, a second group Tamiflu, and a third a saline solution. Some mice in the early tests died unexpectedly because they were being given too much of the compound too fast. In the fourth round of tests, the scientists made the compound more concentrated but the doses less frequent, and the results looked promising. The treated animals had lower concentrations of virus and did not lose weight, as the animals usually do when they’re sick. “By the time we had finished with the mice, there was a high degree of optimism,” Kincaid told me.

Subsequent tests, in September, showed that infected ferrets that got Iversen’s compound had dramatically lower levels of swine flu than those who didn’t get it. The antisense compound also outperformed Tamiflu. “You know, ferrets sneeze, ferrets’ eyes get all runny, their noses get stuffy—they look like they’ve got the flu!” Iversen told me. “The first ferrets we treated were perfect. We had no sneezing, no runny nose, no stuff in the eyes, activity scores were perfect, and the sick guys were sick. So, you know, pretty cool.”

In Washington, on September 28th, Kincaid appeared before more than thirty government officials involved in the swine-flu crisis, from both civilian and military agencies. At this point, the second wave of the pandemic had arrived, but the conventional egg-based vaccine was still weeks away from delivery, and the Blue Angel tobacco-plant-based vaccine remained untested. A White House report warned that the pandemic could place “enormous stress” on the public-health system and cause between thirty and ninety thousand deaths in the United States in the coming months.

In a windowless Pentagon conference room, Kincaid spoke extemporaneously. He acknowledged that [Dr. Darrell Ray Galloway (born 1946)] and T.M.T.I. didn’t have a formal mandate to create a new antiviral drug, but “we saw an opportunity to see whether or not we could.” He described the good news from the four rounds of tests on mice. The exercise had shown “the potential for this capability to respond rapidly to an emerging threat,” Kincaid said, according to his notes. But he was taken aback at the first question: Can you make fifty million doses?

Kincaid insisted that it was just an exercise; the group was not ready to make fifty million doses. The officials pressed him about the remaining obstacles, and he told them that there were two main problems: how to give the drug to a large population, and how to get it approved by the F.D.A., which the group had not even consulted during the exercise. “People were energized,” Kincaid said. They saw the spindly white compound in [Dr. Patrick Lynn Iversen (born 1955)]’s vial as a real response to a deepening crisis.

The questions didn’t stop there. “We pushed it very hard,” said [Andrew Charles Weber (born 1960)], the assistant to the Secretary of Defense for Nuclear and Chemical and Biological Defense Programs. Weber, who took office in May of 2009, told me that, if needed, the new drug and the new vaccine would have been taken immediately into human clinical trials. “We realized in dealing with this declared national emergency that we needed a Plan B and a Plan C,” he said.

In the year after the pandemic began, swine flu infected between fifteen and thirty per cent of the population of the United States. But it was not as lethal as many officials had feared it would be. As a result, neither Galloway nor Callahan got the call to start mass production, and it is not known whether the antisense drug or the vaccine from tobacco plants would have proved safe and effective. Although the early results were promising, laboratory-animal studies often fail to predict how humans will react.

The work of both [Dr. Darrell Ray Galloway (born 1946)] and Callahan, however, resonated strongly in a debate about American preparedness that followed the pandemic. In January, 2010, President Obama, in his State of the Union address, promised “a new initiative that will give us the capacity to respond faster and more effectively to bioterrorism or an infectious disease.” For the next six months, officials met frequently to devise a strategy. The Department of Health and Human Services led the work, but the Defense Department was closely involved. When a new strategy was unveiled, in August, it called for many of the innovations and goals that Galloway had set for T.M.T.I. It also called on the government to support influenza vaccines that do not depend on chicken eggs. The Defense Department decided to make the T.M.T.I. a permanent program, with an annual budget of more than two hundred and fifty million dollars, and the Pentagon issued a formal order that emerging infectious diseases are a proper target for military research.

Kincaid, the scientific director of T.M.T.I., told me that a major lesson was that a rapid response to a biological emergency must be accompanied by an equally rapid process for testing and approval. “There is no sense having brilliant, rapid science without it,” he said. The F.D.A.’s existing system of approval for new drugs, one of the most rigorous in the world, does not move quickly. Emergency fast-track procedures exist, but they are cumbersome. In the case of the most dangerous agents, such as Ebola, it is neither feasible nor ethical to run clinical trials on humans. Licensing for drugs and vaccines against these deadly agents must be based on testing in laboratory animals, despite the limitations of such work. If the country were engulfed by a deadly pandemic or bioterrorism attack, there would be questions of what risks to take, and whether people would be better off with or without a new drug or vaccine that had not been tested in humans.

The Obama Administration’s strategy calls for improving “regulatory science,” which means finding new methods and tools that can help the F.D.A. reach judgments more quickly. One idea is to look for indicators, known as biomarkers—such as protein levels in blood—that can allow you to make an early diagnosis or accurately predict a drug or vaccine’s effectiveness. Another proposal is to create F.D.A. “action teams” of experts and have them start working early with scientists who are developing a high-priority drug or vaccine.

At the end of 2009, [Dr. Darrell Ray Galloway (born 1946)] retired from the Defense Threat Reduction Agency, moved to Utah, and set up a small biodefense consulting company. This past December, AVI BioPharma submitted a formal request to the F.D.A. for approval to begin clinical trials of the antiviral. Meanwhile, there still is not a highly effective antiviral drug for dealing with swine flu. Over the past few months, a new wave of swine flu has hit Britain, sending more than seven hundred people to hospitals. Britain released 12.7 million doses of the pandemic vaccine for immediate use. Wide usage of the vaccine will stop the disease from spreading, but it isn’t going to do much for the people who are already sick. Their instructions are to stay hydrated and warm, and not to go to school or work. A similar outbreak occurred this winter in Cairo.

These outbreaks will probably be contained soon. But no one knows when the next deadly pathogen will show up and whether we’ll be able to respond rapidly to it. Patrick Scannon told me that [Dr. Darrell Ray Galloway (born 1946)] was right to act when he did. “Where could you hide if the flu turned rogue, and was Tamiflu-resistant?” he said. “The only thing left is to grab masking tape and a bottle of water, and lock the door. What is the responsible federal official going to do? Say, ‘Let’s not rush into this?’ What if you were wrong?”

In the event of another crisis, Galloway’s gamble may have pointed the way toward a rapid response. “What has been missing is an example,” Scannon said. “This was the first.” ♦