Sunday, February 21, 2010

A Tale of Three Cities

The following first appeared in WTN News. I had a great time writing it, and enjoyed the feedback it received from readers. You can see the originally published version here. Let me know your thoughts!
Quick, spot the similarities: Silicon Valley, New York City, and….Madison, WI? Let's see. Smog levels aren't quite the same. Slight differences in population base, local cuisine, and fashion sense. But at one investment event in Oct. 2009, it was all about the tech.

Biotech, specifically. Life science entrepreneurs in hot pursuit of funding was the focus of the All Things Life Sciences VC forum, in which female biotech start-up leaders vetted by Springboard Enterprises made pitches to investors in three different cities. Madison was first on the road show, followed by Silicon Valley on 10/15 and NYC on 10/30.

Biotech and Regional Economic Development

At first glance, it seemed an incongruous grouping of locales. Not to cast aspersions, but how does Madison - est. population just under 230,000 - measure up to Silicon Valley and New York City? “Madison is an important biotech center,” said Lauren Flanagan, Managing Director of Phenomenelle Angels Fund. In comparison to larger Midwestern cities, Minneapolis is known for medical device companies; Chicago, for general and medical IT; and St. Louis for agbiotech, chemicals and pharma. Madison's niche is arguably still evolving, with strengths in microbial sciences, stem cells, lab research tools, and diagnostics. But in particular, there is growing recognition that in addition to being a good place to grow cell cultures, Wisconsin is a good place to grow early-stage companies.

Business Bargains
“You can get angel funds in Wisconsin, and keep the burn rate low,” says Flanagan. “Having started four companies and having grown up in the Bay Area, what I like about Wisconsin is the rich repository of talent.” Similar sentiments are echoed in irrepressible fashion by Penelope Trunk, who bluntly titled a Brazen Careerist blog post, “Starting a company in Silicon Valley is stupid”. A 2009 salary survey of life science professionals by The Scientist reported that the average Madison salary was, at $63,050, lower than all other U.S. cities for which data was collected aside from Charlottesville, VA. (However, the reader survey did not use random sampling, so it's entirely possible that entry-level or lower-paying public sector scientific positions were overrepresented.) Considering that the Ph.D. density in Madison is among the highest in the nation, one could speculate that the region is a great place to employ skilled talent on the cheap. Small comfort to job seekers, and likely a topic that state and local politicians would rather avoid, but encouraging to firms wanting to stretch their seed money as long as possible.

And certainly, the cost of living in Madison is miniscule in comparison to Silicon Valley and New York City, allowing a far lower salary-induced burn rate for early-stage companies. But the cost of lab and office space also has significant impact on start-up burn rate. Whether leased or owned, lab space in New York City is the most expensive in the nation, and the Bay Area isn't far behind.

When weighing time versus money, shorter commutes also play a role in lifestyle and work productivity. The average work commute in Madison is 16.4 minutes; in the Bay Area, consider yourself lucky to have a commute time at least double that; and NYC? Unsurprisingly, the longest in the nation.

Show Me the Money

However, a lower bottom line doesn't help much if you can't attract funding to begin with. And this is where the dominance of the carefully cultivated Silicon Valley venture capital scene really makes an impact.

“There's more money in one hallway of a VC firm on Sand Hill Road [in Silicon Valley] than in all of Wisconsin, Michigan, and Illinois combined”, says Flanagan. This is not an exaggeration. Venture capital investments in 2002 in the state of California were 145-fold higher than in the state of Wisconsin.

Seed money and initial funding is however possible to land in Madison. “I navigated the boy's club in Madison enough to know there's tons of money here,” said Trunk during a panel discussion at the ATLS forum. And with angel investor support comes invaluable business advice and mentoring. Recently, state support in Wisconsin in the form of the Act 255 Venture Capital Tax Credits program has helped spur funding as well. But it's not enough; the “black hole” of fundraising from approximately $3-$5 million looms large in the Midwest. Entrepreneurs unable to traverse it will see their companies fail. And despite earnest efforts from state and local government leaders and some progress made by groups of angel investors pooling resources and closing bigger deals than individual angels could have undertaken, this is unlikely to change anytime soon. Wealth creation doesn't happen overnight.

Silicon Valley Redux?

During a Gilson Series seminar in February, a provocative question was raised from the audience. Is Madison at a stage similar to 1975-era Silicon Valley, and if so, what transformative events are needed to propel further its development? Joe Kremer, Director of Wisconsin Angel Network, cited the Vision 2020 report produced by the Wisconsin Technology Council as one potential road map, but cautioned, “We're Wisconsin. We're never going to be Silicon Valley…our strategy will be different than those of the coasts. We'll do it the Wisconsin way.”

Certainly, the allure of Silicon Valley lucre is intoxicating to economic development gurus. The problem, points out Darian M. Ibrahim, Assistant Professor at the UW Law School, is that the Silicon Valley scenario is incredibly difficult to replicate. Its history as a high-tech economic powerhouse is relatively short and serendipitous. As late as 1950, the region was most famous as “The Prune Capital of America”. Shifting from an agricultural economy to a technical economy occurred in several stages, the first having more to do with air - radio airwaves, that is - than silicon. Electronics manufacturing exploded in Bay Area just prior to 1970, spurred by specialty firms producing components that found a voracious market in the U.S. defense industry. Interestingly, this early phase of wealth and labor pool establishment (leading to a skilled electronics work force of 58,000 by 1970) didn't rely on heavy-handed guidance from politicians or economic development gurus. It relied on spontaneous proliferation of companies that just happened to have specialty products, the right organizational structure to out-compete everyone else, and an eager market. Money made in the initial stages began to be funneled back into VC investments for later-stage firms in the burgeoning IT field. While the role of technology transfer from Stanford University and other Bay Area academic institutions is often credited with facilitating technology transfer in Silicon Valley, a 2001 analysis by Christophe Leguyer concludes that academic tech transfer played only a small role in the first critical stage of wealth creation.

So, in that respect, public sector efforts to replicate Silicon Valley may be unlikely to achieve the same effect; certainly, other attempts in the U.S. have failed. If true, this may turn out to be disappointing for politicians and economic development leaders in Wisconsin. For example, the Vision 2020 proposal lays out a plan for hand-picking technology clusters across the state and establishing a research arm of “futurists” and leaders to guide tech transfer envisioned as flowing from the Wisconsin Alumni Research Foundation and the UW System. But will this allow enough flexibility? Arguably, such a plan is more akin to efforts taken in Research Triangle Park in North Carolina, which was inspired by state and local leaders from its inception. But it may not spur the level of explosive growth, market responsiveness, innovation and creativity seen in Silicon Valley.

No Envy for the Big Apple

Still, things could be worse. You could be trying to grow biotech in NYC. As home to Columbia, NYU, Mount Sinai, and Memorial Sloan-Kettering Cancer Center among others - not to mention 19 Nobel Prize winners and 39 Howard Hughes Medical Investigators - there's no shortage of research and potential for technology transfer. But while technology transfer offices in NYC institutions have found a niche in making licensing and royalty deals ($791 M in 2007 revenue for NYU alone), the number of spin-off biotech firms that establish within the metro area is astonishingly small - a city-wide total of 21 in 2007 across seven colleges and universities. (For comparison, WARF/University of Wisconsin alone facilitated 6 start-ups in FY2006-2007 and another 6 in FY2007-2008.) The high cost of labor and real estate certainly has a chilling effect on entrepreneurial activity within NYC. But even competition for the relatively low-lying fruit of SBIR/STTR grants has been lackluster. NYC companies landed only 43 SBIR grants in 2006. Wisconsin firms landed 77 in the same year.

Nature and Nurture

One has to wonder how much cultural norms come into play. Is risk tolerance simply higher in the Bay Area than the Midwest, and if so, will this ultimately limit entrepreneurialism in this region? On the flip side, could “West Coast tunnel vision” lead investors there to overlook high-quality opportunities elsewhere? Could a stereotypical hard-driving NYC negotiation style coupled with a desire for fast payoff be behind the push for licensing revenue over entrepreneurialism, which requires far more patience?

And if Midwestern economic development leaders and politicians are to do some difficult self-assessment, how helpful are our deeply ingrained state rivalries? When press releases trumpet the relocation of tech firms within the Midwest, there is a hint of football-induced jubilation: Wisconsin 1! Michigan 0! Score!

But economic growth is likely to require cross-regional collaboration on a far longer timescale than the next political campaign. As Flanagan noted, “There is a need for strategies like funds-of-funds, where private and public capital are invested into regional opportunities, so that there is sufficient follow-on money for entrepreneurial success.” This takes a long view, collaboration, and stomach for risk.

Game on.


In 2004, Forbes Magazine ranked Madison 1st in the nation for Ph.D.s per capita. In 2009,Forbes Magazine ranked Madison 12th for percentage of population age 25 or higher having at least a bachelor's degree.

PriceWaterhouseCoopers/Venture Economics/National Venture Capital Association MoneyTree Survey, 2002

Leguyer C, “Making Silicon Valley: Engineering Culture, Innovation, and Industrial Growth, 1930-1970”, Enterprise & Society 2001 2, 4:666.

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Friday, February 12, 2010

Youthful Ideas

'Tis February, and a college student's thoughts turn to.....innovation?

For students on the University of Wisconsin-Madison campus, this is certainly the case. This week brought two very fun events: Innovation Days, a competition organized by the UW Department of Engineering; and the Wiscontrepreneur 100 Hour Challenge, offered by the UW-Madison Office of Corporate Relations. 

UW undergrads competing in Innovation Days are pursuing a total of $28,450 in prize money across four different contests. The top prize of $10,000 is for the Schoofs Prize for Creativity, which is intended "to awaken students to the potential embedded in their own talent, and thereby encourage creativity and entrepreneurship". Other categories include the Tong Prototype Prize and awards for best presentation and best design notebook, respectively.

This year’s contestants cover 23 inventions, with titles ranging from “Intelliwindows” to “Tri Crimp”. The presentations were open to the public on Thursday and Friday at the UW School of Engineering. The keynote speaker? Matt Younkle, serial entrepreneur. He co-invented the TurboTap – a device to pour draft beers rapidly – which won the Schoofs Prize in 1996. Younkle’s team later brought the TurboTap to market through their company, Laminar Technologies LLC, and the TurboTap was dubbed “Most Amazing Invention” by Time Magazine. If you’ve had a beer at a major sporting stadium in the past five years, it was probably used to pour your beverage.

And on tap for next week (ok, couldn’t resist that transition)….is the Wiscontrepreneur 100 Hour Challenge, running February 17-21. Taking a cue straight from “Junkyard Wars”, this event allows students a stipend of $15 to gather materials from the UW Surplus With A Purpose shop. Students then put their best creative foot forward to see what working inventions they can come up with in a 100-hour working period. Past winners include a team that developed a working water purification system using $10 worth of material that could be used for bacterial- or sewage-contaminated water.

I can’t wait to see what the kids come up with this year.

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Saturday, February 6, 2010

Strategy, advice exchanged at Biotech VC Forum

This is the second of three articles I wrote last fall for WTN News. You can read it as originally published here. Enjoy!

Forget the recession. Or perhaps, thrive in spite of it.

That seemed to be the prevailing mindset at the AllThingsLifeSciences 2009 Venture Capital Forum held in Madison on October 1, 2009. Total funding sought by all 18 women-owned life science companies presenting at the event exceeded $138.9M – but was nearly matched by total capital raised to-date of $136M. And while the majority of companies were early stage, six reported 2009YTD revenue, including $5 M YTD revenue for EraGen Biosciences, Inc. and $1 M YTD revenue for A&G Pharmaceutical.

That’s not to say that the recession hasn’t had an impact on business plans. Notably, nearly every presentation included mention of exit strategy by acquisition or merger. Given current financial conditions, IPOs seem a distant memory. “Really, it’s only been within the last few weeks that the public market has opened back up again,” noted Laura Strong, CEO of Quintessence Biosciences, Inc. “For 12, 14, 15 months, there were no exits….it creates a backlog in the system.”

After over a year of battered markets and upheavals in the financial sector, investors and entrepreneurs are adapting to the present reality. “Flat is the new up,” quipped Suzette Dutch, Managing Partner of Triathlon Medical Ventures. But while investors may be scrutinizing burn rate and re-calculating potential ROI, angel investors and VC fund managers alike remarked on the opportunities available in Midwest biotech. “We have good relationships with local co-investors and we are seeking to provide our next fund with more Wisconsin-based opportunities by deepening our relationships and forging new ones,” said Dutch.

Throughout the forum, as well as during the training workshop “Equity Matters: the Route to NASDAQ” offered on Wednesday September 30, investors offered strategic advice to entrepreneurs. “Part of what most investors are looking for are [entrepreneurs] who are open to being coached, that there is evidence of flexibility,” said Judy Owen, Managing Director, Calumet Venture Fund. Teresa Esser, Managing Director, Silicon Pastures encouraged entrepreneurs to network actively rather than relying on passive communication such as e-mailed business plans, stating, “I want to invest in people who can sell. You have to be capable of selling to your customers.”

Initial reports indicate that the event was fruitful for at least two of the presenting companies. “Eso-Tech and Michelle's Miracle each closed on investments during the Madison events,” noted Lauren Flanagan, Managing Director, Phenomenelle Angels Fund. Bonnie Reinke, CEO of Eso-Technologies, Inc., announced that the company had not only closed on its Series A round as a result of the forum, but that the series was oversubscribed by 20%. “Based on significant interest by a number of individuals, a major angel network and an out-of-state VC at ATLS, [Eso-Technologies] is considering whether to further increase the current round now, or wait and open a new round upon completion of its first human trial in the next few months,” remarked Joseph Hildebrandt, Managing Director of DaneVest Tech Fund. Funding was raised from DaneVest Tech Fund and its Side Fund, with additional contributions by Phenomenelle Angels Fund and Barbara Israel.

Presenting entrepreneurs who are still seeking funding partners will have further opportunities. The forum’s road show will head next to Silicon Valley, CA on October 15 and New York City on October 30.

Companies presenting at the ATLS2009 Madison forum were: A&G Pharmaceutical; Ativa Medial; Avaxia Biologics, Inc.; CanFel Therapeutics, Inc.; Closys Corp.; Curemark, LLC; Epicardial Technologies; EraGen Biosciences, Inc.; Eso-Technologies, Inc.; Ibogen; Kemeta, LLC; Michelle’s Miracle, Inc.; Moerae Matrix, Inc.; PharmaJet, Inc.; Quintessence Biosciences, Inc.; Sequella, Inc.; SPR Therapeutics, LLC; and Stemina Biomarker Discovery, Inc..

Entrepreneurs presenting 2-minute fast pitches to angel investors at the Equity Matters workshop were: Nancy Fraser of Med Legal Consulting Source; Bobbi Gallina of Divine Baby; Merrill Guerra of Real Kidz; Sarah Manski of PosiPair; Jodi Soriano of Ohmx; and Christine Wheeler of Drazil Food.

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Tuesday, February 2, 2010

Women Biotech Entrepreneurs Take the Stage

While I haven't had a chance to catch up on entries for a while, this is the first of three articles I wrote last fall for Wisconsin Technology Network News (WTN News). The AllThingsLifeSciences VC conference proved to be a fascinating glimpse into the biotech entrepreneurial scene, with a twist - all of the entrepreneurs giving pitches were women (and not just peripherally involved, but women who are founders and/or CEOs of their companies). You can see the original article in context here.

Having been a reader of WTN News for some time, it was rewarding to contribute as a writer. Look for future articles!

- Women CEOs of 18 early stage life science companies will gather at the Fluno Center in Madison on September 30th thru October 1st to compete for venture capital at AllThingsLifeSciences 2009. Attendees will include regional and national investors seeking out promising early-stage companies.

“To our knowledge, this is the first such venture capital forum with this focus," said Lauren Flanagan, Managing Director of Phenomenelle Angels Fund.

Similar events will be held in New York City and Silicon Valley.

“This is unique deal flow, not generally seen in Wisconsin,” said Flanagan, who has roots in the San Francisco area and is currently based in Michigan. Flanagan said that the Midwest offers distinctive opportunities for angel and VC investors. “Silicon Valley and NYC don't see many Midwest companies and will be impressed with the talent, generally lower pre-money valuations, and with the non-dilutive financial support that Wisconsin and some other Midwest states provide early stage companies - benefits which can make investment more attractive to coastal investors grown weary of competing for high priced startups.”

Judy Owen, General Partner of Calumet Venture Fund said, "I am so impressed with the quality of women entrepreneurs I have found in the Midwest focusing on Information Technology and Life Sciences.”

Flanagan and Owen are among investors who are bullish on the Midwest technology start-ups. They believe early-stage companies based in the region are undervalued in comparison to startups on the coasts. Skilled talent is readily available in Wisconsin due to proximity to research universities such as UW-Madison and UW-Milwaukee. State support includes the Act 255 Venture Capital Tax Credits program administered by the Department of Commerce, in which certified funds investing in qualified new business ventures can claim a 25% income tax credit on the investment. The result may be a win-win for investors and entrepreneurs alike.

Single-region investment where money flows from Midwestern investors to Midwestern start-ups, however, may not suffice in the long term as more private equity is available on the coasts than in the Midwest, a point not lost on entrepreneurs seeking to take funding to the next level.

Beth Donley, CEO of Stemina Biomarker Discovery, said, “We are a little more than a third of the way to raising a $3 million round…We hope that at the Springboard events…we will attract the remaining investment need to complete our fundraising [and] make contacts on the coasts for future fund raising and eventual exit through acquisition.”

Echoing the need for cross-regional investment approaches, Suzette Dutch, Managing Partner of Triathlon Medical Ventures, said, “We find the best coastal investments often have competing term sheets as there is significantly more venture money chasing the quality opportunities. For this reason we invest in later stage opportunities there and find that coastal investors prefer investing close to home for early stage opportunities. Being based in the Midwest, we are in place to work hands on very early to shape the investments that have true venture scale return possibilities.”

Since 2001, Springboard Enterprises has presented 18 forums highlighting 383 companies chosen from over 4,000 applicants. Of these 383 companies, 82% have received funding and seven have had IPO's.

Sunday, May 10, 2009

Whine Flu

By now, you’ve probably heard something on the news about a new strain of influenza that’s going around. There’s been just a bit of coverage about it.

While listening to the online and face-to-face chatter, it seemed like most reactions fit neatly into two categories:

1. Fear/caution/preparedness/”The sky is falling”. Symptoms include altering trips or school in absence of personal illness or the advice of public health officials; stockpiling large amounts of food, antiviral medicines, face masks, or other supplies; foregoing pork; and flat-out panic upon hearing someone cough.

2. Indifference/outrage/ridicule of those in Group 1. Symptoms include derisive responses to public health warnings; argument that “the media is making this up” and “thousands of people die of the flu every year and only a handful have even gotten sick with this strain, so it’s all nonsense”. This occasionally advances to government conspiracy theories.

I have the upmost respect for both types of responses, each of which has some kernel of rational thought. Furthermore, many people will shift between one mindset and the other. That being said….

Those in Group 1 are wrong. They’re also right.

Those in Group 2 are right. They’re also wrong.

To understand why this is not just Alice-in-Wonderland doublespeak, let’s consider seasonal influenza in comparison to pandemic influenza. And to do that, it’s worth marveling at the biology of viruses.

Different viruses cause a range of diseases: the common cold, HIV/AIDS, smallpox, polio, influenza – just to name a few. Viral particles, or virions, are at the edge of living and non-living. Mere bits of nucleic acid encoding a very few genes and coated in protein, they don’t even have cells. (They don’t need to; they just hijack them.) They can lay dormant for minutes, hours, or years; in some cases withstand extreme heat or cold; and – rarely, but sometimes to devastating effect – can jump from one host species to another. When they infect a host, if they are successful, they have but one objective: to take over the host’s own cells to make more copies of themselves. If such a scrap of non-life could be said to have an ego, they would be narcissistic to the extreme – constantly muttering, “me, and more of me, and more of me…”

The most virulent types of viruses will do this without regard for the survival of the original host. This might seem short-sighted, until you consider that if their progeny can infect other individuals who come in contact with the first host, then it’s not such a dead end after all. All they have to do is make more of themselves; it matters not in whose body this occurs.

Battles between viruses and hosts occur throughout the biological world. It’s one of the cards living organisms are dealt, and when all goes well, we are unaware of the constant viral bombardment our bodies experience. Human immune systems deftly respond to the viruses we come into contact with, sizing up the danger, dispatching them before they cause trouble.

Until that system fails, and we get sick. Who hasn’t had a case of seasonal influenza? Every year, up to 20% of the U.S. population comes down with it – one in five people! – so it is extremely rare to go through your life and never have experienced the symptoms of fever, sharp headache, fatigue, muscle aches, cough, congestion, and sometimes stomach ailments. The telltale sign: you realize you feel slightly off, and then it’s like you’ve been hit by a truck that parks itself on your chest for at least a week, maybe two. That’s the difference between REAL influenza and all the other minor ailments we refer to as “flu”.

Now, the key thing to understand is that viruses are populations that evolve and change and mutate and recombine over time. It’s not one “virus”. It’s a seething, morphing, moving mass of viral particles that evolves with fury. So the strains of influenza virus that are most dominant in one year are almost never the same strains that will cause trouble the next year.

This is why the seasonal flu vaccine has to be prepared anew each season. Influenza experts in the U.S. do their level best, every year, to predict the future. They assess all the data at hand on what strains of influenza are circulating in the environment and the human population months before the upcoming season.

Then they make a guess as to which strains will win out come fall.

Then they ask the manufacturers of influenza vaccines to please make several million doses of vaccine to cover that year’s predicted cocktail.

Then they wait, and hope that they didn’t screw up.

In a normal year, about 36,000 people in the U.S. will die of seasonal influenza anyway. Maybe less – if the strains going around aren’t terribly virulent, and the flu experts guessed right about the vaccine. Maybe more – if they strains are strong, and the flu vaccine missed the mark, or not enough of the population is immunized*.

But the thing to realize is that the vast majority of people who die from seasonal influenza fall into at least one of three categories: the very old, the very young, and the already-ill. Often it isn’t the influenza that actually causes their demise; it’s a secondary infection such as pneumonia that their inadequate immune systems just can’t overcome.

But every so many years something different happens. A new strain, a new kid on the block, starts going around. It’s different from the others. It likely just recently discovered how hospitable humans could be as a host. Before it started looking at us as prime real estate, it preferred to cause misery in another host species. Birds, say. Or pigs. It helps if it’s a species in which there is a reasonable amount of human-animal contact, because it first makes the jump from the animal to the human caretaker.

Sometimes this ends up being a dead end for the influenza strain. It can jump from pigs to humans as a one-time deal, but can’t transmit farther.

And then sometimes, it accumulates another mutation or two, swaps another gene with a different influenza virus strain, and voila – it’s new and improved. Stronger. Better. It’s capable of human-to-human transmission.

In other words, it’s a potential pandemic strain.

So what do you look for in a pandemic influenza strain? Well, ideally it has a high rate of person-to-person infectivity. It will be completely unknown to the global human population, so it trips up immune systems that have never encountered it before. It will thus have a different pattern of infection: it will hit relatively young adults very hard. Now remember, young adults may get seasonal influenza, but they don’t normally die of it unless they have underlying health problems. With a pandemic strain, though, all bets are off.

So, how bad can pandemic influenza outbreaks get? Well, it depends on the strain and the times. Let’s look at the 1918 global influenza pandemic outbreak, for example. It’s a classic.

In the spring of 1918, there was a global wave of illness that was noticeable, but mild in terms of deaths. Autumn, however, brought the first of two more waves that were absolutely lethal. It’s been estimated that a total of 500 million people - or one-third of the world’s population at the time - fell ill by the time the epidemic was over. Of this, between 50 million and 100 million people worldwide died. The case fatality rates were over 2.5%, as compared to about 0.1% for typical seasonal influenza.

Put in perspective – if the same pandemic were to occur today given an estimated global population of 6.77 billion, 2.25 billion people worldwide would fall ill, and over 56.4 million people would die by the time the epidemic was over.

The thing is, when the 1918-1919 influenza outbreak happened, public health officials didn’t even know it was influenza. It happened too fast, spread too quickly, killed too quickly. In some cases it actually killed within hours, not days. We now know this was due to a violent overreaction by the immune system to the novel strain, causing viral pneumonia and what is termed a “cytokine storm”. The result? Massive, rapid filling of the lungs with fluid.

At the time, medical experts thought the disease was caused by a bacterium, not a virus. The pathogenic agent wasn’t identified until the 1930s. And it wasn’t until the mid-1990s that the genetic sequence was painstakingly reconstructed by researchers at the CDC using preserved autopsy specimens so scientists could try to figure out what was so very different about this strain.

Now keep in mind that there were a lot of other factors at play in 1918-1919. Lifesaving tools like respirators, antiviral medications, and antibiotics to treat secondary infections were either in limited supply or nonexistent because they hadn’t been developed yet. And World War I played a role; fighting was heavy throughout the spring and summer; troops were being shipped to and fro; and millions of people in Europe were displaced, on battlefields, taken prisoner, and otherwise subject to poor sanitation and health. Armistice didn’t occur until November 11, 1918, and the aftermath of war in terms of public health continued for months to years.

Mysteries remain, though we now know more about the strain itself. Virologists classify influenza strains in terms of the “flavor” of two particular proteins that are found on the viral coat: hemagglutinin, or “H”, and neuraminidasae, or “N”. The strain that caused the 1918 epidemic was an influenza A(H1N1) strain. Its origin is still unknown. Genetically, it appears to have started off infecting pigs, but the actual location from which it originated is still unknown. There is no smoking gun, or hog, as it were.

OK, so fast-forward to April 2009. One of the jobs of public health officials all over the world is to keep tabs on disease outbreaks of any kind, and the World Health Organization is charged with coordinating communication and response.

So medical practitioners in Mexico started to notice something. There was a large spike in influenza cases. This is atypical for the warmer months of spring and summer. Influenza virions usually survive and transmit more easily in cold, dry weather, when they hang in the air longer and people are congregated indoors. Even more alarming, it was causing what appeared to be an abnormally high death rate. And further? The people who were dying were young adults – in their 20s and 30s. Preliminary testing indicated it was a strain of influenza A, and appeared to be related to a strain of influenza that is endemic in pigs, but beyond that it couldn’t be typed.

So let’s think back again to the hallmarks of a pandemic influenza strain: novel? Check. Person-to-person transmission? Check. Kills young adults? Check.

You can now see why public health officials all over the world started to sweat.

The response over the next ten days was swift, and from all accounts thus far, effective. Mexico took measures to control the outbreak that included shutting down schools and public gathering places for a period of time. The Centers for Disease Control developed assays to determine the strain and began scaling up test processing. Healthcare officials set guidelines for patient testing and within days the pattern of disease became much clearer. Laboratories with expertise in growing “seed strains” for vaccine development were pressed into service. Clinical diagnostic technicians worked round the clock to process test samples. And by April 27, scientists at the CDC had completed sequencing the genome of the new strain and made the data available for researchers all over the world to examine.

As time progressed, public health officials began to be cautiously optimistic. It looked like the number of cases and deaths were lower in Mexico than initially projected, and although the disease was spreading, the death rate outside of Mexico appeared very low for reasons that are still not completely understood. Analysis of the strain’s genome indicated that while the 1918 pandemic strain was an ancestor, it lacked some of the features of the 1918 strain thought necessary for high lethality.

However, caution is still warranted. Though the number of hospitalizations in the US have remained low, the average age of patients hospitalized with this strain is only 15. The months to come will bring careful monitoring by the WHO and CDC. After all, this strain could easily evolve into a more virulent form. The very worst thing we could do is collectively ignore the advice of public health officials in coming months.

So was the response overblown? In a word, no. That’s the irony of addressing pandemic disease threats: when the response goes as it should, nothing happens. Beautiful, beautiful nothing. Public health experts are always in a difficult bind. If they sound a global alarm, their recommendations can bring travel, trade and economic growth to a screeching halt. And depending on the risk level of a particular outbreak, it is arguably worth it. But second-guessing after the fact is largely fruitless. If disease breaks out in spite of control measures, then we didn’t do enough. If it doesn’t break out, either we did enough, or it wasn’t going to happen anyway. But as you can appreciate, the risk in this case was very, very real – and the response has been dialed back appropriately as new information came in.

For comparison, let’s keep the impact of this in context with other viral diseases. Below I’ve charted average yearly deaths due to AIDS, rabies, ebola, seasonal influenza, and the pandemic influenza of 1918 – all diseases caused by viruses. The viruses with the highest lethality rates are actually rabies, which is 100% lethal if untreated, and ebola, which can be up to 90% fatal. But each of these viruses has fairly limited transmission patterns. Rabies in industrialized nations has been kept in check by vaccination programs for companion animals and sometimes even for at-risk wildlife. Ebola, like other hemorrhagic fevers, is highly lethal and contagious – but since it is transmitted from animals in remote rainforest areas of African nations, outbreaks thus far have been limited to small villages that have little interaction with major population centers. Seasonal influenza results in between 250,000-500,000 deaths annually. AIDS-related deaths top 3.1 million, and AIDS is a much, much more serious threat in the long term because these deaths occur year after year after year; whole generations are being lost, particularly in African nations. However, you can see that as far as death toll within a single epidemic year is concerned, a severe pandemic influenza outbreak tops them all. This is because influenza in general is more easily transmitted. Unlike HIV or rabies, it can be spread by coughing, sneezing, or touching surfaces that have respiratory secretions on them.

(click on image to enlarge)

The moral of the story? Listen carefully to the official CDC and WHO guidelines, and realize that recommendations are made soberly and deliberately by some of the best public health experts in the world. Take low-cost but effective measures like washing your hands and your childrens’ hands, and if you or your family members become sick, take the time needed to recovery fully before heading back to work or school. Don’t live in fear. We are fortunate to be living in a time when science and medicine both allow information to be shared quickly and treatments to be widely available. Don’t stockpile antiviral drugs – save them for people who really need it. If you were to fall ill, you’d get the meds you need. In a pandemic, they are distributed on the basis of need, even to those lacking health insurance. And be a critical consumer of the most sensational news coverage; challenge journalists who you think might be presenting dubious information.

Finally, realize that if the situation changes, often it’s because the virus itself has evolved. It could fizzle out within the population, or it could pick up a few changes here and there and become more fierce.

Note: The title “Whine Flu” came from a very non-scientific Facebook survey in which I solicited from friends some new-and-improved names for influenza A(H1N1). The name “whine flu” was submitted by a very astute 6-year-old. The strain was originally dubbed "swine flu", but the WHO hastily substituted "influenza A(H1N1)" after initial reports on “swine flu” resulted in a backlash against the pork industry, including the culling of all pigs in Egypt. (Cooking pork kills viruses, so the disease cannot be caught eating pork meat. I suppose that if an infected pig was processed in unhygienic conditions, and the meat was covered with pork respiratory secretions, and you stuffed the raw meat up your nose, there might be a chance of a problem. Presumably snorting raw infected pork is not a common pastime. Also, notably, although there are genetic indications that it is related to an endemic strain of swine influenza there is as yet no report of outbreak among livestock.) For more on the naming controversy, see

Other footnotes and sources:
* Despite vigilant public heath campaigns to increase seasonal influenza vaccination rates among the elderly, studies in the U.S. and Italy has found that paradoxically there has been no decrease in deaths among those over age 65 as vaccination rates have gone up. A plausible hypothesis for this is that immune response to vaccines becomes less efficient as one grows older, so increasing vaccination among seniors reaches a point of diminishing returns. In light of this, public health officials are considering re-focusing vaccination strategy on younger members of the population who come in contact with the elderly, thereby protecting seniors by proxy. For more details, see

Avian influenza A(H5N1) is different strain novel swine flu, which is influenza A(H1N1). The avian influenza strain is being monitored as a potential pandemic strain. WHO statistics indicate that through 2009, there have been 423 laboratory-confirmed human cases of avian influenza A(H5N1) and 258 deaths worldwide, which is fairly low suggesting inefficient human-to-human transmission thus far, but the lethality rate is an alarming 61%. Recall that it’s 0.1% for normal seasonal influenza.

Source of statistics for Table 1: HIV/AIDS, Yale AIDS Watch (; rabies, World Health Organization (; ebola, World Health Organization (; seasonal influenza, World Health Organization (; 1918-1919 influenza pandemic, Tumpey TM and Belser JA (2009) Resurrected pandemic influenza viruses. Annual Reviews of Microbiology 63:79-98; Taubenburger JK and Morens DM

Update, May 11, 2009: A research article on the initial epidemiological analysis of the swine influenza A(H1N1) strain confirms that the outbreak appears to be behaving in pandemic fashion, not seasonal fashion. Clinical severity seems on par with the 1957 pandemic, but not the 1918 pandemic. The epicenter of the outbreak has been narrowed to La Gloria, Veracruz, Mexico.

Image credit: Centers for Disease Control, Negative stain EM image of the swine influenza A/CA/4/09.

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Friday, March 6, 2009

Mark Twain on the USPTO, circa 1867

February was a blur; I have three or four new posts in various stages of completion, so check back soon. In the meantime, I offer a quote from The Innocents Abroad, which I'm in the midst of reading. The remark was written by Twain (or Sam Clemens, as it were) while he was touring Rome and the Vatican on an expedition to the Mediterranean in 1867, and published two years later.

The popes have long been the patrons and preservers of art, just as our new, practical republic is the encourager and upholder of mechanics. In their Vatican is stored up all that is curious and beautiful in art; in our Patent Office is hoarded all that is curious or useful in mechanics. When a man invents a new style of horse collar or discovers a new and superior method of telegraphing, our government issues a patent to him that is worth a fortune; when a man digs up an ancient statue in Campagna, the Pope gives him a fortune in gold coin. We can make something of a guess at a man's character by the style of nose he carries on his face. The Vatican and the Patent Office are governmental noses, and they bear a deal of character about them.

Fascinating read, this book - so many deeply imbedded "modern" American personality quirks, assumptions, and unconscious habits are described in full. Try this: read Twain with tongue firmly in cheek. Watch 20 episodes of The Daily Show. Read more Twain. Read America (The Book): A Citizen's Guide to Democracy Inaction. And then tell me if there isn't something to the notion that Jon Stewart is a reincarnation of Twain.

Photo of Mark Twain/Sam Clemens was taken by Matthew Brady in 1871.

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Friday, February 6, 2009

The Best Things in Life are Free, Part II

For science history enthusiasts, this is a banner weekend. Free events at the University of Wisconsin-Madison campus promise to be fascinating glimpses into the lives of two of the most ground-breaking scientists in history, Galileo and Charles Darwin.

The first event is tonight, Friday February 6, at 7:30 pm. A concert by the musical ensemble Galileo's Daughters (Sarah Pillow - soprano, Mary Anne Ballard - viola da gamba, with Ronn McFarlane - lute as Vincenzio Galilei) will present "Perpetual Motion: Revolutions in 17th Century Science and Music". This multimedia performance will include music played on period instruments along with remarks by Dava Sobel, author of Galileo's Daughter: A Historical Memoir of Science, Faith, and Love. Sobel's book is an account of Galileo's relationship with his eldest daughter, a cloistered nun. Over 100 surviving letters between them provide incredible insight into Galileo's scientific struggles, his close relationship with his daughter, and his complex relationship with the Catholic Church. He was ultimately convicted by the Inquisition for maintaining the heretical belief that the earth revolved around the sun. The concert will be held in the Margaret H’Doubler Performance Space of Lathrop Hall.

And on Saturday, an all-day event free to the public will celebrate the 200th anniversary of Charles Darwin, and the 150th anniversary of the publication of "On the Origin of Species by Means of Natural Selection", the first-published account of the theory of evolution. Darwin Day will include talks by Sean Carroll, a UW-Madison professor of Genetics who has written several popular books on evolutionary development; Patricia McConnell, an internationally-known expert on animal behavior; and other lectures, presentations, a workshop for teachers, and a panel discussion on science and the media. Darwin Day will be held from 9 a.m. to 4:30 p.m. in the Microbial Sciences building at the corner of Linden Drive and Babcock Street.

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Friday, January 16, 2009

Talking About the Weather

I would have posted this sooner, if not for the urge to hibernate.

It didn’t use to be this way. When we moved to Madison in late 2001, the first few winters lacked teeth. Sure, there was the occasional snowstorm. The pesky ice that would enrobe power lines and sidewalks. I distinctly recall falling flat on my back once, staring at the sky, and thinking, “I really need to invest in some Yak Trax.” But really, it was all sunshine and lollipops compared to the past two years. We went from an average of about 45 inches of snowfall per season, to a total of 101.4 inches in 2007-2008. Then, in December 2008, 38.6 inches of snow fell in a single month. Periodic blizzards are often punctuated by extreme cold, referred to by meteorologists as “Alberta clippers”, as if calling flesh-freezing winds something jaunty makes them adorable.

But adaptation is a certainty, and it hasn’t taken Madisonites long to become well-versed in snowblowers, roof rakes, and antilock braking. Many of us have become one with our inner bears, as well. When the sun sets at 4:30 PM and the wind chill dips to -25 degrees Fahrenheit, please forgive the occasional cave-seeking and growling behavior.

Which begs the question: if necessity really is the mother of invention, can the need to innovate trump the need to hibernate? Musing, I searched the US Patent and Trade Office issued patent database by inventor city “Madison” and keyword “snow”. Sadly, searching for patents based on geographic limitation is not altogether precise, as the USPTO takes “inventor city” literally and truncates the state. Thus, there were some false hits for Madison, Georgia and the like. However, after scanning over the 109 issued patents (dated from 1976-present) that resulted, two portfolios caught my eye.

The first set of patents is assigned to a heavy trucking and snow removal equipment company in Madison named Burke Truck & Equipment, Inc. This forty-year-old private company manufacturers, tests and sells snow removal trucks. Inventors Daniel and/or Jayson Jones (likely father and son?) have been granted four patents for snowplow edges, mounts, and assemblies. Check back for more information; I’ll request quotes about company history, but this being their busiest time of the year, it may be a while before we hear back.

The second set of patents all have the same assignee, Weather Central, Inc. As it turns out, in the mid-1970s a meteorologist named Terry Kelly – then affiliated with the UW Space Science Center – decided that there might be a role for computer graphic animation in weather reporting. He teamed up with colleague and computer scientist Richard Daly, and together they built some of the first computer graphic systems for weather tracking, forecasting and reporting. According to the Colorado Weather Almanac (thanks, Google Books!), Kelly and Daly founded ColorGraphics Weather Stations - to commercialize a system for computer graphic display of satellite cloud data. Considering that this was in 1979, it was no small feat. The first system actually ran on an Apple II, but there was no connectivity to a TV station routing switcher, so broadcasting the animations required aiming a video camera at the computer screen.

From these humble beginnings, the company became the leading company for meteorological computer graphics. Weather Central was sold to Dynatch Corp. in 1982, but Kelly and Daly bought it back in 1994, carefully cultivating it ever since. It continues to have the highest market share in computer graphics meteorology service for broadcast television, and its patents (at least 13 issued, one pending) cover a range of weather reporting methods. In recent years, it has focused on services and products for HD weather broadcasting, and the type of extensive computer animation that is beloved by weather broadcasters everywhere. And occasionally lampooned or parodied by The Daily Show.

A fascinating August, 2008 interview with Terry Kelly by Wisconsin State Journal writer Melanie Conklin highlighted some of his varied interests. In addition to his involvement with Weather Central, Kelly also launched an online personalized weather reporting company called MyWeather, holds a financial stake in the liberal radio network Air America, and is himself the major production force behind the annual Rhythm and Booms fireworks show in Madison.

Fireworks and meteorology….what’s the connection? Well, during the interview, he shared that “One of my sons, Matt, was about 13 and he said, 'Dad, all your passions are the same. Think about it - you love to garden, you love flowers. You love weather and you love fireworks." I said, 'How are those the same?' He said, 'Don't you get it, they are all fireworks. Flowers are frozen fireworks - in fact most fireworks are named for flowers. And what you really love about weather are the storms and lightning, the booms - those are nature's fireworks. It's obvious to me you have one passion and it just expresses itself in a number of different ways.'”

So comforting to think of fireworks and summer nights now, when the temperature outside is -16 degrees Fahrenheit with wind chill dipping down to -37.

Photo titled “Ice and Sky” (2009) provided by my husband, R. Clint Thayer. See more at

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Saturday, January 3, 2009

Six dots that open the world

The holidays often bring news from friends in all corners of the world, and this year was no exception. One of the most fascinating updates was from a friend living in East Lansing, Michigan, where I attended graduate school at Michigan State University. I met her when I was studying at the MSU-DOE Plant Research Laboratory. A member of the talented staff who keep the institute running, she is a scientific editor and often lent her keen eyes to my first manuscripts. She wrote this year to describe dual and overlapping interests, music and Braille:

“Personally, my life is becoming ever more centered around music. I continue to struggle through violin lessons (with a most wonderfully patient teacher), and to play in a quartet and community orchestra--so thrilling! About five years ago, I was certified as a braille transcriber and joined a group of braillists transcribing textbooks into braille for students. That group disbanded last fall, as most of the younger members were in their 70s and had been brailling for decades. So, I decided to pursue my original idea, which was to work toward certification in music braille. I have read that there are fewer than 40 people in the country who have such certification, so the need is great. I am constantly overwhelmed by the ingenuity of Louis Braille, who devised both of these systems of representation by dots. A braille cell has only six dots, and yet a sheet of music, with different voices, lyrics, whatever, can be reproduced in a series of braille cells. Of course, it's incredibly complex and there are days when I wonder how I could have imagined this old dog could learn a new "language" at my age, but I also really enjoy working at it. It seems to satisfy my urge to work crossword puzzles, yet has the added attraction of being potentially useful. If I manage to finish the course, that is. :)

January 4, 2009, is the 200th anniversary of Louis Braille's birth and the National Federation of the Blind is sponsoring initiatives designed to bring the importance of braille literacy for blind children to national attention. You can view a very moving video, "Braille: Unlocking the Code," on the NFB website: In March, a limited edition coin commemorating Braille's birth will be issued to raise awareness of the needs of blind people.”

My friend’s letter prompted me to learn more about the braille system and the life of Louis Braille. Interestingly, the precursor of the Braille system was a method of military communication developed by Charles Barbier de la Serre for Napoleon’s army called “night writing”. Berbier’s method used a series of twelve raised dots to represent 36 sounds. The military desired such a system so that soldiers could communicate battle plans at night silently, without need for illumination. However, when Berbier demonstrated his system to Louis and other students at the Royal Institute for Blind Children in Paris, Louis immediately realized why the system failed to be adopted: the human finger could not accommodate twelve dots, and the code was too complex. By the age of 15, Louis had developed a new method that relied on a six-dot cell. Braille and its precursors are thought by some linguistic experts to be the first example of a binary written language system in history. In current usage, the English alphabet braille system includes contractions and contextual meaning for needed brevity.

Though Braille’s innovative contribution was enormous, it does not appear that he (a French citizen) ever sought a U.S. patent claiming the braille system, although he did publish a book in 1829 about the system titled “Method of Writing Words, Music, and Plain Songs by Means of Dots, for Use by the Blind and Arranged for Them”. However, a search of the US Patent and Trademark Office site of issued patents with the term “braille” returns 1907 patents, ranging in date from 1926 to the present. Examples include display apparatuses for the braille system, writing devices and printing systems, and even a chess set incorporating braille notation (US Pat. No. 7,347,421).

If you are interested in becoming a certified braille transcriptionist, you can find more information from the National Federation of the Blind. Madison residents can attend a local Braille celebration event hosted by the Wisconsin Council of the Blind and Visually Impaired this Wednesday, January 7; for more information, see If you don’t live in the Madison area, check around for a local event – celebrations and information sessions are being held nationwide.

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Friday, December 26, 2008

Killer mold reveals its romantic side

Take a deep breath. Now, don’t panic, but unless you live in a sterile chamber, you just breathed in between 1 and 100 spores of a killer mold called Aspergillus fumigatus. The spores are lightweight, microscopic, and everywhere – there’s literally no escaping them. However, if your immune system is intact (and I sincerely, absolutely hope that is the case), you need not fear for your life. The spores you just inhaled will be efficiently attacked by your innate immune system, which will render them dead as a doornail. And rest assured that this microscopic drama will continue to occur every day of your life, as it has for as long as you’ve lived.

Unfortunately, this is not always the case for HIV patients in advanced stages of AIDS, and cancer patients or organ transplant patients who are on high doses of immunosuppressants. For these groups, Aspergillus fumigatus can be deadly. It is one of the most frequent causes of hospital-acquired fungal infections. When it takes hold, it can invade the lungs or even other areas of the body, infiltrating through delicate tissue and causing terrific damage. Only a handful of anti-fungal medications are effective. We desperately need more in our arsenal, because some of the existing ones can be dangerous to the kidneys. With a mortality rate of over 50%, invasive aspergillosis is of grave concern.

I spent two years studying Aspergillus fumigatus while I was a postdoc in Nancy Keller’s laboratory at UW. Fungal biology was a new field to me; all of my previous research was in plant biology. We tried to understand how the mold produced certain toxins. Although A. fumigatus is a pathogen, researchers blessed with healthy immune systems (meaning, fortunately, our whole lab) do not have to take extensive protective measures to work on it, although we always used equipment called a laminar flow hood and wielded plenty of ethanol and bleach.

But one of the most frustrating things was that, unlike some of its relatives (including the innocuous model species Aspergillus nidulans), Aspergillus fumigatus had no known sexual stage. That meant we couldn’t use any time-saving classical genetic approaches when we worked on “fumi”, as we sometimes called it. Every time you wanted to study the effect of a particular gene, you had to artificially delete it by a laboratory method: generating naked protoplasts by digesting away the cell wall of spores, then bathing the protoplasts in DNA that had bits of the gene you wanted to delete flanking a “marker” (a gene that would allow transformants to survive on selectable nutrient media). This would ensure that the protoplasts would take up the replacement DNA, insert it in place of the existing gene. The resulting transformed mold strains would survive on the selectable media while those that weren’t transformed would not, since they didn’t have the marker gene. The “gene knock-out” process itself took an entire day, plus whatever length of time it took you to generate the necessary DNA, and screening for the desired strains took days to weeks. Progress was much faster with the sexually reproducing Aspergillus species, because if you found a mutant you were interested in, you could combine that mutation with another one by a simple sexual cross.

Fungal species for which the sexual stage is unknown are called “Fungi Imperfecti”. This used to be a formal taxonomic designation but is now used more loosely to describe sex-starved fungi. Just because a sexual stage hasn’t been discovered, of course, doesn’t mean that it won’t be. Some imperfect fungi do reproduce sexually – but may do so rarely or under conditions that are very hard to replicate in the laboratory. When a sexual stage is discovered, however, it is a big deal. A new Latin name is assigned to the sexual form, and it is fully documented in academic journals. With luck, scientists begin to understand what critical environmental factors are needed for the fungus to become, well, amorous.

A new article released online ahead of print in Nature describes exactly this. Three researchers - Celine M. O’Gorman, Hubert T. Fuller, and Paul S. Dyer of the University of Nottingham in the UK – hit the Aspergillus sexual jackpot. After collecting 91 isolates of Aspergillus fumigatus from soils in Ireland, the scientists did what many had tried before: they placed spores of different pairs of isolates on either side of nutrient-filled petri plates, used several different types of nutrient media, placed the plates in an incubator in the dark and hoped for the best. (No word on whether they played Barry White.)

Six months later, they saw something that no other humans in the world had ever seen before. On the plates containing oatmeal agar media, sexual A. fumigatus fruiting bodies had formed. Glistening spherical cleistothecia emerged in the margin between two compatible strains, the product of their union. As with other studied Aspergillus species, inside the cleistothecia were tucked ascospores, or the progeny. The researchers were able successfully cajole the ascospores into germinating, resulting in fungal baby photos that will be shown for decades to come.

So what does this all mean? Well, as a practical measure, it should speed up the pace of research on Aspergillus fumigatus – which is very much needed considering the impact of invasive aspergillosis on human health. It also helps us understand the biology of this fungus more. This mold is a major component of soils and compost, and plays an important role in recycling nutrients in the environment. We need to know how it grows, adapts, evolves, and genetically recombines to understand its place in the world – even as we try to make sure that our own lungs are not its rightful home.

In this respect, though, confirming that Aspergillus fumigatus reproduces sexually is fairly ominous. Resistance to the few antifungal medications we have available will emerge more quickly for a sexually reproducing species than one that only proliferates the less superior “parasexual” cycle that some mold species have, or by asexual reproduction.

Some years ago, I attended a social function at the UW Department of Medicine and happened to be seated by an oncologist. When I told him I was doing research on aspergillus, his face turned doleful. With the grim pragmaticism of one who has lost far too many patients to a complication, he said simply, “I hate aspergillus.” I can only hope that this and other research articles to come aid his efforts to keep this killer mold from harming more patients.

The scanning electron image of an Aspergillus fumigatus conidiophore was made available by the National Institutes of Health. One of the best information sources on the web for patients, medical professionals, and researchers alike is The Aspergillus/Aspergillosis Website at

Though a more modest contribution to the Aspergillus fumigatus literature, the final article resulting from my postdoctoral research was recently published in the journal Eukaryotic Cell. It focused on a gene and protein involved in chromatin remodeling; a topic for another post….