One Flu Over the Cuckoo’s Nest: Has the New Avian Influenza Virus Achieved Human-to-Human Transmission?

 

By Asu Erden

Human cases of H7N9 – a new avian influenza A virus – were first reported in China between February and March 2013. It is believed that infection with this virus requires exposure to poultry but when and how the virus crossed the species barrier remains elusive. The Centers for Disease Control (CDC) originally estimated that up to 20% of the people that become infected with this virus die. There are currently no vaccines available against this avian flu virus, although clinical trials are under way with the help of the World Health Organization (WHO). The disease caused is severe and mainly affects the respiratory tract. Li et al. recently published a study in the New England Journal of Medicine that sheds light on the epidemiology of the disease caused by H7N9 and suggests that the virus might have achieved human-to-human transmission.

 

In their study, Li et al. investigated 139 confirmed cases of H7N9 from 12 different areas in China (including Shanghai and Beijing). Their aim was to better understand the epidemiology of the lower respiratory illness caused by this avian flu virus newly infecting humans. They were able to identify cases thanks to the Chinese surveillance system for pneumonia of unknown origin, which was put in place in 2004 at the time of the H5N1 avian influenza outbreak. The study confirmed that infection with H7N9 is most likely caused by exposure to live animals (poultry, birds, or swine). Most of the studied cases (77%) occurred in older individuals with the median age of patients being 61. Despite an older age distribution, the H7N9 virus seems to infect people from a broader age range than H5N1 did a decade ago.

 

This emerging zoonosis seems to be particularly virulent. After an incubation period of 7 days, H7N9 caused an acute illness characterized by severe lower respiratory symptoms – including pneumonia and respiratory failure – in all studied patients. The case fatality rate was also high, with 34% of patients dying. This rate is significantly higher than originally estimated by the WHO but remains lower than for H5N1. Further studies are required to establish the true case fatality rate of the disease caused by H7N9 in the overall population.

 

Li’s group also carried out family cluster analyses based on four families in which two or more individuals had confirmed cases of H7N9. In each cluster, one of the individuals became infected due to close contact with poultry (e.g. visits at poultry markets) but the other infected individuals never came in close contact with live animals. This suggests that the virus might have evolved to achieve human-to-human transmission. On the other hand, Li et al. also followed over 2500 close contacts of their 139 confirmed cases and only 1% developed respiratory symptoms, none of which tested positive for H7N9. Of note, however, is that these individuals were only followed for 7 days after contact and only single swabs were collected from them. This likely decreased the likeliness of detecting H7N9 cases among close contacts.

 

The most significant finding from this study also happens to be the only negative data that were presented:  Li et al. were unable to discard the possibility that H7N9 can transmit from human to human. Given the virulence, case fatality rate, and ongoing outbreak of the H7N9 avian influenza virus, the possibility of human-to-human transmission is cause for concern. The establishment of a putative human reservoir would allow for fast spread of the virus worldwide and should be scrutinized by public health officials.

Stopping the Unstoppable: New Drug Candidates Against MRSA

By Elizabeth Ohneck

Rapidly spreading antibiotic resistance is threatening our arsenal of treatment options against bacterial pathogens. One microorganism of particular concern is methicillin-resistant Staphylococcus aureus, or MRSA, which causes diseases ranging from mild skin infections to pneumonia and sepsis. While originally primarily found in immunocompromised patients in hospital settings, MRSA is now being acquired by otherwise healthy individuals in the community. The development of effective new antibiotics requires identification of drug targets essential to bacterial survival, resistant to the development of mutations, and not found in humans. Recently, the MRSA pyruvate kinase (PK) was identified as one such target, as it is an important player multiple metabolic pathways in MRSA. While humans and other mammals also have PK, the MRSA and mammalian PK enzymes significantly differ in structure, allowing specific targeting of MRSA PK. Additionally, because this enzyme is critical in metabolism, it is expected that PK will be less tolerant to the development of mutations, reducing the risk of acquiring resistance to drugs targeting PK.

 

Previous chemical screens identified several indole-based compounds that were able to selectively inhibit MRSA PK and kill a panel of other Gram-positive bacteria. The road from discovery to drug is long, and in a recent paper in Bioorganic and Medicinal Chemistry, Kumar et al. detail their efforts to optimize these compounds for drug development. Using a chemical scaffold based on a compound previously crystallized bound to PK, the researchers created a panel of bis-indole compounds varying slightly in size, shape, charge, or chemical group content, and examined their antibiotic potential. The ideal optimized drug candidates should both inhibit MRSA PK and kill MRSA at low concentrations, and lack both activity against mammalian PK and toxic effects on human cells.

 

Using a photometric assay for purified MRSA PK activity, Kumar et al. were able to identify several potent inhibitors of MRSA PK. Surprisingly, some of the most effective PK inhibitors were ineffective as antibiotics against S. aureus, as determined by minimum inhibitory concentration (MIC) assays. For a few of these compounds, improving solubility lowered the MIC to an acceptable level, likely by improving the ability of these compounds to enter the bacterial cells. For many others, altering the solubility had little to no effect. The research team wondered if the inability of these compounds to kill S. aureus despite their potent PK inhibitory activity was due to removal from the bacterial cell by efflux pumps, molecular machines in the bacterial cell wall that recognize toxic compounds and actively export them from the cell interior. Efflux pumps are major contributors to the multidrug resistance phenotypes of many bacterial pathogens. By administering the efflux pump inhibitor verapamil with the indole compounds, the researchers were able to drastically reduce the MIC of several compounds, demonstrating some of these molecules can be recognized by MRSA efflux pumps, which creates concern for the development of resistance to these particular compounds and places further constraints on the specific bis-indoles that can be pursued as drug candidates.

 

Several compounds from the panel were found to be both effective PK inhibitors and antibiotics, and Kumar et al. demonstrated that the 3 most effective compounds were active against both a laboratory strain of S. aureus and the MRSA strain MW2. Additionally, they determined that the ability of these compounds to kill S. aureus is dependent on PK activity, as these compounds were unable to kill a strain in which PK had been removed. As the ability of S. aureus to survive without PK requires special growth conditions extremely unlikely to be found in a host during infection, the inability of these compounds to kill a PK mutant is not particularly concerning for drug development. Finally, the research team found that even at high concentrations, the indole compounds were both unable to inhibit mammalian PK and not significantly cytotoxic toward HEK 293 cells, a cell line derived from human embryonic kidney cells.

 

In summary, Kumar et al. have identified several indole-based compounds that are able to efficiently inhibit MRSA PK and kill S. aureus without detrimental effects on mammalian PK or human cells. The lead compounds will be further tested for effectiveness in animal infection models. MRSA PK inhibitors may provide a novel drug treatment against this highly multidrug resistant pathogen.

Tag, your turn! – Developments in Contraception for Males

 

By Evelyn Litwinoff

With Valentine’s Day behind us, let’s talk about a more detail-oriented part of relationships: contraception.  The pill, the ring, the patch, the shot… there are so many choices for women to choose from when it comes to picking their contraception.  But for guys?  Condoms, withdrawal (or “pulling out”), and sterilization are their main options, and what dismal options those are.  The effectiveness of women’s contraception far exceeds the options available for men, so no wonder the responsibility tends to fall more on women. Wouldn’t it be great if a high-efficiency contraceptive method existed for guys so that the responsibility for contraception could be more equally shared?  This would not only make a difference in first-world countries where pharmaceutical companies could profit from this type of drug, but it would also help developing countries where there are high rates of maternal death from unsafe abortions and other complications of unwanted pregnancies.

Most contraception options on the market today are based upon the first advances from the mid 1900s, namely the pill and intrauterine devices for females.  These methods are all centered on inhibiting ovulation or interfering with the menstrual cycle.  Methods of contraception for males date back to the 5th century BC where men would soak their testicles in a hot water bath to prevent conception.  Despite this heat-shock technique being far from fool-proof, it is still recommended today in conjunction with other physical barriers. Furthermore, many male hormonal and steroidal drug options have serious side effects, such as irreversibility and loss of libido, which are definitely counterproductive for a contraception device.

However, recent advances in this field may change all that.  In 2012 Matzuk et. al found a small molecule inhibitor, JQ1, that inhibits BRDT, a protein essential for spermatogenesis.  Wild-type mice that lack BRDT are sterile, making it a compelling target for contraception development.  Their mating studies show that the contraceptive effect of JQ1 is dose and time dependent, meaning that treatment with JQ1 will only result in sterility while the drug is administered.  Furthermore, JQ1 does not adversely affect testosterone levels, mating behaviors, or offspring viability.  Taken together, this makes JQ1 an exciting possible drug choice for further development.

I did a quick search on Scizzle to see if anything new had been published on the JQ1 front, but I found more on JQ1 as a possible cancer drug rather than a contraceptive device.  Obviously the effects of JQ1 would need to be studied in humans before a pill could become available.

A Google search on male contraception led me to a different type of approach.  Instead of pursuing an oral drug, the Parsemus Foundation is developing the polymer gel, Vasalgel, to block sperm transport. Vasalgel would be injected into the vas deferens instead of cutting this organ as in a vasectomy.  Then if and when the man decides he wants to have children, the polymer can be flushed out with another injection.  Vasalgel is still under development in the US but the first clinical trials are projected to begin by the end of this year.

It will probably be a few, OK many more years before we see a male equivalent birth control pill on the market, but this is certainly an exciting area of research!

If you’re interested in learning more, check out the Male Contraception Information Project at http://www.newmalecontraception.org/

STAP細胞:ちょっと話が上手すぎる?

 

By Sally Burn. PhD

Translated to Japanese by Jun Seita, M.D., Ph.D.

For the original post in English, click here.

2週間前、私たちは日本の理研・発生・再生科学総合研究センターの科学者が発表した、画期的なSTAP(刺激惹起性多能性獲得)細胞についてレポートしました。STAP細胞は、特定の機能に特化した分化細胞に物理的なストレスを与えることにより作成されます。これにより細胞は未分化で多能性をもった状態へとリプログラム(初期化)され、リプログラムされた細胞は胎児組織だけでなく胎盤などの胎児外組織の両方に分化することが示されました。この発見は、Nature誌に2報[1,2]セットになった論文として発表され、科学界に興奮と驚愕を巻き起こしました。患者特異的再生医療などへの応用の可能性は興奮を、その仕組みの驚くほどの簡単さは驚愕をもたらしたのです。実験で主に用いられた外部刺激とは酸でした。成熟した細胞を酸にさらすだけでリプログラミングが始まるのです。様々な反応の中で最も好意的なものは「ほんとにそんな簡単に出来るの?」でした。一方、数多くの著名な科学者含む多くの人々は懐疑的なコメントを浴びせかけました。

 

論文の発表から今日までに様々なことが起こりました。理研は論文の正当性に付いて公式な調査を始めインターネット上では人々が再現実験の試みを報告し合い、また人々のリクエストに応じてNatureは論文を誰もが無料で読めるようにしました。状況をまとめると、様々なブログによって指摘されたNature論文2報と、同じく著者、小保方博士による2011年の論文における複数の疑義に対して理研は反応をみせました。この疑義は大きく2種類に分けられます。1つは本来別々の実験結果を説明する別々の図表で、同じ画像が使い回されている問題です。もう一つは、他の研究室では結果を再現できないという問題です。理研が現在調査しているのは最初の方の疑義に関してであり、(うっかりミスとして)説明できる可能性があります。もう一つの疑義は実際には理研の調査の対象となっていませんが、多くのニュースは、あたかも論文に発表された実験に不備があったため理研が調査している、と報道しています。

 

これらの一連の出来事の良い側面は実際とてもエキサイティングです。まず、だれもがアクセスできるブログの仕組みを使って、実験を再現しようとする科学者がデータと結果を共有しようとする動きが発生しました。次に、人々からの、論文を誰もが無料で読めるようにしてほしい、という要望をNatureは受け入れました。しかし一方負の側面は苦々しいものです。もしかしたら私が見たり聞いたりした身近な範囲に集中しているだけかもしれませんが、魔女狩りのような雰囲気がはっきりと存在しています。人々の意見が興奮から「ほら言わんこっちゃない」へと悪化するのはあっという間でした。STAPの再現性を問うブログのコメント欄はあら探しであふれています。あるブログは、STAP論文のデータを信じるかどうかの科学的な意義には乏しい一般投票を行っていて、現時点では64%の人が否定的と感じています。

 

ここで白状すると、私は小保方博士が潔白であることを主観的判断と知りながら願っています。私は、30歳の彼女が理研で自分の研究室を持っている?!、ということを知って大興奮しました。彼女が絶え間ない批判と疑義に向かい合いながら研究を続けて行くことの困難さを語ったインタビューを読みました。誰も彼女の発見が本当だとは信じないため、彼女は何度も実験を繰り返し、対照の種類を増やし、証拠を積み上げて行ったと書いてありました。結果としてNatureへの最初の投稿から採択まで5年の歳月を要したそうです。そして査読チームはついに論文を受理し、彼女の仕事は認められたのです!小保方博士は一夜にして科学界全体のスターとなり、STAP細胞の名は世界に轟いたのです。彼女は「非常に成功した若い女性の独立した科学者」という私の新しいロールモデルとなりました。この中で一番重要なのは「女性で独立した科学者」という点です。今日、独立した科学者になることは極めて難しいのです。生命科学分野における大学院生とポスドクの総数は2、30年前と比べて猛烈に増えています。しかし、終身雇用の独立した科学者のポストの数は増えていません。更に、そのレベルでは男性が数的に女性を圧倒しています(以前のすばらしい議論はこちら)。そのため、理系に進もうと考えている女性にとって、具体的なロールモデルはなかなか見つかりません。なので、主観的なバイアスだと指摘される恥を恐れずに言いますが、私は小保方博士が潔白であることを強く願っています。

 

一方、もし小保方博士の研究内容に間違えがあることが判明したら、それは理系の女性達の期待に満ちたロールモデルを失うことを意味します。それはまた一般の人々の「科学的プロセス」という概念への評価を毀損するでしょう。調査がおこなわれていることは、大手メディアが盛んにつたえています。一般の人々は反射的に、科学研究の規律は乱れ、このような事案がしょっちゅうあると考えるようになるでしょう。なんといってもNatureはもっとも評価の高い有名な科学誌の一つなのですから。研究費を拠出する立場の人々の反応はさらに重大な損害をもたらすかもしれません。だから我々は対策を講じなければなりません。実際の科学的不正の件数を減らすだけでなく、不正を働く動機の発生自体に対して。

 

Natureは最上級の科学誌で投稿された論文には厳しい査読が行われます。小保方博士は何年にも渡って疑念と向き合い、自説を強化するための実験を重ねてきたと言っていました。他にできることはなかったのでしょうか?一つは著者たちの責任である、うっかりミスによる画像の重複利用です。これは絶対に起こってはなりません。特に研究者人生を賭けて既成概念を覆すような論文をNatureに投稿する時には。しかし実際には起こります、とくに成功か失敗かの賭けが巨大な時には。一般の人々は知らないかもしれませんが、科学実験を実行するのは完璧なロボットではありません。通常、疲れた、超過労働なのに低賃金の大学院生やポスドクです。彼らは人間で、眠気を覚ますためのブラックコーヒーとセミナーで提供されるピザを燃料に活動しています。彼らにも家があり家庭がありますが、16時間以上帰れないなんてざらです。彼らはミスります。私もミスります。読者のあなたもミスったことがあるでしょう。そしてそういうミスはプレッシャーを受けている時に特に起きやすいのです(ポスターの締め切りまで1時間とか、真夜中にこっそりと新しく思いついた実験に取り組む時とか)。ミスを防ぐにはどうしたいいのでしょうか?これはそう簡単ではありません。根を詰めすぎたり、些細な問題に頭が囚われたりといった科学者の性格によるところはあるかもしれません。しかし、「論文出版か破滅か」の圧力を少し弱めて、働く環境を改善することは確実に効果があるでしょう。論文を出さなければならないことへのプレッシャーはしばしばデータの改ざんも引き起こします。データが出なければ論文は出ず、研究者キャリアに別れを告げることになるからです。

 

もし今回の画像の重複利用が本当にうっかりミスだというなら、透明性について議論されるべきです。理研は調査しているという事実を公表するべきだったのでしょうか?公表したことによってマスコミは蜂の巣をつついたような騒ぎになり、偽造があったので調査することになったと一般の人々に知らしめました。もし調査の結果、すべての疑いが晴れたとしても、小保方博士は今後ずっと偽造の疑いで告発されたという烙印をしょっていくことになります。しかし、この点を考慮しても、私は「公表するべき」だと考えます。科学における不正行為の調査は絶対に公表されるべきです。ここ10年の、誰もが論文を読むことが出来るというオープンアクセスへの動きは、科学をより多くの人のものへと前進させました。私たちは科学の透明性を上げるために出来るだけのことをするべきです。

 

実際に、この調査は科学をさらにオープンアクセスにする鍵となる出来事になるかもしれません。実際、STAP論文が発表されて以降、とっても面白いことが起こっています。ブログでは世界中の科学者が「うわさによればとっても簡単な酸によるリプログラミング」を再現しようとした経験を議論しています(具体的にはPubPeer[3,4]とPaul Knoepfler’s blogを参照してください)。このようなオープンな議論はいままでほとんどありませんでした。現時点で2つのSTAP論文のPubPeerのページは27000回以上閲覧されています。TwitterもSTAPに関する活発な意見交換の場になっているし、RedditにはSTAP論文の責任著者であるCharles Vacantiの研究室の技官を名乗る人物が登場し実験方法の議論が続いています。

 

いまのところ10件の試みが公開されていますが、誰も小保方博士の結果を再現できた人はいません。Natureは公式な調査はまだ開始していないようですが、興味深いことに、独自に聞き取り調査を行った模様です。「Nature news編集部の質問に回答した10人の有名な幹細胞科学者のうち、一人も再現には成功していない」と報じています。これらは必ずしもオリジナルのデータが偽造であったことを示すものではありません。理想的には、科学的事実はつねに再現可能であるはずですが、しばしばそうは上手く行きません。すごい実験結果が出たと思ったら特定のロットの培地でしか成功しなかったり、動物実験の結果が飲み水・食べ物・ストレスに左右されたり、ということはみんな経験しているはずです。科学は、一般の人々がそうあるべきと思う様な、完全無欠の論理的怪物ではないのです。もし20回実験していつも上手く行っていたのに、新しいロットの培地に変わったとたん失敗する様になったとき、あなたは全てのデータを捨ててやり直しますか?理想の解答は「やりなおす」ですが、論文を出すことのプレッシャーの元で、たいがいはそうしません。そのデータを使って論文を書きます。そうでなければ研究者キャリアの破滅が・・・

 

もしかしたら、小保方研究室だけにあって、他では正確に真似ることの出来ないなにかがあるのかもしれません(悪名高き彼女の幸運の亀のペットが居ないとダメとか?)。ほとんどの再現実験では、STAP論文とは違う細胞に刺激を加えています。さらに、彼女の手法は「シンプル」といわれていますが、それらは彼女が何年もかけて磨き上げたものです。実際に、共著者の若山博士は、小保方研究室のある理研では再現できましたが、理研を離れてからはSTAP細胞を再現できていません。理想的には外部の科学者が小保方研究室に行き、彼女のトレーニングを受けて彼女の研究室の設備と試薬を使って再現実験をするべきでしょう。

 

この事件で一つ良かったことは、STAP再現性ブログを主催するPaul Knoepfler教授がtwitterを使ってNatureに、STAP論文を誰でも読めるオープンアクセスにするように呼びかけたことです。(Natureの論文を読むには通常研究所単位か論文ごとに高額の購読料を払う必要があります)。Natureは呼びかけに同意して今では世界中の誰もがSTAP論文を無料で自分自身で読むことが出来ます。これはオープンアクセスの流れの勝利です。STAP細胞の再現をめざす人々からの更なるリクエストは、小保方博士たちが詳細な手法を公開することですが、これはまだ実現していません。現実には小保方博士はなにもコメントを発表していません。とはいうものの、多くの人は見落としているかもしれませんが、彼女はうっかりミスによる画像の重複利用の可能性、についてだけ調査されているのが事実です。私は本当に彼女があらゆる疑いから潔白であることを願っています。なぜなら、そうでなければ彼女のキャリアはもちろん、一般からの科学に対する認識が大きく傷つくからだけではなく、彼女の発見自体が驚異的に素晴らしく画期的だからです。映画『X-Files』の台詞を借りれば「私は信じたい」です。

Mitochondrial Clues for a Long Life

 

By Thalyana Smith-Vikos

Biological clocks that can predict an individual’s lifespan more accurately than chronological time alone have been proposed in multiple molecular, cellular and genetic contexts, but a single clock has yet to be identified. Mitochondria, however, have been identified as promising candidates for a biological aging clock in many organisms. Dong and colleagues report that mitochondrial function in Caenorhabditis elegans young adults provides a highly accurate predictive measure of eventual longevity of individual nematodes.

By visualizing quantal mitochondrial flashes, or mitoflashes, in vivo, the authors were able to show that this optical readout was specific to free-radical production and metabolic rate at the single-mitochondrion level. These mitoflashes exhibited a strong correlation with C. elegans aging and had similar attributes in a mammalian system. Mitoflash measurements in pharyngeal muscles peaked during active reproduction and when the first nematodes began dying off. The mitoflash activity on day 3 of adulthood during active reproduction explained up to 59% of lifespan variation. Day 3 mitoflash frequency was negatively correlated with future lifespan of individual C. elegans, and this negative correlation persisted in the face of various genetic and environmental alterations that extend or shorten lifespan. The authors further showed that day 3 mitoflash frequency was due to glyoxylate cycle activity, and they propose that mitochondrial activity not only predicts but also determines lifespan, as the lifespan of long-lived insulin receptor mutants was at least partially explained by decreased mitochondrial production of superoxide.

These findings indicate that mitochondria can function as a biological clock that predicts lifespan of individual C. elegans in various contexts. Importantly, this clock has already begun ticking very early in life, as mitochondrial flashes in early adulthood during active reproduction have been shown to be most potent predictors of future longevity.

 

Microscopy, Mice, and HIV

 

By Elaine To

Monkeys infected with simian immunodeficiency virus (SIV) have been the traditional animal model for the study of HIV pathology. However, SIV does not result in the same immunodeficiency that HIV does, and monkeys are expensive to care for. Mice without immune cells can be engrafted with human immune cells and used instead. The specific model used by Ladinsky et al transfers human fetal thymic and liver tissues along with hematopoietic stem cells. These mice, known as BLT mice, reconstitute human immune cells in significant levels in many tissues, and HIV infection results in T cell depletion.

Ladinsky et al. use a powerful microscopy technique known as cryoelectron tomography in addition to immunofluorescence to understand the characteristics of HIV infection in the small and large intestines in BLT mice. The interior of the small intestine has an upper layer that includes the villi, known as the lamina propria. Between the villi in the lower layer are intestinal crypts, and this is where the majority of HIV viruses were located. Any villi that had evidence of HIV were also adjacent to an infected crypt.

Looking closer, the researchers were able to see individual viruses in the process of budding out of infected cells. It was possible to distinguish between mature and immature viruses based on the differences in internal structures. An examination of the viral pools located outside cells showed that 90% of the pools were mostly mature, but 10% were mostly immature. This is in contrast with previous studies in cell culture showing all viruses found outside cells are mature, indicating a difference in virus maturation or diffusion between cells organized in tissues and cells cultured in vitro.

After some searching, an isolated infected cell was located that was responsible for the production of all viruses in the nearby region. The single cell produced 63 viruses, but the microscopic methods only saw viruses in the same plane as this cell. Regions above and below the cell could not be examined, so the real number of viruses that can result from a single infected cell is likely much more than just 63.

Antibodies targeting CD4 showed that uninfected cells have CD4 on their outer membranes, whereas infected cells have CD4 on their inner endoplasmic reticulum. This supports the previous finding that the HIV protein Vpu causes the internalization of CD4 to prevent newly released HIV viruses from reattaching to the host cell.

There was also evidence of the virological synapse, the phenomenon that happens when a virus budding out of an infected cell immediately contacts a neighboring cell and infects it. Two of the proteins that help bring two cells close together, LFA-1 and ICAM, were found at the cell-cell junction near the actively budding virus.

Lastly, the researchers looked for evidence of the ESCRT proteins, which are known to help release viruses from infected cells. The ESCRT components hCHMP1B, hCHMP2A, and hALIX were found on the thin membranous necks of actively budding viruses. Some budding viruses with thick necks appeared to be in an early stage of budding, and displayed spoke-like projections originating from the virus. These were proposed to be the early components of ESCRT.

Overall, the combination of advanced microscopy with the BLT mouse model revealed new aspects of the process of HIV infection, and showed that conclusions drawn from in vitro cell culture cannot always be assumed to be true in whole animals. Further evidence was also gained for the virological synapse and use of ESCRT proteins to facilitate the spread of HIV within whole organisms.

The Vampire Myth Through The Lens of Medicine

 

 

by Karina Fatova

Vampire fascination waxes and wanes in mainstream media over time. Over the past several years Sparkly Edward, Brooding Bill, and most recently Dracula himself, played by Jonathan Rhys Myers on NBC, have been subtly, or sometimes not so subtly (think Eric lounging naked on a beach chair in the mountains), shaping our view of “the vampire.” Before these, there were the beautiful and conflicted Lestat and Louis of Anne Rice’s preternatural imagination, the fiercely powerful Blade, and many other enactments in movies and books of the nocturnal, elusive, and immortal. So, do vampires really exist? Yes….and no.

Clinical vampirism, or Renfield’s Syndrome, named after Dracula’s trusty servant, is described as “the compulsion to drink blood.” The diagnosis is not formally in the DSM-5, the psychiatric “manual” of diagnosis and symptomology, and is usually attributed to schizophrenia or a deviant sexual practice, known as a paraphilia. However, before the 1980’s rise of the coded categories of the manual, the psychiatric literature burst with case history reports of “extraordinary disorders of human behavior,” which not only included clinical vampirism, but also lycanthropy (werewolves) and possession with stigmata. According to the case reports, the condition starts with a key event in childhood that causes the experience of bloody injury, or the ingestion of blood, to be exciting. After puberty, the excitement becomes sexual in nature, and in adulthood consumption of blood can create a sense of power and control.

Individuals with Renfield’s are overwhelmingly male, and often start with autovampirism, ingestion of their own blood, before moving on to animal blood, and later human blood. Human blood can be obtained inconspicuously from blood banks and hospitals, from a willing “donor,” or by force, as evidenced by so-called “vampire” serial killers. Richard Trenton Chase, the man who killed six people within the span of a month in the late 1970s, started mixing dog blood with coca-cola and injecting himself with rabbit blood in early adulthood because he thought “someone had stolen his pulmonary artery,” and his heart was shrinking. His MO became shooting people, removing vital organs, and then drinking their blood.

It was later recognized that Chase suffered from a serious mental illness outside of his compulsion to drink blood. Of course, when we think of vampires, drinking blood is but one nail in the coffin (pardon the bad pun). Vampires are supposed to be afraid of garlic, have no reflection in mirrors, and stay away from sunlight for fear of burning to a crisp. But what if the vampire legend, with all its aspects, originated from medical reality? Porphyria, also known as “Vampire Syndrome” is believed to be responsible for the legend of the vampire. Porphyria is a condition marked by a deficiency of enzymes in the pathway to produce heme found in red blood cells. Patients with Porphyria suffer from anemia, aggressive behavior, red tears, photosensitivity, and other symptoms of the heme precursors, porphyrins, building up in the body.

Sufferers of skin, or cutaneous, Porphyria can develop severe burning and blistering on any body part exposed to the sun, and because of facial tissue erosion around the lips, the teeth may look more prominent, as if the individual has “fangs.” It might be difficult for a porphyria sufferer to face his own reflection in the later stages of the disease, when his face has been eaten away and his teeth are exposed in an ugly grin, which gives a nod to the belief that “vampires” have no reflection. Interestingly, some Porphyria patients cannot tolerate garlic because the compounds it contains aggravate symptoms and may cause excruciating pain, especially abdominal pain. Centuries before a name and cause were given to this disease, individuals with porphyria were known to alleviate their anemia by drinking blood. Nowadays, medical treatments include medications for symptoms, blood transfusions, and drawing blood to reduce iron in the body.

We crave vampires in our movies, books, and even Halloween costumes, yet it is important to remember that every myth is based in reality. Greater knowledge and understanding in psychiatry and medicine can help us separate patients who are truly suffering and in need of help, from those who choose to express themselves in an unconventional way. Speaking of the contemporary underground vampire scene, that’s a whole topic for a whole other blog entry…stay tuned.

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STAP cells: too good to be true?

 

By Sally Burn

日本語版はこちらからどうぞ

Two weeks ago we reported on the groundbreaking creation of STAP (stimulus-triggered acquisition of pluripotency) cells by scientists at the RIKEN Center for Developmental Biology in Japan. STAP cells are generated by subjecting specialized cells to physical stress, causing them to reprogram back to a pluripotent state from which they can differentiate into both embryonic and extra-embryonic tissues. The pair of Nature papers [1,2] reporting these findings were received with both excitement and surprise by the scientific community. Excitement because the implications were so fantastic (patient-specific regenerative medicine) and surprise because the system was so amazingly simple. The main stressor used in the experiments was acid; the mature starter cells were subjected to acidic conditions and this was sufficient to send them on the road to reprogramming. At the more positive end of the response spectrum, commentators simply asked: “can it really be that simple?” Responses at the other end were pricklier, with a number of eminent scientists dousing the findings with skepticism.

A number of events have now occurred since publication: a formal investigation by RIKEN into the authenticity of the papers, crowdsourced attempts to repeat the experiments, and successful requests for open access to the papers. The bare bones of the case are this: RIKEN is reacting to concerns raised on blogs by other researchers about the papers plus a 2011 paper by the same author, Dr. Haruko Obokata. These concerns are two-fold: first, that images have been reused in different figures to show different things; secondly, that the results cannot be reproduced by other labs. The first concern is what RIKEN is actually investigating and is potentially explicable (human error). The second issue is not under formal investigation but it is this aspect that has made the news, with reports generally stating that the experiments are flawed and that this is why RIKEN is investigating.

The positive aspects of these events are actually quite exciting. Firstly, freely accessible blog-based discourses between scientists attempting to replicate the studies and sharing their data have sprung up. Secondly, Nature has acquiesced to requests to make the original papers open access. The negative aspect of the fallout, however, leaves a particularly bad taste in my mouth. Perhaps it is just the coverage I’ve seen or the conversations I’ve had, but there is a distinct air of a witch-hunt about the whole affair.  The deterioration in opinion from excitement to “I told you so” sanctimony has been rapid. A number of the comments on the STAP reproducibility blogs are pure nit-picking. One of the blogs even holds weekly public opinion polls which serve no scientific purpose on whether we think the data is real or not (64% of respondents felt on the “not” side of the fence at the time of writing).

I will hold my hands up at this point and say that I am biased in hoping that Dr. Obokata will be exonerated. I was enthralled when I read about her: 30 years old and running her own lab at RIKEN?! I read interviews in which she described the pain of working on her research to the exclusion of all else and being met with constant criticism and skepticism. No one seemed to believe her system worked so she repeatedly went back and tried again, adding more controls, building extra layers of evidence. It apparently took five years from the first time Nature saw an earlier incarnation of the paper to them accepting it. But finally a team of peer reviewers accepted the manuscripts and at last, for a short while, her work was finally validated. Overnight Obokata became a global science sensation; STAP cells were everywhere. She became my new role model: an exceptionally successful young independent female scientist. The important part of that accolade is “independent female”. Achieving scientific independence is exceptionally difficult in 2014. The pool of PhD students and postdoctoral researchers in the biological sciences is drastically larger than it was 20-30 years ago. The number of permanent Principal Investigator (PI) positions, however, is not. Moreover, males greatly outnumber females at the PI level (for a great discussion of this see this). There are therefore fewer visible role models for girls getting into STEM. So I am absolutely, unashamedly biased in hoping that Obokata will be exonerated.

If Obokata’s studies are, however, found to be flawed it will result in the loss of a promising role model for women in STEM. It may also damage the public’s perception of the scientific process. The investigation has been reported by many major media outlets. The knee-jerk response by the public may be to view research as unregulated and to conclude that this kind of affair is commonplace – after all, Nature is one of the most esteemed and well known journals. Similar responses by those with involvement in science funding would be an even worse consequence, which is why we need to take measures to reduce the incidences of not just scientific fraud but also the potential for perceived fraud.

Nature is a top-ranked journal and submitted manuscripts undergo strict peer review. Obokata had faced years of skepticism and accordingly had added more and more experiments to strengthen her case. So what could be done differently? One answer lies with the authors themselves as image duplication can occur as a result of human error. It really shouldn’t, particularly not when you’re submitting your career-defining dogma-shaking paper to Nature, but it does – even more so when the stakes are that high. Despite what the public might think, science isn’t performed in a vacuum by moon-suited automatons; it’s usually performed by tired, overworked, underpaid graduate students and postdocs. They are humans and they are likely humans who are running on a diet of black coffee and seminar pizza. They have homes and lives, but they’ve probably not seen those things in the last 16 hours. They mess up. I’ve done it. You, dear reader, have done it. And messing up is even more likely when under pressure (conference poster due in an hour; carrying out novel experiments at midnight to avoid being scooped). What can be done to prevent such mistakes? No single thing will fix the problem. Indeed it may even be the personality of many scientists which increases the risk of such errors: working too hard, too obsessively on a problem to the extent they do not function optimally. However, improving working conditions would certainly help, as would less emphasis on “publish or perish”. The pressure to publish also often underlies actual falsification of data. If you don’t get the data you don’t get the paper and you can kiss goodbye to tenure.

If the image duplications were genuinely due to human error, this brings us to the subject of transparency. Should RIKEN have announced their investigation? By doing so the press has had a field day informing the public that the investigation happened because the science is bogus. Even if Obokata is cleared of any wrongdoing she will always carry the stigma of being accused of fraudulence. Despite this, my answer is: yes. Investigations into scientific malpractice should absolutely be made public. Open access publishing has made great headway in the last decade with bringing science to a wider audience, and we need to do all we can to promote transparency in the scientific process.

In fact, this investigation could end up being a key event in the drive to make science more openly accessible. A very interesting thing happened in the days after the STAP articles were published. Blog forums started in which scientists from around the world shared their experiences of trying to repeat the purportedly simple acid-reprogramming experiments (see particularly PubPeer [3,4] and Paul Knoepfler’s blog). Such openness is rare with unpublished data, but replicating published data opened the door to free communication. At the time of writing the PubPeer page for the first of the two STAP papers had been viewed over 27,000 times. Twitter is also abuzz with commentary on the STAP situation and Reddit joined in when an alleged technician from the lab of Charles Vacanti (the papers’ final author) started discussing the protocol with interested parties.

Thus far no one has managed to fully reproduce Obokata’s results (ten attempts have been reported). Nature has not launched an official inquiry so far but, intriguingly, seems to be conducting its own crowdsourced investigation: “None of ten prominent stem-cell scientists who responded to a questionnaire from Nature‘s news team has had success”. This does not necessarily mean that the original data was fraudulent. Scientific data should, by definition, by reproducible but all too often it’s not the case. We all know of someone who had the most amazing cell system setup but it only works with one batch of media, or the animal experiments affected by external factors (water, food, stress). Again, science is not the sterile logical beast the public perceive it to be. If you perform an experiment twenty times and it works, then you get a new batch of media and it suddenly fails, do you scrap all your data? The answer idealistically is yes but if you are under pressure to publish all too often it will be no. You publish. Or perish…

It may well be that there is something about Obokata’s lab’s setup that isn’t being accurately reproduced elsewhere (the presence of her infamous “good luck” pet turtle perhaps?). For starters, most of the attempted repeats did not use the same starter cells as in the STAP papers. Furthermore, while her experiments were universally reported as “simple”, they are also something she has been expertly honing for many years. Indeed, a co-author, Teruhiko Wakayama, found that he could not create STAP cells outside of Obokata’s lab but he is adamant that he generated them during his time there. In an ideal world external scientists need to go to Obokata’s lab, be trained by her and use her lab resources to reproduce the data.

A final positive outcome of this case is that Professor Paul Knoepfler, curator of the STAP reproducibility blog, took to Twitter to ask Nature to make the STAP papers open access (Nature is usually accessed via an institution subscription or by paying a large fee per article). Nature agreed and now anyone in the world can read the papers for themselves – a victory for open access publishing. A further request by would-be STAP creators is for the authors to release detailed methods; this currently remains unfulfilled. Indeed, Obokata herself has not issued any comment. But then again she is only being investigated for potentially accidental image duplications – a fact being overlooked by many. I sincerely hope that she will be cleared of any wrongdoing, not just because of the otherwise damaging effects on her career and the public perception of science, but also because her findings are just so amazingly groundbreaking. In the words of the X-Files: I want to believe.

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"Science" Opens Up

 

By Celine Cammarata

When biologist Randy Schekman denounced high impact journals just after winning the Nobel Prize last year, his cry joined a rising tide of voices in favor of open access.  Almost exactly a year ago, Nature announced its partnership with the open access publisher Frontiers, and had even before that offered authors the option of publishing their papers under a creative commons license in exchange for a processing fee. Considering this climate, I was hardly surprised when the journal Science announced last week, via an editorial, that it will be launching a new, open-access digital journal, Science Advances.

The open access debate is often framed in terms of (not surprisingly) accessibility of research, specifically whether papers are free to read. Science, however, has approached the issue predominantly in terms of publishing space.  “The research enterprise has grown dramatically in the past decades in the number of high-quality practitioners and results,” editor in chief Marcia McNutt and AAAS CEO and Science Executive Publisher Alan Leshner state, “but the capacity for Science to accommodate those works in our journal has not kept pace.”  Science Advances, the authors explain, was born out of the desire to stop turning away potentially important papers, as the journal claims it is forced to do by space limitations.  Increased publishing space will also allow the journal to further diversify the research areas represented.

Science downplayed matters of subscription fees and availability, mentioning only briefly that in order to better serve scientists with limited resources and better disseminate authors’ work, the journal will be available to anyone with an internet connection.  As in many open access journals, the costs normally covered by subscriptions will be displaced by authors paying a processing fee.  Science is aiming to keep those costs down, though: Science Advances’ administrative side will be run out of the existing Science offices, and the journal will not feature any commentary or editorials – only research articles and reviews.

The journal also aims for rapid publication; rather than being released weekly, as in its parent journal, papers published in Science Advances will appear as soon as they are ready.  Furthermore, papers rejected from Science’s traditional journals on the basis of space can be shuttled right along for review at Science Advances, to “speed publication, alleviate the burden on the reviewer community, and reduce the risk to authors of having to resubmit elsewhere.”  Of course, this system arguably also protects Science from inadvertently turning away the paper of the century only to have it published by a competing journal.

Despite the gathering steam of open access proponents, high impact journals largely continue to hold center stage; in this filed where prestige is often the going currency, it takes a certain degree of faith and commitment for investigators to choose less established open access platforms over well known traditional journals when it comes time to publish.  Will open access projects from Nature and Science help bridge this divide?  Science apparently anticipates the reputation of its traditional journals to extend to Science Advances; in relating the motivation behind the new journal, McNutt and Leshner mention that “although other journals provide publishing venues for more papers, many authors still desire to be published in Science.”  But the announcement also come a year before Science Advances is set to launch, and before the journal’s editors have even been recruited, making the venture seem rather rushed.  Is Science joining the open access scene truly reflective of, and contributing to, a paradigm shift, or is the journal only seeking to cover its… bases?  Perhaps only time will tell.

5 Tips to Kickstart Your Postdoc Job Search!

 

By Tara Burke

The last few years of your graduate career are both exciting and stressful. If you think you’d like to continue your biomedical training after graduation it’s never too soon to get a jump-start preparing for the next step in your career. As someone who recently went through this transition, I learned a lot about this lengthy process; a transition that can be a little daunting at times. A compounding factor of the postdoctoral job search is the lack of a defined roadmap. While there are numerous graduate school and job fairs, I have yet to come across a postdoc fair.  Below, I offer you 5 tips that will help you make the transition from graduate student to postdoctoral fellow. In my next two follow-up posts, I will provide more tips on the application and interview phases of your search. Together, these tips will help guide you towards your dream postdoc!

 

1) Construct a timeline 

It’s important to consider all the factors of your postdoc search and to assemble a realistic timeline. A general timeline for the entire postdoc job search is about 6 months (from sending the first application to your start date) but you need time before those last 6 months to prepare your materials and decide your direction. You may require less time if you’ve already been networking with a specific lab or if you don’t plan on moving to a new city or university. More than likely however, 6 months may be too conservative if you plan on moving long distance, are unsure about what research you want to explore during your postdoc, or have to coordinate your prospects and location with a significant other’s career. It is also important that you establish a timeline with your advisor. Some advisors may need you to stay in the lab for a bit after your defense to wrap up projects and manuscripts while others may not have the money or space for you to stay.

 

2) Review your current credentials

Your research interests, publications and recommendations will be the main focus of your CV when applying to postdocs. Assessing the quality and quantity of these items a few years before graduation gives you the time to strengthen them. For example, if you feel that you don’t have three strong names to list as a recommendation, now is the time to foster some additional relationships. The more your recommenders interact with you, the more personal your recommendation will be.  If you fear your publication list may be a little thin, you may want to talk to your advisor about helping with another project in the lab or writing a review.

 

3) Seek out career resources 

To prepare for the job application process, find and use all available resources provided to you by your lab, department and university. As career services for graduate students can vary widely depending on the university, you may have to do a little searching to find the right websites and/or offices that can aid you in a number of skills important for securing a position. Career counselors provide helpful services such as proofreading of cover letters and CVs, and help with the interview process (proper etiquette, mock interviews, phone interview guidelines etc.). Additionally, making regular appointments with a career counselor can make you accountable to deadlines you set for preparing your application materials. Don’t forget to seek out help from those around you. Your advisor, postdocs in your lab and fellow graduate students either have experience with this process or are about to go through it themselves.

 

4) Observe your lab environment

Working in close quarters with a spectrum of personalities can lead to a stressful and frustrating environment. As a graduate student you should take note of certain environmental stressors that you don’t want in your next lab. Do you thrive in a highly collaborative lab or would you rather work solely on your own project? You should also assess your relationship with your advisor. Do you enjoy being micro-managed or would you rather be completely autonomous? While most of us fall somewhere in between these two extremes, it’s important to know where you fall. Knowing what you need in a mentor and lab environment will help you find a lab and advisor that will allow you to thrive.

 

5) Get out there!

Although it may be a little early for you to start sending out applications there are other things you can do to prepare for your next career step.  Start making a list of interesting papers you have read recently. This list will be a great start to your online search for potential postdoc labs. Attend more seminars outside your direct research interests. You may discover a lab doing really neat research that you may not come across while reading papers.  Volunteer to help host a speaker at your university. This will allow you to directly network with an investigator whose research you admire. Present posters or give short talks at your university. This will make you more comfortable speaking about your research and this skill will come in handy when you have to sell yourself during a postdoc interview.