The collection, preparation, and analysis of chemical compounds using miniaturized devices are appealing for many reasons: the use of smaller reagent volumes can reduce the time needed to synthesize and analyze a product, the amount of chemical waste produced and the overall costs can be reduced by performing chemical reactions in these ‘lab-on-a-chip’ devices, and compact devices also allow samples to be analyzed at the point of need rather than at a centralized laboratory. For these reasons, chemists are now using these devices to create new molecules and materials, and biologists are employing these devices to study complex biological problems. Furthermore, labs on chips offer ‘point-of-care’ diagnostic abilities that could revolutionize medicine.

To highlight our interest in this exciting field, the July 27th issue of Nature contains an Insight (a collection of topical articles and reviews) which discuss the history, design, current applications, and the promising future of these ‘lab-on-a-chip’ devices:

The origins and the future of microfluidics (Whitesides)

Scaling and the design of miniaturized chemical-analysis systems (Janasek et al.)

Developing optofluidic technology through the fusion of microfluidics and optics (Psaltis et al.)

Future lab-on-a-chip technologies for interrogating individual molecules (Craighead)

Control and detection of chemical reactions in microfluidic systems (deMello)

Cells on chips (El-Ali et al.)

Microfluidic diagnostic technologies for global public health (Yager et al.)

There’s also a news story from Jenny Hogan on microreactors. (And you may want to check out ’Clicks and chips’ and Haswell’s recent News & Views article on Belder et al.)

For a complete list of Insights, click here – we hope you enjoy these reviews!

Joshua

Joshua Finkelstein (Associate Editor, Nature)

There’s a pretty funny article on CNN.com today – it turns out that the cost of the United States one-cent coin (a.k.a. the ‘penny’) has been rising for the last few years. It is currently 97.6% zinc & 2.4% copper, and since the price of “”https://www.usatoday.com/money/2006-05-09-penny-usat_x.htm">zinc is up 76% this year [and the price of] copper is up 68%," the penny currently costs 1.4 cents to make.

So Representative Jim Kolbe wants to implement the Currency Overhaul for an Industrious Nation Act [COIN Act – clever, no?]. If passed, all “”https://money.cnn.com/2006/06/01/news/newsmakers/penny/index.htm">cash transactions ending in 1, 2, 6, or 7 cents [would] be rounded down to the nearest 5 cents, while transactions ending in 3, 4, 8, or 9 cents would round up. Credit and debit card transactions could still be valued to the nearest cent."

Two potential problems with this act? “”https://money.cnn.com/2006/06/01/news/newsmakers/penny/index.htm">Americans overwhelmingly want the penny … They also hate rounding."

Joshua

Joshua Finkelstein (Associate Editor, Nature)

When it comes to marine natural products, there’s certainly no shortage of chemically-interesting, highly toxic molecules: for example, there’s saxitoxin (“”https://www.bt.cdc.gov/agent/saxitoxin/casedef.asp">Exposure to saxitoxin might cause … muscle weakness, vertigo, and cranial nerve dysfunction. Respiratory failure and death might occur from paralysis.“) and brevetoxin (”Gastrointestinal symptoms include abdominal pain, vomiting, and diarrhea. Neurologic symptoms include paresthesias, reversal of hot and cold temperature sensation, vertigo, and ataxia. Inhalational exposure to brevetoxin results in cough, dyspnea, and bronchospasm.").

So ciguatoxin may seem quite mild by comparison: “”https://www.cdc.gov/ncidod/dbmd/diseaseinfo/marinetoxins_g.htm#whatsort">symptoms include nausea, vomiting, diarrhea, cramps, excessive sweating, headache, and muscle aches. The sensation of burning or “pins-and-needles,” weakness, itching, and dizziness can occur. Patients may experience reversal of temperature sensation in their mouth, … unusual taste sensations, nightmares, or hallucinations. Ciguatera poisoning is rarely fatal."

It can be extremely challenging to isolate these molecules (for example, only “”https://pubs.acs.org/cgi-bin/asap.cgi/jacsat/asap/html/ja063041p.html">0.35 mg of ciguatoxin [was] extracted from 4000 kg of moray eels") and many of these molecules (and other marine toxins) have complex molecular architectures that have fascinated synthetic chemists for years.

Although maitotoxin (one of the largest and most toxic marine natural products) has not been synthesised (yet), many other marine toxins have been made in the lab: the synthesis of (+)-saxitoxin was described earlier this year (Fleming & Du Bois), brevetoxin A and B were synthesized years ago (brevetoxin A; brevetoxin B), and earlier this month, the syntheses of the two most toxic ciguatoxins (ciguatoxin and 51-hydroxyCTX3C) were reported in JACS (Inoue et al.). One highlight of the ciguatoxin synthesis involved a radical cyclization reaction which stereospecifically formed a key seven-membered ring in the middle of the molecule (the ‘G’ ring)…

But have no fear, not every natural product made by a marine organism is ultra toxic: Fuwa et al. just reported the synthesis of the proposed structure of brevenal, a pentacyclic polyether natural product. For some reason, this molecule actually “”https://pubs.acs.org/cgi-bin/asap.cgi/jacsat/asap/html/ja062524q.html">displaces tritiated dihydrobrevetoxin-B … from voltage-sensitive sodium channels in a dose-dependent manner and acts as a natural brevetoxin antagonist in vivo."

After making the proposed structure, the authors noticed that “[u]nfortunately, 1H and 13C NMR data … were not identical to those reported for the natural sample … On the basis of these NMR variations, along with the proposed biosynthetic pathway for marine polycyclic ethers, we think that the correct structure of brevenal is most likely represented by the C26 epimer of the [molecule we synthesized].” But keep your eyes peeled for their next paper, as they say that “efforts toward structural determination and total synthesis of brevenal are underway and will be reported in due course.”

Joshua

Joshua Finkelstein (Associate Editor, Nature)

Each month, Nature Chemical Biology includes an editorial; these typically center around an issue of general importance to chemical biologists and seek to raise questions that will be significant in the further development of the field. In the July issue, we talk about how universities and departments may support the development of chemical biologists . As science has expanded from the strict disciplines of chemistry, biology, and physics, certain challenges of redefining scientific borders and academic structure have been met. Yet the experience of researchers working in chemical biology suggests that they face a uniquely difficult task in finding a home for themselves and their work. Everyone involved would benefit from brainstorming on how the integration of chemical biology can be improved or made easier. As such, we would like to initiate conversation among our readers as well as those who have gone through similar fundamental shifts in scientific organization.

Some of the thoughts on our mind:

What is your experience in starting a lab/changing fields/getting funding for chemical biology research?

Are there specific changes that your university has made or could make to support you?

Do you think chemical biologists can continue to work within the confines of diverse (other) disciplines, or do you support the move toward chemical biology departments?

How can we find common ground when self-identified chemical biologists work on extremely disparate topics or use widely varying techniques?

It is our hope that, by sharing ideas and concerns, we can improve the overall understanding of and support for our growing community.

You probably know someone with Celiac disease, as it affects approximately one out of every 250 people, who “”https://digestive.niddk.nih.gov/ddiseases/pubs/celiac/#1">cannot tolerate a protein called gluten, found in wheat, rye, and barley." (Others estimate that the prevalence of this disease is even higher, as it may be underdiagnosed in some populations.)

There’s no cure for this disease, so people with Celiac disease must change their diet and avoid gluten for the rest of their life. This can be challenging (unless gluten-free labels appear on the food), because in addition to the obvious places, “”https://www.csaceliacs.org/celiac_treatment.php#Found">gluten is also ‘hidden’ in many processed foods such as frozen French fried potatoes, soy sauce and rice cereal. Even many non-food items like cosmetics, and household cleansers contain gluten." The risk of cross-contamination from other foods can present problems when eating in restaurants or traveling, and beer lovers will need to switch to gluten-free beer…

In the June 26th issue of Chemistry & Biology, Siegel et al. determined that two enzymes (a glutamine-specific cysteine protease from barley and a prolyl endopeptidase) could be used to degrade gluten in an acidic environment – neither enzyme worked very well on its own, but the combination was able to detoxify “”https://www.chembiol.com/content/article/fulltext?uid=PIIS1074552106001499">grocery store gluten … within 10 min of simulated duodenal conditions."

The hope is that these enzymes could be taken orally by someone with Celiac disease before eating (like Lactaid for lactose-intolerant people), helping them “”https://www.forbes.com/forbeslife/health/feeds/hscout/2006/06/28/hscout533484.html">cope with the ‘hidden’ gluten in everyday life … [and enabling them to] resume a more normal diet."

Joshua

Joshua Finkelstein (Associate Editor, Nature)

[JF – Bronwen Dekker, an Assistant Editor for Nature Protocols has asked me to post this.]

Nature Protocols is a new online journal for the presentation of both new and old methods in a step-by-step/recipe format. Packed full of useful information in the form of CRITICAL STEPs, CAUTIONs and TROUBLESHOOTING tables, these protocols should be a valuable resource for bench researchers. There are two submission routes: protocols that have been commissioned, peer-reviewed and edited will be published in the ‘Nature Protocols’ section and non peer-reviewed material can be posted as ‘Network Protocols.’ The content of Nature Protocols will be free until the end of July, but the Network Protocols will always be freely available.

While most of the content at present is geared toward the biological sciences, we think that this will also become a useful resource for synthetic and analytical chemists as it could be a forum where labs can post their methods thus sharing valuable information on how to perform syntheses or analyses of specific classes of compounds. In the moderated commenting facility, other researchers will be able to suggest modifications to the published steps that improve results in their hands. Other functionality includes links to key information, such as articles where the procedure has been used previously and information about relevant reagents and equipment.

Current content includes methods for analyzing proteins using mass spectrometry (for example, for quantifying changes in the abundance of specific proteins by in-gel isotope labeling – Asara et al.), radiolabeling protocols (for example, labeling proteins with indium-111 and yttrium-90 – Cooper et al.), and the synthesis of reagents (for example, the preparation and use of azido ruthenium, a new photoreactive probe for investigating calcium-binding proteins – Israelson et al.).

Bronwen

Bronwen Dekker (Assistant Editor, Nature Protocols)

If you’re free in early November, you might want to attend the 2006 Nature Chemical Biology Symposium, which will be on November 10th & 11th at the Museum of Science in Boston.

The meeting’s focus is the “frontier of in vivo chemical biology” and there are five sessions:

The nucleus and cell division

Metal ions and metabolites

Cytoplasmic processes

Membranes

Cell and chemical biology moving forward

Carolyn Bertozzi and James Rothman are the Keynote Speakers, and the rest of the program really looks fantastic…

Hope to see you there…

Joshua

Joshua Finkelstein (Associate Editor, Nature)

There’s been quite a bit of buzz about a recent Nature Chemical Biology paper from Chong et al. (the work was featured in CE&N, Chemistry World, and Reuters.com). The authors created a library of 2,687 existing drugs and screened them for inhibitors of the malaria parasite Plasmodium falciparum. (“”https://www.rsc.org/chemistryworld/News/2006/June/03070601.asp">The [Johns Hopkins Clinical Compound Library] contains 1937 drugs that have been approved by the US Food and Drug Administration (FDA), along with 750 drugs that have either been approved for use in other countries or are undergoing Phase II clinical trials.")

The main idea is that if the authors could find a relatively potent inhibitor of multidrug-resistant parasites, the compounds could be put into human clinical trials very quickly (since many of the compounds are already FDA-approved for human use). In fact, you may have already taken astemizole, which was “”https://www.nature.com/nchembio/journal/vaop/ncurrent/full/nchembio806.html">introduced in 1983 under the brand name Hismanal as a nonsedating selective H1-histamine receptor antagonist for treating allergic rhinitis and was sold in 106 countries [over the counter]."

Chong talked about this work at the ASBMB meeting a few months ago – Jennifer Kohler wrote a Meeting Report in the June issue of Nature Chemical Biology, in which she said:

The goal of the initiative is to facilitate the rapid discovery of new treatments for urgent unmet needs and to do so at a reduced cost … By focusing on approved compounds, they hope to avoid much of the time and expense associated with developing a new chemical entity into a drug … Chong is optimistic that use of this library may provide a facile route to desperately needed treatment options for malaria and other diseases of the developing world.

I think that most people would agree that new drugs are desperately needed to combat malaria (and many other diseases that disproportionately affect people living in the developing world). But the “appropriate” relationship between academic research and drug discovery/development is hotly debated – some people think that it is possible for academic scientists and drug companies to work together to develop new drugs. For example, Sanchez-Serrano recently wrote that “[t]he success of [the cancer drug] bortezomib was ultimately due to the tenacity of the people involved and the close collaboration … between academia, the private sector, private investors, public institutions and advocacy groups.” And Lunn & Stockwell wrote that (with respect to orphan genetic diseases) “academics, nonprofit organizations, and industrial groups can work together to develop the equipment, technologies, and assays needed for investigating these devastating and neglected human diseases.” But other scientists feel that academics should focus on “pure” research problems and leave the discovery and development of drugs to the professionals…

What do you think about this debate? Should NIH (or other government) funds be spent trying to discover/develop new drugs? Do you think that academic scientists can help pharmaceutical companies discover new drugs? (If so, what do you think academics can bring “to the table”?)

Joshua

Joshua Finkelstein (Associate Editor, Nature)