A celebration of cryo-EM

Here at Nature Methods, we were quite excited yesterday to wake up to the news that the Nobel Prize in Chemistry had been awarded to Jacques Dubochet, Joachim Frank, and Richard Henderson for their seminal developments in cryo-electron microscopy (better known as cryo-EM) which now enable high-resolution biomolecule structure determination. This is a technique we have been watching closely since 2013, when the first papers (including one of our own) realizing the capability of near-atomic-resolution structure determination with cryo-EM were published.

Though much of the excitement about cryo-EM is quite recent, the Nobel Prize is a good reminder to us all that the essential foundations of this technology were laid decades ago. We celebrated such developments, both old and new, in our 2015 Method of the Year issue featuring cryo-EM.

To commemorate this well-deserved Nobel Prize, Nature Research presents an editorially curated collection of papers published in our pages – including methods and protocols, biological results generated using cryo-EM technology, and reviews, news and comment. Check it out!

Cite responsibly

In this month’s Editorial, we discuss why it is crucial for scientists to give credit to previous work by referencing responsibly. This is not always an easy task, especially in multidisciplinary research, so we provide what we hope are some helpful tips for constructing optimal reference lists.

Other Nature Research journals have also published editorials on this topic in past years (see, for example, pieces written in Nature Cell Biology and Nature Chemical Biology).

Our official policy about referencing states in very general terms that authors must appropriately cite and describe previously published relevant intellectual and technical contributions. The policy allows for citations of preprints and conference abstracts, but if such a paper has been peer-reviewed and published in a journal, the journal paper should serve as the reference. Expert reviewers often identify relevant papers that authors might have missed, and editors can help shape reference lists prior to acceptance, but ultimately, authors bear the responsibility of assigning appropriate credit to work that came before.

We are happy to answer any questions, whether general or paper-specific, about appropriate referencing.

An archive for raw EM data

Earlier this week we published a Correspondence describing EMPIAR, a public archive for raw 2D electron microscopy (EM) image data.

While the established Electron Microscopy Data Bank (EMDB) hosts the 3D EM map data required by most journals for publication, the EM community has long been calling for an archive to host the raw 2D image data underlying the 3D maps, as highlighted in our Method of the Year 2015 feature. EMPIAR, a pilot project from the Protein Data Bank in Europe (PDBe), now fills this need.

At Nature Methods we support this archive as a welcome development in the rapidly growing 3D EM field that will enhance transparency, reproducibility, and facilitate the development and refinement of data analysis tools. Though we do not require that our authors deposit their 2D EM image data in EMPIAR, we do encourage it. We urge researchers to make use of the archive and provide feedback to the developers in order to ensure that it is meeting the needs of the field.

Any interested readers without a subscription or site license may read the full text of the Correspondence here.

Mass spectrometry-based proteomics at Nature Methods

A look back at highlights in proteomics technology developments published in Nature Methods.

The last decade has seen amazing advances in mass spectrometry-based proteomics technology as well as ever-expanding use of the technology for varied biological applications. Here we take a look back at some proteomics technology development highlights published in Nature Methods over the last 10 years. (A second entry covering biological applications of mass spectrometry-based proteomics is planned for the near future; stay tuned.)

Sample preparation

The first step in a successful proteomics experiment is sample preparation. In 2009 Matthias Mann’s lab published a filter-aided sample preparation (FASP) method that is widely used by the proteomics community. In 2014 the same lab published an optimized approach that performs all sample processing tasks in a single enclosed tube.

Proteins are digested into peptides for ‘shotgun’ proteomics analysis. While trypsin is most widely used, it also comes with known limitations. Albert Heck and colleagues and Neil Kelleher and colleagues described useful alternatives to trypsin.

Proteomics researchers are always striving for higher sensitivity. John Yates’s lab’s DigDeAPr method and Bernhard Kuster’s lab’s use of DMSO to enhance electrospray response allow researchers to do deeper proteomic analysis.

Quantitative methods

Proteomics researchers want to quantify, as well as identify, peptides and proteins. Stable isotope labeling, either through metabolic incorporation or chemical labeling during sample preparation, enables researchers to quantitatively compare multiple samples. Spiking in labeled concatenated signature peptides into samples enables absolute quantification, as shown by Robert Beynon and colleagues.

The SILAC metabolic method has proved to be extremely popular, and we have published applications of SILAC for quantifying proteins and phosphorylation sites in human tissues, and in nematodes (Larance et al. and Fredens et al.).

A limitation with SILAC is that it cannot be used to compare more than three samples at one time. Joshua Coon and colleagues provided a clever way around this with their NeuCode SILAC approach, which in theory could enable up to 39-plex experiments.

Chemical labeling approaches (such as iTRAQ and TMT) currently offer higher multiplexing capability than SILAC, but can suffer from problems of quantitative accuracy. Coon’s lab and Steven Gygi’s lab each provided methods to obtain accurate quantitative data in multiplexed experiments.

Shotgun data analysis

In a typical ‘shotgun’ proteomics (discovery-based) experiment, MS/MS fragmentation spectra are generated for all peptides that can be detected by the mass spectrometer. The proteins are identified by matching these experimental spectra to theoretical or actual MS/MS peptide spectra found in databases. Well-performing tools to do this and methods to control for false discoveries are therefore crucial.

To generate good proteomics data, one must tune the mass spectrometer to the best of its ability. The HCD method from Stevan Horning and Matthias Mann and colleagues and a decision tree algorithm from the Coon lab enable researchers to obtain improved MS/MS data for protein identification.

We have published tools for peptide identification – PercolatorSpectraST, and MS-Cluster – and quantitative data analysis (Census). Lennart Martens’ group showed that combining various data processing workflows leads to greater proteome coverage. Proteogenomics-type approaches using custom databases generated using genomic data are becoming popular as they allow novel peptides not found in standard protein databases to be identified (see Evans et al. and Branca et al.).

Researchers must be careful to not overinterpret their proteomics data. Gygi’s lab wrote a useful Perspective on the target-decoy approach for determining false discovery rate, a metric that has become broadly adopted by the field.

In order to keep tools sharp and highlight areas for development, it is important to systematically put them to the test. In 2005, Gygi’s lab performed a comparison of three platforms. In 2009, a large group of researchers tested their ability to identify proteins in a small test sample. This analysis highlighted common problems that occur especially during data analysis in proteomics investigations.

Targeted proteomics

Targeted proteomics, which we chose as our Method of the Year in 2012, offers a fundamentally different way of analyzing data compared to discovery-based proteomics. Targeted approaches, most commonly selected reaction monitoring (SRM), utilize mass spectrometry assays to identify and quantify peptides selected to represent proteins of interest, akin to Western blotting, but in a multiplexed fashion.

These SRM assays can be laborious to generate, however. Methods for high-throughput SRM assay generation are therefore important (see Picotti et al.Stergachis et al. and Kennedy et al.). In 2008 Ruedi Aebersold’s group set up a database of assays for the yeast proteome, called SRMAtlas, which has since grown to include assays for M. tuberculosis and human. Amanda Paulovich and colleagues just this year presented the CPTAC Assay Portal, a new repository of analytically validated targeted proteomics assays.

As in discovery-based proteomics, statistical validation in targeted proteomics is equally important. Aebersold’s lab developed the mProphet tool and also provide a useful guide to SRM in their 2012 Review.

Biological applications of targeted proteomics are growing. Bart Deplancke and colleagues showed that transcription factors could be followed during cellular differentiation using SRM. Olga Vitek’s group showed that targeted proteins could be quantified using sparse reference labeling. In this current 10th Anniversary issue, Claus Jørgensen’s group reports a quantitative method for monitoring human kinases, and Paola Picotti’s lab describes a panel of assays to quantify ‘sentinel’ proteins reporting on 188 different yeast processes.

Data-independent analysis

Our very first issue in October 2004 featured an interesting paper from Yates and colleagues describing a data-independent mass spectrometry scanning approach for acquiring MS/MS spectra. In contrast to the common data-dependent approach, where the most prominent peptide ions are selected for MS/MS, the data-independent approach can enable more reproducible results as it overcomes issues of peptide ion sampling stochasticity. It took nearly a decade for this clever idea to really catch on, but within the last year or so, we have published practical data-independent analysis implementations from Michael MacCoss’s and Stefan Tenzer’s labs.

Anne-Claude Gingras and Stephen Tate and colleagues, along with Aebersold and colleagues, showed how a quantitative targeted data-independent analysis method called SWATH provides advantages for analyzing protein interactomes by affinity purification-mass spectrometry.

We look forward to many more strong advances in mass spectrometry-based proteomics in the decade to come!

Sunset on the PSI

As discussed in this month’s Editorial, the Protein Structure Initiative (PSI), a 15-year, nearly $1 billion structural genomics project funded by the National Institute of General Medical Sciences (NIGMS), will be coming to an end in 2015. The impact of ending this project should be minimized to avoid the loss of valuable resources and expertise.

The PSI was begun in 2000 when the US NIH budget was in the midst of substantial growth, spurring the creation of many new “big science” projects. At that time, protein structure determination was painfully slow. The PSI’s initial goals were to develop tools and methods to improve the speed and ability to solve protein structures, as well as to generate a large resource of novel and unique protein structures to facilitate homology modeling and to promote follow-up functional studies.

Protein Structures

{credit}Image Credit: Erin Boyle{/credit}

The PSI drew criticisms from many in the structural biology community from its inception, however. Critics of the first two phases of the PSI pointed out that it focused mainly on solving small bacterial protein structures that were not biologically very interesting, simply because they were relatively easy to express, purify and crystallize. This led the PSI to substantially change course in the third and current phase, PSI-Biology, which began in 2010. The emphasis on throughput was diminished and shifted to solving important, difficult structures like human membrane proteins and drug targets. This change of course has led to several successful structures for highly interesting yet difficult proteins such as GPCRs.

In 2013, a scientific advisory panel produced a mid-point evaluation report of PSI-Biology for NIGMS (PDF), assessing its strengths and weaknesses. The panel commended the impressive number of high-quality structures and methodological advances of the PSI centers, but noted that outreach to the broader biological community was inadequate. The panel found that the PSI’s community resources – the Structural Biology Knowledgebase, a portal for research, news and resources produced by the PSI (in collaboration with Nature Publishing Group), and the Materials Repository, which provides over 80,000 plasmids and 106 empty vectors to the community – were not widely taken advantage of by researchers outside the PSI. The panel also noted that NIGMS should start planning to transition the PSI from its current set-aside funding structure to a different funding model that maintains its unique resources and capabilities – but that it should also extend PSI-Biology for another 3 to 5 years past 2015 to allow it to reach its full potential.

However, budget cuts and a reassessment of NIGMS’s large-scale research initiatives by its new director, Jon Lorsch, has led the institute to prematurely cut the program after the current phase, PSI-Biology, ends in 2015.

The loss of this large-scale program will certainly shake up structural biology in the US, particularly for all those involved in the PSI but also for the many researchers – even outside of traditional structural biology – who benefit from PSI resources. As we discuss in this month’s Editorial, NIGMS now has the opportunity to set an example for other funding agencies in how to wind down a big science project with minimal negative impact. Internal and external transition planning committees have been created by NIGMS to determine which resources and capabilities developed by the PSI should be preserved and how this can be done. NIGMS has also put out a Request for Information seeking community input on the utility of resources developed by the PSI; the response date (May 23, 2014) has only just passed.

NIGMS is expected to make a decision before the end of 2014 as to what will be done with the substantial high-throughput expression, purification and crystallization facilities developed during the PSI’s tenure. In the Editorial we argue that this infrastructure – and the large-scale raw data and metadata generated that is not in any database, but is valuable for mining and algorithm development – should be preserved as much as possible. We argue that a project to systematically sample protein folds should be continued on a smaller scale. We also argue that NIGMS should continue to facilitate team research – as the internal transition planning committee chair Douglas Sheeley has said it will – to tackle particularly challenging structural biology research problems that require hybrid methods to solve.

We will be watching closely to see whether the negative fallout from the end of the PSI can indeed be minimized.

How to write a cover letter

Part one of our 3-part series on the dos and don’ts of communicating with editors and reviewers.

A good cover letter is a crucial part of the manuscript submission package to Nature Methods. It is not simply an archaic form of communication that is becoming obsolete in a digital world; rather, it should be viewed as an opportunity to convey many important pieces of information about a paper to the editors.

Manuscripts submitted to Nature Methods must first pass an editorial evaluation stage, but as professional editors, we are not experts in every scientific field that the journal covers. Providing context for the paper in a cover letter not only can help the editors reach a quicker decision but also can sometimes tip the balance in favor of sending a borderline paper out for peer review.

Here are some practical tips for potential authors.

The DOs:

  • Do give a brief, largely non-technical summary of the method. Explain how it will have an impact and why the method and its applications will be interesting to a broad biological audience. This can include more forward-looking information about potential future applications that authors may be reticent to share with reviewers or readers of their manuscript. Such a summary is especially crucial for highly technical papers, where the chance that the advance may not be fully appreciated by the editors is often higher.
  • Do put the work in context. Briefly explain the novelty and the specific advances over previous work but be realistic about what the method can and cannot achieve. Many authors are hesitant to compare their work to previous methods for fear that it will appear to reviewers that they are putting down the contributions of other researchers. But editors may not be aware of the nuances of various approaches to address a methodological problem and are more likely to reject a paper without peer review when the advance over previous work is not clear. Authors should not hesitate to discuss freely in the cover letter why they believe method is an advance (most ideally, backed up with strong performance characteristics in the manuscript!).
  • Do suggest referees. If the editors decide to send the paper for peer review, providing a list of potential referees, their email addresses, and a very short description of their expertise, can help the editor assign referees more rapidly. Of course, whether the editor decides to use any of the suggested referees is up to him or her. This is also the place to list researchers that you believe should be excluded from reviewing the paper. (Please note that the names of excluded reviewers should also be included in the relevant field of the online submission form.) The editors will honor your exclusion list as long as you don’t exclude more than five people; if you exclude everyone relevant in a scientific field such that the review process will not be productive or fair, the editor may ask you to shorten the list.
  • Do tell us about any related work from your group under consideration or in press elsewhere. Explain how it relates, and include copies of the related manuscripts with your submission.
  • Do mention any unusual circumstances. For example, known competition with another group’s paper, co-submission to Nature Methods planned with another group, or co-submission of a related results paper to another NPG journal, etc.
  • Do mention if you have previously discussed the work with an editor. As editors, we meet a lot of researchers at conferences and lab visits and many papers are pitched to us. A brief mention of when and where such a conversation occurred can help jog the memory of why we invited the authors to submit it in the first place.

The DON’Ts:

  • Don’t simply reiterate that you have submitted a paper to us and/or copy and paste the title and abstract of the paper. The cover letter should be viewed as an opportunity to present useful meta-information about the paper, and not tossed off simply as a submission requirement.
  • Don’t go on for pages about what the paper is about and summarize all of your results. The editor will always read the paper itself so long cover letters are usually redundant. A one-page cover letter in almost all cases is sufficient.
  • Don’t use highly technical jargon and acronyms. Explaining the advance in a general manner can go a long way in helping the editors reach a quicker decision; cover letters that are largely unreadable are of no help to the editors.
  • Don’t overhype or over-interpret. While a description of why the method will advance the field is definitely appreciated, obvious overstatements about the impact or reach of the work do not help and can even reflect poorly on the authors’ judgment of the needs of a field.
  • Don’t assume that going on about your scientific reputation or endorsements from others in the field will sway us. This is not pertinent to our editorial decision. Our decisions are based on whether we think the paper will be a good editorial fit for the journal, not on the laurels of the authors or because someone important in the field suggested that they submit the work to Nature Methods

And finally, a minor editorial pet peeve:

  • Don’t address your cover letter to “Dear Sir.” This is antiquated language, not to mention often incorrect, given that two-thirds of Nature Methods’ editors are women. Stick to the gender-neutral “Dear Editor” in cases where you are not addressing a specific editor.

Don’t miss parts 2 and 3 of this series of posts covering rebuttal letters and appeal letters. We encourage questions, comments and feedback below. The editors will do their best to answer any questions you have.

How to write an appeal letter

Although usually unsuccessful, a strong appeal letter can be an important tool for authors.

Rejection is never easy. You’ve put long weeks, months, maybe even years of work into a project that you think is perfect to publish in Nature Methods, so your feelings of disappointment, anger, frustration or self-doubt are completely understandable. Your first instinct might be to hit “reply” and send an angry email to the editor. But your best bet is to take some time to cool off, then move on and submit the paper elsewhere. If you are convinced, however, that a serious error has been made or that you can fully address the specific criticisms raised by the editors or by referees, then you may send a constructive appeal letter to the editor.

Nature Methods has different types of rejections, with or without peer review. There are outright rejections (which represent the vast majority), and then there are those rejections where the editor indicates that a manuscript could be reconsidered if the authors can address specific shortcomings. The editorial decision process is of course a subjective and imperfect one. Appeals, however, are usually unsuccessful. Those that are successful are those where the authors make a strong case for reconsideration, typically by proposing to add new data that will strengthen the application or demonstrate how the work is a strong advance over existing methods.

Be aware that appeals are necessarily given a lower priority than manuscripts still under consideration. Decisions on appeals can therefore take a considerable amount of time and the majority of appeals are turned down. Decisions are usually only reversed if the editors can be convinced that the decision to reject was a serious mistake, if the authors can add a substantial amount of data to address certain shortcomings, or if a negative referee is found to have made serious errors or show specific evidence of bias.

An appeal letter is not the same as a rebuttal letter to referees (see the related post, “How to write a rebuttal letter”). An appeal letter is only read by the editors, so sensitive information not meant to be seen by the referees can be included.

Here are some things that do and don’t work when writing an appeal letter.

The DOs:

  • Do consider whether you have a good case for appealing that is worth investing time in the process. By editorial policy, appeals must take second place to new submissions. This means that it can take as long as several weeks for the editors to discuss an appeal, possibly get input from referees, and reach a decision. Unless your case is very strong, it will save you precious time by accepting the editorial decision and submitting the manuscript elsewhere.
  • Do clearly explain the reasons why you disagree with the decision to reject. In some successful cases, authors provide new information, not apparent from the original submission, explaining how the method will have a strong impact on a broad audience. Ideally such information would have been included in the cover letter with the original submission (see the post, “How to write a cover letter”), which can help avoid the need for a lengthy appeals process for a manuscript that is otherwise a good candidate for peer review.
  • Do explain how you plan to rectify any major shortcomings pointed out by the editor or by the referees. If you are willing to add data to the paper to address the shortcomings, explain what this data is and what it shows. If you have figures or tables prepared, include them with your appeal letter. (However, don’t yet rewrite your manuscript – since most appeals are turned down, this is usually just a waste of your time.) If you have a valid reason for not including such data, explain why not. 
  • Do include a separate point-by-point rebuttal letter to referees to assist the editors in reaching a decision (see the post on “How to write a rebuttal letter”). If the editors feel that a rebuttal letter is required to help them reach a decision, and one is not included, they will request one of you.
  • Do provide evidence for any accusations of referee bias. Describe in specific terms why you believe a referee is biased or has made technical errors in their review. In our experience, it is extremely rare that ALL of the referees of a paper would be biased or misjudge its impact. Don’t try to guess who the referees were (you will most often be wrong). In cases where one set of negative referee comments is far out of line with others that are generally positive, we often will consult with the positive referees to determine whether the dissenting referees’ concerns are serious and how they should be addressed.

The DON’Ts:

  • Don’t do anything in the heat of the moment but take some time to cool down and consider whether you would be better off resubmitting elsewhere.
  • Don’t simply reaffirm the importance of the work, write “we think you are making a mistake” or urge us to send a manuscript out for peer review without providing any justification. Appeal letters lacking a good justification will not convince us to change our minds.
  • Don’t try to bribe us with promises of high citations. While of course we hope for high citations for each research paper we publish, citation potential is far from being the most important editorial consideration (and it cannot be accurately predicted, anyway). Papers must first meet our standards of methodological novelty and potential community interest and impact.
  • Don’t assume that the paper must be of interest to us because we have previously published a similar paper. Editorial standards are constantly evolving, and the methodological novelty may be compromised by our previous publication. Additionally, we strive to publish a variety of novel methods across fields, so we must consider what is currently in our pipeline.
  • Don’t bash previous work. As editors, we want to know how a new method addresses certain shortcomings or significantly expands the applicability of a previously published method, but this discussion should be fair and balanced. Don’t simply say “the previous method doesn’t work,” explain why, and ideally provide experimental evidence. Providing a detailed comparison to previous methods in your paper in the first place can help avoid the need for a lengthy appeals process for a manuscript that is otherwise a good candidate for peer review at Nature Methods.
  • Don’t expect us to be swayed by your scientific reputation. While it is informative to give some background of your expertise in a field, we make decisions based on the fit of a paper with our journal in terms of scope, novelty and potential impact, not simply because the work comes from a good lab. The fact that you have coauthored papers in high-impact journals will not lead us to reverse our decision.
  •  Don’t rely on “celebrity endorsements”. It is good to hear that a leader in the field has read and likes your paper, or that 50 people came to view your poster at a conference. But if we feel that the paper is editorially not a good fit for Nature Methods, this is unlikely to make us change our minds about rejection.
  •  Don’t insult the intelligence or competence of the editors or referees. We know that rejections are upsetting and can often seem unfair. But personal attacks and bullying could compromise your success in an otherwise promising appeal situation.
  •  Don’t appeal every decision. Remember the old saying, “you’ve got to pick your battles.”

Don’t miss parts 1 and 2 of this series of posts covering cover letters and rebuttal letters. We encourage questions, comments and feedback below. The editors will do their best to answer any questions you have.

An all-encompassing term to describe protein complexity

Neil Kelleher and Lloyd Smith propose that the scientific community adopt the term ‘proteoform’ to refer to all the different forms that a protein can take. Will the community adopt it?

The field of top-down proteomics, in which intact proteins are analyzed by a mass spectrometer, provides rich information about the genetic variations, alternative splicing and post-translational modifications that can be lost in a bottom-up proteomics approach (where proteins are digested into peptides prior to analysis). An unsolved problem in the top-down field, however, has been what exactly to call these various protein forms. Besides ‘protein forms’, a handful of other terms have been batted around in the literature, including ‘protein variants’, ‘protein isoforms’ and ‘protein species.’

In a Correspondence in the March issue of Nature Methods, Neil Kelleher and Lloyd Smith lay out the reasons why none of these terms are satisfactory. What is needed, they argue, is a novel, unique, intuitive, single-word term with a precise definition that is all-encompassing in describing protein complexity, and is also compatible with a gene-centric approach to protein naming. They believe that they have the perfect term: proteoform.

“It’s not just a term, it’s a movement,” says Kelleher. Kelleher has been one of the key drivers of top down methodology development, and argues that using a controlled vocabulary to describe proteins will serve a catalytic role in moving the field forward. “The implicit thing about this term is that it puts a focal point on the fact that [the proteoforms] are the functional players, insofar as protein primary structure is concerned,” he says. Especially in clinical research, he notes, different proteoforms are tied strongly to function and phenotype.

Kelleher and Smith have been gathering support for their term over the last several months by introducing it at conferences and inviting researchers to comment on a LinkedIn forum. The term also has the full support of the Consortium for Top Down Proteomics. At their latest conference in Florida, about a month ago, Kelleher says that “everyone” was using “proteoform” in their talks. “It just catches on…it fills a void the rolls right off the tongue at conferences and sits well in the gut while digesting text,” he says. The consortium website maintains a repository of proteoforms, which they hope will grow. Kelleher also notes that the term is being embraced by key protein informatics players at UniProt and the Protein Information Resource, both of which have adopted a gene-centric approach to protein naming.

What do you think about the term “proteoform”? Will you adopt it? We’d love to hear from you!

Training the kit generation

Most molecular and cellular biology graduate students regularly use commercial kits to conduct experiments. There is no doubt that these experiments-in-a-box make difficult, time-consuming techniques more accessible. But many worry that the gains in efficiency come with a concomitant loss of scientific intuition.

An editorial in the December issue of Nature Methods argues that preventing this loss is the joint responsibility of vendors, mentors, and students. Vendors should supply sufficient information about how kits work and what artifacts are possible. Mentors must make sure that students understand what occurs at each step in the protocol, and encourage appropriate optimization for custom uses, and students must remember to rely on their minds (rather than just their hands) to conduct experiments.

If you have ideas about how kits can be used creatively, or how to make sure kits do not stifle scientific creativity, please post your comments here.

Building a better mouse test

September’s Editorial praises the new research that more genetic rodent models will enable. However, manipulating important genes in a mouse is not enough. Experimental techniques are also needed. Perhaps nowhere is this more important—and more difficult—than using animals to assess neuropsychiatric diseases. While much can be learned on the level of brain and cell physiology, behavioral tests are important to assess which aspects of physiology are most likely to matter. It’s the behavioral symptoms, not the cell-based ones, that directly affect people’s lives. How useful would a drug be if it cleared away the telltale plaques of Alzheimer’s patients but did nothing to preserve their memories?

To make the most of the ever increasing numbers of rodent genetic models, researchers will need better assays and better ways of assessing their validity for human disease.

Please share your thoughts on how best to assess whether an animal model is relevant for studying neuropsychiatric disease.