abstract: **Trisha Greenhalgh and colleagues** argue that, although evidence based medicine has had many benefits, it has also had some negative unintended consequences. They offer a preliminary agenda for the movement's renaissance, refocusing on providing useable evidence that can be combined with context and professional expertise so that individual patients get optimal treatment
author: Trisha Greenhalgh; Jeremy Howick; Neal MaskreyCorrespondence to: T Greenhalgh <email@example.com>
date: 2014
references:
title: Evidence based medicine: a movement in crisis?

It is more than 20 years since the evidence based medicine working group announced a "new paradigm" for teaching and practising clinical medicine.1 Tradition, anecdote, and theoretical reasoning from basic sciences would be replaced by evidence from high quality randomised controlled trials and observational studies, in combination with clinical expertise and the needs and wishes of patients.

Evidence based medicine quickly became an energetic intellectual community committed to making clinical practice more scientific and empirically grounded and thereby achieving safer, more consistent, and more cost effective care.2 Achievements included establishing the Cochrane Collaboration to collate and summarise evidence from clinical trials;3 setting methodological and publication standards for primary and secondary research;4 building national and international infrastructures for developing and updating clinical practice guidelines;5 developing resources and courses for teaching critical appraisal;6 and building the knowledge base for implementation and knowledge translation.7

From the outset, critics were concerned that the emphasis on experimental evidence could devalue basic sciences and the tacit knowledge that accumulates with clinical experience; they also questioned whether findings from average results in clinical studies could inform decisions about real patients, who seldom fit the textbook description of disease and differ from those included in research trials.8 But others argued that evidence based medicine, if practised knowledgably and compassionately, could accommodate basic scientific principles, the subtleties of clinical judgment, and the patient's clinical and personal idiosyncrasies.1

Two decades of enthusiasm and funding have produced numerous successes for evidence based medicine. An early example was the British Thoracic Society's 1990 asthma guidelines, developed through consensus but based on a combination of randomised trials and observational studies.9 Subsequently, the use of personal care plans and step wise prescription of inhaled steroids for asthma increased,10 and morbidity and mortality fell.11 More recently, uptake of the UK National Institute for Health and Care Excellence guidelines for prevention of venous thromboembolism after surgery has produced significant reductions in thromboembolic complications.12

Despite these and many other successes, wide variation in implementing evidence based practice remains a problem. For example, the incidence of arthroscopic washout of the knee joint, whose benefits are unproved except when there is a known loose body, varies from 3 to 48 per 100 000 in England.13 More fundamentally, many who support evidence based medicine in principle have argued that the movement is now facing a serious crisis (box 1).14 15 Below we set out the problems and suggest some solutions.

# Box 1: Crisis in evidence based medicine?

-   The evidence based "quality mark" has been misappropriated by vested interests

-   The volume of evidence, especially clinical guidelines, has become unmanageable

-   Statistically significant benefits may be marginal in clinical practice

-   Inflexible rules and technology driven prompts may produce care that is management driven rather than patient centred

-   Evidence based guidelines often map poorly to complex multimorbidity

# Distortion of the evidence based brand

The first problem is that the evidence based "quality mark" has been misappropriated and distorted by vested interests. In particular, the drug and medical devices industries increasingly set the research agenda. They define what counts as disease (for example, female sexual arousal disorder, treatable with sildenafil16 and male baldness, treatable with finasteride17) and predisease "risk states" (such as low bone density, treatable with alendronate).18 They also decide which tests and treatments will be compared in empirical studies and choose (often surrogate) outcome measures for establishing "efficacy."19

Furthermore, by overpowering trials to ensure that small differences will be statistically significant, setting inclusion criteria to select those most likely to respond to treatment, manipulating the dose of both intervention and control drugs, using surrogate endpoints, and selectively publishing positive studies, industry may manage to publish its outputs as "unbiased" studies in leading peer reviewed journals.20 Use of these kinds of tactic in studies of psychiatric drugs sponsored by their respective manufacturers enabled them to show that drug A outperformed drug B, which outperformed drug C, which in turn outperformed drug A.21 One review of industry sponsored trials of antidepressants showed that 37 of 38 with positive findings, but only 14 of 36 with negative findings, were published.22

Evidence based medicine's quality checklists and risk of bias tools may be unable to detect the increasingly subtle biases in industry sponsored studies.23 Some so called evidence based policies (such as dementia case finding for the over 75s and universal health checks for the over 40s in the UK) seem to be based largely on political conviction.24 25 Critics have condemned the role of the drug industry in influencing the policy makers who introduced them.26

# Too much evidence

The second aspect of evidence based medicine's crisis (and yet, ironically, also a measure of its success) is the sheer volume of evidence available. In particular, the number of clinical guidelines is now both unmanageable and unfathomable. One 2005 audit of a 24 hour medical take in an acute hospital, for example, included 18 patients with 44 diagnoses and identified 3679 pages of national guidelines (an estimated 122 hours of reading) relevant to their immediate care.27

# Marginal gains and a shift from disease to risk

Evidence based medicine is, increasingly, a science of marginal gains—since the low hanging fruit (interventions that promise big improvements) for many conditions were picked long ago. After the early big gains of highly active antiretroviral therapy for HIV28 and triple therapy for *Helicobacter pylori* positive peptic ulcer,29 contemporary research questions focus on the marginal gains of whether these drug combinations should be given in series or in parallel and how to increase the proportion of patients who take their complex medication regimen as directed.30 31

Large trials designed to achieve marginal gains in a near saturated therapeutic field typically overestimate potential benefits (because trial samples are unrepresentative and, if the trial is overpowered, effects may be statistically but not clinically significant) and underestimate harms (because adverse events tend to be underdetected or underreported). The 74 year old who is put on a high dose statin because the clinician applies a fragment of a guideline uncritically and who, as a result, develops muscle pains that interfere with her hobbies and ability to exercise, is a good example of the evidence based tail wagging the clinical dog. In such scenarios, the focus of clinical care shifts insidiously from the patient (this 74 year old woman) to the population subgroup (women aged 70 to 75) and from ends (what is the goal of investigation or treatment in this patient?) to means (how can we ensure that everyone in a defined denominator population is taking statins?).

As the examples above show, evidence based medicine has drifted in recent years from investigating and managing established disease to detecting and intervening in non-diseases. Risk assessment using "evidence based" scores and algorithms (for heart disease, diabetes, cancer, and osteoporosis, for example) now occurs on an industrial scale, with scant attention to the opportunity costs or unintended human and financial consequences.26

# Overemphasis on following algorithmic rules

Well intentioned efforts to automate use of evidence through computerised decision support systems, structured templates, and point of care prompts can crowd out the local, individualised, and patient initiated elements of the clinical consultation.8 For example, when a clinician is following a template driven diabetes check-up, serious non-diabetes related symptoms that the patient mentions in passing may not by documented or acted on.32 Inexperienced clinicians may (partly through fear of litigation) engage mechanically and defensively with decision support technologies, stifling the development of a more nuanced clinical expertise that embraces accumulated practical experience, tolerance of uncertainty, and the ability to apply practical and ethical judgment in a unique case.33

Templates and point of care prompts also contribute to the creeping managerialism and politicisation of clinical practice.8 As Harrison and Checkland observe: "As the language of EBM becomes ever more embedded in medical practice, and as bureaucratic rules become the accepted way to implement 'the best' evidence, its requirements for evidence are quietly attenuated in favour of an emphasis on rules."34

For example, the Quality and Outcomes Framework (QOF) in UK general practice is incentivised by financial "quality points" and administered largely by non-clinical staff who generate these points by recalling patients for structured reviews and checks. QOF has been associated with significant improvements in blood pressure control, especially in deprived populations.35 But its downside is an audit driven, technocratic exercise in which few patients are offered personalised shared decision making with a senior clinician before having the recommended tests and treatments, and in which clinical consultations are continually interrupted by pop-up point of care prompts.32 36

# Poor fit for multimorbidity

Finally, as the population ages and the prevalence of chronic degenerative diseases increases, the patient with a single condition that maps unproblematically to a single evidence based guideline is becoming a rarity. Even when primary studies were designed to include participants with multiple conditions, applying their findings to patients with particular comorbidities remains problematic. Multimorbidity (a single condition only in name) affects every person differently and seems to defy efforts to produce or apply objective scores, metrics, interventions, or guidelines.37 Increasingly, the evidence based management of one disease or risk state may cause or exacerbate another—most commonly through the perils of polypharmacy in the older patient.38

# Return to real evidence based medicine

To address the above concerns, we believe it is time to launch a campaign for real evidence based medicine (box 2).

## Box 2: What is real evidence based medicine and how do we achieve it?

### Real evidence based medicine:

-   Makes the ethical care of the patient its top priority

-   Demands individualised evidence in a format that clinicians and patients can understand

-   Is characterised by expert judgment rather than mechanical rule following

-   Shares decisions with patients through meaningful conversations

-   Builds on a strong clinician-patient relationship and the human aspects of care

-   Applies these principles at community level for evidence based public health

### Actions to deliver real evidence based medicine

-   Patients must demand better evidence, better presented, better explained, and applied in a more personalised way

-   Clinical training must go beyond searching and critical appraisal to hone expert judgment and shared decision making skills

-   Producers of evidence summaries, clinical guidelines, and decision support tools must take account of who will use them, for what purposes, and under what constraints

-   Publishers must demand that studies meet usability standards as well as methodological ones

-   Policy makers must resist the instrumental generation and use of "evidence" by vested interests

-   Independent funders must increasingly shape the production, synthesis, and dissemination of high quality clinical and public health evidence

-   The research agenda must become broader and more interdisciplinary, embracing the experience of illness, the psychology of evidence interpretation, the negotiation and sharing of evidence by clinicians and patients, and how to prevent harm from overdiagnosis

## Individualised for the patient

Real evidence based medicine has the care of individual patients as its top priority, asking, "what is the best course of action for this patient, in these circumstances, at this point in their illness or condition?"39 It consciously and reflexively refuses to let process (doing tests, prescribing medicines) dominate outcomes (the agreed goal of management in an individual case). It engages with an ethical and existential agenda (how should we live? when should we accept death?) and with that goal in mind, carefully distinguishes between whether to investigate, treat, or screen and how to do so.40

To support such an approach, evidence must be individualised for the patient. This requires that research findings be expressed in ways that most people will understand (such as the number needed to treat, number needed to harm, and number needed to screen41) and that practitioners, together with their patients, are free to make appropriate care decisions that may not match what "best (average) evidence" seems to suggest.

Importantly, real shared decision making is not the same as taking the patient through a series of if-then decision options. Rather, it involves finding out what matters to the patient—what is at stake for them—and making judicious use of professional knowledge and status (to what extent, and in what ways, does this person want to be "empowered"?) and introducing research evidence in a way that informs a dialogue about what best to do, how, and why. This is a simple concept but by no means easy to deliver. Tools that contain quantitative estimates of risk and benefit are needed, but they must be designed to support conversations not climb probability trees.

## Judgment not rules

Real evidence based medicine is not bound by rules. The Dreyfus brothers have described five levels of learning, beginning with the novice who learns the basic rules and applies them mechanically with no attention to context.42 The next two stages involve increasing depth of knowledge and sensitivity to context when applying rules. In the fourth and fifth stages, rule following gives way to expert judgments*,* characterised by rapid, intuitive reasoning informed by imagination, common sense, and judiciously selected research evidence and other rules.

In clinical diagnosis, for example, the novice clinician works methodically and slowly through a long and standardised history, exhaustive physical examination, and (often numerous) diagnostic tests.43 The expert, in contrast, makes a rapid initial differential diagnosis through intuition, then uses a more selective history, examination, and set of tests to rule in or rule out particular possibilities. To equate "quality" in clinical care with strict adherence to guidelines or protocols, however robust these rules may be, is to overlook the evidence on the more sophisticated process of advanced expertise.

## Aligned with professional, relationship based care

Real evidence based medicine builds (ideally) on a strong interpersonal relationship between patient and clinician. It values continuity of care and empathetic listening, especially for people who are seriously and incurably sick.44 Research evidence may still be key to making the right decision—but it does not determine that decision. Clinicians may provide information, but they are also trained to make ethical and technical judgments, and they hold a socially recognised role to care, comfort, and bear witness to suffering.45 The challenges of self management in severe chronic illness, for example, are not merely about making treatment choices but about the practical and emotional work of implementing those choices.46 As serious illness is lived, evidence based guidelines may become irrelevant, absurd, or even harmful (most obviously, in terminal illness).

## Public health dimension

Although we have focused on individual clinical care, there is also an important evidence base relating to population level interventions aimed at improving public health (such as pricing and labelling of consumables, fluoridation of water, and sex education). These are often complex, multifaceted programmes with important ethical and practical dimensions, but the same principles apply as in clinical care. Success of interventions depends on local feasibility, acceptability, and fit with context—and hence on informed, shared decision making with and by local communities, using summaries and visualisations of population level metrics.47

# Delivering real evidence based medicine

To deliver real evidence based medicine, the movement's stakeholders must be proactive and persistent. Patients (for whose care the movement exists) must demand better evidence, better presented, better explained, and applied in a more personalised way with sensitivity to context and individual goals.48 There are already some models of good practice here. In arthritis, for example, patient advocacy groups that emphasise the importance of experiential evidence and patient centred strategies have existed for over 30 years and have influenced the choice of outcome measures used in comparative effectiveness studies.49 Patient input has refocused several NICE guidelines (for example, on psoriasis).50

Third sector advisory and advocacy groups such as the UK's Consumer Association ([www.which.co.uk](http://www.which.co.uk/)), Picker Institute ([www.pickereurope.org](http://www.pickereurope.org/)), and Sense About Science ([www.senseaboutscience.org](http://www.senseaboutscience.org/)) have a crucial role in educating citizens and contributing to public debate about the use and abuse of evidence. The James Lind Alliance ([www.lindalliance.org](http://www.lindalliance.org/)) brings patients, carers, and clinicians together to prioritise research questions. Such groups must remain, as far as possible, independent of vested interests and aware of the distorting influence of tied funding.

## Training must be reoriented from rule following

Critical appraisal skills—including basic numeracy, electronic database searching, and the ability systematically to ask questions of a research study—are prerequisites for competence in evidence based medicine.6 But clinicians need to be able to apply them to real case examples.51

Too often, teaching resources use schematic, fictionalised vignettes in which the sick patient is reduced to narrative "factoids" that can populate a decision tree or a score sheet in an objective structured clinical examination. Rather than focus on these tidy textbook cases, once they have learnt some basic rules and gained some experience, students should be encouraged to try intuitive reasoning in the clinic and at the bedside, and then use formal evidence based methods to check, explain, and communicate diagnoses and decisions.43 They must also be taught how to share both evidence and uncertainty with patients using appropriate decision aids52 and adapt their approach to individual needs, circumstances, and preferences.39

Likewise, there is a strong argument for extending the continuing medical education curriculum beyond "evidence updates." Peer observation and review, reflective case discussion in small groups (with input from patients who want to articulate their experiences, choices, and priorities) and ongoing conversations with fellow professionals can help hone and maintain the ability to manage the challenges of applying evidence based medicine in the real world.53 The linking together of educational theory, cognitive psychology, information mastery, and implementation science into a coherent approach that supports front line decision making with patients54 is rarely taught in practice.

## Evidence must be usable as well as robust

Another precondition for real evidence based medicine is that those who produce and summarise research evidence must attend more closely to the needs of those who might use it. Lengthy and expensive reviews that are "methodologically robust" but unusable in practice often fail to inform, inspire, or influence.55 A recent systematic review of diabetes risk scores revealed that the authors of most studies were primarily concerned with the intellectual concept of improving the predictive value of the score but had given little or no thought to how their score might be used, by whom, or for what—nor what the implications would be for real people who would be designated "at risk" by the score.56

Evidence users include clinicians and patients of varying statistical literacy, many of whom have limited time or inclination for the small print.41 Different approaches such as brief, plain language summaries for the non-expert (as offered by NICE), visualisations,57 infographics,52 option grids,58 and other decision aids59 should be routinely offered and widely used. Yet currently, only a fraction of the available evidence is presented in usable form, and few clinicians are aware that such usable shared decision aids exist.

## Publishers must raise the bar

This raises an imperative for publishing standards. Just as journal editors shifted the expression of probability from potentially misleading P values to more meaningful confidence intervals by requiring them in publication standards,60 so they should now raise the bar for authors to improve the usability of evidence, and especially to require that research findings are presented in a way that informs individualised conversations.

Given that real evidence based medicine is as much about when to ignore or over-ride guidelines as how to follow them, those who write guidelines should flag up the need for judgment and informed, shared decision making. The American College of Cardiology recently published new cholesterol guidelines;61 *JAMA* followed with a pragmatic, patient focused article on how to apply this guideline and when to consider ignoring it, including an online visualisation tool to support conversations with patients.62 As the authors commented, "the target for performance measures is not the percentage of patients who . . . are prescribed statins, but the proportion of eligible patients who participate in shared decision making about statin use."62 Their approach deserves to be emulated widely.

## Research must transcend conflicts of interest

To support real evidence based medicine, and in particular to reassure policy makers, clinicians, and the public that research and the guidance derived from it can be trusted,63 the infrastructure for research and guideline development must show the highest standards of probity. Independent funding of national bodies for medical research is crucial.

## Broader, more imaginative research is needed

The research agenda for real evidence based medicine is much broader than critical appraisal and draws on a wider range of underpinning disciplines. For example, it should include the study of the patient's experience of illness and the real life clinical encounter for different conditions and in different circumstances. The field would be enriched, for example, by qualitative research to elucidate the logic of care–that is, the numerous elements of good illness management that are complementary to the application of research evidence.64

We need to gain a better understanding (perhaps beginning with a synthesis of the cognitive psychology literature) of how clinicians and patients find, interpret, and evaluate evidence from research studies, and how (and if) these processes feed into clinical communication, exploration of diagnostic options, and shared decision making.54 Deeper study is also needed into the less algorithmic components of clinical method such as intuition and heuristic reasoning, and how evidence may be incorporated into such reasoning.43

In relation to producing usable evidence, we need to identify how to balance gold standard systematic reviews with pragmatic, rapid reviews that gain in timeliness and accessibility what they lose in depth and detail.65 In the same vein, we need research on how and in what circumstances to trade detail for brevity in developing guidelines. We need to develop decision aids that support clinicians and patients to clarify the goals of care, raise and answer questions about the quality and completeness of evidence, and understand and contextualise estimates of benefit and harm. We also need to improve both the usefulness and ease of use of these and other evidence based tools (models, scores, algorithms, and so on) including the intellectual, social, and temporal demands they make on users and the resource implications for the healthcare organisation and system.

In the educational field, it is time we extended the evidence base for integrated curriculums that promote reflection and case discussion alongside the application of evidence.66 Discussions on how to interpret and apply evidence to real cases, and the sharing of collective knowledge and expertise in the form of "mindlines" among clinicians53 or within illness communities67 may provide useful data sources for such studies. It is by studying these more sophisticated forms of knowing that we are likely to determine how best to produce expert clinicians and expert patients, and to prevent the harms that arise from overdiagnosis, overtreatment, and overscreening.33

In relation to effectiveness, we need greater attention to postmarketing research in day to day hospital and primary care settings to confirm that subsequent experience replicates the results of licensing trials. This will allow gold standard tests and their cut-off points for ruling out diagnoses and treatments to be revised to minimise overdiagnosis or underdiagnosis.43

Finally, in relation to the collective effort to prevent the misappropriation of the evidence based quality mark, a key research priority remains the study of hidden biases in sponsored research—for example, by refining the statistical techniques for challenging findings that appear too good to be true.

# Conclusion

Much progress has been made and lives have been saved through the systematic collation, synthesis, and application of high quality empirical evidence. However, evidence based medicine has not resolved the problems it set out to address (especially evidence biases and the hidden hand of vested interests), which have become subtler and harder to detect. Furthermore, contemporary healthcare's complex economic, political, technological and commercial context has tended to steer the evidence based agenda towards populations, statistics, risk, and spurious certainty. Despite lip service to shared decision making, patients can be left confused and even tyrannised when their clinical management is inappropriately driven by algorithmic protocols, top-down directives and population targets.

Such problems have led some to argue for the rejection of evidence based medicine as a failed model. Instead we argue for a return to the movement's founding principles—to individualise evidence and share decisions through meaningful conversations in the context of a humanistic and professional clinician-patient relationship (box 2). To deliver this agenda, evidence based medicine's many stakeholders—patients, clinicians, educators, producers and publishers of evidence, policy makers, research funders, and researchers from a range of academic disciplines—must work together. Many of the ideas in this paper are not new, and a number of cross sector campaigns with similar goals have already begun (box 3). We hope that our call for a campaign for real evidence based medicine will open up debate and invite readers to contribute (for example, by posting rapid responses on bmj.com).

## Box 3: Campaigns aligned with real evidence based medicine

1.  *Too much medicine*—A rapidly growing movement, led jointly by clinicians, academics and patients, aims to reduce harm from overdiagnosis, overscreening, and overtreatment.26 33 The second of what will hopefully be an annual "preventing overdiagnosis" conference will be held in Oxford in September 2014 ([www.preventingoverdiagnosis.net](http://www.preventingoverdiagnosis.net/))

2.  *All trials* ([www.alltrials.net](http://www.alltrials.net/))—an international initiative to ensure that all clinical trials are registered at inception and no findings are withheld from publication

3.  *Reducing waste and increasing value in medical research* ([www.thelancet.com/series/research](http://www.thelancet.com/series/research))*—*A recent *Lancet* series highlighting the waste and loss of value caused by research that addresses the wrong questions, uses inappropriate study designs; is weighed down by bureaucracy, or is so badly or inaccessibly reported that practitioners and policymakers simply cannot apply it

4.  *Improving publishing standards* ([www.icmje.org/urm_main.html](http://www.icmje.org/urm_main.html) )*—*A campaign by the International Committee of Medical Journal Editors to improve the quality and transparency of medical publishing by discouraging ghost-writing and raising the standards for declarations of conflicts of interest

5.  *Integrated medical education—*Campaign to strengthen the integration of the different components of the curriculum by developing bedside clinical skills, understanding and applying research evidence, and reflecting and deliberating about complex cases68 69

Cite this as: *BMJ* 2014;348:g3725


abstract: On April 25th 1953, three publications in *Nature* forever changed the face of the life sciences in reporting the structure of DNA. Sixty years later, Raymond Gosling shares his memories of the race to the double helix.
author: Naomi Attar
date: 2013
institute: 1Genome Biology, BioMed Central, 236 Gray's Inn Road, London WC1X 8HB, UK
references:
title: Raymond Gosling: the man who crystallized genes

*It has not escaped our attention that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material*.

James D Watson and Francis HC Crick \[1\]

By including this statement in their April 25th 1953 *Nature* article describing a model for the structure of DNA, Watson and Crick made one of the great understatements in history. In that moment, the seeds for the double helix's infamy - alongside the names 'Watson' and Crick' - were sown. Lesser known outside scientific circles is that this article did not include one iota of experimental data: Watson and Crick, who were based at the University of Cambridge's Cavendish laboratory, contributed deductive reasoning alone to the double helix model, albeit reasoning of an undoubtedly Nobel Prize-worthy standard. Instead, as has now been described many times, the model relied on X-ray diffraction data obtained by others, at King's College, and these data did not reach Watson and Crick by entirely wholesome means \[2\]. To add to the insult, Watson and Crick's report of the double helix did not fully credit the work of King's as being essential to the construction of their model, although the King's team did enjoy co-publication of their data alongside the double helix article, in the form of two articles in the same issue of *Nature* \[3,4\]. One of these articles described the X-ray diffraction work performed by senior researcher Rosalind E Franklin, together with PhD student Raymond G Gosling, and contained the highest quality diffraction patterns yet achieved for DNA \[3\]. It was these data that had proved invaluable in Watson and Crick's quest for the double helix.

Earlier still, before Franklin arrived at King's, Gosling had achieved a major breakthrough in the search for DNA's structure when he became the first person to crystallize genes, under the guidance of Maurice Wilkins, who was the lead author of the other King's article to accompany Watson and Crick's model \[4\].

Watson published his controversial memoir of the discovery, aptly named 'The Double Helix', in the 1960s \[5\], and in doing so propelled the story to worldwide fame, establishing DNA's structure as an icon of science in the popular imagination. However, events were relayed in Watson's book very much from his own point of view and at times, it has been argued, even verged on the fictitious.

Aside from Watson, Ray Gosling is the only surviving member of the select group of seven scientists to feature as an author on one of the three *Nature* articles. Gosling and his wife, Mary, were kind enough to welcome *Genome Biology* into their home, where he shared with us his perspective of the events of 60 years ago.

Elsewhere, *Genome Biology* has marked the anniversary by canvassing our Editorial Board for their opinions on the most important advances in the field since 1953 \[6\].

# The accidental biophysicist

Something curious happened in scientific research in the mid-20th Century. Biology had been the neglected sibling of chemistry and, especially, physics, which had until then monopolized the glitz and glamor of scientific inquiry. Perhaps it was the sense that many of the big questions in physics had now been tackled, or a philosophical shift brought about by the experience of the dark forces of war and fascism in the 1930s and 40s, or perhaps it was just a simple matter of improved methodology; whatever the cause, history shows that many physicists and chemists began to become excited by biology at this time, and to turn their attention to addressing biological questions. Nobel Prize-winning physicist Erwin Schrödinger is often credited with kick-starting this trend in his book 'What is life?' \[7\], which is said to have inspired even Crick and Watson themselves in their quest for the double helix.

So was Prof (Emeritus) Raymond Gosling DSc FKC (Figure 1) similarly inspired when he opted to pursue a PhD in biophysics, in work that would culminate in establishing the molecular structure of DNA? Not a bit of it! Not only was Gosling unaware of Schrödinger's work until "much later", he had not in fact originally wanted to become a scientist at all: "I wanted to do Medicine, but Father said we couldn't afford Medicine because it would take *x* years to qualify and so on. And so the next best thing to doing medicine I thought was to do a fundamental subject like physics. I was very attracted by the thought that the Scots always refer to physics as 'natural philosophy'."

And so a career in physics beckoned. But, having graduated from University College London in 1949, Gosling found himself limited in his options. Edward Andrade was the head of the Physics Department, and if Gosling had stayed on at University College, he would have been bound by Andrade's interests in viscosity and this "didn't appeal." Instead, he was tempted by developments across town at King's College, rivals-in-chief to his own *alma mater* (Box 1), where John Randall (Box 2) had recently taken the Wheatstone Chair of Physics. Instead of being deterred by the rivalry, Gosling impishly thought to himself that it would be "rather fun" to join Randall's laboratory.

# John Randall: the unsung hero of the double helix

If there's one message that Raymond Gosling would like you to take away from this article, it is that the role of John Randall in the pursuit of the double helix cannot be overstated, and that Randall has lamentably not been adequately credited in most tellings of the story. Gosling feels so strongly on this subject that he recently wrote to *The Times* to emphasize the point, prompted by an article that had recognized Rosalind Franklin's contribution but that had omitted Randall's.

Randall's motto at the Medical Research Council (MRC) Biophysics Unit that he headed at King's College was 'to bring the logi of physics to the graphi of biology'. This interdisciplinary philosophy was at the time decidedly modern, and his switch from the questions of physics to those of biology was also, according to Gosling, "ahead of the curve". Randall's modernity extended to his respect for female scientists, many of whom he recruited at King's, as exemplified by his long-standing working relationship with Honor Bell. This facet of Randall's modern outlook was to prove very important with his later recruitment of Rosalind Franklin (Box 2).

"The people in the University and a few other establishments tended to make fun of Randall's approach, his claim that you would need to have different disciplines working together, and they called it 'Randall's Circus'. Now, that's what attracted me in the first place! I heard about this strange bald-headed little man with a Napoleonic complex who was running the circus in biophysics, and it sounded wonderful to me!"

So was it the rebellion that Gosling was attracted to? "Yeah, absolutely!"

Randall's most important legacy was his firm belief that DNA must be the agent of genetic inheritance, a concept not widely recognized at the time (despite good evidence to support it \[8\]), and his consequent determination to discover the structure of what he considered to be the genetic material. This was Randall's circus, and he was the ringmaster - and the ringmaster masterfully guided his troupe in its quest.

# Maurice Wilkins stays awake

After spending a year simultaneously studying zoology at Birkbeck and working as a medical physicist at Middlesex Hospital, prompted by Randall's insistence that he first learn some biology, Gosling joined the MRC Unit as a PhD student. At the outset, he worked alongside Maurice Wilkins (Box 2), another physicist-cum-biologist, and a veteran of the Manhattan Project racked with feelings of guilt. Wilkins and Gosling used ram's sperm as a source of DNA, following Randall's idea that "ram's sperm have very flat heads - unlike human sperm, which is like a rugby football", the benefit of which was that "the long chains must lie in the plane of a ram's sperm head." But Gosling's attempts to obtain X-ray diffraction patterns from these sperm did not meet with much success.

It would take a series of what Gosling describes as "serendipitous" events to bring about a change in their fortunes ("most of my life has been beset or encouraged by serendipitous acts," he says). There happened to be one man who could produce a sample of DNA of far superior quality to that produced by any other laboratory, and that man was Swiss biochemist Rudolf Signer. By one or two strokes of luck, Gosling managed to obtain a fair quantity of this DNA: "Signer gave a lecture at the Royal Society on this method that he'd developed to separate out the DNA from the nuclear protein and so produce high molecular weight pure DNA. Signer asked at the end of the lecture if anybody would like some of this material, and he had a specimen tube full of this freeze-dried material. Only two people put their hand up. I'm glad to say that Maurice was awake enough to put his hand up!"

Was that often not the case? "It was often not the case! He rushed down to the front and got half of all there was, which turned out to be very necessary."

Initially, Gosling only wanted to use Signer's DNA as a control to determine which of six methods he had devised for making ram's sperm lie flat was most successful. Wilkins had "a steady hand enough to pull fibers of 5 to 10 μm. Maurice pulled by wrapping them round a paperclip and then sort of - very scientific! - pushing it open to make them taut. I managed to get him to produce at least 35, so this is a 35 fiber specimen. And little blobs of LePage's cement, priced 6d in Woolworths down The Strand, pulling the fibers together. Very scientific!"

The act of pulling the fiber orientated the molecules along the fiber axis, akin to the orientation that flattening ram's sperm was aiming for. Gosling took the fibers from the Signer sample to the basement of the Chemistry Department, which housed a Raymax X-ray tube. "The first thing I produced was even fuzzier than my ram's sperm! Randall was most amused, and he was delighted to be able to point out that I'd missed a trick because the material that was in my DNA was largely carbon, nitrogen and oxygen, which was just the same as the atoms in the air inside the camera." The result was a diffuse back-scattering of X-rays, which fogged the film, and so Gosling was instructed to displace all the air with hydrogen. And this is where the next piece of serendipity steps in.

# Serendipity, my dear Watson!

"This Raymax tube was already in a frightening place, it was three floors below the ground level, which was the level of the Thames, about 50 yards away, because it was the basement of the Chemistry Department. And it was lead-lined so that the X-rays should be shut in because there were various lecture theatres nearby. So having realized that I needed to keep a watchful eye on the amount of hydrogen I was filling the room up with - so that I wasn't going to blow myself up and repeat the Hindenberg Disaster - I bubbled the hydrogen through water to help judge when the camera had been swept clean of air. It just so happened that this produced enough water vapor in the camera to be taken up by the fibers and produce crystallites. It turns out that freeze-dried DNA from Signer's preparation would form micro-crystallites in a humidity of 92%, and that was by serendipity alone that I just hit that value."

Gosling is in no doubt that this was "the most exciting thing that's happened to me before or since!" He can still remember the moment clearly: "standing in the dark room outside this lead-lined room, and looking at the developer, and up through the developer tank swam this beautiful spotted photograph, you are familiar with them now I'm sure. It took 90-something hours to take the photograph, again, pot luck. But it really was the most wonderful thing. And I knew at the time that what I'd just done was to produce a crystalline state in these fibers, and if then the DNA was the gene material, I must be the first person ever to make genes crystallize."

Did Gosling realize at that moment that it would from then onwards just be a matter of time, that the structure of DNA was now in his grasp? "Yes. Yes, that was why I could truly say it was my 'Eureka!' moment. I went back down the tunnels over to the Physics Department, where Wilkins used to spend his life, so he was still there. Wilkins realized even more certainly than I did that we had just crystallized genes. As with Randall, he was convinced that the DNA was the genetic material, and now he was convinced that the DNA could be made to crystallize. I can still remember vividly the excitement of showing this thing to Wilkins and drinking his sherry by the glass... by the gulpful."

Interestingly, Gosling's account diverges somewhat from that given by Wilkins in his Nobel lecture (Box 3). Another - understandable - omission from Wilkins' lecture is a somewhat unorthodox, and nevertheless essential, contribution he made to Gosling's first X-ray images of crystalline DNA (Figure 2). Gosling had "sealed the conventional camera onto its base and the lid and so forth with vacuum wax and stuff that you used in order to keep air out. This was to keep the hydrogen in, of course. The collimator was made of heavy brass and although I could seal it to the outside of the camera, there was no way I could think of to really prevent the gas coming out of the collimator tube. To my great surprise, when I was showing him how far I had got, this rather shy Assistant Director of the MRC Unit said: 'Try this.' And he pulled out from his pocket a packet of Durex." By a quirky twist of irony, the introduction of condoms to the story occurs after Gosling had ceased working on sperm, having switched to Signer's DNA, which was derived from calf thymus.

Does the 'Assistant Director' refer to Maurice Wilkins? "Yes. But he was painfully shy."

But he was such a dedicated scientist that he was willing to risk the embarrassment... "To risk everything, yes, that's right! It was extraordinary, really."

The condom did the trick, and Gosling was able to produce some high quality X-ray images. This is where Jim Watson first enters the picture: "there was a conference in Naples that was on the structure of biologically active molecules. Randall was invited to talk and said that he couldn't, so he sent Wilkins, and Wilkins showed our beautiful picture and said: 'Look boys!' Or rather more... I mean his lectures were as dry as dust, so in a dusty sort of way, he made it clear that they had crystallized the genetic material. Now, Watson was in the audience, and I was told by somebody else who was there that Watson up until then had been doing his usual trick of pretending to read the newspaper while everybody gave of their best results and so forth. And he actually... when the picture came up on the screen in Wilkins' lecture, he actually put his paper down. And so he was convinced then and there, that if the material could be crystallized, then the structure could be found and it was just a short step from one to the other."

Watson, having seen the fruits of Gosling's serendipity, asked Wilkins if he could join the MRC Unit, but was refused "because Wilkins was afraid of him. He's quite scary, old Jim, on full flight." Instead, he approached Bragg (Box 2) at Cambridge's Cavendish laboratory, where - by another stroke of serendipity (Box 4) - he ended up allocated a desk next to Francis Crick. And the rest, as they say, is history...

# Rosalind Franklin: a friction engineered by Randall?

Meanwhile, Randall was not convinced that Wilkins and Gosling would ever learn enough crystallography "to be able to solve this spotty diagram." For this reason, Rosalind Franklin was recruited to the project; Gosling believes that her appointment is another key pillar of Randall's contribution to the double helix story, as her experimental talent proved invaluable.

Famously, Franklin and Wilkins enjoyed - or, rather, did not enjoy - a very fractious relationship. Gosling sees it as a "pure personality clash", as well as a very unfortunate misunderstanding, which only came to light many years later. "The whole trouble was that there was a meeting in Randall's office, where Rosalind turned up and Alex Stokes and myself were invited along to meet her, and Wilkins was off somewhere else. In his autobiography, I think he says that he was away in Wales with a new girlfriend. But that was the key to what followed, he wasn't there." At this meeting, Gosling was assigned to work under Franklin, having previously been working with Wilkins.

"It was a very curious thing. Randall actually wrote to Rosalind saying that she would be asked to direct the X-ray crystallographic work on the Signer DNA material, and I didn't know that he'd done that." As with Gosling, Wilkins himself was not made aware of this letter until many years later.

Gosling believes that the misunderstanding was "deliberate" on Randall's part, rather than an unfortunate oversight. When he eventually discovered the truth of the matter, Gosling was "really shocked" because "it was against all Randall's principles as I understood them. Up until then, everybody would freely discuss their work and interact with Wilkins probably more often than interacting with Randall directly."

Perhaps most peculiar in the whole episode is that Randall and Wilkins had known each other for many years, and had been close colleagues at several institutions. So what was Randall's motivation? "He definitely subscribed to the divide and rule principle, as lots of people did. He thought it would make them competitive and improve their work."

Another school of thought might be that Randall did not think Wilkins up to the job of the matter at hand, but did not want to confront him directly about these concerns. However, when this theory is put to him, Gosling is unsure. But what is for certain is that Franklin had very much been told by Randall - "this very dynamic Head of Department" - that she was a post-graduate fellow and it was her research, not Wilkins'.

"Wilkins came back to the lab after a few days and, you know, said, 'How are you?' and 'What are you doing' sort of thing, and got her back up. It was very unfortunate." Gosling, in the dark as much as everyone else, joined others in attributing this response to a Bolshie streak in Franklin's character, and also had sympathy for Wilkins, having previously worked closely with him. Now that he was Franklin's student, Gosling was very much caught in the middle: "It was terrible, terrible. I spent my life going from one to the other, giving messages, trying to play the peacemaker."

Eventually, the dispute between Wilkins and Franklin resulted in Randall suggesting to Franklin that she had better leave, even though the DNA work was not yet complete - although he was good enough to "fix her up with his old pal \[JD\] Bernal" at Birkbeck.

Later on, Wilkins was "beset by worry that he had been responsible for not integrating Rosalind into the group" and it very much lingered with him, to the extent that, for the rest of his life, he would frequently ask Gosling whether he had been unkind to her.

# The wrong model

All Hollywood script writers worth their salt know that a successful plot is built around a boy meeting a girl, losing the girl and then winning the girl back. Change a few nouns, and you pretty much have the story of the double helix: Crick and Watson 'discover' the structure, lose the 'discovery' when it turns out to be wrong, and then win back the discovery by coming up with a better model. Where they erred was in rushing to triumphalism with the first, incorrect, model: "we suddenly received a call, in '51 I think it was, from Crick - from Maurice. Crick had got in touch with Maurice to say that he hoped he didn't mind, but they had built - him and Jim had built - a model of DNA as a double helix, following the results that we had deduced in structure 'B'. And would we like to go to Cambridge to see it?"

According to Gosling, it was clear to him then that the King's data, such as it was at the time, had fed into Watson and Crick's model. Nevertheless, Gosling, Franklin and Wilkins, together with their King's colleagues Bill Seeds and Geoffrey Brown, took the Liverpool Street train "with a heavy heart" to Cambridge. But, upon arrival, it was immediately apparent that Watson and Crick had made some elementary mistakes, in both senses of the word.

"We arrived in the lab to be shown the model and to the absolute relief of Rosalind and myself - I don't know about Wilkins, what he thought at the time, because I was dealing with my own thoughts and not observing other people - the boys had built a model with the phosphate linkages going up the middle of the thing, which gave it, of course, rigidity, and so you could hang all the nucleotides and things off the ends of the ionic chain. That must be wrong, because we knew that the water went into that phosphate-oxygen group, and there was an ionic linkage there between the sodium - it was the sodium salt of DNA - and the phosphate group, and you got eight molecules of water going in, quite a lot of water that would go in and come out very easily, as we had shown. So it meant that whatever the structure was, those phosphate groups had to be on the outside. And so we were delighted, and Bragg was embarrassed because it wasn't done to actually work on another man's problem."

Watson and Crick's recklessness, in playing their cards so early, was pounced upon by Franklin, who "tore the model apart point by point." As Gosling notes with some amusement, Crick was later to comment that Franklin's demolition of the model was the only time he ever saw Jim Watson at a loss for words. "And I can believe it!"

So did Franklin deliver her criticism with obvious relish, or did she play it straight? "Oh, no, with obvious relish! She reminded me very much of a particular lady in the University of St Andrews Physics Department that I worked in when I left King's, in which she'd turn up at seminars by new PhD students or the like and she would tear their suggestions apart. 'You're wrong, and you're wrong for the following reasons, one, two, three, four...'"

Gosling had, like Franklin, realized instantly that the model was wrong but did not join her in skewering its inadequacies. Why not? "I left it to her. I didn't need to discuss it at all, I mean she was...she was on top of her form! My word, no."

Perhaps the famously negative portrayal of Franklin in Jim Watson's book 'The Double Helix' was payback for this moment? "Yes. Oh, I'd never thought of it, but yes, that's true. The humiliation. He must have felt - that's the word - he must have felt humiliated. Who the hell is this woman telling me... Yes, you can see it more clearly looking back, can't you?"

Rather than focus on Jim Watson's humiliation, however, Gosling was at the time "just happy that it meant that Rosalind and I could go back to the Strand and just get on with doing the mathematics. And it was ours to take as long as we liked."

Watson and Crick's misplaced haste really did seem to have handed the game to King's. When Wilkins reported what had happened to Randall, he was "furious and stormed off to Cambridge to see Sir Lawrence, and Lawrence was apologetic and actually forbade the lads from doing any more work on DNA, and that it was a King's problem and that Crick had plenty to do on hemoglobin and that he should concentrate on getting his PhD."

# The American competition

With the ban imposed upon Watson and Crick, DNA would have remained a King's problem, were it not for Caltech's Linus Pauling (Box 2) and, moreover, the inexplicable indiscretion of Pauling's son Peter. Not content with having discovered pretty much everything else going in chemistry and molecular biology, Pauling had turned his attention to the structure of DNA. A physicist by training, Pauling had got under the skin of atoms and molecules with great success to describe the nature of the chemical bond and the secondary structure of proteins, and much else besides. So he seemed like a good bet in the race to discover the structure of DNA.

Pauling's son Peter was at the time based in Cambridge, and somehow managed to leak the news of his father's interest in the question to Jim Watson. The prospect of losing to Pauling, who had already beaten him to the alpha-helix and beta-sheet, was too much for Bragg, and he allowed Watson and Crick to start work on DNA again.

It so happens that the first papers Pauling wrote on the subject actually contained the same mistake made by Watson and Crick, in that the phosphates were on the inside. Further, his proposed structure was a triple, rather than a double, helix \[7,8\]. It was very wide of the mark, but the threat of Pauling's intellectual prowess was not to be underestimated.

Does Gosling believe that Bragg's reaction was justified? After all, a draft manuscript written by Franklin shows that she had already drawn many correct conclusions about DNA's structure, including its double helical nature. Would Pauling have arrived at the model before King's with Cambridge out of the race? "That's the problem. That's the \$64,000 question I've been asked so many times. 'How long would it have taken you?' And I don't know."

# King's loses the race

Franklin's methodological approach was not that of someone in a race to the prize, but instead favored slow, steady progress. Franklin's skills as a chemist had borne fruit in determining that there were two crystalline forms of DNA, dependent on the humidity; the respective forms at lower and higher humidity were christened by Gosling and Franklin 'A' and 'B'. It was accepted that 'B' would be the *in vivo* form, due to its formation in humid conditions, and Franklin had taken an exceptionally high quality X-ray diffraction pattern of this form ('photo 51', see Figure 3), which proved invaluable to Watson and Crick. From the King's data, it was clear that 'B' was helical, but this could not be said with certainty for 'A' (Figure 4).

Franklin had set herself the task of deducing the structure of 'A' from first principles, using Patterson functions, and she was having quite some success in doing so. "We were the first people ever to do a cylindrical Patterson. But now nobody does it, because the computer would do it for you in a twink. And so you would probably go straight to an atomic density map, rather than vectors."

But why the focus on 'A', given that this was known not to be the biologically relevant form? "Well, that's hindsight, isn't it. Her answer would have been, 'we've got over 100 diffraction spots, so we can do all the mathematics of the Patterson function.'" Such data were not available for 'B', and Franklin's preference for sticking to first principles, and aversion to playing about with models and "guesswork", was the deciding factor.

Another obstacle for Gosling was his ignorance of space groups. "Alex Stokes (Box 2) had taught me enough crystallography that I had been able, before Rosalind was even appointed, to index the spotty picture that I had produced, and find the unit cell and therefore the symmetry that the molecule must exhibit. I got the space group right, I got all the major indices right. But what I didn't realize was that the C2 space group meant that there must be a dyad axis perpendicular to the fiber axis. The density values, which determine how many strings of the molecule are per unit cell, could in our case be two or four, and we were getting an answer for the density, which was a bit difficult to measure, between two and three. Now Crick realized immediately from my unit cell data that there must be a dyad axis and therefore, if this double diamond was showing a helical pattern, it meant there was a double helix."

The reason Crick knew all about this space group was that he was studying, under Bragg, the structure of hemoglobin, which just so happens to share the same space group. So another bit of serendipity? "Absolutely."

The slow pace at King's was no match for the fury of Watson and Crick's efforts, and so it came to pass that Gosling, Franklin and company were called up to Cambridge a second time...

# That 'eureka!' moment

"We went up, saw the structure, we came back to King's and looked at our Pattersons, and every section of our Pattersons we looked at screamed at you, 'double helix!' And it was just there! - once you knew what to look for. It was amazing."

When Gosling saw this second structure - the double helix we are now so familiar with - for the first time, was it as obvious to him that this model was right as it had been that the first model was wrong? "Absolutely. Absolutely, because it was so elegant. And it also explained the diffraction pattern as being such a clear double helix because the phosphate groups were on the outside, the sodium then was ionically bonded to the phosphorous, and the eight molecules of water went into the same group. So you got this enormous scattering power, due to the electronic number of oxygen, nitrogen and carbon."

It wasn't just the phosphates on the outside that made the model so convincing, but also the "stuff in the middle." For one thing, it made a lot of sense that the identities of the nucleotides could be changed without impacting on the overall structure. For another, the nucleotides' "stair rods looked identical to the X-rays because of the way they were bonded." More importantly, Watson and Crick took Chargaff's (Box 2) finding that "no matter which DNA he studied, there was always a 1:1 ratio of adenine to cytosine, and guanine to thymine, and that meant that these were identical" and incorporated it into the model in the form of complementary base pairing. With this seemingly simple rule, suddenly "the solution to DNA's reproductivity was so simple."

Chargaff's ratio was already in the public domain, before Watson and Crick's model was unveiled, but "no one had made the connection" that this meant the DNA structure would rely on complementary base pairing, nor that this "was necessary to explain how the DNA replicated."

So, given that the double helix and all its features were already present in Franklin and Gosling's data, but had somehow been opaque to them, perhaps it was a good thing that Watson and Crick worked on their model, even if by surreptitious means, and the injustice really was more the lack of attribution? Gosling agrees. "I think so. We would have, I think, got there eventually. But Crick himself has said, and Wilkins has agreed with him, that if they hadn't built the model, we would have got there at King's, but not in one fell swoop, that it would have come out in dribs and drabs about the various aspects."

And, as a consequence, history would have been deprived of a singularly exciting moment? "That's right. That 'eureka!' moment, as Jim himself admits to, when you know that that specific pairing is there, and it's in the literature! And then, I can quite sympathize with him in a way, such a very strange feeling. Because I think it was Bernard Shaw who said that very few people are lucky enough to have an original thought in their whole lives. But there I was presented with mine, the crystallization of DNA, as he was, on a plate. Dong! Light bulb!"

Gosling readily offers his admiration for Crick and Watson's achievement: "they'd not only put together a model showing that the DNA was in the form of a double helix, but that it had this dyad axis and that this meant that these stair rods of the nucleotides had to be specifically paired - now that was worth a Nobel Prize."

Similarly, Franklin reacted to this second model with a level of grace to equal the schadenfreude with which she had destroyed the first. "If you look at the BBC 'Secret of Life' documentary, which is absolutely brilliant - it really is a wonderful thing - they have a shot there, which is of course made up, but it has Rosalind Franklin by herself looking at the model in Crick's lab. And Bragg comes in and says something like, 'Do you have any regrets...' - or something like that - '...Miss Franklin.' And Miss Franklin apparently said, 'No, we all stand on each other's shoulders.' And that stuck in my mind. Whether she said it or not, I don't know. But that was her attitude that she took when she and I were discussing it."

To her credit, Franklin "absolutely" put science before ego. However, at the time, she was not aware of the extent to which Watson and Crick had based their model upon her data. Does Gosling believe she came to know about this before her death in 1958? "Yes. Oh, she did know about that."

# Obscurity and infamy

Perhaps surprisingly, given the iconic nature of the double helix today, the 1953 discovery did not initially have much impact, as Gosling saw it. An illustration of this might be the difficulty he had finding work following his PhD - there were no opportunities for him to stay at King's, which he would have gladly done.

"I talked about DNA for about a year after I wrote my PhD because I was convinced that it would only take a year... that the structure of DNA now being known, the ability to control carcinogenic activity within any tissue you like would be available in two or three years' time. And when two or three years came and went, and nobody had shown that you could... 'Alright, so a double helix, so what?'"

Due to Franklin's enforced move to Birkbeck, Gosling ended up writing his thesis away from King's, under her guidance. This annoyed Randall somewhat, as he was "of the old school, who... in those days, nobody but the Professor had PhD research students." Randall's response to the situation was to appoint himself as Gosling's internal *viva* (thesis defense) examiner, and he roped in Bernal as the external examiner. Oddly, when you consider that the content of his thesis amounted to a not insignificant contribution to the discovery of DNA's structure, the prospect of his *viva* with Randall "scared the pants off" Gosling. In part, he explains, this was because his studentship had begun by "trying to establish what the problem was", due to the "amorphous" state of biophysics, rather than starting off with a "ready-made problem", as his friends in Ingold's Chemistry Department at University College had done.

Given that his studentship had been under Randall's direction, the idea that Randall would then find fault with Gosling's rationale in the *viva* is hard to resolve, outside of a Kafka novel perhaps. "Yes! Very Kafkaesque, yes."

But, still, he surely cannot have been too afraid of defending a thesis describing such successful work? "Well, I can tell you, and I'll tell anybody, that the big difference between writing a paper - especially if you have co-authors - is you can always, when the discussion gets too heated, say you didn't write that bit, it was him! But with a thesis, you're aware that as you are writing each word, it can be attributed to you. And that's an odd feeling, especially when you know who your examiners are."

Gosling's fear did not end with the anticipation of his *viva*, but progressed into the examination itself. "Randall and Bernal had obviously had a very good lunch. I went in there at 2 o'clock, and at half past five, they were still going on talking about the origin of life. I was hardly asked a question. The two of them were at it hammer-and-tongs. I was terrified. I was just terrified, because I was convinced that Bernal was a genius - one of only three I have met in my life, together with Crick and Haldane (Box 5)."

Having become disillusioned about the failure of the double helix to make much of an impression, Gosling lost interest and drifted away from the field. He had in any case wanted to move closer to his original dream, medicine, and did indeed go on to lead a successful career as a medical physicist (Box 6).

But an unexpected development suddenly cast the double helix in the spotlight, and spawned a legend that solidified its place in popular culture. Jim Watson wrote a book. In Gosling's eyes, "that's what did it" for the double helix. And that's where Gosling's praise for Watson's book - 'The Double Helix' \[5\] - ends.

"That book is a novel. A very successful novel, but it is a novel. Wilkins and Crick wrote to Harvard saying they should not publish this book, and they didn't." But someone else did.

Another unhappy reader of 'The Double Helix' was Max Perutz. While Watson and Crick obtained some of the King's data through Crick's friendship with Maurice Wilkins ("Innocently. Because he'd always discussed his work, as Crick had with him, from their undergraduate days."), other data came from a progress report submitted to the MRC, which Watson had obtained from Perutz.

"I actually had a letter that I can no longer find from Perutz saying that he wanted me to be assured that he did not rush down the corridor waving the MRC report containing our contribution about the size and shape of the molecule. It's true they had actually got it from him. But the way Watson tells it, it's sort of Archimedes getting out of the bathtub again, you know."

Key for Crick and Wilkins was their dismay at the portrayal of Rosalind Franklin, which amounted to what you might describe as an *ad hominem* character assassination, and a wildly inaccurate one at that. Worse still, Franklin had died of ovarian cancer several years earlier, and so was not able to defend herself. Was Gosling also angry about how she had been portrayed? "Yes. Very much so."

But he is gratified that many people rose to Rosalind's defense ("her part in it now is if anything overplayed!"), and in particular that Brenda Maddox's "first class" biography of Franklin was able to set the record straight \[2\]. Unwittingly, Watson is responsible for the widespread admiration with which Franklin is viewed today, which is to a large degree a reaction to his book.

How did Gosling feel about his own portrayal in 'The Double Helix'? Was he concerned that his role had been underplayed? "No, not really. But I felt that Watson was so busy criticizing poor Rosalind that he didn't mention and give credit to the work of Alex Stokes and Wilkins and myself. And Randall."

Despite his strong reservations about 'The Double Helix', Gosling acknowledges that Watson has much to be complimented for. "He is very precocious, he is one year younger than me, which annoys me - ha! - and he is without doubt a very lively mind and his ability to spot that specific pairing was worth the Nobel Prize."

# Reconnecting with DNA

As mentioned previously, Gosling's subsequent career deviated from biology (Box 6), and he didn't follow the progress of molecular biology during this time ("not at all!"). This scientific realignment proved problematic on one occasion during his tenure at the University of the West Indies, when he was asked to deliver a lecture to the Trinidad campus on what his discovery was leading to. "I hadn't the foggiest! So I had to bone up, and that was incredible."

Asked jocularly whether he contacted Francis Crick for assistance, Gosling replies that, actually, he did! "Well, yeah, I did have a conversation with Francis. And it was... the whole thing was fascinating, I mean to look into this new world."

When Gosling hears of developments that have come from his work at King's, does he feel connected to it? "No, I feel detached, I really do - it's gone way ahead of where I was. But I realize that I don't go to the literature enough to say that I have kept up."

The 50th anniversary of the double helix reignited the world's interest in Ray Gosling, and suddenly he was invited to events alongside Nobel laureates and other giants of the molecular biology world - most of whom he had never met before, nor even been aware of their work. Gosling was particularly taken with Alec Jeffreys ("a very nice chap") and Paul Nurse ("a very witty fellow indeed"), and was "very flattered" when Nurse invited him to contribute a brief memoir of the double helix to a time capsule for The Francis Crick Institute.

Have any DNA-based developments caused him concern, in the same vein as the conflicted feelings felt by Wilkins and some other alumni of the Manhattan Project? "No. But I do very much feel that I can't stress enough the critical stage we're at. Up until now evolution has occurred spontaneously, set in motion in all sorts of ways. And what is happening now is that our species are the first ever to have their hands on the levers controlling evolution. If you are a pessimist, you would say the glass is half empty, and you would think it's rather a sinister situation. So you have to take an optimistic point of view, at least I think you do."

Work on transgenic animals has made a strong impression on Gosling (he highlights the example of so-called spidergoats), as has the notion of an embryo with three genetic parents, in which maternal chromosomes and mitochondrial DNA originate from different individuals.

Returning to his favorite theme of Randall, Gosling recalls how in later years the ringmaster of the double helix discovery focused his work on cilia. "Randall again was ahead of his time, wasn't he? In concentrating on the cilia. Isn't that fascinating? How long's the old boy been dead? '84, gosh. He would have been so pleased, wouldn't he..."

# Box 1. 'The best rag I ever came across'

To illustrate the level of treachery that his move from University College to King's College might have been perceived as, Gosling relates a practical joke that took place in the 1930s: "The engineers at University College got into the front reception hall in King's and cut a hole in the belly of Reggie the Lion, who's their mascot, and filled it with rotten vegetables that they'd got from Covent Garden, and sealed it up and painted it and put it back where it was, which was on a special plinth above the entrance doors. And it was weeks while the beadles looked for the source of the smell, and that was I think the best rag that I ever came across."

# Box 2. Watson and Crick's key accomplices - willing and unwitting - in the quest for the double helix

## John Randall

A physicist by background, Randall was "ahead of the curve" in setting his sights on biological questions. He established the MRC Biophysics Unit at King's, where his modern approach translated to interdisciplinary research with an unusually large, for the time, quotient of female scientists. Randall was "autocratic" and had a "Napoleonic complex", and the Unit was very much his "circus". But Gosling has immense admiration for Randall, and believes that his drive and vision were the magic ingredient that led to the double helix discovery, rendering him the great "unsung hero" of the story.

## Maurice Wilkins

A long-standing colleague of Randall at a number of institutions, Wilkins became his right-hand man once recruited to the Unit, where he served as Assistant Director. A dedicated scientist, the "painfully shy" Wilkins guided Gosling's early work at King's. Wilkins had first attempted to study DNA using ultraviolet light techniques, but without much success. One of the two King's articles co-published with Watson and Crick's work in *Nature*'s April 25th 1953 edition described Wilkins' work, together with Alex Stokes and Herbert Wilson, on the structure of DNA. This publication focused on how to interpret X-ray diffraction patterns and on showing that DNA from various species adopts the same structure.

For his contributions to the discovery of the double helix, Wilkins shared the Nobel Prize in Physiology or Medicine for 1962 with Watson and Crick (Box 3).

## Rosalind Franklin

Rosalind Franklin was recruited to King's, where Gosling worked under her, by Randall and was key to obtaining the quality of X-ray diffraction pattern necessary to determine the structure of DNA. She had come to Randall's attention for her work on the properties of coal as part of the war effort. At the time, it was "very unusual" for a woman to have a senior research role at King's, although not unusual in Randall's laboratory (see text), and many outside Randall's circle were taken aback by it.

Franklin was "a very good experimental scientist, as you had to be if you were a woman in those days." She fell out with Maurice Wilkins from the beginning of her time at King's, largely due to a misunderstanding engineered by Randall (see text), and then earned Jim Watson's enmity when she proved a caustic foe in the race for the double helix. Franklin viewed her study of the tobacco mosaic virus, performed at Birkbeck under Bernal after her DNA research, as her life's greatest work.

Franklin, like Gosling, was a Londoner, although Franklin hailed from the affluent neighborhood of Notting Hill, as the daughter of a merchant banker, whereas Gosling had more modest origins in the suburbs.

Franklin died of ovarian cancer in 1958 at the age of 37, nearly five years to the day after the publication of the double helix. It is thought that Franklin's work with X-rays might have contributed to her death. Several years later, Jim Watson included a very negative account of Franklin in his book, 'The Double Helix' \[5\], but was met with much opprobrium for doing so. A more recent biography by Brenda Maddox has done much to raise the profile of Franklin and to emphasize the importance of her contribution to the double helix discovery \[2\].

As Nobel Prizes are not awarded posthumously, Franklin was not eligible to be included in the 1962 Nobel Prize shared by Wilkins, Watson and Crick.

## Alex Stokes

Alex Stokes developed mathematical methods for interpreting X-ray diffraction patterns while at King's MRC Unit; without this know-how, Gosling would not have been able to make sense of his DNA data. Stokes was a co-author, with Wilkins and Herbert Wilson, of one of the three articles on DNA structure co-published in *Nature* on April 25th 1953.

## Rudolf Signer

As with Randall, Gosling considers Signer to be an "unsung hero" of the double helix story. Signer was a Swiss biochemist, based at the University of Bern, who could produce a DNA sample of far superior quality to any other available at the time. Maurice Wilkins obtained such a sample, derived from calf thymus, after Signer generously offered it to all takers at a London lecture.

## Lawrence Bragg

Lawrence Bragg was awarded the Nobel Prize in Physics, together with his father William Bragg, at the tender age of 25, making him the youngest ever recipient of this prize to date. Bragg's Nobel was in recognition for the methodology of studying crystal structures by X-ray diffraction, which the Braggs had developed at the University of Leeds. It was also at Leeds that William Astbury obtained early X-ray diffraction patterns of (non-crystalline) DNA.

By the 1950s, Bragg was serving as the Head of the Cavendish Laboratory at Cambridge, where both Crick and Watson worked under him. Also based at Bragg's Cavendish for a time was Peter Pauling, son to Linus, who leaked information of his father's interest in the question of DNA's structure. A fourth key player to work under Bragg at the Cavendish was the chemist Jerry Donohoe, who set Watson and Crick right about errors they were making in the likely chemical form of DNA's bases.

## Linus Pauling

Pauling is most notable for his work on the nature of the chemical bond and on the secondary structure of proteins, and was one of the most prolific scientists of the 20th Century, in terms of major advances credited to his name.

Pauling began work on the structure of DNA while King's were working on the problem, and Crick and Watson used the specter of defeat at the hands of Pauling - who had beaten Bragg to the alpha-helix and beta-sheet - to goad Bragg into allowing them to restart work on DNA's structure. As an American based in California, Pauling also added an element of transatlantic competition to the race, although Cambridge-based Jim Watson was of course himself also American.

Pauling published a model for DNA's structure in February 1953. However, the model did not come close to the true structure, with the most obvious mistakes being the number of strands - he had proposed a triple, rather than a double, helix - and the location of the phosphates on the interior of the helix.

Pauling is the only person in history to have won two individual Nobel Prizes - these were for Chemistry (1954) and Peace (1962), the latter as a result of his political activism, some aspects of which had famously brought him unwelcome attention from the United States government, in the form of travel restrictions. In part for this reason, Gosling was never able to meet Pauling in person.

## Erwin Chargaff

Chargaff had discovered the 1:1 ratio that existed between the complementary base pairs in DNA, but had not made the leap from that discovery to the rules of base pairing. Chargaff personally communicated his discovery - dubbed 'Chargaff's rules' - to Watson and Crick, and was "as cross as two sticks" not to be included in Watson's book.

Originally from the present-day Ukraine, and having spent time at various European research institutions, Chargaff relocated to New York to escape the rise of Nazism. It was here, at Columbia University, that he determined 'Chargaff's rules'.

# Box 3. Serendipity or sagacity?

Gosling claims here and elsewhere \[11\] that he was the first person to crystallize DNA purely by a stroke of luck: he had used water to monitor hydrogen and, serendipitously, the humidity absorbed by the DNA fibers from this water resulted in crystallization (see text).

In his Nobel lecture \[12\], however, Gosling's colleague Maurice Wilkins gives a different version of events: 'One reason for this success was that we kept the fibres moist. We remembered that, to obtain detailed X-ray patterns from proteins, \[JD\] Bernal had kept protein crystals in their mother liquor. It seemed likely that the configuration of all kinds of water-soluble biological macromolecules would depend on their aqueous environment.'

# Box 4. Watson and Crick: the perfect pairing

Gosling relates how, having been refused entry to King's, Jim Watson "was nonetheless convinced that he had to learn some basic crystallography, and then he'd be able to find the structure of DNA." He approached Sir Lawrence Bragg and asked to join his Cavendish Laboratory at the University of Cambridge, and was accepted ("you didn't turn down a pair of willing hands which came self-funded.")

Because of the way the space requirements of his workers happened to be at that time, Bragg gave Watson a spare desk next to Francis Crick ("a thoroughly nice man"), who was "already getting Sir Lawrence rather mad because - as Bragg was heard to say several times - the man never stopped talking. And this is true, the man was incredibly wired for looking at exciting new developments." Crick had just come across the argument about whether DNA or protein was the genetic material, and had come to the conclusion it was the DNA. "And here is this pop-eyed chap from America turning up, who is saying that is exactly what it is and the people in King's have got it, and we should build models - that's the way to go."

As with the base pairs they discovered, Gosling considers Watson and Crick to be the perfect complement to one another: Crick's "genius" and Watson's "persistence".

Gosling notes the contrast between the experimentalists at King's and Watson and Crick, who "never did an experiment in their lives, it was all deductive powers of reasoning." Nevertheless, Gosling believes that those powers were very much worthy of the Nobel Prize in Physiology or Medicine awarded to them, alongside Maurice Wilkins, in 1962.

# Box 5. An encounter with JB Haldane

Gosling believes he has met three geniuses in his lifetime: Francis Crick, JD Bernal and JB Haldane. "Those three, I was lucky to meet. I mean, I don't think there are very many scientists who have the privilege."

He first met Haldane when an undergraduate at University College, but a later encounter was much more memorable.

"JB Haldane came to a conversazione at the Royal Institution, and it was time for the eaties to be dished out, and so I was the one who got the short straw and had to stay by the model in case anybody came to look at it. And there it was, this lovely double helix. And this Haldane shuffled up and started to roll a cigarette, and apparently he used the cheapest possible tobacco and Rizla paper, and made his own, like he was a student. Nowadays, you would have accused him of making a reefer, a joint. But he rolled it, took a few puffs and said, 'Well, now you will have to find an untw... tw... ...twiddlase.' Because he had an awful stammer, and that I remember vividly. I stood there awestruck, thinking about an untwiddlase! I mean, this was before the concept of telomeres. But he was on it. Incredible man."

# Box 6. Gosling after DNA

After the initial double helix data had been published, Gosling and Franklin finished up their research into the structure of DNA with another article in *Nature* \[13\]. Gosling continued to work in crystallography for a few years, focusing on the structure of nucleotides, but spent most of his career as a medical physicist, developing devices for the study and diagnosis of atherosclerosis.

The idea to perform this work originated from a discussion he had while based at the University of the West Indies. "Again, a somewhat serendipitous situation developed, in that I got to know very well indeed the senior lecturer in morbid anatomy. He wanted an explanation as to why the fatty plaques should develop in arteries where the blood was moving fastest, that this was an anomalous situation, and all of the work that was being done on atherosclerosis - on atherogenesis, if you like - at that time was being done by biochemists. And he said, surely, isn't there a big hole here for someone who is a biophysicist to look at the characteristics of the pulsatile flow, and that must play a part in the formation of these plaques."

Gosling began the project while on a sabbatical back in Randall's laboratory at King's and, while there, Randall persuaded him to change tack. "One day in my little lab, Randall appeared. And he had this terrifying habit of doing just that. I mean, he walked around with hush puppies and you couldn't hear him coming, and suddenly you were in an empty lab and then the next thing you know, he's at your elbow. Terribly dangerous! But what he said was illuminating. He'd come down to find me because he wanted me to stop building glass tubes with lumps inside, because if I did, and if I was successful in replicating the conditions, all that would happen is that some bloody physiologist would come along and pooh pooh the whole thing because it was not like the *in vivo* state, and that what I ought to do is to build an animal model and observe it directly in a living situation. And then he disappeared."

Gosling took Randall's advice and, when he returned to Jamaica, switched to working on cockerels, which turned out to be the best animal model available. Later, he continued his work on atherosclerosis at Guy's Hospital, London, where he developed ultrasound devices for the analysis and diagnosis of atheromatous plaques. This phase of his career included an important discovery.

"As the lumps developed, so it changed the elasticity of the artery wall. As you know, you get hardening of the arteries as they build up with atheromatous plaques, but we were able to show that, before that happens, they get three times more distensible, which was an unlooked for, unknown thing - counterintuitive."

Gosling found the direct impact he could see his work making in medical physics more satisfying than fundamental biology, and he also preferred the more steady rate of progress to the manic ups and downs of his years as a crystallographer. His time at King's, therefore, was a preamble to a rewarding and successful career that led Gosling in a very different direction to his fellow actors in the double helix story.

Now retired, Gosling's contribution to science has been recognized in the form of election as a Fellow of King's College and the award of a DSc from the University of the West Indies. Inexplicably, Gosling has never received recognition in the Queen's honors system from the British government, although he was invited to meet Prime Minister Tony Blair at Downing Street in honor of the double helix's 50th anniversary.


abstract: A report of the Biochemical Society/Wellcome Trust meeting 'Protein Evolution - Sequences, Structures and Systems', Hinxton, UK, 26-27 January 2009.
author: John W Pinney; Michael PH Stumpf
date: 2009
institute: 1Centre for Bioinformatics, Division of Molecular Biosciences, Imperial College London, Wolfson Building, London SW7 2AZ, UK
title: Evolving proteins at Darwin's bicentenary

The effects of natural selection are ultimately mediated through protein function. The traditional view that selection on proteins is primarily due to the effects of mutations on protein structure has, however, in recent years been replaced by a much richer picture. This modern perspective was in evidence at a recent meeting on protein evolution in Hinxton, UK. Here we report some of the highlights.

Unsurprisingly, Charles Darwin featured at lot at the meeting. Evolutionary arguments are all-pervasive in the biomedical and life sciences and this is particularly true for the analysis of proteins and their role in cell and molecular biology. From initial investigations of individual proteins in the 1940s and 1950s, which were motivated by even earlier work on blood groups, we can now routinely collect information from a large number of sequenced genomes to help us understand the evolution of proteins in terms of their sequences, structures and functions, and their roles as parts of biological systems.

# Comparative evolution

The primacy of comparative, and thus evolutionary, arguments in the analysis of proteins and their structure was emphasized by Tom Blundell (University of Cambridge, UK), who reviewed almost 40 years of structural bioinformatics. He noted that in the early studies of insulin structure, the common ancestry of all life on Earth meant that lessons learned in the context of one species were transferable to other species. This in turn meant that sequence data could be linked to structure more directly through comparative arguments than would have been possible using biophysical or biochemical arguments. Despite vast increases in computational power and experimental resolution, this continues to be the case to the present day.

The explosion in available whole-genome data has provided us with a much richer understanding of genomic aspects of protein evolution. This was highlighted by Chris Ponting (University of Oxford, UK), who contrasted the distributions of proteins and protein family members in the human and mouse genomes. Such a comparison reveals high levels of sequence duplication - probably in line with what might be expected, given recent findings of copy-number variation - and suggests a scenario where ancient single-copy genes are only rarely gained or lost. Members of larger gene families, however, have experienced much more frequent gene duplication and loss; this may reflect the role of such gene families in adaptive evolution, as seen in the rapid evolution of the androgen-binding proteins in mouse.

The theme of adaptation was elaborated on by Bengt Mannervik (Uppsala University, Sweden), who focused on the evolution of enzymes, a class of proteins with perhaps uniquely well-characterized functionality. Here, he argued, the relative trade-off between substrate specificity and enzymatic activity has given rise to a quasi-species-like evolutionary scenario: abundant protein polymorphisms underlie a complex population of functional enzymatic variants. Such diversity in the metabolic functions available within the population may presumably help to buffer changes in the environment encountered during evolution.

Araxi Urrutia (University of Bath, UK) addressed predominantly the link between gene and protein expression and evolutionary conservation and adaptation. As she pointed out, there is clear emerging evidence that highly expressed genes in humans share certain characteristics such as short intron lengths and higher codon-usage bias and favor less metabolically expensive amino acids. This affects the rate at which protein-coding genes evolve in a manner independent of protein structure. Moreover, this level of selection also appears to depend on the genomic context, as patterns of expression of neighboring genes are statistically correlated.

# Insights from structure

Also fundamental to protein activity is post-translational modification, notably phosphorylation. This is a field of enormous biomedical importance, as kinase and phosphatase activities crucially regulate signaling and metabolic processes. The structural work of Louise Johnson (University of Oxford, UK) and colleagues bridges 'classical' structural biology and systems biology, and she discussed the structural factors underlying the regulation of kinases and phosphorylation. These comprehensive analyses are now also beginning to reveal how biochemical compounds can affect kinase regulation in a manner that may become clinically exploitable.

Keeping to the structural theme, Christine Orengo (University College London, UK) discussed the phenomenal insights that have been gained recently into the evolution of protein domain superfamilies and the ensuing effects that this can have on protein structure, active sites, and ultimately, function. For example, the analysis clearly reveals common structural cores that are shared across the members of the same superfamily but may be modified in individual members. Orengo documented how such differences in the HUP superdomain family lead to differences in the participation of paralogs in protein complexes and biological processes following duplication.

Alex Bateman (Wellcome Trust Sanger Institute, UK) further elaborated on the evolution of families of protein domains. Such a domain-centric point of view adds a valuable and useful perspective. Yet even at the level of shuffling these protein building blocks, the picture becomes more detailed as the available evolutionary resolution increases: for example, the frequency of changes in domain architecture is seen to approximately double following a gene duplication event as compared with a speciation event.

# Protein evolution *in vitro* and *in vivo*

Using extensive and genome-wide data from yeast and humans, Laurence Hurst (University of Bath, UK) demonstrated the substantial role of non-structural selection pressures, such as those imposed by transcription and translation, on the evolutionary dynamics of proteins.

Taking these into account results in a much richer picture of protein evolution, with the contribution of splicing-related constraints being particularly pronounced in mammals. Surprisingly, perhaps, these constraints show the same relative importance for protein evolution as aspects of gene expression do, as discussed by Urrutia. This is in stark contrast to the traditional amino-acid-centered view of protein evolution.

Using analogies with mountaineering, Dan Tawfik (Weizmann Institute, Rehovot, Israel) covered the exciting opportunities afforded by experimental studies of protein evolution. Evolution has sometimes been viewed previously as an observational and mathematical discipline rather than one characterized by experimental work. Tawfik showed how it is possible to explore evolutionary trajectories through the space of possible protein folds or functions in far more detail than had previously been thought possible. One of the exciting possibilities emerging from this work is that we will be able to study the interplay between neutral evolution and the various factors influencing selection. There is already good direct experimental detail from these laboratory studies that demonstrate the link between the rate of protein evolution and 'functional promiscuity' and conformational variability.

One of us (MPHS) described the phage-shock stress response in *Escherichia coli* as an example in which the loss and gain of proteins across bacterial species can only be understood in the context of mechanistic models of the system itself. Loss of individual genes can compromise the functionality of the stress response, which can only be tolerated under certain ecological conditions. As a result, it appears that either the complete set of proteins contributing to the stress response is maintained in bacterial genomes, or all are lost together. This all-or-nothing scenario is probably inextricably linked to the ecological niches inhabited by the bacteria.

David Robertson (University of Manchester, UK) discussed how patterns of gene duplication and diversification have shaped the global structure of protein-protein interaction networks, as well as many of their detailed features. In contrast to previous work, this detailed analysis of the protein-interaction network in *Saccharomyces cerevisiae* clearly shows that the coevolution of interacting proteins cannot simply be explained by observed protein-protein interactions. What emerges from this and related studies is that many of the high-level models of network evolution proposed only a few years ago are too simplistic for dealing with such highly contingent and complex processes. Robertson concluded with a discussion of the evolutionary history of human disease genes, which also highlights the importance of historical levels of gene duplication, and reinforces the need for nuanced assessment of the different factors affecting protein evolution.

Discussing the physical interations of kinases, Mike Tyers (University of Edinburgh, UK) described an exciting new experimental mapping study of physical protein-protein interactions of kinases. The experimental determination of these, frequently weak, protein interactions poses many challenges, requiring considerable reworking of existing platforms for proteomics, but the information produced is expected to be of great value to systems biologists. Preliminary results already suggest that the wealth of material expected from this survey will aid our understanding of the molecular mechanisms involved in these processes.

Two hundred years after the birth of Charles Darwin, we understand a great deal about the processes of evolution and how they have shaped the diversity of life on Earth. The application of the simple idea of "descent with modification" to proteins, their structures, expression patterns, interactions and ultimately their emergent functions continues to produce fundamental insights into how biological systems evolve. But the picture emerging from this unprecedented access to molecular data at all levels of cellular organization is much more nuanced than we would have thought possible only a few years ago.