abstract: A report on the Second EMBL/EMBO Symposium on Functional Genomics: 'Exploring the Edges of Omics', European Molecular Biology Laboratory (EMBL), Heidelberg, Germany, 16-19 October 2004.
author: Gino Poulin; Julie Ahringer
date: 2005
institute: 1The Gurdon Institute and Department of Genetics, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK
title: Living on the edge

EMBL's recent symposium on functional genomics showed how this new field has matured. Work from a broad range of model organisms provided new biological insights, and a plethora of improved high-throughput technologies promised more of these in the future. We focus here on biological networks - a major theme of the meeting.

# Network motifs

The identification of patterns in biological data can uncover mechanisms through which processes are regulated. Uri Alon (Weizmann Institute of Science, Rehovot, Israel) presented evidence that in gene-regulatory networks particular patterns of interconnections (network motifs) are enriched when compared to a randomized network. For example, the three-node feed-forward loop, in which transcription factor X regulates transcription factor Y and both jointly regulate gene Z, is a frequently used network motif; one example is in the L-arabinose utilization system in *Escherichia coli*. Studying this system *in vivo* Alon found that the feed-forward loop is protected against fluctuation of external signals and allows rapid shutdown of transcription. The identification of network motifs is important, as they are thought to perform specific information-processing tasks.

Dissecting networks involved in complex contexts such as animal development is a monumental task. Norbert Perrimon (Harvard Medical School/Howard Hughes Medical Institute, Boston, USA) reported how his group is starting to tackle network complexity by carrying out genome-scale loss-of-function analysis in *Drosophila* cells using RNA interference (RNAi). The strategy is to perform multiple RNAi screens in different defined contexts (different cell lines or different stimuli) using sensitive and reliable reporter assays. Perrimon focused on canonical signaling pathways such as those involving Jaks and Stats, Wingless (Wg) and Hedgehog. From these systematic screens it appears that there are important overlaps between the pathways, and that the signaling components forming these pathways, are more numerous than expected. These findings were illustrated in a network topology map where, for example, 32 components are shared in the Wg and Hedgehog screens, but only two are shared between Wg, Hedgehog and Jak-Stat screens. To try and organize the data, a phenoprint matrix (a color-coded matrix that visually links phenotypes to genes) is being built, which at the moment encompasses about 20 genome-wide screens and more than 7,500 genes. This impressive work showing unexpected connections challenges our current view of how signal information is transduced to form an appropriate response.

An important role of biological networks is transcription regulation. Understanding how DNA-binding transcriptional regulators interpret the genome's regulatory code is essential. Richard Young (Whitehead and Broad Institutes, Massachusetts Institute of Technology, Cambridge, USA) reported the use of genome-wide location data (ChIP-chip) combined with phylogenetic conservation data to describe the promoter architecture and the global behavior of transcription factors in *Saccharomyces cerevisiae*. Four types of architectures were found: single regulators; repetitive binding motifs; multiple regulators; and co-occurring regulators. There are also four global behaviors: condition invariant (the transcription factor binds the same targets regardless of the environment tested); enabled (the transcription factor does not bind its target until enabled by the environment); expanded (the binding pattern is expanded by changes of environment); and altered (different targets depending on the environment). Of particular interest, it was estimated that 17% of DNA-binding factors are found on specific targets but wait for a signal before regulating transcription. This work will provide an excellent framework for modeling global gene expression in other eukaryotes.

# Network hubs

Networks have particular nodes that are more highly connected than others; these nodes are called hubs. Marc Vidal (Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA) described the use of large-scale yeast two-hybrid mapping to derive a protein-interaction network in which he found two types of hub, which behave differently. The first type is called the 'part' hub, and has numerous partners that interact with it simultaneously. The second type is the 'date' hub, which also has many potential partners, but where the interacting partners depend on location and time. The date hubs represent high-level connectors between structural or functional modules such as cellular organelles or particular pathways, whereas party hubs function inside these modules, at a lower level. In yeast, for example, calmodulin is a date hub that connects four different modules, while one of these modules, the endoplasmic reticulum, forms a party hub.

Stuart Kim (Stanford University, USA) has uncovered hubs through analyzing DNA microarray data for conserved gene co-regulation. These hubs, which he calls 'subunits' and 'integrators', also have different properties: subunit components are highly interconnected whereas integrator hubs have a central connection point with few connections between components. Also, subunit components are usually essential, whereas most integrator components are not, suggesting that these latter proteins may have partially redundant functions. He also presented evidence that newly evolved genes are not found in hubs. The uncovering of different properties for different types of hub is fundamental for further studies of biological networks.

# The microRNA network

MicroRNAs (miRNAs) regulate gene expression and are found in all metazoans studied so far. Three presentations addressed different aspects of miRNAs: identification of their targets; identification of novel miRNAs; and analysis of their biological functions. Steve Cohen (EMBL, Heidelberg, Germany) presented the results of systematic *in vivo* analysis of miRNA/target pairing characteristics in *Drosophila*. It was determined that the 5' end of the miRNA is the most important in pairing and that a minimum of seven pairing nucleotides is required for silencing. Three types of target were also identified: canonical (perfect pairing), seed (fork-like) and compensatory (bubble-like). He estimated that half of the genes in the genome are regulated through miRNAs.

How miRNAs work is still not entirely defined. Ronald Plasterk (Hubrecht Laboratory, Utrecht, The Netherlands) has used RNAi in *Caenorhabditis elegans* to identify genes required for miRNA function. His laboratory used a reporter gene (*Hn-14::lacz*) that is regulated by the miRNA *let-7*. In this system, when *let-7* becomes expressed, the level of expression of the protein LACZ diminishes because of a translational inhibition of the reporter gene. Using a candidate-based approach that relies on previous genome-wide RNAi screens, 508 genes were tested by RNAi for causing an absence of silencing; 25 new genes were found with this property, one of which is the gene encoding the small ubiquitin-like modifier protein SUMO.

Victor Ambros's laboratory (Dartmouth Medical School, Hanover, USA) is studying the biological function of miRNAs by generating deletions of the miRNA genes in *C. elegans*. He described how, by studying miRNA loss-of function phenotypes, miRNA activities have been grouped into four classes: coordinated (repression of multiple targets); collaborative (multiple miRNAs acting on common targets); redundant; and modulated. Redundancy within the *let-7* family was shown; double mutants between the two *let-7* family members *mir-48* and *mir-84* display a phenotype, but the single mutants do not.

The meeting was inspiring, presentations were of very high quality and participants were able to interact in a relaxed and comfortable atmosphere. The field of functional genomics has truly become 'functional' and we can look forward to hearing more at the next symposium.

### Acknowledgements

G.P. is supported by the Wellcome Trust and J.A. is a Wellcome Trust Senior Research Fellow (054523).


date: 2017-05
title: WHO LAUNCHES GLOBAL EFFORT TO HALVE MEDICATION-RELATED ERRORS IN 5 YEARS

**29 MARCH 2017 \| GENEVA/BONN -** WHO today launched a global initiative to reduce severe, avoidable medication-associated harm in all countries by 50% over the next 5 years.

The Global Patient Safety Challenge on Medication Safety aims to address the weaknesses in health systems that lead to medication errors and the severe harm that results. It lays out ways to improve the way medicines are prescribed, distributed and consumed, and increase awareness among patients about the risks associated with the improper use of medication.

Medication errors cause at least one death every day and injure approximately 1.3 million people annually in the United States of America alone. While low- and middle-income countries are estimated to have similar rates of medication-related adverse events to high-income countries, the impact is about twice as much in terms of the number of years of healthy life lost. Many countries lack good data, which will be gathered as part of the initiative.

Globally, the cost associated with medication errors has been estimated at US\$ 42 billion annually or almost 1% of total global health expenditure.

"We all expect to be helped, not harmed, when we take medication," said Dr Margaret Chan, WHO Director-General. "Apart from the human cost, medication errors place an enormous and unnecessary strain on health budgets. Preventing errors saves money and saves lives."

Every person around the world will at some point in their life take medicines to prevent or treat illness. However, medicines do sometimes cause serious harm if taken incorrectly, monitored insufficiently or as the result of an error, accident or communication problems.

Both health workers and patients can make mistakes that result in severe harm, such as ordering, prescribing, dispensing, preparing, administering or consuming the wrong medication or the wrong dose at the wrong time. But all medication errors are potentially avoidable. Preventing errors and the harm that results requires putting systems and procedures in place to ensure the right patient receives the right medication at the right dose via the right route at the right time.

Medication errors can be caused by health worker fatigue, overcrowding, staff shortages, poor training and the wrong information being given to patients, among other reasons. Any one of these, or a combination, can affect the prescribing, dispensing, consumption, and monitoring of medications, which can result in severe harm, disability and even death.

Most harm arises from systems failures in the way care is organized and coordinated, especially when multiple health providers are involved in a patient's care. An organizational culture that routinely implements best practices and that avoids blame when mistakes are made is the best environment for safe care.

The Challenge calls on countries to take early priority action to address these key factors: including medicines with a high risk of harm if used improperly; patients who take multiple medications for different diseases and conditions; and patients going through transitions of care, in order to reduce medication errors and harm to patients.

The actions planned in the Challenge will be focused on four areas: patients and the public; health care professionals; medicines as products; and systems and practices of medication. The Challenge aims to make improvements in each stage of the medication use process including prescribing, dispensing, administering, monitoring and use. WHO aims to provide guidance and develop strategies, plans and tools to ensure that the medication process has the safety of patients at its core, in all health care facilities.

"Over the years, I have spoken to many people who have lost loved ones to medication-related errors," said Sir Liam Donaldson, WHO Envoy for Patient Safety. "Their stories, their quiet dignity and their acceptance of situations that should never have arisen have moved me deeply. It is to the memories of all those who have died due to incidents of unsafe care that this Challenge should be dedicated."

This challenge is WHO's third global patient safety challenge, following the Clean Care is Safe Care challenge on hand hygiene in 2005 and the Safe Surgery Saves Lives challenge in 2008.

Available from: <http://www.who.int/mediacentre/news/releases/2017/medication-related-errors/en/>


abstract: Primary malignant melanoma of the duodenum is an unusual oncologic entity. Patients usually present the similar clinical symptoms like other common tumors in this site. And there are no specific radiological features either. The cases with only little melanin pigment or without notable melanin pigment are very misleading, especially in small biopsies or frozen sections. Definite diagnosis depends on both careful histologic examination and the use of proper immunohistochemical stains. Moreover, detailed history and thorough investigation should be made to exclude the preexistence or coexistence of a primary lesion elsewhere. Herein we report the case of a 60-year-old male patient with primary malignant melanoma of the duodenum, which was misdiagnosed as lymphoma or undifferentiated carcinoma in frozen consultation. The patient had achieved disease-free survival for more than 46 months without any evidence of recurrence after surgery.
  .
  # Virtual slides
  .
  The virtual slides for this article can be found here: <http://www.diagnosticpathology.diagnomx.eu/vs/1221457317710561>.
author: Hongxia Li; Qinhe Fan; Zhen Wang; Hai Xu; Xiao Li; Weiming Zhang; Zhihong Zhang
date: 2012
institute: 1Department of Pathology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, P. R. China; 2Department of Radiology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, P. R. China
references:
title: Primary malignant melanoma of the duodenum without visible melanin pigment: a mimicker of lymphoma or carcinoma

# Background

Malignant melanoma, originated from melanocyte, is not a common tumor and accounts for 1 to 3% of all malignancies \[1\]. However, it is the most common metastatic tumor of the gastrointestinal (GI) tract especially the small intestine and can present with fairly common constitutional symptoms \[2\]. Primary malignant melanoma originating in the small bowel, particularly in the duodenum, is extremely rare and very controversial. In addition, some cases with little melanin pigment or without visible melanin pigment are very misleading, especially in small biopsy specimens or frozen sections. Identifying areas showing possible melanin pigment and immunostains with specific markers for melanoma, such as HMB45, Melan-A and S-100 protein, are diagnostically important. We encountered a case of primary malignant melanoma of the duodenum (PMMD) without any visible melanin pigment and misdiagnosed as lymphoma or undifferentiated carcinoma in frozen consultation, to highlight its clinic-pathological features and the diagnostic pitfalls.

# Case presentation

## Clinical summary

A 60-year-old Chinese male patient suffering from durative right abdominal pain and dark stools for one month, a recent episode of nausea and vomiting, was admitted to hospital in May 27, 2008. No history of fever, anorexia, hematemesis, radiating pain or weight loss was reported. Upper GI endoscopy revealed a malignant tumor at the descending part of the duodenum and the biopsy suspected poorly differentiated carcinoma. But there were no enough tumor cells for further immunohistochemical stain. In physical examination, there was no any obvious black nevus or nodule, nor swelled superficial lymph node. Routine hematological and biochemical studies showed no abnormalities. Serum detection showed tumor markers such as alpha fetoprotein (AFP), carcinoembryonic antigen (CEA), carbohydrate antigen 50 (CA-50), carbohydrate antigen 19–9 (CA-19-9) were all in the normal range. FOB (Fecal Occult Blood) Testing was positive. GI tract barium meal revealed a filling defect in the descendant duodenum, without obvious mucosal destruction and barium passed smoothly. Computed tomography scan of the abdomen disclosed the presence of a space-occupying lesion originating from the descending part of the duodenum with stenotic lumens (Figure 1). An exploratory laparotomy was performed through a midline incision in Jun 2, 2008 and confirmed the presence of a solid tumor arising from the lateral part of the descendant duodenum, which invading the duodenal serosa. Enlarged mesentery lymph node and peripancreatic lymph node were identified. Because the surgeons suspected the tumor as lymphoma, so only a palliative operation (tumor resection) was done.

## Pathologic findings

Intraoperative consultation showed a tumor measuring 2.5 cm × 1.5 cm × 1 cm, mesentery lymph node and peripancreatic lymph node measuring 3 cm, 2 cm in diameter respectively. The cut surfaces of the specimens were both pliable and gray red without pigment. Frozen sections were applied. Histologically, the lesion located under the enteric mucosa with diffusely infiltrative tumor cells, however, without obvious mucosal destruction (Figure 2A). The tumor cells were round, oval or polygonal epithelioid, showing markedly cytologic atypia with large eosinophilic nucleoli, abundant mitotic figures and moderate cytoplasm. But there was no obviously visible melanin pigment in cytoplasm (Figure 2B). Mesentery lymph node was positive for tumor cells (1/1), whereas peripancreatic lymph node was negative (0/1). According to above-mentioned features, pathologists consulted malignant tumor, prone to lymphoma or undifferentiated carcinoma. And the surgeons thought it might be lymphoma so only local tumor was resected.

Subsequently, routine hematoxylin-eosin sections (formalin-fixed and paraffin-embedded) and immunostains were done. But the results of immunohistochemical stains didn't support the diagnoses of lymphoma and undifferentiated carcinoma. The tumor cells were strongly positive for melanoma marker (HMB45), Melan-A, S-100 protein (Figure 3A-C) and vimentin, whereas CD20, CD45RO, CD3, CD79α, myeloperoxidase, terminal deoxynucleotidyl transferase, pan cytokeratin (AE1/AE3), keratin 5/6, keratin 7, synaptophysin, chromogranin A, and sarcoma markers such as smooth muscle actin, desmin, CD117, CD34 were all negative. A proliferative index of 60% was noted with Ki-67 immunostaining (Figure 3D). So the diagnosis of malignant melanoma was confirmed.

Thorough postoperative systemic evaluations including a detailed history, clinical examination, endoscopic assessment, and radiologic imaging were done to rule out the presence of a primary cutaneous, anal, or ocular lesion, or a melanoma in any other site; however, no primary site was found. Therefore, the resected tumor was determined to represent a PMMD with mesentery lymph node metastasis. The patient refused chemotherapy and just used Chinese traditional medicine treatment intermittently to improve the immunity. Close follow-up showed that the patient is doing well with no evidence of loco regional recurrence or distant metastasis for more than 46 months after surgery.

# Discussion

Malignant melanoma is a relatively rare tumor comprising 1-3% of all tumors and exhibits an unusual tendency to metastasize to the GI tract \[3\]. Although frequently seen in autopsy series in up to 50 to 60% of patients, only 2 to 5% of patients are diagnosed with metastatic malignant melanoma to the GI tract while they are still alive \[4\]. It is because that there are no specific symptoms of early development, which are general and constitutional; and even if metastases do occur, they are usually accompany with symptoms such as abdominal pain (62%), hemorrhage (50%), nausea and vomiting (26%), mass (22%), intestinal obstruction (18%), or intussusceptions (15%), and are frequently diagnosed in an emergency situation \[5\]. Metastasis to the GI tract is seen most frequently in the small intestine, followed by the colon, stomach, and rectum, but is rare in the esophagus. However, primary malignant melanoma originating in the small intestine and particularly in the duodenum is extremely rare, with only a few case reports \[1,6,7\].

There are different theories concerning the origin of primary malignant melanoma in the small bowel, though the controversy still exists over the presence of primary malignant melanoma in this area. Some proposes that malignant melanoma may originate from neural crest cells. These multipotential cells migrate through the body and can get to the bowel via the umbilical-mesenteric canal, where they later differentiate into specialized cells \[8\]. Although not consistently confirmed, another theory suggests that malignant melanoma might potentially develop from amine precursor uptake and decarboxylation (APUD) cells \[9\]. Besides, it is presumed that the small intestine normally contains melanoblasts, which may support the assumption of primary development of melanoma at this site.

Before making the diagnosis of primary malignant melanoma of the small bowel, thorough systemic examination must be done to rule out the possibility of metastasis from other sites, which may preferentially develop on the skin, retina, anal canal, or under the nail, and less frequently at other locations such as the esophagus, penis, or vagina. In addition, there should be no history of previous removal or spontaneous regression of any atypical melanocytic skin tumor \[10\]. The following diagnostic criteria have been occasionally proposed. According to Sachs *et al.*\[8\], primary malignant melanoma in the small bowel is diagnosed where there are: 1) biopsy-proven melanoma from the intestine at a single focus; 2) no evidence of disease in any other organs including the skin, eye and lymph nodes outside the region of drainage at the time of diagnosis; and 3) disease-free survival of at least 12 months after diagnosis. According to Blecker \[2\], it is diagnosed when there is lack of concurrent or previous removal of a melanoma or melanocytic lesion from the skin and lack of any other organ involvement and in situ change in the overlying or adjacent GI epithelium. In this case, one single focus located in the lateral of the descendant duodenum, and thorough postoperative investigation including a detailed history, clinical examination, endoscopic assessment, and radiologic imaging failed to reveal any evidence of a pre-existing primary tumor or any other metastatic lesion. Moreover, the patient has survived for more than 46 months with no evidence of loco regional recurrence or distant metastasis. Thus, we felt confident in supporting the diagnosis of PMMD.

Although the possibility of primary malignant melanoma in the small intestine does exist, the incidence is extremely low. In addition, melanoma by itself is a great mimicker of other neoplastic conditions \[11\]. It is very easy to diagnose for the cases with obvious melanin pigment, but sometimes, the specimen only with little pigment or without any visible pigment, which may create a major diagnostic challenge, must be differentiated from other common intestinal tumors like lymphoma, carcinoma of poor differentiation, neuroendocrine tumor, leiomyosarcoma, GIST (Gastrointestinal Stromal Tumor), et al. More sections as far as possible and careful observation can help to find valuable diagnositic clues. Furthermore, immunohistochemical staining and electron microscope detection may play an important role for differential diagnosis. In our patient, the initial frozen sections revealed the tumor cells were relatively uniform with markedly cytologic atypia and abundant mitotic figures, so the pathologists favored lymphoma or carcinoma of poor differentiation, which were the most common malignancies of the duodenum. But further immunohistochemical stains provided no evidence for above diagnoses. By more careful observation, we found the discohesive tumor cells had one or more large eosinophilic nucleoli, which were one of the main features of melanoma apart from visible melanin pigment, so malignant melanoma - a very rare malignancy in this site should be taken into consideration. Expression of some specific markers such as HMB45, Melan-A and S-100 protein is required to confirm our conjecture.

Optical treatment for malignant melanoma is an extensive and curative surgery, if possible, because other methods including adjuvant radiotherapy, chemotherapy and immunotherapy cannot offer definite treatment outcome. The time of diagnosis and the presence of metastases are supposed to represent major determinants of prognosis \[10,12\]. The median survival after curative resection of primary malignant melanoma of the small intestine is 49 months \[7\]; the longest reported survival is 21 years \[12\]. To the best of our knowledge, our patient refused chemotherapy and just used Chinese traditional medicine intermittently. Now he has achieved disease-free survival of more than 46 months without any evidence of recurrence. The certain mechanism of Chinese traditional medicine is still unclear and always be regarded as complicated, sometimes even mysterious. Nowadays, one of generally accepted opinions is that it can enhance patients' immunity efficiently. But melanoma is destined to behave aggressively, and widespread metastases may present as a late complication. Furthermore, the Ki-67 labeling index in this case was greater than 60% and the patient had one mesentery lymph node involved. This highlights the need for close and long-term follow-up.

# Conclusion

In conclusion, PMMD is an extremely rare neoplastic lesion of the alimentary tract. There are no specific symptoms and radiologic imaging. Especially, the cases with little melanin pigment or without visible melanin pigment are very misleading. Definite diagnosis depends on not only pathomorphology and immunohistochemical stains, but also detailed history and thorough investigation, the latter are more important to exclude the preexistence or coexistence of a primary lesion elsewhere.

# Consent

Written informed consent was obtained from the patient for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

# Abbreviations

PMMD: Primary malignant melanoma of the duodenum; GI: Gastrointestinal.

# Competing interests

The authors declare that they have no competing interests.

# Authors' contributions

LH conceived and designed the case report and drafted the manuscript; ZZ designed the case report and contributed to the revisions and editing of the manuscript. FQ participated in the histopathological evaluation and gave the final diagnosis; WZ participated in the histopathological evaluation and supplied the literature review; XH provided the relevant radiological details; LX and ZW participated in immunohistochemical analysis. All authors have read and approved the final manuscript.


abstract: Repressingly, a robot scientist can generate functional genomic hypothesis and carry out experiments, increasing the working scientist's feelings of redundancy.
author: Gregory A Petsko
date: 2004
institute: 1Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA 02454-9110, USA
title: Doctor Dunsel

"Dunsel ... is a term used by midshipmen at Starfleet Academy. It refers to a part which serves no useful purpose."

Mr Spock, in *Star Trek*, Episode 53: "The Ultimate Computer"

Paranoia began morphing into depression with the arrival of the 15 January 2004 issue of *Nature*. On page 247 was a paper by King *et al*. entitled 'Functional genomic hypothesis generation and experimentation by a robot scientist'. The paper describes an automated system that uses techniques from artificial intelligence to formulate hypotheses to explain observations. The system then devises experiments to test these hypotheses, and actually carries out the experiments using a simple laboratory robot. But that's not all. It then interprets the results so as to falsify any hypotheses not consistent with the data. Moreover, it can iterate this process, making it capable of developing and testing quite extensive models.

In the paper, the authors used this system to probe the genetic control of aromatic amino-acid biosynthesis in yeast, using various growth conditions and auxotrophic strains. The robot scientist took a series of systematic gene deletion strains and tried growing each in nutritional medium that lacked one of the intermediates in the pathway. If the deleted gene was required to make that intermediate, the strain would not grow and a component of the pathway would have been identified. The machine automatically examined the cultures to see how opaque they were, returned the results to the artificial intelligence package, and then received instructions for what experiments to perform to validate the hypotheses based on the results of the first round, and so on. The final result was the assembled pathway: the set of genes coding for the enzymes that control each step. The authors claim in the end that the automated system carried out the project just as efficiently - and more cost-effectively - than scientifically trained human volunteers.

*Nature*, perhaps feeling guilty about the hordes of scientists who might be losing sleep over the prospect of having to go out and actually work for a living, tried to soften the blow with an editorial comment called 'Don't fear the Robot Scientist' (page 181 of the same issue) that completely missed the point. "Contrary to first impressions," the commentator says cheerily, "an automated system that designs its own experiments will benefit young molecular geneticists. At first glance, it seems to render obsolete the armies of postgrads and postdocs employed in the world's molecular-genetics laboratories."

That wasn't what was worrying me at all. Replacing my graduate students and postdocs with machines that would work around the clock and never pester me for more disk space on the computer or a new set of pipetmen; that would never complain about the temperature in the lab and never forget to clear up after themselves - that didn't sound so bad. It was the thought that it might eventually replace me that was frightening. After all, this thing didn't just carry out the experiments, it designed them and formulated hypotheses based on them. I thought I was supposed to do that.

*Nature* continued, "The team behind the Robot Scientist argues that such automation 'frees scientists to make the high-level creative leaps at which they excel'". Well, the thing already plans, performs and interprets experiments. Just what leaps would those be, guys - designing the next generation of software for the robot? Still, I decided after an initial bad moment or ten, the robot was carrying out functional genomics. As we all know, genomics doesn't require real thought, just the semblance of it. Maybe I would have to surrender my genomics projects to some machine, but that only represented a part of my research effort. The rest of my work is structural biology, a branch of science of such technical sophistication and intellectual rigor that it could never be automated.

Then the 10 February 2004 issue of *Proceedings of the National Academy of Sciences* arrived. On page 1537 - right after a paper of my own, to add insult to injury - was an article by James Holton and Tom Alber (who was once my graduate student, to add injury to insult) entitled 'Automated protein crystal structure determination using ELVES'. It describes an expert system that can fully automatically determine the crystal structure of a protein from the primary X-ray data. True, individual steps in this process had been automated for some time, and the ELVES system had already been used to carry out such steps or even groups of steps, but always under the user's direction. This was different: there was no human intervention at all. The system was able to solve the structure of a 12,000 molecular weight coiled-coil protein from crystallographic data sets in two different crystal forms following a single command that launched the program and directed it to the location of the data files. The entire process, including interpretation of the resulting electron density map and refinement of the atomic model to convergence, took 9.5 hours on a multi-processor computer for one of the crystal forms, and 165 hours - the thing must have stopped for coffee or something - for the other form. The authors concluded that "high resolution structures with well-ordered metals can be determined automatically". To be fair, the protein structure, being all helical, did not present any real challenges in the model-building stage, and the authors are commendably candid about the limitations of the method: "ELVES is incapable of overcoming problems arising from poor data or inadequate phasing signal. Problems such as radiation damage, weak heavy atom signals, twinning, poor heavy atom models, low resolution, or crystal disorder that hinder crystallographic projects are not overcome by automation." Not yet, but just wait, I could hear them say *sotto voce*.

So, now I was about to be replaced as a crystallographer too. The year 2004 was sure turning out to be a terrific year. Well, strictly speaking I'm not paid just to do science anyway. Most of my salary comes from teaching undergraduates, and I consoled myself with the thought that I could always do more of that. Consoled myself, that is, until the arrival of last week's *Boston Globe* newspaper, with a story about a new effort at Massachusetts Institute of Technology (MIT) to revamp its undergraduate curriculum to take advantage of "innovations in educational methods". You know what that means - computer-based instruction. I could see it coming: once my lectures were all on the internet in interactive, self-test form, there would be no need for me to actually do any of the teaching myself anymore, or to be paid to do so - a fact I was sure would not be lost on any Brandeis administrator who might happen to read the article.

Feeling now very much like a horse might have felt about the time Henry Ford began turning out Model Ts, I tried to find something - anything - that I could do that a machine couldn't. Suddenly, it came to me: writing papers and grants. I probably spend half my non-teaching time writing things, things with highly technical content that also have to be comprehensible to people in my field who aren't involved in the work I'm doing or am proposing to do. In fact, if I want to get a grant from a foundation or publish a paper in a high-profile, general journal like *Nature* or *Genome Biology*, I have to try to make this highly technical material comprehensible to people who aren't in my field at all. Automate that, if you can.

Well, that may not be far off, actually. As Clive Thompson has pointed out (*The New York Times Magazine*, 14 December 2003), the music business is making strides towards doing something very like that. An artificial intelligence program called Hit Song Science from the Barcelona-based company Polyphonic HMI tries to determine whether a new song is going to be a hit. It uses a clustering algorithm to locate acoustic similarities between songs, similarities like common bits of rhythm, harmonies or keys. It compares these features of a new tune with all the Top 40 hits of the last 30 years; the closer the features of a new song are to a 'hit cluster', the more likely it is predicted, by the software, to be a hit. Thompson reports that the algorithm produces some strange groupings - the rock group U2 is similar to Beethoven, for example - yet it seems to work. A number of record companies are now using it to help pick which songs on a new album they will promote heavily. And, perhaps ominously, others are using it in the studio to tweak new songs as they are being recorded, changing various aspects of them to bring them closer to the hits in the nearest cluster. All well and good for the record companies, but it seems to me that this process is likely to take the spontaneity - and much of the novelty - right out of the music business. Hit songs tend to sound too much alike as it is, at least to this jaded listener; now they are going to be forced to sound even more alike. And clearly the same approach could be used, theoretically at least, to produce grants with a high probability of being funded, and scientific papers guaranteed to be accepted by top-rank journals. Hot Paper Science would cluster the titles, author names and affiliations, title words and key concepts that are shared by papers published in *Cell*, for example. One then only has to input one's own initial effort, 'The complete sequence of the gerbil genome' by Gregory A Petsko, *et al*., for example, and out would come 'Gerbil genome sequence: signal transduction pathways relevant to cancer, neurodegenerative diseases and apoptosis, with additional insights into systems biology and biodefense', plus a set of suggested coauthors that would help guarantee acceptance. The software would go on to write the paper, of course; submit it; and, if necessary, argue with the referees.

Well, that was it, I thought. Before long, even my writing functions would be taken over by machines. I was rapidly being made redundant, as they say in the UK - a twentieth-century equivalent of Captain Kirk in the *Star Trek* episode "The ultimate computer", his command capabilities handled more efficiently by a machine programmed to replace human beings in space exploration, his plaintive (and sexist) cry, "But there are some things men must do to remain men!" drowned out by the bootsteps of the relentless march of automation.

But then something happened to lift my gloom and restore my self-esteem. It was the arrival of an e-mail reminding me about the curriculum committee meeting scheduled for that afternoon. Of course! I wasn't useless after all. In fact, real human scientists are indispensable, and always will be. Computers may be better at solving crystal structures, and robots may be better at doing genome-enabled, hypothesis-driven experiments - may even be better at interpreting them - and eventually there will probably be software that writes better papers and grants, but we humans can still waste enormous amounts of time at interminable committee meetings. No machine will ever be stupid enough to do that.


author: Charles Darwin
date: 2010-10
institute: First published in *Mind*, *2*, 285–294. (reproduced from Christopher Green's Classics)
title: <img src="ANS1017-0409-17-187-g001.jpg" id="F1" />A biographical sketch of an infant

M. Taine's very interesting account of the mental development of an infant, translated in the last number of MIND (p. 252), has led me to look over a diary which I kept thirty-seven years ago with respect to one of my own infants. I had excellent opportunities for close observation, and wrote down at once whatever was observed. My chief object was expression, and my notes were used in my book on this subject; but as I attended to some other points, my observations may possibly possess some little interest in comparison with those by M. Taine, and with others which hereafter no doubt will be made. I feel sure, from what I have seen with my own infants, that the period of development of the several faculties will be found to differ considerably in different infants.

During the first seven days various reflex actions, namely sneezing, hickuping, yawning, stretching, and of course sucking and screaming, were well performed by my infant. On the seventh day, I touched the naked sole of his foot with a bit of paper, and he jerked it away, curling at the same time his toes, like a much older child when tickled. The perfection of these reflex movements shows that the extreme imperfection of the voluntary ones is not due to the state of the muscles or of the coordinating centres, but to that of the seat of the will. At this time, though so early, it seemed clear to me that a warm soft hand \[p. 286\] applied to his face excited a wish to suck. This must be considered as a reflex or an instinctive action, for it is impossible to believe that experience and association with the touch of his mother's breast could so soon have come into play. During the first fortnight he often started on hearing any sudden sound, and blinked his eyes. The same fact was observed with some of my other infants within the first fortnight. Once, when he was 66 days old, I happened to sneeze, and he started violently, frowned, looked frightened, and cried rather badly: for an hour afterwards he was in a state which would be called nervous in an older person, for every slight noise made him start. A few days before this same date, he first started at an object suddenly seen; but for a long time afterwards sounds made him start and wink his eyes much more frequently than did sight; thus when 114 days old, I shook a paste-board box with comfits in it near his face and he started, whilst the same box when empty or any other object shaken as near or much nearer to his face produced no effect. We may infer from these several facts that the winking of the eyes, which manifestly serves to protect them, had not been acquired through experience. Although so sensitive to sound in a general way, he was not able even when 124 days old easily to recognise whence a sound proceeded, so as to direct his eyes to the source.

With respect to vision, – his eyes were fixed on a candle as early as the 9th day, and up to the 45th day nothing else seemed thus to fix them; but on the 49th day his attention was attracted by a bright-coloured tassel, as was shown by his eyes becoming fixed and the movements of his arms ceasing. It was surprising how slowly he acquired the power of following with his eyes an object if swinging at all rapidly; for he could not do this well when seven and a half months old. At the age of 32 days he perceived his mother's bosom when three or four inches from it, as was shown by the protrusion of his lips and his eyes becoming fixed; but I much doubt whether this had any connection with vision; he certainly had not touched the bosom. Whether he was guided through smell or the sensation of warmth or through association with the position in which he was held, I do not at all know.

The movements of his limbs and body were for a long time vague and purposeless, and usually performed in a jerking manner; but there was one exception to this rule, namely, that from a very early period, certainly long before he was 40 days old, he could move his hands to his own mouth. When 77 days old, he took the sucking bottle (with which he was partly fed) in his right hand, whether he was held on the left or right arm of his nurse, and he would not take it in his left hand \[p. 287\] until a week later although I tried to make him do so; so that the right hand was a week in advance of the left. Yet this infant afterwards proved to be left-handed, the tendency being no doubt inherited – his grandfather, mother, and a brother having been or being left-handed. When between 80 and 90 days old, he drew all sorts of objects into his mouth, and in two or three weeks' time could do this with some skill; but he often first touched his nose with the object and then dragged it down into his mouth. After grasping my finger and drawing it down into his mouth, his own hand prevented him from sucking it; but on the 114th day, after acting in this manner, he slipped his own hand down so that he could get the end of my finger into his mouth. This action was repeated several times, and evidently was not a chance but a rational one. The intentional movements of the hands and arms were thus much in advance of those of the body and legs; though the purposeless movements of the latter were from a very early period usually alternate as in the act of walking. When four months old, he often looked intently at his own hands and other objects close to him, and in doing so the eyes were turned much inwards, so that he often squinted frightfully. In a fortnight after this time (*i.e.* 132 days old) I observed that if an object was brought as near to his face as his own hands were, he tried to seize it, but often failed; and he did not try to do so in regard to more distant objects. I think there can be little doubt that the convergence of his eyes gave him the clue and excited him to move his arms. Although this infant thus began to use his hands at an early period, he showed no special aptitude in this respect, for when he was 2 years and 4 months old, he held pencils, pens, and other objects far less neatly and efficiently than did his sister who was then only 14 months old, and who showed great inherent aptitude in handling anything.

*Anger*. – It was difficult to decide at how early an age anger was felt; on his eighth day he frowned and wrinkled the skin round his eyes before a crying fit, but this may have been due to pain or distress, and not to anger. When about ten weeks old, he was given some rather cold milk and he kept a slight frown on his forehead all the time that he was sucking, so that he looked like a grown-up person made cross from being compelled to do something which he did not like. When nearly four months old, and perhaps much earlier, there could be no doubt, from the manner in which the blood gushed into his whole face and scalp, that he easily got into a violent passion. A small cause sufficed; thus, when a little over seven months old, he screamed with rage because a lemon slipped away and he could not seize it with his hands. When eleven months old, if \[p. 288\] a wrong plaything was given to him, he would push it away and beat it; I presume that the beating was an instinctive sign of anger, like the snapping of the jaws by a young crocodile just out of the egg, and not that he imagined he could hurt the plaything. When two years and three months old, he became a great adept at throwing books or sticks, &c., at anyone who offended him; and so it was with some of my other sons. On the other hand, I could never see a trace of such aptitude in my infant daughters; and this makes me think that a tendency to throw objects is inherited by boys.

*Fear*. – This feeling is probably one of the earliest which is experienced by infants, as shown by their starting at any sudden sound when only a few weeks old, followed by crying. Before the present one was 4 1/2 months old I had been accustomed to make close to him many strange and loud noises, which were all taken as excellent jokes, but at this period I one day made a loud snoring noise which I had never done before; he instantly looked grave and then burst out crying. Two or three days afterwards, I made through forgetfullness the same noise with the same result. About the same time (*viz*. on the 137th day) I approached with my back towards him and then stood motionless; he looked very grave and much surprised, and would soon have cried, had I not turned round; then his face instantly relaxed into a smile. It is well known how intensely older children suffer from vague and undefined fears, as from the dark, or in passing an obscure corner in a large hall, &c. I may give as an instance that I took the child in question, when 2 1/4 years old, to the Zoological Gardens, and he enjoyed looking at all the animals which were like those that he knew, such as deer, antelopes &c., and all the birds, even the ostriches, but was much alarmed at the various larger animals in cages. He often said afterwards that he wished to go again, but not to see "beasts in houses"; and we could in no manner account for this fear. May we not suspect that the vague but very real fears of children, which are quite independent of experience, are the inherited effects of real dangers and abject superstitions during ancient savage times? It is quite conformable with what we know of the transmission of formerly well-developed characters, that they should appear at an early period of life, and afterwards disappear.

*Pleasurable Sensations*. – It may be presumed that infants feel pleasure whilst sucking and the expression of their swimming eyes seems to show that this is the case. This infant smiled when 45 days, a second infant when 46 days old; and these were true smiles, indicative of pleasure, for their eyes brightened and eyelids slightly closed. The smiles arose chiefly when looking at their mother, and were therefore probably of mental origin; \[p. 289\] but this infant often smiled then, and for some time afterwards, from some inward pleasurable feeling, for nothing was happening which could have in any way excited or amused him. When 110 days old he was exceedingly amused by a pinafore being thrown over his face and then suddenly withdrawn; and so he was when I suddenly uncovered my own face and approached his. He then uttered a little noise which was an incipient laugh. Here surprise was the chief cause of the amusement, as is the case to a large extent with the wit of grown-up persons. I believe that for three or four weeks before the time when he was amused by a face being suddenly uncovered, he received a little pinch on his nose and cheeks as a good joke. I was at first surprised at humour being appreciated by an infant only a little above three months old, but we should remember how very early puppies and kittens begin to play. When four months old, he showed in an unmistakable manner that he liked to hear the pianoforte played; so that here apparently was the earliest sign of an æsthetic feeling, unless the attraction of bright colours, which was exhibited much earlier, may be so considered.

*Affection*. – This probably arose very early in life, if we may judge by his smiling at those who had charge of him when under two months old; though I had no distinct evidence of his distinguishing and recognising anyone, until he was nearly four months old. When nearly five months old, he plainly showed his wish to go to his nurse. But he did not spontaneously exhibit affection by overt acts until a little above a year old, namely, by kissing several times his nurse who had been absent for a short time. With respect to the allied feeling of sympathy, this was clearly shown at 6 months and 11 days by his melancholy face, with the corners of his mouth well depressed, when his nurse pretended to cry. Jealousy was plainly exhibited when I fondled a large doll, and when I weighed his infant sister, he being then 15 1/2 months old. Seeing how strong a feeling jealousy is in dogs, it would probably be exhibited by infants at an earlier age than that just specified, if they were tried in a fitting manner.

*Association of Ideas, Reason, &c.*– The first action which exhibited, as far as I observed, a kind of practical reasoning, has already been noticed, namely, the slipping his hand down my finger so as to get the end of it into his mouth; and this happened on the 114th day. When four and a half months old, he repeatedly smiled at my image and his own in a mirror, and no doubt mistook them for real objects; but he showed sense in being evidently surprised at my voice coming from behind him. Like all infants he much enjoyed thus looking at himself, and in less than two months perfectly understood that it was \[p. 290\] an image; for if I made quite silently any odd grimace, he would suddenly turn round to look at me. He was, however, puzzled at the age of seven months, when being out of doors he saw me on the inside of a large plate-glass window, and seemed in doubt whether or not it was an image. Another of my infants, a little girl, when exactly a year old, was not nearly so acute, and seemed quite perplexed at the image of a person in a mirror approaching her from behind. The higher apes which I tried with a small looking-glass behaved differently; they placed their hands behind the glass, and in doing so showed their sense, but far from taking pleasure in looking at themselves they got angry and would look no more.

When five months old, associated ideas arising independently of any instruction became fixed in his mind; thus as soon as his hat and cloak were put on, he was very cross if he was not immediately taken out of doors. When exactly seven months old, he made the great step of associating his nurse with her name, so that if I called it out he would look round for her. Another infant used to amuse himself by shaking his head laterally: we praised and imitated him, saying "Shake your head"; and when he was seven months old, he would sometimes do so on being told without any other guide. During the next four months the former infant associated many things and actions with words; thus when asked for a kiss he would protrude his lips and keep still, – would shake his head and say in a scolding voice "Ah" to the coal-box or a little spilt water, &c., which he had been taught to consider as dirty. I may add that when a few days under nine months old he associated his own name with his image in the looking-glass, and when called by name would turn towards the glass even when at some distance from it. When a few days over nine months, he learnt spontaneously that a hand or other object causing a shadow to fall on the wall in front of him was to be looked for behind. Whilst under a year old, it was sufficient to repeat two or three times at intervals any short sentence to fix firmly in his mind some associated idea. In the infant described by M. Taine (pp. 254–256) the age at which ideas readily became associated seems to have been considerably later, unless indeed the earlier cases were overlooked. The facility with which associated ideas due to instruction and others spontaneously arising were acquired, seemed to me by far the most strongly marked of all the distinctions between the mind of an infant and that of the cleverest full-grown dog that I have ever known. What a contrast does the mind of an infant present to that of the pike, described by Professor Möbius,\[1\] who during three whole months dashed and \[p. 291\] stunned himself against a glass partition which separated him from some minnows; and when, after at last learning that he could not attack them with impunity, he was placed in the aquarium with these same minnows, then in a persistent and senseless manner he would not attack them!

Curiosity, as M. Taine remarks, is displayed at an early age by infants, and is highly important in the development of their minds; but I made no special observation on this head. Imitation likewise comes into play. When our infant was only four months old I thought that he tried to imitate sounds; but I may have deceived myself, for I was not thoroughly convinced that he did so until he was ten months old. At the age of 11 1/2 months he could readily imitate all sorts of actions, such as shaking his head and saying "Ah" to any dirty object, or by carefully and slowly putting his forefinger in the middle of the palm of his other hand, to the childish rhyme of "Pat it and pat it and mark it with T". It was amusing to behold his pleased expression after successfully performing any such accomplishment.

I do not know whether it is worth mentioning, as showing something about the strength of memory in a young child, that this one when 3 years and 23 days old on being shown an engraving of his grandfather, whom he had not seen for exactly six months, instantly recognised him and mentioned a whole string of events which had occurred whilst visiting him, and which certainly had never been mentioned in the interval.

*Moral Sense*. – The first sign of moral sense was noticed at the age of nearly 13 months: I said "Doddy (his nickname) won't give poor papa a kiss, – naughty Doddy". These words, without doubt, made him feel slightly uncomfortable; and at last when I had returned to my chair, he protruded his lips as a sign that he was ready to kiss me; and he then shook his hand in an angry manner until I came and received his kiss. Nearly the same little scene recurred in a few days, and the reconciliation seemed to give him so much satisfaction, that several times afterwards he pretended to be angry and slapped me, and then insisted on giving me a kiss. So that here we have a touch of the dramatic art, which is so strongly pronounced in most young children. About this time it became easy to work on his feelings and make him do whatever was wanted. When 2 years and 3 months old, he gave his last bit of gingerbread to his little sister, and then cried out with high self-approbation "Oh kind Doddy, kind Doddy". Two months later, he became extremely sensitive to ridicule, and was so suspicious that he often thought people who were laughing and talking together were laughing at him. A little later (2 years and 7 1/2 months old) I met him \[p. 292\] coming out of the dining room with his eyes unnaturally bright, and an odd unnatural or affected manner, so that I went into the room to see who was there, and found that he had been taking pounded sugar, which he had been told not to do. As he had never been in any way punished, his odd manner certainly was not due to fear, and I suppose it was pleasurable excitement struggling with conscience. A fortnight afterwards, I met him coming out of the same room, and he was eyeing his pinafore which he had carefully rolled up; and again his manner was so odd that I determined to see what was within his pinafore, notwithstanding that he said there was nothing and repeatedly commanded me to "go away," and I found it stained with pickle-juice; so that here was carefully planned deceit. As this child was educated solely by working on his good feelings, he soon became as truthful, open, and tender, as anyone could desire.

*Unconsciousness, Shyness*. – No one can have attended to very young children without being struck at the unabashed manner in which they fixedly stare without blinking their eyes at a new face; an old person can look in this manner only at an animal or inanimate object. This, I believe, is the result of young children not thinking in the least about themselves, and therefore not being in the least shy, though they are sometimes afraid of strangers. I saw the first symptom of shyness in my child when nearly two years and three months old: this was shown towards myself, after an absence of ten days from home, chiefly by his eyes being kept slightly averted from mine; but he soon came and sat on my knee and kissed me, and all trace of shyness disappeared.

*Means of Communication*. – The noise of crying or rather of squalling, as no tears are shed for a long time, is of course uttered in an instinctive manner, but serves to show that there is suffering. After a time the sound differs according to the cause, such as hunger or pain. This was noticed when this infant was eleven weeks old, and I believe at an earlier age in another infant. Moreover, he appeared soon to learn to begin crying voluntarily, or to wrinkle his face in the manner proper to the occasion, so as to show that he wanted something. When 46 days old, he first made little noises without any meaning to please himself, and these soon became varied. An incipient laugh was observed on the 113th day, but much earlier in another infant. At this date I thought, as already remarked, that he began to try to imitate sounds, as he certainly did at a considerably later period. When five and a half months old, he uttered an articulate sound "da" but without any meaning attached to it. When a little over a year old, he used gestures \[p. 293\] to explain his wishes; to give a simple instance, he picked up a bit of paper and giving it to me pointed to the fire, as he had often seen and liked to see paper burnt. At exactly the age of a year, he made the great step of inventing a word for food, namely *mum*, but what led him to it I did not discover. And now instead of beginning to cry when he was hungry, he used this word in a demonstrative manner or as a verb, implying "Give me food". This word therefore corresponds with *ham* as used by M. Taine's infant at the later age of 14 months. But he also used *mum* as a substantive of wide signification; thus he called sugar *shu-mum*, and a little later after he had learned the word "black," he called liquorice *black-shu-mum*, – black-sugar-food.

I was particularly struck with the fact that when asking for food by the word *mum* he gave to it (I will copy the words written down at the time) "a most strongly marked interrogatory sound at the end". He also gave to "Ah," which he chiefly used at first when recognising any person or his own image in a mirror, an exclamatory sound, such as we employ when surprised. I remark in my notes that the use of these intonations seemed to have arisen instinctively, and I regret that more observations were not made on this subject. I record, however, in my notes that at a rather later period, when between 18 and 21 months old, he modulated his voice in refusing peremptorily to do anything by a defiant whine, so as to express "That I won't"; and again his humph of assent expressed "Yes, to be sure". M. Taine also insists strongly on the highly expressive tones of the sounds made by his infant before she had learnt to speak. The interrogatory sound which my child gave to the word *mum* when asking for food is especially curious; for if anyone will use a single word or a short sentence in this manner, he will find that the musical pitch of his voice rises considerably at the close. I did not then see that this fact bears on the view which I have elsewhere maintained that before man used articulate language, he uttered notes in a true musical scale as does the anthropoid ape Hylobates.

Finally, the wants of an infant are at first made intelligible by instinctive cries, which after a time are modified in part unconsciously, and in part, as I believe, voluntarily as a means of communication, – by the unconscious expression of the features, – by gestures and in a marked manner by different intonations, – lastly by words of a general nature invented by himself, then of a more precise nature imitated from those which he hears; and these latter are acquired at a wonderfully quick rate. An infant understands to a certain extent, and as \[p. 294\] I believe at a very early period, the meaning or feelings of those who tend him, by the expression of their features. There can hardly be a doubt about this with respect to smiling; and it seemed to me that the infant whose biography I have here given understood a compassionate expression at a little over five months old. When 6 months and 11 days old he certainly showed sympathy with his nurse on her pretending to cry. When pleased after performing some new accomplishment, being then almost a year old, he evidently studied the expression of those around him. It was probably due to differences of expression and not merely of the form of the features that certain faces clearly pleased him much more than others, even at so early an age as a little over six months. Before he was a year old, he understood intonations and gestures, as well as several words and short sentences. He understood one word, namely, his nurse's name, exactly five months before he invented his first word *mum*; and this is what might have been expected, as we know that the lower animals easily learn to understand spoken words.


abstract: The technological development of telemedicine has performed important progress, assuming a diagnostic relief role inside of the processes. Among the fields in fast evolution, telepathology is placed among those of greater interest. Up to some years ago, telepathology allowed us to observe at a distance and in real time, histological or cytological slides through the Internet, using a motorized microscope (dynamic telepathology). Currently, telepathology has completed an important step in ahead being possible to digitize completely a slide and to store it. This allows observation of the whole surface of histological or cytological slides remotely with a customary PC, without human intervention (virtual slide). The described systems have exclusive characteristics, so that a "hybrid system" supporting both technologies, turns out to be the best solution applicable in a wide range program. In order to realize the theoretical aspects previously described, we report an organizational model practicable and applicable to a territory in which three hospitals operate. An essential prerequisite in order to arrange an efficient telepathology system turns out to be one structured data transmission network, equipped with elevated guaranteed bandwidth, and one consolidated experience in the registration and management of digital images.
author: Roberto Mencarelli; Adriano Marcolongo; Alessio Gasparetto
date: 2008
institute: 1Department of Surgical Pathology, Azienda ULSS 18, Rovigo, Italy; 2General Manager, Azienda ULSS 18, Rovigo, Italy; 3Department of Information Technology – Azienda ULSS 18, Rovigo, Italy
references:
title: Organizational model for a telepathology system

# Introduction

The acquisition of a telepathology system designed for a district territory that comprises three hospitals managed from two different health administrations (Adria and Rovigo) is inserted in a wide plan of local development of telemedicine. The challenge has been planned from the two administrations and fully financed by the Cariparo Foundation.

In order to achieve the implementation of this telepathology system there was a need for hospitals technology structures innovation. In particular: physical and logical structures for data transport, hardware modernization, software development, processes reorganization.

This technological innovation process is essential for developing and offering to citizens high quality and reliable health services. In particular, a telepathology system needs high hardware and network performance for processing, managing and archiving digital slide images.

The main aims, thanks to the introduction of telepathology, can be summarized as follows:

• Increase of service quality offered to patients thanks to qualified second opinions;

• Sharing and discussion of interesting pathological cases for increasing professional ability;

• Creation of a permanent and available scientific repository.

# Methods

We can distinguish three types of telepathology: static telepathology, dynamic telepathology, virtual slide telepathology. In this paper, we analyze the last two for describing how we can implement a "hybrid telepathology system" that takes advantage of the peculiarities of each one. The dynamic telepathology allows exploration, in real time, of the whole slide surface thanks to a robotized remote controlled microscope; this also permits us to change magnification, focus and digitize the interesting portion. The disadvantages regard the necessary presence of a technician for positioning the desired slide within the microscope and the discontinuous digitization in terms of area and magnification. In virtual slide telepathology, the slide is completely digitized and stored in a repository; this permits a single or multiple user consultation, in every time and without human intervention. The virtual slide allows the exploration of the whole slide surface with different magnification. There are many types of devices that can be used for slide digitization and the right option depends on workload and necessary scan rate \[1\]. Virtual slide telepathology has a a negligible disadvantage \[2\]: it is not possible to focus the areas that were not correctly acquired. During the scan process, the scanning device takes into account a finite point number for the focusing procedure; each point is characterized by its own focal plane. When the sample surface is irregular, the device uses proprietary algorithms to calculate an "in focus surface" above the slide; this allows an average good focus but locally a less accurate one. During this treatment, it can be noted that this problem is directly correlated with sample analysis type and grows with increasing histological or cytological sample surface irregularity. Another characteristic to take into account is the virtual slide file size; this depends principally on the following parameters: the resolution, the compression ratio, the compression algorithm and the color depth. Considering the resolution used for the histological and cytological slide scan (0,5 μm/pixel – 20×), the scan area maximum dimension (9 cm2), an adequate compression ratio (15:1) and an appropriate compression algorithm (JPEG2000) it can be possible to obtain averagely a 500 MB file even if the non compressed file is approximately 7.5 GB \[3,4\]. This file size allows, at present, a selected virtual slide storage for scientific archive creation but doesn't permit complete archiving of all slides; in fact, in case of complete archiving the storage device costs would be much too expensive. Certainly, in the future, the cost/byte reduction for storage and an international agreement about the standard for this storage will permit all slides complete archiving, deleting the conservation necessity. This will lead to many advantages regarding clinical data availability and accessibility. In the end, the necessity of an adequate guaranteed data communication bandwidth for sharing virtual slide must be considered. This problem can be solved thanks to the use of an Image Server and the specific image format (image pyramid); this offers the possibility of selective visualization of images in terms of resolution and portion of interest, without the necessity of a complete transfer of virtual slide from Image Server to a local PC. The complete focusing of the whole slide surface is therefore the real problem to solve, while the archiving and the consultation of virtual slides are effectively faced thanks to scalable and high performance storage devices and dedicated Image Server.

There are mainly two types of second opinions: second opinions in real time on frozen section during surgery (intraoperative consultation) and second opinions on histological or cytological slides which require a complex interpretation. Each type of second opinion has specific characteristics that are directly correlated with previous discussion. In the first second opinion type the analyses are conducted on thick sample or with irregular surface (this arises from the methods through which the samples are obtained and the liquid amount contained into the tissue to analyze); for this reason the automatic scanner device (virtual slide telepathology) can't focus correctly on the whole slide surface but with a motorized microscope (dynamic telepathology) it is possible to focalize each sample surface point. Therefore, the dynamic telepathology represents an important tool for second opinion during intraoperative consultation, especially for the presence on the territory of two hospitals with surgery but without a resident pathologist. Regarding histological and cytological slides, the tissue samples are treated for obtaining thin sections; this deletes the trouble regarding focus due to irregular surface, as previously described. In this case the use of virtual slide telepathology is favorable because it allows the visualization of the morphological picture at any time, remotely with a customary PC, without human intervention. This allows one to obtain a second opinion on complex cases from an expert of personal choice and to perform an external quality control.

Based on previous considerations and for obtaining an effective telepathology system, the best choice is a "hybrid system" composed of motorized microscopes, with remote control, and a scanner for slide digitization, in order to achieve the best characteristics from each system without respective disadvantages. This choice has been applied to Rovigo province health structures, in particular Rovigo, Adria and Trecenta hospitals. For storage purposes it has been used a NAS (Network Attached Storage) device (50 TB capacity – 1 Gb/s transfer rate). The previously described system is completely integrated with the CPOE (Computerized Physician Order Entry) based Hospital information System.

Thanks to complete slides digitization and the use of Image Server with high computational performances, it will be possible to apply filters to acquired images or to apply algorithms for calculating interesting quantities (e.g.: the cellular membrane distribution and continuity). These techniques adequately developed, tested and standardized will be the base for Computer Aided Diagnosis (CAD) introduction.

# Conclusion

The implementation of a telepathology "hybrid system" adequately projected and integrated with the Hospital information System, leads to an increase in the service quality offered by the Pathological Anatomy department, principally thanks to: (a) qualified and real time second opinions on frozen section during surgery or histological-cytological consultation on slides which requires a complex interpretation; (b) continuous education process thanks to the sharing of interesting virtual slides and creation of a permanent scientific archive.

The design and implementation of a telepathology system must be based on real operative demands, supported by a technological structure that can guarantee a reliable and efficient service and projected using hospital experience on digital images acquisition and storage.

### Acknowledgements

This article has been published as part of *Diagnostic Pathology* Volume 3 Supplement 1, 2008: New trends in digital pathology: Proceedings of the 9th European Congress on Telepathology and 3rd International Congress on Virtual Microscopy. The full contents of the supplement are available online at <http://www.diagnosticpathology.org/supplements/3/S1>