Biomedical Ruby Programming

If you're a regular reader of this blog, you've read some of my prior essays about the Ruby Programming Language. My book teaches Ruby, but its content is not exclusively focused on the Ruby Language (there are many excellent Ruby language books available to programmers). My book is mostly about the tasks that confront students and professionals in the biomedical fields... and how you can use Ruby to solve those tasks. So in the book chapters, I may spend more words describing the biomedical tasks (which can be hard to understand) and many fewer words on the Ruby scripts (which are usually quite short).

The basic theme in my books is that if all biomedical workers knew how to program, they would gain some independence (from application vendors), and become more creative.

Once you start using Ruby, you may find that you can integrate your knowledge of medicine and biology with your knowledge of programming, to solve a wide range of new and interesting problems.

I recommend either Perl, Python, or Ruby as excellent languages for anyone in the biomedical sciences. I wouldn't claim that these are the best languages for programmers, in general. But they are superb languages for individuals whose primary interest lies in biology or medicine and who use programming as a creative tool to discover and solve new questions in their fields. These languages are easy to learn, and each has an active community that contributes open source libraries and modules to the language.

- Jules J. Berman

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Science is not a collection of facts. Science is what facts teach us; what we can learn about our universe, and ourselves, by deductive thinking. From observations of the night sky, made without the aid of telescopes, we can deduce that the universe is expanding, that the universe is not infinitely old, and why black holes exist. Without resorting to experimentation or mathematical analysis, we can deduce that gravity is a curvature in space-time, that the particles that compose light have no mass, that there is a theoretical limit to the number of different elements in the universe, and that the earth is billions of years old. Likewise, simple observations on animals tell us much about the migration of continents, the evolutionary relationships among classes of animals, why the nuclei of cells contain our genetic material, why certain animals are long-lived, why the gestation period of humans is 9 months, and why some diseases are rare and other diseases are common. In “Armchair Science”, the reader is confronted with 129 scientific mysteries, in cosmology, particle physics, chemistry, biology, and medicine. Beginning with simple observations, step-by-step analyses guide the reader toward solutions that are sometimes startling, and always entertaining. “Armchair Science” is written for general readers who are curious about science, and who want to sharpen their deductive skills.

Precancers: counter-arguments

This blog continues a collection of essays on precancer.

The bulk of funding in the cancer field is directed toward the most frequently occurring, most highly recognizable cancers that are responsible for the greatest number of cancer deaths in the U.S. population (e.g., lung, colon, breast, and prostate cancers). Never mind that mortality from these common cancers has scarcely budged since the War on Cancer began (in the 70s).

Precancers are the lesions that precede the development of cancers. If we developed effective treatments for precancers, we would virtually eradicate cancer. I have been a precancer activist for decades. During that time, I've listened to countless arguments in favor of the status quo (developing treatments for advanced-staged common cancers) and against funding for the precancers.

The arguments against precancer research usually boil down to non-existence arguments (precancers don't even exist), irrelevance arguments (not our job), impracticality arguments (it just isn't practical to treat the precancers), or priority arguments (just about everything else is more important).

I thought it might be useful to lay out all the anti-precancer arguments here, and I can respond to them in future blogs.

Non-existence arguments:

1. There is no such thing as a precancer. The lesions that are called precancers are simply early (or small) cancers.

2. The transition from precancer to cancer is characterized by the acquisition of invasiveness. However, there is no practical way to determine the precise moment that invasiveness is acquired by a lesion. Therefore, there is no practical method to reliably distinguish a precancer from a cancer in every instance (i.e., there is no way to be confident that a lesion has not acquired the ability to invade). Therefore, precancers have no validity as biological entities.

3. There are many genetic and morphological disparities among the different recognized precancers. Since these lesions seem to have no common properties, other than the defining property of "cancer precedence", it hardly seems as though they should be assigned any biological class.

Irrelevance arguments:

4. The mission of the National Cancer Institute, the primary funding agency for cancer research in the U.S. is to develop cures for cancer, not precancer. If precancers were as important as you say they are, there would be a National Precancer Institute. But there isn't.

5. Precancers regress spontaneously. Why should we try to develop treatments for a disease that usually resolves without treatment?

6. Precancer research is just one aspect of cancer prevention, because when the precancer is eliminated, you prevent the cancer. Cancer prevention is an adequately funded area of cancer research, so we really do not need to assign any special funding to precancer research.

Low-priority argument:

7. People are dying from malignant tumors every day. Even if we could prevent cancers, we cannot abandon our responsibility to cancer patients by diverting our limited resources to the precancers.

Impracticality argument:

8. Treating precancers is not feasible for the majority of precancerous lesions that occur in humans. Reducing the incidence of cervical cancer by treating cervical precancer was possible only because the cervix can be inspected and sampled. There is no equivalent method to find and excise the precancerous lesions of pancreas, lung, prostate and breast. Therefore, procedures to detect and treat most precancers are not practical.

Rebuttals follow.

- Copyright (C) 2008 Jules J. Berman

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In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

I urge you to read more about my book. There's a generous preview of the book at the Google Books site.

tags: common disease, orphan disease, orphan drugs, genetics of disease, disease genetics, rules of disease biology, rare disease, pathology, preneoplasia, premalignant, preneoplastic, incipient neoplasia, pre-cancer, dysplasia, metaplasia, intraepithelial neoplasia, premalignancy, premalignancies, precancers, precancerous, pre-cancer, early cancer, developing cancer, carcinogenesis, cancer development, cancer staging, politics of disease, disease funding, disease geneticfs, cancer genetics, tumor biology

Precancer: one to many relationships

As discussed in an earlier blog, precancers, despite their importance, have not been the subject of much research. We still are confused about some of the most fundamental properties of the precancers.

For example, is each cancer preceded by a precancer that is unique for the cancer? Or may one precancer precede many different cancers?

My own opinion is that there are instances where a single precancer can lead to any one of several different cancers.

The instance that comes to mind is bronchial squamous metaplasia with dysplasia. This precancer seems to precede the three common cancers than arise from the bronchus: squamous carcinoma, adenocarcinoma of bronchus and small cell carcinoma.



This should come as no surprise as adenocarcinomas of lung, that may appear monomorphic on light microscopy, often have tripartite differentiation (squamous, glandular and neuro-endocrine) on electron micrographic examination. Likewise, dysplastic squamous metaplasia often consists of a mixture of these three cell types. How one cell type is selected to dominate in the resulting tumor may just be a function of chance, as dysplastic subclones -- with genetic alterations that confer growth advantage -- are selected over time.


- Copyright (C) 2008 Jules J. Berman

key words: lung cancer, preneoplasia, premalignant, preneoplastic, incipient neoplasia, pre-cancer, dysplasia, metaplasia, intraepithelial neoplasia

Precancer: treatment without detection or diagnosis

Yesterday's blog concerned precancers, and I thought I'd continue the subject.

The paradigm for treating cancer has been:

1. Detect the cancer (usually involves recognizing a sign or symptom or picking up the cancer on a screening text)

2. Diagnose the cancer (usually involves getting a tissue sample through a surgical procedure and sending the sample to a pathologist who renders a diagnosis indicating the type of tumor and its grade (level of malignancy). Diagnosis is sometimes supplemented with special studies, such as cytogenetics).

3. Stage the cancer (determining how far the tumor may have spread at the time of diagnosis)

4. Treat the cancer (one or more of surgery, chemotherapy, radiation therapy).

5. Follow-up

With precancers, we may be able to skip most of these steps, going straight to treatment. This is because the treatment for precancers can be simple and effective. If a precancer can be eradicated with a relatively non-toxic systemic drug, or if the transition from precancer to cancer can be delayed with hormonal manipulation, or if the initiation step of carcinogenesis (leading to precancer development) can be blocked with a dietary supplement or a vaccine (e.g. Gardasil for cervical precancer), why not just forego the detection/diagnosis/staging steps?

The idea of receiving medical treatment for undiagnosed diseases is not new. How many people in the U.S. take statins, even though they have no rason to think that any of their arteries are significantly blocked by atheroma (never had stroke, never had angina, never had claudication, etc.)? How many people in the U.S. are treated for hypertension even if they've never had any of the associated diseases (never had renal failure, never had stroke, etc.)? Virtually everyone in the U.S. has been vaccinated for diseases they do not have (polio, smallpox, tetanus, etc.).

Intelligent people accept treatment for diseases they do not have, because they know how bad such diseases (myocardial infarction, stroke, kidney failure, polio, etc.) can be. So why don't we start treating precancers in high-risk people who have no detected precancers?

Personally, I'd rather accept treatment for an uncertain precancer than for a certain cancer.

In future blogs, I'll discuss precancer treatments.


- Copyright (C) 2008 Jules J. Berman

key words: precancer, pre-cancer, premalignant, premalignancy, incipient neoplasia, preneoplasia, preneoplastic

Precancer principles

Continuing yesterday's theme, I thought I'd write a few blogs on one of my favorite subjects: precancer. Precancers are probably the most important lesion of humans. If you prevent, treat or excise a precancer, the cancer never develops. Even if you simply lengthen the precancer phase of carcinogenesis (which precedes the invasive cancer), you can greatly reduce the number of cancer-related deaths.

Many people, including cancer researchers, mistakenly believe that precancers are merely small or early cancers. This is not true. Precancers have biological properties that differ from invasive cancers.

Here they are:

1. Precancers can be defined and studied as biological entities.

2. Precancers are more prevalent than cancers. (Corollary: many precancers regress or fail to progress).

3. On average, precancers develop in younger individuals than do cancers.

4. If a precancer is eradicated, the cancer cannot develop.

5. Every cancer has a precancer (Corollary: if all precancers were eradicated, there would be no cancers).

6. It is easier to treat a precancer than to treat a cancer.

7. A single precancer may develop into any one of several closely related cancers (Corollary: There are more types of cancers than there are types of precancers.)

8. Precancers contain the characteristic genetic abnormality that distinguish one class of cancrer from another class of cancer. Corollary: Agents that target an essential pathway in a particular cancer will also target the same pathway in the precancer for the cancer and for all of the closely related cancers.

9. Precancers can be distinguished from the cancers into which they develop. (Corollary: precancers can be diagnosed and studies).

10. Precancers can be sensibly classified into classes of lesions that share biological properties.

11. Precancers that progress will progress into cancers and no other type of lesion.

12. All agents that cause cancers will also cause precancers.

- Copyright (C) 2008 Jules J. Berman

key words: intraepithelial neoplasia, premalignant, premalignancy, preneoplasia, pre-cancer, preneoplastic, cancer precursor, incipient neoplasia, neoplasm

Precancer: small representation in the literature

Regular readers of this blog know that I have been a long-time proponent for studying the precancers. Precancers are easy to treat. Cancers are hard to treat. Treat the precancers and eliminate the cancers that would have developed. It's really simple. Unfortunately, cancer researchers spend most of their time and money trying to treat cancers, when they should be devoting more of their effort on the precancers.

Today, I went to pubmed and searched for citations related to cancer and to precancer. Here are the results. Each term is followed by the number of pubmed citations (research articles) that have the term contained in the title.

cancer 388,888
tumor 143,219

precancer 347
premalignant 1,314
permalignancy 66
intraepithelial neoplasia 2,533
preneoplastic 1128
preneoplasia 92

The numbers indicate that precancer receives a tiny fraction of the research effort devoted to cancer.

- Jules Berman

Precancer versus Intraepithelial neoplasia

During carcinogenesis, morphologically identifiable lesions occur that precede the development of invasive cancer. These lesions are called precancers, premalignancies, preneoplastic lesions, incipient cancers, intraepithelial neoplasias, and preinvasive cancers. The plethora of terms reflects the difficulty of choosing a "best" canonical class term for the precancerous lesions. Currently, the term "intraepithelial neoplasia" seems to enjoy wide usage among the community of pathologists, but this term has limitations, as discussed in two prior papers:

   Berman JJ, Henson DE.
   Classifying the precancers: a metadata approach.
   BMC Med Inform Decis Mak. 2003 Jun 20;3:8. 
   Epub 2003 Jun 20.

   Seidman JD, Berman JJ.
   Premalignant nonepithelial lesions: 
   a biological classification.
   Mod Pathol. 1993 Sep;6(5):544-54.

1. Not all epithelial precancers are intraepithelial. Most of the mucosal dysplasias have a well-defined territory bounded by the junction between the epithelium and the underlying stroma. But not all premalignant epithelial lesions can be identified by the presence of atypical cell populations delimited by a basement membrane. Dysplastic lesions of the liver, kidney, thyroid and adrenal are not delimited by a basement membrane.

2.Not all precancers are epithelial. Intratubular germ cell neoplasms of testis, myelodysplasias, and non-autonomous lymphomas are examples of non-epithelial precancers.

3. Not all intraepithelial neoplasms are precancers. Neoplasms that are intraepithelial but that are not precancers include: seborrheic keratoses, intraepidermal nevi, common warts and most so-called benign epithelial tumors.

Likewise, the term pre-invasive cancer raises an existential question. Use of the term "pre-invasive cancer" implies that precancers have attained the biological properties of a cancer. This assumption may not be true. Precancers may lack constitutive properties of cancer or may have certain attributes that are absent in cancers. At this point, there is insufficient knowledge to conclude that precancers are types of cancer.

I like the term "precancers". It conveys only the defining features of the lesions: occurrence prior to cancers, and existence as an identifiable lesion.

- Jules Berman

key words: precancer, pre-cancer, premalignant, neoplasm classification, tumors, carcinogenesis

Diagnostic errors in medicine: excellent paper

On January 10, I wrote a blog on medical errors.

This month, an excellent paper came out on the subject of diagnostic errors.

This citation

Volume 121, Issue 5, Supplement, Pages S2-S23 (May 2008)
Overconfidence as a Cause of Diagnostic Error in Medicine
Eta S. Berner, Mark L. Graber


The authors concentrate on doctor overconfidence. The paper indicates that doctors seldom follow published medical guidelines, seldom refer to books, seldom refer to general omputer-based diagnostic aids, and have a more-or-less reflexive approach to diagnosis. Not surprisingly, the authors' review of the literature also indicates that diagnostic accuracy has not improved much over the decades.

None of this is surprising. A prior publication indicates that many doctors and nurses (less so nurses than doctors) do not wash their hands when they should (See: Lipsett PA, Swoboda SM. Handwashing compliance depends on professional status. Surg Infect (Larchmt). 2(3):241-245, 2001). Some of the most vicious hospital outbreaks of antibiotic-resistant organisms are exacerbated by inadequate handwashing among hospital staff. If doctors can't be bothered to wash their hands, how can you expect them to be responsible in the more demanding areas of patient care?

A prior blog was focused on "failure to rescue". "Failure to rescue" - the failure of hospital staff to recognized and act upon developed symptoms and signs that require immediate action to stem a cascade of events that can lead to death - is a bigger problem than misdiagnosis. Most misdiagnoses resolve in one way or another without leading to a patient's death (the patient gets better despite the misdiagnosis, the patient goes to another doctor who makes the correct diagnosis, the patient's disease is not amenable to treatment whether diagnosed correctly or incorrectly, and so on).

I encourage physicians and other patient-care professionals to read these articles. Understanding the source of medical errors is a good start towards improving care.

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In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

I urge you to read more about my book. There's a generous preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

- Jules J. Berman, Ph.D., M.D. tags: common disease, orphan disease, orphan drugs, rare disease, subsets of disease, disease genetics, errors, handwashing, physicians, standard of care, cad, hand-washing