Archive for 2014


New Drug Approvals

Temperature control plays an important role in industrial processes, pilot plants, and chemical and pharmaceutical laboratories. When controlling reactors, both exothermic and endothermic reactions must be offset with high speed and reliability. Therefore, different conditions and effects must be taken into account when specifying an optimum and highly dynamic temperature control system.

Temperature Control of Reactors

Most temperature control systems are used with chemical reactors made of either steel or glass. The former is more rugged and long-lasting, while the latter enables chemists to observe processes inside the reactor.

However, in the case of glass reactors, extensive precautions have to be followed for safe usage. Reactors usually include an inner vessel to hold the samples, which need temperature control. This inner vessel is enclosed by a jacket containing heat-transfer liquid. This reactor jacket is linked to the temperature control system.

In order to control the reactor’s temperature, the temperature control system pumps the heat-transfer…

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New Drug Approvals

Graphical Abstract

The Application of Flow Microreactors to the Preparation of a Family of Casein Kinase I Inhibitors.
Venturoni, F.; Nikbin, N.; Ley S. V.; Baxendale, I. R.
Org. Biomol. Chem.2010, 8, 1798-1806.
Link: 10.1039/b925327kpdf icon

In this article we demonstrate how a combination of enabling technologies such as flow synthesis, solid-supported reagents and scavenging resins utilised under fully automated software control can assist in typical medicinal chemistry programmes. In particular automated continuous flow methods have greatly assisted in the optimisation of reaction conditions and facilitated scale up operations involving hazardous chemical materials. Overall a collection of twenty diverse analogues of a casein kinase I inhibitor has been synthesised by changing three principle binding vectors.

aInnovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK

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by Aviva Lev-Ari, PhD, RN 

Director and Founder, Leaders in Pharmaceutical Business Intelligence

Dear Board Members, Business Community Members, Clients and Team Members

I welcome all addressees to this e-mail to rejoice with us at LEADERS IN PHARMACEUTICAL BUSINESS INTELLIGENCE — AS WE CELEBRATE OUR 2014 as follows:

A.  PHARMACEUTICALINTELLIGENCE.COM —>>Our Open Access Online Scientific Journal

From: “WordPress.com” <donotreply@wordpress.com>

Date: Tue, 30 Dec 2014 01:49:03 +0000

To: <avivalev-ari@alum.berkeley.edu>

Subject: Your 2014 year in blogging [pharmaceuticalintelligence.com]



The Louvre Museum has 8.5 million visitors per year. This blog was viewed about 230,000 times in 2014. If it were an exhibit at the Louvre Museum, it would take about 10 days for that many people to see it.

The busiest day of the year was December 10th with 2,133 views. The most popular post that day was The History of Hematology and Related Sciences.

In 2014, there were 1,082 new posts, growing the total archive of this blog to 2,609 posts.


B.  OUR EVOLUTION and Record accomplishments


  • In 4/2012 Aviva Launched Leaders in Pharmaceutical Business Intelligence

(LPBI) as an Equity Sharing entity to become a Holding company, initially as

an Electronic Scientific Media entity — The “parmaceuticalintelligence.com” — Open Access Online Scientific Journal


  • In 10/2012 Aviva Launched the BioMed e-Series — 15 title e-Books in FIVE

e-Series in Medicine


  • In 6/2013 we published our first e-Book on Nitric Oxide on Amazon.com,

Kindle edition


  • In 12/2014 we have SIX READY e-Books in Medicine in QA in the Pipeline

Cardiovascular Diseases: Volumes 2, 3, 4

Genomics Volume 1

Cancer Volume 1


Plan for 2015: FIVE e-Books in the Pipeline

Cancer Volume 2 – Internal Editor

Genomics Volume 2 – I am interviewing an Editor

CVD Volumes 5, 6

Physiology, Pharmaco-Therapy and Genomics – Larry H Bernstein, MD, Author and Editor, See it in Series E, Volume 3

  • In 8/2013 we were approached by ASI, Inc and by ValveCure, Inc. – to assist in Funding Finding. The interactions has led to development of new Intellectual Property. We have BDs assigned to both Start Ups.
  • In 9/2013 we were approached by the Chamber of Commerce in Shanghai to organize Scientific Delegations of Patent Holders to meet with Private Investors in China
  • Since 4/2013 — Aviva was granted TEN times a Press Passes to cover for the Scientific Media — BioTech Conferences. Her superior Networking skills with Speakers, attendees and VCs is a very important part for building LPBI Network of Business connections


C.      ALL LPBI TEAM MEMBERS are of Two types:


1.        Expert, Authors, Writers (EAWs) — All are PhDs, MDs, MD/PhDs or 

PharmDs — I INVITE them to JOIN my Team by their publications and

accomplishment in 15 years after earning a PhD, an MD, etc. Exception to this rule is Dr. Irina Robu, less than 15 years since earned her PhD.


2.        Business Development Executives (BDs)— Engineers and Engineers with Technical MBAs. All BDs are Technology Execs NONE is a Finance only professional.

Respectively, we do not DEAL only with the Finance aspect of the Business — WE ARE A PROUD SCIENTIFIC  & TECHNOLOGY TEAM — We are not a Finance Team. In Deals with Clients — it is our own technological expertise and accomplishment that advance a deal, the sheer technical KNOWHOW and professional GRAVITAS of each BD which Aviva has cherry picked to join the Team, will be proven to be the key to all our deals.


BDs among US

Team Members in Business Development Roles — On Record 12/28/2014:

•   BDs with CV on Line: Dr. Yossi Ezer, Dr. Peter Nelboeck,

Yoel Ezra, Dr. Irina Robu, Dr. Demet Sag (EAW), Dr. Stephen J Williams (Sr.

Editor), Ron Shifron



D.      OUR 2015 NEW CLIENTS

  • QTG
  • BioTree
  • CPA GROUP in Switzerland
  • INSYS in Switzerland

We sign NDAs and CDAs

AFTER 1/15 — Aviva will start to schedule BDs and Presentations on each of the CPA Eight Companies

AFTER 2/15 — Aviva will start  to schedule BDs and Presentations on each of INSYS four Technologies




  • ALL LPBI Team members have looked at Aviva’s Profile on LinkedIn, some  called Aviva directly, as well
  • Aviva, has approached them from the Screen of her Profile on LinkedIn, 2-3 out of 20 daily visitors
  • Aviva has +5,600 Life Sciences FIRST level connections on LinkedIn, except to 100 Israeli she asked to connect with, ALL THE REST WITHOUT EXCEPTION HAVE REQUESTED HER TO JOIN THEIR NETWORK
  • Anyone  who join the Team is “at will” and is looking forward to build a Book of Business with us
  • We have ~20 Start Ups as clients and I expect 2015 to be a very active year

Go to


  • When we engage in Funding Finding we may actually be doing STRATEGY Consulting on Technology Licensing, M&A and Exit or Partnerships
  • Focus on Funding, Deals & Partnerships 


1           Corporate Clients for our Services


2           Funding Cardiovascular Medical Devices Development


3           Funding Biologics Development


4           Funding Diagnostics


5           Funding Partnerships in IP Development


6           M&A and Exit


7           Targeting Penetration in New Markets for High Technology Products


8          Management of Engineering Design of Prototypes Outsourcing





  • In Funding Finding all BDs have access to LPBI’s IT Business Intelligence Database created by Aviva
  • In some cases Aviva contact directly the Sources for Introduction of a BD or for Prospecting directly
  • We wish to raise $10 Millions for each Start Up with whom we do business with
  • Our Finder Fee Agreement is for 10%, 7% is for the BD and 3% is for Aviva, she refers BDs to her contacts and functions as Counsel-at-large on concepts and markets via accessing LPBI’s IT Business Intelligence Database created by Aviva
  • All Team members and all Clients will be notifies of ALL new business opportunities and invited to participate
  1. All Team members CV and all Clients Profile MUST be on our System – LIVE 24×7 — we operate in the Cloud of WordPress.com
  2. All Team members and all Clients — for being connected and up-to-date MUST perform the following:
  • FOLLOW by e-mail the Scientific Journal


  • BEFRIEND the venture on Facebook


  • FOLLOW the venture on Twitter


  • JOIN LPBI LinkedIn Group







We are looking forward to a VERY prosperous 2015 — The Year of Biotech,

Pharma, BioMed


I thank all the Team memberes that led projects and contributed to all the milestones achieved in 2014.


Aviva Lev-Ari, PhD, RN


University of California, Berkeley, PhD’83


BioMed e-Books Series – Editor-in-Chief


Founder & Director

Leaders in Pharmaceutical Business Intelligence


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The WordPress.com stats helper monkeys prepared a 2014 annual report for this blog.

Here’s an excerpt:

The Louvre Museum has 8.5 million visitors per year. This blog was viewed about 230,000 times in 2014. If it were an exhibit at the Louvre Museum, it would take about 10 days for that many people to see it.

Click here to see the complete report.

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The human microbiome may have evolved to selectively target older humans, thereby enabling an extended childhood in our earliest human ancestors.


The age structure of human populations is exceptional among animal species. Unlike with most species, human juvenility is extremely extended, and death is not coincident with the end of the reproductive period. If we examine the age structure of early humans with models that reveal an extraordinary balance of human fertility and mortality. A research team now hypothesizes that the age structure of early humans was maintained by mechanisms incorporating the programmed death of senescent individuals, including by means of interactions with their indigenous microorganisms.


First, before and during reproductive life, there was selection for microbes that preserve host function through regulation of energy homeostasis, promotion of fecundity, and defense against competing high-grade pathogens. Second, the scientists hypothesized that after reproductive life, there was selection for organisms that contribute to host demise. While deleterious to the individual, the presence of such interplay may be salutary for the overall host population in terms of resource utilization, resistance to periodic diminutions in the food supply, and epidemics due to high-grade pathogens. In their work, the team provides deterministic mathematical models based on age-structured populations that illustrate the dynamics of such relationships and explores the relevant parameter values within which population viability is maintained. They argue that the age structure of early humans was robust in its balance of the juvenile, reproductive-age, and senescent classes.


These concepts are relevant to issues in modern human longevity, including inflammation-induced neoplasia and degenerative diseases of the elderly, which are a legacy of human evolution.

Source: www.livescience.com

See on Scoop.itCardiovascular Disease: PHARMACO-THERAPY

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Highlights in the History of Physiology

Larry H. Bernstein, MD, FCAP, Curator

Related Articles:

Milestones in the Evolution of Diagnostics in the US HealthCare System: 1920s to Pre-Genomics

Author and Curator: Larry H Bernstein, MD, FCAP


Diagnostics Industry and Drug Development in the Genomics Era: Mid 80s to Present

Author and Curator: Larry H Bernstein, MD, FCAP


The History of Infectious Diseases and Epidemiology in the late 19th and 20th Century

Curator: Larry H Bernstein, MD, FCAP

The History of Hematology and Related Sciences: A Historical Review of Hematological Diagnosis from 1880 -1980
Curator: Larry H. Bernstein, MD, FCAP

Outline of Medical Discoveries between 1880 and 1980

Curator: Larry H Bernstein, MD, FCAP
Selected Contributions to Chemistry from 1880 to 1980

Curator: Larry H. Bernstein, MD, FCAP


The Evolution of Clinical Chemistry in the 20th Century

Curator: Larry H. Bernstein, MD, FCAP


William Harvey can be credited with founding modern physiology, then Claude Bernard, and then the great anatomist John Hunter, all before the twentieth century.

In the 19th century, curiosity, medical necessity, and economic interest stimulated research concerning the physiology of all living organisms. Discoveries of unity of structure and functions common to all living things resulted in the development of the concept of general physiology, in which general principles and concepts applicable to all living things are sought. Since the mid-19th century, therefore, the word physiology has implied the utilization of experimental methods, as well as techniques and concepts of the physical sciences, to investigate causes and mechanisms of the activities of all living things.
One view of the history of physiology is that it was shortened from a macro-
to a microstructural view with the developments of biochemistry and then molecular biology.  Though that view is attractive, it is not really compliant with a holistic view
of human and mammalian development.  But form and function are the concern of anatomy and physiology, even with the emergence of a subcellular domain.

William Harvey

William Harvey, discoverer of blood circulation and heart function, was born in 1578 in England. He graduated in Padua in 1602, returned to England, and practiced medicine for a long time. Among his patients were two kings of England (James I and Charles I), and Francis Bacon. He published the work “Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus (An Anatomical Dissertation Upon the Movement of the Heart and Blood in Animals)  in 1682. It is identified as the beginning of modern experimental physiology. Harvey’s study was based only on anatomical experiments; despite increased knowledge in physics and chemistry during the 17th century, physiology remained closely tied to anatomy and medicine.

The seminal work  lays a basic foundation accurately explaining the circulation. In 1609 Harvey was appointed to the staff of St. Bartholomew’s Hospital. He was elected a fellow of the Royal College of Physicians in 1607. His ideas about circulation of the blood were first publicly expressed in lectures he gave in 1616. The work of Aristotle was the basis for Galen’s De usu partium (“On the Use of Parts”) and a source for many early misconceptions in physiology. Galen, the leading physician in ancient times, never thought that the blood circulates.

Harvey first formulated an opinion about the blood circulation by making a simple calculation. Harvey first studied the heartbeat, establishing the existence of the pulmonary (heart-lung-heart) circulation process and noting the one-way flow of blood. When he also realized how much blood was pumped by the heart, he realized there must be a constant amount of blood flowing through the arteries and returning through the veins of the heart, a continuing circular flow. He estimated that the amount of blood that is emitted by each heartbeat about 2 ounces. Because the heart beats 72 times per minute, the sum is about 540 pounds per hour of emitted blood into the aorta. After formulating this hypothesis, he performed experiments and conducted thorough investigation to determine the details of the circulation of the blood.

Harvey stated that arteries carry blood away from the heart while veins carry blood back to the heart. Although Harvey could not visualize the capillaries, the smallest blood vessels that connect the arterioles to small veins, he concluded that there must be capillaries. Harvey pointed out that the function of the heart is to pump blood into the arteries. His theory of the circulation was not readily accepted, Harvey’s work got recognition at the end of his life. The discovery of capillaries by Marcello Malpighi in 1661 provided factual evidence to confirm Harvey’s theory of blood circulation.

Harvey was also involved in the field of Embryology, although less important than the investigation in terms of the circulation of the blood, not something that should be underestimated. He was a careful observer, and his book On the Generation of Animals (On-generation animal world), published in 1651 showed the beginning of the actual field of Embryology. Harvey rejected the theory that the overall structure of the animal body are the same as young and adult animals, the only difference being size. He rightly declared that an embryo grows to its final structure step by step.


Herman Boerhaave is sometimes referred to as the father of physiology due to his exemplary teaching in Leiden and his textbook Institutiones medicae (1708).

In the United States, the first physiology professorship was founded in 1789 at the College of Philadelphia, and in 1832, Robert Dunglison published the first comprehensive work on the subject, Human Physiology (Encyclopedia of American History, 2007). In 1833, William Beaumont published a classic work on digestive function.

In the 19th century, physiological knowledge began to accumulate at a rapid rate, in particular with the 1838 appearance of the Cell theory of Matthias Schleiden and Theodor Schwann. It radically stated that organisms are made up of units called cells. Claude Bernard’s (1813–1878) further discoveries ultimately led to his concept of milieu interieur (internal environment), which would later be taken up and championed as “homeostasis” by American physiologist Walter Cannon.

Claude Bernard

Claude Bernard’s first important work was on the functions of the exocrine pancreas; this achievement won him the prize for experimental physiology from the French Academy of Sciences. His most famous work was on the glycogenic function of the liver; in the course of his study he was led to the conclusion that the liver is the seat of an internal secretion, by which it prepares sugar from the elements of the blood passing through it.

In 1851, while examining the effects produced in the temperature of various parts of the body by section of the nerve or nerves belonging to them, he noticed that division of the cervical sympathetic nerve gave rise to more active circulation and more forcible pulsation of the arteries in certain parts of the head, and a few months afterwards he observed that electrical excitation of the upper portion of the divided nerve had the contrary effect. In this way he established the existence of vasomotor nerves, both
vasodilator and vasoconstrictor.

Milieu intérieur is the key process with which Bernard is associated. He wrote, “The stability of the internal environment [the milieu intérieur] is the condition for the free and independent life.”

The living body, though it has need of the surrounding environment, is nevertheless relatively independent of it. This independence which the organism has of its external environment, derives from the fact that in the living being, the tissues are withdrawn from external influences and are protected by a veritable internal environment. The constancy of the internal environment is the condition for free and independent life: the mechanism that makes it possible is that which assures the maintenance, within the internal environment, of all the conditions necessary for the life of the elements.

The constancy of the environment presupposes a perfection of the organism such that external variations are at every instant compensated and brought into balance. In consequence, the higher animal is in a close relation with its environment so that its equilibrium results from a continuous and delicate compensation established as if the most sensitive of balances.

In his major discourse on the scientific method, An Introduction to the Study of Experimental Medicine (1865), Bernard described what makes a scientific theory good and what makes a scientist important, a true discoverer. Unlike many scientific writers of his time, Bernard wrote about his own experiments and thoughts, and used the first person.

Physiology as a distinct discipline utilizing chemical, physical, and anatomical methods began to develop in the 19th century. Claude Bernard in France; Johannes Müller, Justus von Liebig, and Carl Ludwig in Germany; and Sir Michael Foster in England may be numbered among the founders of physiology as it now is known. At the beginning of the 19th century, German physiology was under the influence of the romantic school of Naturphilosophie. In France, on the other hand, romantic elements were opposed by rational and skeptical viewpoints. Bernard’s teacher, François Magendie, the pioneer of experimental physiology, was one of the first men to perform experiments on living animals. Both Müller and Bernard, however, recognized that the results of observations and experiments must be incorporated into a body of scientific knowledge, and that the theories of natural philosophers must be tested by experimentation. Many important ideas in physiology were investigated experimentally by Bernard, who also wrote books on the subject. He recognized cells as functional units of life and developed the concept of blood and body fluids as the internal environment (milieu intérieur) in which cells carry out their activities. This concept of physiological regulation of the internal environment occupies an important position in physiology and medicine; Bernard’s work had a profound influence on succeeding generations of physiologists in France, Russia, Italy, England, and the United States.

Müller’s interests were anatomical and zoological, whereas Bernard’s were chemical and medical, but both men sought a broad biological viewpoint in physiology rather than one limited to human functions. Although Müller did not perform many experiments, his textbook Handbuch der Physiologie des Menschen für Vorlesungen and his personal influence determined the course of animal biology in Germany during the 19th century.

It has been said that, if Müller provided the enthusiasm and Bernard the ideas for modern physiology, Carl Ludwig provided the methods. During his medical studies at the University of Marburg in Germany, Ludwig applied new ideas and methods of the physical sciences to physiology. In 1847 he invented the kymograph, a cylindrical drum that still is used to record muscular motion, changes in blood pressure, and other physiological phenomena. He also made significant contributions to the physiology of circulation and urine secretion. His textbook of physiology, published in two volumes in 1852 and 1856, was the first to stress physical instead of anatomical orientation in physiology. In 1869 at Leipzig, Ludwig founded the Physiological Institute (neue physiologische Anstalt), which served as a model for research institutes in medical schools all over the world. The chemical approach to physiological problems, developed first in France by Lavoisier, was expanded in Germany by Justus von Liebig, whose books on Organic Chemistry and its Applications to Agriculture and Physiology (1840) and Animal Chemistry (1842) created new areas of study both in medical physiology and agriculture. German schools devoted to the study of physiological chemistry evolved from Liebig’s laboratory at Giessen.

The British tradition of physiology is distinct from that of the continental schools. In 1869 Sir Michael Foster became Professor of Practical Physiology at University College in London, where he taught the first laboratory course ever offered as a regular part of instruction in medicine. The pattern Foster established still is followed in medical schools in Great Britain and the United States. In 1870 Foster transferred his activities to Trinity College at Cambridge, England, and a postgraduate medical school emerged from his physiology laboratory there. Although Foster did not distinguish himself in research, his laboratory produced many of the leading physiologists of the late 19th century in Great Britain and the United States. In 1877 Foster wrote a major book (Textbook of Physiology), which passed through seven editions and was translated into German, Italian, and Russian. He also published Lectures on the History of Physiology (1901). In 1876, partly in response to increased opposition in England to experimentation with animals, Foster was instrumental in founding the Physiological Society, the first organization of professional physiologists. In 1878, again due largely to Foster’s activities, the Journal of Physiology, which was the first journal devoted exclusively to the publication of research results in physiology, was initiated.

Foster’s teaching methods in physiology and a new evolutionary approach to zoology were transferred to the United States. in 1876 by Henry Newell Martin, a professor of biology at Johns Hopkins University in Baltimore, Md. The American tradition drew also on the continental schools. S. Weir Mitchell, who studied under Claude Bernard, and Henry P. Bowditch, who worked with Carl Ludwig, joined Martin to organize the American Physiological Society in 1887, and in 1898 the society sponsored publication of the American Journal of Physiology. In 1868 Eduard Pflüger, professor at the Institute of Physiology at Bonn, founded the Archiv für die gesammte Physiologie, which became the most important journal of physiology in Germany.

Physiological chemistry followed a course partly independent of physiology. Müller and Liebig provided a stronger relationship between physical and chemical approaches to physiology in Germany than prevailed elsewhere. Felix Hoppe-Seyler, who founded his Zeitschrift für physiologische Chemie in 1877, gave identity to the chemical approach to physiology. The American tradition in physiological chemistry initially followed that in Germany; in England, however, it developed from a Cambridge laboratory founded in 1898 to complement the physical approach started earlier by Foster.

Physiology in the 20th century is a mature science; during a century of growth, physiology became the parent of a number of related disciplines, of which of comparative physiology and ecophysiology, biochemistry, biophysics, and molecular biology are examples. Major figures in these fields include Knut Schmidt-Nielsen and George Bartholomew. Most recently, evolutionary physiology has become a distinct subdiscipline.

Physiology, however, retains an important position among the functional sciences that are closely related to the field of medicine. Although many research areas, especially in mammalian physiology, have been fully exploited from a classical-organ and organ-system point of view, comparative studies in physiology may be expected to continue. The solution of the major unsolved problems of physiology will require technical and expensive research by teams of specialized investigators. Unsolved problems include the unravelling of the ultimate bases of the phenomena of life. Research in physiology also is aimed at the integration of the varied activities of cells, tissues, and organs at the level of the intact organism. Both analytical and integrative approaches uncover new problems that also must be solved. In many instances, the solution is of practical value in medicine or helps to improve the understanding of both human beings and other animals.

Among areas that have shown significant growth in the twentieth century are endocrinology (study of function of hormones) and neurobiology (study of function of nerve cells and the nervous system).

Fye, B. W. 1987. The Development of American Physiology: Scientific Medicine in the Nineteenth Century. Baltimore: Johns Hopkins University Press.

Rothschuh, K. E. 1973. History of Physiology. Huntington, N.Y.: Krieger.

The Nobel Prize in Physiology or Medicine

Year Laureate[A] Country[B] Rationale[C]
1901 Emil Adolf von Behring Germany “for his work on serum therapy, especially its application against diphtheria, by which he has opened a new road in the domain of medical science and thereby placed in the hands of the physician a victorious weapon against illness and deaths”[10]
1902 Sir Ronald Ross United Kingdom “for his work on malaria, by which he has shown how it enters the organism and thereby has laid the foundation for successful research on this disease and methods of combating it”[11]
1903 Niels Ryberg Finsen Denmark
(Faroe Islands)
“[for] his contribution to the treatment of diseases, especially lupus vulgaris, with concentrated light radiation, whereby he has opened a new avenue for medical science”[12]
1904 Ivan Petrovich Pavlov Russia “in recognition of his work on the physiology of digestion, through which knowledge on vital aspects of the subject has been transformed and enlarged”[13]
1905 Robert Koch Germany “for his investigations and discoveries in relation to tuberculosis[14]
1906 Camillo Golgi Italy “in recognition of their work on the structure of the nervous system[15]
Santiago Ramón y Cajal Spain
1907 Charles Louis Alphonse Laveran France “in recognition of his work on the role played by protozoa in causing diseases”[16]
1908 Ilya Ilyich Mechnikov Russia “in recognition of their work on immunity[17]
Paul Ehrlich Germany
1909 Emil Theodor Kocher Switzerland “for his work on the physiology, pathology and surgery of the thyroid gland[18]
1910 Albrecht Kossel Germany “in recognition of the contributions to our knowledge of cell chemistry made through his work on proteins, including the nucleic substances[19]
1911 Allvar Gullstrand Sweden “for his work on the dioptrics of the eye[20]
1912 Alexis Carrel France “[for] his work on vascular suture and the transplantation of blood vessels and organs[21]
1913 Charles Richet France “[for] his work on anaphylaxis[22]
1914 Robert Bárány Austria “for his work on the physiology and pathology of the vestibular apparatus[23]
1919 Jules Bordet Belgium “for his discoveries relating to immunity[24]
1920 Schack August Steenberg Krogh Denmark “for his discovery of the capillary motor regulating mechanism”[25]
1921 Not awarded
1922 Archibald Vivian Hill United Kingdom “for his discovery relating to the production of heat in the muscle[26]
Otto Fritz Meyerhof Germany “for his discovery of the fixed relationship between the consumption of oxygen and the metabolism of lactic acid in the muscle”[26]
1923 Sir Frederick Grant Banting Canada “for the discovery of insulin[27]
John James Rickard Macleod Canada
1924 Willem Einthoven The Netherlands “for the discovery of the mechanism of the electrocardiogram[28]
1925 Not awarded
1926 Johannes Andreas Grib Fibiger Denmark “for his discovery of the Spiroptera carcinoma[29]
1927 Julius Wagner-Jauregg Austria “for his discovery of the therapeutic value of malaria inoculation in the treatment of dementia paralytica[30]
1928 Charles Jules Henri Nicolle France “for his work on typhus[31]
1929 Christiaan Eijkman The Netherlands “for his discovery of the antineuritic vitamin[32]
Sir Frederick Gowland Hopkins United Kingdom “for his discovery of the growth-stimulating vitamins[32]
1930 Karl Landsteiner Austria “for his discovery of human blood groups[33]
1931 Otto Heinrich Warburg Germany “for his discovery of the nature and mode of action of the respiratory enzyme[34]
1932 Sir Charles Scott Sherrington United Kingdom “for their discoveries regarding the functions of neurons[35]
Edgar Douglas Adrian United Kingdom
1933 Thomas Hunt Morgan United States “for his discoveries concerning the role played by the chromosome in heredity[36]
1934 George Hoyt Whipple United States “for their discoveries concerning liver therapy in cases of anaemia[37]
George Richards Minot United States
William Parry Murphy United States
1935 Hans Spemann Germany “for his discovery of the organizer effect in embryonic development[38]
1936 Sir Henry Hallett Dale United Kingdom “for their discoveries relating to chemical transmission of nerve impulses[39]
Otto Loewi Austria
1937 Albert Szent-Györgyi von Nagyrapolt Hungary “for his discoveries in connection with the biological combustion processes, with special reference to vitamin C and the catalysis of fumaric acid[40]
1938 Corneille Jean François Heymans Belgium “for the discovery of the role played by the sinus and aortic mechanisms in the regulation of respiration[41]
1939 Gerhard Domagk Germany “for the discovery of the antibacterial effects of prontosil[42]
1943 Carl Peter Henrik Dam Denmark “for his discovery of vitamin K[43]
Edward Adelbert Doisy United States “for his discovery of the chemical nature of vitamin K[43]
1944 Joseph Erlanger United States “for their discoveries relating to the highly differentiated functions of single nerve fibres[44]
Herbert Spencer Gasser United States
1945 Sir Alexander Fleming United Kingdom “for the discovery of penicillin and its curative effect in various infectious diseases[45]
Sir Ernst Boris Chain United Kingdom
Howard Walter Florey Australia
1946 Hermann Joseph Muller United States “for the discovery of the production of mutations by means of X-ray irradiation[46]
1947 Carl Ferdinand Cori United States “for their discovery of the course of the catalytic conversion of glycogen[47]
Gerty Theresa Cori, née Radnitz United States
Bernardo Alberto Houssay Argentina “for his discovery of the part played by the hormone of the anterior pituitary lobe in the metabolism of sugar[47]
1948 Paul Hermann Müller Switzerland “for his discovery of the high efficiency of DDT as a contact poison against several arthropods[48]
1949 Walter Rudolf Hess Switzerland “for his discovery of the functional organization of the interbrain as a coordinator of the activities of the internal organs”[49]
António Caetano Egas Moniz Portugal “for his discovery of the therapeutic value of leucotomy (lobotomy) in certain psychoses”[49]
1950 Philip Showalter Hench United States “for their discoveries relating to the hormones of the adrenal cortex, their structure and biological effects”[50]
Edward Calvin Kendall United States
Tadeusz Reichstein Switzerland
Year Laureate[A] Country[B] Rationale[C]
1951 Max Theiler South Africa “for his discoveries concerning yellow fever and how to combat it”[51]
1952 Selman Abraham Waksman United States “for his discovery of streptomycin, the first antibiotic effective against tuberculosis[52]
1953 Sir Hans Adolf Krebs United Kingdom “for his discovery of the citric acid cycle[53]
Fritz Albert Lipmann United States “for his discovery of co-enzyme A and its importance for intermediary metabolism”[53]
1954 John Franklin Enders United States “for their discovery of the ability of poliomyelitis viruses to grow in cultures of various types of tissue”[54]
Frederick Chapman Robbins United States
Thomas Huckle Weller United States
1955 Axel Hugo Theodor Theorell Sweden “for his discoveries concerning the nature and mode of action of oxidation enzymes”[55]
1956 André Frédéric Cournand United States “for their discoveries concerning heart catheterization and pathological changes in the circulatory system[56]
Werner Forssmann Federal Republic of Germany
Dickinson W. Richards United States
1957 Daniel Bovet Italy “for his discoveries relating to synthetic compounds that inhibit the action of certain body substances, and especially their action on the vascular system and the skeletal muscles”[57]
1958 George Wells Beadle United States “for their discovery that genes act by regulating definite chemical events”[58]
Edward Lawrie Tatum United States
Joshua Lederberg United States “for his discoveries concerning genetic recombination and the organization of the genetic material of bacteria[58]
1959 Arthur Kornberg United States “for their discovery of the mechanisms in the biological synthesis of ribonucleic acid and deoxyribonucleic acid[59]
Severo Ochoa Spain
United States
1960 Sir Frank Macfarlane Burnet Australia “for discovery of acquired immunological tolerance[60]
Sir Peter Brian Medawar Brazil
United Kingdom
1961 Georg von Békésy United States “for his discoveries of the physical mechanism of stimulation within the cochlea[61]
1962 Francis Harry Compton Crick United Kingdom “for their discoveries concerning the molecular structure of nucleic acids and its significance for information transfer in living material”[62]
James Dewey Watson United States
Maurice Hugh Frederick Wilkins New Zealand
United Kingdom
1963 Sir John Carew Eccles Australia “for their discoveries concerning the ionic mechanisms involved in excitation and inhibition in the peripheral and central portions of the nerve cell membrane[63]
Sir Alan Lloyd Hodgkin United Kingdom
Sir Andrew Fielding Huxley United Kingdom
1964 Konrad Bloch United States “for their discoveries concerning the mechanism and regulation of the cholesterol and fatty acid metabolism[64]
Feodor Lynen Federal Republic of Germany
1965 François Jacob France “for their discoveries concerning genetic control of enzyme and virus synthesis[65]
André Lwoff France
Jacques Monod France
1966 Peyton Rous United States “for his discovery of tumour-inducing viruses[66]
Charles Brenton Huggins United States “for his discoveries concerning hormonal treatment of prostatic cancer[66]
1967 Ragnar Granit Finland/Sweden “for their discoveries concerning the primary physiological and chemical visual processes in the eye[67]
Haldan Keffer Hartline United States
George Wald United States
1968 Robert W. Holley United States “for their interpretation of the genetic code and its function in protein synthesis[68]
Har Gobind Khorana India
Marshall W. Nirenberg United States
1969 Max Delbrück United States “for their discoveries concerning the replication mechanism and the genetic structure of viruses[69]
Alfred D. Hershey United States
Salvador E. Luria Italy
United States
1970 Julius Axelrod United States “for their discoveries concerning the humoral transmittors in the nerve terminals and the mechanism for their storage, release and inactivation”[70]
Ulf von Euler Sweden
Sir Bernard Katz United Kingdom
1971 Earl W. Sutherland, Jr. United States “for his discoveries concerning the mechanisms of the action of hormones[71]
1972 Gerald M. Edelman United States “for their discoveries concerning the chemical structure of antibodies[72]
Rodney R. Porter United Kingdom
1973 Karl von Frisch Federal Republic of Germany “for their discoveries concerning organization and elicitation of individual and social behaviour patterns”[73]
Konrad Lorenz Austria
Nikolaas Tinbergen United Kingdom
1974 Albert Claude Belgium “for their discoveries concerning the structural and functional organization of the cell[74]
Christian de Duve Belgium
George E. Palade Romania
1975 David Baltimore United States “for their discoveries concerning the interaction between tumour viruses and the genetic material of the cell”[75]
Renato Dulbecco Italy
United States
Howard Martin Temin United States
1976 Baruch S. Blumberg United States “for their discoveries concerning new mechanisms for the origin and dissemination of infectious diseases[76]
D. Carleton Gajdusek United States
1977 Roger Guillemin United States “for their discoveries concerning the peptide hormone production of the brain[77]
Andrew V. Schally United States
Rosalyn Yalow United States “for the development of radioimmunoassays of peptide hormones[77]
1978 Werner Arber Switzerland “for the discovery of restriction enzymes and their application to problems of molecular genetics[78]
Daniel Nathans United States
Hamilton O. Smith United States
1979 Allan M. Cormack South Africa “for the development of computer assisted tomography[79]
Sir Godfrey N. Hounsfield United Kingdom
1980 Baruj Benacerraf Venezuela “for their discoveries concerning genetically determined structures on the cell surface that regulate immunological reactions[80]
Jean Dausset France
George D. Snell United States
1981 Roger W. Sperry United States “for his discoveries concerning the functional specialization of the cerebral hemispheres[81]
David H. Hubel Canada “for their discoveries concerning information processing in the visual system[81]
Torsten N. Wiesel Sweden
1982 Sune K. Bergström Sweden “for their discoveries concerning prostaglandins and related biologically active substances”[82]
Bengt I. Samuelsson Sweden
Sir John R. Vane United Kingdom
1983 Barbara McClintock United States “for her discovery of mobile genetic elements[83]
1984 Niels K. Jerne Denmark “for theories concerning the specificity in development and control of the immune system and the discovery of the principle for production of monoclonal antibodies[84]
Georges J.F. Köhler Federal Republic of Germany
César Milstein Argentina
United Kingdom
1985 Michael S. Brown United States “for their discoveries concerning the regulation of cholesterol metabolism[85]
Joseph L. Goldstein United States
1986 Stanley Cohen United States “for their discoveries of growth factors[86]
Rita Levi-Montalcini Italy
1987 Susumu Tonegawa Japan “for his discovery of the genetic principle for generation of antibody diversity”[87]
1988 Sir James W. Black United Kingdom “for their discoveries of important principles for drug treatment[88]
Gertrude B. Elion United States
George H. Hitchings United States
1989 J. Michael Bishop United States “for their discovery of the cellular origin of retroviral oncogenes[89]
Harold E. Varmus United States
1990 Joseph E. Murray United States “for their discoveries concerning organ and cell transplantation in the treatment of human disease”[90]
E. Donnall Thomas United States
1991 Erwin Neher Federal Republic of Germany “for their discoveries concerning the function of single ion channels in cells”[91]
Bert Sakmann Federal Republic of Germany
1992 Edmond H. Fischer Switzerland
United States
“for their discoveries concerning reversible protein phosphorylation as a biological regulatory mechanism”[92]
Edwin G. Krebs United States
1993 Sir Richard J. Roberts United Kingdom “for their discoveries of split genes[93]
Phillip A. Sharp United States
1994 Alfred G. Gilman United States “for their discovery of G-proteins and the role of these proteins in signal transduction in cells”[94]
Martin Rodbell United States
1995 Edward B. Lewis United States “for their discoveries concerning the genetic control of early embryonic development[95]
Christiane Nüsslein-Volhard Federal Republic of Germany
Eric F. Wieschaus United States
1996 Peter C. Doherty Australia “for their discoveries concerning the specificity of the cell mediated immune defence[96]
Rolf M. Zinkernagel Switzerland
1997 Stanley B. Prusiner United States “for his discovery of Prions – a new biological principle of infection”[97]
1998 Robert F. Furchgott United States “for their discoveries concerning nitric oxide as a signalling molecule in the cardiovascular system”[98]
Louis J. Ignarro United States
Ferid Murad United States
1999 Günter Blobel Germany/United States “for the discovery that proteins have intrinsic signals that govern their transport and localization in the cell”[99]
2000 Arvid Carlsson Sweden “for their discoveries concerning signal transduction in the nervous system[100]
Paul Greengard United States
Eric R. Kandel United States
Year Laureate[A] Country[B] Rationale[C]
2001 Leland H. Hartwell United States “for their discoveries of key regulators of the cell cycle[101]
Sir Tim Hunt United Kingdom
Sir Paul M. Nurse United Kingdom
2002 Sydney Brenner South Africa “for their discoveries concerning ‘genetic regulation of organ development and programmed cell death‘”[102]
H. Robert Horvitz United States
Sir John E. Sulston United Kingdom
2003 Paul Lauterbur United States “for their discoveries concerning magnetic resonance imaging[103]
Sir Peter Mansfield United Kingdom
2004 Richard Axel United States “for their discoveries of odorant receptors and the organization of the olfactory system[104]
Linda B. Buck United States
2005 Barry J. Marshall Australia “for their discovery of the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease[105]
J. Robin Warren Australia
2006 Andrew Z. Fire United States “for their discovery of RNA interference – gene silencing by double-stranded RNA”[106]
Craig C. Mello United States
2007 Mario R. Capecchi United States “for their discoveries of principles for introducing specific gene modifications in mice by the use of embryonic stem cells.”[107]
Sir Martin J. Evans United Kingdom
Oliver Smithies United States
2008 Harald zur Hausen Germany “for his discovery of human papilloma viruses causing cervical cancer[108]
Françoise Barré-Sinoussi France “for their discovery of human immunodeficiency virus[108]
Luc Montagnier France
2009 Elizabeth H. Blackburn United States
“for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase[109]
Carol W. Greider United States
Jack W. Szostak United States
2010 Sir Robert G. Edwards United Kingdom “for the development of in vitro fertilization[110]
Bruce A. Beutler United States “for their discoveries concerning the activation of innate immunity[111]
Jules A. Hoffmann France
Ralph M. Steinman United States
“for his discovery of the dendritic cell and its role in adaptive immunity[111]
(awarded posthumously)[112][113]
2012 Sir John B. Gurdon United Kingdom “for the discovery that mature cells can be reprogrammed to become pluripotent[114]
Shinya Yamanaka Japan
2013 James E. Rothman United States “for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells[5]
Randy W. Schekman United States
Thomas C. Südhof United States
2014 John O’Keefe United States
United Kingdom
“for their discoveries of cells that constitute a positioning system in the brain”
May-Britt Moser Norway
Edvard I. Moser Norway


  1. In chronological order with prizes not given during war years.
  2. There are distinct categories to observe: infectious disease; vitamins; neurophysiology; biochemistry and molecular biology; immunology and pharmacology; cancer; endocrinology.
  3. There were deserving scientists who did not receive the Nobel Prize:  Most notable – were…
    Rosalind Franklin, Britton Chance, Bernard Horacker, Allan Wilson, perhaps others..

Excerpt from “Sound and Hearing”, Stevens, S. S., & Warshofsky, Fred,eds., Time-Life Books, NY, 1965. p54  “The molder of the modern theory of basilar-membrane “resonance” is Georg von Bekesy. In 1928 Bekesy was a communications engineer in Budapest, studying the mechanical and electrical adaptation of telephone equipment to the demands of the human hearing mechanism. One day, in the course of a casual conversation, an acquantance asked him whether a major improvement would soon be forthcoming in the quality of telephone systems. The idle remark strarted a chain of thought that eventually posed to Bekesy a more fundamental question: “How much better is the quality of the human ear than that of any telephone system?” His search for the answer has added volumes to our present-day knowledge of hearing.”

a sound impulse sends a wave sweeping along the basilar membrane. As the wave moves along the membrane, its amplitude increases until it reaches a maximum, then falls off sharply until the wave dies out. That point at which the wave reaches its greatest amplitude is the point at which the frequency of the sound is detected by the ear. And as Helmholtz had postulated, Bekesy found that the high-frequency tones were perceived near the base of the cochlea and the lower frequencies toward the apex.”
For his studines of the traveling wave, Georg von Bekesy received the Nobel Prize in 1961. His incredible delicate and elegant experiments had traced sound to the very threshold of sensation. …”

In the 1950s, Wald and his colleagues used chemical methods to extract pigments from the retina. Then, using a spectrophotometer, they were able to measure the light absorbance of the pigments. Since the absorbance of light by retina pigments corresponds to thewavelengths that best activate photoreceptor cells, this experiment showed the wavelengths that the eye could best detect. However, since rod cells make up most of the retina, what Wald and his colleagues were specifically measuring was the absorbance of rhodopsin, the main photopigment in rods. Later, with a technique called microspectrophotometry, he was able to measure the absorbance directly from cells, rather than from an extract of the pigments. This allowed Wald to determine the absorbance of pigments in the cone cells (Goldstein, 2001).

Schack August Steenberg Krogh ForMemRS (November 15, 1874 – September 13, 1949) was a Danish professor at the department of zoophysiology at the University of Copenhagen from 1916-1945.[3][4][5] He contributed a number of fundamental discoveries within several fields of physiology, and is famous for developing the Krogh Principle. In 1920 August Krogh was awarded the Nobel Prize in Physiology or Medicine for the discovery of the mechanism of regulation of the capillaries in skeletal muscle. Krogh was first to describe the adaptation of blood perfusion in muscle and other organs according to demands through opening and closing the arterioles and capillaries.

Although neurobiology (as it is now called) has always been subsumed under physiology, its rapid growth in the twentieth century, along with its institutionalization in separate university departments and separate funding programs, has made it an almost completely autonomous discipline. Neurobiology can be divided into two major areas: neurophysiology, or the study of the process by which nerve cells transmit a message; and neurology, the study of the structure and organization of the nervous system. A general work is The Neurosciences: Paths of Discovery, edited by Frederic G. Worden, Judith P. Swazey, and George Adelman (Cambridge, Mass.: MIT Press, 1975). Two articles in this collection stand out as particularly interesting: Richard Jung’s “Some European Neuroscientists: A Personal Tribute” (pp. 477-511), and Judith P. Swazey and Frederic G. Worden’s “On the Nature of Research in Neuroscience” (pp. 569-587). Swazey and Worden look at the development of twentieth-century neurobiology in terms of Thomas Kuhn’s concept of scientific revolution.

Two major questions confronted neurologists at the end of the nineteenth and beginning of the twentieth centuries: What was the basic anatomical element of the nervous system (individual cells, or a continuous nerve network)? How were parts of the nervous system (e.g., peripheral nerves and spinal cord) integrated to produce an overall functioning system? The first question involved considerable debate in the period of the 1870s through the 1890s, though it was resolved ultimately in favor of the neuron theory (individual nerve cells as the basic structural and functional unit of the nervous system) by the early 1909.

Central to that debate was the work of the Spanish cytologist Santiago Ramón y Cajal (1852-1934), whose autobiography Recollections of My Life, translated by E. Horne Craigie with the assistance of Juan Cano (Philadelphia: American Philosophical Society, 1937), contains considerable information about the debate, the clash of paradigms, and Ramón y Cajal’s exquisite techniques for bringing about the resolution. A more recent and historically oriented account is Susan Billings’s “Concepts of Nerve Fiber Development 1839- 1930,” Journal of the History of Biology, 1971, 4:275-306, which shows how study of the embryological development of the nervous system (which Ramón y Cajal wisely exploited) helped to demonstrate that the nervous system arises from many discrete individual cells.

The structural and functional organization of the nervous system has been an area of great advancement during the twentieth century. Much work on the mode of action of the reflex response (as well as on how reflexes are learned) and on the relation between inhibition and excitation of nerve tracks was done by Russian neurologists in the latter part of the nineteenth and especially the early part of the twentieth century. The chief figures there were Ivan Michailovich Sechenov (1829-1905) and Ivan P. Pavlov (1849-1936). Pavlov’s inerest in digestion led him, under Sechenov’s infuence, to study the now-classic conditioned reflex involved in salivation. Pavlov’s life and work is the subject of one English-language volume: B.P. Babkin’s Pavlov, A Biography (Chicago: Univ. Chicago Press, 1949). This source provides valuable insight into a whole school of neurological work that has had as much influence on psychology as on neurobiology in this century.

While the general features and functions of the reflex were understood by the turn of the century, its manner of organization (especially in terms of connections with the brain) was not. A towering figure in elucidating the relationship between central and peripheral nervous systems, and especially the integrative function of the spinal cord, was the British physiologist Charles Scott Sherrington (1857-1952). Regnar Granit’s biography, Charles Scott Sherrington, An Appraisal (London: Nelson, 1967), and  Judith Swayze’s Reflexes and Motor Integration: Sharington’s Concept of Integrative Action (Cambridge, Mass.: Harvard Univ. Press, 1969) are significant sources. Swayze concentrates on a detailed but clear and insightful analysis of Sherrington’s scientific background, his experimental methods, and the development of his hypotheses about integrative action.

Concerning the development of the neurotransmitter hypothesis (conduction across the synapse between adjacent neurons occurs by a chemical process), its antagonists and protagonists, see Michael V. L. Bennett’s “Nicked by Occam’s Razor: Unitarianism in the Investigation of Synaptic Transmission,” Biological Bulletin, Suppl., June 1985, 168:159-167.


Sir John Carew Eccles (27 January 1903 – 2 May 1997) was an Australian neurophysiologist who won the 1963 Nobel Prize in Physiology or Medicine for his work on the synapse. He shared the prize with Andrew Huxley and Alan Lloyd Hodgkin. Eccles and colleagues used the stretch reflex as a model. When Eccles passed a current into the sensory neuron in the quadriceps, the motor neuron innervating the quadriceps produced a small excitatory postsynaptic potential (EPSP). When he passed the same current through the hamstring, the opposing muscle to the quadriceps, he saw an inhibitory postsynaptic potential (IPSP) in the quadriceps motor neuron. Although a single EPSP was not enough to fire an action potential in the motor neuron, the sum of several EPSPs from multiple sensory neurons synapsing onto the motor neuron could cause the motor neuron to fire, thus contracting the quadriceps. On the other hand, IPSPs could subtract from this sum of EPSPs, preventing the motor neuron from firing.

However, neuroscience has been repositioned in the 21st century. Arvid Carlsson, 77, of the University of Gothenburg in Sweden, as well as Paul Greengard of Rockefeller University in New York City, and Eric Kandel of New York’s Columbia University, shared the 2000 Nobel Prize in Physiology or Medicine.

Carlsson overturned conventional wisdom in 1950 by proving that dopamine–once thought to be a mere building block in the synthesis of the neurotransmitter norepinephrine–was an important nervous system messenger in its own right. He and others later discovered that Parkinson’s disease, which causes rigidity and tremors, results from a lack of dopamine in the brain.

Greengard, 74, took Carlsson’s insights several steps further in the 1960s by exploring how dopamine, norepinephrine, and serotonin control transmission of nerve signals at the synapse, the junction between communicating nerve cells. Greengard showed that the three neurotransmitters trigger the addition or removal of phosphate groups to proteins involved in nerve signaling, prompting them to interact with other proteins in a cascade of phosphorylation in and around the synapse.

The discovery that protein phosphorylation is key to nerve cell signaling helped inspire the research of Kandel, 70, who found that the ease with which ions such as calcium pass through a cell membrane– depends on whether the proteins forming the membrane’s pore are phosphorylated. Based on these findings, Kandel showed that short-term and long-term memory are related to the strength and duration of nerve impulses, and that new proteins are synthesized to maintain long-term memory.

Neuroscientist Thomas Südhof, MD, professor of molecular and cellular physiology at the Stanford University School of Medicine, shared the 2013 Nobel Prize in Physiology or Medicine with James Rothman, PhD, a former Stanford professor of biochemistry, and Randy Schekman, PhD, who earned his doctorate at Stanford under the late Arthur Kornberg, MD, another winner of the Nobel Prize in Physiology or Medicine. They were awarded the prize “for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells.” Rothman is now a professor at Yale University, and Schekman is a professor at UC-Berkeley.

“Tom Südhof has done brilliant work that lays a molecular basis for neuroscience and brain chemistry,” said Roger Kornberg, PhD, Stanford’s Mrs. George A. Winzer Professor in Medicine. Kornberg was awarded the Nobel Prize in Chemistry in 2006. He is the son of Arthur Kornberg, in whose lab Schekman received his doctorate.

“The brain works by neurons communicating via synapses,” Südhof said in a phone conversation this morning shortly after the announcement. “We’d like to understand how synapse communication leads to learning on a larger scale. How are the specific connections established? How do they form? And what happens in schizophrenia and autism when these connections are compromised?” In 2009, he published research describing how a gene implicated in autism and schizophrenia alters mice’s synapses and produces behavioral changes in the mice, such as excessive grooming and impaired nest building, that are reminiscent of these human neuropsychiatric disorders.

Südhof, along with other researchers worldwide, has identified integral protein components critical to the membrane fusion process. Südhof purified key protein constituents sticking out of the surfaces of neurotransmitter-containing vesicles, protruding from nearby presynaptic-terminal membranes, or bridging them. Then, using biochemical, genetic and physiological techniques, he elucidated the ways in which the interactions among these proteins contribute to carefully orchestrated membrane fusion.

The Nobel Prize in Physiology or Medicine 2014 was divided, one half awarded to John O’Keefe, the other half jointly to May-Britt Moser and Edvard I. Moser “for their discoveries of cells that constitute a positioning system in the brain.”

In 1971, John O’Keefe discovered the first component of this positioning system. He found that a type of nerve cell in an area of the brain called the hippocampus that was always activated when a rat was at a certain place in a room. Other nerve cells were activated when the rat was at other places. O’Keefe concluded that these “place cells” formed a map of the room.

More than three decades later, in 2005, May-Britt and Edvard Moser discovered another key component of the brain’s positioning system. They identified another type of nerve cell, which they called “grid cells”, that generate a coordinate system and allow for precise positioning and pathfinding. Their subsequent research showed how place and grid cells make it possible to determine position and to navigate.


History of Physiology
Lois N Magner,
Purdue University, West Lafayette, USA
Published online: April 2001

Major developments in the history of physiology include William Harvey’s demonstration of the circulation of the blood in the seventeenth century and Claude Bernard’s discovery of internal secretions in the nineteenth century.

For a neglected side of the story, see Seymour S. Cohen’s “The Biochemical Origins of Molecular Biology (Introduction),” Trends in Biochemical Sciences, 1984, 9:334-336, which argues that many of the histories of molecular biology have ignored the contributions of biochemistry to molecular genetics in general and to the discovery of DNA in particular.

Rather than covering the vast array of subjects that rightfully fall under the history of physiology (such as plant physiology and pathology, etc.), I focus on three areas that have been major concerns in the twentieth century: general physiology, neurobiology and endocrinology. For a brief introduction and overview of twentieth-century physiology, it is worthwhile to consult Karl E. Rothschuh’s History of Physiology (Huntington, N.Y.: Krieger, 1973). Chapter 7 (pp. 264-361) deals with the twentieth century; while it does not provide in-depth coverage, the broad outline establishes the framework within which more specialized topics can be placed.

The Prussian-born American physiologist Jacques Loeb (1859-1924), a long-time investigator at the Rockefeller Institute and a close professional friend of such figures as T. H. Morgan, Boss Harrison, J. McKeen Cattell, and W.J. V. Osterhout, set the style of experimental and quantitative biology that influenced a whole generation of biologists, especially in the United States. Loeb championed what he called “the mechanistic conception of life”–the title of a major address he gave in 1911 and of a book of essays collected in 1912 (Cambridge, Mass.: Harvard Univ. Press, 1964). The reprint edition benefits from a superb introduction by Donald Fleming. The Mechanistic Conception of Life was a celebration of the mechanistic materialist viewpoint in twentieth-century biology. A new biography of Loeb is Philip J. Pauly’s Controlling Life: Jacques Loeb and the Engineering Ideal in Biology (New York: Oxford Univ. Press, 1987). As the title suggests, Pauly emphasizes that Loeb’s guiding ideal was the scientific control of life.

Opposition to the “mechanistic conception of life” came from a number of sources–principally embryology and areas of general physiology–from the 1920s onward. Prominent among those who advanced a more holistic approach were the physiologist Walter Bradford Cannon (1871-1942) and the physiological chemist Lawrence J. Henderson (1878-1942). Cannon’s work, is summarized in his popular book The Wisdom of the Body (1932; New York: Norton, 1960). Henderson’s work is summarized, along with a number of other chemical topics, in his “The Fitness of the Environment” (1913; Boston: Beacon Press, 1958). The development of the idea of homeostasis is the subject of a superb essay by Donald Fleming, “Walter B. Cannon and homeostasis,” Social Research, 1984, 51:609-640.

Henderson’s work has been the subject of several studies. John Parascandola’s “Organismic and Holistic Concepts in the Thought of L. J. Henderson,” Journal of the Histoty of Biology, 1971, 4:63-113, relates Henderson’s scientific to his philosophical work. Henderson and Cannon were strongly interested in social regulation and equilibrium, as was fitting for products of the “Progressive Era,” and sought in physiological processes analogies for the notion of social and economic balance. A specific discussion of Henderson’s view of the interrelationship between social and physiological equilibrium theory can be found in Cynthia Eagle Russett’s The Concept of Equilibrium in American Social Thought (New Haven, Conn.: Yale Univ. Press, 1968). See also Stephen J. Cross and William R. Albury, “Walter B. Cannon, L.J. Henderson, and the Organic Analogy,” Osiris, 1987, N.S. 3:165-192.

Endocrinology (the study of the nature and effect of hormones, or “chemical messengers,” produced by the endocrine glands) is an area of general physiology that has shown enormous growth in the twentieth century. It has also been the subject of numerous historical studies. Arthur F. Hughes has prepared a brief but useful introduction titled “A History of Endocrinology,” Journal of the History of Medcine and Allied Sciences, 1977, 32(3): 292-313. While it is largely descriptive and chronological, Hughes’s study demonstrates the close link between clinical pathology and the gradual discovery of the role of hormones in maintaining physiological balance.

The history of endocrinology is the subject of a special issue of the Journal of the History of Biology, 1976, 9. A general introduction to the historiography of endocrinology is provided for the volume by Diana Long Hall and Thomas F. Click (pp. 229-233). Hall has explored some social and technical aspects of the history of sex-hormone research in “Biology, Sex Hormones, and Sexism in the 1920s,” Philosophical Forum 1974, 5:81-96. She suggests that sexist biases about the importance of male over female hormones proved to be a barrier to the technical solution of problems associated with extracting, isolating, and characterizing the chemical nature of sex hormones (principally testosterone and estrogen) in the 1920s.

On a somewhat more specific aspect of endocrinology, Michael Bliss’s The Discovery of Insulin (Chicago: Univ. Chicago Press, 1982) provides a close picture of the technical problems that investigators in any field of endocrinology had to surmount in order to identify, isolate, and purify a given hormone. The insulin story also provides a fascinating picture of the role of drug companies in encouraging and financing hormone research in the period (1920s) before government subsidy of basic scientific research.

Cardiovascular Physiology
The Frank–Starling law of the heart (also known as Starling’s law or the Frank–Starling mechanism or Maestrini heart’s law) states that the stroke volume of the heart increases in response to an increase in the volume of blood filling the heart (the end diastolic volume) when all other factors remain constant.  It is based on the late19th century studies by Otto Frank, who found using isolated frog hearts that the strength of ventricular contraction was increased when the ventricle was stretched prior to contraction. This observation was extended by the elegant studies of Ernest Starling and colleagues in the early 20th century who found that increasing venous return, and therefore the filling pressure of the ventricle, led to increased stroke volume in dogs.

The increased volume of blood stretches the ventricular wall, causing cardiac muscle to contract more forcefully. The stroke volume – contractile force model of  Ernest Starling was also based on the earlier observations of Maestrini in 1914.  The hypothesis states that “the mechanical energy set free in the passage from the resting to the active state is a function of the length of the fiber.”  This allows the cardiac output to be synchronized with the venous return without depending upon external regulation to make alterations. Initial length of myocardial fibers determines the initial work done during the cardiac cycle.

The stroke volume may also increase as a result of greater contractility of the cardiac muscle during exercise, independent of the end-diastolic volume. The Frank–Starling mechanism appears to make its greatest contribution to increasing stroke volume at lower work rates, and contractility has its greatest influence at higher work rates.

The first formulation of the law was theorized by the Italian physiologist Dario Maestrini, who on December 13, 1914, started the first of 19 experiments that led him to formulate the “legge del cuore”. Starling, the holder of the Physiology chair at London University, traced Maestrini’s work in 1918. While Starling was identified for the proposed award of the Nobel Prize, Maestrini never received his recognition, and today the “law of the heart” is known worldwide as “Starling’s Law,” though, among the Italian doctors, it is known by the nickname “Legge di Maestrini”.

One mechanism to explain how preload influences contractile force is that increasing the sarcomere length increases troponin C calcium sensitivity, which increases the rate of cross-bridge attachment and detachment, and the amount of tension developed by the muscle fiber (see Excitation-Contraction Coupling).  The effect of increased sarcomere length on the contractile proteins is termed length-dependent activation

It has traditionally been taught that the Frank-Starling mechanism is due to changes in the number of overlapping actin and myosin units within the sarcomere as in skeletal muscle. According to this view, changes in the force of contraction do not result from a change in inotropy. Because we now know that changes in preload are associated with altered calcium handling and troponin C affinity for calcium, a sharp distinction cannot be made mechanistically between length-dependent (Frank-Starling mechanism) and length-independent changes (inotropic mechanisms) in contractile function.

There is no single Frank-Starling curve on which the ventricle operates. There is actually a family of curves, each of which is defined by the afterload and inotropic state of the heart (Figure 2). For example, increasing afterload or decreasing inotropy shifts the curve down and to the right. Decreasing afterload and increasing inotropy shifts the curve up and to the left. To summarize, changes in venous return cause the ventricle to move along a single Frank-Starling curve that is defined by the existing conditions of afterload and inotropy.

Frank-Starling curves show how changes in ventricular preload lead to changes in stroke volume. This graphical representation, however, does not show how changes in venous return affect end-diastolic and end-systolic volume. In order to do this, it is necessary to describe ventricular function in terms of pressure-volume diagrams. When venous return is increased, there is increased filling of the ventricle along its passive pressure curve leading to an increase in end-diastolic volume (Figure 3). If the ventricle now contracts at this increased preload, and the afterload is held constant, the ventricle will empty to the same end-systolic volume, thereby increasing its stroke volume. The increased stroke volume is manifested by an increase in the width of the pressure-volume loop. The normal ventricle, therefore, is capable of increasing its stroke volume to match physiological increases in venous return.



Starling's Law of the heart

Starling’s Law of the heart

Starling's Law of the heart

Starling’s Law of the heart

Skeletal Muscle Contraction

Muscle Contraction and Relaxation

Step 1

A nerve impulse travels down and axon and causes the release of acetylcholine.

Step 2

Acetylecholine causes the impulse to spread across the surface of the sarcolemma.

Step 3

The nerve impulse enters the T Tubules and Sarcoplasmic Reticulum, stimulating the release of calcium ions.

Step 4

Calcium ions combine with Troponin, shifting troponin and exposing the myosin binding sites on the actin.

Step 5

ATP breaks down ADP + P. The released energy activates the myosin cross bridges and results in the sliding of thin actin myofilament past the thick myosin myofilaments.

Step 6

The sliding of the myofilaments draws the Z lines towards each other, the sarcomere shortens, the muscle fibers contract and therefore muscle contracts.

Step 7

ACh is inactivated by Acetylcholinesterase, inhibiting the nerve impulse conduction across the sarcolemma.

Step 8

Nerve impulse is inhibited, calcium ions are actively transported back into the Sarcoplasmic Reticulum, using the energy from the earlier ATP breakdown.

Step 9

The low calcium concentration causes the myosin cross bridges to separate from the think actin myofilaments and the actin myofilaments return to their relaxed position.

Step 10

Sarcomeres return to their resting lengths, muscle fibers relax and the muscle relaxes.

muscle contraction

muscle contraction

sarcomere structure

sarcomere structure



Pulmonary Gas Exchange

Inhalation (breathing in) is usually an active movement. The contraction of the diaphragm muscles causes the thoracic cavity to increase in volume, thus decreasing the pressures within the lung (Intrapleural and Alveolar Pressures). This negative pressure within the lungs acts as a Pressure Gradient, thus pulling air into the lungs. As air fills the lungs, the negative alveolar pressure moves back towards atmospheric pressure, and air flow into the lungs slows down. In contrast, expiration (breathing out) is usually a passive process.

Where Pel equals the product of elastance E (inverse of compliance) and volume of the system V, Pre equals the product of flow resistance R and time derivate of volume V (which is equivalent to the flow), Pin equals the product of inertance I and second time derivate of V. R and I are sometimes referred to as Rohrer’s constants.





Pulmonary circulation

Gas exchange/transport (primarily oxygen and carbon dioxide)




Oxygen-hemoglobin dissociation curve
(Bohr effect, Haldane effect)

The Young–Laplace equation (/ˈjʌŋ ləˈplɑːs/) is a nonlinear partial differential equation that describes the capillary pressure difference sustained across the interface between two static fluids, such as water and air, due to the phenomenon of surface tension or wall tension, although usage on the latter is only applicable if assuming that the wall is very thin. The Young–Laplace equation relates the pressure difference to the shape of the surface or wall and it is fundamentally important in the study of static capillary surfaces. It is a statement of normal stress balance for static fluids meeting at an interface, where the interface is treated as a surface (zero thickness).

The equation is named after Thomas Young, who developed the qualitative theory of surface tension in 1805, and Pierre-Simon Laplace who completed the mathematical description in the following year. It is sometimes also called the Young–Laplace–Gauss equation, as Gauss unified the work of Young and Laplace in 1830, deriving both the differential equation and boundary conditions using Johann Bernoulli‘s virtual work principles.

Dalton’s law (also called Dalton’s law of partial pressures) states that in a mixture of non-reacting gases, the total pressure exerted is equal to the sum of the partial pressures of the individual gases. This empirical law was observed by John Dalton in 1801 and is related to the ideal gas laws. Dalton’s law is not strictly followed by real gases with deviations being considerably large at high pressures.

Histidine residues in hemoglobin can accept protons and act as buffers. Deoxygenated hemoglobin is a better proton acceptor than the oxygenated form.

In red blood cells, the enzyme carbonic anhydrase catalyzes the conversion of dissolved carbon dioxide to carbonic acid, which rapidly dissociates to bicarbonate and a free proton:
CO2 + H2O → H2CO3 → H+ + HCO3
By Le Chatelier’s principle, anything that stabilizes the proton produced will cause the reaction to shift to the right, thus the enhanced affinity of deoxyhemoglobin for protons enhances synthesis of bicarbonate and accordingly increases capacity of deoxygenated blood for carbon dioxide. The majority of carbon dioxide in the blood is in the form of bicarbonate. Only a very small amount is actually dissolved as carbon dioxide, and the remaining amount of carbon dioxide is bound to hemoglobin.

In addition to enhancing removal of carbon dioxide from oxygen-consuming tissues, the Haldane effect promotes dissociation of carbon dioxide from hemoglobin in the presence of oxygen. In the oxygen-rich capillaries of the lung, this property causes the displacement of carbon dioxide to plasma as low-oxygen blood enters the alveolus and is vital for alveolar gas exchange.

The general equation for the Haldane Effect is: H+ + HbO2 ←→ H+Hb + O2; however, this equation is confusing as it reflects primarily the Bohr effect. The significance of this equation lies in realizing that oxygenation of Hb promotes dissociation of H+ from Hb, which shifts the bicarbonate buffer equilibrium towards CO2 formation; therefore, CO2 is released from RBCs, so it can diffuse out into the lungs (vs the Bohr effect being most relevant at non high O2 environment tissues; useful comparison to not confuse the 2 concepts of Haldane vs Bohr- Haldane@lung and Bohr@tissues for their physiological relevance).



In 1957, the french surgeon Claude Couinaud described 8 liver segments. Since then, radiographic studies describe an average of twenty segments based on distribution of blood supply. Each segment has its own independent vascular and biliary branches. Surgeons utilize these independent segments when performing liver resection for tumor or transplantation.

There are at least three reasons why segmental resection is superior to simple wedge resection. First, segmental resection minimizes blood loss because vascular density is reduced at the borders between segments. Second, it results in improved tumor removal for those cancers which are disseminated via intrasegmental branches of the portal vein. Third, segmental resection spares normal liver allowing for repeat partial hepatectomy.

liver triad

liver triad

Each segment of the liver is further divided into lobules. Lobules are usually represented as discrete hexagonal aggregations of hepatocytes. The hepatocytes assemble as plates which radiate from a central vein. Lobules are served by arterial, venous and biliary vessels at their periphery. Human lobules have little connective tissue separating one lobule from another. The paucity of connective tissue makes it more difficult to identify the portal triads and the boundaries of individual lobules. Central veins are easier to identify due to their large lumen and because they lack connective tissue that invests the portal triad vessels.

Lobules consist of hepatocytes and the spaces between them. Sinusoids are the spaces between the plates of hepatocytes. Sinusoids receive blood from the portal triads. About 25% of total cardiac output enters the sinusoids via terminal portal and arterial vessels. Seventy-five percent of the blood flowing into the liver comes through the portal vein; the remaining 25% is oxygenated blood that is carried by the hepatic artery. The blood mixes, passes through the sinusoids, bathes the hepatocytes and drains into the central vein. About 1.5 liters of blood exit the liver every minute.

The liver is central to a multitude of physiologic functions, including:

Clearance of damaged red blood cells & bacteria by phagocytosis

Nutrient management

Synthesis of plasma proteins such as albumin, globulin, protein C, insulin-like growth factor, clotting factors etc.

Biotransformation of toxins, hormones, and drugs

Vitamin & mineral storage


Renal physiology (Latin rēnēs, “kidneys”) is the study of the physiology of the kidney. This encompasses all functions of the kidney, including reabsorption of glucose, amino acids, and other small molecules; regulation of sodium, potassium, and other electrolytes; regulation of fluid balance and blood pressure; maintenance of acid-base balance; the production of various hormones including erythropoietin, and the activation of vitamin D.

Much of renal physiology is studied at the level of the nephron, the smallest functional unit of the kidney. Each nephron begins with a filtration component that filters blood entering the kidney. This filtrate then flows along the length of the nephron, which is a tubular structure lined by a single layer of specialized cells and surrounded by capillaries. The major functions of these lining cells are the reabsorption of water and small molecules from the filtrate into the blood, and the secretion of wastes from the blood into the urine.

Proper function of the kidney requires that it receives and adequately filters blood. This is performed at the microscopic level by many hundreds of thousands of filtration units called renal corpuscles, each of which is composed of a glomerulus and a Bowman’s capsule. A global assessment of renal function is often ascertained by estimating the rate of filtration, called the glomerular filtration rate (GFR).



vit D and receptor complex

vit D and receptor complex

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Nature Biotechnology Podcast Archive: 2/2011 to 12/2014

Reporter: Aviva Lev-Ari, PhD, RN






Previous episodes can be accessed here. To download a show to your computer, right click the Download mp3 link and select ‘Save target as/Save link as’ and save the file to your computer or a CD.

      • December 2014: First Rounders:

        Listen now | Download mp3
        Daphne Zohar is the founder, CEO and managing partner at PureTech, a venture creation company with a new approach to building biotechs, and she sits on the board of several life science firms. Her podcast conversation with Nature Biotechnology covers starting her first company (in high school), the usefulness of Bioentrepreneur courses, and women in venture capital.

      • September 2014: First Rounders:

        Listen now | Download mp3
        Mary Tanner details the Amgen-Immunex buyout, defines ‘wildcatting’ and suggests the years in which children most need a parent around the house.

      • August 2014: Focus issue podcast:

        Listen now | Download mp3
        Anthony Davies discusses the past, present and future of stem cell therapies.

      • July 2014: First Rounders:

        Listen now | Download mp3
        Julian Davies takes us through his long research career in Madison, Wisconsin; Paris and Geneva. He also discusses wrecking his motorcycle and how he met his wife.

      • May 2014: First Rounders:

        Listen now | Download mp3
        Leroy Hood talks through the founding of Applied Biosystems, the beginnings of the Human Genome Project and what drew him to mountain climbing.

      • March 2014: First Rounders:

        Listen now | Download mp3
        Nature Biotechnology talked to West about his initial love for physics, scoring the first funding for Geron and the future of regenerative medicine.

      • December 2013: First Rounders:

        Listen now | Download mp3
        Nature Biotechnology spoke to Harvey Berger about developing Iclusig, the difference between managing a patient’s health and running a company, and how a public entity deals with bad news.

      • October 2013: First Rounders:

        Listen now | Download mp3
        George Yancopoulos talks about the scientific foundation at Regeneron, upholding the family name and giving back through teaching.

      • September 2013: First Rounders:

        Listen now | Download mp3
        Una Ryan discusses the biotech East Coast vs. West; life in Oxford, UK; and her initial foray into industry via a job at Monsanto.

      • June 2013: First Rounders:

        Listen now | Download mp3
        William A. Haseltine talks about his time at HGS, the future of genomics in drug discovery and how innovation might be funded going forward.

      • March 2013: First Rounders:

        Listen now | Download mp3
        Henri Termeer discusses his path to Genzyme, the approval of Ceredase and the drawn-out negotiations with eventual acquirer Sanofi.

      • February 2011:

        Listen now | Download mp3
        A roundtable discussion examining venture capital funding levels for innovative science in biotech.




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Nature Biotechnology Podcast with Daphne Zohar, Founder, CEO and Managing Partner at PureTech

Reporter: Aviva Lev-Ari, PhD, RN


First Rounder: Daphne Zohar

Daphne Zohar is the founder, CEO and managing partner at PureTech, a venture creation company with a new approach to building biotechs, and she sits on the board of several life science firms. Her podcast conversation with Nature Biotechnology covers starting her first company (in high school), the usefulness of Bioentrepreneur courses, and women in venture capital.




PureTech Pipeline


Cross disciplinary

“PureTech has the scientific creativity to really go for the big ideas that can be game changers. The team dreams up technologies and then makes them happen

– Dr. Robert Langer, PureTech co-founder,
Senior Partner & Board Member.
PureTech’s programs have attracted several hundred million dollars in outside funding and PureTech has active strategic partnerships with some of the most forward thinking health and technology companies in the world. Several of our programs are at or beyond the stage of human clinical testing, developing technologies poised to disrupt several multi-billion dollar market segments. Explore our pipeline below to learn more about what we’ve created:

  • Discovery & Preclinical
  • Human Clinical Studies
  • Beta
  • Launch


Valley of Life



Consumer & Digital

Enlight Immersive Health



Drug Delivery


PureTech co-founded but current holdings not significant.

  • Discovery & Preclinical
  • Human Clinical Studies
  • Beta
  • Launch
Fluoro Pharma
AZ Therapies


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The Union of Biomarkers and Drug Development

The Union of Biomarkers and Drug Development

Author and Curator: Larry H. Bernstein, MD, FCAP

There has been consolidation going on for over a decade in both thr pharmaceutical and in the diagnostics industry, and at the same time the page is being rewritten for health care delivery.  I shall try to work through a clear picture of these not coincidental events.

Key notables:

  1. A growing segment of the US population is reaching Medicare age
  2. There is also a large underserved population in both metropolitan and nonurban areas and a fragmentation of the middle class after a growth slowdown in the economy since the 2008 deep recession.
  3. The deep recession affecting worldwide economies was only buffered by availability of oil or natural gas.
  4. In addition, there was a self-destructive strategy to cut spending on national scales that withdrew the support that would bolster support for infrastrucrue renewl.
  5. There has been a dramatic success in the clinical diagnostics industry, with a long history of being viewed as a loss leader, and this has been recently followed by the pharmaceutical industry faced with inability to introduce new products, leading to more competition in off-patent medications.
  6. The introduction of the Accountable Care Act has opened the opportunities for improved care, despite political opposition, and has probably sustained opportunity in the healthcare market.

Let’s take a look at this three headed serpent. – Pharma, Diagnostics, New Entity
?  The patient  ?
?  Insurance    ?
?  Physician    ?

Part I.   The Concept

When Illumina Buys Roche: The Dawning Of The Era Of Diagnostics Dominance

Robert J. Easton, Alain J. Gilbert, Olivier Lesueur, Rachel Laing, and Mark Ratner
http://PharmaMedtechBI.com    | IN VIVO: The Business & Medicine Report Jul/Aug 2014; 32(7).

  • With current technology and resources, a well-funded IVD company can create and pursue a strategy of information gathering and informatics application to create medical knowledge, enabling it to assume the risk and manage certain segments of patients
  • We see the first step in the process as the emergence of new specialty therapy companies coming from an IVD legacy, most likely focused in cancer, infection, or critical care

When Illumina Inc. acquired the regulatory consulting firm Myraqa, a specialist in in vitro diagnostics (IVD), in July, the press release announcement characterized the deal as one that would bolster illumina’s in-house capabilities for clinical readiness and help prepare for its next growth phase in regulated markets. That’s not surprising given the US Food and Drug Administration’s (FDA) approval a year and a half ago of its MiSeq next-generation sequencer for clinical use. But the deal could also suggest illumina is beginning to move along the path toward taking on clinical risk – that is, eventually

  • advising physicians and patients, which would mean facing regulators directly

Such a move – by illumina, another life sciences tools firm, or an information specialist from the high-tech universe – is inevitable given

  • the emerging power of diagnostics and traditional health care players’ reluctance to themselves take on such risk.

Alternatively, we believe that a well-funded diagnostics company could establish this position. either way, such a champion would establish dominion over and earn higher valuation than less-aggressive players who

  • only supply compartmentalized drug and device solutions.

Diagnostics companies have long been dogged by a fundamental issue:

  1. they are viewed and valued more along the lines of a commodity business than as firms that deliver a unique product or service
  2. diagnostics companies are in position to do just that today because they are now advantaged by having access to more data points.
  3. if they were to cobble together the right capabilities, diagnostics companies would have the ability to turn information into true medical knowledge

Example: PathGEN PathChip

nucleic-acid-based platform detects 296 viruses, bacteria, fungi & parasites


This puts the diagnostics player in an unfamiliar realm where it can ask the question of what value they offer compared with a therapeutic. The key is that diagnostics can now offer unique information and potentially unique tools to capture that information. In order to do so, it has to create information from the data it generates, and then to supply that knowledge to users who will value and act on that knowledge. Complex genomic tests, as much as physical examination, may be the first meaningful touch point for physicians’ classification of disease.

Even if lab tests are more expensive, it is a cheaper means for deciding what to do first for a patient than the trial and error of prescribing medication without adequate information. Information is gaining in value as the amount of treatment data available on genomically characterizable subpopulations increases. In such a circumstance
it is the ability to perform that advisory function that will add tremendous value above what any test provides, the leverage of being able to apply a proprietary diagnostics platform – and importantly, the data it generates. It is the ability to perform that advisory function that will add tremendous value above what any test provides.

Integrated Diagnostics Inc. and Biodesix Inc. with mass spectrometry has the tools for unraveling disease processes, and numerous players are quite visibly in or are getting into the business of providing medical knowledge and clinical decision support in pursuit of a huge payout for those who actually solve important disease mysteries. Of course one has to ask whether MS/MS is sufficient for the assigned task, and also whether the technology is ready for the kind of workload experienced in a clinical service compared to a research vehicle.  My impression (as a reviewer) is that it is not now the time to take this seriously.

Roche has not realized its intent with Ventana: failing to deliver on the promise of boosting Roche’s pipeline, which was a significant factor in the high price Roche paid. The combined company was to be “uniquely positioned to further expand Ventana’s business globally and together develop more cost-efficient, differentiated, and targeted medicines.  On the other hand,  Biodesix decided to use Veristrat to look back and analyze important trial data to try to ascertain which patients would benefit from ficlatuzumab (subset). The predictive effect for the otherwise unimpressive trial results was observed in both progression-free survival and overall survival endpoints, and encouraged the companies to conduct a proof-of-concept study of ficlatuzumab in combination with Tarceva in advanced Non Small Cell Lung Cancer Patients (NSCLC) selected using the Veristrat test.

A second phase of IVD evolution will be far more challenging to pharma, when the most accomplished companies begin to assemble and integrate much broader data
sets, thereby gaining knowledge sufficient to actually manage patients and dictate therapy, including drug selection. No individual physician has or will have access to all of this information on thousands of patients, combined with the informatics to tease out from trillions of data points the optimal personalized medical approach. When the IVD-origin knowledge integrator amasses enough data and understanding to guide therapy decisions in large categories, particularly drug choices, it will become more valuable than any of the drug suppliers.

This is an apparent reversal of fortune. The pharmaceutical industry has been considered the valued provider, while the IVD manufacturer has been the low valued cousin. Now, it is by an ability to make kore accurate the drug administration that the IVD company can control the drug bill, to the detriment of drug developers, by finding algorithms that generate equal-to-innovative-drug outcomes using generics for most of the patients, thereby limiting the margins of drug suppliers and the upsides for new drug discovery/development.

It is here that there appears to be a misunderstanding of the whole picture of the development of the healthcare industry.  The pharmaceutical industry had a high value added only insofar it could replace market leaders for treatment before or at the time of patent expiration, which largely depended either introducing a new class of drug, or by relieving the current drug in its class of undesired toxicities or “side effects”.  Otherwise, the drug armamentarium was time limited to the expiration date. In other words, the value was dependent on a window of no competition.  In addition, as the regulation of healthcare costs were tightening under managed care, the introduction of new products that were deemed to be only marginally better, could be substitued by “off-patent” drug products.

The other misunderstanding is related to the IVD sector.  Laboratory tests in the 1950’s were manual, and they could be done by “technicians” who might not have completed a specialized training in clinical laboratory sciences.  The first sign of progress was the introduction of continuous flow chemistry, with a sampling probe, tubing to bring the reacting reagents into a photocell, and the timing of the reaction controlled by a coiled glass tubing before introducing the colored product into a uv-visible photometer.  In perhaps a decade, the Technicon SMA 12 and 6 instruments were introduced that could do up to 18 tests from a single sample.

Part 2. Emergence of an IVD Clinical Automated Diagnostics Industry

Why tests are ordered

  1. Screening
  2. Diagnosis
  3. Monitoring

Historical Perspective

Case in Point 1:  Outstanding Contributions in Clinical Chemistry. 1991. Arthur Karmen.

Dr. Karmen was born in New York City in 1930. He graduated from the Bronx High School of Science in 1946 and earned an A.B. and M.D. in 1950 and 1954, respectively, from New York University. In 1952, while a medical student working on a summer project at Memorial-Sloan Kettering, he used paper chromatography of amino acids to demonstrate the presence of glutamic-oxaloacetic and glutaniic-pyruvic ransaminases (aspartate and alanine aminotransferases) in serum and blood. In 1954, he devised the spectrophotometric method for measuring aspartate aminotransferase in serum, which, with minor modifications, is still used for diagnostic testing today. When developing this assay, he studied the reaction of NADH with serum and demonstrated the presence of lactate and malate dehydrogenases, both of which were also later used in diagnosis. Using the spectrophotometric method, he found that aspartate aminotransferase increased in the period immediately after an acute myocardial infarction and did the pilot studies that showed its diagnostic utility in heart and liver diseases.  This became as important as the EKG. It was replaced in cardiology usage by the MB isoenzyme of creatine kinase, which was driven by Burton Sobel’s work on infarct size, and later by the troponins.

Case in point 2: Arterial Blood Gases.  Van Slyke. National Academy of Sciences.

The test is used to determine the pH of the blood, the partial pressure of carbon dioxide and oxygen, and the bicarbonate level. Many blood gas analyzers will also report concentrations of lactate, hemoglobin, several electrolytes, oxyhemoglobin, carboxyhemoglobin and methemoglobin. ABG testing is mainly used in pulmonology and critical care medicine to determine gas exchange which reflect gas exchange across the alveolar-capillary membrane.

DONALD DEXTER VAN SLYKE died on May 4, 1971, after a long and productive career that spanned three generations of biochemists and physicians. He left behind not only a bibliography of 317 journal publications and 5 books, but also more than 100 persons who had worked with him and distinguished themselves in biochemistry and academic medicine. His doctoral thesis, with Gomberg at University of Michigan was published in the Journal of the American Chemical Society in 1907.  Van Slyke received an invitation from Dr. Simon Flexner, Director of the Rockefeller Institute, to come to New York for an interview. In 1911 he spent a year in Berlin with Emil Fischer, who was then the leading chemist of the scientific world. He was particularly impressed by Fischer’s performing all laboratory operations quantitatively —a procedure Van followed throughout his life. Prior to going to Berlin, he published the  classic nitrous acid method for the quantitative determination of primary aliphatic amino groups,  the first of the many gasometric procedures devised by Van Slyke, and made possible the determination of amino acids. It was the primary method used to study amino acid

composition of proteins for years before chromatography. Thus, his first seven postdoctoral years were centered around the development of better methodology for protein composition and amino acid metabolism.

With his colleague G. M. Meyer, he first demonstrated that amino acids, liberated during digestion in the intestine, are absorbed into the bloodstream, that they are removed by the tissues, and that the liver alone possesses the ability to convert the amino acid nitrogen into urea.  From the study of the kinetics of urease action, Van Slyke and Cullen developed equations that depended upon two reactions: (1) the combination of enzyme and substrate in stoichiometric proportions and (2) the reaction of the combination into the end products. Published in 1914, this formulation, involving two velocity constants, was similar to that arrived at contemporaneously by Michaelis and Menten in Germany in 1913.

He transferred to the Rockefeller Institute’s Hospital in 2013, under Dr. Rufus Cole, where “Men who were studying disease clinically had the right to go as deeply into its fundamental nature as their training allowed, and in the Rockefeller Institute’s Hospital every man who was caring for patients should also be engaged in more fundamental study”.  The study of diabetes was already under way by Dr. F. M. Allen, but patients inevitably died of acidosis.  Van Slyke reasoned that if incomplete oxidation of fatty acids in the body led to the accumulation of acetoacetic and beta-hydroxybutyric acids in the blood, then a reaction would result between these acids and the bicarbonate ions that would lead to a lower than-normal bicarbonate concentration in blood plasma. The problem thus became one of devising an analytical method that would permit the quantitative determination of bicarbonate concentration in small amounts of blood plasma.  He ingeniously devised a volumetric glass apparatus that was easy to use and required less than ten minutes for the determination of the total carbon dioxide in one cubic centimeter of plasma.  It also was soon found to be an excellent apparatus by which to determine blood oxygen concentrations, thus leading to measurements of the percentage saturation of blood hemoglobin with oxygen. This found extensive application in the study of respiratory diseases, such as pneumonia and tuberculosis. It also led to the quantitative study of cyanosis and a monograph on the subject by C. Lundsgaard and Van Slyke.

In all, Van Slyke and his colleagues published twenty-one papers under the general title “Studies of Acidosis,” beginning in 1917 and ending in 1934. They included not only chemical manifestations of acidosis, but Van Slyke, in No. 17 of the series (1921), elaborated and expanded the subject to describe in chemical terms the normal and abnormal variations in the acid-base balance of the blood. This was a landmark in understanding acid-base balance pathology.  Within seven years after Van moved to the Hospital, he had published a total of fifty-three papers, thirty-three of them coauthored with clinical colleagues.

In 1920, Van Slyke and his colleagues undertook a comprehensive investigation of gas and electrolyte equilibria in blood. McLean and Henderson at Harvard had made preliminary studies of blood as a physico-chemical system, but realized that Van Slyke and his colleagues at the Rockefeller Hospital had superior techniques and the facilities necessary for such an undertaking. A collaboration thereupon began between the two laboratories, which resulted in rapid progress toward an exact physico-chemical description of the role of hemoglobin in the transport of oxygen and carbon dioxide, of the distribution of diffusible ions and water between erythrocytes and plasma,
and of factors such as degree of oxygenation of hemoglobin and hydrogen ion concentration that modified these distributions. In this Van Slyke revised his volumetric gas analysis apparatus into a manometric method.  The manometric apparatus proved to give results that were from five to ten times more accurate.

A series of papers on the CO2 titration curves of oxy- and deoxyhemoglobin, of oxygenated and reduced whole blood, and of blood subjected to different degrees of oxygenation and on the distribution of diffusible ions in blood resulted.  These developed equations that predicted the change in distribution of water and diffusible ions between blood plasma and blood cells when there was a change in pH of the oxygenated blood. A significant contribution of Van Slyke and his colleagues was the application of the Gibbs-Donnan Law to the blood—regarded as a two-phase system, in which one phase (the erythrocytes) contained a high concentration of nondiffusible negative ions, i.e., those associated with hemoglobin, and cations, which were not freely exchaThe importance of Vanngeable between cells and plasma. By changing the pH through varying the CO2 tension, the concentration of negative hemoglobin charges changed in a predictable amount. This, in turn, changed the distribution of diffusible anions such as Cl” and HCO3″ in order to restore the Gibbs-Donnan equilibrium. Redistribution of water occurred to restore osmotic equilibrium. The experimental results confirmed the predictions of the equations.

As a spin-off from the physico-chemical study of the blood, Van undertook, in 1922, to put the concept of buffer value of weak electrolytes on a mathematically exact basis.
This proved to be useful in determining buffer values of mixed, polyvalent, and amphoteric electrolytes, and put the understanding of buffering on a quantitative basis. A
monograph in Medicine entitled “Observation on the Courses of Different Types of Bright’s Disease, and on the Resultant Changes in Renal Anatomy,” was a landmark that
related the changes occurring at different stages of renal deterioration to the quantitative changes taking place in kidney function. During this period, Van Slyke and R. M. Archibald identified glutamine as the source of urinary ammonia. During World War II, Van and his colleagues documented the effect of shock on renal function and, with R. A. Phillips, developed a simple method, based on specific gravity, suitable for use in the field.

Over 100 of Van’s 300 publications were devoted to methodology. The importance of Van Slyke’s contribution to clinical chemical methodology cannot be overestimated.
These included the blood organic constituents (carbohydrates, fats, proteins, amino acids, urea, nonprotein nitrogen, and phospholipids) and the inorganic constituents (total cations, calcium, chlorides, phosphate, and the gases carbon dioxide, carbon monoxide, and nitrogen). It was said that a Van Slyke manometric apparatus was almost all the special equipment needed to perform most of the clinical chemical analyses customarily performed prior to the introduction of photocolorimeters and spectrophotometers for such determinations.

The progress made in the medical sciences in genetics, immunology, endocrinology, and antibiotics during the second half of the twentieth century obscures at times the progress that was made in basic and necessary biochemical knowledge during the first half. Methods capable of giving accurate quantitative chemical information on biological material had to be painstakingly devised; basic questions on chemical behavior and metabolism had to be answered; and, finally, those factors that adversely modified the normal chemical reactions in the body so that abnormal conditions arise that we characterize as disease states had to be identified.

Viewed in retrospect, he combined in one scientific lifetime (1) basic contributions to the chemistry of body constituents and their chemical behavior in the body, (2) a chemical understanding of physiological functions of certain organ systems (notably the respiratory and renal), and (3) how such information could be exploited in the
understanding and treatment of disease. That outstanding additions to knowledge in all three categories were possible was in large measure due to his sound and broadly based chemical preparation, his ingenuity in devising means of accurate measurements of chemical constituents, and the opportunity given him at the Hospital of the Rockefeller Institute to study disease in company with physicians.

In addition, he found time to work collaboratively with Dr. John P. Peters of Yale on the classic, two-volume Quantitative Clinical Chemistry. In 1922, John P. Peters, who had just gone to Yale from Van Slyke’s laboratory as an Associate Professor of Medicine, was asked by a publisher to write a modest handbook for clinicians describing useful chemical methods and discussing their application to clinical problems. It was originally to be called “Quantitative Chemistry in Clinical Medicine.” He soon found that it was going to be a bigger job than he could handle alone and asked Van Slyke to join him in writing it. Van agreed, and the two men proceeded to draw up an outline and divide up the writing of the first drafts of the chapters between them. They also agreed to exchange each chapter until it met the satisfaction of both.At the time it was published in 1931, it contained practically all that could be stated with confidence about those aspects of disease that could be and had been studied by chemical means. It was widely accepted throughout the medical world as the “Bible” of quantitative clinical chemistry, and to this day some of the chapters have not become outdated.

History of Laboratory Medicine at Yale University.

The roots of the Department of Laboratory Medicine at Yale can be traced back to John Peters, the head of what he called the “Chemical Division” of the Department of Internal Medicine, subsequently known as the Section of Metabolism, who co-authored with Donald Van Slyke the landmark 1931 textbook Quantitative Clinical Chemistry (2.3); and to Pauline Hald, research collaborator of Dr. Peters who subsequently served as Director of Clinical Chemistry at Yale-New Haven Hospital for many years. In 1947, Miss Hald reported the very first flame photometric measurements of sodium and potassium in serum (4). This study helped to lay the foundation for modern studies of metabolism and their application to clinical care.

The Laboratory Medicine program at Yale had its inception in 1958 as a section of Internal Medicine under the leadership of David Seligson. In 1965, Laboratory Medicine achieved autonomous section status and in 1971, became a full-fledged academic department. Dr. Seligson, who served as the first Chair, pioneered modern automation and computerized data processing in the clinical laboratory. In particular, he demonstrated the feasibility of discrete sample handling for automation that is now the basis of virtually all automated chemistry analyzers. In addition, Seligson and Zetner demonstrated the first clinical use of atomic absorption spectrophotometry. He was one of the founding members of the major Laboratory Medicine academic society, the Academy of Clinical Laboratory Physicians and Scientists.

Davenport fig 10.jpg

Case in Point 3.  Nathan Gochman.  Developer of Automated Chemistries.

Nathan Gochman, PhD, has over 40 years of experience in the clinical diagnostics industry. This includes academic teaching and research, and 30 years in the pharmaceutical and in vitro diagnostics industry. He has managed R & D, technical marketing and technical support departments. As a leader in the industry he was President of the American Association for Clinical Chemistry (AACC) and the National Committee for Clinical Laboratory Standards (NCCLS, now CLSI). He is currently a Consultant to investment firms and IVD companies.

Nathan Gochman

Nathan Gochman

The clinical laboratory has become so productive, particularly in chemistry and immunology, and the labor, instrument and reagent costs are well determined, that today a physician’s medical decisions are 80% determined by the clinical laboratory.  Medical information systems have lagged far behind.  Why is that?  Because the decision for a MIS has historical been based on billing capture.  Moreover, the historical use of chemical profiles were quite good at validating healthy dtatus in an outpatient population, but the profiles became restricted under Diagnostic Related Groups.    Thus, it came to be that the diagnostics was considered a “commodity”.  In order to be competitive, a laboratory had to provide “high complexity” tests that were drawn in by a large volume of “moderate complexity”tests.

Part 3. Biomarkers in Medical Practice

Case in Point 1.

A Solid Prognostic Biomarker

HDL-C: Target of Therapy or Fuggedaboutit?

Steven E. Nissen, MD, MACC, Peter Libby, MD

DisclosuresNovember 06, 2014

Steven E. Nissen, MD, MACC: I am Steve Nissen, chairman of the Department of Cardiovascular Medicine at the Cleveland Clinic. I am here with Dr Peter Libby, chief of cardiology at the Brigham and Women’s Hospital and professor of medicine at Harvard Medical School. We are going to discuss high-density lipoprotein cholesterol (HDL-C), a topic that has been very controversial recently. Peter, HDL-C has been a pretty good biomarker. The question is whether it is a good target.

Peter Libby, MD: Since the early days in Berkley, when they were doing ultracentrifugation, and when it was reinforced and put on the map by the Framingham Study,[1] we have known that HDL-C is an extremely good biomarker of prospective cardiovascular risk with an inverse relationship with all kinds of cardiovascular events. That is as solid a finding as you can get in observational epidemiology. It is a very reliable prospective marker. It’s natural that the pharmaceutical industry and those of us who are interested in risk reduction would focus on HDL-C as a target. That is where the controversies come in.

Dr Nissen: It has been difficult. My view is that the trials that have attempted to modulate HDL-C or the drugs they used have been flawed. Although the results have not been promising, the jury is yet out. Torcetrapib, the cholesteryl ester transfer protein (CETP) inhibitor developed by Pfizer, had anoff-target toxicity.[2] Niacin is not very effective, and there are a lot of downsides to the drug. That has been an issue, but people are still working on this. We have done some studies. We did our ApoA-1 Milano infusion study[3]about a decade ago, which showed very promising results with respect to shrinking plaques in coronary arteries. I remain open to the possibility that the right drug in the right trial will work.

Dr Libby: What do you do with the genetic data that have come out in the past couple of years? Sekar Kathiresan masterminded and organized an enormous collaboration[4] in which they looked, with contemporary genetics, at whether HDL had the genetic markers of being a causal risk factor. They came up empty-handed.

Dr Nissen: I am cautious about interpreting those data, like I am cautious about interpreting animal studies of atherosclerosis. We have both lived through this problem in which something works extremely well in animals but doesn’t work in humans, or it doesn’t work in animals but it works in humans. The genetic studies don’t seal the fate of HDL. I have an open mind about this. Drugs are complex. They work by complex mechanisms. It is my belief that what we have to do is test these hypotheses in well-designed clinical trials, which are rigorously performed with drugs that are clean—unlike torcetrapib—and don’t have off-target toxicities.

An Unmet Need: High Lp(a) Levels

Dr Nissen: I’m going to push back on that and make a couple of points. The HPS2-THRIVE study was flawed. They studied the wrong people. It was not a good study, and AIM-HIGH[8] was underpowered. I am not putting people on niacin. What do you do with a patient whose Lp(a) is 200 mg/dL?

Dr Libby: I’m waiting for the results of the PCSK9 and anacetrapib studies. You can tell me about evacetrapib.[9]Reducing Lp(a) is an unmet medical need. We both care for kindreds with high Lp(a) levels and premature coronary artery disease. We have no idea what to do with them other than to treat them with statins and lower their LDL-C levels.

Dr Nissen: I have taken a more cautious approach with respect to taking people off of niacin. If I have patients who are doing well and tolerating it (depending on why it was started), I am discontinuing niacin in some people. I am starting very few people on the drug, but I worry about the quality of the trial.

Dr Libby: So you are of the “don’t start don’t stop” school?

Dr Nissen: Yes. It’s difficult when the trial is fatally flawed. There were 11,000 patients from China in this study. I have known for years that if you give niacin to people of Asiatic ethnic descent, they have terrible flushing and they won’t continue the drug. One question is, what was the adherence? The adverse events would have been tolerable had there been efficacy. The concern here is that this study was destined to fail because they studied a low LDL/high HDL population, a group of people for whom niacin just isn’t used.

Triglycerides and HDL: Do We Have It Backwards?

Dr Libby: What about the recent genetic[10] and epidemiologic data that support triglycerides, and apolipoprotein C3 in particular as a causal risk factor? Have we been misled through all of the generations in whom we have been adjusting triglycerides for HDL-C and saying that triglycerides are not a causal risk factor because once we adjust for HDL, the risk goes away? Do you think we got it backwards?

Dr Nissen: The tricky factor here is that because of this intimate inverse relationship between triglycerides and HDL, we may be talking about the same phenomenon. That is one of the reasons that I am not certain we are not going to be able to find a therapy. What if you had a therapy that lowered triglycerides and raised HDL-C? Could that work? Could that combination be favorable? I want answers from rigorous, well-designed clinical trials that ask the right questions in the right populations. I am disappointed, just as I have been disappointed by the fibrate trials.[11,12] There is a class of drugs that raises HDL-C a little and lowers triglycerides a lot.

Dr Nissen: But the gemfibrozil studies (VA-HIT[13] and Helsinki Heart[14]) showed benefit.

The Dyslipidemia Bar Has Been Raised

Dr Libby: Those studies were from the pre-statin era. We both were involved in trials in which patients were on high-dose statins at baseline. Do you think that this is too high a bar?

Dr Nissen: The bar has been raised, and for the pharmaceutical industry, the studies that we need to find out whether lowering triglycerides or raising HDL is beneficial are going to be large. We are doing a study with evacetrapib. It has 12,000 patients. It’s fully enrolled. Evacetrapib is a very clean-looking drug. It doesn’t have such a long biological half-life as anacetrapib, so I am very encouraged that it won’t have that baggage of being around for 2-4 years. We’ve got a couple of shots on goal here. Don’t forget that we have multiple ongoing studies of HDL-C infusion therapies that are still under development. Those have some promise too. The jury is still out.

Dr Libby: We agree on the need to do rigorous, large-scale endpoint trials. Do the biomarker studies, but don’t wait to start the endpoint trial because that’s the proof in the pudding.

Dr Nissen: Exactly. We have had a little controversy about HDL-C. We often agree, but not always, and we may have a different perspective. Thanks for joining me in this interesting discussion of what will continue to be a controversial topic for the next several years until we get the results of the current ongoing trials.

Case in Point 2.

NSTEMI? Honesty in Coding and Communication?

Melissa Walton-Shirley

November 07, 2014

The complaint at ER triage: Weakness, fatigue, near syncope of several days’ duration, vomiting, and decreased sensorium.

The findings: O2sat: 88% on room air. BP: 88 systolic. Telemetry: Sinus tachycardia 120 bpm. Blood sugar: 500 mg/dL. Chest X ray: atelectasis. Urinalysis: pyuria. ECG: T-wave-inversion anterior leads. Echocardiography: normal left ventricular ejection fraction (LVEF) and wall motion. Troponin I: 0.3 ng/mL. CT angiography: negative for pulmonary embolism (PE). White blood cell count: 20K with left shift. Blood cultures: positive for Gram-negative rods.

The treatment: Intravenous fluids and IV levofloxacin—changed to ciprofloxacin.

The communication at discharge: “You had a severe urinary-tract infection and grew bacteria in your bloodstream. Also, you’ve had a slight heart attack. See your cardiologist immediately upon discharge-no more than 5 days from now.”

The diagnoses coded at discharge: Urosepsis and non-ST segment elevation MI (NSTEMI) 410.1.

One year earlier: This moderately obese patient was referred to our practice for a preoperative risk assessment. The surgery planned was a technically simple procedure, but due to the need for precise instrumentation, general endotracheal anesthesia (GETA) was being considered. The patient was diabetic, overweight, and short of air. A stress exam was equivocal for CAD due to poor exercise tolerance and suboptimal imaging. Upon further discussion, symptoms were progressive; therefore, cardiac cath was recommended, revealing angiographically normal coronaries and a predictably elevated left ventricular end diastolic pressure (LVEDP) in the mid-20s range. The patient was given a diagnosis of diastolic dysfunction, a prescription for better hypertension control, and in-depth discussion on exercise and the Mediterranean and DASH diets for weight loss. Symptoms improved with a low dose of diuretic. The surgery was completed without difficulty. Upon follow-up visit, the patient felt well, had lost a few pounds, and blood pressure was well controlled.

Five days after ER workup: While out of town, the patient developed profound weakness and went to the ER as described above. Fast forward to our office visit in the designated time frame of “no longer than 5 days’ postdischarge,” where the patient and family asked me about the “slight heart attack” that literally came on the heels of a normal coronary angiogram.

But the patient really didn’t have a “heart attack,” did they? The cardiologist aptly stated that it was likely nonspecific troponin I leak in his progress notes. Yet the hospitalist framed the diagnosis of NSTEMI as item number 2 in the final diagnoses.

The motivations on behalf of personnel who code charts are largely innocent and likely a direct result of the lack of understanding of the coding system on behalf of us as healthcare providers. I have a feeling, though, that hospitals aren’t anxious to correct this misperception, due to an opportunity for increased reimbursement. I contacted a director of a coding department for a large hospital who prefers to remain anonymous. She explained that NSTEMI ICD9 code 410.1 falls in DRG 282 with a weight of .7562. The diagnosis of “demand ischemia,” code 411.89, a slightly less inappropriate code for a nonspecific troponin I leak, falls in DRG 311 with a weight of .5662. To determine reimbursement, one must multiply the weight by the average hospital Medicare base rate of $5370. Keep in mind that each hospital’s base rate and corresponding payment will vary. The difference in reimbursement for a large hospital bill between these two choices for coding is substantial, at over $1000 difference ($4060 vs $3040).

Although hospitals that are already reeling from shrinking revenues will make more money on the front end by coding the troponin leak incorrectly as an NSTEMI, when multiple unnecessary tests are generated to follow up on a nondiagnostic troponin leak, the amount of available Centers for Medicare & Medicaid Services (CMS) reimbursement pie shrinks in the long run. Furthermore, this inappropriate categorization generates extreme concern on behalf of patients and family members that is often never laid to rest. The emotional toll of a “heart-attack” diagnosis has an impact on work fitness, quality of life, cost of medication, and the cost of future testing. If the patient lived for another 100 years, they will likely still list a “heart attack” in their medical history.

As a cardiologist, I resent the loose utilization of one of “my” heart-attack codes when it wasn’t that at all. At discharge, we need to develop a better way of communicating what exactly did happen. Equally important, we need to communicate what exactly didn’t happen as well.

Case in Point 3.

Blood Markers Predict CKD Heart Failure 

Published: Oct 3, 2014 | Updated: Oct 3, 2014

Elevated levels of high-sensitivity troponin T (hsTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) strongly predicted heart failure in patients with chronic kidney disease followed for a median of close to 6 years, researchers reported.

Compared with patients with the lowest blood levels of hsTnT, those with the highest had a nearly five-fold higher risk for developing heart failure and the risk was 10-fold higher in patients with the highest NT-proBNP levels compared with those with the lowest levels of the protein, researcher Nisha Bansal, MD, of the University of Washington in Seattle, and colleagues wrote online in the Journal of the American Society of Nephrology.

A separate study, published online in theJournal of the American Medical Association earlier in the week, also examined the comorbid conditions of heart and kidney disease, finding no benefit to the practice of treating cardiac surgery patients who developed acute kidney injury with infusions of the antihypertensive drug fenoldopam.

The study, reported by researcher Giovanni Landoni, MD, of the IRCCS San Raffaele Scientific Institute, Milan, Italy, and colleagues, was stopped early “for futility,” according to the authors, and the incidence of hypotension during drug infusion was significantly higher in patients infused with fenoldopam than placebo (26% vs. 15%; P=0.001).

Blood Markers Predict CKD Heart Failure

The study in patients with mild to moderate chronic kidney disease (CKD) was conducted to determine if blood markers could help identify patients at high risk for developing heart failure.

Heart failure is the most common cardiovascular complication among people with renal disease, occurring in about a quarter of CKD patients.

The two markers, hsTnT and NT-proBNP, are associated with overworked cardiac myocytes and have been shown to predict heart failure in the general population.

However, Bansal and colleagues noted, the markers have not been widely used in diagnosing heart failure among patients with CKD due to concerns that reduced renal excretion may raise levels of these markers, and therefore do not reflect an actual increase in heart muscle strain.

To better understand the importance of elevated concentrations of hsTnT and NT-proBNP in CKD patients, the researchers examined their association with incident heart failure events in 3,483 participants in the ongoing observational Chronic Renal Insufficiency Cohort (CRIC) study.

All participants were recruited from June 2003 to August 2008, and all were free of heart failure at baseline. The researchers used Cox regression to examine the association of baseline levels of hsTnT and NT-proBNP with incident heart failure after adjustment for demographic influences, traditional cardiovascular risk factors, makers of kidney disease, pertinent medication use, and mineral metabolism markers.

At baseline, hsTnT levels ranged from ≤5.0 to 378.7 pg/mL and NT-proBNP levels ranged from ≤5 to 35,000 pg/mL. Compared with patients who had undetectable hsTnT, those in the highest quartile (>26.5 ng/mL) had a significantly higher rate of heart failure (hazard ratio 4.77; 95% CI 2.49-9.14).

Compared with those in the lowest NT-proBNP quintile (<47.6 ng/mL), patients in the highest quintile (>433.0 ng/mL) experienced an almost 10-fold increase in heart failure risk (HR 9.57; 95% CI 4.40-20.83).

The researchers noted that these associations remained robust after adjustment for potential confounders and for the other biomarker, suggesting that while hsTnT and NT-proBNP are complementary, they may be indicative of distinct biological pathways for heart failure.

Even Modest Increases in NP-proBNP Linked to Heart Failure

The findings are consistent with an earlier analysis that included 8,000 patients with albuminuria in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study, which showed that hsTnT was associated with incident cardiovascular events, even after adjustment for eGFR and severity of albuminuria.

“Among participants in the CRIC study, those with the highest quartile of detectable hsTnT had a twofold higher odds of left ventricular hypertrophy compared with those in the lowest quartile,” Bansal and colleagues wrote, adding that the findings were similar after excluding participants with any cardiovascular disease at baseline.

Even modest elevations in NT-proBNP were associated with significantly increased rates of heart failure, including in subgroups stratified by eGFR, proteinuria, and diabetic status.

“NT-proBNP regulates blood pressure and body fluid volume by its natriuretic and diuretic actions, arterial dilation, and inhibition of the renin-aldosterone-angiotensin system and increased levels of this marker likely reflect myocardial stress induced by subclinical changes in volume or pressure, even in persons without clinical disease,” the researchers wrote.

The researchers concluded that further studies are needed to develop and validate risk prediction tools for clinical heart failure in patients with CKD, and to determine the potential role of these two biomarkers in a heart failure risk prediction and prevention strategy.

Fenoldopam ‘Widely Promoted’ in AKI Cardiac Surgery Setting

The JAMA study examined whether the selective dopamine receptor D agonist fenoldopam mesylate can reduce the need for dialysis in cardiac surgery patients who develop acute kidney injury (AKI).

Fenoldopam induces vasodilation of the renal, mesenteric, peripheral, and coronary arteries, and, unlike dopamine, it has no significant affinity for D2 receptors, meaning that it theoretically induces greater vasodilation in the renal medulla than in the cortex, the researchers wrote.

“Because of these hemodynamic effects, fenoldopam has been widely promoted for the prevention and therapy of AKI in the United States and many other countries with apparent favorable results in cardiac surgery and other settings,” Landoni and colleagues wrote.

The drug was approved in 1997 by the FDA for the indication of in-hospital, short-term management of severe hypertension. It has not been approved for renal indications, but is commonly used off-label in cardiac surgery patients who develop AKI.

Although a meta analysis of randomized trials, conducted by the researchers, indicated a reduction in the incidence and progression of AKI associated with the treatment, Landoni and colleagues wrote that the absence of a definitive trial “leaves clinicians uncertain as to whether fenoldopam should be prescribed after cardiac surgery to prevent deterioration in renal function.”

To address this uncertainty, the researchers conducted a prospective, randomized, parallel-group trial in 667 patients treated at 19 hospitals in Italy from March 2008 to April 2013.

All patients had been admitted to ICUs after cardiac surgery with early acute kidney injury (≥50% increase of serum creatinine level from baseline or low output of urine for ≥6 hours). A total of 338 received fenoldopam by continuous intravenous infusion for a total of 96 hours or until ICU discharge, while 329 patients received saline infusions.

The primary end point was the rate of renal replacement therapy, and secondary end points included mortality (intensive care unit and 30-day mortality) and the rate of hypotension during study drug infusion.

Study Showed No Benefit, Was Stopped Early

Yale Lampoon – AA Liebow.   1954

Not As a Doctor
[Fourth Year]

These lyrics, sung by John Cole, Jack Gariepy and Ed Ransenhofer to music borrowed from Gilbert and Sullivan’s The Mikado, lampooned Averill Liebow, M.D., a pathologist noted for his demands on students. (CPC stands for clinical pathology conference.)

If you want to know what this is,
it’s a medical CPC
Where we give the house staff
the biz, for there’s no one so
wise as we!
We pathologists show them how,
Although it is too late now.
Our art is a sacred cow!

American physician, born 1911, Stryj in Galicia, Austria (now in Ukraine); died 1978.

Averill Abraham Liebow, born in Austria, was the “founding father” of pulmonary pathology in the United States. He started his career as a pathologist at Yale, where he remained for many years. In 1968 he moved to the University of California School of Medicine, San Diego, where he taught for 7 years as Professor and Chairman, Department of Pathology.

His studies include many classic studies of lung diseases. Best known of these is his famous classification of interstitial lung disease. He also published papers on sclerosing pneumocytoma, pulmonary alveolar proteinosis, meningothelial-like nodules, pulmonary hypertension, pulmonary veno-occlusive disease, lymphomatoid granulomatosis, pulmonary Langerhans cell histiocytosis, pulmonary epithelioid hemangioendothelioma and pulmonary hyalinizing granuloma .

As a Lieutenant Colonel in the US Army Medical Corps, He was a member of the Atomic Bomb Casualty Commission who studied the effects of the atomic bomb in Hiroshima and Nagasaki.

We thank Sanjay Mukhopadhyay, M.D., for information submitted.

As a resident at UCSD, Dr. Liebow held “Organ Recitals” every morning, including Mother’s day.  The organs had to be presented in specified order… heart, lung, and so forth.  On one occasion, we needed a heart for purification of human lactate dehydrogenase for a medical student project, so I presented the lung out of order.  Dr. Liebow asked where the heart was, and I told the group it was noprmal and I froze it for enzyme purification (smiles).  In the future show it to me first. He was generous to those who showed interest.  As I was also doing research in Nathan Kaplan’s laboratory, he made special arrangements for me to mentor Deborah Peters, the daughter of a pulmonary physician, and granddaughter of the Peters who collaborated with Van Slyke.  I mentored many students with great reward since then.  He could look at a slide and tell you what the x-ray looked like.  I didn’t encounter that again until he sent me to the Armed Forces Institute of Pathology, Washington, DC during the Vietnam War and Watergate, and I worked in Orthopedic Pathology with Lent C. Johnson.  He would not review a case without the x-ray, and he taught the radiologists.

Part 3

My Cancer Genome from Vanderbilt University: Matching Tumor Mutations to Therapies & Clinical Trials

Reporter: Aviva Lev-Ari, PhD, RN

GenomOncology and Vanderbilt-Ingram Cancer Center (VICC) today announced a partnership for the exclusive commercial development of a decision support tool based on My Cancer Genome™, an online precision cancer medicine knowledge resource for physicians, patients, caregivers and researchers.

Through this collaboration, GenomOncology and VICC will enhance My Cancer Genome through the development of a new genomics content management tool. The MyCancerGenome.org website will remain free and open to the public. In addition, GenomOncology will develop a decision support tool based on My Cancer Genome™ data that will enable automated interpretation of mutations in the genome of a patient’s tumor, providing actionable results in hours versus days.

Vanderbilt-Ingram Cancer Center (VICC) launched My Cancer Genome™ in January 2011 as an integral part of their Personalized Cancer Medicine Initiative that helps physicians and researchers track the latest developments in precision cancer medicine and connect with clinical research trials. This web-based information tool is designed to quickly educate clinicians on the rapidly expanding list of genetic mutations that impact cancers and enable the research of treatment options based on specific mutations. For more information on My Cancer Genome™visit www.mycancergenome.org/about/what-is-my-cancer-genome.

Therapies based on the specific genetic alterations that underlie a patient’s cancer not only result in better outcomes but often have less adverse reactions

Up front fee

Nominal fee covers installation support, configuring the Workbench to your specification, designing and developing custom report(s) and training your team.

Per sample fee

GenomOncology is paid on signed-out clinical reports. This philosophy aligns GenomOncology with your Laboratory as we are incentivized to offer world-class support and solutions to differentiate your clinical NGS program. There is no annual license fee.

Part 4

Clinical Trial Services: Foundation Medicine & EmergingMed to Partner

Reporter: Aviva Lev-Ari, PhD, RN

Foundation Medicine and EmergingMed said today that they will partner to offer clinical trial navigation services for health care providers and their patients who have received one of Foundation Medicine’s tumor genomic profiling tests.

The firms will provide concierge services to help physicians

  • identify appropriate clinical trials for patients
  • based on the results of FoundationOne or FoundationOne Heme.

“By providing clinical trial navigation services, we aim to facilitate

  • timely and accurate clinical trial information and enrollment support services for physicians and patients,
  • enabling greater access to treatment options based on the unique genomic profile of a patient’s cancer

Currently, there are over 800 candidate therapies that target genomic alterations in clinical trials,

  • but “patients and physicians must identify and act on relevant options
  • when the patient’s clinical profile is aligned with the often short enrollment window for each trial.

These investigational therapies are an opportunity to engage patients with cancer whose cancer has progressed or returned following standard treatment in a most favorable second option after relapse.  The new service is unique in notifying when new clinical trials emerge that match a patient’s genomic and clinical profile.

Google signs on to Foundation Medicine cancer Dx by offering tests to employees

By Emily Wasserman

Diagnostics luminary Foundation Medicine ($FMI) is generating some upward momentum, fueled by growing revenues and the success of its clinical tests. Tech giant Google ($GOOG) has taken note and is signing onto the company’s cancer diagnostics by offering them to employees.

Foundation Medicine CEO Michael Pellini said during the company’s Q3 earnings call that Google will start covering its DNA tests for employees and their family members suffering from cancer as part of its health benefits portfolio, Reuters reports.

Both sides stand to benefit from the deal, as Google looks to keep a leg up on Silicon Valley competitors and Foundation Medicine expands its cancer diagnostics platform. Last month, Apple ($AAPL) and Facebook ($FB) announced that they would begin covering the cost of egg freezing for female employees. A diagnostics partnership and attractive health benefits could work wonders for Google’s employee retention rates and bottom line.

In the meantime, Cambridge, MA-based Foundation Medicine is charging full speed ahead with its cancer diagnostics platform after filing for an IPO in September 2013. The company chalked up 6,428 clinical tests during Q3 2014, an eye-popping 149% increase year over year, and brought in total revenue for the quarter of $16.4 million–a 100% leap from last year. Foundation Medicine credits the promising numbers in part to new diagnostic partnerships and extended coverage for its tests.

In January, the company teamed up with Novartis ($NVS) to help the drugmaker evaluate potential candidates for its cancer therapies. In April, Foundation Medicine announced that it would develop a companion diagnostic test for a Clovis Oncology ($CLVS) drug under development to treat patients with ovarian cancer, building on an ongoing collaboration between the two companies.

Foundation Medicine also has its sights set on China’s growing diagnostics market, inking a deal in October with WuXi PharmaTech ($WX) that allows the company to perform lab testing for its FoundationOne assay at WuXi’s Shanghai-based Genome Center.

a nod to the deal with Google during a corporate earnings call on Wednesday, according to a person who listened in. Pellini said Google employees were made aware of this new benefit last week.

Foundation Medicine teams with MD Anderson for new trial of cancer Dx

Second study to see if targeted therapy can change patient outcomes

August 15, 2014 | By   FierceDiagnostics

Foundation Medicine ($FMI) is teaming up with the MD Anderson Cancer Center in Texas for a new trial of the the Cambridge, MA-based company’s molecular diagnostic cancer test that targets therapies matched to individual patients.

The study is called IMPACT2 (Initiative for Molecular Profiling and Advanced Cancer Therapy) and is designed to build on results from the the first IMPACT study that found

  • 40% of the 1,144 patients enrolled had an identifiable genomic alteration.

The company said that

  • by matching specific gene alterations to therapies,
  • 27% of patients in the first study responded versus
  • 5% with an unmatched treatment, and
  • “progression-free survival” was longer in the matched group.

The FoundationOne molecular diagnostic test

  • combines genetic sequencing and data gathering
  • to help oncologists choose the best treatment for individual patients.

Costing $5,800 per test, FoundationOne’s technology can uncover a large number of genetic alterations for 200 cancer-related genes,

  • blending genomic sequencing, information and clinical practice.

“Based on the IMPACT1 data, a validated, comprehensive profiling approach has already been adopted by many academic and community-based oncology practices,” Vincent Miller, chief medical officer of Foundation Medicine, said in a release. “This study has the potential to yield sufficient evidence necessary to support broader adoption across most newly diagnosed metastatic tumors.”

The company got a boost last month when the New York State Department of Health approved Foundation Medicine’s two initial cancer tests: the FoundationOne test and FoundationOne Heme, which creates a genetic profile for blood cancers. Typically,

  • diagnostics companies struggle to win insurance approval for their tests
  • even after they gain a regulatory approval, leaving revenue growth relatively flat.

However, Foundation Medicine reported earlier this week its Q2 revenue reached $14.5 million compared to $5.9 million for the same period a year ago. Still,

  1. net losses continue to soar as the company ramps up
  2. its commercial and business development operation,
  • hitting $13.7 million versus a $10.1 million deficit in the second quarter of 2013.


There has been a remarkable transformation in our understanding of

  • the molecular genetic basis of cancer and its treatment during the past decade or so.

In depth genetic and genomic analysis of cancers has revealed that

  • each cancer type can be sub-classified into many groups based on the genetic profiles and
  • this information can be used to develop new targeted therapies and treatment options for cancer patients.

This panel will explore the technologies that are facilitating our understanding of cancer, and

  • how this information is being used in novel approaches for clinical development and treatment.
Oncology _ Reprted by Dr. Aviva Lev-Ari, Founder, Leaders in Pharmaceutical Intelligence

Opening Speaker & Moderator:

Lynda Chin, M.D.
Department Chair, Department of Genomic Medicine
MD Anderson Cancer Center

  • Who pays for PM?
  • potential of Big data, analytics, Expert systems, so not each MD needs to see all cases, Profile disease to get same treatment
  • business model: IP, Discovery, sharing, ownership — yet accelerate therapy
  • security of healthcare data
  • segmentation of patient population
  • management of data and tracking innovations
  • platforms to be shared for innovations
  • study to be longitudinal,
  • How do we reconcile course of disease with PM
  • phinotyping the disease vs a Patient in wait for cure/treatment


Roy Herbst, M.D., Ph.D.
Ensign Professor of Medicine and Professor of Pharmacology;
Chief of Medical Oncology, Yale Cancer Center and Smilow Cancer Hospital

Development new drugs to match patient, disease and drug – finding the right patient for the right Clinical Trial

  • match patient to drugs
  • partnerships: out of 100 screened patients, 10 had the gene, 5 were able to attend the trial — without the biomarker — all 100 patients would participate for the WRONG drug for them (except the 5)
  • patients wants to participate in trials next to home NOT to have to travel — now it is in the protocol
  • Annotated Databases – clinical Trial informed consent – adaptive design of Clinical Trial vs protocol
  • even Academic MD can’t read the reports on Genomics
  • patients are treated in the community — more training to MDs
  • Five companies collaborating – comparison og 6 drugs in the same class
  • if drug exist and you have the patient — you must apply PM

Summary and Perspective:

The current changes in Biotechnology have been reviewed with an open question about the relationship of In Vitro Diagnostics to Biopharmaceuticals switching, with the potential, particularly in cancer and infectious diseases, to added value in targeted therapy by matching patients to the best potential treatment for a favorable outcome.

This reviewer does not see the movement of the major diagnostics leaders entering into the domain of direct patient care, even though there are signals in that direction.  The Roche example is perhaps the most interesting because Roche already became the elephant in the room after the introduction of Valium,  subsequently bought out Boehringer Mannheim Diagnostics to gain entry into the IVD market, and established a huge presence in Molecular Diagnostics early.  If it did anything to gain a foothold in the treatment realm, it would more likely forge a relationship with Foundation Medicine.  Abbott Laboratories more than a decade ago was overextended, and it had become the leader in IVD as a result of the specialty tests, but it fell into difficulties with quality control of its products in the high volume testing market, and acceeded to Olympus, Roche, and in the mid volume market to Beckman and Siemens.  Of course, Dupont and Kodak, pioneering companies in IVD, both left the market.

The biggest challenge in the long run is identified by the ability to eliminate many treatments that would be failures for a large number of patients. That has already met the proof of concept.  However, when you look at the size of the subgroups, we are not anywhere near a large scale endeavor.  In addition, there is a lot that has to be worked out that is not related to genomic expression by the “classic” model, but has to take into account the emrging knowledge and greater understanding of regulation of cell metabolism, not only in cancer, but also in chronic inflammatory diseases.

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The so-called “streetlight effect” has often fettered scientists who study complex hereditary diseases. The term refers to an old joke about a drunk searching for his lost keys under a streetlight. A cop asks, “Are you sure this is where you lost them?” The drunk says, “No, I lost them in the park, but the light is better here.”


For researchers who study the genetic roots of human diseases, most of the light has shone down on the 2 percent of the human genome that includes protein-coding DNA sequences. “That’s fine. Lots of diseases are caused by mutations there, but those mutations are low-hanging fruit,” says University of Toronto (U.T.) professor Brendan Frey who studies genetic networks. “They’re easy to find because the mutation actually changes one amino acid to another one, and that very much changes the protein.”


The trouble is, many disease-related mutations also happen in noncoding regions of the genome—the parts that do not directly make proteins but that still regulate how genes behave. Scientists have long been aware of how valuable it would be to analyze the other 98 percent but there has not been a practical way to do it.


Now Frey has developed a “deep-learning” machine algorithm that effectively shines a light on the entire genome. A paper appearing December 18 in Science describes how this algorithm can identify patterns of mutation across coding and noncoding DNA alike. The algorithm can also predict how likely each variant is to contribute to a given disease. “Our method works very differently from existing methods,” says Frey, the study’s lead author. “GWAS-, QTL- and ENCODE-type approaches can’t figure out causal relationships. They can only correlate. Our system can predict whether or not a mutation will cause a change in RNA splicing that could lead to a disease phenotype.”


RNA splicing is one of the major steps in turning genetic blueprints into living organisms. Splicing determines which bits of DNA code get included in the messenger-RNA strings that build proteins. Different configurations yield different proteins. Misregulated splicing contributes to an estimated 15 to 60 percent of human genetic diseases.


The combination of whole-genome analysis and predictive models for RNA splicing makes Frey’s method a major contribution to the field, according to Stephan Sanders, an assistant professor at the University of California, San Francisco, School of Medicine. “I’m looking forward to using this tool in larger data sets and really getting sense of how important splicing is,” he says. Sanders, who researches the genetic causes of diseases, notes Frey’s approach complements, rather than replaces, other methods of genetic analysis. “I think any genomist [sic] would agree that noncoding [areas of the genome] are hugely important. This method is a really novel way of getting at that,” he says.

Source: www.scientificamerican.com

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