Karl Link and Warfarin

Karl Paul Gerhard Link (31 January 1901 - 21 November 1978) was an American biochemist best known for his discovery of the anticoagulant warfarin.



In the subsequent years, most of his research focused on plant carbohydrates. However, the most fruitful period began when Ed Carson, a Wisconsin farmer, attracted Link's attention to sweet clover disease, described in 1924 by veterinarian Frank Schofield. In this condition, cows bled to death after consuming hay made from spoilt sweet clover. Carson's stock had been affected, and he brought a dead cow, blood that would not clot, and 100 pounds of sweet clover hay. Under the direction of Link, PhD students Harold Campbell, Ralph Overman, Charles Huebner, and Mark Stahmann crystallised the putative poison - a coumarin - and synthetised and tested it; it turned out to be dicumarol (3,3'-methylenebis-(4 hydroxycoumarin)).



Dicumarol was subjected to clinical trials in Wisconsin General Hospital and the Mayo Clinic. It was for several years the most popular oral anticoagulant.


Warfarin, one of the several compounds synthesised as part of the coumarin research, was patented in 1945 with the Wisconsin Alumni Research Foundation, Link and researchers Stahlmann and Ikawa jointly owning the patent. Initially marketed as rat poison, warfarin would later, in the 1950s, become the second most important anticoagulant for clinical use (after heparin).

Neisser and the flow of seed

Neisseria gonorrhoeae, a gram-negative intracellular diplococci, was identified in 1879 by the German physician, Albert Neisser, and is the causative agent of gonorrhea, one of the oldest recognized sexually transmitted diseases.

The term "gonorrhea" is derived from the Greek language and literally means "flow of seed"; this term was used to describe the white milky appearance of the purulent urethral discharge, which was mistaken for semen.


Neisser was also the co-discoverer of the causative agent of leprosy. In 1879 the Norwegian physician Gerhard Armauer Hansen gave to young Neisser (who had visited him in Norway to examine some 100 leprosy patients) some tissue samples of his patients. Neisser successfully stained the bacteria and announced his findings in 1880, claiming to have discovered the pathogenesis of leprosy. There was some conflict between Neisser and Hansen, because Hansen had failed to culture the organism and demonstrate unequivocally its link to leprosy, although he had observed the bacterium since 1872.

Charles Richard Drew and Blood Transfusion

Charles Richard Drew (3 June 1904 – 1 April 1950) was an African-American physician, surgeon and medical researcher. He researched in the field of blood transfusions, developing improved techniques for blood storage, and applied his expert knowledge to developing large-scale blood banks early in World War II. This allowed medics to save thousands of lives of the Allied forces. The research and development aspect of his blood storage work is disputed. Drew protested against the practice of racial segregation in the donation of blood, as it lacked scientific foundation, an action which cost him his job. In 1943, Drew's distinction in his profession was recognized when he became the first black surgeon selected to serve as an examiner on the American Board of Surgery.

In late 1940, during World War II before the US entered the war, and just after earning his doctorate, Drew was recruited by John Scudder to help set up and administer an early prototype program for blood storage and preservation. He was to collect, test, and transport large quantities of blood plasma for distribution in Great Britain. Drew went to New York to direct the United States' Blood for Britain project. The Blood for Britain project was a project to aid British soldiers and civilians by giving US blood to Great Britain.

Drew created a central location for the blood collection process where donors could go to give blood. He made sure all blood plasma was tested before it was shipped out. He ensured that only skilled personnel handled blood plasma to avoid the possibility of contamination. The Blood for Britain program operated successfully for five months, with total collections of almost 15,000 people donating blood, and with over 5,500 vials of blood plasma. As a result, the Blood Transfusion Betterment Association applauded Drew for his work

Robert Edwards - Nobel '10

The Nobel Prize in physiology or medicine has been awarded this year to Robert G. Edwards, an English biologist who, with a physician colleague, Patrick Steptoe, developed the in vitro fertilization procedure for treating human infertility.

Since the birth of the first test tube baby, Louise Brown, on July 25, 1978, some four million babies worldwide have been conceived by mixing eggs and sperm outside the body and returning the embryo to the womb to resume development. The procedure overcomes many previously untreatable causes of infertility.

Dr. Edwards, a physiologist who spent much of his career at Cambridge University in England, spent more than 20 years solving a series of problems in getting eggs and sperm to mature and successfully unite outside the body. His colleague, Dr. Steptoe, was a gynecologist and pioneer of laparoscopic surgery, the method used to extract eggs from the prospective mother.

Dr. Steptoe, who presumably would otherwise have shared the prize, died in 1988. Dr. Edwards, who born in 1925, has now retired as head of research from the Bourn Hall Clinic in Cambridge, which he and Dr. Steptoe founded as the world’s first center for in vitro fertilization.

Though in vitro fertilization is now widely accepted, the birth of the first test tube baby was greeted with intense concern that the moral order was subverted by unnatural intervention in the mysterious process of creating a human being. Dr. Edwards was well aware of the ethical issues raised by his research and took the lead in addressing them.

The objections gradually died away, except on the part of the Roman Catholic Church, as it became clear that the babies born by in vitro fertilization were healthy and that their parents were overjoyed to be able to start a family. Long-term follow-ups have confirmed the essential safety of the technique.

The deliberations of the prize-giving committee at the Karolinksa Institute in Sweden are confidential, and it is unclear why it took so long to acknowledge Dr. Edwards’s achievement. The committee routinely ignores the stipulation in Alfred Nobel’s will that the prize should be awarded for a discovery made the preceding year, because it takes longer than that to evaluate most scientific claims, but delays of 30 years or more are unusual. The Lasker Foundation in New York, whose jurors often anticipate the Nobel Prize committee, awarded Dr. Edwards its prize in 2001.

Dr. Edwards’s research proved too controversial for the Medical Research Council, a government financng agency that is the British equivalent of the National Institutes of Health. In 1971 the council rejected an application from Dr. Edwards and Dr. Steptoe to work on in vitro fertilization, but they were able to continue with private funds.

“In retrospect, it is amazing that Edwards not only was able to respond to the continued criticism of in vitro fertilization, but that he also remained so persistent and unperturbed in fulfilling his scientific vision,” Christer Höög, a member of the Nobel Prize committee, writes on the Nobel Foundation’s Web page.

Image: Lesley and Louise Brown with her son Cameron and Professor Robert Edwards

Read more at http://www.nytimes.com/2010/10/05/health/research/05nobel.html?ref=global-home

The Belmont Report

The Belmont Report is a report created by the former United States Department of Health, Education, and Welfare (which was renamed to Health and Human Services) entitled "Ethical Principles and Guidelines for the Protection of Human Subjects of Research," authored by Dan Harms, and is an important historical document in the field of medical ethics. The report was created on April 18, 1979 and gets its name from the Belmont Conference Center where the document was drafted. The conference center, once a part of the Smithsonian Institution, is in Elkridge, Maryland, 10 miles south of Baltimore, and is now operated by Howard Community College.

The Tuskegee Syphilis Study

The Tuskegee syphilis experiment (also known as the Tuskegee syphilis study or Public Health Service syphilis study) was a clinical study conducted between 1932 and 1972 in Tuskegee, Alabama, by the U.S. Public Health Service. Investigators recruited 399 impoverished African-American sharecroppers with syphilis for research related to the natural progression of the untreated disease, in hopes of justifying treatment programs for blacks.

The 40-year study was controversial for reasons related to ethical standards, primarily because researchers failed to treat patients appropriately after the 1940s validation of penicillin as an effective cure for the disease. Revelation of study failures led to major changes in U.S. law and regulation on the protection of participants in clinical studies. Now studies require informed consent (with exceptions possible for U.S. Federal agencies which can be kept secret by Executive Order), communication of diagnosis, and accurate reporting of test results.

By 1947 penicillin had become the standard treatment for syphilis. Choices might have included treating all syphilitic subjects and closing the study, or splitting off a control group for testing with penicillin. Instead, the Tuskegee scientists continued the study, withholding penicillin and information about it from the patients. In addition, scientists prevented participants from accessing syphilis treatment programs available to others in the area. The study continued, under numerous supervisors, until 1972, when a leak to the press resulted in its termination. Victims included numerous men who died of syphilis, wives who contracted the disease, and children born with congenital syphilis.

The Tuskegee Syphilis Study, cited as "arguably the most infamous biomedical research study in U.S. history,"led to the 1979 Belmont Report and the establishment of the Office for Human Research Protections (OHRP).It also led to federal regulation requiring Institutional Review Boards for protection of human subjects in studies involving human subjects. The Office for Human Research Protections (OHRP) manages this responsibility within the US Department of Health and Human Services (HHS).

Gram Stain

Gram stain of mixed Stap aureus (Gram positive cocci) and E. coli (Gram negative bacilli)

The Gram staining method, named after the Danish bacteriologist who originally devised it in 1882 (published 1884), Hans Christian Gram, is one of the most important staining techniques in microbiology. It is almost always the first test performed for the identification of bacteria. The primary stain of the Gram's method is crystal violet. Crystal violet is sometimes substituted with methylene blue, which is equally effective. The microorganisms that retain the crystal violet-iodine complex appear purple brown under microscopic examination. These microorganisms that are stained by the Gram's method are commonly classified as Gram-positive or Gram non-negative. Others that are not stained by crystal violet are referred to as Gram negative, and appear red.

Gram staining is based on the ability of bacteria cell wall to retaining the crystal violet dye during solvent treatment. The cell walls for Gram-positive microorganisms have a higher peptidoglycan and lower lipid content than gram-negative bacteria. Bacteria cell walls are stained by the crystal violet. Iodine is subsequently added as a mordant to form the crystal violet-iodine complex so that the dye cannot be removed easily. This step is commonly referred to as fixing the dye. However, subsequent treatment with a decolorizer, which is a mixed solvent of ethanol and acetone, dissolves the lipid layer from the gram-negative cells. The removal of the lipid layer enhances the leaching of the primary stain from the cells into the surrounding solvent. In contrast, the solvent dehydrates the thicker Gram-positive cell walls, closing the pores as the cell wall shrinks during dehydration. As a result, the diffusion of the violet-iodine complex is blocked, and the bacteria remain stained. The length of the decolorization is critical in differentiating the gram-positive bacteria from the gram-negative bacteria. A prolonged exposure to the decolorizing agent will remove all the stain from both types of bacteria. Some Gram-positive bacteria may lose the stain easily and therefore appear as a mixture of Gram-positive and Gram-negative bacteria (Gram-variable).

Finally, a counterstain of basic fuchsin is applied to the smear to give decolorized gram-negative bacteria a pink color. Some laboratories use safranin as a counterstain instead. Basic fuchsin stains many Gram-negative bacteria more intensely than does safranin, making them easier to see. Some bacteria which are poorly stained by safranin, such as Haemophilus spp., Legionella spp., and some anaerobic bacteria, are readily stained by basic fuchsin, but not safranin. The polychromatic nature of the gram stain enables determination of the size and shape of both Gram-negative and Gram-positive bacteria. If desired, the slides can be permanently mounted and preserved for record keeping.

Besides Gram's stain, there are a wide range of other staining methods available. By using appropriate dyes, different parts of the bacteria structures such as capsules, flagella, granules, and spores can be stained. Staining techniques are widely used to visualize those components that are otherwise too difficult to see under a light microscope. In addition, special stains can be used to visualize other microorganisms not readily visualized by the Gram stain, such as mycobacteria, rickettsia, spirochetes, and others. In addition, there are modifications of the Gram stain that allow morphologic analysis of eukaryotic cells in clinical specimens.

Source: http://www.uphs.upenn.edu/bugdrug/antibiotic_manual/gram1.htm