Yevamot 72 a ~ Blood Letting and Permissive Anemia

יבמות עב, ב

א”ר פפא הלכך יומא דעיבא ויומא דשותא לא מהלינן ביה ולא מסוכרינן ביה והאידנא דדשו בה רבים שומר פתאים ה

Rav Pappa said...we should not circumcise on a cloudy day or on a day of severe south winds, and we should not let blood on these days. But now that so many people do in fact do these procedures on these days we can apply the principle “God protects the simple”

Blood-letting was a simple enough and rather brutal procedure. You went to the blood-letter and he sliced into your vein. After a while, when the blood-letter had determined that you'd lost just the right amount of blood, the wound was bandaged, and off you went, looking forward to being cured of whatever had led you to the blood-letter in the the first place. The procedure was thought to be the way to cure any number of illnesses, including fever and  asphyxia (Yoma 84a). It dates back at least to the 5th century BCE, and is mentioned in the writings of Erasistratus (300-260 BCE) who opposed the procedure, and Galen (c. 130-200 CE) who used it and taught that it was an important tool that could heal the sick.

Blood-letting is frequently mentioned in the Talmud. Most famously, in Shabbat 129a, there is an extensive discussion of some of the do's and dont's of blood letting:

Rab Judah said in Rab's name: One should always sell [even] the beams of his house and buy shoes for his feet. If one has let blood and has nothing to eat, let him sell the shoes from off his feet and provide the requirements of a meal therewith. What are the requirements of a meal? — Rab said: Meat; while Samuel said: Wine. Rab said meat: life for life. While Samuel said, Wine: red [wine] to replace red [blood]. ..For Samuel on the day he was bled  a dish of pieces of meat was prepared; R. Johanan drank until the smell [of the wine] issued from his ears; R. Nahman drank until his milt swam [in wine]; R. Joseph drank until it [the smell] issued from the puncture of bleeding. Raba sought wine of a [vine] that had had three [changes of] foliage.

…Rab and Samuel both say: If one makes light of the meal after bleeding his food will be made light of by Heaven, for they say; He has no compassion for his own life, shall I have compassion upon him?

Rab and Samuel both say: He who is bled, let him, not sit where a wind can enfold [him], lest the cupper drained him [of blood] and reduce it to [just] a revi’it,  and the wind comes and drains him [still further], and thus he is in danger.

Samuel was accustomed to be bled in a house [whose wall consisted] of seven whole bricks,  and a half brick [in thickness]. One day he bled and felt himself [weak]; he examined [the wall] and found a half-brick missing.

Rab and Samuel both say: He who is bled must [first] partake of something and then go out; for if he does not eat anything, if he meets a corpse his face will turn green; if he meets a homicide he will die; and if he meets swine, it [the meeting] is harmful in respect of something else.

Rab and Samuel both say: One who is bled should tarry awhile and then rise, for a Master said: In five cases one is nearer to death than to life. And these are they: When one eats and [immediately] rises, drinks and rises, sleeps and rises, lets blood and rises, and cohabits and rises.

Samuel said: The correct interval for blood-letting is every thirty days. Samuel also said: The correct time for bloodletting is on a Sunday, Wednesday or Friday, but not on Monday or Thursday…

Photo of bloodletting in 1860. Yes, that's right, 1860. From the Burns Archive.

Blood Letting - a practice whose time has certainly not come

There is absolutely no place for this intervention today, other than for the rare illness called polycythemia vera.  In this illness, the body makes too many red blood cells (hence its name, poly=many, kytos=cells, hamia=blood), and one way to keep the illness in check is to remove those excess blood cells at a regular intervals.  But other than for this disease, and another one called hemochromatosis, in which the body absorbs too much iron, blood-letting, (called today phlebotomy or venepuncture, which do sound a whole lot more palatable but describe the same procedure) is harmful. Do not try this at home.  

Having made this very clear, let's introduce some nuance. Palliative blood-letting may be useless, but from this is does not follow that it is a good idea to restore the hematocrit (the concentration of red blood cells in the blood) to normal in every disease state. For example, virtually all patients on  dialysis (due to chronic kidney disease) become anemic, but in these patients, trying to restore the hemoglobin concentration to a higher level (~13g/dL for those interested) seems to be associated with increased risk, when compared with those in whom the hemoglobin level was lower. And when tiny premature babies get anemic, there does not seem to be an advantage to keeping the hemoglobin in a higher range (though to be fair, more research needs to be done). But these two examples do not in any way lend support to the notion that blood-letting is anything other than a bad idea.  

The procedure, which had been in use for at least 2,000 years, only stopped being part of standard medical practice in the late 19th century.  Writing in 1875, one Englishman could not bring himself to believe that the era of blood-letting was really over. "Is the relinquishment of bleeding final?" he wrote, 

or shall we see by and by, or will our successors see, a resumption of the practice? This, I take it, is a very difficult question to answer; and he would be a very bold man who, after looking carefully through the history of the past, would venture to assert that bleeding will not be profitably employed any more.

(In fact, blood letting was even suggested as a therapy during a severe influenza outbreak at a British Army camp in northern France in the winter of 1916-17. Amazing.) 

“Venesection has likewise failed to benefit the patient for more than a very short time, though possibly we have not resorted to this treatment sufficiently early.”

— Hammond, JAB. Rolland, W. Shore, TGHG. Purulent Bronchitis. The Lancet, July 14, 1917, 42.

While we no longer practice this all but useless intervention, the prayer associated with it is worth recalling. Maimonides ruled (Berakhot 10:21) that before undergoing blood-letting, the patient should pray the procedure be effective, and this ruling is found as part of normative Jewish practice, recorded in the Shulchan Aruch:

שולחן ערוך אורח חיים רל ס׳ק ד

הנכנס להקיז דם אומר "יהי רצון מלפניך ה' אלהי שיהא עסק זה לי לרפואה כי רופא חנם אתה". ולאחר שהקיז אומר "ברוך רופא חולים

Before undergoing blood letting say: May it be your will Lord my God, that this procedure will heal me, for you are an unconditional healer. And when it is finished he says: Blessed are you God, healer of the sick.

The procedures have changed, but the prayers have stayed the same.

Yevamot 64b~ Circumcision, death, and Hemophilia A

Today’s page of Talmud discusses the complications that may arise following a circumcision:

יבמות סו. ,ב

תניא מלה הראשון ומת שני ומת שלישי לא תמול דברי רבי רבן שמעון בן גמליאל אומר שלישי תמול רביעי לא תמול... א"ר יוחנן מעשה בארבע אחיות בצפורי שמלה ראשונה ומת שניה ומת שלישית ומת רביעית באת לפני רבן שמעון בן גמליאל אמר לה אל תמולי

It was taught: If she circumcised her first son and he died, and her second son and he too died, she should not circumcise her third son, so taught Rebbi. Rabbi Shimon ben Gamliel stated that she should indeed circumcise her third child, but [if he died] she must not circumcise her fourth...Rabbi Yochanan said that there was once a case in Zippori in which four sisters had sons: The first sister circumcised her son and he died, the second sister circumcised her son and he died, the third sister circumcised her son and he died, and the fourth sister came to Rabbi Shimon ben Gamliel and he told her, "you must not circumcise your son" (Yevamot 64:)

The Talmud here is describing a disease that is passed through the maternal line (hence the four sisters - all of whom seem to pass this disease on to their male children). The disease is X-linked Hemophilia A; the term X-linked indicates that the faulty gene is carried on the X chromosome, which is always inherited from the mother. Hemophilia A is an X-linked recessive genetic disease, first described by the American physician John Conrad Otto, who in 1803 described a bleeding disorder that ran in families and mostly affected the men. John Hay from Massachusetts published an account of a "remarkable hemorrhagic disposition" in the New England Journal of Medicine in 1813.

Hay, John. Account of a Remarkable Haemorrhagic Disposition, Existing in Many Individuals of the Same Family. New England Journal of Medicine 1813:2;3;221-225.

 If the mother is a carrier  - as were each of the four sisters in Zippori - then she has a one in four chance of passing on the disease to a child, and that affected child will always be a son:

Courtesy NHLBI

The rabbis argued over a technical point - that is, how many cases of bleeding are needed to establish a pattern. According to Rebbi (that is  Rebbi Yehuda Ha-Nasi, c. 135-217 CE.) two cases were sufficient, while Rabbi Shimon ben Gamliel insisted on three cases before ruling that there was a life-threatening pattern.  Indeed the disease in boys must have been very perplexing, because (as you can see in the diagram above) not every boy would be affected. In fact, if the mother is a carrier and the father is not, there is only a 50% chance of a boy having hemophilia.  It is this fact that perhaps explains the dispute between Rebbi and Rabbi Shimon ben Gamliel regarding how many children need to exhibit the disease before we can assume that any future male child will also have it.  If every boy born in the family would have been a hemophiliac, Rabbi Shimon's ruling would have seemed unnecessarily cruel.  But since by chance, half of the boys born might not have hemophilia, the need to demonstrate the prevalence of the disease (in a society in which its genetic foundations were not known) seems eminently sensible.

In  Hemophilia A there are various genetic mutations that result in low levels of clotting factors. These levels may be only mildly decreased, or so low that severe life-threatening hemophilia results. It is treated with transfusions of clotting factors which restore the levels to normal. Although these transfusions must be given several times a week in those with severe disease, there is hope that recombinant clotting factors can lengthen the time between the needed transfusions.

Later in Yevamot, the Mishnah records the case of a priest who was not circumcised -  because of the deaths of his brothers when they underwent the procedure. So this law was certainly practiced, and the Talmud records not only the earliest known description of hemophilia, but the emphasis on the preservation of life as a normative Jewish practice. 

Yevamot 64b ~ Urinary Tract Infections, and the Class That Went On For Too Long

This is the first of two posts for Yevamot 64 that we will learn on Tuesday. The second part will be published tomorrow.

יבמות סד,ב

רב גידל איעקר מפרקיה דרב הונא רבי חלבו איעקר מפרקיה דרב הונא רב ששת איעקר מפרקיה דרב הונא

Rav Gidel became sterile on account of Rav Huna's lectures, Rav Chelbo became sterile on account of Rav Huna's lectures and Rav Sheshet became sterile on account of Rav Huna's lectures...

Rav Huna had a lot to answer for.  His lectures went on, and on, and on, and on and on and on.  A couple of pages ago, on Yevamot 62b, Rashi explained the relationship between these lengthy classes and infertility:

איעקר מפרקיה דרב הונא.שהיה מאריך בדרשיו וצריכים למי רגלים ומעמידים עצמן ונעקרים כדתניא בבכורות 

Rav Huna would give a lengthy class and people needed to use the toilet. They delayed urinating, and as a result became sterile, as we learn in the tractate Bechorot

The suggestion here is that holding-it-in can lead to problems of fertility, and there is a least a theoretical reason why Rav Huna's lengthy classes had the unintended consequence of lowering the reproductive rates of his students.  There is a clear relationship between male infertility and repeated infections of the genitourinary tract. Here, for example, is  how one urology textbook opens its chapter on male genital tract infections and infertility:

Male Genital Tract Infections and Infertility. Neal, DE, Weinstein, SH. In Male Reproductive Dysfunction ed Kandeel FR. Informa Healthcare 2007

Any male GU infection such as prostatitis, urethritis or epididymo-orchitis can reduce both sperm count and the quality of the seminal fluid. OK, but what does that have to do with not urinating when you feel the urge? Well here's the thing: that not-going-when-you-need-to is not a good idea.

Delayed Micturation and UTIs

It's quite a challenge to determine scientifically the effect of holding-it-in (and hereafter referred to as delayed micturition, because it sounds nicer) on the risk of getting a urinary tract infection.  You can't very easily randomly assign one large group of healthy volunteers to urinating whenever they want, and a second to urinating only three times a day.

However, there are a couple of observational studies that may be able to tell us something about the risk of delayed micturition.  A 1968 study of 112 women with a documented UTI reported that further UTIs could be reduced by voiding  every two hours during the day (which sounds rather too good to be true). And a 1979 study from the (not-very-widely-read-but-it-really-is-a-journal) Scandinavian Journal of Urology and Nephrology reported that the frequency of UTI was significantly higher among women with three or less voidings per day compared with those who have to go four or more times per day. (Whether this is true for women outside of northern Jutland where the study was conducted remains unclear.)

So a decreased voiding frequency is associated with an increased number of infections, and urinary tract infections are associated with decreased fertility. Thus by the rule of transitive relations (or something clever like it) decreased voiding may indeed be associated in a causative way with decreased fertility.  

All this is highly speculative, and it would certainly be unusual for male sterility to directly result from delayed micturition.  But here's the weird thing: teachers are slightly more likely to suffer urinary tract infections when compared with the general population. Is that because they too, like their students, hold-it-in? (Yes, I know it didn't reach statistical significance, but the authors thought it was important to note, and so do I.)   

Kovess-Masféty, V. Do teachers have more health problems? Results from a French cross-sectional survey. BMC Public Health 20066:101;1-13

 Poor Rav Huna, talking on and on and on, while his miserable students had to sit there with their legs crossed and could likely only think of only one thing. We will give the last word to Rav Acha bar Yaakov, another hapless student of Rav Huna. 

אמר רב אחא בר יעקב שיתין סבי הוינא וכולהו איעקור מפרקיה דרב הונא לבר מאנא

Rav Acha bar Yaakov said, we were a group of sixty students, and all of us became sterile because of Rav Huna's lectures - except me (Yevamot 64b).

Students be warned.

Israel's Noble History

ISRAELI NOBEL PRIZE WINNERS FOR $200 PLEASE, ALEX

Quick. Name three Israelis who have won a Nobel Prize. Come on. You can do this. Still need a hint? Click here. See, I told you you'd know.  

OK, those were easy. How about this one.  Which Israel won a Nobel Prize for literature? Need a hint? He was awarded it in 1966 for "his profoundly characteristic narrative art with motifs from the life of the Jewish people" and his photo is shown here. Still not sure? You may have read his work on Rosh Hashanah and Yom Kippur which was translated into English as Days of Awe...Of course; it was Shai Agnon, who was born in Galicia, moved to what was then Palestine (twice) and died in Jerusalem in 1970.

As of this year there have been twelve Israeli winners of the Nobel Prize. We've noted Agnon as the single winner for literature, and (as you may have answered correctly) there have been three winners of the Nobel Peace Prize: Menachem Begin (1978), Yizhak Rabin and Shimon Peres (both in 1994). That leaves eight more prizes. In honor of Yom Ha'atzmaut, Israel's Independence Day, we will pause from our analysis of science in the Talmud and reflect on the Israeli winners of this prize, given each year (in accordance with the will of Alfred Nobel) "to those who, during the preceding year, shall have conferred the greatest benefit on mankind."

DANIEL KAHNEMAN, ECONOMICS, 2002

Following at an eight year prize-drought, Israel picked up her fifth Nobel in 2002, when Daniel Kahneman was awarded the 2002 Prize in Economics. In his biographical sketch, Kahneman credits his early days in the IDF with the first cognitive illusion he discovered.

““… after an eventful year as a platoon leader I was transferred to the Psychology branch of the Israel Defense Forces….We were looking for manifestations of the candidates’ characters… we felt…we would be able to tell who would be a good leader and who would not. But the trouble was that, in fact, we could not tell... The story was always the same: our ability to predict performance at the school was negligible...I was so impressed by the complete lack of connection between the statistical information and the compelling experience of insight that I coined a term for it: “the illusion of validity.” Almost twenty years later, this term made it into the technical literature. It was the first cognitive illusion I discovered.”

— Daniel Kahneman, Biographical sketch at Nobelprize.org

(I was about two-thirds of the way through Kahneman's recent best-seller Thinking Fast and Slow, when I left it on a flight from Tel Aviv. Please let me know if you find it.) 

CIECHANOVER AND HERSHKO, CHEMISTRY 2004

Ubiquitin-mediated Proteolysis.

In 2004 Aaron Ciechanover and Avram Hershko, both from the Technion in Haifa (together with Irwin Rose), were awarded the Nobel Prize in Chemistry for their discovery of how cells breaks down some proteins and not others. They discovered ubiquitin-mediated proteolysis, a process where an enzyme system tags unwanted proteins with many molecules of another protein called ubiquitin. The tagged proteins are then transported to the proteasome, a large multi-subunit protease complex, where they are degraded.

ROBERT AUMANN, ECONOMICS, 2005

Robert Aumann from the Hebrew University won the 2005 Nobel Prize in Economics for his work on conflict, cooperation, and game theory (yes, the same kind of game theory made famous by John Nash, portrayed in A Beautiful Mind). Aumann worked on the dynamics of arms-control negotiations, and developed a theory of repeated games in which one party has incomplete information.  The Royal Swedish Academy of Sciences noted that this theory is now "the common framework for analysis of long-run cooperation in the social science." The kippah-wearing professor opened his speech at the Nobel Prize banquet with the following words (which were met with cries of אמן from some members of the audience):

ברוך אתה ה׳ אלוקנו מלך העולם הטוב והמיטב

The four-minute video of his talk should be required viewing for every Jewish high school student (and their teachers).

ADA YONATH, CHEMISTRY, 2009

Remember ribosomes from high school? They are the machines inside all living cells that read messenger RNA and link amino acids in the right order to make proteins.  In 2009, Ada Yonath from the Weizmann Institute shared the Nobel Prize in Chemistry for her work on the structure and function of the ribosome. Specifically, she reported their three-dimensional structure and her work in the 1980s was "instrumental for obtaining the robust and well diffracting ribosome crystals that eventually led to high resolution structures of the two ribosomal subunits." Why is this important?  Well, many antibiotics target the ribosomes of bacteria, and so knowledge of how antibiotics bind to the ribosome may help in the design of new and more efficient drugs.  

Available structures of antibiotics targeting the small ribosomal subunit (30S). From Franceschi and Duffy. Structure-based drug design meets the ribosome. Biochemical Pharmacology 2006; 71; 1016-1025.

DAN SHECHTMAN, CHEMISTRY, 2011

in 1982, Shechtman was working at the US. National Institute of Standards and Technology. As he was looking through an electronic microscope at the structure of new material that he was studying, and noted that the atoms had arranged themselves "in a manner that was contrary to the laws of nature." 

אין חיה כזו – There is no such entitiy" was how he recalled responding to what he had seen. Shechtman double checked his findings and submitted them for publication; the paper was rejected immediately, not worthy even of being sent on for peer review. But Shechtman did manage to get his work published, work that the Nobel Committee found questioned a fundamental truth of science: that all crystals consist of repeating, periodic patters. Shechtman's discovery of what were later to be called quasicrystals  was important not only because of what he found. It was important that he found. Here's why:

“Over and over again in the history of science, researchers have been forced to do battle with established “truths”, which in hindsight have proven to be no more than mere assumptions. One of the fiercest critics of Dan Shechtman and his quasicrystals was Linus Pauling, himself a Nobel Laureate on two occasions. This clearly shows that even our greatest scientists are not immune to getting stuck in convention. Keeping an open mind and daring to question established knowledge may in fact be a scientist’s most important character traits.”

— The Swedish Academy of Sciences. The Nobel Prize in Chemistry 2011. Information for the Public

ARIEH WARSHEL AND MICHAEL LEVITT, CHEMISTRY 2013

Israelis continued with a winning streak at chemistry. In 2013 Arieh Warshel and Michael Levitt shared the prize in, yes, Chemistry, (together with Marin Karplus, a Jew, but not yet an Israeli). Working together in the 1970s on GOLEM, the supercomputer at the Weizmann Institute, they developed computer programs that could simulate chemical reactions with the help of quantum physics.  These programs, and their offshoots, are used in a variety ways, from optimizing solar panels to designing new drugs.

Joshua Angrist, Economics 2021

The most recent Israeli Nobel laureate is Joshua Angrist, who was awarded the 2021 Nobel Prize in Economics. Angrist, who is a professor at The Massachusetts Institute of Technology, was born in the US but lived in Israel in the 1980s, where he served as a paratrooper. He holds dual US-Israeli nationality, and has spent much of his career analyzing the economics of schooling and the effect of class size on academic achievement. One of his papers looks at the “Maimonides Rule,” named for, well, Maimonides, who apparently noted a correlation between class size and student achievement.

THE LAST WORD

There you have it. Thirteen remarkable Israelis who have contributed to peace efforts, science and literature, and whose efforts were recognized by a Nobel Prize. As we celebrate Yom Ha'atzmaut, let's give the last word to the 2005 winner Robert Aumann, who noted in his banquet speech just what is really important in life. 

“We have participated in the human enterprise – raised beautiful families. And I have participated in the realization of a 2000-year-old dream – the return of my people to Jerusalem, to its homeland.”

— Robert Aumann, Nobel Prize banquet speech, 2005.