Single gene disorders or complex traits: lessons from the thalassaemias and other monogenic diseases
BMJ 2000; 321 doi: https://doi.org/10.1136/bmj.321.7269.1117 (Published 04 November 2000) Cite this as: BMJ 2000;321:1117
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Dear Sir,
Thank you for publishing an interesting review on Science Medicine and the
Future, etc., by David J Weatherall. While scientists working in centres
of excellence are trying to unearth the genetic complexity and clinical
diversity of thalassemic presentation, the bread and butter of the
treatment in under-resourced countries remains the long cherished demand
for a safe transfusion and an arrangement to treat iron abuse with
chelation and other basic support medicine.Even this is extremely
difficult in many countries of Sub-Saharan Africa ,certain regions of
Latin America and South Asia in particular.We have got a suggestion which
we want to narrate here.
In the animal kingdom, even herbivorous animals swallow the placenta
after the birth of their baby (for example, the cow). In the human system,
we do not know about the proper utilization of the placenta and membranes
although there are suggestions regarding this on the basis of research on
placental umbilical cord blood stem cells as an alternative source to bone
marrow transplantation.The CD 34 stem cells constitute .01 percent of the
nucleated cell compartment of the cord blood, the rest 99.99 percent of
the cord blood is discarded.
In Bijoygarh State Hospital, Calcutta, India, we do not discard this
precious gift of nature. In our earlier publications on placental
umbilical cord whole blood transfusion, we wanted to examine the safety
aspect of other components of cord blood transfusion, viz., fetal RBC,
growth factors and cytokine filled plasma, etc., in different indications
of blood transfusion, from the pediatric to the geriatric age group, in
malignant and non-malignant disorders affecting our patients(1-4).
In the present (thalassemic) series we collected 64 units or
umbilical cord whole blood aseptically from the umbilical vein after
caesarean section in standard pediatric blood transfusion bags,* after the
removal of the baby from the operative field and after confirming the
stable condition of the mother. The volume of cord blood varied from 56ml.
to 132ml. with mean 82ml ±16ml SD.
The cord blood was transfused immediately (within three days of
collection) to 12 patients from 2 years to 28 years of age, from 1 April
1999 till date, after taking adequate consent and following the
precautions of standard blood transfusion protocol. On the basis of the
severity of clinical presentation the patients received 2 units to
cumulative 25 units of blood within a span of 2years of initiating the
present fetal hemoglobin rich cord whole blood transfusion. All the
patients tolerated the procedure well ,there is rise of fetal hemoglobin
proportionate to the amount of transfusion and in addition there is a
sense of well being among the recepient of the cord blood. There has not
been a single case of immunological or non immunological reaction in this
series of transfusion so far.
Thalassemia consists of a group of disorders that may range from a
barely detectable abnormality of blood, to severe or fatal anemia. Adult
hemoglobin is composed of two alpha and two beta polypeptide chains. There
are two copies of the hemoglobin alpha gene (HBA1 and HBA2), which each
encode an alpha-chain, and both genes are located on chromosome 16. The
hemoglobin beta gene (HBB) encodes the beta-chain and is located on
chromosome 11. In alpha-thalassemia, there is deficient synthesis of alpha
-chains. The resulting excess of beta chains bind oxygen poorly, leading
to a low concentration of oxygen in tissues (hyopoxemia). Similarly, in
beta thalassemia there is a lack of beta chains. However, the excess of
alpha chains can form insoluble aggregates inside red blood cells. These
aggregates cause the death of red blood cells and their precursors,
causing anemia. The spleen becomes enlarged as it removes damaged red
blood cells from the circulation.
The problem of thalassemia can mostly be combated with risk free
blood transfusion and tackling the problem of iron abuse with
chelation.There are also supportive drugs (anabolic steroid) and some
selective drugs like hydroxyurea etc which can help extend the life of
fetal hemoglobin etc. There are more than 20 million births in India per
year and cord blood contains 60-80 percent fetal hemoglobin. On the basis
of our experience with 64 units of placental umbilical cord whole blood
transfusion in different varities of clinical presentation in anemia and
thalassemia (within three days of collection and preservation, at 1-60C,
in a refrigerator), we are of the opinion that this is a safe transfusion
protocol, which takes advantage of the safety of nature’s finest
biological sieve, i.e., the placenta, as an alternative to adult whole
blood transfusion.It also has the advantage of a higher oxygen carrying
capacity of fetal hemoglobin in addition to many growth factors and other
cytokine filled cord blood plasma along with its hypoantigenicity(5-8) and
the metabolic advantages of neonatal or cord blood .
* Pediatric blood bag contains 14ml. anticoagulant – Citrate
Phosphate Dextrose Adenine solution USP and a 16g needle for transfusion.
References:
1) Bhattacharya N, Mukherjee KL, Chettri MK, Banerjee T, Mani U,
Bhattacharya S, “A Study Report of 174 Units of Placental Umbilical Cord
Whole Blood Transfusion in 62 Patients as a Rich Source of Fetal
Hemoglobin Supply in Different Indications of Blood Transfusion”, Clinical
and Experimental Obstetrics and Gynecology, vol.28, no.1, 2001 : 47-52.
2)Bhattacharya N, Bandopadhyay T, Bhattacharya M, Bhattacharya S, “Do
Not Discard 99.99% of the Human Placental Umbilical Cord Blood for the
Sake of Stem Cells Only”, bmj.com, 6 Oct. 2001, Rapid Response to Proctor
SJ et al, “Umbilical Cord Blood Bank in UK”, Editorial, BMJ, 2001, 323: 60
-1.
3) Bhattacharya N, Bandyopadhyay T, Bhattacharya M, Bhattacharya S,
“Immunization and Fetal Cell /Tissue Transplant : A new strategy for
geriatric treatment 6th April 2002, rapid response to Gott lieb S” Drug
effects blamed for fifth of hospital death among elderly BMJ, 2001; 323 :
1025 b
4)Bhattacharya N et al, “Umbilical Cord Whole Blood Transfusion : A
Suggested Strategy to Combat Blood Scarcity in Ireland”, Rapid Response to
Payne D, BMJ.com, 324 (7330), Jan. 2002: 134.
5)Bhattacharya N, Chhetri MK, Mukherjee KL, Ghosh AB, Samanta BK,
Mitra R, Bhattacharya M, Bhattacharya S, Bandyopadhyay T, “Can human fetal
cortical brain tissue Transplant (upto 20 weeks) sustain its metabolic
and oxygen requirements in a heterotrophic site outside brain ? A study
of 12 volunteers with parkensons disease, Clinical and Experimental
Obstetrics and Gynaecology, Vol-29, No. 4, 2002
6)Bhattacharya N, Chhetri MK, Mukherjee KL, Das SP, Mukherjee A,
Bhattacharya M, Bhattacharya S, “Human Fetal adnenal transplant : A
possible role in relieving intractable pain in advanced rheumatoid
Arthritis, Clinical and Experimental Obstetrics & Gynaecology, vol.
29, No. 3, 2002 .
7)Bhattacharya N, Mukherjee KL, Chettri MK, Banerjee T, Bhattacharya
S, Ghosh AB, Bhattacharya M, “ A Unique Experience with Human Pre-immune
(12 weeks) and Hypo-immune (16 weeks) Fetal Thymus Transplant in a
Vascular Subcutaneous Axillary Fold in Patients with Advanced Cancer: A
Report of Two Cases”, European Journal of Gynecological Oncology, vol.22,
no. 4, 2001 : 273-7.
8)Bhattacharya N, “Fetal Tissue/ Organ Transplant in HLA Randomized
Adult’s Vascular Subcutaneous Axillary Fold: A Preliminary Report of 14
Patients”, Clinical and Experimental Obstetrics and Gynrcology, 2001;
28(4); 233-239.
Competing interests:
None declared
Competing interests: No competing interests
Thalassemia is indeed a very complex genetic disorder.
It may be easier to investigate and cure sickle cell anemia,
hemoglobin S.
The main defect in thalassemia, the lack of production of beta
globin, results from different gene sequences in different populations
However, in sickle cell anemia, the single gene defect is the same in
everyone who has that disease.
Competing interests: No competing interests
Sir,
References
1. Science, medicine, and the future: Single gene disorders or complex
traits: lessons from the thalassaemias
and other monogenic diseases
David J Weatherall.
BMJ 2000; 321: 1117-1120
Competing interests: How we think about cause in disease is often too simplistic (though it promises to make lots of people rich). If medicine is ever to break outof the stalemate it faces regarding "chronic" disease such as cancer, it needs a change of focus. The genome may be an important piece, but it isonly a piece in a very, very complex chess game. This imbalance is highlymisleading and urgently needs correction. Weatherall's article is a firststep. Please BMJ, more of the same!
no room for evolution
The theory of evolution has,until relatively recently,been
promoted mostly via dissertations involving the evidence of fossilised
remains together with various postulates based on the relatively recently
acquired knowledge of genetic composition and expression,knowledge about
nucleotide sequencing/coding/transcription and various surmised mechanisms
of mutation.In addition to this a great deal of thought has been given to
the phenomena which affect populations of organisms and their
interactions,and this whole field of ecology and ecosystems etc.has
received substantial attention,and much of the knowledge on this subject
has been variously invoked in the process of formulating and revising and
teaching and publicising the theory of evolution.
My own experience was grounded in the controversies surrounding the
theory of evolution.And I often wondered about the possibility of a link
between chromosome numbers and the surmised evolutionary"genealogy".After
all,I thought,since evolution is so closely associated with genes and
mutations and inheritance and selection,it would be more rational to take
a closer look at chromosome numbers than at fossilised skeletal remnants
and radiocarbon traces.Now it is impossible,I suppose,to obtain genomic
material from fossils,but we should be able to correlate chromosome
numbers with the surmised evolutionary relationships based on increasing
orders of complexity,comparative anatomy and physiology,and so forth.
Chromosome numbers were not easy to find.So I was delighted when I
discovered www.kean.edu/~breid/chrom2.htm .You can imagine my
surprise at the information on this website-chromosome numbers which did
not correspond in any conceivable fashion with the evolutionary
hierachical order.
Another discovery related to the mechanisms of meiotic cell
division(the first and vital step in sexual reproduction).Since synapsis
of homologous chromosomes requires a certain degree of homology between
homologous chromosomes,and since meiosis(and gametogenesisand sexual
reproduction)cannot proceed in the absence of synapsis between homologous
chromsomes,it becomes exceedingly difficult to postulate how any new and
different(i.e.different in number,at least)set of chromosomes could have
appeared in any new and different organism in such a way as to be sexually
reproducible.Sexual reproducibility would require the appearance of two
new(and almost identical* )sets of homologous pairs of chromosomes(one set
in each of a sexually reproducing couple).*[the synapsis of chromosome
pairs in the gonads of the offspring would demand a degree of homology
between the respective pairs of chromosome pairs in the parents].
If there are any persons who consider it at all feasible to attempt
to postulate how the requirements of meiosis could have accomodated an
evolutionary chain of ancestry which resulted in the chromosome numbers
listed at
www.kean.edu/~breid/chrom2.htm their postulations would make
fascinating reading.Almost as fascinating as would be an account of the
evolution of the haemoglobin molecule-it's evolution from the
beginning,that is.Because the ever pressing need for oxygen would not
allow much time for evolution.
Competing interests:
None declared
Competing interests: No competing interests