Monday, June 11, 2007

Man of Miracle Drugs-Dr. Yellapragada SubbaRow (1895-1948)

Dr. Yellapragada SubbaRow (1895-1948)
He Transformed Science; Changed Lives

Most of the famous scientists around the world
are known only for one major discovery that
has had a lasting impact on our lives : Wilhelm
Roentgen for x-rays, Marie Curie for radium, C V
Raman for the scattering of light by liquids, P M S
Blackett for cosmic rays, Ronald Ross for the life
cycle of the malarial parasite, Alexander Fleming
for penicillin – all awarded the Nobel Prize for
their one major discovery.

There have been a few scientists known for two
discoveries : Albert Einstein for the photoelectric
effect and the theory of relativity, John Bardeen
for transistors and super-conductivity, Hargobind
Khurana for the genetic code and synthesis of

Occasionally a scientist makes a large number of
discoveries albeit in only one field like Robert
Woodward in organic chemistry.
Then there are persons who have made important
contributions but have not received the Nobel Prize
or equivalent honours like Jonas Salk who made
the first polio vaccine, Michael Heidelberger the
father of modern immunology, G N
Ramachandran who discovered the structure of
collagen, the most abundant protein in our body
and also laid the foundations for CT scan and
NMR technologies.

Rarely, extremely rarely, a person comes on the
world scene and transforms science and our lives
by making a large number of major discoveries
in – and otherwise makes important contributions
to – more than one basic field and does not only
not get a Nobel Prize but does not get to be known
by name to most people, including scientists
around the world.

I am referring to Yellapragada SubbaRow. Such
an individual is perhaps born once in a thousand
years or more. I do not believe there is any other
person in the documented history of biology and
medicine over the last 5,000 years who made such
a large number of basic discoveries that are
applied so widely.

SubbaRow was born in India in 1895 and he died
in USA in 1948 at the young age of 53.
He went to the United States in 1923 after
graduating from the Madras Medical College and
worked at Harvard Medical School until 1940
when he went to Lederle Laboratories to direct its
medical research.

The search he directed at Lederle Laboratories for
antibiotics with wider range of cures than the then
available penicillin and streptomycin led to the
discovery of polymyxin widely used even today in
cattle-feed and aureomycin the first of tetracycline
antibiotics which all of us have had some time or
the other in our lives. Tetracyclines have saved
millions of lives over the last 50 years.
Aureomycin was presented to medicine in 1948,
the year SubbaRow died. It was the first broadspectrum
antibiotic, that is, one effective against
both gram-positive and gram-negative germs. It
was thus more powerful than either Fleming’s
penicillin or Waksman’s streptomycin.
When SubbaRow’s centenary year began in 1994,
tetracyclines – especially doxycycline – helped
confine and then eradicate the plague epidemic
that broke out in Gujarat and Maharashtra. It was
a debt SubbaRow paid to his motherland almost
half a century after death which claimed him soon
after the unveiling of Aureomycin before a medical
gathering at the New York Academy of Sciences.
Doxycycline, the third generation tetracycline, has
recently been cleared as a malaria preventive. The
international staff of the United Nations Assistance
Mission in East Timor (UNMET) packed it in their
survival kits when ordered last year into the region
wrested from Indonesia.

SubbaRow and his team of organic and biological
chemists isolated folic acid from liver and a
microbial source and then synthesized it in 1945.
By the clinical trials he organised, SubbaRow had
the satisfaction of knowing that it cures tropical
sprue which took him to the death’s door while a
medical student in Chennai and carried away two
of his brothers. It was subsequently found to cure
a variety of anaemias. The US government has
since January 1, 1988 required that all flour, pasta
and other grain products be enriched with folic
acid to stave off spinal-cord defects in newborns.
In mid-1999 the New England Journal of Medicine
reported that this has already reduced levels of
homocysteine, an amino acid, among the US
population. Homocysteine is a risk factor in
coronary heart diseases. Therefore that report has
started a debate whether folic acid can control a
significant cause of heart diseases.
It is a pity SubbaRow is not given the credit for
laying the foundations for the isolation of Vitamin
B12 the antipernicious anaemia factor. Our daily
requirement of B12 is just one microgram. That is
all you require, but it is extremely important you
get it. If you have those indescribable pains all
over, chances are that you need it. SubbaRow spent
years trying to isolate it from liver and succeeded,
but failed to recognise it. Others opened the door
he found.

In 1965 or 1966, I met Sir Alexander Haddow, a
very distinguished and handsome scientist. He was
then the director of the Chester Beatty Cancer
Research Institute in London. We started talking
about methotrexate which was being used widely
not for curing but alleviating the suffering from
Burkitt’s lymphoma, one kind of cancer, and he
said, “Do you know that methotrexate was
discovered by an Indian?” You can imagine the
sense of pride I felt.

SubbaRow got aminopterin, which reverses the
action of folic acid, synthesized when reports of a
clinical collaborator indicated that chemicals
resembling the vitamin arrest the growth of cancer
cells. He thus initiated the chemotherapeutic
approach to the treatment of cancer. Methotrexate,
a derivative of aminopterin, has since then been
the drug of choice in childhood leukaemia and
many adult cancers. Subsequently, methotrexate
has been used by doctors to control rheumatoid
arthritis and psoriasis. More recently, it has been
employed for medical abortion and in ectopic
pregnancy and Crohn’s colitis. Now comes a
report in Chest that low-dose methotrexate spares
steroid usage in asthma patients. There seems to
be no end to such new SubbaRow miracles!
As Director of Research at Lederle, SubbaRow
established a project for protecting American
soldiers fighting in the Pacific from malaria and
filariasis. He found in Hetrazan the cure for
filariasis. It is today the most widely used drug
against filariasis which leads to the deformitycausing
elephantiasis. For years there was
hesitation in employing diethylcarbamazine (DEC),
the generic name for Hetrazan, in mass
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98 Journal, Indian Academy of Clinical Medicine  Vol. 2, No. 1 and 2  January-June 2001
campaigns against the scourge of elephantiasis
because of certain unpleasant side effects like
nausea. The World Health Organisation (WHO)
has found that these side effects were due to
unnecessarily high dosages previously prescribed
and that it was enough to administer only a single
dose of DEC, concurrently with invermectin, to
keep blood free of filarial worms for a whole year.
And WHO has made DEC a key element of its
worldwide campaign for the elimination of

Let me go backwards in time. When I raise my
hand I am consuming energy. We derive energy
from the food we take. A good part of what we
eat is converted by the body into glucose. A
mechanism in the body metabolises glucose and
in the process generates energy the muscles use
for running, raising hands, and doing the work of
everyday life. That alone wouldn’t be enough.
There must be ways of storing the energy obtained
from food because we are not eating food all the
time. There was a hunt therefore in the 1920s for
the chemical substances in the body acting as
energy stores on which the body draws whenever
it needs energy. It was SubbaRow who codiscovered,
while working with Cyrus Fiske at
Harvard, the two chemicals – phosphocreatine and
adenosine triphosphate (ATP) - that store energy
in our body. In fact, all living organisms store
phosphocreatine as their source of energy. When
the body needs energy, ATP is converted into ADP
(adenosine diphosphate) and ATP is replenished
by phosphocreatine while the body rests.
Not only did he show how important phosphorus
is for our body, SubbaRow also devised the perfect
way of estimating phosphorus in living organisms.
There may not be any biologist of any kind
anywhere in the world who has not some time or
the other used the Fiske-SubbaRow Method of
estimating phosphorus. In all fairness it should
have been called the SubbaRow-Fiske method but
SubbaRow put the name of his supervisor first on
the paper describing it.

Trained first as a mathematician and physicist and
then as a chemist with no formal training in
biology, I got introduced to experimental biology
through estimating phosphorus. And I used the
Fiske-SubbaRow Method. That was in 1953.
Hailing from Andhra as I did, I remember asking
how he spelt his name Row and not Rao. As I
learnt later he would have been the last man ever
to cause a row! If you look at citations of scientific
papers - which is the way others use your scientific
work and quote it in their publications - SubbaRow
turns out to be one of the most highly cited scientists
in the entire history of science.

Thus far about his work. What about the man
himself? I have a wish list of ten persons from the
beginning of human history I would have liked to
meet personally. In it figures SubbaRow along with
Chanakya, Ashoka, Leonardo da Vinci. I regret I
never knew him. My first visit to USA was five years
after he died but I have met and talked about
SubbaRow with people who knew him intimately.
What came through in these talks, apart from his
scientific brilliance, was his tremendous modesty
and self-effacement. This was very difficult to
understand as he was driven by a desire to be
famous. But he was at the same time generous in
giving credit for what he had done to someone
who stood to gain a great deal thereby. It is difficult
to reconcile these two qualities but all of us have
a little bit of such contradictions in us.
Fiske would not have got the position he did at
Harvard but for SubbaRow sharing with him the
credit for the method of estimating phosphorus in
biological fluids. My friend, S P K Gupta, in his
biography of SubbaRow has documented many
such acts of his to get a friend or a colleague get
a promotion or a job or an advantage.
SubbaRow’s cultural pluralism is another thing that
comes through in his documented life and work
and in personal dialogues with people who knew
him. He had this multiplicity of backgrounds which
intermeshed in his personality: He was extremely
Indian and identified himself as an Indian. He was
conversant with our ancient scriptures and his early
work was in Ayurveda. But he also provided
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financial support to the Church, especially to
churches which seemed to have an universal
element in their beliefs and to their education
programmes. It is strange that while he was an
Indian in reality always, an Indian visiting him in
USA told his family in India that SubbaRow had
become totally Americanised. Appearances can
be deceptive!

We must give credit to the United States for giving
him the kinds of facilities to work not previously
given to any Indian. But there is another side to
the story that must be told. Let me quote from the
biography, In Quest of Panacea, some bits that
show how politics operate in the world:
“SubbaRow’s admission to the U.S. and his stay
there for a quarter of a century was possible
because he went there as ‘a physician’ and
qualified himself as a ‘chemist’ – two of the
professions that were exempt from the ban on
immigration of Indians in force from 1917.”
The Supreme Court ruled that Hindus were not
Caucasians and the President excluded from
American citizenship even those Indians who had
been legal immigrants and had met the minimum
residence requirement.

“Although he could get his ‘student’ visa, originally
valid for two years, periodically extended because
he belonged to the excepted category, ‘he was
always mortally afraid ... that he might be picked
up for some minor infraction of the law and be
shipped back to India... Then came the Second
World War and the Alien Registration Act of 1940.
SubbaRow had always to carry from then on a
card bearing his right thumb impression, signature
and registered number (3420564) testifying to his
status as an ‘alien’, one of the 3896 East indians
on the Registry. And he had to report his address
every three months to the Department of Justice
in Washington.

“In 1942, he had to get special clearance because
his position as Director of Research at Lederle was
considered sensitive in view of his supervision of
the processing of blood albumin for supply to the
Navy and of the research on tetanus and gas
gangrene toxoid that was of interest to the Army
and the Navy. The clearance was given after a
declaration by his company that it ‘never had any
reason to doubt his devotion and allegiance to
the United States’ and a thorough investigation
was made of his record both at Boston and at
Pearl River.”

The New Republic fulminated in 1943 against the
notion that natives of India like SubbaRow and
other world-renowned scientists then playing
valuable roles in USA in helping to win the War
were unfit for American citizenship that was ‘freely
granted to the most backward and ignorant
Balkan peasant’. That year a number of bills were
introduced in the Senate and the House of
Representatives for lifting the citizenship bar on
Indians. One of them reached the statute book in
July 1946.

SubbaRow wished to shed the stigma of being an
‘alien’ amidst people with whom he had lived 25
years and had thrown his lot, but it took a year for
him to get the ruling of the Immigration and
Naturalization Service that he had been admitted
legally into the United States. He spread the good
news among his associates but he did not in the
next twelve months he lived file his ‘Declaration
of Intention’ the necessary first step to get the
American citizenship.

SubbaRow felt within he was an Indian and he
died an Indian.
When he died on August 8, 1948, obituaries
appeared in Science, New York Times, New York
Herald-Tribune and newspapers and journals in
many parts of the world. The Herald-Tribune called
him ‘one of the most eminent medical minds of
the Century’.

Yellapragada SubbaRow was not born great; his
mother had to sell the little jewellery she possessed
to provide for his education. Nor was greatness
thrust upon him. He achieved greatness by
imagination, self-confidence, love of fellow
humans, and an inner compulsion to alleviate
human suffering. And he did what no other Indian
had ever done till then on foreign soil: he made
some of the most important and seminal
contributions that were destined to transform a
whole range of basic and applied sciences and
save innumerable human lives. If there were a
Nobel Prize for those who died virtually unknown
but whose accomplishments lit the path of many
who came later, SubbaRow would surely be among
the first to receive it.

Even today in our country very few people know
of him. The efforts of the Centenary Committee
succeeded in getting the government issue a
stamp in his honour in 1995. But he has not
been given the appropriate recognition by the
nation till today. We have given the Bharat Ratna
posthumously to others. Why not to
Yellapragada SubbaRow?

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